The thalamus under stress: impact on cognition and social behaviors – THUNDER

Cognitive and social dysfunctions are widely observed across neuropsychiatric conditions and severely impair patient’s daily life. Stress is a primary risk factor for mental illnesses by favoring their occurrence or triggering relapse. Using mouse models of stress-induced psychopathology and combining ex vivo and in vivo recordings, chemo- and optogenetic circuits modulation, refined molecular genetic tools and compelling behavioral analyses, THUNDER aims at identifying important brain substrates and the underlying cellular and molecular processes engaged in stress-induced cognitive and social dysfunction.

Several cerebral structures such as the prefrontal cortex (PFC) or subcortical structures like the nucleus accumbens (NAc) have been classically linked to cognitive and social deficits. However, it is becoming clear that mental disorders stem from connectivity dysfunctions in brain networks rather than from deregulations of circumscribed structures. Being a major hub between limbic areas and the PFC, the dorsal thalamus is of key interest and has been recently associated to several psychopathologies. While the importance of the dorsal thalamus and its interconnection with prefrontal regions in cognition has been firmly established over the past decade, its role in social abilities has been scarcely studied and little is known on how stress impacts thalamic circuits. Here we propose to investigate the cellular and molecular mechanisms through which stress exposure alters specific thalamo-frontal and thalamo-limbic networks and ultimately lead to deeply engrained cognitive and social disabilities.

This multidisciplinary project involves three partners who are at the forefront of research on stress and/or thalamic functions. We propose to achieve the following aims.

Aim 1: We will study the impact of adult or juvenile repeated social defeat on the activity of virally-identified thalamic neuronal subpopulations in a projection-specific manner in adults. We will then manipulate the activity of these cell populations to test whether we could rescue stress-induced cognitive and social dysfunction. Our preliminary data along with the literature prompt us to focus primarily on thalamic cells projecting to the PFC and to the NAc.

Aim 2: We will investigate the long-term synaptic changes occurring upon stress exposure in key thalamo-recipient networks using opto-stimulation of thalamic terminals and ex vivo recordings. To causally link these synaptic adaptations to behavioral alterations, we will use optogenetic-assisted deep brain stimulations to counteract these plastic changes and assess the behavioral consequences. Further, we propose to perform multi-sites single-units and local field potential recordings and analyze functional connectivity between selected thalamic cells and neurons in their recipient structures in mice performing cognitive and/or sociability tasks under basal conditions or after stress.

Aim 3: To tackle the molecular substrates underlying stress outcomes, we will perform transcriptomic analysis (sci-RNA-seq3) on thalamic nuclei sorted upon their projecting regions on stressed mice and controls. The impact of GR inactivation on the observed gene expression changes will be studied using thalamic GR conditional mutants. This aim will allow identifying new molecular candidates involved in social and cognitive decline upon stress-exposure.

Overall, this project will shed some light on new circuits involved in stressed-induced cognitive and social impairment and improve our knowledge of the molecular events underlying increased vulnerability to psychiatric disorders.