ACh signaling modulates activity of the GABAergic signaling network in the basolateral amygdala and behavior in stress-relevant paradigms

• Published in: Molecular psychiatry 2022-12, Vol.27 (12), p.4918-4927
• Main Authors: Mineur, Yann S., Mose, Tenna N., Maibom, Kathrine Lefoli, Pittenger, Steven T., Soares, Alexa R., Wu, Hao, Taylor, Seth R., Huang, Yaqing, Picciotto, Marina R.
• Format: Article
• Language: English
• Subjects: 14/35; 42/89; 631/378; 631/443; Acetylcholine - metabolism; Acetylcholine receptors (nicotinic); Amygdala; Amygdala - metabolism; Animals; Basolateral Nuclear Complex - metabolism; Behavior; Behavioral Sciences; Biological Psychology; Ca2+/calmodulin-dependent protein kinase II; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; GABAergic Neurons - metabolism; Interneurons; Interneurons - metabolism; Kinases; Male; Medicine; Medicine & Public Health; Mice; Neurons; Neurons - metabolism; Neurosciences; Parvalbumin; Pharmacotherapy; Psychiatry; Signal Transduction - physiology; Social interactions; Somatostatin; Stress, Psychological - metabolism; Vasoactive agents; γ-Aminobutyric acid
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-022-01749-7

The balance between excitatory and inhibitory (E/I) signaling is important for maintaining homeostatic function in the brain. Indeed, dysregulation of inhibitory GABA interneurons in the amygdala has been implicated in human mood disorders. We hypothesized that acetylcholine (ACh) signaling in the basolateral amygdala (BLA) might alter E/I balance resulting in changes in stress-sensitive behaviors. We therefore measured ACh release as well as activity of calmodulin-dependent protein kinase II (CAMKII)-, parvalbumin (PV)-, somatostatin (SOM)- and vasoactive intestinal protein (VIP)-expressing neurons in the BLA of awake, behaving male mice. ACh levels and activity of both excitatory and inhibitory BLA neurons increased when animals were actively coping, and decreased during passive coping, in the light–dark box, tail suspension and social defeat. Changes in neuronal activity preceded behavioral state transitions, suggesting that BLA activity may drive the shift in coping strategy. In contrast to exposure to escapable stressors, prolonging ACh signaling with a cholinesterase antagonist changed the balance of activity among BLA cell types, significantly increasing activity of VIP neurons and decreasing activity of SOM cells, with little effect on CaMKII or PV neurons. Knockdown of α7 or β2-containing nAChR subtypes in PV and SOM, but not CaMKII or VIP, BLA neurons altered behavioral responses to stressors, suggesting that ACh signaling through nAChRs on GABA neuron subtypes contributes to stress-induced changes in behavior. These studies show that ACh modulates the GABAergic signaling network in the BLA, shifting the balance between SOM, PV, VIP and CaMKII neurons, which are normally activated coordinately during active coping in response to stress. Thus, prolonging ACh signaling, as occurs in response to chronic stress, may contribute to maladaptive behaviors by shifting the balance of inhibitory signaling in the BLA.