Steroidogenic factor 1 expressing neurons in the ventromedial hypothalamus regulate feeding, metabolism and risk-associated decision making

The ventromedial hypothalamus (VMH) has long been implicated as one of the centres in the central nervous system (CNS) involved with the control of energy metabolism, feeding, fear, reproductive and aggressive behaviours. Historically, electrical stimulation and lesioning studies pointed to the VMH being a major regulator of feeding and energy metabolism, leading to it being termed the satiety centre. More recently, however, many of these functions have been attributed to the nearby arcuate nucleus (Arc) instead and the focus of the research on the VMH has been on its control of the hypoglycemic response, aggression and fear. The aim of this PhD was to employ cell-type specific optogenetic and DREADD (Designer Receptors Exclusively Activated by Designer Drugs) approaches to disentangle the role of the VMH in energy homeostasis in C57BL/6N mice. I used steroidogenic factor 1 (SF1) Cre recombinase mouse line to limit manipulations to the VMH and hypothesised that activity of SF1-expressing neurons would negatively correlate with feeding behaviour and body weight gain. Indeed, here I show that acute DREADD-mediated modulation of SF1 expressing neurons had rapid, bidirectional effects on feeding and metabolic parameters but also anxiety state. Furthermore, chronic DREADD treatment significantly altered bodyweight, nutrient partitioning and susceptibility to high fat diet (HFD) with limited effects on feeding or other behaviours. Optogenetic modulation of SF1 expressing neuron activity revealed differential prioritising of behaviours depending on the firing frequency of the SF1 neurons which is at least partially due to intrinsic synaptic properties of the SF1 neurons. In summary, I conclude that SF1 neurons have complex functions in integrating internal energy state with risk decision making, appropriate metabolic regulation and feeding behaviour.Open Acces