Hippocampal acetylcholine modulates stress-related behaviors independent of specific cholinergic inputs

Abstract

Acetylcholine (ACh) levels are elevated in actively depressed subjects. Conversely, antagonism of either nicotinic or muscarinic ACh receptors can have antidepressant effects in humans and decrease stress-relevant behaviors in rodents. Consistent with a role for ACh in mediating maladaptive responses to stress, brain ACh levels increase in response to stressful challenges, whereas systemically blocking acetylcholinesterase (AChE, the primary ACh degradative enzyme) elicits depression-like symptoms in human subjects, and selectively blocking AChE in the hippocampus increases relevant behaviors in rodents. We used an ACh sensor to characterize stress-evoked ACh release, then used chemogenetic, optogenetic and pharmacological approaches to determine whether cholinergic inputs from the medial septum/diagonal bands of Broca (MSDBB) or ChAT-positive neurons intrinsic to the hippocampus mediate stress-relevant behaviors in mice. Chemogenetic inhibition or activation of MSDBB cholinergic neurons did not result in significant behavioral effects, while inhibition attenuated the behavioral effects of physostigmine. In contrast, optogenetic stimulation of septohippocampal terminals or selective chemogenetic activation of ChAT-positive inputs to hippocampus increased stress-related behaviors. Finally, stimulation of sparse ChAT-positive hippocampal neurons increased stress-related behaviors in one ChAT-Cre line, which were attenuated by local infusion of cholinergic antagonists. These studies suggest that ACh signaling results in maladaptive behavioral responses to stress if the balance of signaling is shifted toward increased hippocampal engagement.

PDGF‐BB‐Dependent Neurogenesis Buffers Depressive‐Like Behaviors by Inhibition of GABAergic Projection from Medial Septum to Dentate Gyrus

“…[ 33 ] Stimulation of MS‐DG cholinergic pathway ameliorates the deficits of spatial memory. [ 34 ] Optogenetic stimulation of septohippocampal terminals or selective chemogenetic activation of acetylcholine‐positive inputs to hippocampus increases stress‐related behaviors, [ 35 ] however, to date, the function of MS‐DG pathway in depression is largely unknown. In the present study, we identified the MS‐DG pathway as a new circuit in regulating depressive‐like behaviors.…”

Chronic Intermittent Ethanol Exposure Dysregulates Nucleus Basalis Magnocellularis Afferents in the Basolateral Amygdala

“…In the presence of an acute stressor, cholinergic NBM neurons fire rapidly ( Zhang et al, 2004 ; Hangya et al, 2015 ). A variety of acute stressors stimulate NBM cholinergic neuron activity, including mild food shock, predator odor, and exposure to novel/stressful environments ( Jing et al, 2020 ; Rajebhosale et al, 2021 ; Mineur et al, 2022 ). NMB cholinergic neuron firing releases acetylcholine within the BLA and modulates attention, arousal, memory storage, reward processing, and threat-encoding ( Mark et al, 1996 ; Jing et al, 2020 ; Liu et al, 2021 ).…”

How can I measure brain acetylcholine levels in vivo? Advantages and caveats of commonly used approaches

“…This PBP-sensor exhibits rapid activation and decay kinetics at the millisecond level and is independent of most cholinergic drugs. in the vicinity of the indicator (Crouse et al, 2020;Jing et al, 2018Jing et al, , 2020Mineur, Mose, Maibom, et al, 2022;Mineur, Mose, Vanopdenbosch, et al, 2022).…”

“…The resulting fluorescence emission is then collected through the same fiber and detected by a sensitive photodetector. The intensity of the fluorescence signal is directly proportional to the concentration of the analyte (ACh, in this case) in the vicinity of the indicator (Crouse et al, 2020; Jing et al, 2018, 2020; Mineur, Mose, Maibom, et al, 2022; Mineur, Mose, Vanopdenbosch, et al, 2022).…”

“…The combination of fiber photometry with fluorescent ACh sensors has enabled real‐time monitoring of ACh release and uptake in the brain during various physiological and pharmacological conditions. For example, fiber photometry with GRAB_ACh sensors has been used to investigate ACh dynamics in the striatum, hippocampus, cortex, and amygdala during stressful challenges and memory tasks, revealing the role and pattern of ACh signaling in these processes (Crouse et al, 2020; Lohani et al, 2022; Mineur, Mose, Maibom, et al, 2022; Mineur, Mose, Vanopdenbosch, et al, 2022; Skirzewski et al, 2022). Furthermore, this approach has been applied to study the effects of pharmacological manipulation of ACh signaling on neuronal activity and behavior (Jing et al, 2020).…”