Role of dorsal and ventral hippocampal muscarinic receptor activity in acquisition and retention of contextual fear conditioning.

Abstract

The current study further examined the effect of the muscarinic acetylcholine antagonist, scopolamine, on the Context Preexposure Facilitation Effect (CPFE; Robinson-Drummer, Dokovna, Heroux, & Stanton, 2016). In the CPFE, context representations formed during the preexposure phase are retrieved and associated with immediate shock during the training phase and expressed as freezing during a 24-hr retention phase. Scopolamine abolished postshock and retention freezing when administered systemically prior to preexposure (Experiment 1A) or immediate-shock training (Experiment 1B). Pretraining infusion of scopolamine into dorsal hippocampus (dHPC) disrupted both postshock and retention freezing (Experiments 2A) and retention freezing when the postshock freezing test was omitted (Experiment 2B) but did not alter expression of freezing behavior to an auditory fear stimulus (Experiment 2C). Finally, pretraining scopolamine infusion into ventral hippocampus (vHPC) also abolished postshock and retention test freezing (Experiment 3). These findings suggest similar roles for muscarinic receptor activity in both the dHPC and vHPC in the CPFE. This study advances understanding of the neurobiology of the CPFE by showing that context-shock associations are not learned following disruption of the cholinergic and/or hippocampal function on either the preexposure or training day. Existing theories of the CPFE (Rudy, 2009) have inferred this effect based on impaired 24-hr retention observed in previous studies (Matus-Amat, Higgins, Barrientos, & Rudy, 2004; Robinson-Drummer et al., 2016). However, the present study is the first to demonstrate it directly by including a postshock freezing measure. Further, this study is the first to identify vHPC as another important region necessary for context-shock learning during the CPFE paradigm.

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

“…The pharmacology of clozapine is complex and nonspecific having action on, but not limited to, several cholinergic and monoaminergic receptors ( Roth & Driscol, 2011 ). As clozapine potently binds to muscarinic cholinergic receptors (mAChR) and these receptors have been implicated in contextual fear conditioning ( Gale et al, 2001 ; Pinizzotto et al, 2020 ), we explored dentate gyrus application of a selective mAChR agonist and antagonist.…”

“…Consistent with the hypothesis that the hippocampus is selectively involved in context processing as opposed to Context-US association formation, manipulations of hippocampal function only during context pre-exposure will alter the benefits of pre-exposure ( Matus-Amat et al, 2004 ). For example, blockade of hippocampal n-methyl-D-aspartate (NMDA) glutamate receptors, or muscarinic cholinergic receptors, only during pre-exposure eliminates the contextual pre-exposure facilitation effect ( Pinizzotto et al, 2020 ; Stote & Fanselow, 2004 ). Besides these loss of function experiments, optogenetic enhancement of hippocampal cholinergic activity during pre-exposure further facilitates later conditioning at short PSIs ( Hersman et al, 2017 ).…”

Isoxazole‐9 reduces enhanced fear responses and retrieval in ethanol‐dependent male rats

“…For example, the dorsal hippocampus is vital for spatial learning, and is particularly critical in mediating contextual discrimination (Fanselow & Dong, 2010;Wells et al, 2011). However, the ventral hippocampus is strongly associated with negative affective symptoms (Felix-Ortiz et al, 2013;Jimenez et al, 2020;Kaouane et al, 2020;Kim et al, 2020;Pinizzotto et al, 2020;Ponce-Lina et al, 2020). Similar functional differences along the septo-temporal axis of the hippocampus have been noted in humans, with ventral hippocampus demonstrating greater activity in response to negative affective symptoms (Lau et al, 2010;Strange et al, 2014).…”

Role of dorsal hippocampal muscarinic receptor activity in acquisition and retention of single- versus multiple-trial contextual fear conditioning in adolescent rats.

“…Neural cholinergic signaling plays an essential role in many forms of contextual learning and memory (Anagnostaras et al, 1995(Anagnostaras et al, , 1999Chang & Liang, 2012;Pinizzotto et al, 2020;Robinson-Drummer et al, 2016;Wilson & Fadel, 2016). Antagonism of muscarinic acetylcholine receptor (mAChR) signaling via scopolamine administration has amnestic effects during sCFC in rats.…”

“…Antagonism of muscarinic acetylcholine receptor (mAChR) signaling via scopolamine administration has amnestic effects during sCFC in rats. Scopolamine-induced memory deficits are most consistently reported when pre-training injections are used (Anagnostaras et al, 1995(Anagnostaras et al, , 1999Pinizzotto et al, 2020;Robinson-Drummer et al, 2016;Rudy, 1996). The effects of post-training scopolamine administration are less consistent, with most studies generally showing no impairment in subsequent retention performance (Anagnostaras et al, 1995(Anagnostaras et al, , 1999Young et al, 1995; but see Rudy, 1996, for an exception).…”