Distinct hippocampal engrams control extinction and relapse of fear memory

Lacagnina, Anthony F.; Brockway, Emma T.; Crovetti, Chelsea R.; Shue, Francis; McCarty, Meredith J.; Sattler, Kevin P.; Lim, Sean C.; Santos, Silvana Maria Aparecida Viana; Denny, Christine A.; Drew, Michael R.

doi:10.1038/s41593-019-0361-z

Cited by 223 publications

(195 citation statements)

References 52 publications

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“…Shorter stimulation periods are recommended as they have been found to reduce these effects [33]. Reduced expression levels may also help as widespread increases in excitatory activity were not reported in previous ArchT studies that confined silencing to "engram cells" [3,51,52]. In order to properly interpret the effects of targeted optogenetic and chemogenenic manipulations on behavior it is clearly important to determine how they affect network activity [49,50].…”

Section: Discussionmentioning

confidence: 99%

Recently formed context fear memories can be retrieved without the hippocampus

Teratani-Ota

et al. 2019

Preprint

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The current study determined if inactivation of the dorsal hippocampus impairs the retrieval of newly formed context fear memories. This region was silencing by activating inhibitory neurons or by hyperpolarizing pyramidal cells directly. When inhibitory neurons were stimulated with ChR2, memory retrieval was significantly impaired. In contrast, when the same neurons were activated with the excitatory DREADD hM3Dq, retrieval was not affected. This dissociation was not due to differences in inhibition, as both manipulations activated interneurons and reduced excitation throughout the dorsal hippocampus. Therefore, we hypothesize that the retrieval deficit caused by ChR2 stimulation is due to an immediate reduction in hippocampal activity that does not provide enough time for other brain regions to compensate. Stimulation of DREADDs, on the other hand, produces a gradual loss of excitation that takes several minutes to reach asymptote. This appears to be a sufficient amount of time for extra-hippocampal structures to become engaged and express context fear. Implications for theories of hippocampal function, systems consolidation and memory retrieval are discussed.

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Section: Discussionmentioning

confidence: 99%

Recently formed context fear memories can be retrieved without the hippocampus

Teratani-Ota

et al. 2019

Preprint

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“…Prior studies have captured a memory linked to a specific fear-provoking event/context [45,61,62]. Subsequent manipulation of these engrams has revealed essential aspects of memory and its plasticity [63][64][65][66][67]. While this may have therapeutic potential for disorders linked to a specific traumatic event, such as PTSD, it provides less promise for addressing generalized anxiety disorder (GAD) or fear disorders.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic reactivation of prefrontal social memory trace mimics social buffering of fear

Ahuna

Santos

et al. 2019

Preprint

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Social buffering occurs when the presence of a companion attenuates the physiological and/or behavioral effects of a stressful or fear-provoking event. It represents a way in which social interactions can immediately and potently modulate behavior. As such, social buffering is one mechanism by which strong social support increases resilience to mental illness. While the behavioral and neuroendocrine impacts of social buffering are well studied in multiple species, including humans, the neuronal bases of this behavioral phenomenon remain largely unexplored. Previous work has shown that the infralimbic prefrontal cortex (IL-PFC) is important for processing social information and, in separate studies, for modulating fear and anxiety. Thus, we hypothesized that socially-active cells within the IL-PFC may integrate social information to modulate fear responsivity. To test this hypothesis, we employed social buffering paradigms in male and female mice. Similar to prior studies in rats, we found that the presence of a cagemate reduced freezing in fear and anxiety-provoking contexts. In accordance with previous work, we demonstrated that interaction with a novel or familiar conspecific induces activity in the IL-PFC as evidenced by increased immediate early gene (IEG) expression. We then utilized an activity-dependent tagging murine line, the ArcCreER T2 mice, to express channelrhodopsin (ChR2) in neurons active during the social encoding of a new cagemate. We found that optogenetic reactivation of these sociallyactive neuronal ensembles phenocopied the effects of cagemate presence in male and female mice in learned and innate fear contexts without being inherently rewarding or altering locomotion. These data suggest that a social neuronal ensemble within the IL-PFC may contribute to social buffering of fear. These neurons may represent a novel therapeutic target for fear and anxiety disorders.

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“…ArcCreER T2 x eYFP mice and ArcCreER T2 x ChR2-eYFP mice ArcCreER T2 (+) (Denny et al, 2014) x R26R-STOP-floxed-eYFP (enhanced yellow fluorescent protein) (Srinivas et al, 2001) and ArcCreER T2 (+) x R26R-STOP-floxed-ChR2-eYFP (homozygous female mice) were bred with R26R-STOP-floxed-eYFP and R26R-STOP-floxed-ChR2-eYFP (Perusini et al, 2017;Lacagnina et al, 2019) homozygous male mice, respectively (Srinivas et al, 2001). All experimental mice were ArcCreER T2 (+) and homozygous for the eYFP or Chr2-eYFP reporter.…”

Section: Genetic Tagging Of Memory-activated Cellsmentioning

confidence: 99%

Persistent increases of PKMζ in memory-activated neurons trace LTP maintenance during spatial long-term memory storage

Hsieh

Tsokas

Grau‐Perales

et al. 2020

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PKMz-immunohistochemistry reveals persistent increased PKMz in the hippocampus during (A) LTP maintenance, and (B) spatial long-term memory storage.PKMz is an autonomously active, atypical PKC isoform crucial for maintaining synaptic longterm potentiation (LTP) and long-term memory. Unlike other PKCs that are transiently activated by short-lived second messengers, PKMz is persistently activated by long-lasting increases in the amount of the autonomously active kinase during LTP and long-term memory maintenance. Thus, localizing persistent increases in PKMz might reveal traces of physiological LTP maintenance in the circuitry of the brain during long-term memory storage. Using quantitative immunohistochemistry validated by the lack of staining in PKMz-null mice, we visualized the amount and distribution of PKMz during LTP maintenance and spatial long-term memory storage in the hippocampal formation of wild-type mice. Strong afferent stimulation of Schaffer collateral/commissural fibers inducing LTP maintenance increases PKMz in CA1 pyramidal cells for 2 hours in hippocampal slices. Active place avoidance spatial conditioning increases PKMz in CA1 pyramidal cells of the hippocampal formation from 1 day to at least 1 month. The increases in PKMz coincide with the location of cells marked during long-term memory training by Arc promoter-mediated expression of a fluorescent protein, including at dendritic spines. We conclude that increased PKMz forms persistent traces in CA1 pyramidal cells that are sites of molecular information storage during LTP maintenance and spatial long-term memory.

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Distinct hippocampal engrams control extinction and relapse of fear memory

Cited by 223 publications

References 52 publications

Recently formed context fear memories can be retrieved without the hippocampus

Recently formed context fear memories can be retrieved without the hippocampus

Optogenetic reactivation of prefrontal social memory trace mimics social buffering of fear

Persistent increases of PKMζ in memory-activated neurons trace LTP maintenance during spatial long-term memory storage

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