Unit 10: Neural Development and Plasticity

101-20 Neural Development - BN Ch. 7.1-7.3 (p. 199-217)

1. List (in general sequential order) and briefly describe each of the eight processes of neural development.
   1. Neurulation - neural tube develops from the ectoderm
   2. Neurogenesis - mitosis produces neurons from non-neuronal cells
   3. Cell migration - cells move to establish distinct neural cell populations
   4. Differentiation - cells become distinct types of neurons or glial cells
   5. Synaptogenesis - establishment of synaptic connections
   6. Apoptosis (programmed cell death) - selective death of many neurons
   7. Synapse rearrangement - loss (synaptic pruning) and fine-tuning of synapses
   8. Myelination - glial cells wrap axons in myelin sheaths
2. Define and relate to one another the key terms in the process of neuralation (ectoderm, neural plate, neural groove, neural crest, and neural tube) and briefly describe two disorders resulting from failure of neural tube closure.
   1. Neural plate: thickening of the ectoderm that becomes the central nervous system
   2. Ectoderm: outer layer
   3. Neural crest: the ridges of the ectoderm
   4. Neural groove: thickening cell layers of the neural plate form the neural groove
   5. Neural tube: forms from the fusion of the ridges of the neural crest
3. Define and relate to one another the key terms in the process of neurogenesis during development (mitosis, ventricular zone, progenitor cells, neuroblasts) and indicate region(s) of adult neurogenesis.
   1. Neurogenesis: progenitor cells divide through mitosis in the ventricular zone (results in neuroblasts that will migrate and differentiate into neurons or glial cells)
4. Explain how new neurons migrate during corticogenesis, including types of glial cells and molecules important in that process.
   1. During cell migration: which occurs formation of cerebral cortex (corticogenesis) proceeds from inner to outer layers, the radial glial cells act as guides for cells to migrate along and cell adhesion molecules (CAMs) promote adhesion to radial glia
5. Explain the process by which neurons differentiate, referencing the example of spinal motor neuron differentiation, and briefly discuss implications for using neural stem cells as therapeutic medical treatments.
   1. After the cells migrate to reach thor destinations, neurons differentiate into appropriate cell type of their location, they begin to express particular genes in order to make the proteins they need, differentiation allows neuron (or glial) to acquire its specific appearance and function
      1. Cell-cell interactions: developmental process in which one cell affects differentiation of another nearby cell, cells in developing brain send signals that shape development of the other surrounding cells in neural development
         1. Induction is influence of one set of cells on the fate of nearby cells (type of cell-cell interaction) ex: cells in notochord release protein (sonic hedgehog) that induces some cells in ventral horn to become spinal motoneurons
      2. Neural stem cells: undifferentiated neural progenitor cells that can assume a number of possible cell fates, undifferentiated neural stem cells placed in particular brain region may be coaxed to differentiate into the appropriate cell type
6. Explain how growth cones find their target cells during process outgrowth, including definitions of the key terms lamellipodia, filopodia, CAMs, chemoattractants, and chemorepellants. Characterize the timing and result of developmental synaptogenesis.
   1. Process outgrowth: growth of axons and dendrites, extensions (processes) emerge from growth cones at the tips of axons and dendrites to make contact with target cells
      1. Growth cones (filopodia): fine finger-like outgrowths emerging from growth cones, filopodia pull the growth cone in a particular direction by adhering to the environment via cell adhesion molecules (CAMs)
   2. Synaptogenesis: formation of synapses, synapses form rapidly on dendrites and dendritic spines, spines proliferate after birth and connections are affected by experience, neuronal cell bodies increase in volume to support dendritic trees, new synapses continue to be formed throughout life
   3. Growth cone chemotaxis: growth cones are guided by chemicals released by target cells (chemotaxis)
      1. Chemoattractants: chemical signals that attract certain growth cones
      2. Chemorepellents: repel certain growth cones so they also "know" where not to go
7. Explain why many neurons undergo apoptosis during development (and how many other neurons and prevented from undergoing apoptosis). Make sure to define key biochemical factors that promote or inhibit apoptosis and describe how the Diablo pathway leads to apoptosis.
   1. Neurons compete for neurotrophic factors released by target cells, without enough they die
   2. Neurotrophins taken up by the axons of innervating neurons keep neurons alice by aborting the default apoptotic program, common neurotrophins are nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)
   3. By overproducing neurons followed by apoptosis, ensures there are a proper number of neurons to innervate target organs
   4. Diablo: mitochondria releases protein diablo (which binds to and blocks inhibitors of apoptosis proteins - IAPs which normally inhibit the caspases)
      1. Caspases are proteases that cut up proteins and DNA, without inhibition of caspases they dismantle cell
   5. Bcl-2 blocks apoptosis by preventing Diablo release
8. Briefly describe the process of synapse rearrangement (synaptic pruning) and factors influencing it.
   1. Synaptic rearrangement: refines synaptic connections as they are added, removed, and refined (pruning due to net loss of synapses from late childhood through mid-adolescence), neurons compete for synaptic connections to target cells, major influence on synaptic growth/survival is neural activity resulting from experience (active synpases tend to outcompete inactive synapses), neurotrophic factors like BDNF may also contribute, more synapses re formed than needed and then roughly half of initially formed synapses die (some stand in reserve to injury or new skills)
9. Explain the sculpting metaphor (Kolb, 1989) of neural development.
   1. Brain over produces neurons and synapses followed by apoptosis and synaptic pruning, experience, hormones, and genetic signals shape the brain as a sculptor chisels away at stone
10. Describe the importance of myelination and the implications of demyelinating disorders such as multiple sclerosis.
    1. Myelination by glial cells (oligodendrocytes in CNS, Schwann cells in PNS) continues through adulthood, increases conduction speed and efficiency with which axons send messages, MS destroys myelin thereby disrupting sensory and motor function
    2. Yelination through adulthood in hierarchy gradient (peripheral nerves myelinated at birth, sensorimotor cortices mature early in life, cortical association areas continue myelination process through adulthood)
11. Describe trends for regional differences in the timing of neurodevelopmental maturation (i.e., processes of synaptogenesis, synaptic pruning, and myelination) in the brain and relate these trends to maturation of behavioral and cognitive abilities.
    1. Neural structures underlying the concurrent-discrimination task mature sooner than those underlying the nonmatching-to-sample task
    2. Cortical thinning process continues through maturation, reaching prefrontal cortex last which may contribute to impulsivity in childhood and adolescence

101-21 Neuroplasticity: Sensorimotor Development and Plasticity - BN Ch. 7.3-7.4 (p. 217-225) & BN Ch. 8.3 (p. 250-251)

1. Describe various influences on synaptogenesis, including genetically determined (chemoaffinity or experience-independent), experience-expectant, and experience-dependent influences, and when during the lifespan they predominate.
   1. Genetically determined: chemoaffinity hypothesis (during early prenatal development, neurons or their axons and dendrites are drawn toward a signaling chemical that indicates the correct pathway - retinotopic mapping in superior colliculus are driven by chemical gradients) and experience dependent (late prenatal and postnatal development and fine-tuning of connections proceeds in an activity-dependent manner - development of ocular dominance slabs in layer IVC of primary visual cortex depend upon visual input)
   2. Experience expectant: ocular dominance histogram shows response preferences of neurons in visual cortex to stimuli presented to either eye
2. Describe some of the neural effects of living in an enriched environment.
   1. Heavier and thicker cortex, enhanced cholinergic activity, more dendritic branches and spines on cortical neurons, larger cortical synapses more neurons in hippocampus, and enhanced recovery from brain damage
3. Briefly explain Hebb's co-activity principle, and relate it to Hebbian plasticity and Hebbian synapses.
   1. Co-activity principle: fire together, wire together (A and B must both be active at the same time)
   2. Hebian learning: when a presynaptic and postsynaptic neuron are both active the connection between neurons will strengthen at a hebbian synapse
4. Describe evidence that illustrates plasticity of sensory cortices during development from correlational (i.e., congenitally blind people) and experimental (i.e., blinded opossums) studies. Explain how this evidence supports the role of experience-expectant influences on synaptogenesis.
   1. Correlational: neuroimaging studies found visual association cortical areas more activated in blind people when engaged in Braille reading and other tactile tasks
   2. Experimental: different cortical mapping was observed in opossums blinded at birth and showed unique multimodal areas and responded to combination of auditory and tactile stimuli in what would be visual cortex
5. Describe the findings from the monocular visual deprivation, binocular deprivation, and one eye deviated experiments in kittens (visually represented with ocular dominance histograms) and provide a neurobiological explanation for these findings.
   1. Monocular visual deprivation: temporarily covering one eye disrupts ocular dominance where cat and visual cortical neurons only respond to stimulation of the eye that was not previously covered (histogram shows uneven connections)
      1. When one eye covered, the other open the eye open will fire synchronously and drive postsynaptic neuron to fire which will strengthen synapses to drive postsynaptic cells, when covered there is no stimulations so cells fire at random which cause postsynaptic neuron to fire and loses ineffective inputs and therefore hebbian synapses are lost
   2. Binocular deprivation: no imbalance if both eyes were deprived, though fewer binocular cells and some atrophy
   3. One eye deviated: misalignment of eyes leads to extreme ocular dominance
6. Describe the findings from the experiments with horizontally-experienced and vertically-experienced cats, where kittens experienced environments with only horizontal contours or only vertical contours, and provide a neurobiological explanation for these findings.
   1. Sensitive period the same, raising in an environment with only horizontal stripes or vertical disrupts orientation selectivity, they will only respond to the orientation they experienced
   2. On center horizontal: stimulated simultaneously in horizontal environment
   3. On center vertical: random asynchronous activity in horizontal environment
7. Define the term sensitive period and explain the survival benefit of extreme developmental plasticity during this time.
   1. Deprivation only has strong effects during sensitive period of 3 weeks to 3 months for cats
8. Describe evidence for experience-dependent plasticity of sensorimotor cortices in monkeys (i.e., rotating disk), rats (i.e., precise reaching and grasping task), and humans (i.e. professional and amateur musicians).
   1. Musicians: professional keyboard players have thicker gray matter in task-relevant sensorimotor cortical areas
   2. rats: expanding cortical areas in green areas of digits and wrist into those previously associated with shoulder and elbow
9. Explain the phenomenon of phantom limbs seen in human amputees and how using a mirror box can relieve phantom limb pain.
   1. After loss of limb, cortical regions take over and others expand, and lack of sensory input from hand allows cortical neurons to become innervated by neighboring cortical neurons, the mirror seems to show that both limbs are intact and subject is asked to command both hands to move in symmetry and observe them and illusion of controlling missing hand relieves the phantom sensation that missing hand is painfully clenched shut (brain sees missing hand and associates it with pain)

Unit 11: Memory Systems

101-22 Memory Systems I: The Hunt for the Engram - BN Ch. 17.1-17.3 (p. 557-575) -or- ONI Ch. 13.1-13.2 (p. 1-13)

1. Provide specific and general formal definitions of learning and memory, define the term engram (memory trace), and define the systems problem and molecular problem in the neuroscience of memory.
   1. Learning: process of acquiring new information
   2. Memory: ability to store and retrieve information and the specific information stored in the brain
   3. Engam: record of a learning experience (site of synaptic change representing the memory)
   4. Memory systems: brain damage can impair learning and memory, and reveal different types of memory
   5. Molecular problem: how is information stored in the brain? (how do neurons change their structure and function as a result of experience, information storage and synaptic change)
2. Describe the multiple memory stores and processes in the Atkinson-Shiffrin information-processing model of cognition and memory, including sensory or iconic memory, short-term (STM) or working memory (WM), and long-term memory (LTM). Describe the flow of information via the processes of attention, encoding, storage and consolidation, and retrieval as defined by Dr. Gobel and in the slides.
   1. Sensory memory: briefest memory store, briefly holding sensory impressions
   2. Short-term memories (STMs): usually ast only for seconds (30) or throughout rehearsal and quickly lost unless encoded into LTM
   3. Working memory (WM): contains short term memories
   4. Long term memory: more permanently stored memories (days to years) can be retrieved in the future (encoded short term, and then retrieval)
   5. First you are paying attention to something which then goes into your WM or STM and encodes into your LTM which then acts as storage and consolidation and are able to retrieve
3. Explain the view of associationism as formally described by William James.
   1. Experience links ideas in the mind, remembering one idea would spread along links and retrieve a complex episode, links are physically formed in brain and providing an early link between psych and neuro
4. Briefly describe historical approaches in the hunt for the engram and define the principles Lashley derived from his findings: equipotentiality and mass action; explain why these principles are not truly accurate.
   1. Equipotentially: all parts of the cortex contribute equally to complex behaviors such as learning and nay part of the cortex can substitute for any other (failed to localize the engram)
   2. Mass action: cortex works as a whole, the more cortex the better
      1. Limitations: only lesioned cerebral cortex, running a maze might be learned in multiple ways because memory isn’t unitary
5. Summarize the case study of H.M., including the purpose for his surgery, the parts of his brain that were surgically removed, and his cognitive deficits (what memory abilities and processes were impaired), as well as those abilities that were preserved.
   1. Surgery to treat severe epilepsy where medial temporal lobes were removed on both sides (hippocampus, amygdala, and nearby cortical areas), relieve intractable temporal lobe epilepsy
   2. Profound anterograde amnesia and graded retrograde amnesia
   3. STM and WM were preserved as long as he was attending to and working with the information
   4. Impaired encoding process (working memory did not transfer to LTM)
6. Describe evidence of impaired LTM and preserved WM for those with medial temporal lobe (MTL) damage using serial position curves. Indicate what these results indicate about the impairment of memory processing following MTL damage.
   1. Primacy effect: higher performance for items at the beginning of a list (LTM), impaired in H.M. and others with amnesia
   2. Recency effect: shows better performance for items at end of the list (STM/WM), preserved in H.M. and others with amnesia
7. Differentiate between declarative memory and nondeclarative memory, provide a dissociation between the two for those with MTL damage, and explain what those findings indicate about that nature of long-term memory
   1. Declarative: things you know that you can tell others, MTL dependent, tested readily through talking
   2. Nondeclarative (procedural): things you know that you can show by doing, independent of MTL, like learning a skill

101-23 Memory Systems II: Declarative Memory and Consolidation - BN Ch. 17.1-17.3 (p. 557-575) -or- ONI Ch. 13.1-13.2 (p. 1-13)

1. List the subregions of the medial temporal lobe (MTL) and characterize their basic connections between one another and with the rest of the cortex.
   1. Encoding of declarative memories depends on MTL (hippocampus, surround cortex regions like entorhinal, perirhinal, and parahippocampal cortices, amygdala sometimes considered part of MTL)
2. Describe findings from human neuropsychology (Rey-Osterrieth complex figure) and behavioral tasks with animals (delayed non-matching-to-sample task, radial arm maze) that link the MTL to episodic declarative memory, including a description of place cells in the hippocampus.
   1. Delayed nonmatching-to-sample task: monkeys must choose object that wa not seen previously (measure LTM with long delay), test of object recognition memory that requires monkeys to “declare” what they remember
   2. Radial arm maze: healthy rats learned to find food at end of all arms with few errors, rats with hippocampal lesions made many errors, losing track of which rewards they had already eaten
   3. Spatial memory: place cells in hippocampus become active when in particular location in environment or moving toward the location, and fire when in specifical spatial location or place field within local environment, can be remapped in other environmental contexts, evidence from electrode recordings (rodents when they explore environment and human neuropsychology patients as they explore VR town)
3. Differentiate between anterograde amnesia and retrograde amnesia, describe the pattern of amnesia usually seen in those with MTL damage (such as H.M. and E.P.) and in experimentally lesioned animals, and explain how this Ribot gradient provides evidence for a systems consolidation period.
   1. Ribot gradient: evidence for a systems consolidation period, those with anterograde amnesia may also experience graded retrograde amnesia where they have no ability to retrieve recent memories prior to injury, but remote memories are intact
   2. E.P could copy but could not draw again after delay from memory
   3. Retrograde: before injury anterograde: after injury memory loss
4. Explain the standard model of systems consolidation for episodic declarative memory (including processes of encoding, storage, and retrieval).
   1. Standard consolidation theory: episodic memory is distributed representation of components in sensory and association cortices where during learning, storage, and retrieval of recent memories the MTL serves as a “hub” binding these cortical components and overtime however cortical representations strengthen their corticocortical connections and memories become MTL-independent (older memories are consolidated, newer are not fully)
5. Describe a double dissociation between declarative and procedural (nondeclarative) memory in rats with experimental brain lesions (hippocampal vs. basal ganglia lesions) using different versions of the radial arm maze, and explain the results.
   1. Declarative: all arms have food, but no markings. Rats search baited arms, remembering which have been visited and when (declarative) (damage to MTL impairs declarative but spares procedural)
   2. Procedural: illuminated version, half arms are lit indicated there is food, animals need to learn that light means food (basal ganglia damage impairs skill learning, but spares declarative memory)
6. Diagram the taxonomy of memory systems, including subtypes of declarative and nondeclarative memory, along with their general brain substrates.
   1. Episodic memory: detailed memory for specific events embedded in spatiotemporal context (declarative)
   2. Semantic: generalized memory for facts and general knowledge, devoid of context (declarative)
   3. Skill learning, priming (more likely to use a word you heard recently), conditioning (salivating when you see food) all nondeclarative

Unit 12: Neurobiology of Memory and Memory Disorders

101-24 Neurobiology of Memory - BN Ch. 17.4-17.5 (p. 576-588) -or- ONI Ch. 13.3-13.4 (p. 14-24)

1. Define the term neuroplasticity and describe various physiological and structural changes that may underlie synaptic changes that store information.
   1. Neuroplasticity: ability of nervous system (neurons and neural circuits) to change in response to (be remodeled by) experience and/or environment
   2. Physiological changes: at synapses (pre or postsynaptic) may store information, changes include increased/decreased NT release, number and/or effectiveness of receptors, rate of inactivation of transmitters and modified modulatory inputs from other neurons might increase or decrease NT release
   3. Structural changes: at synapse may support long-term storage where new synapses can form or existing synapses be eliminated with learning and learning and training can bring about synaptic reorganization
2. Recite or paraphrase Hebb's key quote summarizing his connectionist theory, relate this to the co-activity principle and Hebbian learning, and explain how Hebbian synapses could account for memory storage.
   1. Connectionist theory: memories stored via changes in connections among neurons where hebbian synapse could act together to store memory
   2. Neurons that fire simultaneously strengthen their synaptic connections to each other (fire together, wire together)
3. Define long-term potentiation (LTP) and describe the result of LTP.
   1. Long-term potentiation (LTP): well-studied synaptic mechanism of hebbian plasticity which is a stable and enduring increase in synaptic effectiveness
   2. Same synaptic input (AP in presynaptic neuron) results in larger output (larger EPSP in postsynaptic neuron), various forms occur during many types of learning
4. Describe the experimental paradigm and electrophysiological recordings for hippocampal associative LTP in the Schaffer collateral pathway. Explain the principle of specificity in LTP and how potentiated synapses behave like Hebbian synapses.
   1. Measure EPSP to weak test stimulus before HFS, then high-frequency stimulation or tetanus which is a burst of strong electrical stimulation that triggered a train of APs, and measure EPSP to weak test stimulus after HFS
   2. After brief tetanus, EPSP response increases markedly and remains high, the greater responsiveness is called long-term potentiation, only synapses that were active during LTP induction are potentiated
   3. Behave like hebbian synapses because Cell A repeatedly takes part in firing cell B, and tetanus drives repeated firing (in A) and postsynaptic targets fire repeatedly due to the stimulation (in B), A’s efficiency increased as cells firing B are increased, synapses are stronger than before larger EPSP to test stimulus
5. Explain how LTP is first induced (i.e., how LTP induction activates a coincidence-detector, what that coincidence-detector is, and the result of activating that coincidence-detector).
   1. NMDA receptors are “coincidence-detectors” that allow calcium influx when two events happen concurrently where the binding of glutamate opens NMDA ion channel and strong postsynaptic depolarization relieves the magnesium block
6. Explain the processes of LTP-related synaptic change at the molecular level, including the signaling cascades activated after LTP induction, short-term effects of early LTP and long-term effects of late LTP at the synapse, and how these changes strengthen the synapse.
   1. Large calcium influx activates certain intracellular enzymes called protein kinases in signaling cascades like calcium-calmodulin kinase II (caMKII)
   2. Short term LTP: recruits existing AMPA receptors and inserts them into the cell membrane of the active synapse, increases conductance of membrane-bound AMPA receptors to sodium ions, and causes more AMPA receptors to be produced and inserted in the postsynaptic membrane (all increase synaptic sensitivity to glutamate, strengthening synapse) postsynaptic cell releases retrograde transmitters that makes presynaptic neuron release more glutamate which strengthens further (more NT released, more AMPA receptors present in membrane, increased AMPA receptor conductance)
   3. Long term: activated protein kinases also trigger protein synthesis, where kinases activate cAMP responsive element-binding protein (CREB) and CREB binds to cAMP responsive elements (CREs) in DNA promoter regions, thus altering the transcription rate of particular genes and then up-regulated genes produce proteins that alter synaptic structure/function and contribute to late LTP (synthesis of new AMPA receptor proteins and growth-related proteins that increase the number and/or size of active synaptic contacts)
7. Cite various lines of research evidence that LTP is actually a synaptic mechanism of learning and memory formation, and be able to propose a research study in support of that association.
   1. LTP generates larger EPSPs to the potentiated synapse creating stronger bonds through the cells synapses therefore the stronger the synapse the stronger the connection, and you can use tetanus to see this
8. Differentiate between synaptic consolidation and systems consolidation, and describe Duncan's classic experiment demonstrating a synaptic consolidation period.
   1. Synaptic consolidation: hours to days, stabilization of engram as long term changes in synaptic strength through DNA transcription and morphological changes (late LTP), evidence from los of recently encoded memories following brain disruption like electric shock therapy
   2. Systems consolidation: days to years, migration of engram as corticocortical connections are strengthened, evidence from ribot gradient of retrograde amnesia following hippocampal/MTL damage
   3. Duncan zapped people after intervals to see how long it would take to remember or if they could after a certain amount of time
9. Provide at least one line of evidence supporting the hypothesis that neural replay (i.e., reactivation) of episodic memory traces during sleep underlies memory consolidation by promoting corticocortical LTP.
   1. Sleep is critical for memory consolidation, reactivation (replay) of memories during sleep is possible mechanism
   2. While awake participants learned object-spatial location associations while listening to corresponding sound, burning post-learning nap half sounds were presented during slow-wave sleep, spatial memory was then better for cued objects than uncued, cues induced neural replay of associated memory and consolidating the memory to increase memory strength
10. Briefly describe reconsolidation and therapy implications for those with traumatic memories and/or phobias.
    1. Reconsolidation: protein synthesis-dependent return of memory trace to stable long-term storage, after vulnerable labile period induced by retrieval
    2. Process of retrieving LTM can cause memories to become unstable and susceptible to disruption or alteration (for traumatic memories)

101-25 Memory Disorders (PTSD and Addiction), Cognitive Aging, and Alzheimer's Disease - BN Ch. 4.8 (p. 126-136), BN Ch. 7.5 (p. 225-230), BN Ch. 16.4 (p. 548-549), & BN Ch. 17.6 (p. 589-593) -or- ONI Ch. 11.2 (p. 8-10), ONI Ch. 11.5 (p. 21-24), ONI Ch. 11.6 (p. 25-28), & ONI Ch. 13.5 (p. 25-30)

1. Briefly explain the memory component of several psychiatric and neurological disorders mentioned in class.
   1. Amnesia: memory impairment resulting from brain damage (MTL or diencephalon) or psychogenic causes
   2. Phobias: crippling emotional reactions associated with particular class of stimuli
   3. PTSD: repeated reexperiencing of traumatic event, often triggered by otherwise innocuous stimuli
   4. Addiction: reinforcement learning gone awry
   5. Alzheimer's disease: dementia resulting from progressive degeneration of MTL and other cortical areas
2. Describe the symptoms of post-traumatic stress disorder (PTSD).
   1. Obsessive thoughts, nightmares, or flashbacks persist long after exposure to the traumatic event, individuals fail to extinguish normal fear response, and may involve overactive stress hormones
   2. Trigger: any different stimuli reminiscent of original trauma (generalization)
3. Explain the role of the amygdala in the stress response and interactions between the stress response and memory encoding.
   1. Emotional stimuli causes release of stress hormones including epinephrine, which stimulates brainstem nuclei to release norepinephrine (NE), brainstem NE stimulates the basolateral nucleus (BLA) to boost memory encoding (rhythmic BLA firing may induce rhythmic firing in its projection sites, thus facilitating LTP in coactive neurons
   2. Lateral nucleus: collects emotionally relevant information from cortex and thalamus
   3. Central nucleus: coordinates expression of behavioral and physiological emotional responses
   4. Basolateral nucleus: modulates brain centers related to memory and learning
4. Describe a possible neurobiological cause and propose possible treatments to prevent or reduce PTSD.
   1. Traumatic events may produce an excessive and/or prolonged stress hormone response that further strengthens the memory (more lTP in Hpc)
   2. Drug treatments: adrenergic receptor blockers that may reduce effect of emotion on memories especially if administered immediately after initial trauma (with propranolol administration may be less likely to develop PTSD), controlled retrieval followed by drugs that inhibit reconsolidation - protein synthesis inhibitors - may weaken the traumatic memory)
   3. Extinction therapy: expose patient to anxiety-inducing cues, but in the absence of danger
5. Explain evidence that reduced hippocampal volume is a risk factor for PTSD, and interpret this finding.
   1. MRi studies indicate that individuals with PTSD (and their unexposed twins) typically have smaller hippocampal volumes (risk factor for those later exposed to traumatic event)
6. Differentiate between drug dependence (addiction) and substance abuse.
   1. Drug dependence (addiction): overwhelming desire to self-administer a drug of abuse (patterns of consumption, craving, tolerance, withdrawal, expenditure of time and energy and impact on one's life - mild, moderate, or severe)
   2. Substance abuse is a less severe pattern of use that did not fully meet the criteria for dependence
7. Describe the drug self-administration paradigm and findings about the neural consequences of drug administration using microdialysis. Connect neural findings to reinforcement learning and cue-induced craving.
   1. Addictive drugs directly or indirectly increase dopamine release in nucleus accumbens, dopaminergic axons terminating ere originate in the ventral tegmental area (VTA) and are apart of the mesolimbic reward pathway, the addictive power of ugs and behavioral addictions may come from stimulation this pathway (reinforcement learning gone awry)
8. Describe four models of drug abuse, and indicate contributions of each to the integrative model presented by Dr. Gobel (adapted from Dackis & O'Brien, 2005).
   1. Moral model: blames abuser for a lack of moral character or lack of self-control (executive control deficits in decision-making, impulse control but not necessarily a lack of morality)
   2. Positive reward model: drug use is behavior controlled by seeking of positive rewards like drug euphoria (positive reinforcement - drug administration produces euphoria)
   3. Physical dependence model: abusers use drugs to avoid withdrawal symptoms like dysphoria, strong negative feelings that can only be relieved by the drug (negative reinforcement - drug administration relieves withdrawal symptoms)
   4. Disease model: abuser requires medical treatment for abnormal brain conditions (atypical brain function - cue induced craving, neuroadaptations)
9. Briefly describe various neuropharmacological approaches to treat drug abuse, explaining the rationale of each.
   1. Drugs for detoxification: benzodiazepine and other drugs to help ease withdrawal symptoms
   2. Taper off with agonists or partial agonist analogs of the addictive drug: partially activate the same pathways, such as methadone or nicotine patches
   3. Antagonists of the addictive drug: block effects of abused drug, but may produce withdrawal symptoms
   4. Medications that alter drug metabolism: antabuse makes drinking alcohol produce unpleasant side effects
   5. Reward-blocking medications: block positive reward effects of the abused drug, but may produce a generalized lack of all pleasurable feelings (anhedonia)
   6. Anticraving medications: reduce the appetite for he abused substance
   7. Immunization: prompts the immune system to remove targeted drugs from circulation before reaching the brain (rats example)
10. Characterize memory decline during normal cognitive aging and describe accompanying age-related neural changes, drawing connections between the locus of neurological changes and type of memory decline. Include a discussion of compensation in high-functioning older adults.
    1. Impairments of encoding and retrieval accompanied by less cortical activation in some tasks (intact memory function show compensatory increases in cortical activation - bilateral recruitment (bilateral compensation) and/or recruitment of additional brain regions)
    2. Loss of neurons and synapses - some parts of brain lose a larger proportion of volume
    3. Impaired coding by hippocampal place cells - neurons encode less spatial information
    4. Deterioration of cholinergic pathways - less cholinergic output from basal forebrain, which projects to hippocampus and cortex (also in AD)
11. Describe the behavioral and cognitive symptoms of Alzheimer's disease (AD).
    1. Plaques and tangles with memory and emotional disorders (most common type of senile dementia) drastic failure of cognitive ability, begins as declarative memory impairment for recent events - episodic memory failure - followed by gradual cognitive decline
    2. Early symptom: declarative memory impairment with largely preserved procedural learning
    3. Declines in learning, attention, and judgment, disorientation in time and space, difficulties in word finding and communication, decline in personal hygiene and self-care?ADL skills, inappropriate social behavior, changes in personality
    4. Progression generally faster with earlier disease onset
    5. Sundowning: symptoms are worse in the evening
12. Describe the neuropathology of AD as seen in cortical atrophy, reduced resting state brain metabolism, amyloid plaques, neurofibrillary (tau) tangles, cortical cellular neurodegeneration, and cholinergic deterioration.
    1. Gross atrophy of cerebral cortex: begins in MTL then progresses to other association cortical areas, sensory cortex generally spared
    2. Reduced brain metabolism
    3. Cellular neuropathology
       1. Amyloid plaques from buildup of b-amyloid protein (also called neurotic plaques or senile plaques) (dark center spot surrounded by degenerating cells)
       2. Neurofibrillary tangles from clustering of the tau protein (darkened areas)
       3. Neurodegeneration of neurons and their processes
    4. Neurochemical changes: cholinergic neurons in basal forebrain nuclei die, greatly decreasing ACh levels in the cortex and hippocampus
13. Identify the genes linked to early-onset AD and late-onset AD and briefly explain why we study AD-linked mutations.
    1. Early onset: rare, has significant genetic component, mutations found in genes coding for proteins involved in amyloid processing are linked to early-onset AD (amyloid precursor protein - APP and presenilin (PS1, PS2) mutations
    2. Late onset: 99% of cases more influenced by environmental factors also linked to ApoE4 mutation of gene for apolipoprotein E
    3. Mutations cause b-amyloid protein to accumulate and cluster into plaques
14. Explain one hypothesis of AD - the amyloid cascade hypothesis - and explain how the various AD-linked mutations could partly contribute to the neuropathological process in this model.
    1. B-amyloid buildup occurs when amyloid precursor protein (APP) is cleaved by two enzymes, b-secretase and presenilin
    2. B-amyloid breakdown is normally done by apolipoprotein E (ApoE)
    3. Mutations of the APP, preselin, and/or ApoE genes 0 associated with increased risk for alzheimer's - may increase rate of amyloid deposition (plaques)
15. List and describe possible treatments and preventative measures for AD, explaining the rationale for each.
    1. Cholinergic agonists: ACh has widespread cortical and hippocampal projections, AChE inhibitors (Aricept)
    2. Methods to decrease b-amyloid accumulation (Ab 1-42 vaccine, antioxidants)
    3. Prevention: remain active cognitively, socially, psychically (promotes neuronal survival and hippocampal neurogenesis, slows cognitive aging in both healthy and disease states)