The role of acetylcholine in negative encoding bias: Too much of a good thing?

Abstract

Optimal acetylcholine (ACh) signaling is important for sustained attention and facilitates learning and memory. At the same time, human and animal studies have demonstrated increased levels of ACh in the brain during depressive episodes and increased symptoms of anxiety, depression, and reactivity to stress when ACh breakdown is impaired. While it is possible that the neuromodulatory roles of ACh in cognitive and affective processes are distinct, one possibility is that homeostatic levels of ACh signaling are necessary for appropriate learning, but overly high levels of cholinergic signaling promote encoding of stressful events, leading to the negative encoding bias that is a core symptom of depression. In this review, we outline this hypothesis and suggest potential neural pathways and underlying mechanisms that may support a role for ACh signaling in negative encoding bias.

Mechanisms of Nicotine Addiction

“…The observation that increased ACh signaling can lead to symptoms of depression and anxiety in human subjects and mouse models is at odds with the idea that nicotine can be rewarding in smokers and vapers, and that ACh signaling is most associated with increased attention and learning (see below). One possibility is that whereas optimal levels of ACh con-tribute to encoding of both rewarding and aversive stimuli, suprathreshold increases in ACh signaling, mediated by chronic stress or other stimuli that can lead to depression, favor encoding of aversive stimuli and lead to the type of negative encoding bias observed in human subjects with anxiety and depressive disorders (Mineur and Picciotto 2019).…”

Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia

“…Correspondingly, administration of nicotine (i.e., nAChR agonist) in healthy subjects undergoing functional magnetic resonance imaging (fMRI) leads to enhanced attention and increased neuronal activity during attentional tasks [ 32 – 34 ]. Indeed, the involvement of ACh signaling in attention is one of the best-documented contributions of the cholinergic system to cognitive processes [ 29 , 35 , 36 ].…”

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities

“…It has been suggested that whereas stress-enhanced cholinergic release can be adaptive behaviorally, chronic elevation of acetylcholine may lead to psychopathology such as MDD (Higley and Picciotto, 2014 ). An additional hypothesis put forth by this group is that high levels of cholinergic signaling may enhance encoding of stressful events, leading to negative encoding bias that is a principal feature of MDD (Mineur and Picciotto, 2019 ). Future preclinical and human subjects studies will be needed to better understand the complex interplay between cholinergic signaling, attentional processing, and psychosocial stress.…”

“…Since MDD can be induced in human subjects more significantly by chronic stress or trauma than by a single acute stressor of minor magnitude, this review has focused on how AChEIs may counteract the deleterious effects of chronic stress. Acute stress can increase synaptic release of acetylcholine and have an alerting effect, whereas severe or prolonged stress may elevate cholinergic signaling to the extent that it has a variety of negative consequences for the organism including increased depression-like behavior, as part of an Janus-faced curve (Mineur and Picciotto, 2019 ). It is noteworthy that many of the rodent behavioral assays we have been discussing (including in the context of chronic stress), such as the FST, are themselves acute stressors that presumably modulate cholinergic signaling.…”