CRF-locus coeruleus interplay in mediating resilience against chronic stress – NoReSt

Major depression is a severe and far too common mental disorder. Its global burden poses a substantial challenge for our societies. Despite well-defined and evidence-based strategies that can address depression, less than half of patients suffering from this condition achieve remission with current antidepressants. It is thus imperative to develop more effective treatments but also innovative therapies to prevent the emergence of stress-related disorders. Although depression is highly precipitated by adverse life events, response to stress greatly varies between individuals: while it can precipitate the onset of psychiatric disorders in some individuals, others will escape these conditions, an ability defined as resilience. I propose here to approach depression from this perspective, in the context of resilience, to uncover unforeseen biological pathways underlying inter-individual variability in response to stress.
The locus coeruleus-noradrenergic (LC-NE) system plays a key role in the circuitry of resilience, notably via its downstream inhibition of dopaminergic neurons. How this system is controlled by upstream stress integrative structures is however not clear. The corticotropin releasing factor (CRF) system, a main effector of the stress response, has direct connections with the LC, originating from the paraventricular nucleus (PVN) but also from extra-hypothalamic limbic structures such as the bed nucleus of the stria terminalis (BNST) and the central amygdala (CeA). However, these CRF-LC sub-circuits are quite distinct: CRF neurons originating from the PVN are glutamatergic, while those originating from the BNST are GABAergic and those from the CeA are both. These features predict a markedly different response of LC neurons according to the origin of its CRF afferents. The precise control of LC-NE neurons by these different CRF sub-circuits and how the LC integrates and balances these different inputs has never been described. Moreover, while both CRF and NE systems have been implicated in resilience to stress, the role of the CRF-NE crosstalk in controlling the outcome of chronic social defeat stress exposure remains unknown. The goal of this proposal is to characterize the functional control of the LC-NE system by distinct CRF sub-circuits originating from the PVN, the BNST and the CeA, and to investigate their role in shaping inter-individual variability in response to chronic stress.
The LC-projecting CRF neurons from the PVN, BNST and CeA will be isolated using retrograde viral vectors, allowing the expression of sensors and effectors in order to map, record and manipulate the activity of CRF-LC projecting neurons exclusively. With this approach, these CRF-LC pathways will be characterized at the anatomical and electrophysiological level before to assess their functional input onto LC-NE neurons in vivo. Then, to investigate whether the status of these functional connections can be associated with changes in stress susceptibility and resilience, in vivo fiber photometry coupled with calcium imaging will be used to record CRF-LC neuronal activity simultaneously in the PVN, BNST and CeA, at different timepoints during exposure to the chronic social defeat stress model of depression. Ultimately, our goal is to address whether optogenetic manipulation of LC-projecting CRF neurons can promote resilience or normalize maladaptive behavior in response to chronic social defeat stress.
By taking into account the functional heterogeneity of CRF sub-circuits and their complex modulatory effect on the LC, this proposal will generate novel results and advance our understanding of the cerebral network controlling individual responses to stress and resilience. By extending our knowledge of brain networks controlling individual stress responses, this project aims at providing new leads for innovative treatments of stress-related disorders.