Thesis defense – Cécile Pagèze

Venue : BBS

Cécile Pagèze

Team : Emotion, Motivation and Cognition (EMOTIV)
INCIA

Title

social emotional profile and circuits in two mouse strains expressing alpha5 nicotinic receptor mutations linked to alcohol use disorders

Abstract

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 of transgenic mice expressing different mutations of the CHRNA5 gene, which encodes the α5 subunit of cholinergic nicotinic receptors (α5-nAChRs), exhibit both increased alcohol consumption and sex-modulated emotional recognition deficits. These lines include: (i) α5KI mice, which carry the rs16969968 (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 recognition through an approach combining behavioral analyses and exploration of the neural circuits involved. Three main questions were addressed: (1) Are emotion recognition deficits a pre-existing vulnerability trait or a consequence of chronic alcohol exposure? (2) Does the amygdalo-ventro-hippocampal circuit (BLA-vCA1) mediate the effects of α5-nAChRs on emotion recognition? ; and (3) Do causal photomanipulations of BLA-vCA1 activity modulate emotion recognition 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 impairs the performance of females, with no additional effect on males. Neurobiologically, these deficits are accompanied by opposite changes in synaptic plasticity in the BLA-vCA1 circuit: hyper potentiation in α5KI versus no potentiation in α5KO. These alterations correspond to opposite 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 in α5KO mice. Finally, optogenetic manipulations confirmed the causal role of this circuit: photostimulation of BLA-vCA1 projections alters the performance of control mice but restores that of α5KO mice, while photoinhibition exacerbates the deficits of α5KI mice without affecting the controls.

Keywords: α5 nicotinic receptors, emotion recognition, amygdalo-hippocampal pathway, alcohol use disorder

Jury