Jessica Jillian Walsh - US grants

DESCRIPTION (provided by applicant): Major depressive disorder (MDD) afflicts about 9.5% of the U.S. population over the age 18. There is an urgent need for a novel, more effective therapeutic strategy for MDD treatment, as less than 50% of depressed patients achieve full remission and many individuals are not responsive to currently available monoamine-based traditional antidepressants. While there has been over 50 years of effort made to understand the neural mechanism underlying this disease, current therapeutics have not drastically changed from the monoamine hypothesis. Recent studies have shown Deep Brain Stimulation (DBS) to be robustly efficacious in treating MDD patients and thus research has focused on discovering the underlying mechanisms of this therapy. In this way, a new paradigm has emerged with MDD being viewed as a neural circuit disorder. Therefore, it is crucial to understand the neural circuits underlying MDD, and more importantly, the specific projection pathways implicated in this disease. In recent years, an increasing body of evidence shows that depression-like behaviors such as social avoidance and anhedonia are associated with altered activity of ventral tegmental (VTA) dopamine (DA) neurons that project to three emotion-related brain regions: the nucleus accumbens (NAc), medial prefrontal cortex (mPFC) and amygdala. In a chronic social defeat mouse model of depression, Dr. Han and colleagues previously found that the activity of VTA DA neurons in the brain reward circuit is a key determinant of susceptibility vs. resilience to social defeat stress. The firing rate and bursting events of these neurons was significantly increased by chronic defeat in susceptible mice, but not in resilient subgroup, a subpopulation of mice that went through chronic social defeat, but do not show depression-like behaviors. Furthermore, an experimentally (virally or optogenetically) induced increase in the firing rate and burst firing of projection-mixed VTA DA neurons promoted a susceptible phenotype, while a decrease in the firing rate promoted resilience. Interestingly, the level of BDNF is upregulated in the VTA target area NAc only in susceptible mice. On the basis of these and other previous studies, this proposal hypothesizes that chronic social defeat induces an increase in VTA DA firing rate and bursting mechanisms specifically in VTA DA neurons projecting to the NAc, in susceptible mice. Furthermore, it is hypothesized that the behavioral phenotypes of susceptibility and resilience are determined by pathway specific dopamine neurons and specific firing patterns. This proposal seeks to intensively characterize the projection specific VTA DA neurons to the NAc, mPFC, and amygdala through the use of viral-mediated gene transfer, electrophysiological and optogenetic techniques. These proposed molecular, cellular and behavioral studies will provide very useful and highly novel information both for improving our knowledge of the circuitry of depression and for identifying new therapeutic circuitry targets to develop more effective treatments for depression. PUBLIC HEALTH RELEVANCE: Chronic stress can play a key role in the development of depression; an important question is why some people are resilient to stress, while others are not resilient. My proposed project seeks to investigate systems level analysis of stress induced social avoidance through investigations of the neural circuits governing these abnormal behaviors. I will use electrophysiological techniques, in addition to optogenetics, to test if reversing the firing patterns of abnormal circuits can reverse social avoidance.

DESCRIPTION (provided by applicant): There is an urgent need for more targeted therapies to treat Panic Disorder (PD), a mental disorder which is characterized by recurring and often unexpected panic attacks. The NIMH estimates that 6 million Americans currently suffer from PD, with about one-third of patients becoming housebound due to the severity of their symptoms. Although it is a widespread mental illness, there is a dearth of medical therapies to treat the disorder. Many patients are prescribed anti-depressants, which do not specifically target the symptoms of PD, have numerous negative side effects, and can lead to the exacerbation of panic attacks in some individuals. Alternatively, benzodiazapenes, often prescribed as anti-anxiety medication, are extremely powerful drugs that can only be used for short periods of time and put one at risk for developing dependence. The lack of available therapies stems, in part, from the paucity of knowledge of the underlying neurological basis of anxiety disorders. Although previous research has shown that the brain stem and the limbic system are involved in PD, very little is known about the specific circuits responsible for mediating the various aspects of the disorder. Recent studies have found hypocretin-releasing neurons in the lateral hypothalamus to be necessary for the onset and maintenance of PD. Dr. de Lecea and his colleagues have previously studied the role hypocretin plays in setting an arousal threshold. This suggests hypocretin is involved in anxiety disorders, which are associated with a state of hyper-arousal. Hypocretin is also known to be involved in regulating many of the physiological alterations which accompany panic attacks, including increased breathing and heart rate and exaggerated responses to interoceptive stimuli. This proposal hypothesizes that different subpopulations of neurons in the lateral hypothalamus have distinct electrophysiological properties and adaptations in response to anxiety-provoking stimuli. Experimentally I plan to investigate, through projection-specific optogenetic activation, the role each subpopulation may play in mediating anxiety-like behaviors. Furthermore, preliminary studies on a group of nucleus solitarious tract neurons (A2), which receive innervation from hypocretin cells in the lateral hypothalamus, have revealed that activation of these cells instigat anxiety-like behaviors. By studying the projections of these neurons, this project seeks to identify and characterize the synaptic targets of A2 neurons which contribute to anxiety disorders. These proposed molecular and cellular studies will provide very useful and highly novel information, both for improving our knowledge of the circuitry of PD and for identifying new drug targets to develop more effective treatments for anxiety disorders.