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BIOL 404 > Article 5 > Flashcards

Article 5 Flashcards

1
Q

what is the key requirement for regaining sensory and motor function after a stroke?

A

surviving neural circuits must reorganize and form new connections

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2
Q

how do therapies that promote neural rewiring impact stroke recovery outcomes?

A

they lead to better functional outcomes in stroke recovery

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3
Q

why has most research focused on cortical circuits in stroke recovery?

A

cortical activity in the damaged hemisphere is depressed for several weeks after a stroke when sensorimotor deficits are most pronounced

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4
Q

what is the role of the thalamus in stroke recovery?

A

the thalamus is crucial for sensory-evoked cortical activity

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5
Q

what is the surprising fact about thalamocortical circuits that make them potential targets for stroke therapy?

A

they can be modified well into adult life, suggesting they could be targeted for stroke therapy

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6
Q

what happens to thalamic circuits during focal ischemia

A

reduces neural excitability in thalamic nuclei and leads to scattered cell death and gliosis

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7
Q

what is optogenetics?

A

a technique that uses light to manipulate specific neural circuits. allows precise control of neural activity

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8
Q

what brain pathologies have shown promise in being treated w optogenetics?

A

shown promise in treating retinal degenerative disease, epilepsy, pain, and psychiatric disorders

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9
Q

what have previous studies attempted w optogenetics in stroke recovery and what remained unknown?

A

focused on brief and localized stimulation of specific motor circuits (ChR2) using optogenetics.
-> precise impact of rewriting damaged circuits remained unknown

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10
Q

what were the primary goals of this study and what did it uncover about stroke effects?

A

aimed to understand how stroke disrupts thalamocortical connections. it found that stroke leads to a loss of synaptic connections in the peri-infarct cortex and dampens the excitability of thalamocortical boutons

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11
Q

what is the significance of the peri-infarct region in stroke recovery?

A

is crucial for the recovery of sensorimotor functions after a stroke
-> study focuses on this region to investigate the neural changes that occur during recovery

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12
Q

describe the experimental model used to induce stroke in this study

A

used focal photothrombotic stroke induced in the primary forelimb somatosensory cortex of mice as a model to mimic stroke conditions

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13
Q

what specific aspect of thalamocortical projections to FLS1 is the study trying to determine, and why is it important?

A

aimed to determine how much thalamic projections to FLS1 survive the focal stroke. important to understand how stroke affects these projections and potential implications for recovery

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14
Q

explain the method used to label and trace thalamocortical axons

A

thalamocortical axons were labeled using adeno-associated virus (AVV) and enhanced green fluorescent protein (eGFP) to visualize their structure and track their pathways

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15
Q

which thalamic nuclei are likely the sources of thalamocortical projections to S1FL and how was this determined?

A

ventral posterior lateral (VPL) nucleus and the posterior medial (PoM) nucleus are likely sources based on the location of injection sites and known connectivity patterns

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16
Q

what was observed one week after the stroke in terms of axon density in the peri-infarct cortex?

A

significant reduction (>25%) in axon density in the peri-infarct cortex compared to baseline. this reduction persisted for 4 weeks after the stroke

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17
Q

describe the findings of the thalamus analysis after the stroke, and what does ‘reactive gliosis’ mean?

A

did not reveal signs of neuronal degeneration or cell loss.
-> reactive gliosis: refers to a response to injury characterized by glial cell activation and increased glial cell numbers

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18
Q

how did they label and visualize thalamocortical axons 5 weeks before injection?

A

were labeled w AAV to express GCaMP6s for calcium imaging and mCherry to visualize axon structure

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19
Q

what was the purpose of mapping the FLS1 and hindlimb sensory cortex using intrinsic optical signal (IOS) imaging before and after stroke?

A

was done to verify proper labeling of thalamic projections and assess changes in sensory cortex activity

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20
Q

why were mice w/o extensive axon labeling within the FLS1 cortex excluded?

A

ensures that study focuses on cases with proper thalamocortical axon labeling

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21
Q

what kind of sensory stimuli were used to test the responsiveness of thalamocortical boutons?

A

vibrotactile stimulation (1.5s at 100hz) of the contralateral forepaw was used

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22
Q

how did the responsiveness of thalamocortical boutons change after the focal stroke?

A

dropped at 1 week after stroke and remained below baseline for up to 4 weeks

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23
Q

what was the response of thalamocortical boutons to contralateral hindlimb stimulation?

A

relatively minimal compared to forepaw

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24
Q

did the stroke affect the latency of forelimb evoked responses and what does latency refer to?

A

did not significantly alter the latency of responses. latency refers to the time it takes for a response to occur after a stimulus

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25
Q

describe the changes observed in peak amplitude of responses following the stroke

A

there was an initial drop in the peak amplitude of responses 1-2 weeks after the stroke, followed by an increase during the recovery period

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26
Q

what were the findings regarding the responsiveness of boutons in the sham stroke group?

A

did not show significant changes -> serves as a control

27
Q

what was the behaviour of noramlized axonal GCaMP6s fluorescence over the 5 week imaging period?

A

did not change significantly

28
Q

how does the dampening of thalamocortical axon excitability relate to impaired cortical layer responses in the stroke-affected hemisphere?

A

is consistent w previous studies that showed impaired responses in the superficial cortex layers to sensory stimuli in the hemisphere affected by stroke

29
Q

what were the initial experiments conducted to validate the optogenetic approach?

A

by confirming that AAVs could drive ChR2 and mCherry expressing and by assessing the impact of optogenetic stimulation on cortical neurons

30
Q

describe the method used to deliver chronic optogenetic stimulation

A

through a removable magnetic head mounted LED that allowed stimulation of freely moving mice in their home cage

31
Q

what parameters were used for the optical sitmulation

A

involved 5ms light pulses at 5hz (1s on/4s off) for 60/day. were selected to mimic the natural frequency of thalamic neuron firing and mouse limb strides

32
Q

what impact did successive pulses of optogenetics stimulation have on the peak amplitude of cortical potentials

A

successive pulses led to a decrease in the peak amplitude of cortical potentials, similar to mechanical stimulation of the forepaw

33
Q

did 60 minutes of optogenetic stimulation induce axonal damage?

A

no

34
Q

how did optogenetics stimulation influence blood flow?

A

had little impact on cerebral blood flow
-> demonstrated that this low intensity regime did not induce detectable changes in blood flow

35
Q

what were the results of the positive control related to blood flow?

A

continuous 10hz stimulation of ChR2-expressing thalamic axons and exposure to 6% co2 led to increase in cerebral blood flow

36
Q

how was the rewiring of thalamocortical boutons assessed in response to chronic stimulation after stoke?

A

were imaged in vivo at weekly intervals to assess rewiring of thalamocortical boutons

37
Q

what precaution was taken during imaging to distinguish between presynaptic and post-synaptic structures?

A

the AAV used for labeling only infected neuronal cell bodies in the thalamus

38
Q

when did optogenetic stimulation commence after stroke?

A

three days after to avoid overstimulating the cortex in the acute phase which could exacerbate ischaemic damage

39
Q

how long did the optogenetic stimulation continue?

A

for 6 weeks post-stroke, with 5 consecutive sessions per week. control groups included mice w light stimulation without ChR2 expression and mice w ChR2 expression but no light.

40
Q

what were the effects of optogenetic stimulation on the growth and retraction of thalamocortical axon branches after stroke?

A

while stroke led to a significant reduction in axonal branch length, optogenetic stimulation did not have a significant effect on branch growth or retraction. Some large-scale remodelling of branches was observed.

41
Q

how are synapses characterized and what are the two types?

A

as varicosities
- terminaux boutons (TB)
- en passant boutons (EPB)

42
Q

what is the difference between TB and EPB?

A

TB: have a bulbous head connected to the parent axon by a short neck and project 1-5mm away from parent shaft
EPB: ‘beads on string’ appearance and are bright fluorescent swellings that exceed two times the medium fluorescence of the shaft

43
Q

what percentage of bouton types are EPBS

A

84%, TBS make up 14%

44
Q

did optogenetic stimulation affect the proportion of TBS relative to EPBs?

A

did not effect porportion

45
Q

what is TB turnover ratio and how did it change following stroke and optogenetic stimulation?

A

measures the rate of turnover of TBs. following stroke, TOR was elevated relative to baseline values and remained higher for up to 5 weeks in stimulated mice due to increased rates of TB elimination and formation

46
Q

what factors contributed to the increased EPB turnover in stimulated mice w stroke?

A

driven by increase in EPB formation at 2-3 weeks of recovery

47
Q

how did the density of EPBs change?

A

density increased in stimulated mice, control mice had lower levels

48
Q

what did the correlation between increased EPB formation and distance from the infarct border suggest?

A

that EPB plasticity is highest in regions proximal to the infarct

49
Q

how did optogenetic stimulation impact the survival of preexisting EPBs vs EPBs that formed after stroke?

A

Optogenetic stimulation did not affect the survival of preexisting EPBs but significantly enhanced the survival of new ChR2-expressing EPBs formed at 1 and 2 weeks of recovery. There was also a trend towards enhanced survival of ChR2-negative EPBs in the stimulated group.

50
Q

how did optogenetic stimulation affect the return of sensorimotor function after stroke?

A

enhanced the recovery, leading to greater improvement of forelimb-evoked response amplitude and cortical territory area

51
Q

why was IOS imaging used instead of two photon imaging of GCaMP6s signals for tracking stroke-related changes in the forepaw sensory representation?

A

it uses dim light (635nm) that would not activate ChR2 expressing axons

52
Q

describe the changes observed in the forepaw sensory representation in mice that underwent sham stroke combined w optogenetic stimulation or w/o

A

for mice that underwent sham stroke combined w optogenetic stimulation or without, the area and peak response amplitudes of the cortex activated contralateral forepaw stimulation did not sig change over time

53
Q

how did stroke affect forelimb map representation and response amplitude in mice?

A

two days after stroke, mice from both stroke groups had lost a sig. portion of the forelimb map and exhibited a less responsive forelimb-evoked response amplitude

54
Q

what differences were observed in the recovery of sensorimotor function between stimulated and control mice?

A

stimulated show more correct placements and fewer partial placements in the ladder walking test than control.

55
Q

what correlation was found between EPB formation rates and functional performance in behavioural tests?

A

sig correlation between EPB formation rates at 2-3weeks of recovery and performance on the tape test
-> suggests structural growth is associated w functional improvements in sensorimotor function

56
Q

what have most studies examining the recovery of sensorimotor function after stroke primarily focus on?

A

changes in the cortical neuron structure or function when examining the neural mechanisms underlying the recovery

57
Q

what deficits in cortical responses to sensory stimuli are associated with stroke and what changes are observed in intracortical inhibition and synaptic connections?

A

stroke leads to deficits in superficial (layers 1-3) cortical responses to sensory stimuli, which are associated w changes in intracortical inhibition and loss of excitatory synaptic connections

58
Q

why did the study examine thalamocortical axon excitability after stroke?

A

to determine whether a loss of cortical sensory responsiveness could be traced to a disruption in circuits upstream, such as those from the thalamus

59
Q

what did the GCamP6s imaging experiments reveal about thalamocortical bouton responsiveness after stroke?

A

normally, 25% of thalamocortical boutons respond to brief (1.5s) vibrotactile sitmulation of the contralateral forepaw. the proportion of responsive boutons dropped sig 1 week after stroke and partially recovered from 2-4 weeks

60
Q

how did thalamocortical bouton turnover rates change after stroke, and what effect did optogenetic stimulation have on these rates?

A

turnover rate increased after stroke due to loss of boutons in the peri-infarct area. stimulation enhanced the production of new and stable boutons at 2-3 weeks recovery but did not sig impact TB formation until later stages of recovery (3-4 weeks)

61
Q

what was the impact of optogenetic stimulation on IOS based cortical responses to forelimb stimulation

A

improved IOS based cortical responses to forelimb stimulation in terms of both amp and area. this suggests that functional changes in circuits downstream of thalamic inputs, such as intracortical circuits that propagate sensory driven activity horizontally, are likely involved in the recovery of sensorimotor function after stroke

62
Q

what is unique about this study regarding the impact of optogenetic stimulation on axonal bouton dynamics?

A

is the first to describe the impact of optogenetic stimulation on axonal bouton dynamics in vivo

63
Q

what is the significance of enhanced synaptic bouton formation in relation to sensorimotor paw function recovery?

A

correlated w better recovery of sensorimotor paw function, aligns w previous studies where motor learning correlated w increased cortical dendritic spine production

64
Q
A

BIOL 404 (20 decks)

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