Cholinergic regulation of fear learning and extinction

Abstract

Cholinergic activation regulates cognitive function, and particularly long term memory consolidation. Here we present an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release using microdialysis similarly support a critical role of cholinergic neurotransmission in cortico-amygdalar or cortico-hippocampal circuits during acquisition of fear extinction. Although a few studies suggest a complex role of cholinergic neurotransmission in the cellular plasticity needed for extinction learning, more work is needed to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies will be important for elucidating the role of cholinergic neurotransmission in disorders such as post-traumatic stress disorder (PTSD) that involve deficits in extinction learning as well as developing novel therapeutic approaches for such disorders.

Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction

“…These attentional effects might be mediated via orexin effects in the basal forebrain cholinergic system, or direct modulation of attentional processes in regions like the prefrontal cortex [25]. OxB activates basal forebrain cholinergic neurons [88], and cholinergic regulation influences both consolidation of fear memories and extinction [89]. OxA injections into the basal forebrain or the PFC enhance acetylcholine release in the PFC, and either intrabasalis or i.c.v.…”

Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies

“…The NTS has direct and indirect projections to brain regions that mediate learning and memory. In addition to VNS effects on norepinephrine release from the LC, activity in the basal forebrain is increased following VNS and there is evidence that acetylcholine signaling in the amygdala, hippocampus, and prefrontal cortex acts to modulate memory for fear and extinction (Wilson and Fadel 2017). Stimulation of the vagus nerve also activates the dorsal raphe nucleus (DRN) via indirect projections from the LC and monosynaptic projections from the NTS.…”

Effects of M1 and M4 activation on excitatory synaptic transmission in CA1

“…While it is clear that mAChRs modulate the learning and memory functions of the hippocampus (Deiana et al, ; Thiele, ; Wilson & Fadel, ), the contributions of specific mAChR subtypes in mediating these effects remain unclear. Early immunohistochemical (Hersch & Levey, ; Levey et al, ) and in situ hybridization (Brann, Buckley, & Bonner, ; Buckley et al, ) studies showed predominant M1, M2, and M4 mAChR protein and gene expression within the hippocampus, with G i/o ‐coupled M2 and M4 receptors largely located presynaptically (Levey et al, ; Rouse, Edmunds, Yi, Gilmor, & Levey, ), and G q/11 ‐coupled M1 receptors largely located postsynaptically (Levey et al, ; Rouse et al, ; Volpicelli & Levey, ).…”