Molecular (Ionic/Receptor) Mechanisms of Susceptibility and Resilience
In our previous work and preliminary studies, the increase in the excitability of VTA dopamine neurons in susceptible mice was consistently found both in vitro and in vivo. However, the ionic and receptor mechanisms that underlie this increased excitability remain incompletely understood. The purpose of this project is to intensively explore these mechanisms, with a particular focus on the ionic basis of active resilience in VTA dopamine neurons. In the successful coping process of resilient animals, K+ channels appear to play an important active role in driving the increased pathological firing back to normal level in resilient mice. Intrinsic K+ channel plasticity in VTA dopamine neurons is one of the major focuses of this project.
Relationship Between Cellular and Behavioral Plasticity
Our in vivo recording data show that the bursting properties of VTA dopamine neurons is dramatically increased by chronic social defeat in susceptible mice, but not in the resilient subgroup. The main purpose of this project is to test whether optical manipulation of the firing patterns of these neurons can reverse defeat-induced behavioral pathology in freely-behaving susceptible mice, by use of advanced optogenetic techniques. This study will provide insight into the cellular neurophysiological mechanisms of promoting resilience and susceptible phenotypes.
Neural Circuit Mechanisms of Susceptibility and Resilience
The VTA contains dopamine neurons that project to prefrontal cortex, nucleus accumbens and amygdala (see “emotional” neural circuit below). In this project, we investigate whether chronic social defeat selectively regulates VTA dopamine neurons that project to specific targets such as prefrontal cortex, nucleus accumbens or amygdala. The long-term goal of this project is to identify projection-specific biomarker for VTA dopamine neurons and further to study behavioral responses to stress by projection-specific manipulation of dopamine neurons in the VTA.
Established antidepressants were discovered originally based on clinical efficacy and all clinically available antidepressants work through promoting serotonin or noradrenaline function in the brain. In our laboratory, we study antidepressant actions from a new angle: whether today’s antidepressants, or putative novel antidepressants, use any naturally occurring resilience (active coping) mechanisms. These studies will yield novel knowledge of antidepressant actions and offer critical information to imitate active resilience processes for new antidepressant development. Resilience mechanism-based antidepressants may provide more effective treatments for depression with fewer side effects.
Cellular Mechanisms of Mesolimbic Dopamine System Regulation after Chronic Social Defeat Stress
NARSAD Young Investigator Award, 2007-2009
Studies of animal models of depression and brain imaging of human patients have shown many brain regions are likely involved in depression. This includes the ventral tegmental area (VTA) dopamine system in the brain reward neural circuitry. In the supported studies, using a chronic social defeat model of depression, we found that the electrical activity of these dopamine neurons was increased by defeat stress, an effect which lasts at least two weeks after the end of the stressful period. Importantly, animals subjected to the same defeat, but which did not exhibit behavioral abnormalities associated with defeat stress—we refer to these animals as resilient—failed to show this increase in activity of mesolimbic dopamine neurons. Our proposed studies used several advanced approaches, such as viral-mediated gene delivery and local knockdown of BDNF in dopamine-producing cells, to further characterize the regulation of mesolimbic dopamine neurons by defeat stress. These studies provide a fundamentally new insight into the role of the mesolimbic dopamine system in depression models, and provide useful information to search for potential targets for new medications.
Neurophysiological Basis of Susceptibility and Resilience to Social Defeat Stress
R01 MH092306-01, 2011-2016
In this project, we investigate (1) whether the physiologically important firing patterns of VTA DA neurons encode the signal of stress vulnerability and play a role in active coping or deleterious behaviors; (2) whether we can find potential drug targets by understanding the molecular (ion channel and receptor) mechanisms of susceptibility and active resilience. Accordingly, we propose to use advanced optogenetic techniques to directly link specific firing patterns to stress susceptibility and resilience in freely-behaving animals. We are also intensively exploring the channel and receptor basis of defeat-induced changes in the firing properties of VTA DA neurons and particularly investigate the ionic mechanisms of active resiliency. Moreover, the roles of these new ionic and receptor mechanisms in mediating standard antidepressant action will be systematically investigated. These proposed molecular and cellular studies will provide very useful and highly novel information for improving our knowledge of depression and for identifying new drug targets to develop more effective treatments for major depressive disorder.
“Active Antidepressants”: The Potential Use of KCNQ Potentiators for Depression Treatment
Johnson & Johnson / IMHRO Rising Star Translational Research Award, 2011-2014
In a social defeat stress model of depression, we previously found that chronic social defeat consistently increased the firing rate and bursting events of ventral tegmental area (VTA) dopamine (DA) neurons in the brain reward circuitry in susceptible mice, but not in the resilient subgroup. Moreover, experimentally induced decreased firing of these neurons promotes a resilient phenotype (an antidepressant effect), while increased firing rate or bursting events promotes a susceptible phenotype. Therefore, in our ongoing studies towards translational research, we hypothesize that ion channel blockers or activators, that inhibit the pathological hyperactivity of VTA DA neurons, are antidepressant or pro-resilient. In this proposed study, on the basis of our preliminary findings about Ih inhibitors’ rapid and long-lasting antidepressant effects, we are investigating KCNQ channel potentiators as “active antidepressants”, which imitate the active ionic mechanisms of naturally occurring resilience.
Ih and K+ Channels as Mechanistically Novel Targets for Depression Treatment
Allyson Friedman’s NRSA (F32), 2012-2014
Despite over 50 years of tremendous efforts, only one or two classes of mechanistically new drugs have been developed for major depressive disorder (MDD) treatment. By employing viral-mediated gene transfer and optogenetic approaches, we defined neuronal plasticity, in ventral tegmental area dopamine neurons of the brain reward circuitry, that are both sufficient and necessary to underlie susceptibility and resilience to chronic social defeat in a stress model of depression. In this model, we found that the current of Ih (hyperpolarization-activated cation channels) was increased in susceptible mice, and surprisingly, increased even significantly more in the resilient subgroup. We also found that potassium (K+) channel function was selectively increased only in resilient mice. We therefore proposed to study Ih and K+ channels as promising new drug targets for MDD treatment, which are mechanistically different from traditional monoamine-based antidepressants.
Neural Circuit Basis of Behavioral Susceptibility and Resilience to Social Defeat
Jessica Walsh’s NRSA (F31), 2012-2015
Recent studies have shown deep brain stimulation 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. In a social defeat stress model of depression, we previously found that chronic social defeat consistently increased the firing rate and bursting events of VTA DA neurons in the brain’s reward circuitry in susceptible mice, but not in the resilient subgroup. In this ongoing study toward understanding the neural circuit mechanisms of the behavioral susceptible and resilient phenotypes, we propose to investigate the functional roles of three subgroups of VTA DA neurons that project to the emotion-related brain regions: medial prefrontal cortex, nucleus accumbens, and amygdala.
Optogenetic Dissection of Neural Circuits Underlying Alcohol Drinking Behaviors
Barbara Juarez’s NRSA (F31), 2014-2017
Alcohol-use disorders are the second most prevalent mental health burden in the world, yet there have been few advances in the discoveries of new therapeutic targets. This could be due to alcohol’s complex actions on the brain. An interesting phenomenon with alcohol use is the variability in alcohol consumption across a population. While some individuals can consume alcohol in a controlled manner, others are susceptible to succumbing to a pathological consumption of alcohol that ultimately leads to alcohol-use disorders. Thus, our goal is to understand the neural circuit adaptations underlying the emergence of individual alcohol drinking behaviors. Using a genetically identical mouse model, we are able to parse out low and high alcohol drinking behaviors. This provides us with an ideal model to understand the different neurophysiological alterations of ventral tegmental dopamine neurons between the two alcohol drinking groups. Furthermore, using circuit dissecting virogenetic fluorescent and optogenetic tools, we are parsing out how different subgroups of dopamine neurons that project to the nucleus accumbens or the medial prefrontal cortex mediate individual alcohol drinking behaviors. This investigation strives to identify novel therapeutic targets for the personalized treatment of alcohol-use disorders.
Ming-Hu Han, PhD
Icahn Medical Institute
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