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FEB 18 Flashcards

1
Q

paper abstract takeaways: “distinct hippocampal engrams control extinction and relapse of fear memory”

A
  1. LEARNED FEEAR often RELAPSES after extinction

^ suggests extinction training generates a NEW MEMORY that COEXISTS with og fear memory

  1. MECHANISM for these competing fear and extinction memories is unclear
  2. used activity-dependent NEURAL TAGGING to investigate reps of fear and extinction memories in DENTATE GYRUS
  3. showed that EXTINCTION TRAINING SUPPRESSES REACTIVATION of contextual fear engram cells while ACTIVATING A SECOND ENSEMBLE (putative extinction engram)
  4. results indicate that HIPPOCAMPUS generates FEAR EXTINCTION REP and that INTERACTIONS between hippocampal fear and extinction representations GOVERN the SUPPRESSION and RELAPSE of FEAR after EXTINCTION
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2
Q

paper general findings

A
  1. extinction training suppresses reactivation of contextual fear engram cells
  2. extinction training activates a putative extinction engram
  3. optogenetic inhibition of neurons active during extinction training increased fear after extinction training
  4. optogenetic silencing of neurons active during fear training reduced spontaneous recovery of fear
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3
Q

key fact about fear learning and extinction learning

A

they’re two distinct processes

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4
Q

this paper wants to know what about fear learning and extinction learning?

A

wants to know how these two forms of learning are REPRESENTED AT LEVEL OF SMALL GROUPS OF NEURONS

in the HIPPOCAMPAL DENTATE GYRUS

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5
Q

hippocampal dentate gyrus

A

area known to be important for contextual fear learning

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6
Q

extinction therapy

A

repeated exposure to a fear-evoking stimulus in the absence of threat

used to treat anxiety disorders

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7
Q

major limitation of extinction therapy

A

extinction isn’t permanent

fear/anxiety with relapse

(understanding more about these processes may lead to better therapies to treat maladaptive fear)

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8
Q

contextual fear learning

A

(used as a model of fear memory in the lab)

  1. mouse placed in novel context, given 1+ footshocks
  2. when mouse = returned to same context without any further footshocks, it will exhibit the conditioned fear responses (ie. freezing)
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9
Q

freezing in rodents

A

species-specific defensive behaviour (absence of all moving except that required for breathing)

BEHAVIOURAL INDICATOR of fear in rodents

in test of fear conditioning, the AMOUNT the animal freezes = a measure of fear learning/memory

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10
Q

the CR

A

freezing

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11
Q

trends present in ACQUISITION versus EXTINCTION of contextual fear learning

A

ACQUISITION: upward trend in freezing time across trials (shock is present)

EXTINCTION: gradual decrease in freezing time over repeated exposures to context where shock was previously encountered

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12
Q

does extinction erase the original fear memory?

A

no! extinction isn’t erasure of original learning

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13
Q

3 phenomena that show that fear memory can RETURN after extinction

A
  1. reinstatement
  2. renewal
  3. spontaneous recovery
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14
Q

reinstatement

A

after extinction, RE-EXPOSING animals to the REINFORCER (footshock)

leads to RE-EXPRESSION of original fear memory

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15
Q

renewal

A

following extinction of a CUE-SHOCK association in one CONTEXT

the fear memory REAPPEARS when animals are LATER TESTED for fear to the CUES of the OG TRAINING CONTEXT

(renewal is more specific - associated with cues like tones)

(essentially, train the association in one context, then extinguish in a different context, and then when placed back in og context the response will return)

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16
Q

spontaneous recovery

A

following extinction of a fear memory, when animals are tested SHORTLY AFTER extinction, they’ll FAIL to show evidence of fear memory

but when tested AFTER LONG DELAY, the fear memory will REAPPEAR

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17
Q

what do renewal, reinstatement and spontaneous recovery show?

A

that the FEAR MEMORY REMAINS INTACT, but INACCESSIBLE after extinction

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18
Q

extinction is what type of form of learning?

A

inhibitory

it prevents the fear memory from being expressed as a fear response

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19
Q

Marr’s 3 levels of analysis when applied to FEAR LEARNING

A

COMPUTATIONAL LEVEL:

^ learning to not be afraid of something

ALGORITHMIC LEVEL:

^ extinction is a form of new learning (not forgetting the fear memory)

IMPLEMENTATION LEVEL:

^ plasticity in ‘extinction engram; cells

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20
Q

contextual fear learning activates what ensembles?

A

fear engram cells

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21
Q

where are fear engram cells located?

A

in the HIPPOCAMPAL DENTATE GYRUS

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22
Q

engram

A

PHYSICAL or BIOCHEMICAL change in the brain

formed when an experience OCCURS and PERSISTS OVER TIME

allows memories to later be recalled

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23
Q

what allows memories to be recalled later on?

A

engrams

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24
Q

how and where is contextual fear conditioning encoded?

A

HOW: sparsely, in activated ensembles of cells

WHERE: hippocampal dentate gyrus

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25
what happens when we optogenetically stimulate fear engrams?
freezing increases (after forgetting or amnestic treatments)
26
what happens when we optogenetically inhibit fear engrams?
freezing is suppressed
27
what does optogenetics do?
confers HIGH TEMPORAL RESOLUTION induces SINGLE ACTION POTENTIALS, time-locked to stimulation over milliseconds to minutes
28
we know that fear engrams in DG = important for fear memories, but how does extinction training change the activity of fear engrams?
extinction is encoded in a DISTINCT EXTINCTION ENGRAM
29
in order to determine how extinction is affecting the fear engrams, have to do what?
LABEL the cells that are active during learning (and ONLY these cells) do this using a transgenic mouse (ArcCreERT2)
30
ArcCre mouse
genetically modified mouse used to TAG cells that are active during a SPECIFIC TIME WINDOW (ie. during learning or memory retrieval)
31
mouse and Cre
mouse expresses Cre - only activated by tamoxifen hormone tamoxifen activates Cre - this mediates a change in the cell depending on what else is present Cre is only active in cells that are strongly activated after tamofixen injection THIS CAN BE USED TO SPECIFICALLY ACTIVATE Cre IN CELLS ACTIVE AT TIME OF A LEARNING EXPERIENCE
32
mouse and Arc
Arc (an immediate early gene) rapidly TURNED ON when neurons are strongly activated another tool to LABEL CELLS
33
Halo-eYFP, ChR2eYP 'floxed' mice
only express optogenetic protein when Cre is active in this way, MEMORY CELLS CAN BE SPECIFICALLY and PERMANENTLY TAGGED allows them to open a tagging window by injecting tamoxifen
34
in practice, what does ArcCreERT2 allow for?
allows for the OPENING OF A TAGGING WINDOW upon tamoxifen injection any neurons active during this period will be tagged tag can be: 1. label to know which cells were active (ie. eYFP) 2. optogenetic protein to later control activity of these neurons (ie. ChR2)
35
what can the tags be?
1. label ie. eYFP 2. optogenetic protein to later control activity ie. ChR2
36
behavioural design
1. fear conditioning (fear assessed by freezing time) 2. extinction sessions (started one day after conditioning, sessions occurring once a day - 5 min unreinforced exposures to conditioning context)
37
what happens on the first extinction session after fear conditioning?
mice FREEZE A LOT in the conditioned context but over course of extinction, freezing decreases
38
how do they tag the fear memory?
inject tamoxifen at the time of conditioning these are the green eYFP labeled cells
39
green eYFP labelled cells
these are the cells tagged during fear conditioning (tagged by tamoxifen injection)
40
tagging the cells active during retrieval test
these ones express Arc purple Arc cells were active during retrieval we can see how many of the tagged cells (eYFP) are ALSO ACTIVE during a retrieval test (ie. REACTIVATED)
41
how can reactivation be assessed?
by seeing how many of the eYFP tagged cells (from fear learning) are also active during a RETRIEVAL TEST reactivation is assessed by COUNTING THE TAGGED CELLS that are ALSO ACTIVE at the SECOND TIME POINT (these are the green cells that are also purple)
42
what does extinction to do the number of fear acquisition tagged cells?
extinction REDUCES the number of fear aqcuisition tagged cells that are active compared to mice who didn't undergo extinction means that EXTINCTION REDUCES ACTIVITY OF FEAR ENGRAMS
43
"no extinction" group will have a higher proportion of what?
reactivated cells because extinction reduces the activity of fear engrams
44
because we can alter timing of tamoxifen injection in separate groups of mice...
we can tag either the FEAR memory or the EXTINCTION memory allows us to see how these two diff memories are active during spontaneous recovery
45
what does tagging either the FEAR or EXTINCTION memory allow us to do?
allows us to see how these two diff memories are active during SPONTANEOUS RECOVERY
46
spontaneous recovery: following extinction, the original fear memory returns when tested after...
a long delay 27-28 days after extinction
47
extinction and recovery each reactive which engram?
EXTINCTION reactivates the EXTINCTION ENGRAM (^ cells tagged during extinction are more active during extinction) SPONTANEOUS RECOVERY reactivates the FEEAR ENGRAM (^ cells tagged during fear conditioning are more active during spontaneous recovery)
48
what does observing the reactivation of fear (ie. conditioning tagged) and extinction engrams suggest?
suggests that during extinction... the FEAR ENGRAM IS SUPPRESSED in favour of the EXTINCTION ENGRAM
49
when spontaneous recovery occurs, which engram is more active?
the fear engram is more active (extinction engram is less active)
50
does inhibiting the extinction engram cause spontaneous recovery?
silencing extinction memories INCREASES FREEZING use halorhopsin to inhibit certain cells (optogenetics) when stimulated by green light
51
how do they silence extinction engram cells?
tag cells that were active during EXTINCTION with HALORHODOPSIN halorhodopsin: inhibitory opsin stimulated by green light
52
silencing extinction memories increases what during extinction?
freezing
53
silencing extinction memories has no effect when?
in a novel context not previously associated with shock when there's no fear memory associated with the context, there's no effect of inhibiting the extinction memory
54
what happens when silencing extinction memories during spontaneous recovery?
no effect because during spontaneous recovery the fear engrams are more active
55
what reduces spontaneous recovery?
silencing fear memories (silence fear memories by tagging cells active during fear conditioning with halorhodopsin - allows them to later be silenced using optogenetics)
56
when would silencing fear memories have no effect?
1. during extinction (because fear memories are already being repressed by the active extinction engrams) 2. in a novel context (because there's no fear response to suppress in a novel context)
57
silencing fear memories suppresses what?
spontaneous recovery
58
DISTINCT effects of ACTIVATING FEAR memory or EXTINCTION memory - optogenetic setup
tagged cells will express channelrhodopsin (ChR2) ChR2 is an EXCITATORY OPSIN - when stimulated in SEPARATE groups of mice, tag cells active during FEAR CONDITIONING or EXTINCTION with ChR2 these cells can later be activated
59
ChR2 versus halorhodopsin
ChR2 = excitatory ^ blue light stimulation will activate them halorhoposin = inhibitory ^ green light stimulation will inhibit them
60
in novel context, activating which engram increases freezing?
the fear engram
61
in test during extinction, activating which engram suppresses freesing?
the extinction engram
62
in test of spontaneous recovery, activating which engram suppresses freezing?
the extinction engram
63
when are extinction engrams more active?
when fear expression is low ie. shortly after extinction
64
spontaneous recovery is associated with what kind of engram activity?
with reduced activity of extinction engrams and increased activity of fear engrams
65
findings suggest that neuronal ensembles in the ________ _______ ______ play what kind of role in the expression of _____ and ______
HIPPOCAMPAL DENTATE GYRUS play a CAUSAL ROLE expression of FEAR and EXTINCTION
66
Marr's 3 levels of analysis for fear extinction
COMP: ^ learning to not be afraid of something ALG: ^ extinction is a new form of learning (it's not about forgetting the fear memory) IMP: ^ in the hippocampal dentate gyrus, extinction recruits a new engram that competes with the existing fear engram to control expression of learned fear

Psyc 443 (20 decks)

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