Development of activity-based anorexia requires PKC-δ neurons in two central extended amygdala nuclei.

Anorexia nervosa (AN) is a serious psychiatric disease, but the neural mechanisms underlying its development are unclear. A subpopulation of amygdala neurons, marked by expression of protein kinase C-delta (PKC-δ), has previously been shown to regulate diverse anorexigenic signals. Here, we demonstrate that these neurons regulate development of activity-based anorexia (ABA), a common animal model for AN. PKC-δ neurons are located in two nuclei of the central extended amygdala (EAc): the central nucleus (CeA) and oval region of the bed nucleus of the stria terminalis (ovBNST). Simultaneous ablation of CeAPKC-δ and ovBNSTPKC-δ neurons prevents ABA, but ablating PKC-δ neurons in the CeA or ovBNST alone is not sufficient. Correspondingly, PKC-δ neurons in both nuclei show increased activity with ABA development. Our study shows how neurons in the amygdala regulate ABA by impacting both feeding and wheel activity behaviors and support a complex heterogeneous etiology of AN.

Dissecting a disynaptic central amygdala-parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression.

OBJECTIVE: Cholecystokinin (CCK) plays a critical role in regulating eating and metabolism. Previous studies have mapped a multi-synapse neural pathway from the vagus nerve to the central nucleus of the amygdala (CEA) that mediates the anorexigenic effect of CCK. However, the neural circuit downstream of the CEA is still unknown due to the complexity of the neurons in the CEA. Here we sought to determine this circuit using a novel approach. METHODS: It has been established that a specific population of CEA neurons, marked by protein kinase C-delta (PKC-δ), mediates the anorexigenic effect of CCK by inhibiting other CEA inhibitory neurons. Taking advantage of this circuit, we dissected the neural circuit using a unique approach based on the idea that neurons downstream of the CEA should be disinhibited by CEAPKC-δ+ neurons while being activated by CCK. We also used optogenetic assisted electrophysiology circuit mapping and in vivo chemogenetic manipulation methods to determine the circuit structure and function. RESULTS: We found that neurons in the parasubthalamic nucleus (PSTh) are activated by the activation of CEAPKC-δ+ neurons and by the peripheral administration of CCK. We demonstrated that CEAPKC-δ+ neurons inhibit the PSTh-projecting CEA neurons; accordingly, the PSTh neurons can be disynaptically disinhibited or "activated" by CEAPKC-δ+ neurons. Finally, we showed that chemogenetic silencing of the PSTh neurons effectively attenuates the eating suppression induced by CCK. CONCLUSIONS: Our results identified a disynaptic CEA-PSTh neural circuit that mediates the anorexigenic effect of CCK and thus provide an important neural mechanism of how CCK suppresses eating.

A bed nucleus of stria terminalis microcircuit regulating inflammation-associated modulation of feeding.

Loss of appetite or anorexia associated with inflammation impairs quality of life and increases morbidity in many diseases. However, the exact neural mechanism that mediates inflammation-associated anorexia is still poorly understood. Here we identified a population of neurons, marked by the expression of protein kinase C-delta, in the oval region of the bed nucleus of the stria terminalis (BNST), which are activated by various inflammatory signals. Silencing of these neurons attenuates the anorexia caused by these inflammatory signals. Our results demonstrate that these neurons mediate bidirectional control of general feeding behaviors. These neurons inhibit the lateral hypothalamus-projecting neurons in the ventrolateral part of BNST to regulate feeding, receive inputs from the canonical feeding regions of arcuate nucleus and parabrachial nucleus. Our data therefore define a BNST microcircuit that might coordinate canonical feeding centers to regulate food intake, which could offer therapeutic targets for feeding-related diseases such as anorexia and obesity.