Ryan McLaughlin, PhD
Adjunct – Assistant Professor Integrative Physiology and Neuroscience
Washington State University College of Veterinary Medicine

Novel Pathways Underlying Endocannabinoid Modulation of Stress-Related Behavior
Stress is a pervasive aspect of daily life and a significant risk factor for a host of mental illnesses, including major depression. In the brain, chronic stress causes adaptations in the mesolimbic dopamine system that increase vulnerability for developing depression-related behavior. One area of the brain that has gained attention as of late is the lateral habenula (LHb), in part because of its ability to tightly constrain midbrain monoaminergic neurotransmission. Notably, the LHb is hyperactive in individuals suffering from major depression, while restoring normal activity in this area has emerged as a viable therapeutic strategy in treatment-resistant patients. Although we still do not know how chronic stress leads to LHb dysfunction, one intriguing possibility is through stress-induced alterations in the endogenous cannabinoid (ECB) system. The primary role of the ECB system in the brain is to provide activity-dependent, on demand negative feedback, which helps to maintain synaptic homeostasis. With this in mind, our laboratory sought to examine the role of the ECB system in the LHb under conditions of acute and chronic stress. Our data indicate that stress augments ECB signaling in the LHb, while local CB1 receptor activation increases depression-related behavior in a manner consistent with LHb hyperactivation. Importantly, intra-LHb CB1 receptor blockade elicits proactive stress coping, decreases anxiety-like behavior, and increases the firing rate of ventral tegmental area (VTA) dopamine neurons in vivo. These data support a model of major depression wherein stress-induced alterations in LHb ECB signaling lead to downstream alterations in monoaminergic systems that give rise to
behavioral deficits. Ongoing studies are identifying whether ECB signaling modulates LHb function in a synapse- and projection-specific manner, how this is impacted by chronic stress exposure, and whether this system can be targeted to reverse stress-induced perturbations in monoaminergic activity and depression-related behavior.

This free lecture is made possible by a generous endowment from Professor Roger B. Loucks.