A paraventricular thalamus to insular cortex glutamatergic projection gates "emotional" stress-induced binge eating in females.

It is well-established that stress and negative affect trigger eating disorder symptoms and that the brains of men and women respond to stress in different ways. Indeed, women suffer disproportionately from emotional or stress-related eating, as well as associated eating disorders such as binge eating disorder. Nevertheless, our understanding of the precise neural circuits driving this maladaptive eating behavior, particularly in women, remains limited. We recently established a clinically relevant model of 'emotional' stress-induced binge eating whereby only female mice display binge eating in response to an acute "emotional" stressor. Here, we combined neuroanatomic, transgenic, immunohistochemical and pathway-specific chemogenetic approaches to investigate whole brain functional architecture associated with stress-induced binge eating in females, focusing on the role of Vglut2 projections from the paraventricular thalamus (PVTVglut2+) to the medial insular cortex in this behavior. Whole brain activation mapping and hierarchical clustering of Euclidean distances revealed distinct patterns of coactivation unique to stress-induced binge eating. At a pathway-specific level, PVTVglut2+ cells projecting to the medial insular cortex were specifically activated in response to stress-induced binge eating. Subsequent chemogenetic inhibition of this pathway suppressed stress-induced binge eating. We have identified a distinct PVTVglut2+ to insular cortex projection as a key driver of "emotional" stress-induced binge eating in female mice, highlighting a novel circuit underpinning this sex-specific behavior.

Glucose Availability Predicts the Feeding Response to Ghrelin in Male Mice, an Effect Dependent on AMPK in AgRP Neurons.

Metabolic feedback from the periphery to the brain results from a dynamic physiologic fluctuation of nutrients and hormones, including glucose and fatty acids, ghrelin, leptin, and insulin. The specific interactions between humoral factors and how they influence feeding is largely unknown. We hypothesized that acute glucose availability may alter how the brain responds to ghrelin, a hormonal signal of energy availability. Acute glucose administration suppressed a range of ghrelin-induced behaviors as well as gene expression changes in hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons after ghrelin administration. Knockdown of the energy-sensing molecule AMP-activated protein kinase (AMPK) in AgRP neurons resulted in loss of the glucose effect, and mice responded as though pretreated with saline. Conversely, 2-deoxyglucose (2-DG), which decreases glucose availability, potentiated ghrelin-induced feeding and increased hypothalamic NPY mRNA levels. AMPK knockdown did not alter the additive effect of 2-DG and ghrelin on feeding. Our findings support the idea that computation of energy status is dynamic, is informed by multiple signals, and responds to acute fluctuations in metabolic state. These observations are broadly relevant to the investigation of neuroendocrine control of feeding and highlight the underappreciated complexity of control within these systems.

Investigational drugs for alcohol use disorders: a review of preclinical data.

INTRODUCTION: Alcohol use disorders (AUDs) are one of the leading causes of preventable death in the developed world. In the U.S., only three FDA-approved pharmacotherapies for AUDs currently exist, but at a population level they display poor efficacy, low compliance rates, and adverse side effects. Therefore, identifying novel neurobiological targets for pharmacological treatment of AUDs is of urgent concern. AREAS COVERED: We discuss recent preclinical data on investigational drugs that have been assessed for their therapeutic potential in AUDs. We focus on three neurobiological domains underlying AUDs: neuropeptide systems, neuroinflammatory/neuroimmune mediators, and epigenetic modifications. We iterate the therapeutic potential of ghrelin receptor antagonists, oxytocin, neurokinin 1 receptor antagonists, and glucagon-like peptide-1 receptor agonists. In the context of neuroinflammatory/neuroimmune modulators, we draw attention to P2X4 receptor positive allosteric modulators and phosphodiesterase inhibitors. Finally, we highlight the prospects of histone deacetylase inhibitors and DNA methyltransferases that modulate the dysregulated epigenetic landscape in alcohol dependence. EXPERT OPINION: We propose that several of the compounds discussed may be suitable to be repurposed for AUD treatment. We allude to the possibility of combined pharmacotherapy for AUDs and anticipate the efforts that must be enacted to advance the field of personalised medicine for the treatment of this devastating condition.