Module 2 Flashcards
(324 cards)
1
Q
What are critical periods in neural development?
A
Critical periods are 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 these windows is often required for normal acquisition or skilled execution of certain behaviors, and once the period closes, that behavior’s circuitry becomes much less malleable.
2
Q
What is the primary purpose of critical periods?
A
The purpose of critical periods is to fine-tune neural circuitry so each individual’s brain becomes optimally adapted to their specific life demands by incorporating relevant environmental inputs into circuit architecture.
3
Q
What leads to the closure of critical periods?
A
As mammals mature, the efficacy of cellular mechanisms for modifying connectivity declines, ending periods of heightened plasticity and making circuits less malleable.
4
Q
How are developmental plasticity and lifelong learning related at the molecular level?
A
Similar molecular pathways underlie both developmental plasticity during critical periods and the synaptic modifications that support learning and memory throughout life, linking early circuit refinement to ongoing experience-dependent changes.
5
Q
What are the four main mechanisms of activity-dependent change?
A
- Extracellular signals (neurotrophins and neurotransmitters) secreted in response to neural activity. 2. Signal transduction via second messengers and effectors converting extracellular cues into intracellular responses. 3. Gene expression changes modulating transcription and protein production for structural remodeling. 4. Structural outcomes including axon and dendrite growth, synapse formation, stabilization, and pruning.
6
Q
What roles do neurotrophins and neurotransmitters play in activity-dependent plasticity?
A
Neurotrophins provide slow, long-term modulation of synaptic strength, while neurotransmitters trigger rapid, immediate activity-dependent responses; both are secreted in response to neural activity and guide synaptic modifications.
7
Q
How do second messengers and effectors contribute to synaptic change?
A
Second messengers and effectors transduce extracellular signals into intracellular cascades that ultimately regulate cytoskeletal dynamics and other processes required for structural remodeling of neurons.
8
Q
In what way does gene expression influence structural plasticity?
A
Activity-elicited signals modulate local transcription, adjusting the production of proteins (e.g., cytoskeletal elements, receptors, adhesion molecules) needed for axon/dendrite growth and synapse modification.
9
Q
What structural outcomes result from activity-dependent mechanisms?
A
Activity-dependent mechanisms lead to final adjustments in axonal and dendritic arborization patterns, growth of new synaptic contacts, strengthening and stabilization of correlated synapses, and pruning of weak or uncorrelated ones.
10
Q
What is ocular dominance plasticity?
A
Ocular dominance plasticity is the process by which connections between the eyes and the visual cortex are adjusted based on differential activity levels: more active eye inputs are strengthened and less active ones are weakened, optimizing binocular integration and depth perception.
11
Q
How does ocular dominance plasticity enhance depth perception?
A
By strengthening synapses from the more active eye and refining binocular circuitry, ocular dominance plasticity improves the brain’s ability to integrate slightly different images from each eye, which is fundamental for perceiving depth.
12
Q
What postnatal changes occur in the human cortex that reflect experience-dependent plasticity?
A
Postnatal changes include region-specific increases and decreases in cortical thickness and surface area, reflecting growth of new connections and pruning of excess synapses driven by environmental interactions.
13
Q
Why is experience-dependent plasticity clinically relevant?
A
Disruption of experience-dependent plasticity is implicated in intellectual disability, developmental delays, autism spectrum disorders, and psychiatric illnesses such as schizophrenia, highlighting its importance for normal cognitive and behavioral development.
14
Q
What is Hebb’s postulate?
A
Hebb’s postulate, formulated in 1949, states that ‘cells that fire together wire together’: coordinated presynaptic–postsynaptic activity strengthens synapses, whereas uncorrelated activity leads to synaptic weakening and potential elimination.
15
Q
How are correlated and uncorrelated inputs treated during development?
A
Correlated inputs lead to strengthening of existing synapses and sprouting of new branches, while uncorrelated inputs result in synaptic weakening, pruning, and in extreme cases, neuronal death.
16
Q
What are the functional consequences of Hebbian plasticity in development?
A
- Emergence of new behaviors and skills. 2. Enhanced capacity for complex skill acquisition during critical periods. 3. Postnatal brain growth driven by rapid synapse formation, followed by pruning that refines circuitry for efficiency.
17
Q
What characterizes the progressive phase of postnatal brain growth?
A
During the progressive phase, there is a rapid increase in dendritic and axonal arborization and synapse number, driving substantial brain enlargement in infancy and early childhood.
18
Q
What happens during the elimination phase around age 6?
A
Around age 6, many of the superfluous dendritic and axonal branches formed early in life are pruned away, leaving a refined, more efficient circuit shaped by the most active synapses during that early window.
19
Q
Describe synaptic pruning during adolescence.
A
In adolescence, total synapse count continues to decrease through pruning, but overall brain growth persists due to elaboration (strengthening and expansion) of the retained, functionally relevant connections.
20
Q
What is the difference between intrinsic wiring and experience-driven refinement?
A
Intrinsic wiring mechanisms guide initial axon targeting, map formation, and first synapse establishment to create a basic connectivity blueprint, while experience-driven refinement uses sensory and motor inputs to validate, adjust, and prune that initial circuitry.
21
Q
What role does experience play in circuit refinement?
A
Typical sensory and motor experiences reinforce appropriate synaptic connections and eliminate mismatches, ensuring that the developing brain’s circuits are fine-tuned for the individual’s environment.
22
Q
What are the consequences of diminished sensory input during development?
A
Sensory deprivation or transduction failure halts proper refinement, leading to altered connectivity and behavioral deficits; while permanent loss may allow some adaptive reorganization, temporary deprivation can produce long-lasting impairments.
23
Q
How do innate and experience-dependent behaviors differ?
A
Innate behaviors (e.g., feeding, predator avoidance, parental recognition) are generated by intrinsic developmental mechanisms and are present at birth, whereas more complex repertoires (e.g., human language) require environmental interaction for refinement and full expression.
24
Q
What distinguishes sharp versus extended critical windows?
A
Sharp windows (e.g., imprinting in hatchling birds) occur within narrow timeframes of hours to days and require immediate exposure to specific stimuli, while extended windows (e.g., song learning, language acquisition) unfold over weeks to months with gradual experience accumulation.
25
What are the four essential components of every critical period?
1. A defined temporal window of elevated plasticity. 2. Instructive environmental experiences without which development fails. 3. Neural readiness (appropriate receptor expression and baseline circuit activity). 4. A behavioral outcome that depends on the interaction of experience and neural plasticity.
26
What role do subthreshold oscillations play in critical period initiation?
Subthreshold patterned activity (graded potentials) in developing circuits primes them for later sensory-driven refinement, demonstrating that intrinsic oscillations precede and prepare for experience-dependent plasticity.
27
What are retinal waves and when do they occur?
Retinal waves are spontaneous bursts of action potentials (accompanied by Ca²⁺ influx) that sweep across the fetal or neonatal retina every few seconds before eye opening and phototransduction, informing early visual circuit formation.
28
What happens if neurotransmitter systems are blocked during retinal waves?
Pharmacological or genetic blockade of the neurotransmitter systems driving retinal waves abolishes the waves, disrupting the subthreshold oscillations necessary for proper visual pathway development.
29
How do asynchronous retinal waves drive Hebbian competition in the LGN?
Each eye generates retinal waves independently and asynchronously; this lack of correlation causes afferents from the two eyes to compete in the LGN, segregating into eye-specific layers based on relative activity levels.
30
What are ocular dominance columns and where do they form?
Ocular dominance columns are alternating bands of cortical neurons in layer 4 of primary visual cortex (V1) that preferentially respond to input from one eye, establishing a cortical map of eye-specific information.
31
Outline the anatomical pathway of visual information from retina to cortex.
Visual signals travel from the retina to the lateral geniculate nucleus (LGN) of the thalamus and then project to the primary visual cortex (V1), where eye-specific inputs terminate in layer 4 and are further integrated in superficial and deep layers.
32
What are the physiological differences between layer 4 and layers 2/3 & 5/6 in V1?
Layer 4 neurons in V1 are strongly or exclusively driven by one eye, while neurons in layers 2/3 and 5/6 integrate inputs from both eyes and exhibit graded binocular responsiveness.
33
What properties are shared by all critical periods?
All critical periods depend on adequate instructive stimuli and intrinsic circuit oscillations; they vary in onset, duration, and closure abruptness, but consistently demarcate when experience can tune a particular behavior.
34
How is ocular dominance measured experimentally?
Ocular dominance is measured by recording the activation of individual visual cortical neurons in response to stimulation of each eye separately, then classifying their responses into categories based on eye preference.
35
What are the seven ocular dominance groups?
Group 1: responds only to contralateral eye; Group 7: responds only to ipsilateral eye; Group 4: responds equally to both eyes; Groups 2,3 and 5,6 represent intermediate biases toward one eye or the other.
36
What is the normal distribution of ocular dominance in adult cats?
In adult cats (all layers except layer 4), ocular dominance follows a Gaussian distribution, with most neurons responding to both eyes (group 4) and fewer neurons showing strong preference for one eye.
37
What are the effects of monocular deprivation during the critical period?
Monocular deprivation during the critical period causes the cortex to become nearly unresponsive to the deprived eye, resulting in a functional 'cortical blindness' in that eye despite normal retinal and LGN responses.
38
What are the effects of monocular deprivation after the critical period?
Post–critical period deprivation produces minimal shifts in ocular dominance distribution; most neurons remain binocular or respond to the deprived eye, and visual behavior remains largely unaffected.
39
How do ocular dominance column widths change with deprivation?
With monocular deprivation, columns representing the non-deprived eye expand in width while deprived-eye columns shrink, though they are not eliminated entirely.
40
What changes occur in LGN axon arbors with short-term deprivation during the critical period?
After about one week of monocular 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, whereas axons from the open eye exhibit expanded, more complex arborizations.
41
What happens to LGN axon arbors with long-term deprivation?
Long-term deprivation yields minimal additional arbor change beyond the rapid initial remodeling, indicating that the major structural adjustments occur early in response to altered activity.
42
What is meant by competitive interaction in ocular dominance during the critical period?
Geniculocortical axons from each eye compete for postsynaptic territory in the visual cortex; if one eye is deprived (monocular deprivation), the active eye’s axons gain a competitive advantage and usurp territory from the inactive eye.
43
What happens to ocular dominance distribution under binocular deprivation?
When both eyes are deprived equally (binocular deprivation), the ocular dominance distribution remains approximately normal—both eyes retain territory—showing that relative, not absolute, activity levels drive competitive segregation.
44
What is dark rearing and how does it affect visual development?
Dark rearing—raising animals in total darkness—delays but does not prevent normal development; upon later light exposure, even after the typical critical period, visual acuity and ocular dominance patterns can recover to near-normal levels, unlike monocular deprivation.
45
How is strabismus experimentally induced, and what does it demonstrate?
Strabismus is induced by cutting one extraocular muscle to misalign the eyes; although both eyes receive normal input levels, corresponding retinal points are no longer synchronously stimulated, demonstrating that correlation of activity, not absolute input, is critical for normal binocular circuit formation.
46
How does strabismus affect ocular dominance columns in layer 4 of V1?
Strabismus enhances segregation in layer 4, producing sharper, narrower ocular dominance stripes for each eye, because increased asynchrony between eyes boosts Hebbian competition and reinforces same-eye inputs while weakening cross-eye inputs.
47
What effect does strabismus have on binocularity in supragranular and infragranular layers?
With strabismus, nearly all neurons in layers 2–3 and 5–6 lose binocularity and become strictly monocular (groups 1–2 and 6–7), abolishing the typical binocular convergence seen in normal development.
48
How do binocular neurons in young cortex (pre–critical period) tune to orientation?
Pre–critical period, binocular neurons exhibit weak and mismatched orientation preferences for each eye, with different peak firing orientations and low response amplitudes for identical stimuli.
49
What occurs to orientation tuning during the critical period under normal binocular experience?
During the critical period, coincident activation of both eyes by identical visual stimuli strengthens synapses from each eye onto the same neuron, aligning their orientation responses and producing neurons sharply tuned to the same angle regardless of which eye is stimulated.
50
How does monocular deprivation disrupt orientation tuning?
Monocular deprivation during the critical period abolishes binocular competition, leaving orientation tuning unmatched after reopening; subsequent experience cannot restore congruence between the eyes’ orientation maps.
51
Why does closing one eye after the critical period have no effect on orientation tuning?
After the critical period closes, the circuitry is no longer malleable enough to rewire orientation maps, so monocular closure has no effect on the already established orientation tuning congruence.
52
What functional deficits arise from amblyopia and strabismus?
Amblyopia and strabismus produce reduced visual acuity, impaired stereopsis (depth perception), and poor binocular fusion, because disrupted binocular competition during the critical period leads the brain to suppress input from the misaligned or deprived eye.
53
How does the brain prevent double vision in strabismus?
To avoid diplopia, the brain suppresses input from the misaligned eye, giving the fellow eye’s inputs a competitive advantage in the LGN and visual cortex.
54
What is the prognosis for unilateral deprivation corrected before ~4 months?
If congenital cataracts or corneal scarring in one eye are corrected before about 4 months of age, the previously deprived eye can attain near‐normal visual acuity; beyond this window, amblyopia becomes largely irreversible.
55
Why is prognosis better in bilateral deprivation?
In bilateral deprivation, balanced lack of input preserves relative ocular dominance, allowing both eyes to recover substantial acuity even if treatment (e.g., restoration of vision) is delayed.
56
What defines the cellular and molecular regulation of critical periods?
Critical periods depend on molecular machinery that converts activity-driven synaptic signals into lasting connectivity changes, but only within a defined developmental window; after closure, these pathways become refractory to large-scale rewiring.
57
What roles do NMDA and AMPA receptors play in glutamate-mediated Ca²⁺ signaling?
AMPA receptors mediate Na⁺ currents and produce slight depolarization under weak stimulation, while NMDA receptors (blocked by Mg²⁺ at rest) permit Ca²⁺ and Na⁺ influx upon sufficient depolarization, initiating downstream plasticity signaling.
58
What happens at synapses under weak glutamatergic stimulation?
Under weak stimulation, only AMPA receptors are activated, causing slight depolarization but leaving NMDA receptors blocked by Mg²⁺, preventing Ca²⁺ influx at those synapses.
59
What occurs when stimulation is sufficient at glutamatergic synapses?
Sufficient stimulation activates AMPA receptors strongly and binds glutamate to NMDA receptors, relieving the Mg²⁺ block; NMDA channels open to allow localized Ca²⁺ influx, triggering intracellular signaling cascades.
60
What are metabotropic glutamate receptors (mGluRs)?
mGluRs are G-protein–coupled receptors that respond to glutamate by engaging intracellular second-messenger cascades, modulating processes like local protein synthesis and cytoskeletal dynamics.
61
What role do voltage-sensitive Ca²⁺ channels (L-VSCCs) play?
L-VSCCs open upon significant membrane depolarization, allowing additional Ca²⁺ entry that complements NMDA receptor–mediated Ca²⁺ influx for plasticity signaling.
62
How do CaMKII and CaMKIV contribute to synaptic plasticity?
Postsynaptic Ca²⁺ activates CaMKII and CaMKIV, which phosphorylate AMPA receptors to increase their conductance and promote trafficking/insertion of new AMPA receptors into the synaptic membrane.
63
What distinguishes early LTP from late LTP?
Early LTP involves Ca²⁺-activated kinases driving AMPA receptor insertion and increased EPSPs, while late LTP requires gene transcription and protein synthesis to stabilize structural and receptor changes for long-term maintenance.
64
What is the function of ubiquitin ligase Ube3a in synaptic plasticity?
Ube3a targets proteins involved in AMPA receptor endocytosis for ubiquitination, reducing their removal from the synapse and thereby helping to maintain elevated synaptic strength.
65
What are neurexins and neuroligins?
Neurexins (presynaptic) and neuroligins (postsynaptic) are cell-adhesion molecules that form trans-synaptic complexes to organize synaptic structure and regulate synapse function.
66
What roles do scaffolding proteins play at synapses?
Scaffolding proteins (e.g., PSD95, GKAP, SHANK, HOMER) organize synaptic components, anchor receptors and signaling molecules, and adapt synapse structure in response to neuronal activity.
67
How does the mTOR pathway support synaptic plasticity?
The mTOR pathway regulates local protein synthesis, ensuring that new receptors and structural proteins are produced at active synapses precisely where and when needed for plasticity.
68
What is the role of BDNF-TrkB signaling in experience-dependent plasticity?
Activity-induced BDNF release binds TrkB receptors, activating the Ras→RAF→ERK kinase cascade; together with CaMK signals, this pathway drives CREB-mediated gene expression to embed long-term synaptic changes.
69
Why are mutations in plasticity-related genes clinically significant?
Mutations in genes encoding molecules like BDNF, CaMKII, Ube3a, neurexins, neuroligins, and scaffolding proteins disrupt synaptic plasticity and are implicated in intellectual disability and autism spectrum disorders.
70
What is the role of GABAergic interneurons in critical-period plasticity?
GABAergic interneurons regulate the timing and extent of critical-period plasticity by establishing inhibitory synapses whose maturation balances excitation and shapes the window of heightened plasticity.
71
What is excitatory/inhibitory (E/I) balance and why is it important?
E/I balance refers to the shift from predominantly excitatory early networks to a balanced excitatory and inhibitory state, which is essential for proper critical-period plasticity and network stability.
72
How does evidence for a language critical period differ from the visual system?
Language critical-period evidence relies on behavioral milestones (e.g., babbling) and neuroimaging, rather than direct circuit-level measurements; it shows similar age-restricted windows for optimal acquisition.
73
When do hearing infants begin vocal babbling and why is it important?
Hearing infants start producing speech-like syllables around seven months, a practice that refines later speech production and marks the onset of the language critical period.
74
What happens to congenitally deaf infants without early linguistic access?
Without early exposure to a linguistic modality, congenitally deaf infants fail to develop coherent symbolic language, demonstrating the necessity of critical-period input for language acquisition.
75
What is manual babbling in deaf infants?
Deaf infants born to signing parents exposed to sign language from about six months produce hand-shape “babble” between 10–14 months, mirroring the timetable of vocal babbling in hearing infants.
76
What are the effects of hearing loss before puberty on language?
Children who acquire speech and then lose hearing before puberty suffer declines in spoken language fluency, underscoring the need for ongoing auditory feedback during the latter portion of the critical window.
77
What is perceptual narrowing in phoneme discrimination?
Very young infants can distinguish phonetic contrasts across all human languages, but by six months they focus on native-language sounds, and by 12 months their ability to differentiate non-native phonemes declines markedly.
78
What neuroimaging evidence supports developmental changes in language processing?
fMRI studies comparing children (7–10 years) with adults on the same word-processing tasks show different patterns and loci of cortical activation, indicating age-dependent reorganization of language circuits.
79
What are the implications of age-dependent shifts in language-related activation?
These shifts suggest that brain circuits for language undergo functional or structural reorganization during early life, analogous to synaptic remodeling in sensory critical periods, to optimize language processing.
80
Why does the adult mammalian brain produce very few new neurons compared to tissues like skin or liver?
Once prenatal/early postnatal neurogenesis completes, most regions of the adult mammalian brain have quiescent neural stem cells and lack the proliferative cues present in epithelia, blood, bone, or liver, resulting in minimal production of new neurons.
81
How do peripheral axons regenerate after injury?
Severed sensory or motor axons in peripheral nerves regrow robustly by extending through residual Schwann‐cell basal laminae (nerve sheaths), which guide regenerating growth cones back to their original skin receptors or muscle endplates.
82
Why is true regeneration limited in the central nervous system (CNS)?
CNS injuries typically do not regenerate neurons, axons, or dendrites; instead, any observed recovery after brain injury reflects reorganization of surviving circuits rather than true regeneration, due to inhibitory factors and lack of growth‐promoting environment.
83
What are the four principal barriers to CNS regeneration?
1. Neuron loss: injury‐induced apoptosis or necrosis of damaged neurons. 2. Glial inhibition: reactive astrocytes and oligodendrocytes secrete molecules (chondroitin sulfate proteoglycans, myelin‐associated inhibitors) that block axon growth. 3. Restricted neural stem cells: adult progenitors in most brain regions remain quiescent with limited proliferation or differentiation. 4. Immune‐mediated cytokines: microglia and astrocytes release inflammatory cytokines and reactive oxygen species that impede regrowth.
84
How can functional recovery occur after stroke without true tissue regeneration?
Recovery occurs via functional reorganization of surviving circuits: unmasking latent pathways, activity‐dependent synaptic plasticity (LTP/LTD), modest sprouting of new dendritic spines and axon collaterals, and ipsilateral compensation by the undamaged hemisphere.
85
What is the unmasking of latent circuits in post-stroke recovery?
Latent circuits are normally silent pathways that become unmasked when primary pathways are damaged; these hidden connections in adjacent or parallel regions become active to compensate for lost motor or language functions.
86
Describe the role of synaptic plasticity in stroke recovery.
Surviving synapses undergo strengthening or weakening (akin to LTP/LTD) to rebalance excitation and inhibition, optimizing the efficiency of remaining circuits and supporting the relearning of lost functions.
87
What is modest sprouting following CNS injury?
Modest sprouting refers to growth of new dendritic spines and axon collaterals by surviving neurons near the lesion, which form new synaptic connections and alternative pathways for information flow.
88
How does ipsilateral compensation contribute to motor recovery after stroke?
The undamaged (ipsilateral) motor cortex increases its output to ipsilateral spinal tracts or via brainstem relays, helping control movements of the affected limb when contralateral pathways are compromised.
89
What fMRI changes are observed in primary motor cortex plasticity after stroke?
Early post-stroke fMRI shows bilateral hyperactivation in motor and visual areas; as rehabilitation proceeds, activation contracts toward more localized, ipsilesional patterns, with persistent hyperactivation correlating with poorer recovery.
90
What are the three fundamental types of neuronal repair in the damaged nervous system?
1. Axonal regrowth from surviving neurons. 2. Sprouting and repair of existing central neurons. 3. Neuronal replacement via adult neurogenesis.
91
What is involved in axonal regrowth from surviving neurons?
Surviving neurons—either peripheral sensory/motor neurons or central neurons with intact cell bodies—reactivate developmental growth programs (cytoskeletal extension, guidance responsiveness, synaptogenesis) to extend axons and reinnervate original targets.
92
What mechanisms must be reactivated for developmental axon‐growth programs?
Programs include cytoskeletal polymerization, responsiveness to guidance cues (e.g., netrins, semaphorins), growth‐cone motility, and synaptogenic signals to form functional connections at the correct targets.
93
What is activity‐dependent matching during axon regrowth?
Newly regrown axons compete for postsynaptic sites in a Hebbian manner: inputs that fire in synchrony with target neurons stabilize and maintain connections, ensuring appropriate numerical balance between regrown inputs and denervated targets.
94
What clinical outcome is associated with robust peripheral nerve regeneration?
Peripheral nerve injuries often recover motor or sensory function effectively when axons regrow through Schwann‐cell basal laminae, making this the most robust form of neural repair in mammals for limb nerve injuries.
95
How does sprouting and repair of existing central neurons occur?
Surviving CNS neurons near a lesion reinitiate developmental programs for polarity (axon vs. dendrite specification), adhesion‐mediated process extension, and neurotrophic signaling, allowing them to regrow short branches and form new synapses.
96
What factors limit CNS sprouting near injury sites?
Reactive astrocytes and oligodendrocytes form a glial scar rich in inhibitory molecules (chondroitin sulfate proteoglycans, myelin inhibitors), while microglia and infiltrating immune cells release cytokines that further suppress neuronal outgrowth.
97
What are the typical distances CNS axon sprouting can achieve post-injury?
Sprouting in the CNS is generally restricted to short distances—only a few hundred micrometers to millimeters—from the lesion border, due to the dense inhibitory environment.
98
What is neuronal replacement via adult neurogenesis?
The generation of entirely new neurons from adult stem/progenitor cells in specific niches (e.g., olfactory epithelium, hippocampal dentate gyrus) that migrate, differentiate, and integrate to replace lost cells.
99
What is an established example of adult neurogenesis in mammals?
Olfactory receptor neurons are continuously replaced throughout life, with their axons guided by olfactory‐ensheathing cells to integrate into the olfactory bulb.
100
What conditions are necessary for successful CNS neuronal replacement?
1. Presence of multipotent stem cells in or near the lesion. 2. A permissive microenvironment with supportive trophic and adhesion cues. 3. Recapitulation of developmental processes: migration, process outgrowth, synaptogenesis, and accurate long‐distance targeting.
101
What were the two phases of sensory recovery described by Hugh Head after peripheral nerve transection?
1. Protopathic recovery: rapid return of basic touch and pressure sensations via large, less specialized fibers. 2. Epicritic recovery: slower return of fine touch, temperature, and pain via small, specialized fibers requiring precise reconnection.
102
Why do protopathic sensations recover more quickly than epicritic sensations?
Protopathic fibers are larger and less specialized, making them easier to regenerate and reinnervate targets, whereas epicritic fibers are smaller, more specialized, and need exact molecular cues (neurotrophins, adhesion molecules) for precise reconnection.
103
How does fine motor control recovery compare to gross extension strength after nerve injury?
Fine motor control (epicritic modality) lags behind gross extension strength (protopathic modality) because fine control relies on precise reconnection of small specialized fibers, which regenerate more slowly and less accurately.
104
What surgical factors maximize functional recovery after peripheral nerve injury?
Timely and precise microsurgical repair that aligns perineurial/endoneurial sheaths preserves the basal lamina scaffold, promoting accurate axon regrowth and minimizing persistent deficits in fine sensation and dexterity.
105
Which cellular players guide and support peripheral nerve regeneration?
Schwann cells and macrophages are the key cellular players: Schwann cells form bands of Büngner and secrete growth‐permissive matrix and neurotrophins, while macrophages clear debris and modulate Schwann‐cell behavior.
106
What roles do Schwann cells play after peripheral nerve injury?
They proliferate, align within basal lamina tubes to form bands of Büngner guiding regenerating axons; secrete extracellular matrix components; upregulate adhesion molecules; and produce neurotrophins for fiber‐specific regrowth.
107
How do Schwann cells contribute to protopathic versus epicritic recovery?
Early after injury, Schwann cells produce broad-acting neurotrophins promoting rapid protopathic fiber regrowth; later they express specific Trk ligands (e.g., BDNF, NT-3) to guide mechanoreceptive and proprioceptive fibers needed for epicritic recovery.
108
What is the role of macrophages in Wallerian degeneration and regeneration?
Macrophages infiltrate the distal stump to phagocytose myelin and axonal debris (Wallerian degeneration) and secrete cytokines that activate Schwann cells and create a regenerative milieu.
109
Describe Wallerian degeneration and how it creates a regeneration scaffold.
After axon severance, the distal segment undergoes programmed degeneration; debris clearance by macrophages leaves intact basal lamina sheaths that act as continuous extracellular matrix conduits guiding proximal axon regrowth.
110
How do crush injuries differ from transections in nerve regeneration outcomes?
Crush injuries preserve some Schwann‐cell alignment and basal lamina continuity, leading to faster and more accurate axon regrowth; transections require surgical reapposition and are more prone to misalignment and imprecise reconnection.
111
What gene‐expression changes occur in injured motor and sensory neurons?
Injured neurons upregulate regeneration‐associated genes—including cytoskeletal proteins, growth‐associated protein‐43 (GAP-43), neurotrophin receptors, and adhesion molecules—recapitulating developmental transcriptional programs.
112
How can peripheral nerve grafts induce CNS axon outgrowth?
Peripheral nerve grafts provide Schwann cells, basal lamina, and growth‐permissive cues; when CNS axons are inserted into these grafts, they can extend and partially regenerate, demonstrating that the CNS neurons retain intrinsic growth potential but lack supportive environment.
113
What do peripheral nerve graft experiments imply about CNS regenerative capacity?
They suggest that CNS neurons have latent growth potential that can be unleashed if provided with a permissive peripheral‐type environment, highlighting that lack of regeneration in the CNS is due more to extrinsic inhibitory factors than intrinsic neuronal deficits.
114
115
What distinguishes peripheral from central nervous system regeneration?
Peripheral axon regrowth is robust—severed sensory or motor axons extend through residual Schwann-cell basal laminae to reinnervate targets—whereas CNS repair is minimal, with observed recovery reflecting reorganization of surviving circuits rather than true regeneration of damaged neurons, axons, or dendrites.
116
What are the four principal barriers to CNS regeneration?
1. Neuron loss: injury triggers apoptosis/necrosis of damaged neurons. 2. Glial inhibition: reactive astrocytes and oligodendrocytes secrete inhibitory molecules (chondroitin sulfate proteoglycans, myelin-associated inhibitors) that block axon extension. 3. Restricted neural stem cells: adult progenitors in most brain regions remain quiescent with limited proliferation and differentiation. 4. Immune-mediated cytokines: microglia and astrocytes release inflammatory cytokines and reactive oxygen species that impede regrowth and exacerbate damage.
117
What role does neuron loss play in inhibiting CNS regeneration?
Local injury frequently triggers apoptosis or necrosis of neurons whose axons or cell bodies are damaged, removing cells capable of regrowth.
118
How do reactive astrocytes and oligodendrocytes inhibit CNS axon growth?
They secrete inhibitory molecules such as chondroitin sulfate proteoglycans and myelin-associated inhibitors that actively block axon extension and hinder neural repair.
119
Why is limited neural stem cell activation a barrier to CNS repair?
Although niches like the subventricular zone and hippocampal dentate gyrus harbor neural stem cells, progenitors in most brain regions remain quiescent, exhibiting limited proliferation, migration, or differentiation into functional neurons.
120
How do immune-mediated cytokines impede CNS regeneration?
Microglia and astrocytes release inflammatory cytokines and reactive oxygen species after injury, which further impede axon regrowth and can exacerbate tissue damage.
121
What mechanisms enable functional recovery after stroke without true regeneration?
Recovery involves functional reorganization: unmasking latent circuits, synaptic plasticity (LTP/LTD) to rebalance surviving synapses, modest sprouting of dendritic spines and axon collaterals, and ipsilateral compensation by the undamaged hemisphere.
122
What is meant by unmasking of latent circuits in stroke recovery?
Latent circuits are normally silent pathways that become unmasked when primary pathways are damaged, allowing adjacent or parallel regions to assume lost functions in the absence of new tissue growth.
123
How does synaptic plasticity contribute to post-stroke recovery?
Surviving synapses undergo strengthening or weakening akin to long-term potentiation or depression, adjusting the excitatory/inhibitory balance in remaining circuits to optimize compensatory function.
124
What is modest sprouting after CNS injury?
Surviving neurons near the lesion grow new dendritic spines and axon collaterals to form alternative pathways and new synapses, aiding functional compensation.
125
Describe ipsilateral compensation in motor recovery.
The uninjured hemisphere increases its output to ipsilateral spinal tracts or via brainstem relays, helping control the affected limb when contralateral motor pathways are compromised.
126
What fMRI changes characterize primary motor cortex plasticity post-stroke?
Early fMRI shows bilateral hyperactivation in motor and visual areas, which contracts toward more localized ipsilesional activation as rehabilitation progresses; persistent hyperactivation often correlates with poorer functional recovery.
127
What are the three fundamental types of neuronal repair?
1. Axonal regrowth from surviving neurons. 2. Sprouting and repair by existing central neurons. 3. Neuronal replacement via adult neurogenesis.
128
What does axonal regrowth from surviving neurons entail?
Peripheral axons or central neurons with intact cell bodies reactivate developmental growth programs—cytoskeletal extension, guidance-cue responsiveness, synaptogenesis—and regrow axons to reinnervate their original targets.
129
What developmental programs must be reactivated for axon regrowth?
Programs include cytoskeletal polymerization, growth-cone motility, responsiveness to guidance cues (e.g., netrins, semaphorins), and synaptogenic signaling to form functional connections.
130
What is activity-dependent matching in axonal regrowth?
Newly regrown axons compete for postsynaptic sites via Hebbian processes: inputs that fire synchronously with target neurons stabilize, ensuring appropriate numerical balance between regrown inputs and denervated targets.
131
Why is peripheral nerve regeneration considered robust?
Peripheral nerves regenerate effectively through Schwann-cell basal lamina tubes, guiding regenerating axons to reinnervate skin receptors or muscle endplates, making it the most robust form of mammalian neural repair.
132
What characterizes sprouting and repair of existing central neurons?
Surviving CNS neurons near a lesion reinitiate polarity specification, adhesion-mediated process extension, and neurotrophic signaling to sprout new dendrites or axon collaterals and form synapses.
133
How do glial scars limit sprouting in the CNS?
Reactive astrocytes and oligodendrocytes form a dense glial scar rich in inhibitory molecules that insulate lesions, contain inflammation, but also block axon reextension and reconnection.
134
Over what distances does CNS sprouting typically occur?
Sprouting in the CNS is restricted to short distances—on the order of hundreds of micrometers to a few millimeters—from the lesion border due to inhibitory extracellular environment.
135
What is neuronal replacement via adult neurogenesis?
The generation of new neurons from adult stem/progenitor cells in niches like the SVZ and SGZ that migrate, differentiate, and integrate to replace lost cells, although this is rare in most CNS regions.
136
What is a well-established example of adult neurogenesis?
Olfactory receptor neurons are continuously replaced throughout life, with their axons guided by olfactory-ensheathing cells to integrate into the olfactory bulb.
137
What conditions are necessary for successful neuronal replacement in the CNS?
Three conditions: presence of multipotent stem cells in or near the lesion; a permissive microenvironment with trophic and adhesion cues; and recapitulation of developmental processes—migration, process outgrowth, synaptogenesis, long-distance targeting.
138
What are the protopathic and epicritic phases of sensory recovery described by Hugh Head?
Protopathic recovery (basic touch and pressure) occurs rapidly through regeneration of larger, less specialized fibers, while epicritic recovery (fine touch, temperature, pain) is slower and often incomplete, requiring precise reinnervation by small specialized fibers.
139
Why do protopathic sensations recover faster than epicritic sensations?
Protopathic fibers are larger and less specialized, making them easier to regenerate and reinnervate, whereas epicritic fibers are small, highly specialized, and require precise molecular cues for correct reconnection.
140
How does fine motor control recovery compare to gross strength after peripheral nerve injury?
Fine motor control (epicritic modalities) lags behind gross extension strength (protopathic modalities) because precise reconnection of specialized fibers is slower and more error-prone.
141
What surgical factors optimize peripheral nerve repair outcomes?
Timely, precise microsurgical alignment of severed nerve ends ensures continuity of basal lamina conduits and accurate axon regrowth, minimizing persistent deficits in fine sensation and dexterity.
142
What roles do Schwann cells play in peripheral nerve regeneration?
After injury, Schwann cells proliferate, align into bands of Büngner within basal lamina tubes, secrete extracellular matrix and neurotrophins, and upregulate adhesion molecules to guide and support regenerating axons.
143
How do Schwann cells support protopathic versus epicritic fiber regrowth?
Initially, they secrete general neurotrophins (e.g., NGF, BDNF) promoting protopathic fiber regrowth; later, they express specific Trk ligands to guide mechanoreceptive and proprioceptive fibers needed for epicritic recovery.
144
What is the role of macrophages in Wallerian degeneration?
Macrophages infiltrate the distal stump, phagocytose myelin and axonal debris, and secrete cytokines that modulate Schwann-cell behavior, clearing the path for regeneration.
145
What is Wallerian degeneration and how does it facilitate regeneration?
Following axotomy, the distal axon segment undergoes programmed degeneration; debris clearance by macrophages leaves intact basal lamina sheaths that serve as scaffolds guiding proximal axon regrowth.
146
How do crush injuries differ from transections in nerve regeneration?
Crush injuries preserve Schwann-cell alignment and basal lamina continuity, resulting in faster, more accurate regrowth; transections disrupt continuity, requiring precise surgical reapposition to avoid misalignment.
147
What gene-expression changes occur in injured neurons supporting regeneration?
Injured motor and sensory neurons upregulate regeneration-associated genes—cytoskeletal proteins, GAP-43, neurotrophin receptors, adhesion molecules—reinstating developmental transcriptional programs for outgrowth.
148
How can peripheral nerve grafts induce CNS axon regrowth?
Peripheral grafts supply Schwann cells, basal lamina, and growth-permissive cues; when CNS axons extend into these grafts, they can regenerate, showing that CNS neurons have latent growth potential but lack supportive environment.
149
What ensures persistence of synaptic basal lamina at the NMJ after injury?
The synaptic portion of the muscle basal lamina, including specialized ECM components, remains intact for weeks after axon degeneration, preserving a scaffold for regenerating axons to reform synapses.
150
How do trophic factor levels change at the NMJ after denervation?
Levels of neurotrophic factors like NGF and BDNF are upregulated at damaged NMJ sites to attract regenerating axons and promote synapse reformation, while factors that maintain stable synapses are downregulated to increase receptivity.
151
What mechanisms maintain postsynaptic receptor clusters at denervated NMJs?
Neuregulin–ErbB signaling sustains acetylcholine receptor (AChR) clusters in the absence of nerve fibers, preserving postsynaptic scaffold readiness for rapid synapse regeneration.
152
Describe the agrin–Lrp4–MuSK pathway in NMJ regeneration.
Agrin secreted by regenerating nerve terminals and Schwann cells binds Lrp4, activating MuSK to cluster and stabilize AChRs at the postsynaptic membrane, ensuring precise alignment for functional reconnection.
153
What roles do synaptic ECM components play at the NMJ?
Synaptic ECM provides structural support, organizes the synaptic cleft, and concentrates essential molecules such as growth factors and acetylcholinesterase to facilitate efficient neurotransmission post-regeneration.
154
Why is acetylcholinesterase localization important in NMJ repair?
Anchored AChE in the synaptic cleft ensures rapid and precise hydrolysis of acetylcholine, preventing neurotransmitter spillover and allowing accurate muscle control during and after regeneration.
155
How do basal lamina tubes guide regenerating motor axons at the NMJ?
Even if muscle fibers degenerate, the preserved basal lamina tubes containing synaptic ECM cues direct regenerating motor axons back to the original synaptic sites to reform functional junctions.
156
What is polyneuronal innervation at the regenerating NMJ?
Initially after regeneration, muscle fibers are innervated by multiple motor axons—recapitulating early developmental innervation patterns—before synapse elimination refines single innervation.
157
What triggers apoptosis in neurons after CNS injury?
Apoptosis can be triggered by hypoxia/ischemia, excitotoxic glutamate release, trophic factor withdrawal, DNA damage, and oxidative stress, initiating programmed cell death cascades.
158
What molecular cascade executes neuronal apoptosis?
Inhibiting Bcl-2 leads to cytochrome c release from mitochondria, activating caspases, which then drive DNA fragmentation, chromatin condensation, membrane blebbing, and cytoskeletal breakdown.
159
What is the role of autophagy in injured neurons?
Basal autophagy recycles damaged organelles and proteins to maintain energy homeostasis and support neuron survival under mild stress, but dysregulated autophagy can contribute to neurodegenerative diseases and may culminate in cell death if overwhelmed.
160
How does glutamate-mediated excitotoxicity damage neurons?
Injury-induced glutamate release causes prolonged NMDA/AMPA receptor activation, leading to massive Ca²⁺ influx, activation of degradative enzymes (proteases, lipases), mitochondrial damage, and propagation of inflammation via DAMPs.
161
What are astrocyte and microglia responses to CNS injury?
Astrocytes hypertrophy and proliferate to form a glial scar rich in inhibitory molecules, while microglia phagocytose debris and secrete cytokines and reactive oxygen/nitrogen species that can be both neurotoxic and neuroprotective.
162
How do developmental chemorepellent cues form chemical barriers after CNS injury?
Injured CNS tissue re-expresses guidance molecules (e.g., semaphorins, ephrins) that act as chemorepellents, creating biochemical obstacles that prevent regenerating axons from crossing the scar boundary.
163
What extrinsic factors contribute to poor CNS regeneration?
Injured CNS neurons fail to upregulate growth-associated transcription factors and cytoskeletal genes, lack Schwann-cell-like support, have limited ECM permissiveness, and receive minimal neurotrophic factor production at lesion sites.
164
What is the net effect of inhibitory signals on injured CNS axons?
Axons are repelled from the injury epicenter, fail to cross the scar boundary, and retract, resulting in permanent disconnection and loss of function.
165
How does blood–brain barrier disruption affect CNS injury?
Mechanical or ischemic damage opens tight junctions in the BBB, allowing serum proteins and immune cells to infiltrate the CNS parenchyma, exacerbating inflammation and neural damage.
166
Where do adult neural stem cells reside in the mammalian brain?
Neural stem cells persist primarily in two niches: the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus.
167
What is the fate of neural progenitors from the SVZ?
SVZ progenitors migrate along the rostral migratory stream to the olfactory bulb, where they differentiate into GABAergic interneurons involved in olfaction.
168
What is the fate of neural progenitors from the SGZ?
SGZ progenitors differentiate into granule neurons that integrate locally into the dentate gyrus, contributing to hippocampal functions like memory encoding.
169
How does injury affect adult neurogenesis?
Injury can transiently increase proliferation in SVZ and SGZ niches, but most new neurons fail to survive or integrate outside these regions, resulting in minimal functional replacement.
170
What cellular composition characterizes NSCs in neurosphere assays?
In neurosphere assays, single NSCs can self-renew and differentiate into neurons, astrocytes, and oligodendrocytes, demonstrating their multipotency.
171
What are the lineage stages of adult NSCs?
Type B cells (NSCs) are slow or nondividing; Type C cells (transit-amplifying progenitors) divide rapidly; neuroblasts/glioblasts migrate to target regions before differentiating into specialized neurons or glia.
172
How do neuroblasts migrate to the olfactory bulb?
Newborn neuroblasts travel through the rostral migratory stream in glial tubes formed by astrocyte-like cells, adhering via ECM-integrin interactions and employing polysialylated NCAM and Neuregulin–ErbB4 cues for chain migration.
173
What molecular factors facilitate chain migration in the RMS?
ECM components and integrins mediate adhesion, polysialylated NCAM reduces cell-cell adhesion to enable movement, and Neuregulin–ErbB4 signaling provides chemokinetic cues for directed migration.
174
What is the survival rate of adult-born neurons?
Most adult-born neurons undergo apoptosis unless they successfully form synaptic connections and receive trophic support, limiting their integration and long-term contribution.
175
What potential functions do adult-born neurons serve?
Adult neurogenesis may aid in olfactory discrimination, hippocampus-dependent learning and memory, and mood regulation, although the precise mechanisms remain under investigation.
176
What challenges limit CNS repair via endogenous neurogenesis?
Lack of migratory routes beyond the RMS, restricted lineage potential of NSCs, and survival/integration hurdles due to high attrition of newborn cells restrict widespread CNS repair.
177
Is there evidence of cortical neurogenesis in the adult human brain?
No reliable evidence exists for the generation of new projection neurons or interneurons in the adult human neocortex, indicating that endogenous stem cells cannot repopulate cortical circuits after injury or degeneration.
178
179
Define learning in the context of neuroscience.
Learning is the process by which experiences alter the nervous system and behavior through enduring changes in neural circuits.
180
Define memory according to Carlson.
Memory is the long-term changes in neural circuits produced by learning, encompassing enduring synaptic modifications and, in some cases, adult neurogenesis, rather than a storage of discrete events.
181
What is neural plasticity?
Plasticity is the capacity of the nervous system to change its structure and function—chiefly through synaptic modification (LTP/LTD) and adult neurogenesis—underlying all forms of learning and memory.
182
Name the four types of learning described by Carlson.
The four types of learning are stimulus–response learning, motor learning, perceptual learning, and relational (cognitive) learning.
183
What is stimulus–response learning?
Stimulus–response learning forms associations between a specific stimulus and a behavioral response, linking sensory pathways to motor/output pathways.
184
What is classical (Pavlovian) conditioning?
Classical conditioning associates a conditioned stimulus (CS) with an unconditioned stimulus (US), so that the CS alone eventually elicits the response originally produced by the US.
185
What is operant (instrumental) conditioning?
Operant conditioning links an action to its consequence, strengthening behaviors that are followed by reinforcing outcomes rather than reflexive responses.
186
Which circuits underlie stimulus–response learning?
Stimulus–response learning engages sensory pathways that detect the stimulus and motor/output pathways that produce the behavioral response.
187
What is motor learning?
Motor learning is the acquisition and refinement of skilled movements, progressing from cognitively demanding stages to automatized performance.
188
Which brain structures are involved in motor learning?
Motor learning involves the motor cortex, cerebellum, and basal ganglia, each contributing to planning, error correction, and habit formation.
189
Describe the stages of motor learning.
Motor learning begins with an early, attention‐demanding phase requiring cognitive control, and transitions to an automatic phase where movements are executed skillfully with minimal conscious effort.
190
What is perceptual learning?
Perceptual learning is the enhanced ability to discriminate sensory stimuli—such as phonemes or textures—through practice, reflecting changes in sensory cortical tuning.
191
What is relational (cognitive) learning?
Relational learning links multiple stimuli, events, or spatial locations into coherent representations, dependent on the hippocampus and medial temporal lobe.
192
Which brain structures underlie relational learning?
Relational learning relies on the hippocampus and related medial temporal lobe structures to form spatial maps and episodic memories.
193
What is reinforcement in learning?
Reinforcement increases the likelihood that a particular stimulus will evoke a specific response in the future by strengthening connections between perceptual and motor circuits.
194
How are different learning types integrated during complex tasks?
Complex tasks—like learning an instrument—combine perceptual learning (recognizing notes), motor learning (finger placement), stimulus–response learning (cue–movement associations), and relational learning (sequencing and expression).
195
What are the four stages of memory formation?
The stages are encoding (acquisition of new information), consolidation (stabilization of changes), storage (maintenance of traces), and retrieval (reactivation to guide behavior).
196
What is sensory memory?
Sensory memory holds raw sensory impressions for fractions of a second to seconds, allowing initial processing before rapid decay unless attended.
197
Describe echoic memory.
Echoic memory is the brief auditory trace of sounds that persists for a few seconds after the sound ends.
198
Describe iconic memory.
Iconic memory is the fleeting visual afterimage that lasts only a fraction of a second after a visual stimulus disappears.
199
What is the capacity of sensory memory?
Sensory memory has a very large capacity—capturing nearly all incoming stimuli—but information decays rapidly or is displaced unless attended.
200
What is short-term (working) memory?
Short-term memory holds information for seconds to minutes with a limited capacity (about 7 ± 2 chunks) and relies on rehearsal to maintain items.
201
How does rehearsal affect short-term memory?
Rehearsal—repeating or actively thinking about information—prolongs its retention in short-term memory and increases the chance it transfers to long-term storage.
202
What is chunking and how does it aid memory?
Chunking groups discrete items into larger, meaningful units (e.g., phone number segments), effectively expanding short-term memory capacity.
203
What determines which information transfers from STM to LTM?
Only information deemed salient or that undergoes rehearsal in short-term memory is gated for consolidation into long-term memory.
204
Define long-term memory.
Long-term memory stores information from minutes to a lifetime with effectively unlimited capacity, maintained through consolidated structural and functional changes in neural circuits.
205
What processes comprise long-term memory?
Long-term memory involves consolidation (stabilizing traces), storage (maintaining changes), and retrieval (reactivating stored information), with repeated retrieval further strengthening memories.
206
What is nondeclarative (implicit) memory?
Nondeclarative memory is unconscious and automatic, encompassing motor skills, perceptual skills, and stimulus–response habits—'knowing how' without conscious recall.
207
List forms of nondeclarative memory.
Forms include motor skills (e.g., riding a bike), perceptual skills (e.g., shape discrimination), and stimulus–response habits from classical and operant conditioning.
208
What are the neural substrates of nondeclarative memory?
Nondeclarative memory depends on the basal ganglia, cerebellum, and sensorimotor cortices for skill learning and habit formation.
209
What is declarative (explicit) memory?
Declarative memory is conscious and reportable—'knowing that'—including episodic memories of personal experiences and semantic memories of facts.
210
What is episodic memory?
Episodic memory stores personal events with contextual details (what, where, when) acquired in a single time-stamped episode, dependent on the hippocampus and medial temporal structures.
211
What is semantic memory?
Semantic memory stores facts and general knowledge—meanings and concepts—acquired gradually and decontextualized from specific learning episodes, relying on distributed neocortical networks.
212
How does perceptual learning translate stimuli into responses?
Perceptual learning changes circuits that detect stimuli, which then drive changes in motor circuits during motor learning, culminating in the appropriate behavioral response.
213
Outline the information-processing model of memory.
The model flows from sensory input to sensory memory, through attention to short-term memory, encoding into long-term memory, and retrieval back into short-term memory when needed.
214
What role does attention play in memory processing?
Attention selects which sensory inputs enter short-term memory; unattended information in sensory memory is lost before encoding.
215
How does the hippocampus contribute to declarative memory?
The hippocampus encodes and consolidates episodic memories by binding contextual details into coherent representations for long-term storage.
216
What role do the basal ganglia and cerebellum play in nondeclarative memory?
The basal ganglia support habit learning and action selection, while the cerebellum refines motor skills and timing in procedural memory.
217
Describe how conditioned emotional responses are learned in the amygdala.
During fear conditioning, coincident activation by a tone (CS) and a shock (US) strengthens synapses in the lateral amygdala, so the tone alone later elicits a fear response.
218
How is auditory information routed to the lateral amygdala during fear conditioning?
The tone (CS) travels via the auditory system—ears to auditory cortex—then reaches the lateral amygdala to become associated with the US.
219
How is somatosensory information routed to the lateral amygdala during fear conditioning?
The shock (US) travels via the somatosensory system—body to somatosensory pathways—then reaches the lateral amygdala for associative learning.
220
Which plasticity mechanism underlies CS–US association in the amygdala?
NMDA-receptor–dependent LTP in the lateral amygdala strengthens CS-evoked responses by inserting additional AMPA receptors at active synapses.
221
Outline the output pathway for conditioned fear responses from the amygdala.
The lateral amygdala signals the basal nucleus, which activates the central nucleus; from there, projections to the hypothalamus and brainstem elicit autonomic and freezing responses.
222
What autonomic and behavioral responses are triggered by the central nucleus of the amygdala?
The central nucleus sends signals to the hypothalamus to control heart rate, sweating, and hormones, and to the brainstem to trigger reflexive freezing behaviors.
223
What roles do NMDA receptors play in LTP?
NMDA receptors require glutamate binding and sufficient postsynaptic depolarization to relieve Mg²⁺ block, allowing Ca²⁺ influx that initiates synaptic strengthening cascades.
224
What conditions activate NMDA receptors during LTP induction?
NMDA receptors activate when glutamate binds and the postsynaptic membrane is depolarized enough—typically by AMPA receptor–mediated currents—to eject the Mg²⁺ block.
225
How does Ca²⁺ influx lead to LTP?
Localized Ca²⁺ influx through NMDA receptors activates kinases (e.g., CaMKII) that phosphorylate and promote insertion of AMPA receptors, increasing synaptic efficacy.
226
What is the role of AMPA receptor insertion in LTP?
Ca²⁺-dependent kinase cascades drive trafficking and insertion of additional AMPA receptors into the postsynaptic membrane, enhancing EPSP amplitude and synaptic strength.
227
What are dendritic spikes and how do they relate to LTP?
Dendritic spikes are action potentials that backpropagate into dendrites, depolarizing spines, unblocking NMDA receptors, and facilitating LTP induction at coincidence-detecting synapses.
228
What is retrograde signaling in synaptic plasticity?
Retrograde signals—such as nitric oxide—are produced postsynaptically in response to Ca²⁺ and travel back to presynaptic terminals to increase neurotransmitter release probability.
229
Why is NMDA–AMPA LTP considered a universal mechanism?
NMDA-dependent LTP with Ca²⁺-triggered AMPA insertion is observed across multiple brain regions—hippocampus, amygdala, cortex, and basal ganglia—for diverse learning types.
230
Where in the hippocampus is classic NMDA-dependent LTP observed?
Classic LTP is seen at the perforant-path→dentate gyrus synapse and the Schaffer-collateral→CA1 synapse, both requiring NMDA-receptor activation and AMPA insertion.
231
How does LTP in the amygdala support fear conditioning?
LTP at thalamic and auditory inputs to the lateral amygdala underlies CS–US associations in fear learning, relying on NMDA activation and AMPA-receptor–mediated strengthening.
232
In which cortical and subcortical areas does NMDA-dependent plasticity operate?
NMDA-dependent plasticity occurs in sensory and motor association cortices for perceptual learning and in basal ganglia circuits for habit learning.
233
What is the transcortical (cortico-cortical) pathway?
The transcortical pathway routes information through sensory association cortex → motor association cortex (premotor & supplementary) → primary motor cortex to execute consciously controlled, rule-based actions.
234
When is the transcortical pathway primarily used?
It is used for learning new tasks, following instructions step-by-step, and consciously controlling actions based on rules and planning.
235
Which brain areas support transcortical processing?
Transcortical processing relies on the prefrontal cortex for planning and decision making, and the medial temporal lobe (including hippocampus) for declarative memory support.
236
Describe the basal ganglia–thalamocortical loop.
The loop connects cortex → basal ganglia → thalamus → cortex in a feedback system that selects, initiates, and fine-tunes movements through disinhibition and inhibition balance.
237
What are the input nuclei of the basal ganglia and their functions?
The caudate nucleus receives information from sensory and prefrontal areas (plans), while the putamen receives sensorimotor information (actual motor commands).
238
What is the output nucleus of the basal ganglia and its role?
The globus pallidus internal segment (GPi) is the main output, sending inhibitory signals to VA/VL thalamic nuclei; its inhibition or disinhibition controls movement initiation.
239
What is disinhibition in the direct basal ganglia pathway?
In the direct pathway, inhibition of GPi releases (disinhibits) the thalamus, allowing it to excite motor cortex and facilitate movement execution.
240
Describe the indirect pathway for movement fine-tuning.
The indirect pathway involves GPe inhibiting STN; when STN is disinhibited, it excites GPi, increasing thalamic inhibition to suppress or dampen movement, refining motor output.
241
What roles do the GPe and STN play in the indirect pathway?
GPe tonically inhibits STN to permit movement; if GPe activity decreases, STN activates GPi to increase thalamic inhibition and suppress unwanted movements.
242
What is the main functional difference between the direct and indirect pathways?
The direct pathway enables movement by disinhibiting thalamic excitation of cortex, while the indirect pathway suppresses or refines movement by enhancing thalamic inhibition.
243
What is reinforcement learning at the synaptic level?
"Reinforcement learning detects reinforcing events and facilitates synaptic changes that strengthen connections between neurons encoding discriminative stimuli and those driving the appropriate response."```csv
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245
What are the key neural circuits involved in reinforcement?
The key neural circuits are the mesolimbic pathway (VTA → NAC, amygdala, hippocampus) and the mesocortical pathway (VTA → prefrontal and limbic cortices, hippocampus), with the mesolimbic dopamine system playing a central role.
246
What is the mesolimbic pathway?
The mesolimbic pathway consists of dopaminergic neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAC), amygdala, and hippocampus, signaling unexpected rewards and reinforcing actions.
247
What is the mesocortical pathway?
The mesocortical pathway comprises VTA dopaminergic projections to the prefrontal cortex, anterior cingulate, orbitofrontal cortex, and hippocampus, modulating executive functions like decision making, goal evaluation, and updating action values.
248
Which dopamine system plays a central role in reinforcement?
The mesolimbic dopamine system plays a central role in reinforcement by signaling reward prediction errors and driving synaptic plasticity in basal ganglia circuits.
249
What are the three elements required for operant conditioning?
Operant conditioning requires (1) a discriminative stimulus (cue), (2) a response (action), and (3) a reinforcing stimulus (outcome).
250
How does reinforcement trigger synaptic plasticity?
Reinforcement triggers phasic dopamine release, which enables long-term potentiation at synapses that were active during the discriminative stimulus and response.
251
What have L-DOPA studies shown about dopamine and learning?
L-DOPA studies demonstrate that enhanced dopamine levels accelerate and improve human learning of novel vocabulary by facilitating synaptic potentiation during reinforcement.
252
What is the function of prefrontal cortex in early learning?
In early learning, the prefrontal cortex maintains task rules and stimulus–response mappings in working memory and guides selection of appropriate actions when multiple choices are available.
253
How does PFC engagement change as actions become habitual?
As actions become habitual via basal ganglia loops, prefrontal engagement diminishes, though the PFC can re-engage to override habits if task contingencies change.
254
What plasticity mechanisms underlie reinforcement in the basal ganglia?
Basal ganglia plasticity likely involves dopamine-modulated long-term potentiation (LTP) and long-term depression (LTD) at corticostriatal synapses.
255
What plasticity mechanisms underlie early rule-based learning in cortex?
Early rule-based learning engages NMDA-receptor–dependent Ca²⁺ influx and Ca²⁺-dependent AMPA receptor insertion, mediating synaptic strengthening in prefrontal and sensorimotor cortices.
256
What is the origin and projection of the mesolimbic pathway?
The mesolimbic pathway originates in the midbrain VTA and projects to the nucleus accumbens, amygdala, and hippocampus.
257
What is the function of phasic dopamine release in the nucleus accumbens?
Phasic dopamine release in the NAC signals unexpected rewards, driving corticostriatal synaptic plasticity that reinforces actions leading to the reward.
258
What is the origin and projection of the mesocortical pathway?
The mesocortical pathway originates in the VTA and projects to the prefrontal cortex, anterior cingulate, and orbitofrontal cortices, as well as the hippocampus.
259
What is the function of dopamine in the mesocortical pathway?
Dopamine in the mesocortical pathway modulates executive functions such as decision making, goal evaluation, and updating action values.
260
What role does the basal ganglia play in habit formation?
The basal ganglia automate stimulus-driven skills by strengthening S–R mappings through dopaminergic reinforcement, critical for nondeclarative motor memory.
261
Which basal ganglia structure is involved in early, deliberate motor learning?
The caudate nucleus is involved in early, goal-directed phases of motor learning, making behaviors deliberate and conscious.
262
Which basal ganglia structure is involved when behaviors become automatic?
The putamen becomes dominant as behaviors become automatic and habitual, freeing up cognitive resources.
263
What movement disorders illustrate basal ganglia involvement in learning?
Parkinson’s disease (striatal dopamine depletion) and Huntington’s disease (striatonigral degeneration) illustrate basal ganglia involvement in operant learning.
264
How do Parkinson’s and Huntington’s diseases affect operant tasks?
Parkinson’s patients show impaired visually cued operant tasks, while Huntington’s patients fail to learn button-press sequences due to basal ganglia dysfunction.
265
How does PFC interact with VTA during reinforcement?
The PFC sends glutamatergic signals to the VTA, increasing dopaminergic neuron firing to reinforce actions deemed beneficial for achieving goals.
266
How can PFC override habits?
When contingencies change, the PFC re-engages cortical–basal ganglia loops to shift behavior from habitual to goal-directed control.
267
What are the neural substrates of the discriminative stimulus in operant conditioning?
The discriminative stimulus is processed by sensory association cortices, which send input to the basal ganglia.
268
What are the neural substrates of the response in operant conditioning?
The response is executed by motor cortices that receive output from basal ganglia–thalamic circuits.
269
What are the neural substrates of the reinforcer in operant conditioning?
The reinforcer is represented by a dopamine burst from the VTA to the nucleus accumbens (mesolimbic) and PFC (mesocortical).
270
What is the learning rule for operant conditioning at the synaptic level?
Synapses in sensory-to-motor pathways that are active when dopamine bursts occur are selectively potentiated, cementing the S–R association.
271
What loops are essential for automatizing stimulus–response mappings in operant conditioning?
Basal ganglia–thalamocortical loops are essential for automatizing stimulus–response mappings, enabling habitual performance.
272
What is the role of mesolimbic dopamine in operant conditioning?
Mesolimbic dopamine signals reinforcement and drives synaptic plasticity in basal ganglia circuits to strengthen S–R associations.
273
What is the role of mesocortical dopamine and PFC in operant conditioning?
Mesocortical dopamine and PFC inputs shape, evaluate, and gate reinforcement based on goals and changing contingencies.
274
What are the cortical contributions to learning and movement?
Cortical contributions include primary motor cortex for precise movements, SMA for sequence organization, premotor cortex for cue-guided actions, and ventral premotor cortex for imitation via mirror neurons.
275
What role does the primary motor cortex play in learned movements?
The primary motor cortex controls precise muscle movements and undergoes practice-dependent adaptation.
276
What is the function of the supplementary motor area?
The SMA organizes movement sequences and contributes to their automatization over time.
277
What is the function of the premotor cortex?
The premotor cortex uses external sensory cues to plan and guide movements.
278
What is the role of ventral premotor cortex in learning?
The ventral premotor cortex contains mirror neurons that facilitate learning by imitation and understanding others’ actions.
279
How do learning phases influence consolidation?
Fast learning occurs rapidly during practice, while deeper improvements occur offline—between sessions and during sleep—via consolidation processes.
280
What are the ventral and dorsal cortical streams and their functions?
The ventral stream (inferior temporal cortex) processes 'what' information (object recognition), and the dorsal stream (posterior parietal cortex) processes 'where' information (spatial location).
281
What perceptual problem results from ventral stream damage?
Damage to the ventral stream causes visual agnosia—an inability to recognize objects despite intact vision.
282
What perceptual problem results from dorsal stream damage?
Damage to the dorsal stream causes spatial perception deficits, impairing the ability to locate and interact with objects.
283
How does perceptual learning alter cortical responses?
Perceptual learning sharpens neuronal tuning to practiced stimuli and reduces responses to familiar, uninformative inputs.
284
Which brain areas hold sensory information for short-term retention?
Sensory association and prefrontal-parietal cortices hold sensory information briefly for recognition and working memory.
285
What is the sensory trace maintained by extrastriate cortex?
Extrastriate cortex maintains a fading representation of recent stimuli via persisting activity, with durations from milliseconds to a few seconds.
286
What is the working memory buffer in prefrontal cortex?
The PFC working memory buffer holds and manipulates perceptual information across delays when stimuli are absent.
287
What is the neural signature of PFC working memory?
Delay-period firing in dorsolateral PFC neurons correlates with the amount and fidelity of information held in working memory.
288
What functions does PFC serve in perceptual retention?
The PFC filters irrelevant inputs, maintains and manipulates multiple items, and strategically organizes information for efficient retrieval.
289
How does perceptual learning produce long-term circuit changes?
Long-term plasticity in extrastriate areas encodes precise stimulus features, stabilizing improvements from perceptual practice.
290
How are visual memories retrieved?
Retrieval reactivates the same cortical loci—extrastriate cortex, fusiform gyrus, and MT/MST areas—where the original perceptual traces were stored.
291
What two stages does short-term retention use?
Short-term retention uses a sensory-specific buffer in extrastriate cortex for immediate traces and a prefrontal working-memory system for maintenance and manipulation over seconds.
292
Where do new hippocampal neurons originate in adult rats?
New hippocampal neurons originate in the subgranular zone of the dentate gyrus.
293
How many granule neurons are produced daily in the rat dentate gyrus?
Approximately 5,000–10,000 new granule neurons are generated daily in the adult rat dentate gyrus.
294
What aspect of learning doubles survival of new dentate granule cells?
Relational (hippocampus-dependent) learning doubles the survival rate of newborn dentate granule neurons.
295
Does stimulus–response learning affect adult hippocampal neurogenesis?
No, nonrelational stimulus–response learning does not change the rate of adult hippocampal neurogenesis.
296
What is the implication of learning-dependent neurogenesis?
Adult-born neurons specifically contribute to hippocampus-dependent relational memory consolidation.
297
What effects does environmental enrichment have on hippocampal neurogenesis?
Environmental enrichment increases hippocampal neurogenesis, enhances LTP, and improves performance in spatial learning tasks like the water maze.
298
How does aging affect neurogenesis?
Aging decreases hippocampal neurogenesis, but enriched environments can attenuate this decline.
299
How do stress hormones and antidepressants modulate neurogenesis?
Stress hormones decrease neurogenesis, whereas antidepressants increase neurogenesis and reduce anxiety- and depression-like behaviors in animal models.
300
What is olfactory bulb neurogenesis dependent on?
Olfactory bulb neurogenesis depends on adult-born interneurons that integrate soon after migration; LTP inducibility in these neurons declines with their age.
301
What is required for odor-learning tasks according to Belnoue et al.?
Adult-born olfactory bulb neurons are required for successful performance on odor-learning tasks.
302
What cortical region degeneration causes semantic dementia?
Progressive degeneration of the anterolateral temporal neocortex causes semantic dementia.
303
What memory is lost in semantic dementia?
Semantic dementia leads to the loss of factual knowledge, such as word meanings and object identities.
304
Which memory remains intact in semantic dementia?
Recent episodic memories remain intact in semantic dementia despite loss of semantic knowledge.
305
What characterizes anterograde amnesia?
Anterograde amnesia is the inability to form new conscious memories after brain damage, while older memories and nondeclarative learning remain preserved.
306
What characterizes retrograde amnesia?
Retrograde amnesia is the inability to recall events that occurred before injury, typically being less severe than anterograde amnesia.
307
What is the temporal gradient of hippocampal dependency?
The hippocampus is transiently required for consolidation and retrieval of recent relational memories, but remote memories become independent of the hippocampus and reside in neocortex.
308
What is the hippocampus’s role in consolidation?
The hippocampus binds disparate elements (locations, cues, contexts) into cohesive relational representations for new episodic memories.
309
Is hippocampus required for nonrelational perceptual or motor skills?
No, the hippocampus is not required for acquisition or retention of nonrelational perceptual or motor skills.
310
When is hippocampus required for retrieval?
The hippocampus is required for retrieval of recently formed memories (weeks to months old).
311
Is hippocampus required for retrieval of remote memories?
No, retrieval of remote memories relies on neocortical storage and does not require the hippocampus.
312
Can amnesic patients show perceptual learning?
Yes, patients with anterograde amnesia exhibit perceptual learning (e.g., preferences, improved recognition) without conscious recall of the learning episode.
313
What learning types are preserved in anterograde amnesia?
Nondeclarative learning—stimulus–response habits, motor skills, and perceptual tasks—is preserved in anterograde amnesia.
314
What learning types are lost in anterograde amnesia?
Declarative learning (episodic and semantic memory) is lost in anterograde amnesia.
315
What is an example of visual perceptual learning in amnesia?
Johnson et al. demonstrated that amnesic patients later preferred a previously labeled 'nice' unfamiliar face over a 'nasty' one despite having no conscious memory of the exposure.
316
What is an example of auditory perceptual learning in amnesia?
In the same study, amnesic patients later preferred previously heard unfamiliar Korean melodies over novel ones, with no explicit memory of having heard them.
317
What types of hippocampal spatial cells exist?
Hippocampal spatial cells include place cells (location-specific firing), grid cells (patterned spatial mapping), border cells (edge detection), head-direction cells (orientation tracking), and path/intention cells (location with planned movement).
318
What is Hebbian learning?
Hebbian learning is the principle that synaptic connections strengthen when pre- and postsynaptic neurons are activated together ('cells that fire together wire together').
319
How was LTP discovered?
LTP was discovered in the hippocampus when repeated high-frequency stimulation produced long-lasting increases in synaptic strength lasting weeks to months.
320
What induction conditions are required for LTP?
LTP induction requires high-frequency stimulation to depolarize the postsynaptic membrane, relieve the NMDA receptor Mg²⁺ block, and allow Ca²⁺ influx.
321
How does Ca²⁺ influx lead to LTP?
Ca²⁺ influx activates kinases (e.g., CaMKII), leading to AMPA receptor phosphorylation and insertion, synaptic growth, and enhanced postsynaptic responses.
322
What presynaptic changes accompany LTP?
Retrograde signals generated postsynaptically (e.g., nitric oxide) travel to presynaptic terminals to increase neurotransmitter release probability.
323
In which brain regions does LTP occur besides the hippocampus?
LTP also occurs in the amygdala, cortex, and basal ganglia, supporting various forms of learning and memory.
324
What two coincident events are required for LTP induction?
LTP induction requires the coincidence of synaptic activation (glutamate release) and strong postsynaptic depolarization at the same dendritic spine.
