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FAU / Human Development / HDFS 4006 / How does entry of ca ions into dendritic spine cause ampa receptors to

How does entry of ca ions into dendritic spine cause ampa receptors to

How does entry of ca ions into dendritic spine cause ampa receptors to

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How does entry of ca ions into dendritic spine cause ampa receptors to move into postsynaptic membrane?



Exam Two Study Guide

Chapter Thirteen: Learning and Memory

∙ Learning refers to process by which experiences change our nervous system and hence  our behaviors; refer to these changes as memories

∙ Sensory memory (SM) – info is first processed here; it’s a brief period of time that the  initial sensation of environmental stimuli is initially remembered; fleeting, lasts seconds o Iconic – visual memory store; echoic – auditory

∙ Short-term memory (STM) – only a small fraction of info passes from sensory memory to  second stage, which is working memory; the info must be meaningful to pass here o Memory capacity is limited to a few items, but length of STM can be extended  through rehearsal or chunking; info can be retrieved after very short delay o Working memory – system that temporarily stores and allows manipulation of  info to perform complex activities


Here do new ampa receptors come from?



If you want to learn more check out How does the tryptophan operon work?

∙ Long-term memory (LTM) – final stage, relatively permanent; info that’ll be retained  from STM is consolidated in LTM

o Declarative (explicit) – memory of events and facts we think and talk about ▪ Memories we can say aloud, we can declare what the memory is

▪ Dependent on medial temporal lobe  

memory system – diencephalon (limbic  

system), hippocampus (HP),  


How could process that begins postsynaptically (in dendritic spines) cause presynaptic changes?



Don't forget about the age old question of What are 3 primary ethical guidelines involved in social research?

hippocampal formation (HPF)

▪ Semantic memory – memory of facts  

and general info; don’t include info about  

context in which facts were learned

∙ Example – knowing what a stop sign  

or clock means

∙ Occurs once, learned at once; lacks  

sense of conscious recollection

▪ Episodic – collection of event perception memories organized in time and  identified by a particular context

∙ Conscious awareness, encode experience, method of storing in  

durable form, retrieval method; generally over time

o Non-declarative (implicit) – memories we’re not conscious of; operate  automatically, don’t require memorization, facts, or experiences; instead, they  control behaviors; demonstrate via behavior We also discuss several other topics like What is an example of inoculation?

▪ Not aware of all movements while we’re performing them – driving

▪ Have the information, but don’t know where acquired the memory from ▪ Skills and habits – dependent initially on the HP, but once it’s learned it is  stored in the striatum, motor cortex, and cerebellum We also discuss several other topics like What are the stages of general adaptation syndrom (gas)?
We also discuss several other topics like Why is self-defense justified?

▪ Priming – when you’ve been exposed to stimuli at some point and it  

influences your behavior later; completely dependent on neocortex

∙ Presentation of an item influences subsequent perception or  

processing; occurs across a range of senses; verbal memory  

priming can be used to test implicit memory

∙ Usually dependent on reinstating the physical conditions under  

which encoding occurred

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▪ Basic associative learning – emotional responses (amygdala, HP), skeletal  musculature (cerebellum, HP); association between two stimuli

∙ Classical conditioning – when stimulus that initially produces no  

particular response is followed several times by an unconditioned  

stimulus (US) that produces a defensive or appetitive response  

(unconditioned response, UR); the first stimulus (now conditioned  

stimulus, CS) itself evokes that response (conditioned response,  

CR)

o UR occurs without any special training; US – stimulus that  

elicits an unlearned reflexive response

o Example: dogs paired sound of bell with food and after  Don't forget about the age old question of Who won the sino japanese war?

several pairings, dogs would salivate to the bell

▪ Non-associative learning – habituation; no longer noticing a smell or  sensitization (the feel of something after a prolonged period of time);  

reflex pathways

∙ Instrumental conditioning (AKA operant conditioning) – effects of a particular behavior  or particular situation increase (reinforce) or decrease (punish) the probability of behavior  o Reinforcer increases likelihood of behavior occurring while punisher decreases it o Entails strengthening connections between neural circuits that detect particular  response; strengthening synapses among neurons that have just been active o Learn from interacting with environment

o Role of basal ganglia (BG) – two pathways

▪ Transcortical connections – involved in acquisition of declarative episodic  memories, complex perceptual memories of events and complex behaviors  that involved deliberation/instruction

▪ BG connections – as learned behaviors become automatic and routine,  they’re transferred to BG

∙ As we deliberately perform complex behavior, BG receives info  

about stimuli present and the responses we’re making

∙ At first, BG is a passive observer of the situation, but as the  

behaviors are repeated continuously, BG learns what to do;  

eventually BG takes over most of the details of the process, leaving  

the transcortical connections free to do something else

o We no longer need to think about what we’re doing

▪ Parts of BG – caudate and putamen receive sensory info from c. cortex  and frontal lobe about movements that are planned or are actually in  

progress; outputs are sent to globus pallidus, which are sent to frontal  

cortex, the premotor and supplementary motor cortices (where plans for  movements are made), and to the 1º motor cortex where they’re executed

Prefrontal cortex – TBs  

o Reinforcement: mesolimbic system of DA neurons begins in VTA of midbrain  

connecting prefrontal cortex  with VTA secrete  

glutamate; devising  

strategies, making plans,  evaluating progress made,  judge appropriateness of  one’s own behavior

and project to forebrain regions (amygdala, HP, and nucleus accumbens (NAC) which projects to ventral BG for learning); mesocortical system begins in VTA  but projects to prefrontal and limbic cortices, and HP

▪ DA reinforcers stimulate medial forebrain bundle or VTA

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▪ The systems must detect presence of stimulus and strengthen connections  between neurons that detect discriminative stimulus and the neurons that  produce operant response

▪ Reinforcement occurs when neural circuits detect reinforcement stimulus  and cause activation of DA neurons in VA; activation depends on state of  animal/environment the stimuli occur in; activity of neurons sends signal  that there’s something to be learned – if delivery of reinforcer is already  expected, then there’s nothing needed to be learned

∙ Classical vs. operant conditioning

o Classical involves automatic reflexes that don’t have to be learned; operant  involves new behaviors that are learned

o Classical involves association between two stimuli; operant involves association  between stimulus and response

o Operant permits organism to change its behavior according to consequences of  that behavior

∙ Trisynaptic pathway of HP (HP system = HPF and nearby parahippocampal region) o HPF – HP proper (cornu Ammonis), dentate gyrus, subiculum, entorhinal cortex o Most important input to HPF is entorhinal cortex – receives input from amygdala,  

limbic cortex, and all association neocortex regions, axons terminate in  dentate gyrus, CA3, and CA1

▪ Input is either directly or via two adjacent limbic cortex regions –

perirhinal and parahippocampal cortices

o Outputs from HP system comes from CA1 and subiculum, which are  relayed back through entorhinal, perirhinal, and parahippocampal cortex to  same association cortex regions via fornix, which select and modulate  

functions of HPF

o Entorhinal cortex ???? dentate gyrus ???? CA3 ???? CA1

▪ CA1 ???? subiculum ???? entorhinal cortex

o Three synapses to know – utilize glutamate, unidirectional pathway

▪ Perforant path – entorhinal to dentate gyrus

▪ Mossy fibers path – dentate gyrus to CA3 of HP; high-frequency  

stimulation of mossy fibers produces LTP that gradually decays over a  period of several hours

∙ LTP in CA3 field involves only presynaptic changes, no alterations  are seen in structure of dendritic spines after LTP has taken place

▪ Schaffer collateral path – CA3 to CA1, bypasses CA2

o The wiring diagram of the hippocampus is traditionally presented as a trisynaptic  loop. The major input is carried by axons of the preforant path, which convey  polymodal sensory information from neurons in layer II of the entorhinal cortex to  the dentate gyrus. Perforant path axons make excitatory synaptic contact with the  dendrites of granule cells: axons from the lateral and medial entorhinal cortices  innervate the outer and middle third of the dendritic tree, respectively. Granule  cells project, through their axons (the mossy fibers), to the proximal apical  dendrites of CA3 pyramidal cells which, in turn, project to ipsilateral CA1  pyramidal cells through Schaffer collaterals and to contralateral CA3 and CA1  pyramidal cells through commissural connections. In addition to the sequential

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trisynaptic circuit, there is also a dense associative network interconnecting CA3  cells on the same side. CA3 pyramidal cells are also innervated by a direct input  from layer II cells of the entorhinal cortex (not shown). The distal apical dendrites  of CA1 pyramidal neurons receive a direct input from layer III cells of the  entorhinal cortex. There is also substantial modulatory input to hippocampal  neurons.  

∙ Long-term potentiation (LTP) – long-term increase in excitability of neuron to particular  synaptic input caused by repeated high-frequency activity of that input; long-lasting  increase in synaptic strength after presentation of high-frequency stimulation

o Intense electrical stimulation of axons leading from entorhinal cortex to dentate  gyrus caused long-term increase in magnitude of excitatory postsynaptic  potentials in the postsynaptic neurons (increase is known as LTP)

o HPF – specialized region of limbic cortex located in temporal lobe; it’s folded in  one dimension and then curved in another; includes HP proper, dentate gyrus,  subiculum

▪ Primary input to HPF comes from entorhinal cortex, axons of entorhinal cortex pass through preforant path and form synapses with the granule  cells of the dentate gyrus

∙ A stimulating electrode is placed in the preforant path and a  

recording electrode is placed in the dentate gyrus, near the granule  

cells

∙ First, a single pulse of electrical stimulation is delivered to the  

preforant path, and then the resulting population EPSP is recorded  

in the dentate gyrus

∙ The size of the first population EPSP indicates the strength of the  

synaptic connections before LTP has taken place

∙ LTP can be induced by stimulating axons in preforant path with a  

burst of ~100 pulses of electrical stimulation, delivered within a  

few seconds

o Evidence that LTP has occurred is obtained by periodically  

delivering single pulses to preforant path and recording  

response in dentate gyrus – if response is greater than it  

was before the burst of pulses was delivered, LTP has  

occurred

▪ Associative LTP – an LTP in which concurrent stimulation of weak and  strong synapses to a given neuron strengthens the weak ones

▪ Non-associative LTP – requires some sort of additive effect; a series of  pulses delivered at a high rate all in one burst will produce LTP, but the  same number of pulses given at a slow rate will not

∙ A rapid rate of stimulation causes EPSP to summate, because each  successive EPSP occurs before the previous one has dissipated,  

which means that rapid stimulation depolarizes the postsynaptic  

membrane much more than slow stimulation does

∙ Low frequency stimulation leads to long-term depression (LTD)

o Synapse specific; can induce prolonged enhancement of EPSP (several hours to a  year); HP, cortex, amygdala, cerebellum

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o Properties of LTP

▪ Coincident activation – coincident pre-synaptic and post-synaptic activity  (state dependent); critical number of presynaptic fibers must be  

simultaneously activated by the high-frequency stimulus (must occur  within 100ms of release of NT from presynaptic terminals)

∙ A threshold degree of depolarization must be achieved

▪ Input specificity – LTP is induced at one set of synapses on a postsynaptic  cell, not other inactive synapses that make contact with same cell ∙ Consistent with formation of memory for specific info

▪ Associativity – LTP produced at synapses stimulated at low-frequency  when activated at same time as another set of synapses on same cell ∙ Cellular equivalent of classical conditioning – pairing weak  

stimulation with strong stimulation

o NMDA receptor found in HPF, especially in CA1; NMDA activation is  necessary for LTP and LTD

▪ Coincident activation, specificity, and associativity are required to active  NMDA glutamate receptors

▪ At baseline, NMDA receptors are permeable to calcium but ion channel is  blocked by magnesium, which is voltage dependent

▪ Requires both glutamate binding and depolarization of postsynaptic  membrane for ion channel to open – coincident activation

▪ Receptor ion channel only opens at synaptic inputs that are active and  releasing glutamate – specificity

▪ Weak stimulation (input) cannot depolarize membrane enough to remove  magnesium block, but if neighboring inputs are strongly stimulated, they  provide associative depolarization that will  

lift magnesium from channel pore –

associativity

▪ Ca entry though ion channels controlled by  

NMDA receptors is an essential step in LTP

▪ Therefore, NMDA receptor activation is a  

necessary first step in LTP establishment: the  

entry of Ca ions into dendritic spines

▪ Dendritic spikes – AP that occurs in the  

dendrite of some types of pyramidal cells;  

only occur when AP is triggered in axons of  

pyramidal cell

∙ The backwash of depolarization  

across the soma triggers a dendritic spike, which is propagated up  the trunk of the dendrite, which means that whenever the axons of  a pyramidal cells fires, all of its dendritic spines become  

depolarized for a brief time

∙ Are necessary for synaptic potentiation to take place  

o Dendritic spines on CA1 pyramidal cells contain two types of glutamate  receptors: NMDA and AMPA receptors; responsible for increase in synaptic  strength that occur during LTP

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o AMPA receptor – ionotropic glutamate receptor that controls sodium channel;  when open, it produces EPSPs in membrane of dendritic spine

▪ Strengthening of an individual synapse is accomplished by insertion of  additional AMPA receptors into postsynaptic membrane of dendritic spine

Synaptic strengthening – when conditions for LTP  are met, Ca enter dendritic  spine through NMDA  receptors; Ca activates  enzyme in spine, which  cause AMPA receptors to  move into spine; an  

increased number of  AMPA receptors in  

postsynaptic membrane  strengthens the synapse

∙ With more AMPA receptors present, the release of glutamate by  TB causes a larger EPSP, causing the synapse to become stronger ▪ Where do new AMPA receptors come from? LTP establishment first  caused movement of AMPA receptors into postsynaptic membranes of  dendritic spines from adjacent non-synaptic regions of dendrites ∙ Several minutes later, AMPA receptors were carried from interior  of cell to dendritic shaft, where they replaced AMPA receptors that  had been inserted in the postsynaptic membrane of the spines ▪ How does entry of Ca ions into dendritic spine cause AMPA receptors to  move into postsynaptic membrane? Process begins with activation of  several enzymes, including CaMKII in dendritic spines

∙ CaMKII – type II calcium-calmodulin kinase, enzyme that must be  activated by calcium; plays role in LTP establishment

▪ Under low-frequency/baseline conditions, stimulation only activates  AMPA receptors, not NMDA

▪ AMPA receptors can be modified with protein kinases to affect longer  lasting forms of LTP

∙ PKA ???? cAMP response element-binding protein CREB ???? protein  transcription/translation ????expansion of dendritic spines to  accommodate more receptors (expands surface area)

o LTP alters synaptic structure and produces new synapses, causes growth of new  dendritic spines, which form synaptic connections with terminals of nearby axons ▪ How could process that begins postsynaptically (in dendritic spines) cause  presynaptic changes? Nitric oxide (NO) can communicate messages from  one cell to another

∙ NO is a soluble gas produced by arginine by activity of nitric oxide  synthase; once produced, NO lasts only a short time before it’s  

destroyed; thus, if it were produced in dendritic spines in HPF, it  could diffuse only as far as the nearby TBs, where it might produce  changes related to LTP induction

∙ NO is a retrograde messenger (from spine back to TB) that  

contributes to LTP formation – Ca-activated NO synthases is  

found in several regions of brain, including dentate gyrus and  

CA1/CA3 fields of HP

∙ NO acts by stimulating production of cyclic GMP, a second  

messenger, in presynaptic terminals

o LTP occurs in multiple stages:

▪ Early LTP (E-LTP) – membrane depolarization, release of glutamate,  NMDA receptor activation, Ca ion entry, CaMKII activation, movement of AMPA receptors into postsynaptic membrane

▪ Long-lasting LTP (L-LTP) – LTP that lasts more than a few hours,  requires protein synthesis

PKM-zeta has several effects  besides stimulating AMPA  receptor transportation into  postsynaptic membrane; it also  starts a positive feedback loop by  binding to Pin1, causing Pin1’s  deactivation, which guarantees that  its own synthesis will continue; the  self-sustaining PKN-zeta synthesis  makes L-LTP possible

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∙ Protein synthesis not required for establishing E-LTP, but it is  required for L-LTP, which normally occurs within an hour of E LTP establishment

∙ PKM-zeta – the gene responsible for PKM-zeta’s production is  constantly active (constantly pumps out mRNA in cell nucleus),  transcribing DNA of gene into mRNA, which is transported to  vicinity of dendritic spines

o Pin1, an enzyme, inhibits translation of PKM-zeta mRNA  into PKM-zeta protein

o Because mRNA has only a limited life, only a limited  amount of this mRNA accumulates

o LTP conditions are met – dendritic spine is depolarized,  glutamate released by TB, NMDA receptors open, Ca  enters spine, which activates CaMKII so it can bind to Pin1  to deactivate Pin1, which permits PKM-zeta synthesis

o PKM-zeta moves AMPA receptors laterally from dendritic  shaft into postsynaptic membrane of spine

o Addition of AMPA receptors produce first stage, E-LTP

Calcium acts as a  second messenger to  activate enzymes

o Role of calcium – high frequency stimulation triggers NMDAR activation, which  provides an increase in postsynaptic calcium, an essential trigger/second  messenger

▪ Rise of calcium activates α-CaMKII, PKA, and protein kinase C ▪ α-CaMKII auto-phosphorylation is necessary for maintenance of LTP  (inhibition of α-CaMKII blocks LTP)

▪ Synaptic transmission is strengthened during LTP via increase in  sensitivity of post-synaptic cell to glutamate

∙ Postsynaptic receptor sensitivity is increased by:

o α-CaMKII phosphorylates Ser on GluR1, a subunit of  

AMPAR

o LTP maintenance depends on GluR1 subunit of AMPA  

receptors and protein kinase C isoform M zeta

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o Trafficking of AMPA receptors to membrane and insertion  

into postsynaptic membrane is fundamental for increase in  

postsynaptic neuron’s responsiveness to glutamate (LTP)

∙ Removal of AMPA receptors from postsynaptic membrane is

fundamental for decrease in postsynaptic neuron’s responsiveness  

to glutamate (LTD)

o LTP accomplished through NMDA receptor activation and the insertion of  additional APMA receptors in postsynaptic membrane

▪ These changes serve to increase EPSP to postsynaptic cell

▪ Blockings steps involved in LTP impairs establishment of conditioned  emotional response (CER)

∙ CER established by pairing neutral stimulus (tone) with an  

aversive stimulus (brief foot shock)

∙ After these stimuli have been paired, the tone becomes a CS; when  it’s presented by itself, it elicits the same type of responses as the  

US does

∙ After being processed by auditory cortex, CS info (tone) reaches  

lateral nucleus of amygdala, which also receives info about US  

(foot shock) from somatosensory system

o These two sources of info converge in lateral nucleus,  

which means that synaptic changes responsible for learning  

could take place here

∙ Long-term depression (LTD) – long-term decrease in excitability of neuron to a particular  synaptic input caused by stimulation of TB while postsynaptic membrane is  hyperpolarized or only slightly depolarized

o Low-frequency stimulation of synaptic inputs to a cell decreases, rather than  increases, their strength

o Plays role in learning – neural circuits that contain memories are established by  strengthening some synapses and weakening others

o Involves decrease in the number of AMPA receptors in dendritic spines; AMPA  receptors are removed from spines in vesicles during LTD

o Receptors that produce LTD permit less Ca to enter cell, but if they’re stimulated  slowly over a long period of time, they permit the buildup of a modest but  prolonged increase in intracellular calcium

∙ Motor learning – learning to make a new response; establishment of changes (responses)  within motor systems following a stimulus

o Can’t occur without sensory stimulus from environment; the more novel the  behavior, the more neural circuits in the motor system that must be modified o Role of the cortex: motor learning involves periods of fast learning when motor  movements to be learned show rapid improvement during initial trials

▪ Memory of this motor behavior improved in period of time following  initial trials when no additional practice occurs

▪ Improvement made through consolidation and reconsolidation of memory,  sleep (REM/SWS)

o Role of BG: Parkinson’s (impaired on learning visually cued operant conditioning  task); Huntington’s (failed to learn sequence of button presses)

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∙ Perceptual learning – learning to recognize a particular stimulus; 1º function is the ability  to identify and categorize objects and situations

o Role of cortex: objected recognized by neuron circuits in extrastriate cortex ▪ Striate receives info from LGN of thalamus; after first level of analysis in  striate, sent to extrastriate; after analyzing particular attributes of visual  scene, sub-regions of extrastriate send results to next level

∙ Ventral stream for object recognition and dorsal stream for object

perception

▪ At later time, when same stimulus seen again and again, and the same  pattern of activity is transmitted to cortex, these circuits become active  again; this activity constitutes recognition of stimuli – read out/replay of  visual memory

o Recognition of stimulus occurs when sensory input activates these established  new neural circuits

▪ STM involves activity of these circuits that continue even after stimulus  has disappeared: learning to recognize friend’s face (extrastriate),  

recognizing she’s present involves activation of circuits, remembering 

she’s still in the room involves continuous activity of these circuits

o Role of extrastriate for specific STM types

▪ Fusiform face area – facial recognition, ventral stream

▪ Parahippocampal place area – place recognition, dorsal stream

o Role of prefrontal cortex to manipulate and organize to-be-remembered info,  devise strategies for retrieval, monitor outcome of these processes

∙ Relational learning – learning relationships among individual stimuli o Spatial learning – perception of spatial location

o Role of HP – HPF consists of dentate gyrus. CA fields, and subiculum ▪ Most important input to HPF is entorhinal cortex; neurons there have  axons that terminate in dentate gyrus, CA3, and CA1; cortex receives its  inputs from amygdala, limbic cortex, and all association neocortex  

regions, either directly or via two adjacent limbic cortex regions

▪ Outputs of HP system come from CA1 and subiculum, which are relayed  back through entorhinal, perirhinal, and parahippocampal cortices to same  association cortex regions that provide inputs

▪ HPF receives input from subcortical regions via fornix, which select and  modulate functions of HPF

∙ Fornix carries DA axons from VTA, noradrenergic axons from LC,  5-HT neurons from raphe nuclei, ACh axons from medial septum

∙ Fornix also connect HPF will mammillary bodies in posterior  

hypothalamus

o Memory consolidation – HPF and declarative memories

▪ SWS consolidates declarative memories, REM consolidates non

declarative memories

▪ HP receives info from sensory and motor association cortices and from  subcortical regions (BG/amygdala); processes info and modifies memories  that are consolidated there through efferent connections, which links them

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together that permits us to remember relationships among elements of  memories

▪ Acquisition of both major categories (episodic and semantic) of relational,  declarative memories requires HP participation  

▪ Without HPF, we’d be left with individual isolated memories without  linkage that makes it possible to remember episodes/context

▪ Episodic memories, which consist of integrated sequence of perceptual  memories, are located in sensory association cortex

▪ Semantic memories are not simply perceptual memories

∙ HPF and limbic cortex of MTL involved in consolidation and  

retrieval of declarative memories, both episodic and semantic; but  

semantic are stored in neocortex, the anterolateral temporal lobe

▪ Reconsolidation of memories – memories of vents as time goes on

∙ Established memories can be altered/connected to newer memories ∙ Memories are altered or connected to newer memories

▪ Role of hippocampal neurogenesis in consolidation – new neurons can be  produced in HP and olfactory bulbs, which form connections with neurons  in dentate gyrus and CA3; the number of new neurons produced in HP  decrease with age

∙ Antidepressants increase HP neurogenesis, stress hormones reduce o Dentate gyrus is one of the two places where adult stem cells can divide and give  rise to new neurons, which establish connections with neurons in CA3 field and  participate in learning and formation of new memories

∙ Reward pathways – involves VTA, NAC, and prefrontal cortex; when activated by a  rewarding stimulus (food, water, sex), information travels from VTA to NAC, and then  up to prefrontal cortex

o Involves the mesolimbic DA system; activation of the pathways tells the  individual to repeat what it just did to get the reward

▪ Also tells memory centers in brain to pay particular attention to all  features of the rewarding experience so it can be repeated in the future

o VTA – site of DA neurons, which tell organism whether an environmental  stimulus (natural reward, drug abuse, stress) is rewarding or aversive

o NAC – principle target of VTA DA neurons, mediates rewarding effects of  natural rewards and drugs of abuse

o Amygdala – helps organism establish associations between environmental cues  and whether that particular experience was rewarding or aversive

▪ Interacts with mesolimbic pathway to determine the rewarding or aversive  value of an environmental stimulus (natural reward, drug of abuse, stress) o LC – primary site of noradrenergic neurons, which modulate brain function to  regulate state of activation and mood of organism

o Raphe nuclei – primary site of serotonergic neurons, which modulate brain  function to regulate state of activation and mood of organism

o Frontal regions (prefrontal cortex, ACC) – provide executive control over choices  made in environment

▪ For example, whether to seek a reward

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o Hypothalamus – coordinates individual’s interest in rewards with body’s  physiological state; integrates brain function with physiological needs of  organism

o HP – declarative memories; along with amygdala, it establishes memories of drug  experiences, which are important mediators of relapse

∙ Spatial memory

o People with anterograde amnesia are unable to consolidate information about  location of rooms, corridors, buildings, roads, and other environment factors o Bilateral MTL lesions produce impairment in spatial memory

o Damage to right hemisphere – to right parahippocampal gyrus causes inability to  find a way around a new environment

▪ Right hippocampal formation becomes active when a person is  

remembering or performing a navigational task

o HP activated in subjects who followed spatial strategy and the caudate nucleus  (structure in BG that plays role in stimulus-response learning) was activated in  subjects who followed the response strategy

o Place cell – neuron that becomes active when the animal is in a particular location  in the environment; most typically found in the HPF

▪ Respond when animal is in a particular location, which implies that the HP  contains neural networks that keep track of the relationships among  

stimuli in the environment that define the anima’s location

o HPF, especially the right posterior HP, is involved in spatial memory; neurons  HPF reflect where an animal “thinks” it is

∙ Medial temporal lobe (MTL) memory system – the amygdala is comprised of a group of  nuclei located at the end of the temporal lobe

o Cortico-medial group (central nucleus) – olfactory bulb, hypothalamus, visceral  brain stem nuclei; autonomic function

o Baso-lateral group – thalamus and prefrontal cortex; conscious processes o Inputs: olfactory bulb, hypothalamus, thalamus, septal nuclei, VTA, and  parabrachial area project to cortico-medial group

▪ Thalamus, prefrontal cortex, temporal region, and cingulate gyrus project  to baso-lateral group (lateral nuclei)

o Outputs: most connections are reciprocal with input

▪ Amygdala (Ce) projects to PAG – CER (fear)

∙ PAG projects to brain stem regions involved in movement

o Amygdala and conditioned fear response – CS info is relayed from thalamus to  the lateral nucleus of amygdala, to central nucleus of amygdala, to PAG and  additional autonomic and somatic cell groups

▪ Lateral amygdala is the site of convergence of CS and US

∙ Amnesia – without memory; material lost will never be retrieved, memories not  perceived or not encoded

o Anterograde amnesia – inability to remember events experienced after a  disturbance to the brain (head injury, degenerative disease)

▪ Can remember events that occurred in past prior to brain damage

o Retrograde amnesia – inability to remember event that preceded a disturbance to  the brain (head injury, electroconvulsive therapy)

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▪ Usually includes a period of time just before brain disturbance occurred o Korsakoff’s syndrome – severe anterograde amnesia usually due to chronic  alcohol abuse and/or malnutrition (thiamine, vitamin B1 deficit)

▪ Preventable disease, sometimes treated with thiamine replacement,  

typically permanent

▪ Degeneration of mammillary bodies that are connected to HP via fornix ∙ Located at base of brain in posterior hypothalamus

▪ Alcohol interferes with intestinal absorption of thiamine, which produces  brain damage

∙ Henry Molaison (HM) – bicycle accident at 7, seizure activity at 10, major seizures at 16 o Intractable epilepsy that disrupted life by age 27; anticonvulsants did not work o To control epilepsy, HM underwent experimental procedure that removed medial  temporal lobe bilaterally

▪ Structures removed include HP, anterior hippocampal gyrus, amygdala o Post-surgery: well-adjusted, sensory and motor intact, high intelligence, STM  intact, didn’t have memories for events up to two years before surgery but the  older memories were intact

▪ Could not form new memories such as address, people he met, etc.  

o Had retrograde amnesia – normal memory for remove events (childhood), ~3  years for HM; had anterograde amnesia

o After death, his brain was studied, which enabled the identification of the medial  temporal lobe system – HP, perirhinal, entorhinal, and parahippocampal cortices ▪ Now know that HM’s severe memory deficit was due to fact that damage  was not restricted to HP, but damage that included parahippocampal gyrus  that resulted in severe deficits as opposed to HP damage alone

o He as able to sustain attention – could hold a conversation, intact digit span (7  digits), could maintain info for up to 15 min if used rehearsal and mnemonic  devices ???? this supported the idea of different memory systems (STM, LTM) ▪ He had preserved motor skill learning/procedural memory

∙ Declarative memory dependent on HP structures; non-declarative  

memory relies on different brain structures such as BG,  

cerebellum, amygdala, and neocortex

o He was impaired in recognizing the faces of people he met after MTL surgery, but  could recognize those he knew prior to surgery – MTL is not site for LTM storage o Could remember events from his early life prior to surgery – early memories  appear to remain intact unless damage extends to lateral temporal lobe and/or  frontal lobe

▪ HPF and associated structures important for formation of LTP and  

acquisition of new info

▪ Memory eventually dependent on neocortex and is independent of HP and  MTL

Chapter Fifteen: Neurological Disorders

∙ Tumor – cell mass whose growth is uncontrolled and serves no useful function; only cells  that are capable of division

o Malignant – cancerous, lacks distinct borders and may metastasize, a process by  which cells break off of a tumor and travel through vascular system, growing

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elsewhere in the body (serve as seeds for growth of new tumors in different  locations)

▪ Cell invades neighboring tissue, enter blood vessels, and metastasize to  different sites

o Benign – noncancerous, has a distinct border and can’t metastasize

▪ Grow only locally and can’t invade or metastasize

o Gliomas – typically malignant and develop fast

▪ Malignant gliomas contain tumor initiating cells – cells that originate from  transformation of neural stem cells; they rapidly proliferate and give rise  to a glioma

o Tumors are removed surgically first; some are completely removed by surgery, if  not, then chemotherapy, radiation, or bevacizumab (inhibitor of angiogenesis) o Damage brain tissue by compression and infiltration – compression can directly  destroy brain tissue or can do so indirectly by blocking CSF flow, causing  hydrocephalus

▪ Malignant tumors can cause compression and infiltration – as they grow,  they invade surrounding regions and destroy cells

o Tumors don’t arise from nerve cells, which are not capable of dividing; they arise  from other cells found in the brain or from metastases originating elsewhere

Type of Tumor

Tumors arise from

Gliomas

Glioblastoma  

multiformae

Poorly differentiated glial cells

Astrocytoma

Astrocytes

Ependymoma

Ependymal cells from ventricles

Oligodendrocytoma

Oligodendrocytes

Medulloblastoma

Cells in roof of 4th ventricles

Meningioma

Cells of the meninges

Neurinoma

Schwann cells or cells of connective tissue  covering cranial nerves

Angioma

Cells of blood vessels

Pinealoma

Cells of pineal gland

Pituitary  

adenoma

Hormone secreting cells of the pituitary  gland

∙ Seizures – period of sudden, excessive activity of cerebral neurons

o Convulsion – violent sequence of uncontrollable muscle movements caused by  seizure; not all seizures cause convulsions

o Causes – scarring due to injury, stroke, developmental abnormality, high fever,  alcohol/barbiturate withdrawal, genetic factors (genes involved with production of  ion channels)

o Consequences – brain damage (particularly HP damage), damage correlated with  number and severity of seizures

o Partial seizures – focal, local; begins at a focus and remains localized, not  generalizing to rest of brain

▪ Simple partial seizures – starting from a focus and remaining localized;  doesn’t produce loss of consciousness

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∙ With motor systems – focal motor without march, focal motor with march (Jacksonian), versive, postural, phonatory (vocalization or  arrest of speech)

∙ With somatosensory or special sensory systems – somatosensory,  visual, auditory, olfactory, gustatory, vertiginous

∙ With autonomic symptoms or signs (including epigastric, pallor,  sweating, et cetera)

▪ Complex partial seizures – partial, starting from a focus and remaining  localized; produces loss of consciousness

∙ With psychic symptoms (disturbance of higher cerebral function) – impairment of consciousness and classified as complex partial

o Dysphasic, cognitive (distortions of time sense), dysmnesic  

(deja-vu), affective (fear), illusions, hallucinations

∙ Simple partial onset followed by impairment of consciousness ∙ Impairment of consciousness at onset – with impairment of  

consciousness only, with automatisms

▪ Partial seizures (simple or complex) evolving to secondarily generalized  seizures

o Generalized seizures – involves most of brain

▪ Non-convulsive (absence) – typical, 3/sec spike and slow wave complexes  on EEG, idiopathic; atypical, <3/sec spike and sow wave complexes,  occurs with severe symptomatic epilepsies

∙ Absence seizures – children; periods of inattention that aren’t  subsequently remembered, “petit mal seizure”

▪ Convulsive – myoclonic, clonic (rhythmic), tonic (muscles contracted),  tonic-clonic (grand mal), atonic (drop attacks, loss of muscle tone,  temporary paralysis)

∙ Grand mal – most severe form, generalized, tonic-clonic

o Warning symptoms – changes in mood, sudden jerks of  

muscular activity upon awakening (people normally  

experience this before falling asleep), aura (occurs few  

seconds before seizure, caused by neuron excitation  

surrounding a focus)

∙ Tonic phase – first phase of grand mal in which all of patient’s  skeletal muscles are contracted; at this point, patient is unconscious ∙ Clonic phase – patient shows rhythmic jerking movements; quickly  at first, then slowly, eyes roll, facial muscle contraction, tongue  

biting; convulsions occur

o Intense activity of autonomic NS causes sweating,  

salivation; after short time period, muscles relax, then  

regular breathing occurs; person may fall into unresponsive  

sleep lasting a few minutes, then awaken and fall asleep  

again, lasting a few hours

∙ Status epilepticus – patient undergoes series of seizures without  regaining consciousness; causes significant HP damage; damage

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caused by excessive glutamate release during seizure, which  

causes glutamate excitotoxicity

Type

Duration

Seizure Symptoms

Postictal (post-seizure)  symptoms

Simple  

partial

90  

seconds

No loss of consciousness, sudden jerking,  sensory phenomena

Possible transient  

weakness or loss of  sensation

Complex  

partial

1 to 2  

minutes

May have aura, automatisms (such as lip  smacking, picking at clothes, fumbling),  unaware of environment, may wander

Amnesia for seizure  events, mild to  

moderate confusion,  sleepy

∙ Stroke – cerebrovascular accidents, risk increases with, high blood pressure, smoking,  diabetes, high cholesterol (LDL)

o Hemorrhagic stroke – rupture of cerebral blood vessel; usually malformed vessel  or one weakened by high blood pressure  

▪ Blood that leaks out of defective vessel accumulate within brain, putting  pressure on surrounding tissue and damaging it

▪ Treatment – if caused by high blood pressure, medication given to  

decrease blood pressure

∙ If caused by weak/malformed vessels, surgery used to seal off  

faulty vessels to prevent another hemorrhage

o Ischemic stroke – occlusion of a vessel and interruption of blood supply to region  of brain; caused by thrombi (clots forming within vessel that may occlude it) or  by embolus (piece of matter (clot, fat, bacteria) that dislodges from origin site and  occludes artery, leads to stroke in brain)

▪ Ischemia – loss of blood flow

▪ When blood supply to brain region is interrupted, oxygen and glucose in  that region are quickly depleted

∙ Consequences – Na/K transporters stop functioning, neural  

membrane depolarize, causing glutamate release; activity of  

glutamate receptors increases inflow of Na and causes cells to  

absorb excessive Ca amounts through NMDA channels; the  

presence of excessive Na and Ca within cells is toxic

o Intracellular Na causes cells to absorb water, causing  

inflammation that attracts microglia and activates them,  

causing them to become phagocytic, causing destruction of  

injured cells

▪ Inflammation also attracts white blood cells, which  

can adhere to capillary walls near ischemic region  

and obstruct them

o Excess Ca amount activates Ca-dependent enzyme, which  

destroys molecules that are vital for normal cell functioning

o Damaged mitochondria produce free radicals that destroy  

nucleic acids, proteins, and fatty acids

▪ Immediate cause of neuron death is presence of excessive amounts of  glutamate; damage produced by blood flow loss is an excitotoxic lesions

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∙ Blood supply blocked→ Na/ K transporter fails→ membrane  

depolarization → glutamate release → increased Na+ influx &  

Ca²+ absorption → swelling from water absorption → phagocytic  

microglia

∙ Ca²+→ Ca²+ dependent enzymes→ destroy molecules

∙ Damaged mitochondria → free radicals → destroy nucleic acids,  

proteins, & fatty acids

▪ Treatment – if caused by thrombus, dissolve/physically remove blood clot  or use anticoagulants

∙ If embolus broke away from bacterial infection, antibiotics used to  suppress infection

o Pharmaceutical treatment for stroke/general treatments

▪ Tissue plasminogen activator (tPA) – clot-dissolving drug that works if  given within three hours of stroke

∙ tPA is an enzyme that causes dissolution of fibrin, a protein  

involved in clot formation

∙ Has toxic effects in CNS, tPA is potentially neurotoxic if it’s able  

to cross BBB and reach interstitial fluid

∙ tPA increases excitotoxicity, further damages BBB, cause cerebral  hemorrhage

∙ In cases in which tPA quickly restores blood flow, BBB is less  

likely to be damaged and enzyme will remain in vascular system,  

where it’ll do no harm

▪ Desmodus rotundus plasminogen activator (DSPA) – AKA desmoteplase,  clot-reducing treatment that’s an anticoagulant enzyme (from vampire  bats); causes no excitotoxic injury when injected directly in brain

∙ Restores blood flow and symptoms if given within 9 hours of  

stroke

▪ Mechanical embolectomy

∙ Corkscrew system – corkscrew is delivered to brain via catheter  

and placed behind blood clot; balloon is inflated in neck, shutting  

off blood flow to brain as the clot is pulled and sucked out of brain

∙ Suction – utilizes flexible catheters and “cleaning wires” that are  

used to directly suck blood clot from brain

o Less chance of causing intracerebral bleeding

▪ Carotid endarterectomy – surgical removal of plaque from artery

▪ Carotid stenting – artery is expanded and help open by implanted stent ∙ Traumatic brain injury (TBI) – blow or jolt to head, or penetrating head injury that  disrupts function of brain”

o Severity of such an injury ranges from:

▪ Mild (brief change in metal status) – short-term problems with  

independent function

∙ Headache, nausea/vomiting, dizziness, loss of balance, tinnitus,  

difficulty concentrating, sleep pattern changes, loss of sense of  

smell

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▪ Severe (extended period of unconsciousness or amnesia after injury) – long-term problems with independent function

∙ All of mild symptoms plus – seizures (HP sclerosis associated with  intractable seizure disorder in moderate to severe patients), fatigue  

to stupor to coma, slurred speech, limb weakness or numbness,  

confusion, restlessness/agitation, spasticity

o Head and brain injuries – injuries that are anatomically uncomplicated involving: ▪ Scalp injury, skull fracture, epidural and subarachnoid hemorrhage,  cerebral contusion, diffuse TBI, penetrating head injury, and child abuse o Primary traumatic injury – traumatic effects following head trauma involves: ▪ Receptor dysfunction, free-radical effects, calcium damage, cell  

dysfunction, cell death

o Secondary traumatic injury – neuropathological damage subsequent to head  trauma involves:

▪ Intracranial hypertension, vascular failure, ischemia, endogenous brain  defenses, axonal injury, neuronal injury

o People having greatest risks: 0-4 y/o, 15-19 y/o; combat veterans, athletes (CTE),  motorcyclists without helmets, skiers without helmets

o Chronic traumatic encephalopathy (CPE) – neurodegeneration due to repeated  head trauma; abnormal tau protein accumulation in cortex

▪ Reduced brain volume, enlarged ventricles; corpus callous, cortex, limbic  system are damaged, resulting in deficits in executive control and mood  regulation

∙ Parkinson’s disease – caused by degeneration of nigrostriatal system (the DA-secreting  neurons of substantia nigra that send axons to BG)

o Primary symptoms – muscular rigidity (joints appear stiff), slowness of  movement, resting tremor, postural instability

▪ Motor deficits are a deficiency of automatic, habitual responses caused by  damage to BG

▪ Tremor and rigidity are not the cause of slowness

o Brain shows near disappearance of nigrostriatal DA neurons; the surviving ones  show Lewy bodies – abnormal circular structure with dense core consisting of α synuclein protein, found in cytoplasm of nigrostriatal neurons

o Akinesia – difficulty initiating movements; associated with decreased activation  of supplementary motor area (SMA) and tremors associated with abnormality of  neural system involving pons, midbrain, cerebellum, thalamus

o Caused by mutation of gene on chromosome 4; this gene produces α-synuclein,  which is involved in synaptic plasticity and is normally found in presynaptic  terminals

▪ Abnormal α-synuclein becomes misfolded and forms aggregations – Lew  bodies’ core consist of this aggregation along with neurofilaments and  synaptic vesicle proteins  

▪ Mutation produces toxic gain of function because it produces a protein  that results in effects that are toxic to cell

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▪ Mutations that cause toxic gain of function are dominant because toxins  produced whether one or both members of chromosome pairs contain  

mutations

o Caused by mutation of gene on chromosome 6, which produces parkin; this  causes loss of function, which makes it recessive

▪ Parkin – transfers defective/misfolded proteins to proteasomes, which  destroy them; tags abnormal proteins with ubiquitin

▪ Causes high levels of defective proteins to accumulate in DA neurons,  damaging them

o Occurs in people without family history of disease, caused by toxins in  environment, faulty metabolism, or unrecognized infectious diseases

▪ All these chemicals inhibit mitochondria function, which leads to  

aggregation of α-synuclein misfolded, especially in DA neurons

o Drug treatment – L-dopa to alleviate symptoms; deprenyl slows disease  progression and decreases symptoms, but doesn’t slow degeneration of DA  neurons

o Surgical – damage to GPi may relieve symptoms

o Deep brain stimulation of STN to suppress tremors

∙ Huntington’s disease – caused by degeneration of caudate nucleus and putamen o Causes uncontrollable movements, jerky limb movements, involuntary o Progressive, includes cognitive and emotional changes; death

o First signs of degeneration occur in putamen in GABAergic medium spiny  inhibitory neurons; loss of this control leads to involuntary movements o Hereditary disorder caused by dominant gene on chromosome 4; deficit identified  as CAG repeats, which produces huntingtin (Htt)

o Abnormal Htt misfolds and forms aggregations that accumulate; the abnormal Htt  causes harm

o Mutation causes disease through toxic gain of function

o Cause of death of neurons is apoptosis (cell suicide) – abnormal Htt may trigger  apoptosis by impairing ubiquitin, a protease system function

o No treatment; HAPP 1 – antibody that targets Htt

∙ Dementia – loss of cognitive abilities such as memory, perception, verbal ability, and  judgment; caused by multiple strokes and Alzheimer’s

o Alzheimer’s – most common form of dementia; causes progressive memory loss,  motor deficits, eventual death

▪ Produces degeneration of HP, entorhinal cortex, neocortex, nucleus  basalis, locus coeruleus, and raphe nuclei

▪ Brain develops amyloid plaques – extracellular deposits that consist of  dense core of β-amyloid , surrounded by degenerated axons/dendrites,  along with activated microglia and reactive astrocytes, which are involved  in destruction of damaged cells

∙ Eventually, phagocytic glial cells destroy degenerated axons and  

dendrites, leaving only core of β-amyloid

∙ Production of β-amyloid gene encodes β-amyloid precursor protein  (APP) production, which is then cut apart in two places by  

secretases to produce β-amyloid

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o β-secretase first cuts the “tail” end of off; γ-secretase then  cuts the “head” off

▪ Brain also develops neurofibrillary tangles, which consist of dying  neurons that contain intracellular accumulation of twisted filaments of  hyper-phosphorylated tau protein

∙ Tau protein serves as a component of microtubules, which provide  the cell’s transport mechanisms

∙ During progression of the disease, excess phosphate amounts  become attached to tau strands, changing molecules structure o Abnormal filaments are seen in soma and proximal  

dendrites of pyramidal cells in cerebral cortex, which  

disrupts transport of substances within cell

o Eventually, the cell dies, leaving behind tangle of protein  filaments

▪ ACh neurons in basal forebrain are first cells to be affected ▪ Causes – hereditary, TBI, education level

▪ Treatment – ACh inhibitors such as donepezil, Exelon, galantamine, and  NMDA receptor antagonist (Namenda)

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