Cholinergic Signaling Controls Conditioned Fear Behaviors and Enhances Plasticity of Cortical-Amygdala Circuits

Abstract

Summary We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photo-stimulation of endogenous cholinergic input: (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs); (2) enhances glutamatergic synaptic transmission in the BLA and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories.

The Input-Output Relationship of the Cholinergic Basal Forebrain

“…Afferents from the medial division of the central nucleus, excited during fear expression, are likely suppressing ACh efflux in BLA under conditions of learned fear expression, whereas interpreting the influence of lateral central amygdala (CeL) input cells will require further study, as CeL contains both fear-excited and fear-inhibited cells (Ciocchi et al, 2010). As the action of ACh in BLA is dependent on both motivational state and state of the BLA principal cells (Power and McGaugh, 2002; Unal et al, 2015), cholinergic input to the BLA may facilitate memory formation by biasing the synaptic competition in favor of the strongly activated neurons (Jiang et al, 2016). …”

The role of basal forebrain cholinergic neurons in fear and extinction memory

“…Non-specific excitotoxic lesions in the NBM have no effects on cued FPS (Schauz and Koch, 1999), but studies using optogenetic and pharmacological methods in the Pavlovian fear conditioning paradigm suggest that BF amygdalopetal cholinergic neurons are critical for cued fear memory (Jiang, Kundu, Lederman, Lopez-Hernandez, Ballinger, Wang, Talmage, and Role, 2016). Optogenetic-induced inhibition of BF amygdalopetal cholinergic input to the BLA has no effect on acquisition, but disrupts expression, of cued fear memory (Jiang et al, 2016).…”

“…Optogenetic-induced inhibition of BF amygdalopetal cholinergic input to the BLA has no effect on acquisition, but disrupts expression, of cued fear memory (Jiang et al, 2016). MAChR antagonism in the BLA has no effect on cued Pavlovian fear conditioning (Baysinger, Kent, and Brown, 2012; Jiang et al, 2016), but simultaneously antagonizing mAChRs and nAChRs during fear conditioning disrupts expression of cued fear memory (Jiang et al, 2016). Interestingly, mAChR antagonism in the lateral amygdala (LA) disrupts trace fear conditioning (Baysinger et al, 2012), which does raise the possibility that BF amygdalopetal cholinergic input to mAChRs in the BLA are selectively critical for trace fear memory.…”

“…While a previous study has shown that activation of BF amygdalopetal cholinergic input to the BLA during fear conditioning has effects on acquisition and maintenance of fear extinction (Jiang et al, 2016), no study to date has selectively examined the role of BF amygdalopetal cholinergic neurons in cued extinction memory.…”

Molecular Mechanisms of Reward and Aversion

“…But other cholinergic neurons (nucleus basalis of Meynert, the horizontal nucleus of the diagonal band of Broca and the magnocellular preoptic area) project to the neocortex, olfactory bulb, amygdala and limbic cortex (Brady et al, 2012). Modern studies, utilizing optogenetics to investigate the role of the forebrain acetylcholine projections, have confirmed the previous views on the role of acetylcholine in cognitive functions (Hersman et al, 2017;Jiang et al, 2016;Zant et al, 2016;Pinto et al, 2013). Interestingly, the brain also has specific cholinergic neuropopulations innervating motivational brain areas such as NAc and VTA.…”