Sexually dimorphic muscarinic acetylcholine receptor modulation of contextual fear learning in the dentate gyrus

Yavas, Ersin; Fanselow, Michael; Fanselow, Michael S.

doi:10.1016/j.nlm.2021.107528

Cited by 11 publications

(23 citation statements)

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“…To test the role of α5-GABA A Rs expressed on interneurons and pyramidal neurons in etomidate’s suppression of hippocampus-dependent memory, we employed the Context Preexposure Facilitation Effect (CPFE) learning paradigm (Fig. 2a) – a variant of contextual fear conditioning that separates the contextual learning and aversive phases of conditioning 39, 40, 41, 42 . This paradigm takes advantage of the “immediate shock deficit” 43 , wherein mice that are shocked immediately after they are placed in a novel context fail to associate the context and shock, whereas mice that were pre-exposed to the context on the preceding day recall the context rapidly and successfully associate it with the shock 44, 45 .…”

Section: Resultsmentioning

confidence: 99%

“…We used a preexposure-dependent contextual fear conditioning paradigm adapted from Cushman et al, 2012 108 . This paradigm, which is often referred to in the literature as the Context Preexposure Facilitation Effect (CPFE) paradigm 40, 41, 42 takes advantage of the so-called “immediate shock deficit” 39, 43 , wherein animals that are shocked immediately (within several seconds) upon entry into a novel environment do not freeze on subsequent re-exposure, whereas mice that had been exposed on a prior day do exhibit a freezing response. The proposed explanation is that preexposed mice establish a hippocampus-dependent representation of the environment (i.e.…”

Section: Methodsmentioning

confidence: 99%

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Control of contextual memory through interneuronal α5-GABA_Areceptors

Zhu

Abdulzahir

Perkins

et al. 2022

Preprint

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Abstractγ-aminobutyric acid type A receptors that incorporate α5 subunits (α5-GABAARs) are highly enriched in the hippocampus and they are strongly implicated in the control of learning and memory. Receptors located on pyramidal neuron dendrites have long been considered responsible, but here we report that selective elimination of α5-GABAARs from either interneurons or pyramidal cells prevented the general anesthetic etomidate from suppressing contextual learning. Using Ca2+ imaging of hippocampal neuronal activity in freely exploring mice, we also found that etomidate interfered with the development of place cells and spatial engrams in wild type mice but not in interneuron-specific α5-GABAAR knockout mice. These findings show that α5-GABAARs on interneurons as well as pyramidal neurons mediate etomidate-induced amnesia.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Control of contextual memory through interneuronal α5-GABA_Areceptors

Zhu

Abdulzahir

Perkins

et al. 2022

Preprint

Self Cite

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“…Upon arrival in the facility, all mice were placed on a 40 mg/kg DOX diet (Bio-Serv, product F4159, Lot 226766) and left undisturbed for a minimum of 3 d prior to surgery with ad libitum access to food and water. We originally tested our hypotheses in males because contextual fear conditioning in rodents is sexually dimorphic, where males typically show higher freezing levels than females 76 – 78 and wanted to ensure that our effect was large enough to warrant further experimentation. We also decided to use female exposure as a positive stimulus, and exposure to males may not necessarily be a positive experience for the females.…”

Section: Methodsmentioning

confidence: 99%

Reactivating hippocampal-mediated memories during reconsolidation to disrupt fear

et al. 2022

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Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system in mice, we label dorsal dentate gyrus neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells are artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory is sufficient to update the memory during reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrate operant responding for reactivation of a positive memory, confirming its rewarding properties. These results show that interference from a rewarding experience can counteract negative affective states. While memory-updating, induced by memory reactivation, involves a relatively small set of neurons, we also find that activating a large population of randomly labeled dorsal dentate gyrus neurons is effective in promoting reconsolidation. Importantly, memory-updating is specific to the fear memory. These findings implicate the dorsal dentate gyrus as a potential therapeutic node for modulating memories to suppress fear.

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“…Though we did not see any darting in either sex in our study, our findings support the growing notion that males and females show a distinct behavioral pattern of responses during fear learning, recall and extinction when compared with males. 22,43,[50][51][52]…”

Section: Discussionmentioning

confidence: 99%

ChAT::Cre transgenic rats show sex‐dependent altered fear behaviors, ultrasonic vocalizations and cholinergic marker expression

Tryon

Kaigler

Gee

et al. 2023

Genes Brain and Behavior

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The cholinergic system is a critical regulator of Pavlovian fear learning and extinction. As such, we have begun investigating the cholinergic system's involvement in individual differences in cued fear extinction using a transgenic ChAT::Cre rat model. The current study extends behavioral phenotyping of a transgenic ChAT::Cre rat line by examining both freezing behavior and ultrasonic vocalizations (USVs) during a Pavlovian cued fear learning and extinction paradigm. Freezing, 22 kHz USVs, and 50 kHz USVs were compared between male and female transgenic ChAT::Cre+ rats and their wildtype (Cre‐) littermates during fear learning, contextual and cue‐conditioned fear recall, cued fear extinction, and generalization to a novel tone. During contextual and cued fear recall ChAT::Cre+ rats froze slightly more than their Cre‐ littermates, and displayed significant sex differences in contextual and cue‐conditioned freezing, 22 kHz USVs, and 50 kHz USVs. Females showed more freezing than males in fear recall trials, but fewer 22 kHz distress calls during fear learning and recall. Females also produced more 50 kHz USVs during exposure to the testing chambers prior to tone (or shock) presentation compared with males, but this effect was blunted in ChAT::Cre+ females. Corroborating previous studies, ChAT::Cre+ transgenic rats overexpressed vesicular acetylcholine transporter immunolabeling in basal forebrain, striatum, basolateral amygdala, and hippocampus, but had similar levels of acetylcholinesterase and numbers of ChAT+ neurons as Cre‐ rats. This study suggests that variance in behavior between ChAT::Cre+ and wildtype rats is sex dependent and advances theories that distinct neural circuits and processes regulate sexually divergent fear responses.

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Sexually dimorphic muscarinic acetylcholine receptor modulation of contextual fear learning in the dentate gyrus

Cited by 11 publications

References 50 publications

Control of contextual memory through interneuronal α5-GABA_Areceptors

Control of contextual memory through interneuronal α5-GABA_Areceptors

Reactivating hippocampal-mediated memories during reconsolidation to disrupt fear

ChAT::Cre transgenic rats show sex‐dependent altered fear behaviors, ultrasonic vocalizations and cholinergic marker expression

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Sexually dimorphic muscarinic acetylcholine receptor modulation of contextual fear learning in the dentate gyrus

Cited by 11 publications

References 50 publications

Control of contextual memory through interneuronal α5-GABAAreceptors

Control of contextual memory through interneuronal α5-GABAAreceptors

Reactivating hippocampal-mediated memories during reconsolidation to disrupt fear

ChAT::Cre transgenic rats show sex‐dependent altered fear behaviors, ultrasonic vocalizations and cholinergic marker expression

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Product

Resources

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Control of contextual memory through interneuronal α5-GABA_Areceptors

Control of contextual memory through interneuronal α5-GABA_Areceptors