Unit 8 // Week 1
Define the ascending arousal system and the transmitters it uses.
AAS: a complex polysynaptic pathway comprised of monoaminergic, cholinergic, and histaminergic neurons that project to the intralaminar and reticular nuclei of the thalamus which, in turn, project diffusely to wide regions of the cortex including the frontal, parietal, temporal, and occipital cortices . -NE, serotonin -ACh -Histamine
Describe the structures of neurons and relate them to neuronal function (axon)
In general, each neuron has only one Same diameter along length Some are as long as dendrites, some can be a meter long first part of the axon (aka "initial segment") arises from the soma (or sometimes from a proximal dendrite), from axon hilock Axons may also receive information from other neurons, information that mainly modifies the transmission of APs. End in "terminal arborization" -- see the branches at the end of the axon in the image (called telodendria).
Discuss the significance of the topographic organization of the brain and the relationship of sensory receptive fields to that organization.
Topographic Organization: The sensory and motor systems have information that is encoded in neural maps. The somatotopic map is formed by an array of neurons that receive information from and send information to specific locations on the body. Topographic coding is preserved at each level of the nervous system - as high as the cerebral cortex. Topographic representation is called retinotopic in the visual system. In the auditory system it is called the tonotopic.
Define the characteristics of medulloblastoma including response to treatment.
response to treatment. - prognosis for untreated patients is dismal - Tumor is exquisitely radiosensitive -- With total excision and irradiation, 5-year survival rate may be as high as 75%
List the criteria used to designate a substance as a neurotransmitter.
• Must be synthesized in the presynaptic cell • Must be released by the presynaptic cell on stimulation • If the substance is applied exogenously to the postsynaptic membrane at physiologic concentration, the response of the postsynaptic cell must mimic the in vivo response.
Classify the common neurotransmitters based on their chemical structures.
"ABCs of Neurotransmitters" Amino Acids -Glutamate, glycine, y-Aminobutyric Acid (GABA) Biogenic Amines (NE, EP, DA) - common precursor → tyrosine -a common biosynthetic pathway (see next SO) Serotonin (also a biogenic amine) - tryptophan in serotonergic neurons in brain & GI Histamine (also a Biogenic Amine) - histidine (by histidine decarboxylase) Choline Esters (ACh) In presynaptic terminal → choline + acetyl CoA = ACh, catalyzed by choline acetyltransferase Neuropeptides - synthesized in the nerve cell body. - long and growing list of neuropeptides that function as neuromodulators, neurohormones, and neurotransmitters. Neuromodulators: • Substances that act on the presynaptic cell, altering the amount of NT released in response to stimulation. e.g. ACTH, CCK, Glucagon, oxytocin, secretin, substance P, TRH, ADH, VIP
Describe the structure & function of microglia
- monocyte-derived - So they're motile When activated (damage or microorganisms), they retract their processes, proliferate, and assume the morphologic characteristics and functions of APCs important role in immune responses within the CNS. - help remove the cellular products of the damage by phagocytosis. - remove microbial invaders - secrete immunoregulatory cytokines - may have important roles in normal brain development and function, including pruning of excess synapses that are formed during development and synaptic plasticity. Clinical: T lymphocytes and microglia, which phagocytose and degrade myelin debris, play major roles in progression of MS. The destructive actions of these cells exceed the capacity of oligodendrocytes to produce myelin and repair the myelin sheaths.
List the factors that determine prognosis in brain tumors.
-Regardless of benign/malignant, *growth and location* are vital for prognosis. -*Amenability to surgical resection* -CNS tumors rarely leave the CNS, unless they encroach upon the subarachnoid space and may be spread through *CSF dissemination* (CSF dissemination = poor prognosis). -Prognosis for glioblastoma is very poor, although chemo can have some benefit. -*Increase in number of blood vessels*, often with thickened walls or vascular cell proliferation = poor prognosis. -Oligodendrogliomas have a better prognosis than astrocytomas. -Individuals with anaplastic oligodendrogliomas have an overall worse prognosis.
REVIEW the mechanism of chemical synaptic transmission, using the neuromuscular junction as an example.
1. Action potential in presynaptic cell causes Ca2+ channels to open 2. Ca2+ influx, down its electrochemical gradient neurotransmitter vesicles dock and fuse with membrane 3. Smallest amount of ACh that can be released is the content of one synaptic vesicle (one quantum) -- NTs are released into the synaptic cleft (exocytosis) 4. NTs diffuse across cleft, bind receptors on the postsynaptic membrane -- If it's the motor end plate, these are nicotinic receptors --- These are ligand-gated ion channels (Na+ IN, K+ OUT) 5. ACh is degraded by AChE (acetylcholinesterase) 6. ~50% of the choline is returned to the presynaptic terminal by Na+-chline cotransport, to be recycled.
Give examples of classification of neurotransmitter receptors based on their agonist binding properties (i.e., based on their pharmacology).
Acetylcholine Receptors: Nicotinic receptors: • Present within the CNS. • Members of the cys-loop family. Contain a relatively non-selective cationic channel Muscarinic receptors: • Five known types - M1-M5 • All are metabotropic receptors ○ coupled to different G proteins and have distinct effects ○ M1, M3, and M5 are coupled to pertussis toxin-insensitive G proteins ○ M2 and M4 are coupled to pertussis toxin-sensitive G proteins. Inhibitory Amino Acid Receptors: GABA and Glycine • Glycine-mediated in spinal cord, GABA in brain. • Both have ionotropic receptors that are members of the cys-loop family. Each of these receptors has a Cl- channel opening
Describe the structures of neurons and relate them to neuronal function (dendrites, body)
Body: main genetic and metabolic center of the neuron. Includes Nissl bodies, which are stacks of RER, and a prominent Golgi apparatus Does receive some synaptic input (although most is dendrites... 90%) Dendrites: Referred to as "dendritic tree" Primary (from soma) or higher order (branching) Become thinner as they branch, and extend May have "spines" = small mushroom- or lollipop-shaped protrusions from the main dendrite, specialized for synaptic contact (usually, but not always) from excitatory inputs. Dendritic spine morphology depends on actin filaments and changes continuously as synaptic connections on neurons are modified. Changes are of key importance in the process of neural plasticity during embryonic brain development, as well as adaptation, learning, and memory postnatally.
Describe the relationship of the brain stem to the spinal cord and to the rest of the brain.
Brainstem: Medulla -Rostral extension of the spinal cord. -Contains autonomic centers the regulate breathing and BP -Also contains centers that coordinate swallowing, coughing, and vomiting reflexes Pons -Rostral to medulla -With the medulla - participates in balance and maintenance of posture and regulation of breathing. -Also relays information from the cerebral hemispheres to the cerebellum Midbrain: -Rostral to pons; participates in control of eye movements -Contains relay nuclei of auditory and visual systems. Spinal Cord: -Most caudal portion of CNS; extends from base of skull to L1. -31 pairs of spinal nerves containing motor and sensory nerves.
Describe the divisions of the nervous system.
CNS: -Spinal cord, brain stem (medulla, pons, midbrain) -Cerebellum -Diencephalon -Cerebral hemispheres (cortex, white matter, basal ganglia, hippocampal formation & amygdala). PNS: -Sensory receptors, sensory nerves, ganglia outside the CNS. Sensory: visual receptors, auditory receptors, chemoreceptors, and somatosensory receptors Motor: Carries information out of the nervous system to the periphery. -Resulting in contraction of skeletal muscle, smooth muscle, and cardiac muscle or secretion by endocrine and exocrine glands.
Describe the structures of the two pathways for transmission of somatosensory information to the CNS (the dorsal column system and the anterolateral (or spinothalamic) system).
Dorsal Column: -Somatosensory info pertaining to touch, pressure, vibration, proprioception -Mainly group I & II nerve fibers. -Ascend ipsilaterally to the nucleus gracilis or cuneatus (upper body). -1st order neurons synapse on 2nd order and cross over in the medulla -2nd order ascend to the contralateral thalamus --> synapse on third-order --> somatosensory cortex --> 4th order neurons Anterolateral (Spinothalamic) System: -Somatosensory info pertaining to pain, temp, light touch -Mainly group III and IV fibers (slow conduction) -1st order neurons synapse on 2nd order in the spinal cord --> crossing the midline and ascending to the contralateral thalamus. -In the thalamus --> 2nd order synapse on 3rd order --> ascending to somatosensory cortex --> synapse on 4th order neurons
REVIEW the mechanism that establishes the resting membrane potential of excitable cells.
Equilibrium potential: the diffusion potential that exactly balances or opposes the tendency for diffusion down the concentration difference. Normal resting potential of a neuron is -70 mV. • This is close to the resting membrane potential of both K+ and Cl-, because at rest, those have the highest permeability. - Na/K ATPase maintains K+ concentration gradient -- which is responsible for the diffusion potential of K+, which drives the membrane potential closer to K+ • K+ makes the greatest contribution to the resting membrane potential of excitable cells.
Define facilitation, post-tetanic potentiation, and long-term potentiation.
Facilitation: • Referred to by Berne & Levy as "Paired-pulse facilitation" • When a presynaptic axon is stimulated twice in rapid succession, it is often found that the postsynaptic potential evoked by the second stimulus is larger in amplitude than the one evoked by the first • distinct from temporal summation, in which two EPSPs overlap and sum to a larger response In facilitation, the second EPSP is larger Post-tetanic potentiation: - similar to facilitation; however, the responses are compared before and after stimulation of the presynaptic neuron tetanically (tens to hundreds of stimuli at a high frequency). - causes an increase in synaptic efficacy (see figure). - like PPF, it is an enhancement of the postsynaptic response, but it lasts longer: tens of seconds to several minutes after the cessation of tetanic stimulation. - repeated stimulation leads to an increased number of quanta of transmitter being released, *thought* to be due to residual amounts of Ca ++ that remain in the presynaptic terminal after each stimulus and help potentiate subsequent release of transmitter. long-term potentiation: • Can also be long-term depression. • Repetitive stimulation can produce more persistent changes in the efficacy of transmission at these synapses • can persist for days to weeks and are believed to be involved in the storage of memories. • "probably" involves both presynaptic (greater transmitter release) and postsynaptic (greater sensitivity to transmitter) changes
Explain why the thalamus is called the "gateway to the cerebral cortex" and how its nuclei function in that capacity.
Gateway to the cerebral cortex: because it processes virtually all information that reaches the cortex. The thalamus also receives input from the cortex. Two groups of nuclei: those that project diffusely to wide areas of the neocortex (midline and intralaminar nuclei) -Those that project to discrete regions of the neocortex and limbic system (specific sensory relay nuclei). --Medial and lateral geniculate bodies relay auditory and visual impulses to the auditory and visual cortices, respectively --Ventral posterior lateral (VPL), and ventral posteromedial nuclei that relay somatosensory information to the postcentral gyrus.
Outline (broadly) the functions of glia.
Glia: major nonneuronal cellular elements of the nervous system outnumber neurons by an order of magnitude: there are about 1013 glia and 1012 neurons. functions include: - regulation of the microenvironment - myelination of axons. - act to modulate synaptic and nonsynaptic transmission - important roles in synaptogenesis and maintenance
Describe the major excitatory and inhibitory neurotransmitters in the CNS.
Glutamate: • major excitatory significant role in the spinal cord and cerebellum. Glycine: • Inhibitory NT found in the spinal cord and brain stem MOA = increase Cl- conductance of the postsynaptic cell membrane = membrane potential is driven closer to Cl- equilibrium potential = hyperpolarizing/inhibiting. y-Aminobutyric Acid (GABA): Inhibitory, distributed widely in the CNS in GABAergic neurons. synthesized from glutamic acid via glutamic acid decarboxylase (unique to GABAergic neurons) • Following release from presynaptic membrane and action at postsynapse - can be recycled back to the presynaptic terminal - can be degraded by GABA transaminase to enter the citric acid cycle.
Discuss ways to increase conduction velocity.
Increase velocity: - Increasing nerve diameter - Myelination -- Myelin SLOWS conduction, because it increase resistance and decreases capacitance. THUS-- the current is forced to flow along the path of least resistance (axon interior) vs high resistance axonal membrane. Less current is LOST across the cell membrane THUS -- at breaks in the myelin sheath (nodes of Ranvier, "saltatory conduction"), there are concentrations of Na+ and K+ channels, the axonal membrane depolarizes faster in response to inward current. = increased conduction velocity. Myelin also causes an increase in the space constant (no clue what this means, but, it's true.) Clinical correlate: MS. Demyelination in CNS = decreased membrane resistance = current "leaks out" across the membrane during conduction = because of this decay they may be insufficient to generate action potentials when they reach the next node.
REVIEW the mechanisms that generate an action potential at the initiating segment and propagate it along the axon.
Initiating segment: Voltage gated Na+ channel is responsible for the upstroke of the action potential in nerve and skeletal muscle. Inward current: flow of positive charge into the cell (depolarizes). Action potentials have three basic characteristics: 1. Stereotypical size/shape 2. Propagation 3. All-or-none response
Define intra-axial versus extra-axial lesions.
Intra-axial - a lesion that is within the brain parenchyma Extra-axial - lesions outside the brain
Define "ionotropic" and "metabotropic" types of receptors and compare their mechanisms of action.
Ionotropic receptors are linked to ion channels. NTs can activate or inhibit . • e.g. GABAa receptors, when activated, increase Cl- conductance → hyperpolarizing the membrane. • protein complexes that both have an extracellular binding site for the transmitter and form and ion channel through the membrane. • Receptor is made up of several protein subunits (usually 3-5). • NT alters (usually increases) the probability of an ion channel being in the open state. Metabotropic receptors act through second messenger cascades. G-protein-coupled receptors.
Describe the function of oligodendrocytes & Schwann cells
MYELIN! single oligodendrocyte typically helps myelinate multiple axons in the CNS (no regeneration) Single Schwann cell helps myelinate only a single axon in the PNS (yes regeneration) Unmyelinated axons In CNS are bare, In the PNS they are not bare they are surrounded by Schwann cell processes; the Schwann cell, however, does not form a multilayered covering (i.e., myelin), but instead extends processes that surround parts of several axons (the Schwann cell with its set of unymyelinated axons is called a Remak bundle )
List the layers of neocortex, define what is meant by a "column" in the cortex, and indicate the significance of the inputs to layer IV.
Neurons within a column have similar response properties, suggesting they comprise a local processing network (eg, orientation and ocular dominance columns in the visual cortex). Afferents from the specific nuclei of the thalamus terminate primarily in layer IV; the nonspecific nuclei project to layers I-IV. Spiny stellate cells are excitatory, multipolar interneurons that release glutamate; located primarily in layer IV and are a major recipient of sensory information arising from the thalamus.
Differentiate pilocytic astrocytoma from glioblastoma with particular attention to gross/histo features
PA: • Histologically separated from other astrocytomas by: ○ The rarity of TP53 mutations ○ Or molecular signatures of infiltrating astrocytomas. • Gross: ○ Often cystic ○ If solid - may be well-circumscribed or (less frequently) infiltrative. • Tumor is composed of bipolar cells with long, thin "hairlike" processes that are GFAP-positive and form dense fibrillar meshworks. • Rosenthal fibers and eosinophilic granular bodies are characteristic findings. • Tumors are often biphasic ○ With both loose "microcystic" and fibrillary areas. • An increase in # of blood vessels, often with thickened wells or vascular cell proliferation is seen ○ Does not imply unfavorable prognosis. • Necrosis and brisk mitotic activity are uncommon. GBM: • Marked anaplasia • florid vascular endothelial hyperplasia secondary to VEGF. • Psuedopalisading necrosis ○ Areas of necrosis and hemorrhage surrounded by rows of malignant cells • GFAP positive
Differentiate pilocytic astrocytoma from glioblastoma with particular attention to anatomic location
PA: • Usually in the cerebellum • May also occur in: ○ Floor and walls of the third ventricle ○ Optic nerves ○ Occasionally the cerebral hemispheres. GBM: • Located within white matter of cerebral hemispheres (often in the centrum semiovale • Can spread to the contralateral hemisphere via the corpus callosum ○ Straddling the cerebral hemispheres to form the classic "butterfly glioma"
Differentiate pilocytic astrocytoma from glioblastoma with particular attention to clinical features
Pilocytic Atrocytoma: • Relatively benign • children and young adults • Grow very slowly • May be treated by resection (especially in the cerebellum). • Symptomatic recurrence of incompletely resected lesions is often associated with cyst enlargement - rather than growth of the solid component. Glioblastoma: • High aggressive, rapidly-growing neoplasm of astrocytes in adults • Very poor prognosis • Glioblastoma multiforme is the most common primary intracranial CNS neoplasm in adults. ~1-year medial survival
Describe the mechanism of presynaptic inhibition.
Presynaptic inhibition refers to when the binding of presynaptic receptors leads to a decrease in release of NT could be from two mechanisms: 1. opening of channels decreases membrane resistance and creates a current shunt that diverts the current associated with the action potential from the active zone lessening the depolarization of the active zone → less activation of Ca2+ channels -> less Ca2_ entry -> less release of NT. 2. The change in membrane potential caused by the opening of presynaptic ionotropic (ligand gated ion) channels. - no clue what the text means and it doesn't feel important.
Describe the principal, putative molecular targets thought to be responsible for the action of anesthetics.
Putative targets of anesthetic action. Anesthetic drugs may (A) enhance inhibitory synaptic activity or (B) diminish excitatory activity.
Distinguish sedation from general anesthesia.
Sedation: regional or local anesthesia supplemented with midazolam or propofol and opioid analgesics (or ketamine) may be a more appropriate and safer approach than general anesthesia for superficial surgical procedures. Deep sedation: is similar to a light state of general anesthesia characterized by decreased consciousness from which the patient is not easily aroused.
List the two primary factors responsible for the selectivity of CNS drug action.
Selectivity of CNS drug action is based on the fact that: 1. Different groups of neurons use different NTs, and 2. They are segregated into networks that subserve different CNS functions.
Describe the structure & function of ependymal cells
Single layer of columnar or cuboidal cells that line the fluid-filled ventricles of the brain and the central canal of the spinal cord Similar to epithelium, but unlike a true epithelium, there is no basal lamina In some CNS locations, the apical ends have cilia, which facilitate the movement of CSF, and long microvilli, which are likely involved in absorption. CSF is secreted mostly by these cells in choroid plexuses located in the ventricular system. Many substances diffuse readily across the ependyma, which lies between the extracellular space of the brain and the CSF.
Discuss the significance of synaptic plasticity, including long-term potentiation.
Synaptic plasticity is the fundamental mechanism that underlies learning. The responsiveness of postsynaptic neurons (synaptic strength) is not fixed but rather depends on the previous level of synaptic traffic. Potentiation is repeated activation of a neuronal pathway leads to increased responsiveness of the postsynaptic neurons in that pathway. This can last for days or weeks (long-term potentiation). In habituation, increased synaptic activity causes decreased responsiveness of the postsynaptic neuron. The mechanism of long-term potentiation involves synaptic pathways that use the excitatory neurotransmitter glutamate and its NMDA receptor.
Describe the synthesis of neurotransmitters from tyrosine, and briefly define the function of the enzymes MAO and COMT.
Synthesis: Tyrosine --> to l-dopa by tyrosine hydroxylase --> DA by dopa decarboxylase --- if dopamine B-hydroxylase in small dense-core vesicles of the nerve terminal = DA is converted to NE. --- phenylethanolamine-N-methyl transferase (PNMT) = NE is methylated to EP Degradation: • Catechol-O-methyltransferase (COMT) ○ Methylating enzyme - two forms membrane bound and soluable. membrane bound is the form present in the brain. ○ Distributed widely in other tissues including the liver • Monoamine oxidase (MAO) ○ Located in presynaptic nerve terminals ○ Catalyzes oxidative deamination ○ If a NT is to be degraded by MAO, there must be reuptake of the NT from the synapse. Each of the biogenic amines can be degraded by MAO alone, COMT alone, or by both (in any order).
Describe the structures and basic functions of the cerebellum, thalamus, hypothalamus, and the cerebral hemispheres.
Thalamus processes almost all sensory information going to the cerebral cortex and almost all motor information coming from the cerebral cortex to the brainstem and spinal cord. Hypothalamus lies ventral to the thalamus -Contains centers that regulate body temp., food intake, and water balance. -Also is an endocrine gland that controls hormone secretions of the pituitary. -Also contains cell bodies of neurons on the posterior pituitary gland. Cerebral Hemispheres Consist of the cerebral cortex, underlying white matter, and three deep nuclei (basal ganglia, hippocampus, and amygdala). -Functions are perception, higher motor functions, cognition, memory, and emotion. -Within these areas the motor and sensory areas and be further designated as primary, secondary, and tertiary - depending on how directly they deal with sensory or motor processing. Basal Ganglia -Consists of the caudate nucleus, the putamen, and the globus pallidus. Hippocampus and Amygdala -Hippocampus is involved in memory -Amygdala is involved with the emotions and communicates with the autonomic nervous system via the hypothalamus.
Describe the origin of the waves recorded as an electroencephalogram (EEG).
The EEG waves originate from alternating excitatory and inhibitory synaptic potentials that produce sufficient extracellular current flow across the cortex to be detected by surface electrodes. The EEG recorded from the scalp is a measure of the summation of dendritic postsynaptic potentials NOT action potentials. Current flow to and from active synaptic knobs on the dendrites produces wave activity, while all-or-none action potentials are transmitted along the axon. When the sum of the dendritic activity is negative relative to the cell body, the neuron is depolarized; when it is positive, the neuron is hyperpolarized.
Discuss the structures comprising the blood-brain barrier and the function of the choroid plexus.
The barrier between cerebral capillary blood and CSF is the choroid plexus. This barrier consists of three layers: capillary endothelial cells and basement membrane, neuroglial membrane, and epithelial cells of the choroid plexus. Anatomically, the blood-brain barrier consists of capillary endothelial cells and basement membrane, neuroglial membrane, and glial end feet (projections of astrocytes from the brain side of the barrier). Functionally, the blood-brain barrier differs in two ways from the analogous barrier in other tissues. (1) The junctions between endothelial cells in the brain are so "tight" that few substances can cross between the cells. (2) Only a few substances can pass through the endothelial cells: Lipid-soluble substances (e.g., oxygen and carbon dioxide) can cross the blood-brain barrier, but water-soluble substances are excluded.
Summarize the direct and indirect pathways of the basal ganglia and the structures and basic functions of the motor cortex.
The basal ganglia aids in planning and executing smooth movements of the cortex. Direct: Begins in the cortex -Cortex --> striatum (putamen and caudate nucleus) --> internal globus pallidus & substantia nigra pars reticulata --> thalamus --> cortex -It is excitatory and promotes movement Indirect: Also begins in the cortex -Cortex --> striatum (caudate and putamen) --> external globus pallidus --> subthalamic nuclei --> internal globus pallidus & substantia nigra pars reticulate --> VL of the thalamus --> back to the cortex -Inhibitory.
List the functions of the cerebrospinal fluid.
The functions of CSF are to provide a constant, controlled environment for the brain cells and to protect the brain from endogenous or exogenous toxins. CSF also may function to prevent escape of local neurotransmitters into the general circulation. Non-ionized (lipid-soluble) drugs penetrate the brain readily, whereas ionized (non-lipid-soluble) drugs do not penetrate. Inflammation, irradiation, and tumors may increase the permeability of the blood-brain barrier and allow substances normally excluded to enter the brain. ---These substances include cancer chemotherapeutic drugs, antibiotics, and radiolabeled markers.
Describe the significance of shunting to neuronal excitation
Two EPSP very close to each other, in fact result in a smaller EPSP at the initial segment than it would have generated in isolation. - See synapses 2 and 4 (and "D") - that is, when synapse 2 is active, channels are opened in the cell membrane, which means that it is more leaky. - Therefore, when synapse 4 is also active, more of its Excitatory Postsynaptic current will be lost (shunted) through the dendritic membrane, and less current will be left to travel down the dendrite to the initial segment. ( caption from photo attached) A, Comparison of EPSPs evoked by proximal versus distal synapses (2 versus 1). B, Temporal summation. EPSPs in response to two spikes in the same axon occurring in rapid succession (axon 2). C, Spatial summation. Responses evoked by synapses that are electrically distant from each other (1 and 3). D, Sublinear summation of two synapses located near each other because of shunting (2 and 4).
Characterize the output of the cerebellar cortex and disorders of the cerebellum.
Two systems carrying excitatory output: Climbing fiber system: -Inferior olive nucleus of medulla --> purkinje cells -Climbing fibers make multiple synapses along dendrites of purkinje cells. -Climbing fibers condition purkinje cells --> modulating responses to mossy fiber output. Mossy fiber system: -Majority of cerebellar input -- including vestibulocerebellar, spinocerebellar, pontocerebellar afferents. -Project onto granule cells (excitatory interneurons in glomeruli). -Axons from granule cells ascend to the molecular layer --> becoming parallel fibers -Parallel fibers contact purkinje cells Disorders: Ataxia, delayed onset of movement
Describe the significance of spatial and temporal summation to neuronal excitation.
Types of synaptic arrangements: • One-to-one ○ NMJ • One-to-many ○ uncommon • Many-to-one - Very common in nervous system Integration of synaptic information: • Spatial ○ 2 or more inputs arrive at a postsynaptic cell simultaneously... both are excitatory, great = greater depolarization. ○ if one is excit. & one is inhib., they cancel each other out. • Temporal ○ When two inputs arrive in rapid succession • Repeated stim can = greater expected response from postsynaptic cell Results in one of these: ○ Facilitation ○ Augmentation ○ Post-tetanic potentiation • Synaptic fatigue: ○ May occur where repeated stimulation produces a *smaller* than expected response in the postsynaptic cell, possibly resulting from the depletion of NT stores from presynaptic terminal
List the five primary effects of the neurophysiologic state produced by general anesthetics and the characteristic actions of an ideal anesthetic drug.
Unconsciousness, Amnesia, Analgesia, Inhibition of autonomic reflexes, Skeletal muscle relaxation.
Briefly summarize the idea of wakefulness and REM sleep as opposite states of transmitter release and brain area activity (see Figure 14-4 of Reading 3 and the text discussion of it).
Wakefulness: adult, awake but at rest (mind wandering and the eyes closed)... EEG shows alpha rhythm (most marked in the parietal and occipital lobes) --Associated with decreased levels of attention. Awake, alert individual with their eyes open, the alpha rhythm is replaced by irregular, low-voltage activity, the beta rhythm (arousal or alerting response) --Can be produced by any form of sensory stimulation or mental concentration. REM Sleep (aka paradoxical sleep): characterized by the appearance of rapid, low-voltage EEG activity that resembles that seen in the awake, aroused state --Large phasic potentials originate in the cholinergic neurons in the pons and pass rapidly to the lateral geniculate body and from there to the occipital cortex.
Define the characteristics of medulloblastoma including: a. clinical features, b. anatomic location
a. clinical features, ○ predominantly children ○ highly malignant ○ Most common malignant brain tumor in childhood. ○ Can compress 4th ventricle, causing noncommunicating hydrocephalus - headaches, papilledema. (<-- from first aid, not robbins) b. anatomic location, ○ Cerebellum (exclusively) § Midline ○ When in adults, more commonly lateral cerebellum ○ Dissemination through the CSF is a common complication § = nodular masses at some distance from the primary tumor (e.g. as far as the cauda equina) - termed "drop metastases."
Describe the structure & function of astrocytes
cell body from which several main branches arise (then hundreds to thousands of branchlettes) help regulate the microenvironment of the CNS, under normal conditions & in response to damage to the nervous system. -can actively take up K + ions and NT substances, which they metabolize, biodegrade, or recycle. Connected by gap junctions foot processes contact the capillaries (part of BBB) and connective tissue at the surface of the CNS (pia mater) cytoplasm contains glial filaments that provide mechanical support for CNS tissue. - Under conditions of hypoxia, [K+] in the extracellular of brain can increase by a factor of 20 = neurons depolarize = release of NTs (glutamate) = more K+ release....-- astrocytes suck up the K+ by a K+/Cl− symporter After injury --> reactive astrocytes ("reactive gliosis") - can form glial scar around an area of focal damage -- segregates damaged tissue, allows inflammatory processes to act selectively at the site of damage, minimizing the impact on surrounding normal tissue.
Define the characteristics of medulloblastoma including: - histopathologic features, - gross morphology
histopathologic features ○ often largely undifferentiated ○ Form of primitive neuroectodermal tumor (PNET) ○ densely cellular, with sheets of anaplastic cells ○ Individual cells: § are small, § scant cytoplasm § hyperchromatic nuclei that are frequently elongated or crescent shaped. § Abundant mitoses ○ may express neuronal (neurosecretory) granules ○ May form Homer-Wright rosettes, as occur in neuroblastoma § a type of rosette in which differentiated tumor cells surround the neuropil. § Concentric clusters -- arrangement of tumor cells ○ At the edges of the main tumor mass, the tumor cells have a propensity to form linear chains of cells infiltrating through cerebellar cortex and penetrating the pia, spreading into the subarachnoid space. Gross morphology: ○ often well circumscribed, gray, and friable § Friable = easily crumbled ○ may be seen extending to the surface of the cerebellar folia and involving the leptomeninges
Describe structure & function of Satellite cells.
surround the nerve cell bodies -- thus are found only in ganglia dorsal root and cranial nerve ganglion cells regulate their microenvironment in a fashion similar to that of astrocytes.
Define ependymoma and describe the relationship between tumor location and clinical features of this neoplasm.
tumors that most often arise next to the ependyma-lined ventricular system, including the oft-obliterated central canal of the spinal cord. -In kids, occur near 4th ventricle, in adults, occur in spinal cord. -Associated with neurofibromatosis type 2 (NF2) (first aid and Robbins says so) 1. Posterior fossa ependymomas: - Manifest with hydrocephalus secondary to progressive obstruction of 4th ventricle - CSF dissemination is common = poor prognosis - Worst overall outcome (younger children have 50% 5 year survival) 2. Supratentorial and spinal ependymomas have much better prognosis.
Briefly describe the mechanism of action of cocaine, opioids, strychnine, ketamine, and methylxanthines.
• Cocaine: inhibits excitation of nerve endings or blocks conduction in peripheral nerves. Reversibly binds/inactivates Na channels (no depolarization, propagation). - binds differentially to the dopamine, serotonin, and NE transport proteins and directly prevents the reuptake of dopamine, serotonin, and NE into presynaptic neurons. Dopamine levels/effects are most responsible for the addictive property of cocaine. • Opioids: ○ Inhibit synaptic activity through direct activation of opioid receptors as well as through release of the endogenous, inhibitory opioid peptides. ○ Postsynaptic activation of these receptors can open K+ ion channels to hyperpolarize (IPSP). ○ Presynaptic opioid receptor activation can close voltage-gated Ca ion channels to inhibit NT release (ACh, norepi, serotonin, glutamate, and substance P). • Strychnine (rat poison): Block glycine receptors (more numerous in the cord than in the brain), spinal convulsant. Antagonizes inhibitory tone in motor neurons of the spinal cord, resulting in powerful and uncontrollable muscle contractions. • Ketamine: noncompetitive NMDA receptor antagonist that blocks glutamate. • Methylxanthines: inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP, -- thus increase cAMP. - also block adenosine receptors in the central nervous system (CNS) and elsewhere.
Compare excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs).
• Excitatory = Trying to drive the end plate potential (EPP) to it's equilibrium potential -MEPP = miniature end plate potential... a group of these summate to try and get an EPP.... one synaptic vesicle creates one MEPP • Inhibitory = Hyperpolarize - by opening Cl- channels --NTs 𝛾-aminobutyric acid (GABA) and glycine will do this
Compare "hierarchical" and "diffuse" neuronal systems.
• Hierarchical System: ○ Large myelinated, rapidly conducting fibers ○ Control major motor and sensory pathways ○ Major excitatory transmitters: aspartate and glutamate ○ Numerous small inhibitory interneurons using GABA or glycine ○ Drugs impacting hierarchical system impact overall excitability of CNS • Diffuse System: ○ Broad distribution, widespread branches of fine axons forming many synapses ○ Periodic enlargements (varicosities) containing transmitter vesicles ○ Transmitters are often amines (norepi, dopamine, serotonin) or peptides acting on metabotropic receptors. ○ Impact attention, appetite or emotional states.
Briefly describe the mechanism of action of reserpine, amphetamine, capsaicin, tetanus toxin.
• Reserpine: depletes vesicular stores of both serotonin and norepinephrine in CNS neurons. • Amphetamine: CNS stimulant by increasing dopaminergic activity by inducing biogenic amine release from storage in synaptic terminals. • Capsaicin: "hot" ingredient of chili peppers, facilitates release of substance P from stores in nerve endings and depletes the peptide (Katzung). Newer studies suggest a "desentization" theory of altering nerve conduction by hyperpolarization (NCBI). Tetanus toxin: binds the presynaptic receptor of the NMJ, internalized and transported retroaxonally to the spinal cord, inducing spastic paralysis by cleaving vesicle-associated membrane protein (VAMP), blocking neurotransmission from spinal inhibitory interneurons.
List the steps at which drugs can alter synaptic transmission.
• Some drugs directly impact ion transmission along axons, but MOST CNS drugs act at the synapse (presynaptically, postsynaptically, or second messengers). • Synaptic drugs may alter: (1) Action potential in presynaptic fiber; (2) synthesis of transmitter; (3) storage; (4) metabolism; (5) release; (6) reuptake into the nerve ending or uptake into a glial cell; (7) degradation; (8) receptor for the transmitter; (9) receptor-induced increase or decrease in ionic conductance; (10) retrograde signaling.
Differentiate the GABA receptors (A, B, and C types), and describe the mechanism of action of the benzodiazepines and barbiturates
• The GABAA receptor is directly linked to a Cl- channel - ionotropic, hyperpolarizing (inhibiting). - site of action of benzodiazepines and barbiturates in the CNS. - GABAB receptor is coupled via G protein to a K+ channel and is thus metabotropic , stimulating and increasing K+ conductance and hyperpolarizing the synaptic cell. • The GABAC receptors, also ionotropic, structurally similar to As... but have a different pharmacologic profile, & do not respond to benzodiazepines.
