Question:
- Whether the internal presentation (generated by conscious or unconscious recall, dreaming, and imagination) can be combined with external stimuli to generate new memories (?)
- Or in this study, whether artificially activating a previously formed contextual fear memory engram, would create a false fear memory in a shocks-free context (?)
- Or whether a light-activated contextual memory in the DG or CA1 can serve as a functional CS in fear conditioning(?)
Lessons from the past experiments: a small subpopulation of granule cells in the DG identified as contextual memory- engram cells. Optogenetic stimulation of these cells were enough to bring back the freezing behavior.
The hippocampus processes mnemonic information by altering the combined activity of subsets of cells within defined subregions in response to discrete episodes, so next question was:
whether applying the same parameters and manipulations to CA1 as they did to the DG could form a false memory (?)
Note: Similar to the DG, the overlap of active CA1 cells was significantly lower across contexts (A and C) as compared with that of a reexposure to the same context (A and A). How- ever, the degree of overlap for the two contexts was much greater in CA1 (30%) than in the DG (~1%).
- In this experiments, it is possible that the light-activated DG
cells encoding ctxA interfered with the acquisition or expression of the genuine fear memory for ctxB -----> Indeed, upon reexposure to ctxB, the experimental group froze significantly less than the group that did not receive
light during fear conditioning or the group expressing mCherry alone.
- During light-on epochs in the ctxB test, freezing increased in the experimental group and decreased in the group did not receive light during FC.
- They did similar experiments with manipulation targeted to the CA1----> no differences in the experimental or control groups during either light-off or light-on epochs of the ctxB test.
- Cells activated previously in the DG can subsequently serve as a functional CS in a fear-conditioning paradigm when artificially reactivated during the delivery of a US. The consequence is the formation of a false associative fear memory to the CS that was not naturally available at the time of the US delivery.
- Robust activity in the hippocampus during the recall of both false and genuine memories reported in humans. However, fMRI techniques have not been able to delineate the hippocampal subregions and circuits responsible for the generated false memories.
- They speculate the formation of at least some false memories in humans may occur in natural settings through the internally driven retrieval of a previously formed memory and its association with concurrent external stimuli of high valence.
- Whether the internal presentation (generated by conscious or unconscious recall, dreaming, and imagination) can be combined with external stimuli to generate new memories (?)
- Or in this study, whether artificially activating a previously formed contextual fear memory engram, would create a false fear memory in a shocks-free context (?)
- Or whether a light-activated contextual memory in the DG or CA1 can serve as a functional CS in fear conditioning(?)
Lessons from the past experiments: a small subpopulation of granule cells in the DG identified as contextual memory- engram cells. Optogenetic stimulation of these cells were enough to bring back the freezing behavior.
Method related notes:
c-fos-tTA transgenic mice were used.
c-Fos gene promotor------> tTA -------> TRE -----> gene of interest expression (?)
They injected AAV encoding TRE-ChR2-mCherry in to the DG or CA1 of c-fos-tTA mice.
On Dox diet -----> No (ChR2)-mCherry expression in the DG
Optical stimulation of (ChR2)-mCherry expressing DG cells -----> cFos expression from anterior - posterior axis of DG
Experiment design:
Off Dox in ctxA--- On Dox--- Next day fear-conditioned in ctxB while optically re-activating ctxA labeled cells --- 2 days later tested in ctxA or ctxC
If the light-reactivated
cells labeled in ctxA can produce a functional CS during fear conditioning in ctxB, then
the animals should express a false fear memory
by freezing in ctxA, but not in ctxC. *
Q: The degree of overlap of cells activated in ctxA and ctxC?
Off Dox in ctxA--- On Dox right away--- Next day half mice exposed to ctxA, the other half to ctxC--- 1.5h later sacrifice ------> Statically different populations of DG cells in ctxA and ctxC with overlapping cell populations in dorsal DG in ctxA
*The following result is not due to generalization, since the mCherry control group does not show the same effect.
New Experimental design:
Off Dox in ctxA----- Next day in ctxC while back On Dox -----> Only ctxA cells were re-activation during fear-conditioning by light
Results:
- All groups showed background freezing in ctxC
- The experimental group showed freezing to ctxA unlike the control group, confirms recalls of the false memory is specific to ctxA
- This effect was not seen in a group, in which an immediate shock was applied in ctxB with light stimulation of ctxA cells
The hippocampus processes mnemonic information by altering the combined activity of subsets of cells within defined subregions in response to discrete episodes, so next question was:
whether applying the same parameters and manipulations to CA1 as they did to the DG could form a false memory (?)
Note: Similar to the DG, the overlap of active CA1 cells was significantly lower across contexts (A and C) as compared with that of a reexposure to the same context (A and A). How- ever, the degree of overlap for the two contexts was much greater in CA1 (30%) than in the DG (~1%).
Labeled CA1 cells activated in
ctxA----- Reactivation of these cells with light
during fear conditioning in ctxB-----> No increase
in freezing, regardless of whether the animals
were exposed to ctxC or not before fear conditioning in ctxB:
Consideration & observations:
- During light-on epochs in the ctxB test, freezing increased in the experimental group and decreased in the group did not receive light during FC.
- They did similar experiments with manipulation targeted to the CA1----> no differences in the experimental or control groups during either light-off or light-on epochs of the ctxB test.
Learned from past studies: Memory recall can be induced for a genuine
fear memory by light reactivation of the corresponding engram in the DG, now the question is: Whether this is true for a false fear memory
More c-fos+ cells in BLA, CeA during the re-call of a false fear memory compared to the control:
Mice got trained in a conditioned place avoidance (CPA) paradigm:
Conclusions:
- Cells activated previously in the DG can subsequently serve as a functional CS in a fear-conditioning paradigm when artificially reactivated during the delivery of a US. The consequence is the formation of a false associative fear memory to the CS that was not naturally available at the time of the US delivery.
- Robust activity in the hippocampus during the recall of both false and genuine memories reported in humans. However, fMRI techniques have not been able to delineate the hippocampal subregions and circuits responsible for the generated false memories.
- They speculate the formation of at least some false memories in humans may occur in natural settings through the internally driven retrieval of a previously formed memory and its association with concurrent external stimuli of high valence.
- The previous study (Mayford- 2012) applied a similar experimental protocol with pharmacosynthetic methods and
failed to see increased freezing upon reexposure to either ctxA or ctxB. Instead, they
observed a synthetic memory that could only be
retrieved by the combination of both ctxsA
and B.
A key difference in their system is that the c-Fos–expressing cells in the entire forebrain were labeled and reactivated over an extended period by a synthetic ligand. In this newer study, they propose activating neurons in much wider spatial and temporal domains may favor the formation of a synthetic memory, which may not be easily retrievable by the cues associated with each individual memory. In contrast, activating neurons in a more spatially (only small populations of DG cells) and temporally restricted manner (only a few minutes during light stimulation) may favor the formation of two distinct (false and genuine) memories as observed in our case.
- When they manipulated CA1 cells by the same procedures as the ones used for DG cells, no false memory created (freezing in context A).
In CA1, the overlap of the cell populations activated by consecutive exposures to a pair of contexts is much greater than in the DG. Although additional work is needed to reveal the nature of CA1 engrams, we hypothesize that our negative CA1 behavioral data could be a result of contextual engrams relying less on a population code and increasingly on a temporal code as they travel through the trisynaptic circuit.
A key difference in their system is that the c-Fos–expressing cells in the entire forebrain were labeled and reactivated over an extended period by a synthetic ligand. In this newer study, they propose activating neurons in much wider spatial and temporal domains may favor the formation of a synthetic memory, which may not be easily retrievable by the cues associated with each individual memory. In contrast, activating neurons in a more spatially (only small populations of DG cells) and temporally restricted manner (only a few minutes during light stimulation) may favor the formation of two distinct (false and genuine) memories as observed in our case.
- When they manipulated CA1 cells by the same procedures as the ones used for DG cells, no false memory created (freezing in context A).
In CA1, the overlap of the cell populations activated by consecutive exposures to a pair of contexts is much greater than in the DG. Although additional work is needed to reveal the nature of CA1 engrams, we hypothesize that our negative CA1 behavioral data could be a result of contextual engrams relying less on a population code and increasingly on a temporal code as they travel through the trisynaptic circuit.
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