Alcohol use disorders (AUD) are very frequently associated with impairments in social cognition,particularly a deficit in emotion recognition. Recently, it has been shown that two lines oftransgenic mice expressing different mutations of the chrna5 gene, which encodes the α5 subunitof cholinergic nicotinic receptors (α5-nAChRs), exhibit both increased alcohol consumption andsex-modulated emotional recognition deficits. These lines include: (i) α5KI mice, which carry thers16969968 (D398N) polymorphism identified as a genetic risk factor for AUD, and (ii) α5KO mice,which carry an invalidating mutation of the gene.The objective of this thesis was to examine the role of the α5 subunit in emotion recognitionthrough an approach combining behavioral analyses and exploration of the neural circuitsinvolved. Three main questions were addressed: (1) Are emotion recognition deficits a preexistingvulnerability trait or a consequence of chronic alcohol exposure? (2) Does the amygdaloventro-hippocampal circuit (BLA-vCA1) mediate the effects of α5-nAChRs on emotionrecognition? ; and (3) Do causal photomanipulations of BLA-vCA1 activity modulate emotionrecognition abilities?Our results show that both α5KI and α5KO mice exhibit stable deficits in emotional recognition,regardless of chronic alcohol exposure. In contrast, in control mice, exposure selectively impairsthe performance of females, with no additional effect on males. Neurobiologically, these deficitsare accompanied by opposite changes in synaptic plasticity in the BLA-vCA1 circuit:hyperpotentiation in α5KI versus no potentiation in α5KO. These alterations correspond toopposite profiles of neuronal reactivity in the ventral CA1 region during emotional detection:hyperactivation in response to the distress of a conspecific in α5KI mice, and no activation inα5KO mice. Finally, optogenetic manipulations confirmed the causal role of this circuit:photostimulation of BLA-vCA1 projections alters the performance of control mice but restoresthat of α5KO mice, while photoinhibition exacerbates the deficits of α5KI mice without affectingthe controls.
Cécile Pageze (Tue,) studied this question.