Physio Exam 4

Neurofibbulary tangles

- Present long before we start to see symptoms - 10-15 years before onset - Pretty reasonable plaques and tangles are already formed - Mild changes in cognitive functions before you get Alzheimer's disease - We need to figure out a way to catch these things earlier

temporal stages of memory formation

Incoming information is picked up from the sensory nuerons Goes through the sensory buffers and either gets lost within seconds or -> gets encodes into short term memory Sensory buffers -> loses info quickly Working memory-> Loses information quickly INtermediate term memory Long-term memory -> can have info forever

- Memories are going to linger and hang on the hippocampus for as long as it can but once it is consolidated, what happens?

Once it's been full consolidated and formed it moves from the hippocampus and moves to other parts of the brain So at this point of you lesion the hippocampus it won't affect the memory

Typical and atypical drugs for schizophrenia

Typical: Chlorpromazine thoridaizne haloperidol Raclopride Atypical Remoxipride Clozpine Risperidone

Schizophrenia cognitive symptoms

difficulty sustaining attention, problems holding information in memory, and inability to interpret information and make decisions

- Different forms of LTP, but most are

glutamate

- Early writing predicted AD risk

o "Idea density" analysis - is there something we can learn from this population § Discrete ideas per 10 written words: he took a bunch of their writings and analyzed their early writings. Number of ideas you had for every ten words § The more ideas you had, the higher the idea density § If they had a higher idea density score, they had a lower risk of Alzheimer's or another form of dementia.

- Episodic memory in the brain

mainly parietal cortex

We think positive symptoms is because of

mesolimbic system and DA

a more complex envionrment will result in

o A complex environment o A more complex dendritic tree will have a more complex neural network

Brian and declarative memory

o Amygdala- not important for declarative memory o Hippocampus- impaired performance on these NMTS tasks o Entorhinal o Parahippocampal cortex o Perirhinal cortex- much worse

MDD and twins

§ Dizygotic twins = 20% § Monozygotic twins = 60%

LTP was first discovered in the

§ First discovered in the Sheffer pathway in the hippocampus- it is how our brain is creating the cell connections by enduring an intense stimulus.

• Procedural memory

non declarative memory • Memory about perceptual or motor procedures • Shown by performance rather than by consciousa

Lesions to hippocampus impair?

spatial learning

Schizophrenia means

split mind -Thinks there's separation b/t what brian is perceiving and reality. -We see that mainly in hallucinations and delusions -Halusitonaltions are auditory mostly -Inability to recognize that the voice is internally generated, is the definifn characteristics

Entorhinal Cortex

• Largely responsible for our perception of space and time • Most sensory information passes through here and it is responsible for associations between things we see and hear • Important role in mental mapping

Prevention of Glu toxicity

- Anti-inflammatory drugs o NSAID's (nonsteroidal anti-inflammatory drugs) § These drugs might offer some protection § There seems to be some sort of mechanism in anti-inflammatory drugs and decreasing the risk of dementia or Alzheimer's § Once someone has Alzheimer's or dementia, these NSAID's won't help at all - Lifestyle interventions o Exercise § Aerobic is the best § This is the best way to prevent this o Diet § Green leafy vegetables o Education § People with higher degrees are at a lower risk of dementia § This can also be social engagement

Habituation

- At the synaptic level the stimulus is getting picked up by the sensory neuron and then goes to the motor neuron to make the gill withdrawal - After multiple presentation, there are less synaptic connections to the motor neuron o RETRACTION OF SOME SYNAPTIC TERMINALS THAT CONNECT FROM THE SENSORY NUERON TO THE MOTOR NUERON o Stimulus gets picked up by affterent sensory-> motor neuron-> habituation - Long term, loss of some synaptic connections will now be retracted. Still get action potential but not strong enough to get retraction of gill

Kuru "to shake" symptom phases

- Ambulatory phase: balance issues but still mobile - Sedentary phase: can't walk on their own. Also see emotion regulation and cognitive issues - Body tremors, loss of coordination, emotional instability Emotions at an inappropriate time

Maturation stages

- Cell survival o They will stay within the glandular layer of the dentate gyrus o In order for them to form these connections, they are hyperexcitable, so it has a lower threshold for LTP and get NDMA activation in these cells much easier

Treatments AD

- Cholinesterase inhibitors o Cholinergic systems are targeted because this degenerates quickly o If you block the cholinesterase the ach will stay out longer and help the degradation o Slows down cognitive decline but doesn't halt it o There is a point that this drug doesn't help any longer o Side effects: nausea, diarrhea, changes in appetites, etc. - Memantine o Helps slow cognitive decline o Glutamate receptor antagonist - Antidepressants - mood o Depression is common - Antipsychotics - delusions/ psychosis o Not uncommon for there to be hallucinations and delusions later

People with Korsakoff's frequnetly cof____

- Confabulation - make up stories that are made up and really out there o Ex. I went to the moon and caught a giant fish o Tend to lie

Beta-amyloid (Aβ) plaques (BAP)

- Extracellular deposits o AB core o Degenerating axons and dendrites - Misfolded AB proteins - Trigger microglia cells o Inflammation - Start to have issues with cellular communication - If there is just AB plaques you won't see a ton of destruction in the brain -as neurons die off, you can see things like axons and dendiretes getting stuck in the plaques -The extracellir plaquues will trigger microgli -Start to have issues with celluar communication -BAP prob are not a dirver of cell death. Not great but prob do not kill them off

People with Korsakoff's syndrome frequently

- Frequently deny anything is wrong with them and they..... - Confabulation - make up stories that are made up and really out there o Ex. I went to the moon and caught a giant fish o Tend to lie

Pittsburgh compound B (PIB)

- Initially the only way we could confirm someone had diagnosis was to wait until someone passed away in with you could look and the plaques and tangles - Now we can monitor these using this compound to monitor beta amaloyed plaques o Red and yellow is bound at a higher level o Blue and purple is lower levels of binding - Positron emission tomography (PET) - Scan a living person to look at the plaque deposits - We can look at both tau and beta amyloid plaques - Not commonly done with the common patient o More used in research o Can we reverse some of the deposits? o Get additional information

Lesions to the fornix revieled that...

- Lesions to the fornix, which interconnects with the hippocampus and mammillary bodies confirm that they are involved in forming declarative memories.

Risk factors for schizophrenia

- Paternal age - Prenatal infection --> Seasonality effect -Delivery complications --> Hypoxia (oxygen deprivation) --> Reduced oxygen supply or other complications during delievery --> Reduced blood to brain - Life stress and drug abuse can trigger skitz later in life

Cognitive deficits in AD is mainly relatted to ____ but also includes deficits in ___

- Mainly related to death of cholinergic cells in the basal forebrain o Basal forebrain (AcH) has major protection to cortical structures -> Big aid with focus and ability to maintain attention - Basal forebrain o Mediating many of the short-term deficits - Medial temporal lobe - Hippocampal -> forming new memories are effected

TAKE AWAY: From Patient N.A

- Mammillary bodies may serve as a processing system connecting the medial temporal lobes to the thalamus with the mamilothalic tract and from there to other cortical sites

what do microglia do to help ?

- Microglia o They try to phagocytize the weird proteins, but they are more resistant to break down o They can help control it for a little while o Chronic neural inflammatory state - Temporary junk storage

Plaques are

- Misfolded - Sticky - Insoluble o Hydrophobic

Common population that develop Korsakoff's syndrome

- More related to chronic alcoholics and they feel less hungry and don't eat o Then there are enough vitamins from normal food o This effects the thymine/ Vitamin B o This decoration effects the mammillary bodies o Anterograde amnesia - Initially with the thymine deficiency there are often hemorrhages and growths that will lead to cell death

Most cases prion dieases are

- Most cases are just sporadic mutations

Neural stem cells (NSC)

- Most take place during embryonic development (neurogenesis)

Changes in sleep in major depression

- NREM 3 o When you look at sleep cycles, they have lower amounts of non-rem sleep 3. - Individual may never go into deep sleep. o Rem sleep-> changes in when it is occurring, should see mostly deep sleep at beginning and more rem in the morning. We see a lot of rem sleep at the beginning of the night. When they go to bed more time in rem. - REM latency o Rem latency-> correlates w severity of depression o Those with depression have a faster onset of REM. o The faster they go into rem the greater the severity of the symptoms. o Sleep disruption altering symptoms of sleep

Glutamate toxicity: excitotoxicity

- Neurons are being excited to death - Often happens with brain damage or stroke that releases excessive amount of glutamate in the extracellular space o This activates AMPA and NMDA receptors o Get depolarization of the AMPA receptors and the voltage gated calcium channel and the NMDA receptors open to flood calcium into the cell o This has to be 5-10x higher than the normal amount of calcium o Proteases breaks down protein o Endonucleases will start breaking down the chromosomes o Mitochondria can no longer produce energy the cells need o Activates enzyme that break down proteins and DNA - Ca2+ influx o Exceeds psychological range (100-1000nM) o Ca2+ pumps (efflux) inhibited o Self-destructive enzymes o Self-prorogating § Depolarizes - Neurons and oligodendrocytes are the first to die off - Astrocytes o Excitatory amino acid transporter 2 (EAAT2) § These protect the astrocytes, so they don't go through the excitotoxicity process - If we have a cell that dies, the astrocytes will pull in the extra glutamate that comes from the synapse - The EAAT2 can't clean up the glutamate fast enough so that's what leads to the death of Neurons and oligodendrocytes - Even in a healthy brain this is not fully cleaned out but if an individual has Alzheimer's there will be more of an effect

Kuru "to shake"

- Really prevalent in the Fore tribe o High numbers in women and children o Kuru means shaking -> Would start to show tremors o Progresses quickly but there is a 5-10-year incubation period - Women and children o Funerary cannibalism - Body tremors, loss of coordination, emotional instability - Ambulatory phase: balance issues but still mobile - Sedentary phase: can't walk on their own. Also see emotion regulation and cognitive issues o Emotions at an inappropriate time - Terminal phase: can't even sit up by themselves, severely impaired cognitive function and can speak or comprehend o Soon after they would pass away - It was originally thought to be a virus o After several years of studying this, they found that when a member of the tribe dies, the tribe would eat them ->Men would eat the muscle -> Women and children would eat the brain tissue o Once they stopped this, there was a dramatic drop in cases - The long incubation period made it hard to figure out the initial trace of it

Extra synaptic NMDA receptors

- Receptor subunits o GluN1 (two) § Found uniformly across all NMDA receptors (2 on each) o GluN2 (two) § GluN2A (synaptic: LTP) · found on the postsynaptic element · Mediated the beneficial effect (i.e., long term potentiation or other intracellular processes that are beneficial § GluN2B (extrasynaptically: LTD and cell death) · They are there to help monitor extra synaptic levels of glutamate · These receptors are mediated apoptosis · LTD is long term depression § Depending on which type determines the location and when it is activated - We think when we give memantine to Alzheimer's, it has low affinity for the NMDA receptors and wont bind to the synaptic NMDA but blocks the extra synaptic ones it is actually helping and not impairing their cognitive function.

Early signs for schizophrenia

- Social Adjustment • Generally show issues w social interactions, less positive affect. - Motor abilities • Eye tracting seems disrupted • Eye tracker on kids, and follow stimulus on screen • Get basic patten but its jerky, • This is about 70% predictive. - Developmental delays • don't walk and talk at the same time as individuals who do not get skitz - Can be genetic - social withdrawal-hostility or suspiciousness-deterioration of personal hygiene-flat, expressionless gaze-inability to cry or express joy-inappropriate laughter or crying-depression-oversleeping or insomnia-odd or irrational statements-forgetful; unable to concentrate-extreme reaction to criticism-strange use of words or way of speaking - Postnatal factors o Stress § May be a bigger factor

Where are NSC stored/adult stem cells

- Subregion of the hippocampus and olfactory bulb

What does not hold memories but is involved in forming them?

- The hippocampus does not hold the memories

What can a mutant copy to do a normal prion?

- The mutant copy can cause a normal copy to convert it structure into the mutant form - Self-propagating o PrPsc converts PrP to mutated form o There have been some thoughts that this process may be happening in other diseases such as Alzheimer's, but there is no way to fix this

Prion mutations

- The mutant form has the exact same amino acid sequence of the normal copy, but there are differences in the structures o They get folded differently o This makes it hard to identify mutant copies o The mutant copy is extremely difficult to get broken down (which is a problem) § Even when you try to destroy it from heat or chemicals, they are protected

What is a normal prions job?

- Their job is to shape how proteins should look

Creutzfeldt Jacob Disease

- Usually around 60 years old o Hereditary risk is very low - Leads to the same degeneration in the tissue - Rapidly progressing disease o Passing away within a year o Starts with cognitive or motor issues - Changes in emotionality o Easily aggressive - More likely to fall - Neurodegenerative prion disease o Transmissible spongiform encephalopathies (TSE) - Symptoms o Rapidly progressing dementia o Personality changes o Uncoordinated movements - Microglia phagocytosis (hole) o You can only see this in postmortem o Microglia clears out the tissue as it starts to die off

Vaccination

- Vaccination against AB protein o Helps clearance - There has been some hope that we can develop some sort of a vaccine for Alzheimer's - When you get antibodies, your body can react to this by creating its own antibodies to react to the treatment o It was reducing the plaque burdens, but they started getting protein aggregates braking up and going into the extra cellular space o Not everyone showed benefits from the drugs - There is a new vaccine that they are starting - They think older research was targeting the wrong beta amyloid

Prions

- We all produce prion proteins that produce a variety of functions o When they become mutated, this is when we start to see these diseases

Enagram and hippocampus

- We think it's the job of the hippocampus to link all these neurons to create an engram o Initial encoding -> hippocampus -> process and encoding the memory by creating an interaction between the cells -> now the retrieval cue will no longer need to be processed in the hippocampus -> goes into the cortex and leave the hippocampus -> it goes back into the original cells to create and engram (same neurons that pick it up initially are the ones that hold onto it and bring it back to create the neural network) o Attending to some sensory input and then neurons are going to grab these and put them in the appropriate subdivision of the cortex to link all of the coded material together o Acquisition of the information

Overactive dopamine system which correlates with

- positive symptoms 1. If you block DA receptors, it can eliminate positive symptoms 2. Mesolimbic pathway starting in VTA and projecting to cortical strucures and limic systems -> Seems to link with positive symptoms 3. IN PREFORNTOL CORTEX DOPAMINE IS LOWER

Patient K.C takeaway

parietal cortex is where episodic memeories are stored

If you damage the medial temporal lobe

- you will basically lose the consolidation effect, so you never end up with the fully formed memory, but that means the encoding process isn't affected which is why people still have a working memory when MTL is effected

bipolar onset

-Bipolar equal across men and women Starts ages 15-25

Anxiety disorder and the brain

-Changes in prefrontal, usually hyperactivity in most of these structures. Overall general increase of prefrontal cortex, likely related to issusin concentration, excessive thoughts. Usually see increase activity in amygdala, ACC is altered. Hippo can see some reduce activity or reduced volume. Varry by anxiety condition

-Different forms of bipolor

-Cyclothymia -> never have full amnic episode, may have hypomainia. Often don't show impulsive wreckless behavior -This is then followed by dysthymia-> reduced form of depression. Low mood, low affect, mild motivational issues. Often times ppl with cyclothima are diagnosed with MDD because its hard to see their versions of manic episodes.

****

-Different components of the memory -We can have recolaection. When we have a complete memory recolation, we get all the details. A complete conscience recall -We can have memory like a sense of familiarity. We think they are mediated by different brain structures. -When you damge the substructures, you may damange one structure and not the other but when you take out everything, you loose both components -Hippo -Links all compentsof memory and complete the whole memory -Parahippocampus Sensory info ???

Disorganized hippocampus -CAfields Schitz

-Disorganization of hippo -The cells are misaligned set up where cells are projecting to other places -This disorganization is most common but don't see it in everyone

Types of memory (2)

-Engram-> whatever memory is in the brain. The representation of the memory in the brain -Consolidation -> converting information into a long term memory.

Schizophrenia - Etiology

-Genetic component -> Difficult to predict risk factors for genetics -Alliel mutations that are pretty small, do not account for large portion of population -Risk factors account for some cases, not all, individuals need to have combo of different risk factors and certain allel variant. -Little things that add up. -Does run in families -Risk reduced as you get father out -Co-varies with bipoloar. Co occur in families -Acts w envionrment , modulated by envionrment -Adopted. Genetic influence from bio parents, but no risk factors -> less likely to develop it -Not adopted -> genetic influence shitt envionrment -> more likely - Adoption studies o If a child has a biological parent that has schizophrenia, they are going to have a higher risk o But the environment has a large factor in it o Environment by gene interaction - Twin studies o If you have an identical twin, it will be about 50% the other one will get it in identical twins o Fraternal kids are more like 17% o 13% if a parent has them

Delayed Non-Matching- to-Sample Task and Lesions

-Hippocampus is not the only important structure in the medial temporal lobe -They lesioned different portions of the medial temporal lobe Looking at a delayed NMTS task -Parahippocampal and Perirhinal connect tp the hippocampus -Lesion just hippocampus -> Suttle deficit -> Reasonable performance -Lesion entorhinal cortex and parahippocampus ->Larger defieint ->Lesion even more, Super deficit --> Input to the hippocampus -Hippo -- > Links all compents of memory and complete the whole memory

MDD genetics

-In MDD its about 40% concordance rate

Accelerated Cortical Gray Matter Loss in Adolescents Schitz

-Loss of brain matter -Takes place during adolences -But when you look at the rate of loss, you see there is a faster rate of loss in adolencents w skitz. -Happens faster in skitz, loosing brian matter -Likely result of abnoramility of prining process. Should have loss of ineffeicent connections. In skitz they prune at a faster rate, eliminate way more synapses compared to typical individual -We don't know if the skitz star with less gray matter or if they just loose it faster over time

Obsessive-Compulsive Disorders

-Lots of prefrontal activity compared to someone without ocd Likely related to intrusive thoughts -changes in basal ganglia -We think the BG is involved with behavioral outputs -The orbital cortex should regulate the repetitive behavior -The prefrontal thoughts klee-ps activating the BG which temporarily gets rid of throught but hten it will come abck -

MDD SYmptoms and prevelance

-MDD -5 or more sysmtoms with one or more being depressed mood -High preverlence -10-20% of pop -Leans towards female having more cases

Brain and MDD

-Prefrontal and amygdala are hyperactive -Greater amounts of metabolic acitivity -When you treat MDD< and elevate symptoms, prefrontal quiets but amygdala remains more active. We don't know if the hyperactivity is learned or an cause -Volume of hippo is reduced. -Likely the result of kicking on stress systems -Damage to hippo in response to stress

Genetic risk factors for AD early onset

-Processing and production of the BAP -Instances in the 40s where symptoms come on -Related how we cleve protein o Presenilin 1 and 2 genes -APP protein is the starting point and then we have 2 proteins, Beta and Gamma . Beta makes the first cut, gamma makes the second cut -After they cut APP protein, that's where we end up with BAP -Mutations of preslin 1 and 2 -> people with mutants are more likely to make AB42. Both make proteins that help form Gamma and this going to affect how they make the cut of APP. Which then stick together and now you have plaques in the brian -Different form fo BAP depending on where they are cut § Cleavage of APP proti § Both help form the gamma secretase · Determine where they are going to make the cut § If you have this, you are more inclines to make AB42 o Amyloid beta precursor protein (APP) § Beta secretes (makes the first cut) and gamma secretes (makes the second cut) § Then you get a functional protein § If you overproduce APP you will be increasing production overall and end up with higher amounts of AB42 § When the APP gene is on the 21st chromosome this is overproduced and leads to downs syndrome but also leads to Alzheimer's like symptoms later in life (30s) o In the healthy brain you should see much more AB40 than AB42 § This depends on where the secretes make the cut § AB42 is more sticky · This is when we start to get those plaques

-We think the BAP is generated throgugh

-Shifting the priotien we are making protein -Issues with clearence -Over abundance of the protein

Differneces between atypical and typical drugs for skitz

-Typical = first generation of drugs -Atypical= developed later on -All of them are D2 receptor antagonists -When you look at this, it shows the affinity, the typical drugs have high affinity for d2 receptor. -atypical, affinity for d2 is less -Serotinin -Some hypothesis that delusions are from serotonin system -Higher affinty to block serotonin receptor -We think the drugs w lower affinity for D2 receptor, wont block it quite intensely. It will dampin the amount it stops DA, but it does not effect motor as much. -Atypical are better because less change of dyskeineisa, still get motor symtoms from these drugs compared to typical drugs. Both will alleviate positive symptoms -The typicals don't really do aything to negative or cognitive symptoms -There has been some suggestions that the atypicals target both positive and negative, deff posititve, probably don't target negative

bipolar used to be in the same category as ___ but now its...

-Used to be under same category as depression but now we recognize that it is more related to skitz -A lot of the same allie varrients or mutations that show up in skitz show up in bipolor -Theres a good chance If someone has bipoloar, aother fam member prob has skits.

-Mania and MDD

-Usually you see manic first, and then depressive. -In maniic-> sense of invincibility. - -Manic followe dby MDD, which is longer -Longer manic, going to extend manic. Usually depressive episode is 2-3x longer than manic

what do we see in the brain of bipolor

-We do see, in the brain -Parrelle things in skitz -Ventricles enlarged -Volume of amygdala is bigger -Prefrontal cortex is reduced. Not in everyone but common things youll see

Biology of depression

-We know genetic, not as strong of bipolar, 50-60% concordance -Related to certain genes, but really looking at risk factors. •Strong hereditary contribution •Dizygotic twins = 20% •Monozygotic twins = 60% -We believe that changes in monoamine not have info -Aka seratonine signaling -Hpa acess -Not getting appropriate negative feedback may be contributing to it

Amphetamine psychosis

1. A delusional and psychotic state, closely resembling acute schizophrenia, that is brought on by repeated use of high doses of amphetamine. 2. if you give them amphetamine that actives DA signaling, and they produce more DA, and it correlates with positive symptoms -> As a consequence of drug tolerance (see Chapter 4), some daily users of amphetamine reach the point of taking astonishingly high doses—as much as 3000 milligrams (mg) per day—in order to experience the drug's "high." (Compare this with the normal 5-mg dose used to combat sleepiness.) Many individuals taking these large doses of amphetamine develop symptoms of paranoia, often involving delusions of persecution with auditory hallucinations, and

encoding, consolidation, retrieval Memory processes

1: A subset of the sensory information that enters sensory buffers is encoded and placed into short-term memory 2: If the information is rehearsed or used, it may be consolidated into long-term memory, lasting for minutes or up to a life time 3: When we probe a participant's memory, she must retrieve information from LTM and place it into STM to preform a task, such items in a list. 4: At any stage of the process, information may be forgotten - Hang onto memory in the sensory buffer, of it is something that is not important, it will just go away. - Most things that get into sensory information get forgotten - Short term memory has limited capacity, things dont stay here very long

What links with positive symptoms?

1. Mesolimbic pathway starting in VTA and projecting to cortical strucures and limic systems -> Seems to link with positive symptoms DA

- Antipsychotic

1. Thorazine -> Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias. Its primary use in medicine was the treatment of schizophrenia. 2. DA2 receptor antagonist -> Affinity for d2 receptor, is changed across drugs. If we have a high affinity at a low dose, the dose is low for effective symptom alleviation. -> If you gave drugs that blocked signaling specifically D2 receptor ->Reduced positive symptoms 3. Tardive dyskinesia -> Side effects: as people take D2 recpptor antagonist, over long term usage they can devlop movement disorders -> Tardive dys-> motor ticks, cant control it . Messing w indirect pathway bc weare effecting basal ganglia signaling -> Common w long term use of these drugs. They can dampin it by regulating does -> Once people have this it does not go away

Treatments for Schizophrenia

1. typical antipsychotics (block d2 dopamine receptors, can cause permanent distressing motor side effects) 2. atypical antipsychotics (influence d2 receptors, associated with weight gain, increased risk for heart issues, type 2 diabetes, mortality) 3. psychological intervention (cognitive remediation & cognitive enhancement therapy)use 1. Thorazine § Thioridazine was voluntarily discontinued by its manufacturer, Novartis, worldwide because it caused severe cardiac arrhythmias. Its primary use in medicine was the treatment of schizophrenia. 2. DA2 receptor antagonist § Affinity for d2 receptor, is changed across drugs. If we have a high affinity at a low dose, the dose is low for effective symptom alleviation. § If you gave drugs that blocked signaling specifically D2 receptor § Reduced positive symptoms 3. Tardive dyskinesia § Side effects: as people take D2 recpptor antagonist, over long term usage they can devlop movement disorders § Tardive dys-> motor ticks, cant control it . Messing w indirect pathway bc weare effecting basal ganglia signaling § Common w long term use of these drugs. They can dampin it by regulating does § Once people have this it does not go away

LTP study

1.) Baseline electrical recording; 2.) (Test) initial weak stimulus; 3.) (Induction) Tetnus- high-frequency stimulus; 4.) (Test) record response after weak stimulation i.e., the formation that goes into people in a crowd doing the "wave"

Theories of etiology: MDD

1.Monoamine hypothesis 2.HPA axis dysfunction -Not getting appropriate negative feedback may be contributing to it

2 major types of LTP

2 major types Ampa receptors-> ionartpic-> open sodium channels o EVERYDAY COMMUNICATION NMDA -> gated require ligand and voltage changes. o Have to have ligand binding to receptor and depolarization around the receptor to get the magnesium block out of the way. When you depolarize the mag will leave. Now calcium can come through o RESERVED FOR LEARNING BIG NOVEL THINGS

Long-term memory storage Patient K.C

A person who sustained damage to the cortex that rendered him unable to form and retrieve new episodic memories, especially autobiographical memories. Upon his death we learned that his name was Kent Cochran. Brain scans of K.C. revealed: - extensive damage to the cerebral cortex -severe shrinkage of the hippocampus and nearby parahippocampal cortex K.C.'s inability to recall any autobiographical details of his life, even memories from years before his accident, may instead be a consequence of the extensive damage to his: - frontal and parietal cortex -Got in an accident and suffered damage to selective areas of his parietal and prefrontal cortex -started showing evidence of retrograde amnesia, but selective for declarative episodic memory -Had factual info but not personal information. -Could not tell you what his plans are for next year etc. could not put himself in future situations

o In the healthy brain you should see much more

AB40 than AB42

Korsakoff's syndrome

Antegrade amnesia for declarative memories

Korsakoff's syndrome is ___amnesia

Antegrade amnesia for declarative memories

Patient N.A had? Why?

Anterograde amnesia- specifically verbal material - Damage to the Dienceplon (thalamus and hypothalamus) --> They have connections to the hippocampus, especially the dorsomedial thalamus, and to both Mammillary bodies

Genetic risk factors for AD late onset

Apolipoprotein (ApoE) metabolizes beta-amyloid Going to have 2 copies of these 3 different alleles: ApoE2, ApoE3, ApoE4 ApoE2 → reduced AD risk, increased vascular disease risk (least common) - if you have 1 or 2 copies, its protective ApoE3 → best at metabolizing beta-amyloid (most common) ApoE4 → poor at metabolizing beta-amyloid 10-30x greater risk of developing AD w/ ApoE4 double 40-65% AD carry at least one allele of ApoE4 1/3 AD are ApoE4 negative · You will have two copies of these (any combination) · Most individuals have ApoE3 (neutral) · If you have more ApoE4, you're at a higher risk of going on to get Alzheimer's disease · ApoE2 are at a lower risk o Least common allele o Sort of protects you § Risks but not guarantees · There are plenty of people who carry copies of ApoE4 that don't get it · There are also people with Alzheimer's who don't carry ApoE4 (only 25% have it)

Non-declarative Impaired when there is damage to:

Basial ganglia, amygdala, motor cortex and cerebellum

H.M was unable to decode ...

Because of damage to medial temporal lobe structures, H.M was unable to encode new declarative memories. Upon his death we learned his name was Henry Molaison.

Why is it easier to trigger an AP after LTP?

Becuase the resting potential is now lower

Classical conditioning and neural circuit detail

Before Airpuff causes eye to blink Via the polysynapptic pathway Airpuff -> trigeminal nucleus -> Cerebellum->Crnial motor nucli -> eyebilink After Bell -> cerebellum -> cranial motor nuculi

Takeaway from classical conditioning

Conditioning of the eye-blink response in the rabbit is crucially dependent on the cerebellum. This simple mammalian system provides a model for understanding the formation of associations in the mammalian brain.

Patient K.C take away

Cortex is important for episodic memory once they are formed o damage to cerebral cortex, shrinkage of hippocampus and parahippocampal cortex.

Spatial learning rely on Motor skills rely on object recognition rely on

Different kinds of learning depend on different brain regions. Spatial learning requires an intact hippocampus, while motor skills rely on the basal ganglia, and object recognition relies on the visual cortex.

Encoding, consolation, and retrieval

Encoding: o Sensory buffer-> encoding happens- > STM. Encoding pictorial elements involves activation of the right prefrontal cortex parahippocampal--- words are the left prefrontal and left parahippocampal. o Flow of information into and out of working memory->central executive Consolidation to LTM: o Medial temporal lobe is crucial for consolidation o Permanent storage of information is in the cortex whereas information was first processed and held in STM Retrieval of stored memory: o LTM can be changed and updated when retrieved o Reconsolidation is re-storing the updated memories

Long term potentiation

Enduing change in synaptic strength and responsivity of synaptic strength

Subtypes of declarative memory

Episodic • Personal memories. Personal significance to you • Patient K.C • Parietal cortex is important for episodic memory Semantic • Lacks personal significant. First president, 2+2, general knowledge that lack personal content or emotions. • Perirhinal, Hippocampus, temporal, parahippocampal cortex

Parts of brian involved in episodic and semantic memory

Eposodic: Hippocampus Medial temporal lobe neocotex Semantic: Lateral and anterior temporal cotex prefrontal cortex

What is used to measure changes in dendritic branching?

Golgi stain

delayed non-matching-to-sample task Medial Temporal Lobe Hippocampus

Hippocampus - is not the only important structure in the medial temporal lobe - acts as the final stage of convergence for adjacent regions of cortex, resulting in storage of declarative memories in the cortex. -They lesioned different portions of the medial temporal lobe to look at different memory formations: -Lesion just hippocampus= Subtle deficit and Reasonable performance -Amygdala- NOT important for declarative memory. Entorhinal (input) -Input to the hippocampus Parahippocampal (contextual) -Connect to the hippocampus Perirhinal (familiarity) -Connect to the hippocampus

DA and GA in Skitz

Hyperactive dopaminergic state --> overactive DA system Hypoactive glutamatergic state -- >underactive GLU system

long-term relapse rates with and without antipsychotics

If you look at relapse rates, and compare across people taking and not taking anti psychotics, people who so not take drugs, have reduced relapses compared to individuals who are While these drugs are beneficial, overtime they may loose or reverse their effectiness with longer treatments -We want them to take these drugs, but we need to figure smething else to prevent the reversal pattern -Potatnial for CBT that gets couple with this with ephasis of reducing stress. -Stress procuedes an onset of spisde, so if we can dampen their ability to manage stress it can reduce the chane of them having a pscyolitc eposide -Some evidence to ge thtem to recognize that the voices are not real

Non-declarative facts

Implicit or procedural memories, specifically motor memories. Examples include: Knowing how to do something. Skill learning, mirror tracing task, riding a bike, juggling

In the brain in Korsakoff's

Korsakoff's o Temporal lobe structures including hippocampus are NORMAL o But shrunken mammillary bodies and damage in the dorsomedial thalamus. o Sometimes, damage to the basal frontal cortex and causes the denial and confabulation

Difference between Learning and Memory: ***

Learning Learning is the acquisition of something. Takes repetition and going over material Memory Memory is immediate. Storage and retrieval of information

Morris water maze task take away

Leasion the hippocampus, and the rats cannot use spatial cues in the room to find the podium underwater. From a variable start location, they had a high consistent latency and didn't really improve. The start position had to be variable so they did not depend on non-declarative procedural memory

Frankland et a., 2005 Long-term memory storage

Lesioned the hippocampus 1, 7, 14 or 28 days after training. - DIscorvered Hippcampus is not where we store long-term memories The hippocampus is involved in the formation of memories, but does not retain information over time This study - Was a version of fear condition dependent on the hippocampus -The context of where the shock occurred is important because it shows pairing it with the memory of the environment - Animals were shocked in an environment, and when they put the animals back in the environment where they were shocked, they will freeze more. The more they freeze stronger the memory is - During the training they had a full hippo, then they lesioned it -Hippocampus should have formed that memory, but can they get rid of that memory? -Depending on when the hippocampus was lesioned, they freeze less - learning and lesioning on day 1, the animal did not freeze at all. Meaning, they did not format long-term memory of the shock -7 or 14 days - There was reduced freezing, but there is still some evidence that the memory of the shock was not yet consolidated - 28 days lesioning - Freezing just as much as the control group, signifying that the memory has left the hippocampus. -Conclusion: Declarative memories will linger and become dependent on the hippocampus. Once it's been consolidated and formed, the memory no longer lives there.

Treatments for MDD

Lithium -Naturally occurring element -Studies have shown higher lithium concentrations in people who swim in lakes in areas have reduce influence of psychiatric disorders -Very effective -Can reduce the manic phase -Decrease onset of manic and then decreases depressive episodes -Anti inflammatory, increases 5-HT, has broad effects In the brain, don't really know what thing is elevating symptoms -Low therapeutic index-> those that are therapeutic and those that are dangerous is limited. -Often see people who take this have normal side effects like being tired or gaining weight, higher doses headache, tremors coma. -Can build up in the blood. Want to make sure the person is clearing it out so it doesn't build up -People have to have regular blood tests. While it works, there are side effects -Valproate -You can use anti convulsices -TARGET GABA SYSTEM-> gaba agonist -Increase gaba signaling in brain -Block manic phase and block depressive episode -These people try this first bc no regular blood monitoring -Anridirepessents -With this we avoid anti depressants bc it can push them to the manic phase. -Only give them this if they are on another mood stabilizer before you give this -Avoid this bc you don't want to push them to manic episode

Takeaway LTP

Long-term potentiation (LTP) is a lasting increase in amplitude of the response of neurons, caused by brief high-frequency stimulation of their afferents (tetanus). In the hippocampus, LTP depends on the activation of NMDA receptors, which induces an increase in the number of postsynaptic AMPA receptors and greater neurotransmitter release. These are examples of Hebbian synapses, which become stronger if they successfully drive the postsynaptic cell, and weaker if they are unsuccessful.

Parts involved in LTM

Medial Temporal Lobe- Is responsible for storing and categorizing DECLARITIVE memories -> Located in the temporal lobe Hippocampal region of MTL -> Injury: Cannot process/form new declarative memories

Phencyclidine:

NMDA antagonist - PCP - induced psychosis o Seems to reproduce some of the things related to positive symptoms

Phencyclidine: NMDA antagonist

PCP is a non-competitive NMDA antagonist. while PCP is bound, no other ligand can activate NMDA receptor. Changes in Glu system Related to what we see when you activate or inhibit the system -PCC antagonist. Prevents accumilation of MDMA receptor by blocking pore -Can recreate similar effects related to cognitive function of skitz. -So while we think positive is meso limbic we think negative is bc of reduced glutamate activiyty in brain

Episodic memory in the brain

Parietal cortex is important for episodic memory

What can dampin psycotic episodes?

dampining stress through CBT

People with specific hippocampal damage appear to have difficulties with _______ while _________ aspects are spared

People with specific hippocampal damage appear to have difficulties with recollection while familiarity-based aspects are spared.

Semantic memory in the brain

Perirhinal, Hippocampus, temporal, parahippocampal cortex

Braak stages

Prodromal -Get plaques first compared to tangles in the early stage -Deposit in hippo and surrounding temporal lobe -Symptoms: loose track of conversations mild cognitive impairments -Whereever it started its going to get worse there and then spread -Early- Moderate -Tangles spread and get worse in hippo and entorhinal, spread to frontal and Medial temporal lobe. -Spread occipital lobe etc. -Likely to get diagnosis of AD -Not just normal cognitive decline -Severe working memory and attentional issues -Still going to have most old memories in tact -Dependent of caretaker -Moderate-late -Plaques and tangels are widespread -tangles worse in hippo -This is where they are fully dependent on caretaker -Memory short and long term is impaired -Conversations are not possible -Cannot preform simple tasks -Language strats to fall down -Often see issues with motor function like swallowing -Moar often diw beuae of chocking because they don't have the reflexinve response to swallow - Missing slide of the severity across afe. We need to initiate treatment earlier since we can't get rid od deposits

-Because we see changes early in basal forebrain

See cognitive symptoms

Declarative Memory Sense of Fimiliaraity comes from? Sense of recollection comes from? Contextual aspects of memory?

Sense of familiarity -> Perirhinal cortex Sense of recollection -> Hippocampus Contextual aspects of memory (spatial cognition)-> parahippocampal cortex`

sensory vs short term memory

Sensory = information is there for a few seconds or less Short term = Information fades away after 30s or less

Types of non-declarative memory types and brain regions

Skill learning • Basal ganglia, motor cortex, and cerebellum. Primming • Reduced activity in bilateral occipitotemporal cortex • Reduced activation of the left frontal cortex • Perirenal cortex also involved in priming Conditioning • Cerebellum • Hippocampus • Ventral striatum Cerebral cortex

Different kinds of learning depend on different brain regions. Spatial learning requires an intact_____ , while motor skills rely on the________, and object recognition relies on the _____.

Spatial learning-> hippocampus motor skills-> basal ganglia, and object recognition -> visual cortex.

Overall, brain and declarative memory

The hippocampus, mammillary bodies, and dorsal thalamus are part of a network that must be intact to form new declarative memories—memories that we can declare to others. Damage to these regions can cause amnesia, the impairment of memory.

Neurosurgery: OCD

Treatments Anti depressants CBT -> recognize or stop that patten which can reduce anxiety feelings -In extreme cases they have done signalomities-> serving whit matter tract so you don't have info from pre frontal cortex to striatum can reduce the production of those behaviors -Ment to replace abomitomies -

Where the The hypofrontality hypothesis is linked with ______ the DA hypothesis is linked with_______

Where the The hypofrontality hypothesis is linked with NEGATIVE SYMPTOMS the DA hypothesis is linked with POSITIVE SYMPTOMS

Cognitive map

a mental representation of the layout of one's environment o Is an understanding of the relative special organization of objexts

mutated prions are shaped like

a piece of paper folded many times PrPsc

Cognitive behavioral therapy (CBT)

a popular integrative therapy that combines cognitive therapy (changing self-defeating thinking) with behavior therapy (changing behavior) CBT is aimed at breaking the self perpetuating cycle -Negative thoughts-> low mood-> influence behavior -CBT is aimed at changing throughts -If we can reduce influence of negatie thoughts will help mood and promote behavior - -60% aveliation just with CBT -

Patient N.A

a still-living patient who is unable to encode new declarative memories, because of damage to the dorsomedial thalamus and the mammillary bodies (leasions to the fornix) damage to the Diencelphon Normal short term memory, but cannot make new declarative Anterograde amnesia

Induction of LTP-> absolute have to have ______________. OR ELSE DO NOT get long term potentiation taking place

absolute have to have NMDA receptors for LTP. OR ELSE DO NOT get long term potentiation taking place

LTP- increase density of _________on post synaptic element. Not nessacairly for induction of LTP, They are the result of LTP and now we can get a bigger response to a weak stimulus.

ampa recptors on paost synaptic element. Not nessacairly for induction of LTP, They are the result of LTP and now we can get a bigger response to a weak stimulus. **If we block calcium LTP CANNOT happen If we block CAmKII we can get LTP If we block AMPA we can still get LTP **If we block NMDA we WONT get LTP

Dendritic Branching and Environmental Enrichment

brain has some ability to recongnize itself into the response expierience Enriched animals have a higher number of these branches

Hippocampus is closely associated with the limbic system and crucial for ability to

consolidate short-term memory into longer term memory.

Cell assemblies are called

engram Networks of neurons that are linked together \knock out enough of the cells in cell assembly you will loose that info · Most information goes into the hippocampus through the entorhinal cortex · Cell bodies live in the dentategyrus, CA3, CA1, and subiculum

Two types of cells in the entorhinal cortex that help animals learn local spatial environment:

entorhinal cortex o Border cells (shown in humans) o Responds to borders of environments § These cells don't respond to curves, it responds to straight parts or corners § Different then the place cells because it has to be on the edge of the environment o Grid cells § Fire when an animal crosses the intersection of points of an abstract grid map of the envionrment. (discovered in rats)

place cells Boarder cells

hippocampal neurons tuned to particular spatial locations, responding best when an animal is in a particular place and looking in a particular direction Group of cells that process a particular type of information. A cognitive map -Activated in response of being in a particular area or some in an environment -Different cells activated throughout the map -Individual group of cells that link together to create a mental map of the location. -Ex: walk around the house without actually having to go there if the lights are off. Border cells - Respond to edges - on edge of map, figure out where we are in a mental map. For border when we are at the edge of it - Responding to the location in the map- All together they create overert map, but respond to different things

semantic memory

is generalized declarative memory, such as knowing the meaning of a word without knowing where or when you learned that word

If you block DA receptors,

it can eliminate positive symptoms

There are a few rare individuals who have incredibly extensive episodic memories, who can tell you exactly what they had for breakfast on June 20, 2002, or any other date (Price, 2008). A group of 11 such people with extreme autobiographical memory were found to have

larger temporal lobes, including a larger parahippocampal gyrus, than controls We don't know whether these people were born with larger temporal lobes, and so had great autobiographical memory, or developed great autobiographical memory, which caused their temporal lobes to enlarge.

Sleep and Depression

less slow-wave sleep, less latency more total REM, repeated awakenings and early-morning awakening (important screening question)

- Mad cow disease

o Bovine spongiform encephalopathy --> Holes within the brain o Agitated, aggressive, and uncoordinated cows -> Slightly like sham rage by getting upset at things that aren't there o Food contaminated w/CNS or digestive tract o Cows will look uncoordinated and lose the ability to stand up on their own o Scraping of the fur - If one animal in the herd has it, its likely the others will get it too o Think its transmitted through the urine o Prions can survive much longer so if the animal pees in the field a month ago, another animal can still get it - From the 80s to 90s this was spread to humans (mostly in the UK) o Consuming meat - only spreads if the meat has central nervous system in it or digestive tract - The animals don't start showing symptoms until 2 or 3 years after infection

- If you look at healthy individuals and psychiatric control, there is a normal range of cortisol but in MDD

o But 2/3 of the depressive population show heightened cortisol levels o Arguing a deficiency in this pathway - Cortisol has many hormones released at different levels throughout the day o May be impairments in the cycadean rhythm - If you alleviate the depressive symptoms, cortisol goes down.

- Glutamatergic neurons

o Entorhinal cortex o CA3 o Hyper-excitability

Alzheimer's disease (AD) - Familiar vs sporadic

o Familiar is hereditary § Earlier onset o Sporadic is of unknown cause § Risk goes up at 60-65

- Many of the nuns donated their brains when they died back to Snowden

o He found that many of these women had had the pathologies in the brains, but they didn't translate to these cognitive deficits o Still had a lot of plaques and tangles o Something is either protecting the group, or there is another reason § Cognitive reserve? - Just because there are plaques and tangles doesn't mean you will show dementia symptoms

What part of the brain is important for spatial learning?

o Hippocampus is important in spatial learning-> animals learna bout their environment by moving through it

- Theories of etiology MDD

o Monoamine hypothesis o HPA axis dysfunction

- Tardive dyskinesia

o Motor ticks in the face and the head o Repetitive o Can't control it o Messing with the indirect pathway through he D2 receptors o Common with long term use of this drug

- Plaques and tangles are

o Protein aggregates

Prion diseases Scrapie

o Sheep and goat o Symptoms o Scratch/scrape coat o Progressive muscle weakness o Ataxia o Anorexia/wasting - lose weight Holes in brain

Classical conditioning and neural circuit

o Strengthening the synaptic connections from the cerebellum to your motor neurons o Puff of air and noise will converage at cerebellum. o Basal ganglia and motor cortext can get involved but generally cerebellum o Strengtherning the synaptic connections between sound andf cerebellum

Neurofibrillary tangles (NFTs)

o Tau is a protein we all have that pulls together the microtubular cell units (in the axon terminal) o Tau acts as glue to hold these subunits together o In AD Phosphate groups attach and cause the tau's to stop holding the microtubules -The tau disassociates the microtubles and it starts to club togehter into these NFT § Intercellular § Interferes with axon transport - Microtubule-associated protein o Axon transport - You get mitochondria that can't perform at its normal level - NTFs don't account for all of the degeneration of cells

Korsakoff's syndrome in the brain

o Temporal lobe structures including hippocampus are NORMAL o But shrunken mammillary bodies and damage in the dorsomedial thalamus. Sometimes, damage to the basal frontal cortex and causes the denial and confabulation

Disorganized hippocampus in skitz CA fields

o They need to be lined up and oriented to the same direction o In schizophrenia they seem to be disorganized and aren't oriented to one direction most common stuctural change

• Structural changes in the brain seen in bipolar disorder

o Ventricles enlarged -> which is also reminiscent of changes seen in schizophrenia -> The more manic episodes the person has experienced, the greater the ventricular enlargement suggesting a worsening of brain loss over time o Volume of amygdala is bigger o Prefrontal cortex is reduced/thinned o Shrinking of the Hippocampus -> Linked to depression -> Frustration -> irritability

- In the presence of a mutant protein in which it sticks to other things and causes these aggregates

o We see them in most forms of dementia o Presence of these plaques informs us of the neuron death

Protein prion gene (PRNP)

o Wild type prion (PrP) protein o PrPsc mutated protein o Structure changes o Resistant to degradation o Plagues (aggregations)

Mankato Nun Study

o Worked with a group of nuns in Minnesota o Nuns live longer compared to everyone else o Tend to be healthier, eat better food, engage in more cognitive activities o In terms of dementia, they have a lower incidence of dementia

Place cells:

o process a particular type of information and the environment we are in § Are activated in a particular area or zone when an animal move through it § Different cells will be activated in different parts and the cells link together to create a mental map of the environment § Lesions to hippocampus impair spatial learning

Why is it har dto break down mutaint copies of prions?

o they are made up of the same sequence as normal ones and it makes it hard to identify mutant copies ,akling it hard to breakdown in the body

Where is DA lower in skitz?

prefrontal cortex

We think negative symptoms is because of ...

reduced glutamate activity in the brain

Schizophrenia (negative symptoms)

refers to characteristics that are absent but should be present Disturbance of affect: expression of emotion Blunting: severe reduction in the intensity of affect expression Flat affect: no signs of emotional expression Inappropriate affect: (ex. schizophrenic starts laughing when talking about someone's death) Avolition: decreased engagement in purposeful, goal-directed actions

Schizophrenia (positive symptoms)

symptoms that should not be there, but are Psychotic disorder; associated with high dopamine levels Positive symptoms Delusions of reference: (ex. person believes characters in a TV show are talking to him directly) Delusions of persecution: (ex. person believes he is being deliberately interfered with, discriminated against, plotted against, threatened) Delusions of grandeur: (person is remarkable in some significant way such as being a historical figure or religious icon) Thought broadcasting: believe one's thoughts are broadcast directly from one's head to external world Thought insertion: belief that thoughts are being placed in one's head) Hallucinations: hearing voices Disorganized thought: loosening of associations; ideas shift from one thought to another; word salad; schizophrenics invent new words (neologisms) Disorganized behavior: inability to carry out activities of daily living; patient will either spontaneously move or remain rigid (catatonia)

what gets protein aggregates first

temporal lobe structures

- Frankland Take away

that once memories have been consolidated, lesioning the hippocampus will not remove the memory. study this in the freezing response in rats. shocked a rat in a chamber, and then lesioned the hippocampus immediately after to weeks after. Rats who were lesioned weeks after the shock in the cage still froze.

Nueroplascity

the ability of neurons and neural circuits to be remodeled by events o If we have instance of not super interactive synapses, and the other one is more active, the active one can steal the post synaptic sites o Activity dependent process o New synapses can be added as a function of trianing o All these htings are happening through some type of learning experience

spatial memory and hippocampus water maze

the ability to recall where objects are in relationship to each other in space -Water maze -Tub of water and the platform is under the surface of the water. Around the maze, you have spatial cues. -Only works if you vary the start locations -When you do that, force them to use the cues. -If you don't vary the start, -Then its stimulus reponse -variable start -How quickly did they find a platform. -Sham group gets faster -Same start -Poor performance -Hippocampus is important for spatial info because you need to remember where the platform is and not relay on spatial

The Hebb rule

the hypothesis proposed by Donald Hebb that the cellular basis of learning involves strengthening of a synapse that is repeatedly active when the postsynaptic neuron fires § Strengthened over time (e.g., releasing more neurotransmitters, more synaptic potential, etc.) - "Cells that fire together, wire together"

The hypofrontality hypothesis

the idea that schizophrenia may reflect underactivation of the frontal lobes reductions in glutamate signaling - Reduction of dopamine in the frontal cortex - Generally, link negative and cognitive system with glutamate, but dopamine may be helping drive these changes - Linked with the negative symptoms

Patient KC

the late Kent Cochrane, a patient who sustained damage to the cortex that rendered him unable to form and retrieve episodic memories o Could tell all sorts of factual information but couldn't put himself in future situations or remember specific memories from the past

- Initially plaque deposits are a good thing because

they trap the misfolded protein, but over time they become inflamed and trap things we need

adult stem cells

undifferentiated cells found among differentiated cells in a tissue or organ

o Electrical and chemical now in our short term or working memory Working memory:

· Phonological loop · Visuospatial skill · Episodic Buffer

• Patient H.M. damage and symptoms

• A person who, had severe epilepsy, and had surgery to remove a part of his brain. Because of damage to medial temporal lobe structures, H.M was unable to encode new declarative memories. Upon his death we learned his name was Henry Molaison. • Henrys surgery- removed the amygdala, most of the hippocampus, and some surrounding cortex from both temporal lobes • Anterograde amnesia- could not form new memories but had normal working memory • Caused by the medial temporal lobe removal including the hippocampus • Because other patients with damage to the amygdala did not exhibit comparable memory loss. • Henry could get better at completing the mirror tracing task over the course of days, but he did not remember ever completing the memory task in the first place. • In rats, we can't ask them if they remember completing the task which is why it is hard to study declarative memory in lab rats. Because they can just be exhibiting non-declarative memory.

Perirenal Cortex

• Comprised of 2 areas • Brodmann's area 35 • Brodmann's area 36 Fimiliarity Involved in the retrieval and storage of declarative memory Injury: cause people to struggle with associating meaning to objects. Ex: Differences between a unopened umbrella and a cane may be hard to distinguish

• Types of memory (declarative subtypes and non-declarative/procedural) • Memory subtypes:

• Declarative Memory • Information that you can verbally describe and explain to other people. They include explicit memories or facts and information acquired through learning. You are aware when you are accessioning declarative information. Take form of requests for information that has been learned previously • Answer "what" questions • Difficult to test in animals Subtypes of declarative memory: • Episodic • Personal memories. Personal significance to you • Semantic • Lacks personal significant. First president, 2+2, general knowledge that lack personal content or emotions. • Non-declarative • Implicit or procedural memories, specifically motor memories. • Examples include: Knowing how to do something. Skill learning, mirror tracing task, riding a bike, juggling • Difficult to articulate, we cant explain how what muscles are used to juggle but we can show you how to juggle. • Conditioning is non-declarative • Procedural memory • Memory about perceptual or motor procedures • Shown by performance rather than by conscious • Use for "how" problems • Often non verbal • Types of non-declarative memories: • Skill learning • Primming Conditioning

• Circuity of the hippocampus

• Entorhinal cortex (input to hippo) -> Dentate gyrus • Perforant pathway • DG -> CA3 (Pyramidal cells) • Mossy fibers • CA3 -> CA1 • Schaffer collaterals • CA1 -> subiculum -> entorhinal Project backout to the enterrhinal

Declarative memory facts

• Information that you can verbally describe and explain to other people. They include explicit memories or facts and information acquired through learning. You are aware when you are accessioning declarative information. Take form of requests for information that has been learned previously

Patient H.M Takeaway

• Short-term memory is different from long term memory • Memory deficit seemed to come from the loss of the medial temporal lobe including the hippocampus. Because other patients who damaged the amygdala but not the hippocampus had not acquired the same memory impairment • However, animals did not aquire the same deficits... why? Probably because H.M experienced declarative memory loss

Prevalence of Schizophrenia

•Affects 1% of the world's population •Affects men and women equally -On graph, males peak at abut 18-25 and drop off -Females, a little more extended, peak in 20s and 30s , but second peak around 40 -Both average to 18-25 but women have a bit more diagnoses later in life compared to men •Young age onset, typically around 18-25 onset

HPA axis dysfunction

•Cushing's disease •Cortisol is elevated •Normalizes with treatment -Individuals with Cushing disease o Constant release of cortisol throughout the day, due to a mass o Much higher incidence of depression -Higher instances of depression when there is high levels of cortisol -If you look of cortisol in blood, -Noral- low levels -Psychoricatic conditons - normal controls -MDD- you get a large protrtion of population w highetneed cortisol -Likely an imparment in negative feedback -This si arguing for the fact that there is a dificincy In the HPA and cant shut down cortisol -Should have higher cortisol In morning and decreases during the day

AD in the brain

•Degeneration in frontal cortex, basal forebrain, temporal lobe, hippocampus and entorhinal cortex o Symptoms can last for decades o Tends to be progressive and they continue to get worse

Other treatments for depression

•Electroconvulsive shock therapy (ECT) 30-40% who do nto respond to meds or CBT-> treatment resistant -ECT -Have a faster onset. -Used when people are sucicuidal or having a bad MDD bout -General treatment as well but usually not first treatment -Mini sezures in the brian. JUST helps with mdd not skitz or bipolor - -Give someone a mucle relaxant, usually under anestesia, put a electrodes and pass a little electrical current to enduce a mile sezuire. 3-4 times a week for 4 weeks -Common sysmptom is memory loss or confused. -Memory loss used to be severe but it got better Deep brain stimulation •Electrodes •Subcallosal cingulate gyrus •White matter bundle •Treatment resistant •Double-blind -Isnt going to be used as a first line of trestment -Going to be different in terms of what we do with different things -Evidence for targeting SCG, which is usually hyperactive in MDD, which connects to network of structures that play a role in emotion endocrine activity, etc. -Put electrodes in CG and the stimulator quiets activity in that structure -Not everyone shows benefits. Already deling with the worst of the worst. Can about 50 % responding by this

Anxiety disorders

•Generalized anxiety disorder (GAD) -Least specific -People feel generally worried or restless or fatigue -Impariments in concetioation or attention distrubted -Spread scorss all social situations and envionrments •Phobic disorders •-Specific -Subset of events or creatures •Social anxiety disorder -Focused on interactions -More fear of offending other juedge by others -Worry over interactions and what people think of them

Bipolar disorder genetics

•High genetic risk •70% concordance in monozygotic twins •Several genes ->PBRM1 (polybromo 1) -->chromatin remodeling or"epigenetics," risk factor. Tend to be genes that are affecting several processes. This one has widespread effects bc the main function is an epigenetic process. Can have changed dozens of changes and we cant figure out which one is causing the change

Revised DA hypothesis for schizophrenia

•Hyperactive dopaminergic state •overactive DA system •Hypoactive glutamatergic state •underactive GLU system

early signs of schizophrenia

•Lower IQ •Social adjustment •Motor abnormalities -social withdrawal -hostility or suspiciousness -deterioration of personal hygiene -flat, expressionless gaze -inability to cry or express joy -inappropriate laughter or crying -depression -oversleeping or insomnia -odd or irrational statements -forgetful; unable to concentrate -extreme reaction to criticism -strange use of words or way of speaking

Prenatal factors of schizophrenia

•Paternal age •Prenatal infection •Seasonality effect •Delivery complications •Hypoxia (oxygen deprivation) -Maternal infections during pregnancy -Influenza during the first or second trimester -Nutritional deprivation during early gestation -Lead exposure during the second trimester -Birth complications -Severe prenatal maternal stress

gene by environment interaction

•Postnatal factors •Stress •Drug abuse

Mirror-Tracing Task

•Procedural memory •H.M. -Because he had damage to hipp parahipp -> - he lost sense of familiarity and declarative memory -Could learn new procedural or skill learning activities, like mirror tracing -He got better over time learning the motor task -If you ask the individual "have you done this before" they wont remember they did this task in the past.

Structural changes in CNS

•Ventricles are enlarged •Disorganizded CA feild is most common • Accelerated cortical gray matter loss in adolescents - account for some proportion o there is not one change we see across everyone - expansion of the ventricles is commonly seen o it's hard to know if this existed when they were born, or if they happened over time