Mitchell, C.S†, Campbell1, E.J†, Fisher, S.D, Stanton, L.M, Burton, N.J, Pearl, A.J, McNally, G.P, Bains, J.S, Füzesi, T, Graham, B.A, Manning, E.E*, Dayas, C.V*.

bioRxiv - 2023

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another, mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stressand reward-related brain regions drives these behaviours. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons one hour/day for 5 consecutive days and showed increased acute stress-related behaviours and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioural changes may, in part, be driven by PVNCRH synaptic projections to the LH.