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

Abstract

Nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition and consolidation of fear-and anxiety-like behaviors.However, it is unclear whether the alterations in the NBM-BLA circuit promote negative affect during ethanol withdrawal. Therefore, we performed ex vivo whole-cell patch clamp electrophysiology in both the NBM and the BLA of male Sprague-Dawley rats following 10 days of chronic intermittent ethanol (CIE) exposure and 24 hours of withdrawal (WD). We found that CIE exposure and withdrawal enhanced the neuronal excitability of NBM putative 'cholinergic' neurons. We subsequently used optogenetics to directly manipulate NBM terminal activity within the BLA and measure cholinergic modulation of glutamatergic afferents and BLA pyramidal neurons. Our findings indicate that CIE and withdrawal upregulate NBM cholinergic facilitation of glutamate release via activation of presynaptic nicotinic acetylcholine receptors. Ethanol withdrawal-induced increases in NBM terminal activity also enhance BLA pyramidal neuron firing. Collectively, our results provide a novel characterization of the NBM-BLA circuit and suggest that CIE-dependent modifications to NBM afferents enhance BLA pyramidal neuron activity during ethanol withdrawal. 3 Significance statementChronic alcohol dysregulates the neural circuitry controlling behavioral responses to stress, emotion, and motivation, and produces maladaptive behaviors that cause relapse. Since nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition/consolidation of fear and anxiety, we used electrophysiology to understand how alcohol withdrawal alters NBM neurons and measure downstream effects on their BLA projections. Our results provide a novel characterization of the NBM-BLA circuit and illustrate that alcohol withdrawal strengthens NBM cholinergic neurotransmission and upregulates glutamate signaling in the BLA through the activation of nicotinic acetylcholine receptors. Collectively, these findings illustrate that modifications in NBM projections may disrupt the excitatory/inhibitory balance in the BLA and help promote BLA pyramidal neuron activity during alcohol withdrawal.