Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions-models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.

Background: Motivation for high-fat food is thought to contribute to excess caloric intake in obese individuals. A novel regulator of motivation for food may be neuromedin U (NMU), a highly-conserved neuropeptide that influences food intake. Although these effects of NMU have primarily been attributed to signaling in the paraventricular nucleus of the hypothalamus (PVN), NMU has also been found in other brain regions involved in both feeding behavior and motivation. We investigate the effects of NMU on motivation for food and food intake, and identify the brain regions mediating these effects. Methods: The motivational state for a particular reinforcer (e.g., high-fat food) can be assessed using a progressive-ratio schedule of reinforcement under which an increasing number of lever presses are required to obtain subsequent reinforcers. Here, we have used a progressive-ratio operant responding paradigm in combination with an assessment of cumulative food intake to evaluate the effects of NMU administration in rats, and identify the brain regions mediating these effects. Results: We found that peripheral administration of NMU decreases operant responding for high-fat food in rats. Evaluation of Fos-like immunoreactivity in response to peripheral NMU indicated the PVN and dorsal raphe nucleus (DRN) as sites of action for NMU. NMU infusion into either region mimics the effects of peripheral NMU on food intake and operant responding for food. NMU-containing projections from the lateral hypothalamus (LH) to the PVN and DRN were identified as an endogenous source of NMU. Conclusions: These results identify the DRN as a site of action for NMU, demonstrate that the LH provides endogenous NMU to the PVN and DRN and implicate NMU signaling in the PVN and DRN as a novel regulator of motivation for high-fat foods.

Obesity is a growing public health concern, with 37.5% of the adult population in need of therapeutics that are more efficacious with a better side effect profile. An innovative target in this regard is neuromedin U, a neuropeptide shown to suppress food intake and attenuate weight gain in animal models. These effects of neuromedin U on feeding behavior are thought to be related to agonism at the centrally expressed neuromedin U receptor 2 (NMUR2). As peptides present unique challenges that limit their therapeutic potential, the discovery of small‐molecule NMUR2 agonists is needed to validate the targets therapeutic value, but to date, none have been evaluated in any animal model of disease. We therefore assessed two small‐molecule NMUR2 agonists for their in vitro signaling and their in vivo efficacy. The NMUR2 agonists were synthesized and both NMUR2 agonists, NY0116 and NY0128, decreased cAMP while stimulating calcium signaling in stably expressing NMUR2 HEK293 cells. When small‐molecule NMUR2 agonists were tested in vivo, acute administration significantly decreased high‐fat diet consumption. Repeated administration of the compounds decreased body weight and more specifically, decreased the percentage of visceral adipose tissue (VAT) in obese mice. These results have confirmed small‐molecule NMUR2 agonists are efficacious in animal models to decrease fat content, food intake, and body weight, suggesting NMUR2 is a promising therapeutic target for metabolic disorders.