Role of endocannabinoid signaling in a septohabenular pathway in the regulation of anxiety- and depressive-like behavior.

Enhancing endocannabinoid signaling produces anxiolytic- and antidepressant-like effects, but the neural circuits involved remain poorly understood. The medial habenula (MHb) is a phylogenetically-conserved epithalamic structure that is a powerful modulator of anxiety- and depressive-like behavior. Here, we show that a robust endocannabinoid signaling system modulates synaptic transmission between the MHb and its sole identified GABA input, the medial septum and nucleus of the diagonal band (MSDB). With RNAscope in situ hybridization, we demonstrate that key enzymes that synthesize or degrade the endocannabinoids 2-arachidonylglycerol (2-AG) or anandamide are expressed in the MHb and MSDB, and that cannabinoid receptor 1 (CB1) is expressed in the MSDB. Electrophysiological recordings in MHb neurons revealed that endogenously-released 2-AG retrogradely depresses GABA input from the MSDB. This endocannabinoid-mediated depolarization-induced suppression of inhibition (DSI) was limited by monoacylglycerol lipase (MAGL) but not by fatty acid amide hydrolase. Anatomic and optogenetic circuit mapping indicated that MSDB GABA neurons monosynaptically project to cholinergic neurons of the ventral MHb. To test the behavioral significance of this MSDB-MHb endocannabinoid signaling, we induced MSDB-specific knockout of CB1 or MAGL via injection of virally-delivered Cre recombinase into the MSDB of Cnr1loxP/loxP or MgllloxP/loxP mice. Relative to control mice, MSDB-specific knockout of CB1 or MAGL bidirectionally modulated 2-AG signaling in the ventral MHb and led to opposing effects on anxiety- and depressive-like behavior. Thus, depression of synaptic GABA release in the MSDB-ventral MHb pathway may represent a potential mechanism whereby endocannabinoids exert anxiolytic and antidepressant-like effects.

Development of metabolic inflammation during pre-hibernation fattening in 13-lined ground squirrels (Ictidomys tridecemlineatus).

Obesity is a worldwide pandemic with significant comorbidities. It is often accompanied by mild inflammation of the intestine followed by inflammation of metabolic tissues such as liver, adipose tissue, and skeletal muscle. Several laboratory models of obesity exist, but seasonal models like hibernators may be valuable for understanding the pathogenesis of obesity independent of genetic or high-fat diet-induced changes. As part of their annual cycle, obligate hibernators, like the 13-lined ground squirrel (Ictidomys tridecemlineatus), undergo a rapid shift from a lean to an obese state to store energy in the form of fat for their prolonged winter fast. Here, we show that ground squirrels gained mass steadily throughout the active season despite a drop in energy intake starting around 9 weeks post-hibernation. Glucose tolerance tests revealed a significant decrease in tolerance late in the active season. In visceral adipose, we found increases in adipocyte size, tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels. IL-6 levels also increased in liver and muscle and TNF-α increased in the ileum late in the active season. Levels of the anti-inflammatory cytokine, IL-10, decreased in visceral adipose and colon tissues around the same time. These data suggest metabolic inflammation develops along with adiposity late in the squirrels' active season.