Characterising how chronic stress and natural rewards impact lateral hypothalamic circuitry

The lateral hypothalamus (LH) is anatomically positioned to receive and send an array of afferent and efferent signals within the brain. This is important as distinct behaviours relating to homeostasis are coordinated and executed by LH cells and signalling pathways. The LH can control appetitive behaviour as well as motivation and reward-seeking, as well as being sensitive to stress signals. Importantly, the LH has a heterogenous composition, comprising of many diverse cell types. The functional importance of these intra-LH populations is incompletely understood. Further, neuroscience research is only recently beginning to unravel the complex nature of afferent signals which can help control output from the LH. Afferent projections from brains areas such as the paraventricular nucleus of the hypothalamus (PVN) and nucleus accumbens shell (NAcSh) can control stress and reward-related behaviour, respectively. These regions are well positioned anatomically and physiologically to send important communications to the LH in order to help maintain homeostatic functioning. This thesis firstly demonstrated that early life stress-induced motivational deficits have the capacity to be overcome by chemogenetic manipulation of the LH. Next, we saw that repeated optogenetic stimulation of the PVN can reduce motivational drive for natural rewards. Importantly, these changes could be recapitulated by isolating the PVN→LH pathway. Lastly, using fibre photometry we found that orexin neurons almost exclusively respond to approach behaviour to food pellets and that the activity of orexin neurons depended on metabolic state and the palatability or caloric value of the food. Additionally, we provide electrophysiological evidence that this behaviour may be mediated by an inhibitory projection from the NAcSh. Overall, this work demonstrates that hypothalamic and extra-hypothalamic brain regions can provide vital input to the LH in mediating stress and motivated behaviours.