Stephan Lammel - US grants

Depression is a debilitating disease that can dramatically affect a person's health and life. People suffering from depression experience extended periods of sadness, despair, reduced motivation and hopelessness, and they are often unable to enjoy activities once found pleasurable. At present, effective treatments for depression and other dysfunctional emotional states remain elusive. Traditional treatment perspectives have conceptualized depression as a dysfunction of specific monoaminergic neurotransmitter systems. Recently, more nuanced conceptual frameworks have arisen as a result of efforts to correlate disease symptoms with dysfunction of specific brain networks mediating mood and reward responses. The lateral habenula (LHb), a part of the reward circuit that provides ?negative value? to midbrain dopamine neurons in the ventral tegmental area (VTA), has emerged as a key brain region for the pathophysiology of depression. LHb neurons projecting to the VTA are hyperactive in an animal model of depression, and reducing synaptic transmission onto LHb neurons through deep brain stimulation can ameliorate depression-related behaviors. However, the identities of afferent pathways that drive hyperactivity of these neurons are largely unknown. Here, we propose an innovative experimental strategy that employs a combination of state-of-the-art methods, including novel molecular and genetic tools, electrophysiology, optogenetics and behavioral paradigms to investigate how chronic stress, an important cause for depression in humans, alters synaptic transmission in specific LHb afferent pathways. Our goals are to (1) identify precisely which LHb pathways are altered following chronic stress exposure, (2) describe the underlying synaptic mechanisms and (3) develop circuit-specific strategies to reverse chronic stress-induced behavioral changes. Linking chronic stress-induced synaptic adaptations to relevant LHb pathways will provide important insights into how the brain processes chronic stress in order to generate maladaptive behavioral responses, which may inspire novel treatment strategies that involve reprogramming of specific brain circuits for treating depression.

The mesolimbic dopamine (DA) system is composed of DA neurons in the ventral tegmental area (VTA) projecting to the nucleus accumbens (NAc). It plays a pivotal role in reinforcement learning and is often considered the center of the brain's reward system. Drugs of abuse such as cocaine, morphine, nicotine and amphetamine have different pharmacological effects, yet they all significantly impact reward and motivation at least in part by activating the mesolimbic DA system. An important research topic over the last decade has been to elucidate how drugs of abuse induce synaptic adaptations of glutamatergic inputs on VTA DA neurons. This body of work has led to the well-accepted theory that addiction is an aberrant form of learning and memory. In particular, a single injection of cocaine induces a strong and long-lasting (> 3 weeks) potentiation of excitatory inputs on DA neurons projecting to NAc medial shell. However, so far the origin of these inputs remains unknown due to major technical limitations. In recent years, state-of-the-art combinations of viral tracing methods and optogenetic tools made it possible to fully map the functional connectivity of the mesolimbic circuitry. As the result of these efforts, the next important step in addiction research is to identify specific inputs to mesolimbic DA neurons that are susceptible to drug-evoked synaptic plasticity. We hypothesize that different inputs to the VTA participate in related but independent circuits that are differentially modulated by drugs of abuse. To assess input-specific effects of cocaine-evoked synaptic potentiation, we will employ a multidisciplinary approach combining synaptic electrophysiology, viral tracing, immunohistochemistry and in vivo and ex vivo optogenetic experiments in mice. Because drug- evoked synaptic plasticity may contribute to addictive behaviors we will also investigate if optogenetic manipulations of specific VTA afferents promote or suppress drug-adaptive behaviors (e.g., cocaine-induced locomotor sensitization, cocaine-induced conditioned place preference). Given that the VTA is a major site of action of addictive drugs, and DA neurons projecting to NAc medial shell are particularly prone to undergo long-lasting drug-evoked synaptic adaptations, selective manipulations of inputs to these cells will provide a more comprehensive understanding of the precise nature of circuit remodeling caused by addictive drugs. Outcomes of this study may reveal important information for the development of more effective treatments of substance abuse and other mental disorders.