An Inhibitory Septum to Lateral Hypothalamus Circuit That Suppresses Feeding

Abstract

Feeding behavior is orchestrated by neural circuits primarily residing in the hypothalamus and hindbrain. However, the relative influence of cognitive and emotional brain circuits to the feeding circuitry in the hypothalamus and hindbrain remains unclear. Here, using the cell-type selectivity of genetic methods, circuit mapping, and behavior assays, we sought to decipher neural circuits emanating from the septal nucleus to the lateral hypothalamus (LH) that contribute to neural regulation of food intake in mice. We found that chemogenetic and optogenetic activation of septal vesicular GABA transporter (vGAT)-containing neurons or their projections in the LH reduced food intake in mice. Consistently, chemogenetic inhibition of septal vGAT neurons increased food intake. Furthermore, we investigated a previously unknown neural circuit originating from septal vGAT neurons to a subset of vGAT neurons in the LH, an area involved in homeostatic and hedonic control of energy states. Collectively, our data reveal an inhibitory septohypothalamic feeding circuit that might serve as a therapeutic target for the treatment of eating disorders such as anorexia nervosa.

Neural Circuit Mechanisms Underlying Emotional Regulation of Homeostatic Feeding

“…Another recently identified origin of inhibitory inputs to LH GABAergic neurons consists of septal GABAergic neurons that relay appetitive suppressive information to LH GABAergic neurons [35]. Similar to NAc D1R neurons, synaptic and neural alterations in the septal nucleus are also implicated in emotion-based feeding disorders [36–38].…”

“…In particular, inhibition of lateral septum neurons blocked stress-induced reductions in food intake [38], although it remains unclear if septal GABAergic projections to LH GABAergic neurons are involved in the role of lateral septum in stress-induced alterations in feeding, or other components of emotional behavior. However, given that septum both modulates feeding [35, 39–41] and affective behaviors [31], septal inputs to LH appear poised to govern emotional components of feeding behavior.…”

“…In summary, synaptic inputs from lateral septum and nucleus accumbens modulate the activity of LH GABAergic neurons [32, 35]. LH GABAergic neurons in turn project to VTA to potently stimulate the mesolimbic dopamine reward circuitry and drive appetitive and approach behaviors [27].…”

“…However, the postsynaptic population in LH mediating the anxiolytic role of BNST to LH projections remains unknown. Since LH glutamatergic and LH GABAergic neurons have opposite functions in feeding and emotion-related behaviors [22, 26–29, 35, 42, 43], it appears that different emotion centers in brain (NAc, BNST, septum) selectively target opposing cell types in the LH to bi-directionally control feeding and emotion-related behaviors. Further studies are needed to determine if these cell type-specific projections to distinct postsynaptic neurons in LH are static in nature or if these connections are altered under diverse metabolic and emotional conditions.…”

Optogenetic mapping of feeding and self-stimulation within the lateral hypothalamus of the rat

“…Definition of ChR2 plumes as elevations 874 above those produced by laser illumination in control eYFP brains helps minimize the risk of 875 confounds induced by local heat or light effects on neuronal function that are independent of 876 ChR2-induced depolarization (42). We also used relatively low power outputs, 2-5 mW/mm2, to 878 studies (43,44). Lower laser power seems likely to produce smaller regions of activation than 879 higher illumination intensities, and stimulating smaller regions with intensities that are still 880 behaviorally effective may also help precise localization of function for optogenetic effects.…”