Psych 230 FINAL EXAM

patients in state and municipal mental hospitals

"Deinstitutionalization" -within 8 months of the introduction of chlorpromazine, approximately 2 million patients had received the drug -Chlorpromazine was 70% effective in relieving the hallucinations, delusions, and disorganized thought associated with schizophrenia

How exactly does CS-UCS convergence (mossy + climbing fiber convergence) change Purkinje cells and result in LTD?

- first, the CS, via mossy fibers and via granule cells and their parallel fiber system, DEPOLARIZE spins on purkinje dendritic tree: glutamate released upon ionotropic and metabotropic glutamate receptors -calcium release from intracellular stores (caused through a complex 2nd messenger mechanisms) SLOWLY and PARTLY INACTIVATES glutamate receptors -the "slowness" is KEY for understanding CS-UCS delays: CS: glutamate receptors are "tagged" and vulnerable for a while (couple of 100 ms) -if a UCS is administered in time, climbing fibers depolarize and the postsynaptic effects "meet" tagged and vulnerable AMPA receptors, KNOCKING THEM OUT FOR GOOD, and for a good while: LTD -if a UCS is not administered in time, glutamate receptors loose their tag and thus a late UCS will not result in LTD

cerebellum as a component of the sensorimotor system

-cerebellar inputs: from diverse sensory and motor regions -cerebellar outputs: from Purkinje cells to deep cerebellar nuclei and to motor systems in general, Cerebellum processes programs for SKILLED (automated) movements; cognitive operations

mechanisms altering synaptic strength

-changes in receptor DENSITY and COMPOSITION and thus AFFINITY for the neurontransmitter

patient NA and the MEDIODORSAL THALAMIC NUCLEUS

PATIENT N.A.: -miniature fencing foil entered brain through right nostril and destroyed LEFT DORSAL THALAMAS, mammillary bodies -limited RETROGRADE AMNESIA; marked anterograde amnesia for DECLARATIVE information -TEMPORAL LOBE systems plus midline THALAMIC-PREFRONTAL systems involved in DECLARATIVE INFORMATION PROCESSING

causes (2)

4) GENETICS: incomplete concordance- what does that really mean? -even with monozygotic twins concordance rate is only about 50% -being a relative does not capture half of the...genetic? -or environmental? -or both?...mechanisms at work -prevalence stable across cultures and continence...

iclicker question:

After LTP is induced and established, expression of LTP is blocked by a) blocking NMDA receptors b) blocking AMPA receptors c) blocking Ca++ influx into the postsynaptic site d) increasing the amount of glutamate released from presynaptic neurons per stimulus e) none of the above

navigation taxi drivers (cont.)

does that mean that for largescale, detailed spatial info recall we never go beyond (b)? always requiring detailed spatial referencing, map recall and reintegration into spatial map

RETROGRADE vs. ANTEROGRADE amnesia

RETROGRADE amnesia: -eg. don't recall where I was on 9/11; don't recall where I was born, or the name of my parents -loss of memory or access to events that occurred, or information that was learned, BEFORE the accident ANTEROGRADE amnesia: -cannot commit new information to memory -loss of the ability to create new memories AFTER the accident, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact

incidence vs. prevalence

INCIDENCE: -measures the rate of occurrence of NEW cases of a disease or condition -incidence is calculated as the number of NEW CASES of a disease/condition IN A SPECIFIED TIME PERIOD (usually a year) divided by the size of POPULATION under consideration who are initially disease free PREVALENCE: -is a frequently used epidemiological measure of how COMMONLY A DISEASE OR CONDITION OCCURS IN A POPULATION -prevalence measures how much of some disease or condition there is in a population AT A PARTICULAR POINT IN TIME **2.2 million people with schizophrenia vs. total number of staffed beds in US hospitals: 924,333 **Schizophrenia thus has an immense impact on public health and is among the five leading causes of disability worldwide

Korsakoff's syndrome/ psychosis

Korsakoff's syndrome/ psychosis: -massive RETROGRADE amnesia, plus anterograde deficits -thiamine (vitamin B1) deficiency primary cause in alcoholics -degeneration of midline thalamus (including MEDIODORSAL thalamus), mammillary bodies, similar to NA -MAMMILLARY BODIES: a route connecting temporal lobe/hippocampal with dorsal thalamic and frontal lobe structures

taxonomy of memory

LONG TERM MEMORY has two categories: 1) DECLARATIVE memory: -things you know that you can TELL others -declarative memory can be tested readily in humans because they can talk -HM was unable to form new declarative memories 2) NONDECLARATIVE memory (procedural): -things you know that you can SHOW other by DOING -nondeclarative memory can be tested readily in other animals, as well as humans -HM was capable of this form of memory, exemplified by the skill of mirror tracing

LTD: the inverse of LTP

LTD, the inverse of LTP, resulting from low frequency stimulation and low Ca++ -low frequency stimulation of the sensory neuron: produces LTD (d= depression) -this can also be shown in the hippocampus and elsewhere -intracellular mechanisms of LTD also depend Ca++ influx, but the difference is the LTD makes VERY LOW LEVELS OF CALCIUM, as opposed to high levels of Ca++ influx during induction of LTP -low Ca++ activates protein phosphatases that DE-phosphorylate AMPA receptors, DEactivating these receptors, as well as key second messenger proteins -high Ca++ levels, during LTP, activate kinases that phosphorylate such proteins -so: Hebb applies to habituation as well, except that the low stimulation reduces synaptic strength ("fires together at low frequency---> unwires") -Hebb's rule (modified) wins again (even though the change in synaptic strength goes into the opposite direction)

Long-term depression (LTD)

LTD: more relevant to associative learning, such as classical conditioning (CS-->UCS--> UR; CS--> UR) -LTP induced be applying a tetanic stimulus (several 100 stimuli/s) to the medial portion of the perforant path -LTD induced be applying a low frequency stimulus (eg. 1 stimulus/s or less) to the lateral portion of the perforant path

Lecture 25:

Last lecture: • More rare mutations/susceptibility genes and relationships to Autism and Intellectual Disabilities. • Father's age matters • Main brain targets of all these mutations • Expression vs. code • How chlorpromazine was found • Delay and Deniker • De-insitutionalization

Lecture 24:

Last lecture: • diagnosis and disease course • incidence and prevalence • why adolescent onset? • Kraepelin and Bleuer • Theory versus Nosology • Enlarged ventricles, atrophy?, dysmorphogenesis • Causes: From Freud to breast-feeding (" book Fig. 16.15 - what is wrong with living in big cities?") • Causes: Twin studies and gene-environment interactions (?) • The Scottish family tree - family genetics remain "private" • New genetics: multiple, individually rare mutations • Microdeletions and copy number variants • >8,000 SNPs confer risk - tip of the iceberg.

Lecture 21:

Last lecture: •General concepts: how to change synaptic efficacy (with and without morphological correlates) • Non-associative learning in Aplysia • Hippocampal LTP as an example of the type of neuronal plasticity that may underlie learning.

iclicker:

Mechanisms triggered by NMDA receptor-mediated Ca2+ influx: a) incorporation of more AMPA receptors into postsynaptic membrane b) incorporation of AMPA receptors more sensitive to glutamate c) more glutamate release per impulse as a result of retrograde messenger d) changes in dendritic morphology indicating enhanced post-synaptic contact sites e) all of the above

Iclicker question:

Mechanisms triggered by NMDA receptor-mediated Ca2+ influx: a) incorporation of more AMPA receptors into postsynaptic membrane b) incorporation of AMPA receptors more sensitive to glutamate c) more glutamate release per impulse as a result of retrograde messenger d) changes in dendritic morphology indicating enhanced post-synaptic contact sites e) all of the above ANSWER= e

memory systems: medial temporal lobe and declarative memory

Medial temporal lobe & Declarative memory: -delayed non-matching to sample performance impaired by temporal lobe lesions Delayed non-matching task: 1) monkey is originally presented with a sample object (a key). when he displaces it, he finds a pellet of food beneath it 2) after a variable delay (seconds-minutes), the monkey is presented with the original object (key) and another object (a bowl) 3) over a series of trials with diff pairs of non-matching objects, the monkey learns that the food is present under the object that differs from the sample (food is found under the nonmatching object) CONCLUSION: -processing of DECLARATIVE information in the TEMPORAL lobe is necessary for memory formation

atypical antipsychotics: serotonin/muscarinic receptor antagonists?

likewise outdated: delayed onset of antipsychotic efficacy: -Kapur and Colleages: efficacy demonstrated within 2-4 hours of first dose (in terms of unusual thought content, hallucinatory behavior, and conceptual disorganization

the brain of schizophrenics:

the brain of schizophrenics: 1) ENLARGED VENTRICLES, but nothing obvious -Mice expressing "disrupted in schizophrenia 1": reduced synaptic spine density --> larger ventricles? 2) NEOCORTICAL VOLUMN REDUCTION: -small but significant -increased rate of gray matter loss 3) morphological dismorphogenesis-- but not degeneration-- in HIPPOCAMPUS (and elsewhere): -sporadic, unreliable findings -disorganized neuronal connections 4) FRONTAL CORTEX HYPOMETALOBISM: controversial finding -they do not show much activation in frontal cortex

Donald O. Hebb (1904-1985)

"The organization of behavior" (1949): -Hebb wrote this book largely while working at the Yerkes Laboratory of Primate Biology (whose director was Karl Lashley) -Hebb returned to McGill in 1948 "Hebbian (or Hebb) Synapse"

Hebb's Postulate

"when an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased" -D.O.Hebb, 1949 "Inputs that fire together, wire together" - Mark Bear, 1996

simple forms of changes in synaptic strength:

(1) FORMATION OF NEW SYNAPSES: -make new synapses to increase synaptic strength (2) REARRANGMENT OF SYNAPSES: -shift in synaptic input

imaging studies help us understand NONDECLARATIVE MEMORY

(1) SKILL MEMORY: -all three kinds of skill learning (sensorimotor, perceptual, cognitive) are impaired in people with damage to the BASAL GANGLIA -damage to other brain regions, esp the motor cortex and cerebellum, also affects aspects of some skills -basal ganglia, cerebellum, and motor cortex are important for sensorimotor skill learning in normal people -cerebellum provides error correction during learning (2) REPETITION PRIMING: -priming is not impaired by damage to the basal ganglia -perceptual priming (priming based on the visual form of words) is related to REDUCED activity in BILATERAL OCCIPITOTEMPORAL CORTEX -conceptual priming (priming based on word meaning) is associated with reduced activation of the LEFT FRONTAL CORTEX (3) CONDITIONING: -cerebellar circuits are crucial for simple eye-blink conditioning -cerebellum, but also the hippocampus, the ventral striatum, and regions of the cerebral cortex are all important for conditioning

LTP as a model of a Hebbian synapse

-"what fires together wires together" -TETANUS: highly correlated firing of pre- and postsynaptic neurons, as presynaptic neurons are depolarized at high frequency by tetanus -high levels of glutamate release from the presynaptic neuron during tetanus -via ionotropic glutamate receptors (AMPA receptor= Na+ channel), postsynaptic neurons fire at high frequency -thus, during tetanus: Hebbian conditions

THORAZINE

-"when the patient lashes out against "them"-- thorazine quickly puts an end to his violent outburst

SUMMARY: schizophrenia...

-...a disease of defects in neuronal migration and connectivity (and perhaps to a smaller degree neuronal survival) -genetic risk variants confer risk to schizophrenia, autism, ADHD, intellectual disability and some forms of epilepsy -unusually complex? certainly not (eg. 110 genetic loci conferring risk for multiple sclerosis... -"missing heritability"? environmental causes or unknown genetic/post-translational mechanisms?

family tree genetics...remains in families

-4 successive generations affected; illness in all branches where there is the translocation -distribution of mental illness consistent with single genetic lesion -studies point eventually to genes relevant for neurodevelopment, such as "disrupted in Schizophrenia-1 (DISC-1) -DISC-1: neuronal proliferation, differentiation, migration, cAMP signaling, cytoskeletal modulation, translational regulation via various signaling pathways-interesting and relevant neuroscience- but does not indicate association with disease

older fathers' aging SPERMATOGENESIS...

-Because the male germ cell undergoes many more cell divisions across the reproductive age range, copy errors taking place in the paternal germline are associated with de novo mutations in the offspring of older men. -...in a 20-year-old man, the spermatogonial cells have under-gone approximately 150 cell divisions. By age 50 years, this number is 840. Each time these cells divide, the entire genome is replicated and copy errors (i.e., mutations) inevitably occur: paternal age increases risk for schizophrenia, autism, mental retardation. -men transmit a much higher number of mutations to their children than women -it is the age of the father that is the dominant factor in determining the number of de novo mutations in the child -seeing an association between father's age and mutation rate is not surprising, but the large linear effect of more than two extra mutations per year, of the estimated exponential effect of paternal mutations doubling every 16.5 years, is striking

NMDA receptors and AMPA receptors collaborate in LTP (cont.)

-CREB is a TRANSCRIPTION FACTOR (a protein that binds to promoter region of genes and causes those genes to change their rate of expression) that is activated by protein kinases, including CaMKII and chemical cousins like MAPK, PKC, and TK -a direct result of the activation of NMDA receptors is the activation of CREB and changes in the expression of genes encoding a wide range of proteins -this action can have profound and long-lasting consequences for the neuron -the long-term changes in neurons after LTP range from formation of additional synapses, and enhancement of existing ones, to the construction of whole new dendritic branches and spines -the earlier stages of LTP, lasting only an hour or so, appear not to require protein synthesis, but thereafter, inhibition of protein synthesis prevents longer-lasting LTP -neurons can make proteins that selectively block CREB's actions, possibly providing means to erase or inhibit the formation of unwanted memories -not all of the changes in LTP are postsynaptic -when postsynaptic cell is strongly stimulated and NMDA receptors admit Ca++, an intracellular process causes the postsynaptic cell to release a RETROGRADE MESSENGER that travels back across the synapse and alters the functioning of the PRESYNAPTIC neuron -by affecting the presynaptic cell, the retrograde messenger ensures that more glutamate will be released into the synapse than previously, thereby strengthening the synapse

during conditioning, CS and UCS pathways are simultaneously active

-CS and UCS information "meet" at the purkinje cell-- interpositus intersection -thus: purkinje cells and projections to Int are the likely site of plasticity, allowing the tone to become a CS -Hebbian: both MF and CF take part in firing Purkinje cells -Purkinje cells: targeted by MF-PF as well as CF, importing CS and UCS information, respectively

eye blink conditioning circuit: CS

-CS: auditory projections, via the cochlear nucleus to the pontine nucleus (PN) -PN sends fibers, via mossy fiber pathway (MF) to granule cells and interpositus -from there via parallel fibers (PF) to purkinje cells -prior to conditioning, CS cannot drive Int output because inhibition of Int by purkinje cells

the dopamine hypothesis

-Chlorpromazine and other antipsychotic drugs, known as NEUROLEPTICS, share a specific action: they BLOCK POSTSYNAPTIC DOPAMINE RECEPTORS, particularly dopamine D2 receptors -researchers proposed the DOPAMINE HYPOTHESIS: that people with schizophrenia suffer from an excess of either dopamine release or dopamine receptors -at about the same time, people were also abusing drugs -as a consequence of drug tolerance, some daily users of amphetamine take astonishingly high doses -many individuals taking high doses of amphetamine exhibit symptoms strikingly similar to those of schizophrenia and are referred to as AMPHETAMINE PSYCHOSIS -amphetamine exacerbates the symptoms of schizophrenia -it turns out that amphetamine promotes the release of dopamine and prolongs the action of the released transmitter by blocking reuptake -chlorpromazine treatment rapidly reverses amphetamine psychosis

Principles of memory systems as reflected by HM's lesion and neuroanatomy

-Schematic view of the MEDIAL TEMPORAL LOBE memory system for DECLARATIVE memory, which is composed of the HIPPOCAMPUS and the PERIRHINAL, ENTORHINAL, and PARAHIPPOCAMPAL cortices -there are also weak projections from the perirhinal and parahippocampal cortices to the CA1- SUBICULUM BORDER -The hippocampus is not visible from the surface and in the human lies beneath the cortex of the medial temporal lobe -the hippocampus's anterior extent lies below the posterior entorhinal (red ) and perirhinal ( purple) cortices, and the main body of the hippocampus lies beneath the parahippocampal cortex -In the rat, the parahippocampal cortex is termed postrhinal cortex

synaptic plasticity can be measured in simple hippocampal circuits

-DONALD HEBB proposed that when a presynaptic neuron repeatedly activates a postsynaptic neuron, the synaptic connection between them will become stronger and more stable -DONALD HEBB'S maxim: "CELLS THAT FIRE TOGETHER WIRE TOGETHER" -ensembles of neurons linked via synchronized activity of these HEBBIAN SYNAPSES could then act together to store memory traces -in experiments, electrodes were placed within the rat hippocampus, positioned so that the researchers could stimulate a group of presynaptic axons and immediately record the electrical response of a group of postsynaptic neurons: -normal, low-level activation of the presynaptic cells produced stable and predictable excitatory postsynaptic potentials -but when researchers applied a brief high-frequency burst of electrical stimuli (called a TETANUS) to the presynaptic hippocampal neurons, thus inducing high rates of action potentials, the response of the postsynaptic neurons changed -now the postsynaptic cells responded to normal levels of presynaptic activity by producing much LARGER EPSPs; in other words, the synapses appeared to have become STRONGER or more effective -this stable and long-lasting enhancement of synaptic transmission is termed LONG-TERM POTENTIATION (LTP) -the opposite, a weakening of synaptic efficicacy is termed LONG-TERM DEPRESSION

patients in state and municipal mental hospitals

-De-institutionalization -Chlorpromazine was relieving hallucinations, delusions, and disorganized thought associated with schizophrenia

LTP: summary

-Hebbian situation -NMDA receptor: prototype of a Hebbian receptor -Pre- and Postsynaptic neurons engaged in a "synaptic dialogue" informing LTP (and also LTD) -several experiments demonstrated impairments in memory formation following manipulations that interfere with LTP induction -enhancement of memory formation by NMDA receptor agonists? -synaptic strength changes underlie the formation of memory

CHAPTER 17:: LEARNING AND MEMORY

-Henry Molaison, patient HM: a surgeon removed most of the anterior temporal lobes on both sides -HM lost ability to form new memories. He could retain any new facto only briefly -his IQ was a little above average -because he had no memories from the years since his surgery, or even memories from earlier the same day

Karl Lashley (1890-1958)

-Karl Lashley did NOT find the location of the memory trace -"I sometimes feel in reviewing the evidence of the localization of the memory trace that the necessary conclusion is that learning just is not possible"- Lashley, 1950 -he tested the effects of brain lesions on the performance (or recall) of rats that were WELL-TRAINED to navigate mazes 1) MASS ACTION LAW: the more brain matter is destroyed, the more severe the memory decific 2) EQUIPOTENTIALITY LAW: specific area of destruction does not matter...

LTP

-LTP can be generated in conscious and freely behaving animals, in anesthetized animals, and in tissue slices -LTP is evident in a variety of invertebrate and vertebrate species -LTP also lasts for weeks or more -LTP appears to have the hallmarks of a cellular mechanism of memory

Things to know this lecture

-LTP: molecular mechanisms -Long-term depression: broadening of the HEBBIAN RULE to behaviorally relevant stimulus administration regimen -cerebellar circuitry and eye blink conditioning (way beyond the book) *this is clearly the hardest part of this third section of 230

Hippocampus and spatial attribute coding; introduction to neuronal mechanisms of memory formation

-PTSD and modifying the attribute space -the not-so-great opposite of amnesia: HYPERTHYMESIA -hippocampus and spatial memory formation: Chickadees, sparrows, place cells, and taxi drivers -SYNAPTIC MECHANISMS: Hebb's postulate -changes in synaptic strength as a major mechanism underlying behavioral change and learning and memory -environmental enrichment effects as an early indication of the capacity for neuronal plasticity

What is LTP?

-Tetanus: >100 pulse/sec

UCS also "reaches" Purkinje cells and nc interpositus

-UCS information also reaches interpositus (Int) and Purkinje cells, via interior olive (IO) and climbing fibers (CF)

treatment and course: the optimistic version

-about 60% of people with Schizophrenia will improve and can live independently with support and treatment -about 20% of those diagnosed with schizophrenia will have an episode or two, and then never experience symptoms again -for about another 20%, symptoms are more persistent, treatments are less effective and greater support services are needed

Long-term LTP

-additional synapses -additional dendritic branches and spines -long-term changes are protein-synthesis-dependent and initiated by CREB activation: blocking CREB blocks long-term changes and also long-term memory formation

eye blink conditioning

-air puff to the cornea: unconditioned stimulus; causes eyeblink (unconditioned response) -sensory fibers from the cornea run along the TRIGEMINAL nerve (CN5) to cranial motor nucleus and then activate motor projections to cause the eyelids to close

typical vs. atypical neuroleptics

-all of the various antipsychotic drugs that are now classified as TYPICAL NEUROLEPTICS are D2 RECEPTOR ANTAGONISTS -they have an affinity for D2 receptors -although some evidence supports dopamine hypothesis, there are also several problems with this hypothesis -thus, the relation of dopamine to schizophrenia is more complex than just hyperactive dopamine synapses -some people with schizophrenia don't respond to dopamine antagonists at all -the search for new neuroleptics to avoid motor side effects, which are debilitating in some patients, led to the development of ATYPICAL NEUROLEPTICS -these drugs generally don't have a selective high affinity for dopamine receptors that is the hallmark of the typical neuroleptics, and they feature high affinity for other types of receptors -for ex., atypical neuroleptic CLOZAPINE selectively blocks serotonin receptors as well as other receptor types -atypical neuroleptics are just as effective as the older generation of drugs -so if the problem is just as simple as over-stimulation of dopamine receptors, why are atypical neuroleptics effective? -for ex., clozapine can INCREASE dopamine release in frontal cortex -supplementing neuroleptic tretaments with L-dopa (thereby increasing dopaminergic activity) actually helps reduce symptoms of schizophrenia -until recently, almost all clinicians believed atypical neuroleptics were more effective, esp for relieving negative symptoms -but a large british study comparing the outcome the two types found no difference -although the atypical neuroleptics are less likely than typical neuroleptics to cause side effects in motor function, they are more likely to cause weight gain

spatial memory and the evolution of hippocampal size

-animals who hide their food and need to retrieve it have enlarged hippocampus

the GLUTAMATE hypothesis

-another drug that was initially developed as an anesthetic has a much different relationship with schizophrenia -PHENCYCLIDINE (PCP) was soon found to be a potent PSYCHOTOMIMETIC...it produces phenomena strongly resembling both the positive and negative symptoms of schizophrenia -PCP acts as an NMDA receptor antagonist; blocks the NMDA receptor's central calcium channel, thereby preventing the endogenous ligand GLUTAMATE from having its usual effects -these observations prompted the GLUTAMATE HYPOTHESIS: that schizophrenia results form an underactivation of glutamate receptors -underactivation of ALL glutamate receptors, not just NMDA subtype, contributes to schizophrenia -perhaps they reduce schizophrenia symptoms indirectly, by boosting mGluR responsiveness

origins of the dopamine story

-antipsychotic drugs: D2 antagonists -amphetamine psychosis: positive symptoms following high amphetamine doses -repeated amphetamine exposure "sensitizes" dopaminergic systems -schizophrenic episodes can be triggered or exacerbated by amphetamine -high doses of L-Dopa: psychotic symptoms D2 receptor blockade D2 stimulation: inhibition of adenylate cyclase (2nd messenger pathway) **AGONIST: -amphetamine promotes the release of dopamine and fosters symptoms of schizophrenia -both amphetamine and cocaine block reuptake of dopamine and foster symptoms of schizophrenia **ANTAGONIST: -chlorpromazine, a drug that blocks symptoms of schizophrenia, occupies the dopamine site on the D2 receptor, preventing receptor activation by dopamine

limbic system abnormalities

-because the HIPPOCAMPUS and AMYGDALA help form some of the walls of the lateral ventricles, atrophy in these regions could cause the ventricular enlargement in patients with schizophrenia -the hippocampus and the amygdala are smaller in the twin who has schizophrenia -patients with schizophrenia reveal abnormalities in several parts of the limbic system, including hippocampus, amygdala, and parahippocampal regions -the hippocampal pyramidal cells of people with schizophrenia appear disorganized, possibly resulting from abnormal synaptic arrangements of both the inputs and outputs of these cells -the cellular disorganization of schizophrenia probably arises during early cell development -because we know that humans make new neurons throughout life, esp. in the hippocampus, abnormal neurogenesis or disordered integration of newly born cells could contribute to the development of schizophrenia

PTSD and therapy

-blocking stress-induced enhancement of affective attribute consolidation: treating PTSD by locking adrenergic receptors with propranolol during reconsolidation -PTSD: attributes as compulsive, automatic retrieval cues, involving amygdala circuitry: flashbacks, intrusive recollections of traumatic events -THERAPY: recall under pharmacological conditions that weakens the reconsolidation of affective attributes

Biology of Schizophrenia

-book by Sylvia Nasar John F. Nash Jr. (1928): Nobel in '92 in Economics "The mental disturbances originated in the early months of 1959 at a time when Alicia happened to be pregnant. And as a consequence I resigned my position as a faculty member at M.I.T. and, ultimately, after spending 50 days under "observation" at the McLean Hospital, traveled to Europe and attempted to gain status there as a refugee. I later spent times of the order of five to eight months in hospitals in New Jersey, always on an involuntary basis and always attempting a legal argument for release."

Warning!

-changes in synaptic efficacy, or synaptic strength, MAY have morphological correlates (such as those illustrated in the prior figures) -however, such correlates ARE NOT NECESSARY and their presence may be a striking exception from the rule -MORPHOLOGICAL CHANGES: "ceiling effects" (how much morphological "enrichment" can you install before running out of spacE?) RULE: increases in synaptic strength based on changes in release mechanisms and postsynaptic signaling pathways, without readily detectable morphological correlates

major antipsychotic drugs

-chlorpromazine: Thorazine (brand name) -haloperidol: Haldol -clozapine: Clozaril Antipsychotic D2 antagonist are not just that: -but may be D2 antagonism is all that matters -D2 antagonism, measured biochemically (ordinate) vs. clinical potency (abscissa)- there is no other correlation like this...

causes: genetic vs. nongenetic?

-concordance rate for identical twins: 48% -fraternal (dizygotic) twins: 17% -incidence rate: stable across continents, cultures, socioeconomic conditions -efforts to identify viral and other obvious causes were not or not reliably substantiated by massive longitudinal studies -BUT: obstetric complications, maternal infections etc: early insults that can affect brain development, or interactions with genetic vulnerabilities? -concordance rate: truly reflecting environmental variables or hitherto unknown genomic mechanisms for bestowing genetic vulnerability? (such as epigenetic, copy number variations, microdeletions, microduplications, etc.)

different mechanisms are used for CONSOLIDATING and RETRIEVING DECLARATIVE information

-consolidation of declarative long-term memories involves the hippocampus -we refer to the physical changes in the brain that underlie a long-term memory as an ENGRAM -animals with lesions of hippocampal formation have impaired memory for items learned recently but material learned a bit earlier were unaffected. this is evidence that the hippocampus cannot be the repository of engrams -instead, although HIPPOCAMPUS is important over the shorter term for CONSOLIDATION of a memory, after that period the memory is STORED IN THE CORTEX **permanent storage of information tends to be in the regions of the cortex where the information was first processed and held in short-term memory

schizophrenia has a heritable component

-developmental and environmental factors greatly affect the probability of schizophrenia -SCHIZOPHRENIA IS POLYGENIC: multiple genes play a role in the emergence of schizophrenia -CONCORDANT: when both individuals of a twin pair suffer from schizophrenia -DISCORDANT: if only one member of a pair exhibits the disorder -more concordant in monozygotic twins (they share more genes) -there is strong evidence of a genetic factor in schizophrenia -however, genes alone cannot fully explain whether a person will develop schizophrenia -the twin who develops schizophrenia tended to be the one who was more abnormal throughout life -the symptomatic twin frequently weighed less at birth and had an early developmental history that included more instances of physiological distress -this affected twin was more submissive, tearful, and sensitive -during childhood the developmental difficulties of twins who later suffer from schizophrenia are reflected in behavioral, cognitive, and other neurological signs, such as impairments in motor coordination -these patients tend to be unable to use normal smooth movements of the eyes to follow the moving target and instand show an intrusion of rapid, jerky eye movements

learning and memory change as we age

-differences in motivation, earlier education, and other confounding factors may masquerade as age-related memory problems -spatial-memory problems may become much more severe in dementias like Alzheimer's disease Age-related impairments of memory have several causes: -impairments of encoding and retrieval: older subjects show less cortical activation than younger subjects when encoding or retrieval is self-initiate -loss of neurons and/or neural connections -problems with cholinergic neurotransmission: acetylcholine transmission improve aspects of memory performance in human subjects

how CHLORPROMAZINE was found

-during WWII, early Japanese victories denied Allies access to quinine-producing areas; Gilman et al. synthesized synthetic antimalarial drugs, phenothiazine derivatives (did not work) -in France, these compounds were studied for use as antihistamines, found to be highly sedative, for surgeries -1950: Charpentier synthesizes chlorpromazine: prolongs sleep induced by barbiturates, inhibits conditioned avoidance response in mice -drug got passed around, including to Delay and Deniker. Administered to a 57-year old laborer, exhibited delusional and bizarre behaviors. within 1 day improved, within 3 weeks discharged as "normal" -1954: marketed in the states by Smith, Kline, and French as Thorazine

NMDA receptors and AMPA receptors collaborate in LTP

-during normal, low-level activity, the release of glutamate at the CA1 synapse activates only the AMPA receptors -the NMDA receptors cannot respond to the glutamate, because MAGNESIUM IONS block the NMDA receptor's integral CALCIUM ION channel -thus, few calcium ions can enter the neuron -however, NMDA receptors are activated if larger quantities of glutamate are released (in response to a barrage of action potentials), thus stimulating the AMPA receptors more strongly -AMPA receptors admit SODIUM IONS when activated, the increased activation of AMPA receptors DEPOLARIZES the postsynaptic membrane...and if a threshold value of about -35 mV is reached, the Magnesium plug is driven out of the NMDA receptors and now the NMDA receptors can be activated by glutamate -the NMDA receptors are now able to respond to glutamate, admitting large amounts of CALCIUM into the postsynaptic neuron -thus, NMDA receptors are fully active only when gated by a combination of voltage and the ligand (glutamate) -the large influx of Ca++ at NMDA receptors activates intracellular enzymes, called PROTEIN KINASES, that alter or activate a variety of other proteins -one of the protein kinases CaMKII (calcium/calmodulin-dependent protein kinase II) which affects AMPA receptors in several important ways -activated CaMKII causes MORE AMPA receptors to be produced and inserted into the postsynaptic membrane, and existing nearby AMPA receptors are induced to move to the active synapse -the membrane-bound AMPA receptors are also modified to increase their conductance of Na+ and K+ ions -the net effect of these changes is to enhace the sensitivity of the synapse to release glutamate -a second major effect of the activated protein kinases involves a substance called CREB

simple forms of changes in synaptic strength: CHANGES IN TRANSMITTER RELEASE

-more transmitter is released from axon terminal -postsynaptic membrane becomes larger and/or more sensitive to transmitter -synapse enlarges both pre-and postsynaptically -the end result is increased PSP (post-synaptic potential?)

complex eye-blink conditioning

-early studies showed that destruction of the hippocampus has little effect on the acquisition or retention of the conditioned eye-blink response in rabbits **therefore, HIPPOCAMPUS IS NOT required for this conditioning CEREBELLUM= learning associated to activity of individual neurons -the trigeminal pathway that carries information about the corneal stimulation to the cranial motor nuclei also sends axons to the brainstem (inferior olive) -these brainstem neurons, then send axons called CLIMBING FIBERS to synapse on cerebellar neurons in a region called the INTERPOSITUS NUCLEUS -the same cells also receive information about the auditory CS by a pathway through the auditory nuclei and other brainstem nuclei -so the US and CS converge in the INTERPOSITUS NUCLEUS of the cerebellum -after conditioning, the occurrance of the CS (tone) has an enhanced effect on the cerebellar neurons, so they now trigger eye blink even in the absence of an airpuff -local cooling or drugs that block the neurotransmitter (GABA) have the effect of reversibly shutting down the interpositus nucleus -if this manipulation is performed at the beginning of training, then no conditioning occurs until after the effect wears off -conversely, if animals are fully trained before treatment, subsequent injection of a GABA antagonist causes the conditioned behavior to disappear, subsequent injection of a GABA antagonist causes the conditioned behavior to disappear **CEREBELLUM'S INTERPOSITUS NUCLEUS appears to be the key location for storing this type of memory (eye-blink conditioning) -LTP plays a role in human eye-blink conditioning

hippocampal mechanisms are important in SPATIAL memory

-expeirments show that rats and other animals don't just learn a series of turns but instead form a COGNITIVE MAP (an understanding of the relative spatial organization of objects and information) in order to solve a maze ***in parallel with its role in other types of declarative memory, the HIPPOCAMPUS IS A CRUCIAL NEURAL PARTICIPANT IN SPATIAL LEARNING -within the hippocampus are found many neurons that selectively encode spatial location -these PLACE CELLS become active when the animal is in-- or moving toward-- a particular location TWO types of cells discovered in nearby entorhinal cortex probably help the animal to learn the local spatial environment: 1) GRID CELLS fire selectively when the animal crosses the intersection points of an abstract grid map of the local environment, acting like an innate system of latitude and longitude 2) BORDER CELLS (entorhinal) are activated when arrival at the perimeter of the local spatial map

summary

-eye blink conditioning confirms that synaptic strength changes are sufficient to produce learning -example of learning supported by REDUCTION in synaptic strength (reduced PC- interpositus synaptic strength) -example of plasticity occurring in a superordinate circuit (as opposed to changes within the reflex circuit itself) -FIRE TOGETHER--WIRE TOGETHER: conditioning requires overlapping US and CS: climbing fibers and mossy fibers are activated together, thereby changing purkinje-- interpositus regulation -cerebellum is involved in learning and memory

anatomy of the cerebellum ("little brain")

-folded surface, similar to the cortex -3 layers: granule cells, purkinje cells, molecular layer -gray matter outside and white matter inside, with deep nuclei -parallel fibers on the surface are axons of granule cells -purkinje cells are output cells; they project to deep cerebellar nuclei (such as the interpositus) and vestibular nucleus -5 classes of interneurons

neural mechanisms of memory storage

-formation of memories may require the formation of new synapses, or even birth of new neurons -NEUROPLASTICITY! -plastic changes at synapses can be physiological or structural -such changes include greater release of neurotransmitter molecules and/or greater effects because the receptor molecules become more numerous or more sensitive -the result of such changes would be an increase in the size of the postsynaptic potential -changes in the rate of inactivation of the transmitter -new synapses could form or synapses could be eliminated as a function of training -training could also lead to reorganization of synaptic connections...it could cause a more used pathway to take over sites formerly occupied by a less active competitor -GLIA also play a role in learning and synaptic activity -nearby astrocytes mark which synapses will change in strength; blocking astrocyte activity prevents the synapse from changing -people learning a new skill show changes in white matter that indicate changes in myelination from oligodendrocytes SYNAPTIC CHANGES that may store memories: 1) changes involving SYNAPTIC TRANSMITTERS: more transmitter is released from the axon terminal; postsynaptic membrane becomes larger and/or more sensitive to transmitter -synapse enlarges both pre- and postsynaptically 2) changes involving INTERNEURON MODULATION: interneuron modulation causes increased transmitter release 3) FORMATION OF NEW SYNAPSES: new synapses formed 4) REARRANGEMENT OF SYNAPTIC INPUT: shift in synaptic input

Individual genes

-genetic analyses suggest that genes influencing the development of schizophrenia are scattered across many different human chromosomes -nonetheless, a few genes have been identified that appear to be abnormal in a substantial proportion of schizophrenia cases -these include the genes encoding neuregulin 1, whcih participates in NMDA, GABA, and ACh receptor regulation -in one large scottish family, the several members who had schizophrenia shared a mutant, disabled version of a gene now known as disrupted in schizophrenia 1 (DISC1) -an interesting epigenetic factor in schizophrenia is PATERNAL AGE: older fathers are more likely than younger men to have children with schizophrenia -perhaps sperm of older men, which are the product of more cell divisions than the sperm of younger men, have accumulated more mutations caused by errors in copying the chromosomes; these mutations may increase the likelihood of schizophrenia

patient HM

-most old memories remained intact, but he had difficulty recollecting any events after his surgery -loss of memories formed prior to an event is called RETROGRADE AMNESIA -what was striking about HM was a far more unusual symptom: his apparent inability to retain NEW MATERIAL for more than a brief period -an inability to form new memories AFTER an event is called ANTEROGRADE AMNESIA -henry's case provided clear evidence that short-term and long-term memory are different -HM's surgery removed the amygdala, most of the hippocampus, and some surrounding cortex from both temporal lobes -memory deficit seemed to be caused by loss of hippocampus

summary

-neuronal plasticity: changes in synaptic strength -hebb's postulate -changes in strength: transmitter release, morphological changes -enrichment effects: illustrate potential of synaptic plasticity -habituation of the gill withdrawal reflex

aplysia

-if you squirt water at an aplysia's SIPHON (a tube through which it draws water) the animal protectively retracts its delicate gill -with repeated stimulation, the gill retracts less and less -demonstrated that this habituation is caused by changes in the synapse between the sensory cell that detects the squirt of water and the motorneuron that retracts the gill -as this synapse releases less and less transmitter, the gill slowly stops retracting in response to stimulation -similarly, both the number and size of the synaptic junctions vary with training in aplysia -if aplysia is tested in habituation paradigm over a series of days (long-term habituation), each successive day the animal habituates faster than it did the day before -in this case there is a reduction in the number of synapses between the sensory cell and motorneuron -elements of the aplysia gill withdrawal system are similarly capable of sensitization in which strong stimulation anywhere on the skin causes subsequent stimulations of the siphon to produce LARGER gill withdrawals -the strong stimulation of the skin activates a FACILITATING NEURON that releases the transmitter serotonin onto the presynaptic nerve termianls in the gill withdrawal reflex circuit -SEROTONIN boosts the activity of the sensory neuron's synapses onto the motorneuron, leading to a longer-lasting response **information can be stored in the nervous system by changes in both strength and number of synaptic contacts **neural activity changes the strength of synaptic connections

cerebellar circuitry and eye blink conditioning

-in contrast to Aplysia and LTP: mammalian learning paradigm, classical conditioning -complete explanation in terms of neuronal pathways involved in the generation of the unconditioned response (eye blink reflex, UR) by the unconditioned stimulus (US; US--> UR) -after conditioning, the bell (conditioned stimulus, CS) elicits this response (CS--> CR) -provides us also with an opportunity to talk a bit about the cerebellum in general

Learning in the sea slug APLYSIA californica

-ink color is a result of consumption of red algae BEHAVIOR of aplysia: -locomotion -siphon extended, gill spread out (usual posture) -minor defensive response: siphon and gill retracted -major defensive response: head retracted, ink released

simple forms of changes in synaptic strength: INTERNEURON MODULATION

-interneuron modulation causes increased transmitter release -and thus increased PSP

residual capacities of HM

-learned and improved his performance in a mirror-tracing task -however: he could not recall training episodes or having experienced the task -amnesia for DECLARATIVE (facts) but not PROCEDURAL (perceptual, motor) information

some simple learning in mammals relies on circuits in the CEREBELLUM

-learning that involves relations between events, between a stimulus and a response, is called ASSOCIATIVE LEARNING -instrumental conditioning, operant conditioning, is an association formed between the animal's behavior and the consequences of that behavior -if an experimenter rang a bell just before putting meat powder in the dog's mouth, repeating this sequence a few times would cause the dog to respond to the bell itself by salivating -in this case, the meat powder in the mouth is the UNCONDITIONED STIMULUS (US), which already evokes an UNCONDITIONED RESPONSE (UR) -the sound is the CONDITIONED STIMULUS (CS) and the learned response to the CS alone is the CONDITIONED RESPONSE (CR) -if the air puff (US) immediately follows an acoustic tone (CS), a simple conditioned response develops rapidly: the rabbit comes to blink (CR) when the tone is sounded -basic circuit of the eye-blink reflex is simple, involving cranial nerves and some interneurons that connect their nuclei -sensory fibers from the cornea run along CN5 (trigeminal) to its nucleus in the brainstem -from there, some interneurons send axons to synapse on other cranial nerve motor nuclei (CN 5,7), which in turn activate the muscles of the eyelids causing them to close

brain vs. computer

-learning, by changing synaptic strength, takes place in the circuits which actually mediate the response -for example, learning to throw a ball involves changes in the strength of many synapses in neuronal circuits planning, executing, and controlling the actual throw -likewise, recalling the face of your first S.O. may be based on enhanced processing in the same circuitry that mediated perception of the face -brains may not separate processing and storage...but computers still do

spatial map (cont.)

-many lines of evidence suggest that the HIPPOCAMPUS and surrounding cortex is involved in spatial memory -because almost ALL DECLARATIVE memory have spatial attributes (ie. "i recall exactly where i was on 9/11; i know where on the pg the verb was listed but can't recall its translation") it is conceivable that destruction of this brain region impairs the coding of spatial attributes and thus broadly disrupts declarative memory formation

ventricular abnormalities

-many patients with schizophrenia have ENLARGED cerebral ventricles, especially the lateral ventricles -the extent of enlargement predicts responsiveness to antipsychotic drugs : patients with more enlarged ventricles tend to show poorer response to these drugs -enlarged ventricles appears to be a stable trait in patients -recall that a disabled version of the gene DISC1 is associated with schizophrenia in one large family -the DISC1 protein normally interacts with a bewildering array of other proteins during brain development -when DISC1 gene is mutated in experimental mice, they exhibit enlarged lateral ventricles -what is the significance of enlarged ventricles? -because overall brain size does not seem to be affected in people with schizophrenia or mice expressing mutant DISC1, the enlarged ventricles must come at the expense of brain tissue

brain regions involved in learning and memory

-many regions of the brain are involved in learning and memory -different forms of memory rely on at least partly different brain mechanisms -the same brain structure can be a part of the circuitry for several different forms of learning

ANTIPSYCHOTIC medications revolutionized the treatment of schizophrenia

-more and more physicians were sketical that lobotomy was effective for any disorder, and a drug was discovered in 1954-- CHLORPROMAZINE (trade name Thorazine) which quickly replaced lobotomy as treatment for schizophrenia -chlorpromazine was originally developed as an anesthetic, but it could powerfully reduce the "POSITIVE" symptoms of schizophrenia, including auditory hallucinations, delusions, and disordered thinking -the drug treatment was reversible as well -the drug helps ONLY POSITIVE SYMPTOMS

emotions and memory

-not all memories are created equal -emotion can powerfully enhance our memory for past events -but if people are treated with PROPRANOLOL (a beta-adrenergic antagonist that blocks the effects of epinephrine), this emotional enhancement of memory vanishes -it's not that they perceive the story as being any less emotional; propranolol directly interferes with the ability of adrenal stress hormones to act on the brain

multiple brain regions are involved in ENCODING

-only a few brain areas predicted which stimuli would later be recognized -when the stimuli were PICTURES, the RIGHT PREFRONTAL CORTEX and the PARAHIPPOCAMPAL CORTEX in both hemispheres are activated -when stimuli were WORDS, the LEFT PREFRONTAL CORTEX and the LEFT PARAHIPPOCAMPAL CORTEX were activated **these results indicate that the PARAHIPPOCAMPAL and PREFRONTAL CORTEX are crucial for CONSOLIDATION

a variety of brain regions are involved in different attributes of working memory

-only animals with hippocampal lesions were impaired on this predominantly spatial task -only animals with lesions of the caudate nucleus were significantly impaired on the response recognition memory (based on habit) -object recognition memory (nonmatching to sample) was impaired in rats with extrastriate visual cortex lesions -the lack of overlap between the symptoms of different lesions nicely illustrates how memories involving different attributes are parceled out of diverse brain regions for storage

polygenic disorder:

-overlap of genes bearing NONSYNONYMOUS (NS) de novo mutations overrepresented in schizophrenia, autism spectrum disorder, and intellectual disability -"...show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity- regulated cytoskeleton- associated protein (ARC)2 and N-methyl-D-aspartate receptor (NMDAR) complexes." -if mutations of the first two are present in schizophrenics: greatest cognitive impairments -"...we demonstrate a convergence of de novo mutations on multiply defined sets of functionally related proteins, pointing to the regulation of plasticity at glutamatergic synapses as a pathogenic mechanism in schizophrenia. -How disruption of these synaptic mechanisms affects brain function to produce psychopathology cannot be answered by genetic studies alone, but our identification of de novo mutations in these gene sets provides the basis to address this. -Our findings of overlaps between the pathogenic mechanisms underlying schizophrenia and those in autism and intellectual disability lend support to recent, controversial suggestions that our understanding of these disorders might be advanced better by research that integrates findings across multiple disorders and places more emphasis on domains of psychopathology (for example, cognition) and their neurobiological substrates rather than current diagnostic categories."

patients with KORSAKOFF'S SYNDROME show damage to medial diencephalic structures and to the frontal cortex

-people with KORSAKOFF'S SYNDROME also have ANTEROGRADE amnesia for declarative memories -they frequently deny that anything is wrong with them, and they often fill a gap in memory with a falsification that they seem to accept as true -main cause of korsakoff's syndrome is lack of the vitamin thiamine (B1) -temporal lobe structures, including hippocampus, are typically normal in patients with Korsakoff's syndrome -but their brains show shrunken, diseased MAMMILLARY BODIES, as well as some damage in the DORSOMEDIAL THALAMUS **Mammillary bodies may serve as a processing system connecting medial temporal regions to the thalamus via the mammillothalamic tract, and, from there, to other cortical sites

cortical abnormalities and differences in brain activation

-people with schizophrenia differ from controls in the structure and functional activity of the CORPUS CALLOSUM -reported more accelerated loss of gray matter at adolescence in schizophrenics -people with schizophrenia tend to be IMPAIRED on neuropsychological tests that are sensitive to FRONTAL CORTICAL LESIONS -frontal cortex was impaired in schizophrenia -patients with schizophrenia show relatively LESS METABOLIC ACTIVITY in the FRONTAL LOBES (compared with their posterior lobes), while control subjects have more-equal activation of frontal and posterior cortex -this observations is referred to as the HYPOFRONTALITY HYPOTHESIS -subjects with schizophrenia show no increase in their PREFRONTAL ACTIVATION above resting levels during the task -treatment with drugs that alleviate symptoms of schizophrenia is associated with increased activation of frontal cortex -neurons in the frontal cortex of patients with schizophrenia have dendrites with a reduced density of synaptic spines compared with control subjects

genomic mechanisms involved in LTP induction

-protein kinases phosphorylate, and thereby activate, cAMP responsive element-binding protein (CREB) -cAMP-responsive elements are sequences of code in the promotor regions of genes -the result is an increase in the rate of transcription of certain proteins (new synapses, dendritic spines, and entire branches) -most of these ~100 genes regulate the development and differentiation of neurons -CREB has been demonstrated to play a necessary role in long-term memory formation

LTP: mechanisms of memory?

-quickly induced, lasts for days/weeks -NMDA receptor blockade impairs learning in many neuronal systems -following conditioning: LTP-like phenomena or accelerated LTP induction in brain slices -KO of NMDA-receptor activated kinases: impairment in LTP and learning

Great Hollywood story but unusual case:

-relatively "clean" schizophrenia dominated by positive symptoms -hallucinations were exclusively AUDITORY -fairly late and relatively sudden onset (26 years), 3 decades of illness -"positive" symptoms recover in 30-40% of patients as they get older-- but his recovery is remarkable -cognitive facilities fundamentally spared: highly rare, usually tend to worsen with aging

What is responsible: hippocampus or amygdala, or both, or what?

-removal of amygdala, hippocampus, and surrounding temporal lobe cortex -patient R.B.: selective CA1 damage after cardiac arrest causing memory impairment, but limited severity -additional damage to adjacent cortical regions greatly exacerbates the memory impairment -also: later scans like this one showed cortical thinning and subcortical atrophy, infarcts

more on Lashley

-why did Lashley fail to find effects of large lesions on memory in rats, while destruction of just the hippocampus and surrounding cortex suffices in yielding complete anterograde amnesia in primates? -because he searched for the circuits of procedural memory in regions mediating memory for declarative information

Hebb vs. Habituation in Aplysia

-why is it, that after repeated stimulation of the siphon skin, and after repeated firing of the sensory neuron and thus the motor neuron-- establishing a Hebbian situation for sure-- this synapse is not strengthening, but rather weakening. is this in conflict with Hebb's rule?

different brain regions process different ASPECTS of memory

-roles of different parts of the medial temporal lobe in the formation of declarative memory **MEDIAL TEMPORAL LOBE structures are crucial for DECLARATIVE MEMORY **the amygdala is not crucial for performance on tests of declarative memory -removal of adjacent hippocampus significantly impaired performance on these tests and the deficit was even more pronounced when the hippocampal damage was paired with lesions of the nearby entorhinal and parahippocampal cortex -hippocampus acts as the final stage of convergence for adjacent regions of cortex, resulting in storage of declarative memories in cortex -crucial importance of medial temporal (hippocampal) and diencephalic systems in forming long-term memories -these regions are activated during both encoding and retrieval -the autobiographical passages cause greater activation of RIGHT FRONTAL and TEMPORAL lobe regions than do nonautobiographical passages **AUTOBIOGRAPHICAL MEMORIES and SEMANTIC MEMORIES appear to be processed in DIFFERENT LOCATIONS

Short versions of concepts and points to be taken from last lecture

-schizophrenia is a POLYGENIC disorder, likely caused by accumulation and combinations of rare mutations (mainly CNVs, SNPs) -mutations are INHERITED (paternal) and/or new -rare mutations of genes coding for proteins playing a role on neuronal migration, circuit formation, glutamatergic and GABAergic synapses, and voltage-regulated ion channels -risk-conferring mutations overlap in schizophrenia, autism, intellectual disability -two risk-conferring genes worth singling out: ARC and SCN2A -evidence for modifications of synapses of CHANDELIER CELLS -we still know little about gene EXPRESSION levels and contributions by epigenetic gene silencing or activation -cannabis and other psychotropic drugs: increasing the severity of the disease and trigger acute (psychotic) disease periods

invertebrate nervous system show plasticity: APLYSIA

-sea slug APLYSIA have a compact nervous system that are capable of the simplest type of learning: NONASSOCIATIVE LEARNING -in each of the three forms of nonassociative learning-- HABITUATION, DISHABITUATION, and SENSITIZATION-- a single stimulus is presented once or repeatedly -HABITUATION is a decrease in response to a stimulus as the stimulus is repeated -DISHABITUATION: once habituation has occurred, a strong stimulus will often cause the response to the habituated stimulus to increase sharply or even larger than the original response...so if a loud firecracker is set off behind you, the next ring of the door chime will startle you..in this case you have been temporarily dishabituated -SENSITIZATION: even a response that has not been habituated, may increase in amplitude after a strong sitmulus....the response is greater than the baseline level because of prior stimulation...after firecracker, you may overreact to someone standing up nearby

long-term effects of antipsychotic drugs

-some people develop maladaptive motor symptoms (dyskinesia) -TARDIVE DYSKINESIA: characterized by repetitive, involuntary movements, esp involving the face, mouth, lips, and tongue -elaborate, uncontrollable movements of the tongue are particularly prominent -some people claim that it arises from the chronic blocking of dopamine receptors -tardive dyskinesia tends to be irreversible -prolonged blockage of dopamine receptors seems to increase the number of dopamine receptors and lead to receptor supersensitivity -atypical neuroleptics have fewer dyskinesia side effects than traditional neuroleptics have

evidence indicating that alterations in the synaptic contacts between Purkinje cells and interpositus underly CS--> CR

-stimulation of mossy and climbing fibers simultaneously: long-term depression of purkinje cell activity -during conditioning: interpositus activity increases -electrical stimulation of mossy fibers: replaces presentation of CS -electrical stimulation of climbing fibers: replaces presentation of US -inactivation of the interpositus during learning, or STIMULATION of GABA receptors in the interpositus: block conditioning -mutant mice showing purkinje cell degeneration exhibit impaired eye blink conditioning

psychobiological model of schizophrenia emphasizes the interaction of multiple factors

-stressful events significantly increase the risk of schizophrenia -schizophrenia usually appears during a time in life that many people find stressful RISK FACTORS: -prenatal stress is also a risk factor -pregnant woman who contracts influenza in the first trimester of pregnancy is 7 times more likely to develop schizophrenia -why people born late winter and early spring are more likely to develop schizophrenia: their mothers may be more likely to have gotten sick during the winter before, perhaps at some fetal stage that is particularly vulnerable -low birth weight -birth complications that deprive the baby of oxygen also increase the probability of schizophrenia -schizophrenia is caused by the interaction of genetic factors and stress -related disorders depends on whether a person who is genetically susceptible to schizophrenia is subjected to environmental stressors

side effects

-target dosing: minimal and periodic dosage levels, to control acute symptoms -parkinsonian tremor -akinesia (absense of movement) or bradykinesia (slowness of movement) -tardive dyskinesia: tic-like, elaborate, incontrollable repetitive movements of lips, tongue, jaws, and face (15% of patients treated with typical antipsychotics)

damage fo the medial diencephalon can also cause amnesia

-temporal lobe is not the only brain region involved in formation of declarative memories -PATIENT N.A: damage to the diencephalon (thalamus and hypothalamus) also impaired memory formation -NA has a striking case of ANTEROGRADE amnesia, primarily for verbal material -NA shows normal short-term memory but is impaired in forming DECLARATIVE long-term memories ***MEDIAL TEMPORAL REGION damaged in HM and MIDLINE DIENCEPHALIC region damaged in NA are normally parts of a larger memory system

Neuronal mechanisms of learning and memory

-why was Lashley unable to find the 'engram'? -from H.M. to contemporary views on the MEDIAL TEMPORAL LOBE and DECLARATIVE MEMORY -the importance of classifying types learning materials -additional brain regions -Patient R.B., N.A., and B.J., and Korsakoff's syndrome -learning and recall: attribute systems and memory systems -reconsolidation and PTSD

after conditioning

...

LTP occurs at several sites in the hippocampal formation

-the HIPPOCAMPAL FORMATION consists of two interlocking C-shaped structures: the hippocampus itself and the dentate gyrus-- along wit the adjacent cortex -three major divisions within the hippocampus (CA1, CA2, CA3) Three pathways in the hippocampal formation that display LTP: 1) PERFORANT PATHWAY: the main input pathway to the hippocampal formation; originating in nearby entorhinal cortex and terminating at synapses in dentate gyrus 2) MOSSY FIBER PATHWAY: dentate gyrus to CA3 pryamidal cells 3) SCHAFFER COLLATERALS (CA3 pyramidal cells to CA1 pyramidal cells) -in CA1, LTP occurs at synapses that use the excitatory neurotransmitter GLUTAMATE, and it is critically dependent on a glutamate receptor subtype called NMDA RECEPTOR -treatment with drugs that selectively block NMDA receptors completely prevents new LTP in the CA1 region, but it does not affect LTP that has already been established -these postsynaptic NMDA receptors-- working in conjunction with related glutamate receptors called AMPA RECEPTORS-- have some unique characteristics

CHAPTER 16:: PSYCHOPATHOLOGY

-the aim in this chapter is to explore the biological underpinnings of the most prevalent psychiatric disorders: Schizophrenia -schizophrenia tends to appear in adolescence and young adulthood -EUGEN BLEULER identified the key symptoms as DISSOCIATIVE THINKING, a major impairment in the logical structure of thought -Bleuler also described a mix of accompanying symptoms, including loosened associations, emotional disturbance, delusions, and hallucinations -German psychiatrist EMIL KRAEPELIN described numerous clinical features common to varied forms of schizophrenia: paranoia, grandiose delusions, abnormal emotional regulation, biazarre disturbances of thought, and auditory hallucinations

declarative vs. nondeclarative memory

-the important distinction is between two kinds of long-term memory: (1) DECLARATIVE: facts and information acquired through learning -it is memory we are aware of accessing, which we can DECLARE to others -this type of memory was impaired in H, (2) NONDECLARATIVE: -aka. procedural memory -memory about perceptual and motor procedures-- shown by PERFORMANCE -things that you learn by DOING -declarative memory deals with WHAT, and nondeclarative memory deals with HOW

retrieving memories can strengthen them, or distort them

-the process of retrieving information from LTM seems to make the memories temporarily unstable and susceptible to disruption or alteration before undergoing RECONSOLIDATION and returning to stable status -but, if care is taken to be sure the information retrieved is accurate, reconsolidation can be used to strengthen memories you want to keep (ie. repeated retrieval is very effective for memory)

memory has temporal stages: short, intermediate, and long

-the span of time that a piece of information will be retained in the brain varies -the briefest memories are called ICONIC MEMORIES (ex. fleeting impression of a glimpsed scene that vanishes from memory seconds later) (these are also known as sensory buffers) -somewhat longer than iconic memories are SHORT-TERM MEMORIES (STMs) -some memories last only a little longer than STMs but are far from being permanent-- these are called INTERMEDIATE-TERM MEMORY -chances are good that you can remember what you had for lunch today or yesterday, but not most of your lunches last week (intermediate-term memory)

positive and negative symptoms of schizophrenia

-the symptoms considered indications of schizophrenia include: (1) AUDITORY HALLUCINATIONS, (2) highly personalized DELUSIONS (false beliefs), (3) changes in affect (EMOTION) -a major division of schizophrenic symptoms into two separate groups: positive and negative (1) POSITIVE SYMPTOMS: refers to behavioral states that have been GAINED -hallucinations, most often auditory -delusions of grandeur, persecution, etc. -disordered thought processes -bizarre behaviors (2) NEGATIVE SYMPTOMS: refers to behavioral functions that have been LOST -social withdrawal -flat affect (blunted emotional responses) -anhedonia (loss of pleasurable feelings) -reduced motivation, poor focus on tasks -alogia (reduced speech output) -catatonia (reduced movement)

functional perspectives on memory

-there are different FORMS of learning and memory, and that multiple brain regions are involved -study of different types of memory impairment has revealed different classes of learning and memory

in adult brain, newly born neurons may aid learning

-there is no doubt that new neurons are produced in the brains of adult mammals -ADULT NEUROGENESIS occurs primarily in the DENTATE GYRUS of the hippocampal formation -turning off neurogenesis in the brains of adults resulted in a marked impairment in spatial learning with little effect on other behaviors **thus neurons born in adulthood play a role in learning and memoryd

treatment and course : the reality version

-there were no significant differences in effectiveness between the conventional drug perphenazine and the other second-generation drugs -cognitive impairments: unaddressed by antipsychotic medication -it is now accepted that patients with a diagnosis of schizophrenia have a broad-based cognitive impairment of, on average, about 1 SD below the norm across a range of cognitive abilities (attention, speed of processing, working, and long term memory, executive function, and social cognition

brain damage can destroy AUTOBIOGRAPHICAL memories while sparing general memories

-two subtypes of declarative memory -Patient K.C.: sustained brain damage and can no longer retrieve any personal memory of his past, although his general knowledge remains good -detailed autobiographical declarative memory of this sort is known as EPISODIC MEMORY -in contrast, SEMANTIC MEMORY is generalized declarative memory -K.C. can acquire new semantic knowledge, but cannot acquire new episodic knowledge -KC had extensive damage to the cerebral cortex and severe shrinkage of the hippocampus and parahippocampal cortex -bilateral hippocampal damage probably accounts for KC's anterograde declarative amnesia but not for the selective loss of nearly his entire autobiographical memory ***autobiographical memory loss may be a consequence of CORTICAL INJURIES -a group of 11 people with extreme autobiographical memory were found to have LARGER TEMPORAL LOBES, including a larger parahippocampal gyrus

Is LTP a mechanism of memory formation?

-we are unlikely to conclude that LTP is the only mechanism of learning -LTP bears strong similarity to the time course of memory formation -LTP tend to impair learning: NMDA receptor blocking interferes with performance in the morris water maze -drugs that inhibit CaMKII and other protein kinases also generally interfere with aspects of memory formation -training in animal in a memory task can induce LTP in the brain **LTP is a kind of synaptic plasticity that underlies certain forms of learning and memory

treatment realities at this point

1) ANTIPSYCHOTICS: -even the atypical ones-- are merely anti-psychotic, not anti-schizophrenic -in fact, they are as efficacious for psychosis in other conditions as they are for the psychosis of schizophrenia 2) DOPAMINERGIC DYSREGULATION: -the dopaminergic dysregulation is, in all likelihood, a secondary consequence of some other more primary pathophysiology -current treatments block the behavioral consequences of hyperdopaminergia and will remain limited until the underlying primary pathophysiology is identified and targeted 3) the negative-cognitive-oddness spectrum may have a pathophysiologic basis distinct from that of psychosis -thus, hopes of an ideal anti-psychotic that will erase these symptoms is probably mislaid -treatment of these symptoms may require therapeutic axes distinct form those embodied in the current antipsychotics

SUMMARY: causes and course

1) CAUSES: -genetic, environmental, and developmental vulnerability factors interact -or NOT: random, new, and sporadic genetic abnormalities with large effect sizes (imprinting, epigenetics, microdeletions, microduplications) -"multiple hits" accumulate/interact (8,000 SNPs?) 2) COURSE: -mild deficits in social, motor, and cognitive functions in childhood and adolescence -twin studies: affected twin "was always" the one that was more abnormal -prodromal symptoms develop over time and environmental events may serve as "stressors on vulnerable neural circuits that exceed their adaptive capacity..." triggering behavioral symptoms that mark the onset of the disease

Brain regions involved in different kinds of memory (overview)

1) DECLARATIVE: -EPISODIC: storage in cortex, perhaps esp in right frontal and temporal regions -SEMANTIC: storage in cortex, perhaps esp in temporal lobes 2) NONDECLARATIVE: -SKILL LEARNING: basal ganglia (habit), motor cortex, cerebellum -PRIMING: (1) Perceptual priming reduces activity in bilateral occipito-temporal cortex (2) Conceptual priming reduces activity in left frontal cortex -CONDITIONING: (1) simple conditioning= cerebellar circuit (2) complex conditioning= hippocampus and cortex

encoding, consolidation, retrieval

1) ENCODING: -medial temporal lobe, distributes the attributes of an event, and linkages between them, in corresponding regions of the cortex -fmri: prediction of retrieval depends on material/attributes 2) RETRIEVAL of memory before it is consolidated: -before a memory is consolidated it is sensitive to damage in medial temporal lobe, including hippocampus -possibly because such early recall employs access routes that are similar to encoding mechanisms -hippocampal lesions disrupt recently learned material, not memories that were learned a long time prior to the lesion 3) RETRIEVAL of consolidated memory: -after a memory is consolidated, access routes become embedded into more general schemes for memory access -no longer dependent on mirroring the encoding mechanisms -no longer dependent on temporal lobe

iclicker

1) Following successful conditioning a) a corneal airpuff no longer elicits an eyeblick response b) the demonstration of a UR requires an intact cerebellum c) the demonstration of a CR requires an intact cerebellum d) aandb e) all of the above 2) Following conditioning a) Purkinje cells are more profoundly depolarized by a CS-UCS pairing then before conditioning b) Purkinje cells tend to remain silent in response to a CS-UCS pairing c) More GABA is released from Purkinje cells in response to a CS- UCS pairing than before conditioning d) Interpositus neurons are more readily depolarized than before e) bandd 3) Following conditioning a) The CS can depolarize interpositus neurons b) The CS alone can recruit, via several synapses, the motor neurons that cause an eye blink c) The UCS no longer has access to the eyeblink reflex circuit d) aandb e) all of the above 4) After conditioning, which of the following manipulations can block the demonstration of the CR a) Stimulation of GABA receptors expressed by interpositus neurons by, e.g., applying an agonist b) Administering glutamate receptor antagonists onto the dendritic tree of Purkinje cells c) Lesioning the climbing fiber system d) Lesioning of the granule cells and thus the parallel fiber system e) a andd

eye blink conditioning (cont.)

1) INDUCTION: CS--> 250 ms--> UCS 2) EXPRESSION: where is the site of neuronal plasticity that allows the bell now to elicit the eye blink response?

major dopamine projection systems

1) MESOLIMBIC dopaminergic systems: -cognition, reward -schizophrenia -addiction -ADHD? 2) NIGRO-STRIATAL dopaminergic system: -parkinson's disease

basic structure of the cerebellum

1) OUTPUTS: -PURKINJE CELLS are the sole OUTPUT neurons of the cerebellum, projecting to cerebellar nuclei, including INTERPOSITUS NUCLEUS, and from there to dorsal motor systems and spinal motor tracts (generally inhibitory) 2) INPUTS: -"climbing fibers": from inferior olive to purkinje cells -one climbing fiber input per purkinje cell -but, extensive contacts allow for massive depolarization of purkinje cells -"MOSSY FIBERS": from brain stem regions (eg. pontine nucleus) and spinal cord to granule cells which, via their extensive parallel fiber network, excite Purkinje cells; also collaterals to cerebellar nuclei **note: MOSSY FIBERS (MF) and climbing fibers both converge onto Purkinje cells -also, note that MF could drive the output if it were not for...???

the mess clinical classification made of it...

1) POSITIVE SYMPTOMS: -hallucinations, most often auditory -delusions of grandeur, persecution, etc. -disordered thought processes -bizarre behaviors 2) NEGATIVE SYMPTOMS: -social withdrawal -flat affect (blunted emotional responses) -anhedonia (loss of pleasurable feelings) -reduced motivation, poor focus on tasks -alogia (reduced speech output) -catatonia (reduced movement) 3) COGNITIVE DYSFUNCTIONS: -attention -working memory -executive functions

Causes

1) PSYCHODYNAMIC CONCEPTS: diagnosis and classification as a fruitless endeavor; not a brain disease; rather, focus on the nature and cause of intrapsychic conflicts -FREUD: "disharmonious" mental states that were exaggerations of normal psychic functions, rejected the idea of a brain disease -prominent psychoanalyst FRIEDA FROMM-REICHMANN, MD: argued, in 1948, that schizophrenia was caused by mothers who were simultaneously over-involved with and rejecting of their affected children 2) CORRELATIONAL EVIDENCE: prenatal influenza and other early stressors? -first trimester influenza increases risk-- but not a universally confirmed hypothesis -SMALL increases in risk by: general maternal illness during 2nd trimester, birth complications (hypoxia), winter birth/summer -challenging the hypothesized link to season of birth in patients with schizophrenia (by Tammie Lee Demler, pharmD, MBA): in light of the absence of predicted seasonal differences in births of the individuals in our study sample... 3) MORE CORRELATION-BASED SPECULATIONS: -the nithsdale schizophrenia surveys 16 breast-feeding and schizophrenia (preliminary results and hypotheses) by Robin G. McCreadie -fewer schizophrenic patients than normal were breast-fed -lack of breast milk maybe a risk factor in the neurodevelopmental form of schizophrenia • One possible explanation of these results is that aspects of personality in mothers, or possibly fathers, of schizophrenic patients lead to a decision not to breast-feed. • A lack of important fatty acids, such as DHA, in bottle-feeds increases the risk of the neurodevelopmental form of schizophrenia in the individual predisposed to the illness by genetic factors or previous environmental insult. • In addition, although the evidence is that prenatal rather than postnatal infection may be an etiological factor in schizophrenia, maternal antibodies transmitted through breast milk may be an additional protective factor. • Another possibility is that genetic factors determine both the personality characteristics which lead to the decision not to breast-feed, and the child's abnormal development and subsequent neurodevelopmental schizophrenia.

incidence rates

1) Schizophrenia INCIDENCE rates (per 10,000), for MEN: -9.4 for ages 15-19 -5.6 for ages 20-24 -3.3 for ages 25-29 -.9 for ages 30-34 2) Schizophrenia INCIDENCE rates (per 10,000), for WOMEN: -1.6 for ages 15-19 -1.3 for ages 20-24 -4.1 for ages 25-29 3) PREVALENCE: 1-2% (of the population)= 2.2 million people in the US

atypical antipsychotics: may be not so atypical at all

1) TYPICALS: -block D2 receptors in striatal and mesolimbic regions -side effects reflecting striatal D2 blockade -less effective or even detrimental with respect to cognitive impairments 2) ATYPICALS: -more selective for mesolimbic systems and may be beneficial cognitive effects ... or is this all an old and outdated view, and patients treated with typical antipsychotic drugs are all over-dosed because the practicing psychiatrist primarily observes motor side effects and sedations? BUT: atypicals more effective against psychosis-- they are now the pharmacological shotgun therapy

anatomy we need to know

1) UCS (air puff): inferior olive (IO) --> climbing fibers (CF) 2) CS: pontine nucleus (PN) --> mossy fibers (MF) granule cells (GR)--> parallel fibers (PF) 3) purkinje cells (PC) release GABA onto nc. interpositus 4) nucleus interpositus (Int): inhibited by PC and stimulated by MF

iclicker:

1) You can block the induction of LTP by a) blocking NMDA receptors b) blocking AMPA receptors c) giving a drug that replaces Mg++ as a NMDA receptor blocker and that cannot be removed by depolarization of the receptor d) administering TTX e) all of the above 2) After LTP is induced and established, expression of LTP is blocked by a) blocking NMDA receptors b) blocking AMPA receptors c) blocking Ca++ influx d) increasing the amount of glutamate released from presynaptic neurons per stimulus e) none of the above

Disease course

1) the onset of schizophrenia is typically in adolescence or early adulthood, and the course of illness is often LIFELONG and typified by exacerbations, remissions, substantial residual symptoms, and functional impairment 2) Individuals affected by schizophrenia have elevated morbidity and mortality, a lifetime risk of suicide exceeding 10%, and substantial comorbidity with other psychiatric disorders, including major depressive disorder and substance abuse

summary: gross anatomical mechanisms of memory

1) while there are some overlaps, there are also clear differences between the main neuronal systems mediating the formation of memories about different types of information (declarative, semantic, procedural, affective) 2) prefrontal regions are generally involved in memory operations, as they generally process "executive" components of complex mental operations (attentional resources, working memory capacity, cognitive and behavioral planning) 3) Hippocampus/temporal lobe and midline structures are crucial for the formation and recall of the memory; the actual representation of the memory is based on patterns of neuronal activity distributed over large, parallel networks

synaptic mechanisms of LTP induction and expression: 1) Baseline 2) Induction of LTP 3) Expression

2) INDUCTION of LTP: -massive glutamate release -NMDA receptor blockade removed (at approx. -35 mV) -Glu at NMDA: now large influx of Ca++ -activates Ca-dependent protein kinases (protein kinase A [PKA] and C [PKC], calcium-calmodulin kinase [CaM, CaMK], tyrosine kinase [TK]) **which in turn activates (phosphorylates) AMPA receptors and increases AMPA receptor density -retrograde effects change glutamate release dynamics -long-term effects via activation of CREB (cAMP response element-binding protein) and genomic effects

synaptic mechanisms of LTP induction and expression: 1) Baseline 2) Induction of LTP 3) Expression

3) EXPRESSION: As a result of a single stimulus application: -possibly more GLU release and, more importantly... -greater depolarization of the postsynaptic site because of more and more and more sensitive AMPA receptors

susceptibility genes impair synaptic functions and plasticity

5) causes: CANNABIS USE and Schizophrenia? -in 2008 over 15% of 12th graders reported using cannabis daily for at least a month at some point in their lives -the risk of developing schizophrenia increases in a dose-dependent manner with increasing frequency of cannabis use -reviews of these and other longitudinal and case-control studies confer that lifetime cannabis use increases the risk of developing psychosis -evidence for effects of EXOGENOUS cannabinoids on pruning of glutamatergic contacts during adolescence and altering the LTD/LTP balance in forebrain glutamatergic circuitry -BUT ATTENTION: cannabis use higher in clinical high risk patients, for mood enhancements etc.; cannabis as a trigger? -heavy cannabis use (multiple joints/day routinely) associated with an earlier onset of schizophrenia in vulnerable populations (family history; schizotypic or paranoid personality) -cannabis use causes relapse in patients

Cause (more)

A POLYGENEIC DISORDER: 1) rare copy number variations? 2) not-so rare SNPs, but lots of them? 3) rare disruptive mutations Missing heritability? perhaps not...

different attributes of memory may be processed by different brain systems

ATTRIBUTES OF MEMORY: -SPACE= hippocampal formation -TIME= hippocampal formation -AFFECT= amygdala -SENSORY PERCEPTION= extrastriate cortex -RESPONSE= own locomotor response in caudate nucleus

Encoding, consolidation, retrieval

BEWARE: retrieving memories makes them PLASTIC again, by adding new attributes or limiting the impact of old ones **memory becomes vulnerable to re-encoding problems (good & bad)

Dr. William A. Decker

Dr. William A. Decker: Kalamazoo Psychiatric Hospital from 1953-1987 -salesman was selling a drug called SERPASIL -Decker said he was treating a farmer from Wayland who was in the hospital in a state of catatonic schizophrenia. He was not eating, drinking or washing himself. The staff crushed the pills and put them in his feeding tube. -Within three days the man was out of bed, talking and cooperating with his treatment. -He was back with his family three weeks later. -It was the first in a line of neuroleptic or antipsychotic drugs, such as Thorazine, that would revolutionize psychiatric treatment and the role of psychiatric hospitals in society. -Patients who had been in the hospital for decades were suddenly responsive, able to care for themselves, and moving back to live with their families -the number of patients at Decker's hospital plummeted from 3600 to 550 -recognition by the Department of Social Security that people with mental disorders had a disability the same as people with physical disorders

iclicker:

During conditioning a) climbing fibers are now inactive b) mossy fiber action potentials translate into depolarization of Purkinje dendritic membrane c) climbing fiber action potentials "import information" about the corneal airpuff to Purkinje cells d) the convergence of mossy and climbing fiber depolarization changes Purkinje cells so that they become less excitable e) b,c and d

in contrast to nosological classes of symptoms: Schizophrenia as a COGNITIVE disorder

EMIL KRAEPELIN (1856-1926): -Schizophrenia was first described in 1896 by Kraepelin: "dementia praecox" -"the more distractable a man is, the less perception is controlled by inner motives arising from experience, and the less coherent and uniform is the conception of the external world" EUGEN BLEULER (1857-1939): -"Schizophrenia" (split-mind") -referring to the division of psychological processes that are normally coordinated (eg. an adequate) emotion experienced when perceiving an event

environmental enrichment illustrates the capacity of neurons to alter their connectivity

ENRICHMENT: increased density of dendritic branches, increased spine density= increased number of synapses -increased postsynaptic "active zones" (apical= close to the tip)

illustration of the anatomy of the hippocampus (coronal section)

Entorhinal cortex --> subiculum --> via perforant path --> dentate gyrus --> via mossy fiber pathway --> CA3 --> via Schaffer collaterals --> CA1 --> subiculum --> output to mainly diencephalic regions

mechanisms underlying habituation of the gill withdrawal response

Eric Kandel 1) SHORT TERM HABITUATION: progressively less neurotransmitter release (glutamate) from the sensory neuron -reduced glutamate release appears to be a result of a smaller number of vesicles moved to the active zone; effect lasts for minutes -TAIL SHOCK: sensitization; serotonin connection to sensory neuron terminals rescues glutamate release and thus the withdrawal response... (can ignore this statement) 2) LONG TERM HABITUATION: retraction of synaptic contacts between sensory and motor neuron -conclusion: in Aplysia, as well as other species, information can be stored by changing the STRENGTH and/or number of synapses-- in circuits that actually underlie the expression of the behavior that was modified by learning

habituation

HABITUATION: decreasing response as a result of repeated stimulus presentation (non-associative form of learning) -in Aplysia, the gill and siphon withdrawal reflex: tactile or electrical stimulation of the siphon causes withdrawal of the gill and siphon -in Aplysia, 20,000 neurons total -has head and abdominal ganglion CIRCUITRY, measures and possible mechanisms underlying habituation: SIPHON-GILL WITHDRAWAL REFLEX CIRCUIT: -24 sensory neurons directly contact and stimulate 6 gill motor neurons; glutamate

HYPERTHYMESIA

HYPERTHYMESIA: -Jill Price (one of the 8 known cases) A.J (later self-identified as Jill Price): -superior, complete AUTOBIOGRAPHICAL MEMORY (eg. when was Easter, for the years 1980-2003, what did you do, what was the weather...) -"I go automatically back to that day...exhausting..." -AUTOMATIC and OBSESSIVE REHEARSAL OF AUTOBIOGRAPHIC DETAILS -five years of study -touch of compulsive focus on autobiographical sorting early in life (diaries, scheduling calendars) -PREDOMINANT ATTRIBUTE SPACE: DATES/CALENDAR -average student, memorizing poems were painfully difficult -perfect recall precisely limited to and associated with her own life "SELECTIVE and ORDINARY" -calls herself a "terrible memorizer" -executive functions (eg. concept formation and shifting) were IMPAIRED **uncontrollable EPISODIC retrieval mode, mostly based on semantic memories **semantic also because no updating of attribute space-- frozen memories

Lecture 20:

Hippocampus and spatial attribute coding; introduction to neuronal mechanisms of memory formation: -memory attributes, encoding, immediate and subsequent retrieval -PTSD and automatic compulsive retrieval; adrenaline -hyperhtymesia: Jill Price -chickadees, sparrows, and taxi drivers: spatial information processing by specialized neurons in the hippocampus, entorhinal cortex, and diencephalon (PLACE CELLS and GRID CELLS) -summary: gross anatomical systems necessary for declarative encoding and retrieval

Strong and precise memories are KEY to our cognitive capacity

Memories are FRAGILE...and often FALSE, even in adults: -ex: there was no video of the first plane hitting the World Trade Center on Sept. 11, but 73% of people nationwide said they saw it

NMDA receptors

NMDA receptors: transmitter-regulated AND voltage-regulated Ca++ channels: -if the membrane is POLARIZED, Mg++ blocks the channel of the NMDA receptor (NMDA= n-methyl D-aspartate) -glutamate binding to this receptor remains ineffective at this point -the AMPA receptor is a Na+ channel *AMPA= alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -glutamate can depolarize the membrane via AMPA receptors

Navigation-related structural change in the hippocampi of taxi drivers

Navigation around London by a taxi drive with bilateral hippocampal lesions -We found that the hippocampus is not required for general orientation in the city either in first person or survey perspectives, detailed topographical knowledge of landmarks and their spatial relationships, or even for active navigation along some routes -However, in his navigation TT was very reliant on main artery or 'A' roads, and became lost when navigation depended instead on non-A roads -We conclude that the hippocampus in humans is necessary for facilitating navigation in places learned long ago, particularly where complex large-scale spaces are concerned, and successful navigation requires access to detailed spatial representations -TT had limbic encephalitis associated with voltage gated potassium channel antibodies ... MRI brain scan showed damage throughout the length of both hippocampi. There was some generalized atrophy, but in this context, entorhinal, perirhinal and parahippocampal cortices appeared intact, as did the mamillary bodies, fornix and thalamic nuclei.

synaptic mechanisms of LTP induction and expression: 1) Baseline 2) Induction of LTP 3) Expression

PKC= protein kinase C TK= tyrosine kinase CaM= calmodulin CamK= calmodulin kinase CREB, cAMP- responsive element-binding protein: transcription factor 1) BASELINE: -limited amount of glutamate release stimulates exclusively AMPA receptors -NMDA receptor remain blocked by Mg++

Hippocampal PLACE cells

PLACE CELLS: -in hippocampus -neurons which code for a particular space (receptive fields for spaces) -context-dependent, code for a different space in a different context -considered to be important "players" in the formation of "spatial maps" (or "cognitive maps") -Grid and Border cells in ENTORHINAL cortex (fire when crossing abstract grid coordinates and approaching the perimeters of such a grid -head orientation cells in ventral hippocampus and medial diencephalon: contribute to spatial map formation

encoding under stress

PROPRANOLOL: a beta-adrenergic receptor antagonist -during reconsolidation blocks the memory-- (re)enhancing effects of STRESS

Patient Henry Molaison (H.M)

Patient Henry Molaison (HM): ANTEROGRADE and RETROGRADE amnesia -had surgery for intractable seizures -bilateral medial temporal lobectomy (1953) -surgery was effective in reducing seizures -but surgery caused ANTEROGRADE amnesia: no formation of NEW memories -he could not remember the name of someone he met 30 minutes prior -he also had RETROGRADE amnesia: memories covering ~3 years before surgery cannot be retrieved -he cannot name new world leaders or performers -but his short-term memory (eg. digit recall) is normal -IQ= 138 -died in 2008 -"every day is alone in itself, whatever enjoyment i've had, and whatever sorrow i've had"- HM

Patient K.C.

Patient K.C.= complete RETROGRADE amnesia for EPISODIC memory -FRONTOPARITAL damage (motorcycle accident) -Magnetic resonance imaging (MRI) performed in 1996 revealed a pattern of diffuse brain damage that includes almost complete loss of HIPPOCAMPAL TISSUE and clear signs of atrophy to the PARAHIPPOCAMPUS in both hemispheres -Also of note is a large lesion in LEFT OCCIPITAL-TEMPORAL cortex, which extends into RETROSPLENIAL cortex, as well as lesions to MEDIAL OCCIPITAL-TEMPORAL-PARIETAL, MEDIAL OCCIPITAL, and LEFT FRONTAL-PARIETAL regions -Other LIMBIC structures such as the mammillary bodies, the septal area, and the fornices are also noticeably atrophic -in addition to anterograde amnesia, similar to HM-- and presumably reflecting the damage in the TEMPORAL lobe, KC has a complete RETROGRADE amnesia for BIOGRAPHICAL INFORMATION -this latter aspect differs from the more restricted retrograde amnesia in HM, and likely reflects the massive loss of cortical tissue, the likely storage site of such information and the associated attribute space

iclickker

Purkinje cells... a) are the output neurons of the cerebellum b) release GABA onto neurons of the nucleus interpositus c) are postsynaptic to climbing fibers and granule neurons d) aandc e) all of the above

iclicker

Q. In class, we speculated that there are so many vulnerability genes for schizophrenia because a) massive disruption of normal brain development is needed, as indicated for example, by extensive loss of neurons in the hippocampus, to trigger schizophrenia. b) a wide range of individually subtle abnormalities in the development of brain circuitry may be sufficient to render the subject vulnerable for the disease. c) schizophrenia really consists of multiple diseases which individually are caused by one major gene defect, thereby explaining the >90% concordance rate among monozygotic twins. d) bandc e) all of the above Q. Numerous genetic vulnerabilities are hypothesized to bestow vulnerability for schizophrenia. Generally, these genetic vulnerabilities are thought to a) directly control the size of the ventricles of the brain b) to interfere with the development, migration and connectivity of certain groups of neurons, particularly cortical inhibitory interneurons c) cause major cortical atrophy, comparable to the atrophy seen in Alzheimer's disease d) be all inherited, in a mendelian manner, from the parents, thereby accounting for the high probability (over 80%) that children of a schizophrenic parent will also have schizophrenia e) all of the above

iclicker

Q. The highly linear regression between the ability of antipsychotic compounds to bind to D2 receptors and their effective clinical dose a) is proof that D2 receptor abnormalities contribute to schizophrenia b) can be interpreted as indicating that drugs with less affinity for D2 receptors (i.e., higher drug concentrations are needed to occupy these receptors) will also be much less beneficial for treating the disease, no matter what the dose c) indicates that drugs that are not binding to D2 receptors will not be effective treatments d) aandc e) none of the above

iclicker

Q. The results from PET studies demonstrated unambiguously that a) dopaminergic neurons are hyperactive in schizophrenics b) in schizophrenics, administration of amphetamine results in the displacement of more radioligand from D2 receptors than in controls c) in schizophrenics amphetamine releases more dopamine d) bandc e) all of the above

SNPs

SNPs- what are those? an example from my research: choline transporter SNPs in humans

iclicker:

Say I were a schizophrenic and had a healthy monozygotic twin. Contemporary genetics would suggest that a) my healthy twin sibling must have been exposed to a partly different environment, yielding the absence of the gene-environment interactions that made me sick. b) my, but not my sibling's, genes may have accumulated several hundreds of new rare variants that together may have significantly affected the development and maturation of my brain's circuits. c) despite me having the disease and my sibling not, and because we have the same parents, by definition we have exactly the same genes, including the same number and types of CNVs and SNPs, rejecting a purely genetic explanation of the disease. d) I necessarily must have inherited a mutated DISC-1 gene. e) None of the above.

Lecture 23:

Summary from previous lecture: -eye blink conditioning confirms that synaptic strength changes are SUFFICIENT to produce learning -example of learning supported by REDUCTION in synaptic strength (reduced PC-interpositus synaptic strength) -example of plasticity occurring in a superordinate circuit (as opposed to changes within the reflex circuit itself) -"FIRE TOGETHER-WIRE TOGETHER": conditioning requires overlapping US and CS: climbing fibers and mossy fibers are activated together, thereby changing purkinje-interpositus regulation -cerebellum is involved in learning and memory

Lecture 19:

Summary of last lecture: • Why was Lashley unable to find the 'engram'? Equipotentiality Law, Mass Action law • Patient H.M., Milner, Scoville • The importance of classifying types learning materials • From H.M. to the contemporary views on the medial temporal lobe and declarative memory • Expansion of memory circuitry to include mammillary bodies and mediodorsal thalamic nucleus and projections to cortex: Patients N.A. and B.J, fencing foils and billiard cues (and alcohol); Korsakoff's syndrome • K.C, massive cortex loss; retrograde amnesia ("loss of attribute space") • encoding, consolidation and retrieval: the attribute space

TWO essential criteria for diagnosis

TWO essential criteria for diagnosis: 1) IMPAIRMENT IN REALITY TESTING: -individual must evaluate the accuracy of thoughts incorrectly and as a consequence must make incorrect interferences about reality -this is the essence of Psychosis 2) THE DISTURBANCE MUST AFFECT SEVERAL PSYCHOLOGICAL PROCESSES, including thought, perception, emotion, communication, and psychomotor behavior: -disturbances of thought take the form of DELUSIONS (false beliefs that resist all argument) and HALLUCINATIONS (false perceptions that have a compelling sense of reality)

eye blink conditioning circuit: US --> UR

US --> UR: -sensory projections to 5th cranial nucleus -stimulate motor neurons originating in cranial motor nuclei

iclicker question:

You can block the induction of LTP by a) blocking NMDA receptors b) blocking AMPA receptors c) giving a drug that replaces Mg++ as a NMDA receptor blocker and that cannot be removed by depolarization of the receptor d) administering TTX e) all of the above **TTX is a toxin that blocks blocks voltage-gated sodium channels

successive processes capture, store, and retrieve information in the brain

a functional memory system must incorporate THREE ASPECTS of information processing: (1) ENCODING of raw information from sensory channels into STM (2) CONSOLIDATION of the volatile short-term traces into more durable long-term memory (3) and eventual RETRIEVAL of the stored information for use in future behavior ***a problem with any of these processes can cause us to forget information

taxonomy of memory (2)

declarative and nondeclarative memory can be further broken down: 1) DECLARATIVE: -episodic: remembering your first day in school -semantic: facts; knowing the capital of France 2) NONDECLARATIVE: -skill learning: knowing how to ride a bicycle -priming: being more likely to use a word you heard recently -conditioning: salivating when you see a favorite food

cont.)

in other locations of the hippocampus, such as the MOSSY FIBER PATHWAY, LTP can occur without NMDA receptor activity: -some forms of LTP are blocked by drugs with completely different modes of action, such as opiate antagonists

experimental environments to test the effects of enrichment on learning and brain measures

in standard studies of environmental enrichment, rats are randomly to three housing conditions: 1) STANDARD CONDITION (SC): animals are housed in small groups in standard lab cages 2) IMPOVERISHED CONDITION (IC): animals are housed individually in standard lab cages 3) ENRICHED CONDITION (EC): animals are housed in large social groups in special cages containing various toys and other interesting features -EC animals have heavier, thicker cortex, with enhanced cholinergic activity -cortical neurons in EC animals also have more dendritic branches, esp on dendrites closer to the cell body

most direct support for the role of dopamine:

most direct support for the role of dopamine: sensitized DA systems in schizophrenia -[C] raclopride binds to, and marks, D2 receptors -released dopamine competes for these receptors and displaces raclopride -amphetamine increases dopamine release in animal exp -in acutely psychotic patients: amphetamine release more dopamine (not that dopamine release itself was not measured...hypothesis!) and thus replaces more raclopride; thus: sensitized dopamine system in psychosis

prominent susceptibility genes as indicated by relatively reliable neuronal markers of schizophrenia

prominent susceptibility genes as indicated by relatively reliable neuronal markers of schizophrenia: 1) CORTICAL GABAergic INTERNEURONS: -chandelier cells and number of GABAergic contacts reliably decreased by 40% in PFC of schizophrenics 2) CALCIUM CHANNELS -Emerging Genetic Evidence on Complex Brain Disorders Converges on Specific Molecular Complexes (A) Multiple subunits of voltage-gated calcium channels are among the genome's strongest associations to schizophrenia and bipolar disorder. (B) Genes encoding the postsynaptic components of excitatory synapses are implicated by both rare and common variants in schizophrenia. 3) METABOTROPIC GLUTAMATE RECEPTORS 4) Altered levels of gene expression in the brain? -prefrontal expression patterns! -In particular, we observe gene expression changes associated with various aspects of neuronal communication and alterations of processes affected as a consequence of changes in synaptic functioning."

In vitro preparation

stimulation electrode on perforant pathway and recording electrode on mossy fibers 1) PERFORANT PATH: subicular neurons projecting to dentate gyrus 2) MOSSY FIBERS: dentate gyrus projections to CA3 3) SCHAFFER COLLATERALS: CA3 projections to CA1 -stimulation of perforant path, recording from dentate gyrus neurons -can also elicited by stimulating the other two pathways and by recording from their postsynaptic neurons

posttraumatic stress disorder (PTSD)

stress and emotional arousal do enhance memory, and a suite of transmitters are involved, including: -opioids -GABA -and esp. the adrenergic transmitters EPINEPHRINE and NOREPINEPHRINE -epinephrine, released by the adrenal glands, during times of stress and strong emotion, appear to affect memory formation by influencing the AMYGDALA -injecting PROPRANOLOL, a blocker of beta-adrenergic receptors, into the BLA blocks the memory-enhancing effects of stress

Lecture 22:

study hard and rehearse the COMPLEX EYEBLINK CONDITIONING CIRCUITRY in the CEREBELLUM

the role of diencephalic pathology in human memory disorder

the role of diencephalic pathology in human memory disorder: -B.J. was 27 when he sustained a penetrating head injury on Oct 4, 1986 -this injury taking place in England, during a game of snooker (pool), a brawl developed and in the ensuing disturbance a snooker cue was pushed up his left nostril -MAMMILLARY BODIES were gone! (normally give rise to massive projection to the MEDIAL THALAMUS -BJ's pattern of memory disorder was strikingly similar to that shown by NA -the focal VERBAL MEMORY DEFICIT which BJ displayed is as severe as that found in patients with the amnesic syndrome, and contrasts with the normal and mildly impaired scores on corresponding nonverbal memory tasks

how exactly does CS-UCS convergence (mossy + climbing fiber convergence) change Purkinje cells and result in LTD?

the simplified version: -AMPA receptors in the dendritic membrane of Purkinje cells: "marked for death" by the CS- and for a little while- couple 100 ms -if UCS follows with another glutamate pulse onto these receptors- they are actually "killed", so to speak -thus, purkinje cells rendered to be less excitable, less GABA release...

different forms of nondeclarative memory serve varying functions

there are several different types of nondeclarative memory: (1) SKILL LEARNING: -subjects perform a challenging task on repeated trials in one ore more sessions (2) PRIMING: (repetition priming) is a change in the processing of a stimulus as a result of prior exposure to the same stimulus or related stimulus (3) CONDITIONING: learning simple associations between stimuli -different brain areas are responsible for conditioning

LTP

what is LTP? LTP (1973): Tim Bliss, Terje Lomo -an increase in the amplitude and/or the slope of EPSPs measured in postsynaptic neurons -result of a brief tetanus (high frequency electrical stimulation) of the pre-synaptic neuron -enduring increase in synaptic strength -Tetanus: INDUCTION of LTP -post-tetanic stimulation: EXPRESSION of LTP

what is so special about the hippocampus?

what is so special about the hippocampus? SPATIAL ATTRIBUTE PROCESSING -birds that store foods for later use (chickadees, acorn woodpecker) have relatively larger hippocampi than non-storing birds -lesions of the hippocampus disrupts CACHE retrieval

what is the coding supported by hyper-dopaminergic activity?

what is the coding supported by hyper-dopaminergic activity? aberrant salience of (internal) cues -hallucinations arise from a conceptually similar but a more direct process: the abnormal salience of internal representations of percepts and memories leads to the subjective experience of these internal representations in a manner that is vivid and real, such that one is led to mistake this internal (virtual) experience with that of an external reality -this is mediated (somehow!) by a hyperdopaminergic state -because delusions are constructed by the individual, they are imbued with the psychodynamic themes relevant to the individual and are embedded in the cultural context of the individual -this explains how the same hyperdopaminergic dysregulation leads to variable phenomenological expression: a patient in Africa struggling to make sense of ABERRANT SALIENCE experiences is much more likely to accord them to the evil ministrations of a Shaman, whereas the one living in Toronto is more likely to see them as the maneuverings of the Royal Canadian Mounted Police

summary of causes- the basics

• Genetic mutations do not make symptoms-they result in altered proteins that affect the development of neuronal connections (e.g., Chandelier cells), the composition of ion channels (e.g., calcium channels), and the workings of synapses (e.g., glutamatergic metabotropic receptors). • Altered connectivity and altered synaptic mechanisms confer risk for disease. • Different sets of mutations may be sufficient to produce the same outcome in different patients - in other words, in terms of mutations underlying the disease, no two patients may be alike ("thousands of roads toward the same disease"). • Not fully clear whether developmental- environmental risk factors interact with SNPs, copy number variations, etc., to increase the risk for the disease, or whether we are still not capturing the full genetic variances that by itself can produce the disease. • Epigenetics as a potentially powerful way for developmental- environmental factors to further affect gene expression machinery. • Older fathers- greater risk for their children: more SNPs and CNVs accumulated or epigenetics? • Post-translational mechanisms (regulation of neuronal gene expression) remains purely understood and may be a major risk factor.

need to know for this lecture

• Hebb's rule and changes in synaptic strength as a major mechanism underlying behavioral change and learning and memory • Environmental enrichment effects as an early indication of the capacity for neuronal plasticity • Non-associative learning in Aplysia • Hippocampal LTP as an example of the type of neuronal plasticity that may underlie learning.

this lecture topics

• More rare mutations/susceptibility genes and relationships to Autism and Intellectual Disabilities. • Father's age matters • Main brain targets of all these mutations • Expression vs. code • Treatment: De-institutionalization • Patient brain data support DA dysfunction • D2 receptor antagonism as a main mechanisms • Side effects • Atpycial antipsychotics may not be that • Beyond dopamine: PCP and glutamatergic treatments

beyond dopamine: PCP ("angel's dust"

• introduced in 1963 by Park Davis as a surgical anesthetic without depressing properties; • Pulled in 1965 because half of the patients exhibited signs of psychosis. • Effects less predictable than LSD or other hallucinogenics • Horror trips • Hallucinations concern mostly distortion of body parts, particularly size; suicide and self-mutilation • Amnesia as secondary effect • Today: ~120 designer drug variations of PCP • Ketamine: identical mechanism (Special K) **PCP (or ketamine) psychosis: delusional, paranoid, and cognitive impairments BUT: treatment of patients with pro-Glu drugs (mGLU agonists): disappointing

how can changes in the contacts between Purkinje cells and the Interpositus allow the tone to serve as a CS, triggering eye blinks?

•Following conditioning, LTD has occurred in Purkinje cells •thus the CS inhibits Purkinje cell output, thereby taking away inhibition from interpositus neurons •interpositus neurons fire more readily in response to the CS and thus stimulate the red nucleus which in turn stimulates the cranial motor neurons to elicit the CR.