Module Two Flashcards
(241 cards)
1
Q
Define critical periods.
A
Discrete developmental windows—often late prenatal through early postnatal life—during which neural circuits are maximally sensitive to activity driven by specific environmental stimuli. Experience during a critical period is not merely facilitative, but often required for normal acquisition or skilled execution of certain behaviors. Once a critical period closes, that behavior’s neural circuitry becomes much less malleable.
2
Q
What is the purpose of critical periods?
A
To fine-tune circuitry so each individual’s brain becomes optimally adapted to their specific life demands.
3
Q
What marks the closure of critical periods?
A
As mammals mature, the efficacy of cellular mechanisms for modifying connectivity declines, ending these periods of heightened plasticity.
4
Q
How do molecular pathways of developmental plasticity relate to learning and memory?
A
Similar molecular pathways underlie both developmental plasticity and the synaptic modifications that support learning and memory throughout life.
5
Q
Name the two main types of extracellular signals involved in activity-dependent change.
A
Neurotrophins (slow, modify synaptic strength long-term) and neurotransmitters (rapid, trigger immediate activity).
6
Q
What is the role of signal transduction in activity-dependent plasticity?
A
Second messengers and effectors convert extracellular cues into intracellular responses.
7
Q
How does gene expression contribute to structural remodeling?
A
Activity-elicited signals modulate local transcription, adjusting the production of proteins required for structural remodeling.
8
Q
What are the structural outcomes of activity-dependent change?
A
Axon and dendrite growth (final adjustments in arborization patterns) and synapse formation and stabilization (growth of new contacts and pruning of weak or uncorrelated ones).
9
Q
Define ocular dominance plasticity.
A
The brain’s adjustment of connections between the eyes and the visual cortex based on activity levels: when one eye is used more, its connections are strengthened, while less active eyes have weaker connections, improving integration for tasks like depth perception.
10
Q
What postnatal changes in the human cortex reflect experience-dependent plasticity?
A
Changes in cortical thickness and surface area—varying by region—reflect experience-dependent growth and pruning of connections.
11
Q
How does disruption of experience-dependent plasticity processes relate to clinical conditions?
A
Disruption is implicated in intellectual disability, developmental delays, autism spectrum disorders, and psychiatric illnesses such as schizophrenia.
12
Q
State Hebb’s postulate.
A
’Cells that fire together wire together.’ Coordinated presynaptic–postsynaptic activity strengthens synapses; synapses active in concert are stabilized and strengthened, while those with uncorrelated or divergent activity are weakened and pruned.
13
Q
How do correlated inputs affect synapses during development according to Hebb’s postulate?
A
Correlated inputs lead to strengthening and sprouting of new branches.
14
Q
How do uncorrelated inputs affect synapses during development according to Hebb’s postulate?
A
Uncorrelated inputs lead to weakening, eventual elimination, or neuronal death.
15
Q
List the functional consequences of Hebbian developmental remodelling.
A
(1) Emergence of behaviors: skills not present at birth develop and refine via experience. (2) Enhanced early learning: superior capacity for complex skill acquisition during critical periods. (3) Postnatal brain growth: progressive phase (rapid increase in dendritic/axonal arborization and synapse number drives brain enlargement) and elimination phase (around 6 years, pruning of superfluous branches; adolescence synapse pruning reduces total count while growth continues due to elaboration of retained connections).
16
Q
What are intrinsic wiring mechanisms?
A
Mechanisms that guide initial axon targeting, map formation, and first synapse establishment—producing a ‘blueprint of connectivity.’
17
Q
What is the role of experience in circuit refinement?
A
Experience validates and adjusts connections: typical sensory and motor experiences reinforce appropriate connections and eliminate mismatches.
18
Q
What happens when input is diminished during development?
A
Sensory deprivation or transduction failure halts proper refinement, leading to altered connectivity and behavioral deficits; may confer adaptive advantages in permanent sensory loss but can produce long-term impairments after transient deprivation or trauma.
19
Q
Contrast innate vs. experience-dependent behavior in critical periods.
A
Intrinsic developmental mechanisms (axon guidance, topographic map formation, first synapse establishment) generate basic survival behaviors in newborns, while animals with complex repertoires (notably humans) require environmental interaction to refine and expand these behaviors.
20
Q
Describe a sharp window example of a critical period.
A
Imprinting in hatchling birds: occurs within a narrow window (hours to days); failure to encounter the right stimulus prevents proper imprinting.
21
Q
Describe an extended window example of a critical period.
A
Sensorimotor and complex behaviors like song learning in birds and human language acquisition occur over gradual learning windows (weeks to months).
22
Q
List the essential components of every critical period.
A
(1) Temporal window: defined age range when plasticity is elevated. (2) Instructive experience: specific environmental inputs (visual patterns, tutor song, spoken language) without which normal development fails. (3) Neural readiness: underlying circuit mechanisms (receptor expression, baseline activity) must be in place to respond. (4) Behavioral outcome: successful interaction yields mature behavior; absence or disruption yields deficits.
23
Q
What is the role of subthreshold oscillations in establishing critical periods?
A
Subthreshold patterned activity long before sensory experience primes circuits; recognition grew that such oscillations are instrumental for proper maturation.
24
Q
Define retinal waves and their timing.
A
Retinal waves are bursts of calcium influx that sweep across the flat-mounted retina every few seconds in fetal or neonatal retina before eye opening and phototransduction.
25
How do retinal waves relate to neurotransmitter systems?
Pharmacological or genetic blockade of the neurotransmitter systems abolishes the retinal waves.
26
Explain how asynchronous retinal waves drive Hebbian competition.
Each eye generates retinal waves independently; their lack of correlation creates competition in shared targets (LGN), leading afferents from each eye to segregate into eye-specific layers due to asynchronous signals.
27
What is the function of the lateral geniculate nucleus in ocular dominance plasticity?
The LGN relays visual information from the retina to the visual cortex; afferents from the left and right eyes segregate into eye-specific layers due to asynchronous retinal waves, creating distinct maps of visual information for each eye.
28
Where do afferents from the eyes terminate in primary visual cortex layer 4?
In alternating ‘ocular dominance columns’ that prefer input from one eye over the other.
29
How are bursts of neural activity in neonatal V1 related to retinal waves?
Bursts in neonatal V1 are closely synchronized with retinal waves.
30
What analogous activity do human infants exhibit in visual cortex?
Spindle bursts in EEG, reflecting synchronized subthreshold and spiking activity in visual cortex.
31
Name a property shared by all critical periods.
Dependence on both adequate instructive stimuli and intrinsic circuit oscillations.
32
How do critical periods vary?
They vary in onset, duration, and abruptness of closure, but always demarcate when a particular behavior is tuned by experience.
33
What happens if proper activity is absent during a critical period?
Circuit refinement is incomplete and behavioral capacity remains impaired.
34
How is ocular dominance measured?
By recording activation of visual cortical neurons by each eye; individual neurons' responses determine ocular dominance.
35
How are neurons classified into ocular dominance groups?
Based on their response: Group 1 responds only to the contralateral eye; Group 7 only to the ipsilateral eye; Group 4 responds equally to both eyes; intermediate groups represent graded preferences.
36
Describe normal ocular dominance distribution in adult cats.
In all layers except layer 4, ocular dominance follows a Gaussian distribution: most neurons activated by both eyes, with a minority more responsive to one eye.
37
What are the effects of monocular deprivation during the critical period?
The cortex becomes nearly unresponsive to the formerly closed eye, resulting in functional ‘cortical blindness’ in the deprived eye despite normal retina and LGN responses.
38
What are the effects of monocular deprivation after the critical period?
There is minimal shift in ocular dominance distribution; most neurons remain binocular or respond to the deprived eye; visual behavior remains unaffected.
39
How does ocular dominance column width change with deprivation?
Columns representing the non-deprived eye expand in width; deprived-eye columns shrink but are not eliminated entirely.
40
Describe individual LGN axon arbor remodeling after short-term deprivation during the critical period.
Axons from LGN neurons driven by the deprived eye show dramatically reduced branch complexity and territory in V1 layer 4, while axons from the open eye exhibit expanded, more complex arborizations.
41
What is observed during long-term monocular deprivation?
Further deprivation yields minimal additional arbor change, indicating rapid initial remodeling.
42
What drives competitive interaction between geniculocortical axons during the critical period?
Competition for postsynaptic territory: imbalance (monocular deprivation) gives active eye’s axons advantage, allowing them to usurp territory from the inactive eye.
43
What does binocular deprivation reveal about competitive segregation?
With balanced lack of input from both eyes, ocular dominance distribution remains approximately normal—both eyes retain territory—showing that relative activity levels drive segregation.
44
What is dark rearing and its effect on visual development?
Rearing in total darkness without patterned light delays normal development but does not prevent it; upon later light exposure, acuity and ocular dominance patterns can recover to near-normal, unlike monocular deprivation.
45
Define strabismus and its effect on eye alignment.
Strabismus is a misalignment of the two eyes induced by cutting one extraocular muscle; both eyes continue to receive normal input but corresponding retinal points are no longer stimulated synchronously.
46
How does strabismus affect ocular dominance columns in layer 4?
Enhanced segregation: sharper, narrower stripes of input from each eye appear due to increased asynchrony boosting Hebbian competition.
47
What happens to binocularity in supragranular and infragranular layers with strabismus?
Nearly all neurons across layers 2–3 and 5–6 become strictly monocular—driven exclusively by one eye—abolishing typical binocular convergence.
48
Describe orientation tuning in the young cortex before the critical period.
Binocular neurons show weak, mismatched orientation preferences for each eye, with different peak firing orientations and low response amplitudes.
49
How does orientation tuning change during the critical period under normal development?
Coincident activation of both eyes with identical stimuli strengthens synapses from each eye onto the same neuron; over time, orientation responses align and neurons become sharply tuned to the same angle regardless of eye.
50
What is the effect of monocular deprivation on orientation tuning?
Binocular competition is lost; orientation tuning remains unmatched after reopening, and no subsequent experience restores congruence.
51
What happens if one eye is closed after the critical period ends?
There is no effect on orientation tuning congruence, underscoring the necessity of temporally restricted competition for feature-map refinement.
52
What functional deficits arise from amblyopia and strabismus during the critical period?
Reduced acuity, impaired stereopsis (depth perception), and poor fusion arise when binocular competition is disrupted; the brain suppresses input from the misaligned eye, giving the fellow eye a competitive advantage.
53
What is the outcome of unilateral deprivation from congenital cataracts if corrected before ~4 months?
The deprived eye attains near-normal acuity; beyond ~4 months, amblyopia is largely irreversible.
54
How does bilateral deprivation prognosis compare to unilateral deprivation?
Bilateral deprivation has a better prognosis because balanced lack of input preserves relative ocular dominance, allowing substantial recovery of acuity even if treatment is delayed.
55
What determines the cellular and molecular regulation of critical periods?
Molecular machinery that converts activity-driven synaptic signals into lasting changes in connectivity, but only within a defined developmental window; once the window closes, pathways become refractory to large-scale rewiring.
56
What are the roles of NMDA and AMPA receptors in glutamate receptor–mediated calcium signaling?
AMPA receptors (Na⁺/K⁺ currents) activate with weak stimulation causing slight depolarization; NMDA receptors (Ca²⁺/Na⁺ currents) remain blocked by Mg²⁺ until sufficient stimulation removes the block, permitting Ca²⁺ influx localized to active synapses.
57
What are metabotropic glutamate receptors (mGluRs)?
G-protein–coupled receptors that modulate intracellular second messengers and protein synthesis in response to glutamate.
58
What are voltage-sensitive Ca²⁺ channels (L-VSCCs)?
Channels that open upon depolarization, further contributing to Ca²⁺ entry.
59
What role do CaMKII and CaMKIV play in calcium-dependent signaling?
They are kinases activated by Ca²⁺ that increase conductance of AMPA receptors and promote synaptic insertion of new AMPA receptors into the spine membrane.
60
Differentiate early LTP and late LTP.
Early LTP: Postsynaptic Ca²⁺ activates CaMKII and other kinases → trafficking and insertion of additional AMPA receptors → increased AMPA currents and larger EPSPs. Late LTP: Gene transcription and protein synthesis stabilize structural and receptor changes for long-term maintenance.
61
What is the function of ubiquitin ligase Ube3a in synaptic plasticity?
Targets specific proteins that normally help remove AMPA receptors from the synapse, allowing AMPA receptors to remain at the synapse.
62
What are neurexins and neuroligins?
Neurexins (presynaptic) and neuroligins (postsynaptic) are proteins that mediate trans-synaptic adhesion, organizing the synaptic cleft and regulating synaptic function.
63
What is the role of scaffolding proteins in plasticity?
Proteins such as PSD95, GKAP, SHANK, and HOMER organize the synapse and adapt it based on neuronal activity, ensuring proper communication and plasticity.
64
How does the mTOR pathway contribute to plasticity?
The mTOR pathway ensures that new receptors and structural proteins are produced where and when needed for plasticity.
65
Describe the role of BDNF in activity-dependent plasticity.
BDNF is released from active afferents, binds TrkB, activates the Ras → RAF → ERK cascade, and converges with CaMK signals to drive CREB-mediated gene expression, embedding plastic changes in the transcriptional state.
66
Why are mutations in plasticity-related genes clinically significant?
Many genes encoding molecules like NMDA receptors, AMPA receptors, scaffolding proteins, and BDNF are mutated in intellectual disability and autism spectrum disorders, disrupting normal plasticity.
67
What is the role of GABAergic interneurons in critical-period plasticity?
The maturation and placement of inhibitory synapses by GABAergic interneurons are exquisitely sensitive to early activity levels.
68
Why is excitatory/inhibitory (E/I) balance important during critical periods?
Proper critical-period plasticity requires a shift from predominantly excitatory early networks to a balanced E/I state for normal circuit refinement.
69
When do hearing infants begin vocal babbling, and why is it important?
Hearing infants begin vocal babbling around 7 months; this practice refines later speech.
70
What happens to congenitally deaf infants without early linguistic access?
They fail to develop any coherent symbolic language.
71
What is manual babbling in deaf infants?
Deaf infants born to signing parents produce hand-shape 'babble' between 10–14 months when exposed to sign language, mirroring vocal babbling timeline in hearing infants.
72
What is the effect of losing hearing before puberty on speech fluency?
Children who acquire speech then become deaf before puberty suffer declines in spoken language fluency, underscoring the need for ongoing auditory feedback during the latter portion of the critical window.
73
What is phoneme discrimination and perceptual narrowing in infancy?
Very young infants can distinguish phonetic contrasts from all human languages; by around 6 months, they focus more on native language sounds, and by 12 months, their ability to differentiate non-native phonemes diminishes significantly.
74
What do fMRI comparisons between children (7–10 years) and adults during word-processing tasks show?
Children and adults show different patterns and loci of cortical activation, suggesting brain circuits for language undergo functional or structural reorganization during early life, analogous to synaptic remodeling in sensory critical periods.
75
Compare neuron production in adult mammalian brain to epithelia, blood, bone, liver.
Adult mammalian brain produces very few new neurons once prenatal/early postnatal complement is set, unlike epithelia (skin, lung, gut), blood, bone, and liver, which regenerate more robustly.
76
Describe peripheral axon regrowth capacity.
Peripheral axon regrowth is robust: severed sensory or motor axons can extend through residual Schwann‐cell basal laminae (“nerve sheaths”) to reinnervate skin receptors or muscle endplates.
77
Explain CNS repair capacity in adult mammals.
Central nervous system (CNS) repair is minimal; observed recovery after brain injury predominantly reflects reorganization of surviving circuits, not true regeneration of damaged neurons, axons, or dendrites.
78
List the four principal barriers to CNS regeneration.
Neuron loss; Glial inhibition; Restricted neural stem cells; Immune‐mediated cytokines.
79
How does local injury lead to neuron loss in CNS?
Local injury frequently triggers apoptosis or necrosis of neurons whose axons or cell bodies are damaged.
80
Define glial inhibition in CNS regeneration.
Reactive astrocytes and oligodendrocytes secrete inhibitory molecules (e.g., chondroitin sulfate proteoglycans, myelin‐associated inhibitors) that actively block axon extension.
81
What limits neural stem cell–mediated repair in most brain regions?
Although adult neural stem‐cell niches exist (e.g., SVZ, hippocampal dentate gyrus), progenitors in most brain regions remain quiescent with limited proliferation, migration, or differentiation into functional neurons.
82
How do immune‐mediated cytokines impede CNS regrowth?
Microglia and astrocytes release inflammatory cytokines and reactive oxygen species that further impede regrowth and can exacerbate tissue damage.
83
Define functional reorganization after stroke.
Functional reorganization refers to recovery of motor or language functions through reorganization of surviving circuits rather than true tissue regeneration.
84
What is unmasking of latent circuits?
Some brain circuits are normally inactive; after injury, these latent circuits in nearby areas are unmasked and begin to take over lost functions.
85
Explain the role of synaptic plasticity in post-stroke reorganization.
Synaptic plasticity strengthens or weakens connections between neurons (similar to LTP/LTD), adjusting excitatory/inhibitory balance in surviving synapses to support lost functions.
86
What is modest sprouting after stroke?
Surviving neurons grow new dendritic spines or axon collaterals, forming new connections to create alternative pathways for communication between neurons.
87
Describe ipsilateral compensation in stroke recovery.
The uninjured side of the brain (opposite hemisphere) increases output to ipsilateral spinal tracts or communicates via brainstem relays to compensate for lost motor abilities.
88
Summarize fMRI correlates of primary motor cortex plasticity after stroke.
Early after stroke, fMRI shows bilateral hyperactivation; over time with rehabilitation, hyperactivation declines toward normal levels. Persistent hyperactivation often indicates poorer functional recovery. Initial scans show widespread activation in both contralesional and ipsilesional motor and visual areas; activation contracts as recovery continues.
89
Identify the three types of neuronal repair in the damaged nervous system.
Axonal regrowth from surviving neurons; Sprouting and repair of existing central neurons; Neuronal replacement via adult neurogenesis.
90
Describe axonal regrowth from surviving neurons.
Occurs when peripheral axons are severed or central neurons retain intact cell bodies but lost projections; requires reactivation of developmental axon-growth programs (cytoskeletal extension, guidance-cue responsiveness, synaptogenesis); newly regrown axons compete for postsynaptic sites via Hebbian-like processes; peripheral nerve regeneration is robust and underlies recovery after limb nerve injuries.
91
What reactivation is necessary for axonal regrowth from surviving neurons?
Developmental axon-growth programs including cytoskeletal extension, guidance-cue responsiveness, and synaptogenesis must be turned back on.
92
Explain activity-dependent matching of regrown axons.
Newly regrown axons compete for postsynaptic sites, requiring Hebbian-like processes to ensure appropriate numerical balance between regrown inputs and denervated targets.
93
Summarize clinical outcome of peripheral nerve regeneration.
Peripheral nerve regeneration is the most robust form of neural repair in mammals and underlies recovery after limb nerve injuries.
94
Define sprouting and repair of existing central neurons.
Occurs when cell bodies survive local CNS injury but lose dendrites, axons, or synaptic contacts; surviving neurons must reinitiate developmental programs for polarity (axon vs. dendrite), adhesion-mediated process extension, and neurotrophic signaling to support outgrowth and synapse formation.
95
How do glial scarring and inflammation affect CNS sprouting?
Reactive astrocytes and oligodendrocytes proliferate and secrete inhibitory molecules (CSPGs, myelin-associated inhibitors) forming a dense glial scar; microglia and immune cells release cytokines that further suppress neuronal regrowth.
96
What limits the distance of sprouting in the CNS?
Sprouting is typically restricted to short distances near the lesion because scar-mediated insulation of damaged regions contains inflammation but also blocks axon reextension and reconnection.
97
Describe neuronal replacement via adult neurogenesis.
Generation of entirely new neurons to replace lost ones is rare in adult mammals; olfactory receptor neurons are continuously replaced with axons guided to the olfactory bulb by olfactory-ensheathing cells.
98
List necessary criteria for CNS replacement via adult neurogenesis.
Presence of multipotent stem cells; Permissive microenvironment with local cues supporting proliferation, differentiation, and survival; Recapitulation of developmental processes (migratory pathways, process outgrowth, synaptogenesis, long-distance targeting).
99
Differentiate protopathic and epicritic sensory recovery phases.
Protopathic sensations (basic touch and pressure) recover quickly because large, less specialized fibers regenerate rapidly with coarse targeting. Epicritic sensations (fine touch, temperature, pain) take much longer and may never fully recover due to smaller, specialized fibers requiring precise molecular cues for reconnection.
100
What did Hugh Head’s study reveal about sensory recovery?
He tracked sensory deficits and recovery over two years after nerve transection, identifying that protopathic fibers regenerate rapidly with coarse targeting, while epicritic fibers require precise molecular cues (neurotrophins, cell-adhesion molecules, guidance factors) and take much longer to recover, with full recovery often not achieved.
101
How does fine motor control recovery compare to gross extension strength after peripheral nerve injury?
Fine motor control lags behind gross extension strength, mirroring the protopathic/epicritic distinction in sensory fibers.
102
How does timing of microsurgical repair affect peripheral nerve recovery?
Timely and precise microsurgical repair of severed peripheral nerves maximizes functional recovery; delays or misalignment result in persistent deficits in fine sensation and dexterity.
103
Identify key cellular players in peripheral nerve repair.
Schwann cells and macrophages.
104
Describe Schwann cells’ role after peripheral nerve injury.
Schwann cells proliferate, align within basal lamina tubes forming bands of Büngner to guide regenerating axons, secrete extracellular matrix components to recreate a growth-permissive substrate, upregulate cell-adhesion molecules, and produce neurotrophins to promote nociceptive fiber regrowth and later guide mechanoreceptive and proprioceptive fibers.
105
When do Schwann cells produce neurotrophins and what is their role?
Initially they produce neurotrophins to promote nociceptive (protopathic) fiber regrowth; later they produce Trk ligands to guide mechanoreceptive and proprioceptive (epicritic) fibers.
106
What is the role of macrophages in Wallerian degeneration?
Macrophages rapidly infiltrate the distal stump, phagocytose myelin and axonal debris (Wallerian degeneration), and secrete cytokines that modulate Schwann-cell behavior.
107
Explain Wallerian degeneration and the regeneration scaffold.
After axon severance, the distal segment undergoes programmed degeneration; debris is cleared by macrophages. Preserved basal lamina tubes formed by perineurial/endoneurial sheaths create continuous extracellular matrix conduits (bands of Büngner) guiding regrowing proximal axons.
108
Contrast crush versus transection injuries in peripheral nerves.
Crush injuries leave some axonal fragments and Schwann-cell alignment intact, leading to faster recovery. Transection requires reapposition of nerve ends; misalignment reduces precision, especially for fine epicritic modalities.
109
What gene-expression changes occur in injured neurons?
Injured motor and sensory neurons upregulate regeneration-associated genes—cytoskeletal proteins, growth-associated protein-43 (GAP43), receptors for neurotrophins and adhesion molecules—mirroring developmental transcriptional programs.
110
What does inducing CNS axon outgrowth via peripheral nerve grafts demonstrate?
CNS axons can regenerate if provided a supportive peripheral environment (Schwann cells and basal lamina); without these cues, CNS repair remains limited, suggesting CNS neurons have growth potential restricted by lack of regenerative signals.
111
Describe persistence of synaptic basal lamina at the NMJ after injury.
After axon degeneration, the synaptic portion of the muscle basal lamina, including synapse-specific ECM components, remains intact for weeks, preserving a scaffold for synapse reformation.
112
How do trophic factors modulate NMJ regeneration?
Upregulated factors (NGF, BDNF) increase at damaged sites, attracting regenerating axons and promoting synapse reformation. Downregulated factors that maintain stable synapses decrease, making the site receptive to new nerve endings.
113
What maintains postsynaptic receptor clusters at denervated NMJs?
Acetylcholine receptors (AChRs) and Neuregulin–ErbB signaling sustain receptor clusters at the postsynaptic membrane even when nerve fibers are lost.
114
Explain the Agrin–Lrp4–MuSK pathway at the NMJ.
Agrin secreted by nerve terminals and Schwann cells binds to Lrp4, activating MuSK, which stabilizes AChRs at the postsynaptic membrane to ensure receptors remain precisely aligned for reconnection.
115
Role of synaptic ECM components at the NMJ.
Synaptic ECM components provide structural support for the NMJ and concentrate essential molecules like growth factors and acetylcholinesterase (AChE) in the synaptic cleft.
116
Why is AChE localization important during NMJ regeneration?
AChE localization and anchoring ensure rapid, precise clearing of acetylcholine, which is essential for accurate muscle control and movement during NMJ regeneration.
117
How are regenerating axons guided to reform functional NMJs?
Basal-lamina “tubes” containing synaptic ECM cues direct motor axons to reform functional NMJs at the correct sites, even if muscle fibers degenerate.
118
Define polyneuronal innervation after peripheral nerve regeneration.
Immediately after regeneration, muscle fibers are often innervated by multiple motor neuron axons, resembling early developmental stages of muscle innervation.
119
List neuronal death pathways activated after CNS injury.
Apoptosis triggers (hypoxia/ischemia, excitotoxicity, trophic withdrawal, DNA damage & oxidative stress); Molecular cascade: Bcl-2 inhibition → cytochrome c release → caspase activation → DNA fragmentation, chromatin condensation, membrane blebbing, cytoskeletal breakdown → programmed cell death.
120
Explain autophagy’s role in injured neurons.
Basal autophagy recycles damaged organelles and proteins, supporting neuron survival under mild stress by maintaining energy homeostasis; dysregulation (excessive or defective) contributes to neurodegenerative diseases, and autophagy can delay apoptosis but may lead to cell death if overwhelmed.
121
Describe glutamate-mediated excitotoxicity after CNS injury.
Injury-induced glutamate release floods synapses, causing prolonged NMDA- and AMPA-receptor activation, massive Ca²⁺ influx, activation of degradative enzymes (proteases, lipases), mitochondrial damage, and exacerbation of inflammation via DAMPs.
122
What glial cell responses occur after CNS injury?
Astrocytes hypertrophy and proliferate around the lesion border, interweaving processes to deposit inhibitory molecules forming a glial scar. Microglia phagocytose debris and secrete pro-inflammatory cytokines and reactive oxygen/nitrogen species that can be neurotoxic or neuroprotective in regulated amounts.
123
What is the effect of upregulated developmental chemorepellent cues after CNS injury?
Re-expression of guidance molecules forms chemical barriers, creating biochemical obstacles to regeneration that complement physical barriers of the glial scar.
124
List barriers to regeneration in adult CNS.
Lack of pro-regenerative signals, absence of Schwann-cell–like support (no bands-of-Büngner), limited ECM permissiveness, minimal neurotrophic factor production, extensive neuronal apoptosis, autophagic imbalance, excitotoxic overactivation, glial-mediated physical/chemical barriers, absence of developmental growth cues.
125
What is the net effect of these barriers on CNS axons?
Axons turn away from the injury epicenter, fail to cross the scar boundary, and retract, leading to permanent disconnection.
126
How does disruption of the blood–brain barrier affect CNS injury outcomes?
Mechanical or ischemic damage opens tight junctions, allowing serum proteins and immune cells to enter the CNS parenchyma, exacerbating inflammation and impeding repair.
127
Where do adult neural stem cells (NSCs) exist in the brain?
In the subventricular zone (SVZ) and the subgranular zone (SGZ) of the hippocampal dentate gyrus.
128
What is the fate of NSC-derived cells from the SVZ?
Cells from the SVZ become GABAergic interneurons that migrate to the olfactory bulb, important for smell.
129
What is the fate of NSC-derived cells from the SGZ?
Cells from the SGZ become granule neurons that integrate into the dentate gyrus of the hippocampus, important for memory.
130
Describe the neurogenic response to injury in adult brain.
Injury can transiently boost proliferation in neurogenic niches (SVZ, SGZ), but few new neurons survive or integrate outside these areas.
131
List cell types in SVZ neurogenic niche architecture.
Radial glia–like NSCs (Type B cells) expressing GFAP and Sox2; intermediate progenitors (Type C cells) that divide quickly; neuroblasts/glioblasts that migrate to become specialized neurons (mostly interneurons).
132
Describe lineage progression of NSCs in adult neurogenesis.
NSCs (Type B cells) → Transit amplifying cells (Type C) → Neuroblasts/glioblasts (no longer divide, migrate to become specialized neurons).
133
Explain RMS-mediated neuronal migration.
Newborn neuroblasts travel to the olfactory bulb through the rostral migratory stream (RMS) inside glial tubes formed by astrocyte-like cells; ECM + integrins aid adhesion and movement; polysialylated NCAM reduces cell-cell adhesion for chain migration; Neuregulin→ErbB4 provides chemokinetic signaling.
134
What is the survival rate of new neurons in adult neurogenesis?
Most new neurons die unless they successfully form connections and receive trophic support, similar to developmental competition.
135
Suggest functions of adult-born neurons.
They may contribute to smell discrimination, learning and memory, and mood regulation, though exact roles remain under study.
136
Identify challenges for CNS repair via endogenous neurogenesis.
Lack of migratory routes outside SVZ and SGZ, restricted lineage potential, high attrition of newborn cells, limited survival and integration, absence of cortical neurogenesis in adult human neocortex.
137
What is absent in adult human neocortex that limits endogenous repair?
No reliable evidence for generation of new projection or interneurons in the adult human neocortex, implying endogenous stem cells cannot repopulate cortical circuits after injury or degeneration.
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139
Define learning.
Process by which experiences alter the nervous system and behavior.
140
Define memory.
Long-term changes in neural circuits produced by learning; enduring synaptic and (in some cases) neurogenic changes, not storage of events.
141
Define plasticity.
Underlying mechanism of learning and memory, chiefly synaptic modification (LTP/LTD) and, in select systems, adult neurogenesis.
142
List the four types of learning.
Stimulus–response; Motor; Perceptual; Relational.
143
Describe stimulus–response learning.
Learning by forming associations between a particular stimulus and a behavioral response.
144
Describe motor learning.
Acquisition and refinement of skilled movements (e.g., riding a bicycle) involving motor cortex, cerebellum, and basal ganglia.
145
Describe perceptual learning.
Enhanced ability to discriminate sensory stimuli through practice, altering responsiveness and tuning of sensory cortical areas.
146
Describe relational learning.
Learning to form associations among multiple stimuli, events, or spatial locations, dependent on hippocampus and medial temporal lobe.
147
Define encoding.
Initial neural changes when new information is acquired.
148
Define consolidation.
Processes that stabilize and strengthen neural changes into lasting memories.
149
Define storage (in memory context).
Maintenance of consolidated traces within neural circuits.
150
Define retrieval.
Reactivation of stored changes to guide perception, thought, or behavior.
151
Outline the information-processing model of memory.
Encoding → Consolidation → Storage → Retrieval, each with distinct molecular and circuit mechanisms.
152
Describe classical (Pavlovian) conditioning.
Form of stimulus–response learning where a conditioned stimulus is paired with an unconditioned stimulus to evoke a learned response.
153
Describe operant (instrumental) conditioning.
Form of stimulus–response learning linking behavior to outcome (action ↔ consequence), producing learning of new actions rather than reflexes.
154
Which brain areas are involved in motor learning?
Motor cortex, cerebellum, and basal ganglia.
155
What characterizes early vs. automatized phases of motor learning?
Early phase is cognitively demanding; later phase is automatized performance.
156
What changes occur in sensory cortical areas during perceptual learning?
Responsiveness and tuning of neurons are altered to improve discrimination of sensory stimuli.
157
Which structures are critical for relational learning?
Hippocampus and related medial temporal lobe structures.
158
Define reinforcement (neural context).
Process by which a reinforcing stimulus strengthens the connection between perceptual and motor circuits, making a particular stimulus more likely to evoke a specific response.
159
Explain integration of learning types in complex tasks.
Complex tasks (e.g., learning an instrument) combine perceptual learning (recognize notes), motor learning (finger placement), stimulus–response learning (visual cue → movement), and relational learning (sequence and expression).
160
Define sensory memory.
Stage of memory holding raw sensory impressions for fractions of a second to a few seconds for initial processing.
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Give examples of sensory memory modalities.
Echoic memory (auditory)—brief echo of sounds; Iconic memory (visual)—fleeting visual afterimage.
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What is the capacity of sensory memory?
Large (nearly all incoming stimuli), but information decays rapidly or is displaced unless attended.
163
Define short-term (working) memory.
Memory stage lasting seconds to minutes with limited capacity (~7 ± 2 chunks) where rehearsal and chunking prolong retention.
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What is maintenance rehearsal?
Repeating or actively thinking about information in short-term memory to prolong retention.
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What is chunking?
Grouping discrete items into larger, meaningful units to effectively enlarge short-term memory capacity.
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What determines transfer from short-term to long-term memory?
Only information deemed salient or rehearsed transfers to long-term storage.
167
Define long-term memory.
Memory stage with duration from minutes to a lifetime and effectively unlimited capacity.
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What processes maintain long-term memory?
Consolidation stabilizes traces via synaptic and systems-level changes; storage maintains enduring circuit changes; retrieval reactivates stored information.
169
List nondeclarative (implicit) memory forms.
Motor skills, perceptual skills, stimulus–response habits.
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Which neural substrates support nondeclarative memory?
Basal ganglia, cerebellum, sensorimotor cortices.
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List declarative (explicit) memory forms.
Episodic memory and semantic memory.
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Describe episodic memory.
Conscious memory of personal experiences—what happened, where and when, contextual details, temporal sequence—encoded in a single event, hippocampus-dependent.
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Describe semantic memory.
Conscious memory of facts and general knowledge—meanings, concepts—gradually accumulated and stored in distributed neocortical networks (temporal and frontal cortices).
174
Explain how a stimulus leads to a response via perceptual and motor learning.
Stimulus → changes in sensory circuit detecting the stimulus (perceptual learning) → changes in motor circuit controlling behavior (motor learning) → response.
175
Outline information processing from input to long-term storage.
Sensory input → Sensory memory → Attention → Short-term memory → Encoding → Long-term memory → Retrieval.
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What happens to unattended information in sensory memory?
It is lost if not attended.
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What role does attention play in memory processing?
Attention selects sensory input for transfer to short-term memory.
178
Compare declarative vs. nondeclarative memory retrieval.
Declarative retrieval is conscious and hippocampus-dependent; nondeclarative retrieval occurs via subcortical and cortical circuits without conscious awareness.
179
Describe sensory inputs to the amygdala in conditioned emotional responses.
Tone (CS) via auditory system to lateral amygdala; shock (US) via somatosensory system to lateral amygdala.
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Explain synaptic plasticity in amygdala during fear conditioning.
Concurrent CS and US signals strengthen lateral amygdala synapses via LTP, making the tone alone evoke fear.
181
Outline the output pathway triggering emotional response after conditioning.
Lateral amygdala → Basal nucleus → Central nucleus → Hypothalamus (autonomic responses) and Brainstem (reflexive behaviors).
182
Define NMDA receptor’s role in glutamatergic LTP.
Requires glutamate binding and sufficient postsynaptic depolarization (to eject Mg²⁺ block) to allow Ca²⁺ influx.
183
Describe AMPA-receptor insertion during LTP.
Elevated Ca²⁺ triggers kinase cascades that insert additional AMPA receptors into postsynaptic membrane, increasing EPSP amplitude.
184
What is the function of dendritic backpropagating action potentials?
Depolarize dendritic spines, help unblock NMDA receptors, and enable LTP at active synapses.
185
Define retrograde signaling in synaptic plasticity.
Postsynaptic Ca²⁺-triggered molecules (e.g., nitric oxide) travel back to presynaptic terminal to increase neurotransmitter release probability.
186
Where are NMDA-dependent LTP mechanisms found?
Hippocampal perforant-path→dentate gyrus, Schaffer-collateral→CA1 synapses; amygdala thalamic/auditory inputs; cortex and basal ganglia sensory/motor association areas.
187
Describe the transcortical (cortico-cortical) pathway for stimulus–response learning.
Sensory association cortex → Motor association cortex (premotor & supplementary) → Primary motor cortex → Behavior; involves prefrontal cortex and medial temporal lobe for conscious rule-based control.
188
What is the role of prefrontal cortex in transcortical pathway?
Responsible for planning, decision making, conscious control of actions.
189
Explain the basal ganglia–thalamocortical loop in movement selection.
Cortex → Basal ganglia → Thalamus → Cortex feedback loop selects, initiates, and fine-tunes movements.
190
Describe direct modulation in basal ganglia loop.
Caudate/putamen input → GPi inhibits VA/VL thalamus → when GPi is inhibited, thalamus excites motor cortex → movement occurs.
191
Define disinhibition in the basal ganglia direct pathway.
Inhibition of GPi lifts tonic inhibition on thalamus, allowing excitatory signals to motor cortex and movement execution.
192
Explain indirect pathway in basal ganglia modulation.
GPe inhibits STN; STN activates GPi to inhibit thalamus further → suppresses movement; GPe inhibition of STN fine-tunes movement.
193
What is the main function of the indirect pathway?
Dampen or stop movement to prevent excessive or unintended actions.
194
Summarize reinforcement learning and synaptic change.
Reinforcement learning uses past outcomes to shape future actions; reinforcing stimuli trigger mechanisms that facilitate synaptic changes between neurons encoding stimuli and responses.
195
Name key neural circuits for reinforcement learning.
Mesolimbic pathway (VTA→NAC, amygdala, hippocampus) and Mesocortical pathway (VTA→PFC, limbic cortices).
196
List the three elements required for operant conditioning.
Discriminative stimulus (cue), Response (action), Reinforcing stimulus (outcome).
197
Explain how reinforcement triggers synaptic plasticity.
Reinforcement triggers dopamine release, enabling LTP at synapses active during stimulus and response.
198
What effect did L-DOPA studies show on human learning?
Enhanced dopamine accelerated and improved learning of novel vocabulary.
199
Describe prefrontal cortex function in early learning and reinforcement.
Maintains task rules and stimulus–response mappings in working memory, guiding action selection when multiple responses are possible.
200
How does control shift during habit formation?
As actions become habitual, control shifts from prefrontal cortex to basal ganglia loops, reducing prefrontal engagement.
201
Identify plasticity mechanisms in basal ganglia for reinforcement.
LTP/LTD at corticostriatal synapses, modulated by dopamine.
202
Identify plasticity mechanisms in cortex for early rule-based learning.
NMDA- and AMPA-receptor–dependent strengthening in prefrontal and sensorimotor cortices.
203
Describe the mesolimbic dopamine pathway’s origin and projections.
Originates in VTA; projects to nucleus accumbens, amygdala, and hippocampus.
204
What is the function of phasic dopamine release in NAC?
Signals unexpected rewards and drives cortical–striatal synaptic plasticity, reinforcing actions.
205
Describe the mesocortical dopamine pathway’s origin and projections.
Originates in VTA; projects to prefrontal cortex, anterior cingulate, and orbitofrontal cortex.
206
What functions does mesocortical dopamine modulate?
Executive functions such as decision making, goal evaluation, and updating action values.
207
Explain early vs. later basal ganglia involvement in habit learning.
Early learning involves caudate nucleus for deliberate control; later habitual behavior shifts to putamen facilitating automatic execution.
208
Name two disorders related to basal ganglia dysfunction in habit learning.
Parkinson’s Disease (striatal DA depletion) and Huntington’s Disease (striatonigral degeneration).
209
Describe prefrontal cortex role in overriding habits.
PFC evaluates actions, sends glutamate signals to VTA to reinforce goal-consistent actions, and can re-engage control when contingencies change.
210
List the three elements of operant conditioning and neural substrates.
Discriminative stimulus (sensory association cortices → basal ganglia input); Response (motor cortices ← basal ganglia–thalamic outflow); Reinforcer (DA burst in VTA → NAC & PFC).
211
State the learning rule for operant conditioning synaptic change.
Synapses in sensory→motor pathways active when dopamine bursts occur are selectively potentiated, cementing the stimulus–response association.
212
Which cortical areas contribute to learning and movement?
Primary motor cortex, Supplementary Motor Area, Premotor cortex, Ventral Premotor cortex.
213
What is primary motor cortex’s role in learning?
Controls precise muscle movements and adapts with practice.
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What is supplementary motor area’s role?
Organizes movement sequences, making them automatic over time.
215
What is premotor cortex’s role?
Uses external cues (sights or sounds) to guide movement.
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What is ventral premotor cortex’s function?
Contains mirror neurons that help learning by imitation and understanding others.
217
When do deeper improvements in learning occur?
Between sessions and during sleep when the brain strengthens connections.
218
Distinguish ventral and dorsal streams in cortical recognition.
Ventral stream (inferior temporal cortex) recognizes objects (‘what’); dorsal stream (posterior parietal cortex) locates objects (‘where’).
219
What is perceptual learning’s effect on cortical neurons?
Repeated exposure sharpens neuron selectivity and reduces responses to familiar stimuli.
220
Describe short-term perceptual retention mechanisms.
Extrastriate cortex holds a sensory-specific buffer for immediate traces; prefrontal cortex provides working memory buffer for maintaining and manipulating information over seconds.
221
What functions does prefrontal cortex serve in short-term perceptual memory?
Filtering irrelevant inputs, maintenance of multiple items beyond sensory buffers, and strategic control for efficient retrieval.
222
Where do adult hippocampal neurogenic stem cells reside?
In the subgranular zone of the dentate gyrus.
223
How many granule neurons do adult rat DG stem cells produce daily?
Approximately 5,000–10,000 granule neurons.
224
How does relational learning affect survival of new dentate granule cells?
Relational learning doubles survival of newborn dentate granule cells.
225
How does nonrelational (S–R) learning affect neurogenesis?
It does not change adult hippocampal neurogenesis.
226
Name environmental modulators of hippocampal neurogenesis.
Enrichment (running wheels, toys, tunnels) increases neurogenesis; aging decreases it but enrichment attenuates decline; stress hormones decrease neurogenesis; antidepressants increase neurogenesis.
227
What is unique about olfactory bulb neurogenesis in adults?
LTP is readily inducible in newborn interneurons soon after migration and declines with neuron age; adult-born olfactory neurons are required for odor-learning tasks.
228
Describe semantic dementia’s effect on memory.
Progressive degeneration of anterolateral temporal neocortex causes loss of factual knowledge (word meanings, object identity) while episodic memory remains intact.
229
Define anterograde amnesia.
Inability to form new memories after brain damage, with intact old memories and preserved procedural and perceptual learning.
230
Define retrograde amnesia.
Inability to recall events before injury, often less severe than anterograde amnesia.
231
What is the hippocampus’s role in memory consolidation?
Transiently required for binding disparate elements into cohesive relational representations; after consolidation, remote memories are stored and retrieved via neocortex.
232
When is hippocampal retrieval necessary?
For recently formed memories (< weeks–months old); not required for remote memories that have been reorganized in cortex.
233
How do amnesic patients demonstrate perceptual learning?
Despite no conscious recollection, they show preferences or improved recognition of visual faces and auditory melodies presented earlier.
234
What dissociation is seen in amnesia regarding learning types?
Nondeclarative learning (stimulus–response, motor, perceptual) is preserved; declarative (episodic, semantic) learning is lost.
235
Give an example of perceptual learning in amnesia (Johnson et al. 1985).
Amnesic patients preferred a previously seen face labeled “nice” over one labeled “nasty” and preferred previously heard unfamiliar melodies despite no explicit memory.
236
Compare declarative vs. nondeclarative memory in amnesia.
Nondeclarative (implicit) tasks (e.g., eyeblink conditioning, serial reaction) are learned without awareness; declarative (explicit) (episodic, semantic) memories are lost.
237
List hippocampal spatial cell types.
Place cells (fire in specific locations), Grid cells (patterned map), Border cells (detect edges), Head-direction cells (track orientation), Path/intention cells (combine location with planned movement).
238
Define Hebbian learning rule.
When two inputs activate a neuron together, their connection strengthens over time if paired repeatedly (’cells that fire together wire together’).
239
Where was LTP first discovered and what does it entail?
Discovered in hippocampus; repeated high-frequency stimulation leads to long-lasting synaptic strengthening via NMDA receptor activation, Ca²⁺ influx, AMPA receptor insertion, and presynaptic changes.
240
What conditions are required for LTP induction?
High-frequency stimulation causing summation and depolarization, removal of Mg²⁺ block from NMDA receptors, Ca²⁺ influx triggering kinases for synaptic strengthening.
241
Can LTP occur outside hippocampus?
Yes; also observed in amygdala, cortex, and basal ganglia, supporting learning in general.
