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

Abstract

Cholinergic input to the neocortex, dorsal hippocampus (dHipp), and basolateral amygdala (BLA) is critical for neural function and synaptic plasticity in these brain regions. Synaptic plasticity in the neocortex, dHipp, ventral Hipp (vHipp), and BLA has also been implicated in fear and extinction memory. This finding raises the possibility that basal forebrain (BF) cholinergic neurons, the predominant source of acetylcholine in these brain regions, have an important role in mediating fear and extinction memory. While empirical studies support this hypothesis, there are interesting inconsistencies among these studies that raise questions about how best to define the role of BF cholinergic neurons in fear and extinction memory. Nucleus basalis magnocellularis (NBM) cholinergic neurons that project to the BLA are critical for fear memory and contextual fear extinction memory. NBM cholinergic neurons that project to the neocortex are critical for cued and contextual fear conditioned suppression, but are not critical for fear memory in other behavioral paradigms and in the inhibitory avoidance paradigm may even inhibit contextual fear memory formation. Medial septum and diagonal band of Broca cholinergic neurons are critical for contextual fear memory and acquisition of cued fear extinction. Thus, even though the results of previous studies suggest BF cholinergic neurons modulate fear and extinction memory, inconsistent findings among these studies necessitates more research to better define the neural circuits and molecular processes through which BF cholinergic neurons modulate fear and extinction memory. Furthermore, studies determining if BF cholinergic neurons can be manipulated in such a manner so as to treat excessive fear in anxiety disorders are needed.

Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline

“…Given that the basal lateral amygdala (BLA) appears to receive the densest cholinergic innervation of any structure besides the striatum, and cholinergic input to the BLA exerts an important influence on acquisition and retention of emotional memories (Knox, 2016), detailed single neuron mapping of the cholinergic neurons that project to the amygdala should be very revealing.…”

“…Cholinergic signaling specifically within the amygdala is vital for encoding emotionally salient memories (Fig 2; Knox, 2016). Optogenetic stimulation of cholinergic signaling in the amygdala strengthens emotionally salient memories, and optogenetic inhibition weakens them: both nAChRs and mAChRs appear to be involved (Jiang et al, 2016).…”

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

“…cBF neurons, through their release of acetylcholine, have been implicated in a wide range of cognitive processes and behaviours, including attention, fear-related processes and reward-mediated behaviour, addiction, memory updating, extinction and renewal [57][58][59][60][61]. Much of the early research that revealed the role of these neurons in the behavioural outcomes used lesioning methods, in which a saporin-conjugated p75 NTR -specific antibody was used to create a lesion that was specific to cBF neurons [62].…”

Basolateral amygdala, nicotinic cholinergic receptors, and nicotine: Pharmacological effects and addiction in animal models and humans

“…Depending on the behavioral paradigm, nAChRs in different brain regions of the network encoding and expressing fear memories mediate the effects of nicotine. Hippocampal nAChRs are modulated by exogenous nicotine in contextual fear conditioning and contextual fear extinction memory, although regulation by cholinergic neurons projecting to BLA appears to be essential for contextual extinction (Knox, ). The acquisition and expression of cue‐conditioned fear memory also involve cholinergic regulation of BLA neurons by nAChRs (Duvarci & Pare, ; Jiang et al., ); yet, systemic nicotine does not modulate conditioning in this fear paradigm (Gould & Leach, ), although BLA circuit activity is affected by nicotine in vitro (Jiang & Role, ).…”