Melissa R. Warden, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Major depressive disorder affects an estimated 20% of the United States population and is one of the nation's leading causes of lost productivity, resulting in an estimated 200 million lost workdays each year. In order to design targeted and effective treatments for depression it is essential to understand the neural mechanisms underlying the entry into, maintenance of, and exit from the depressed state. The goals of this proposal are to discover the functional cellular-level neural signatures of depression by monitoring and decoding the network activity of large populations of identified single neurons. Leveraging the power of the most recently developed technologies for probing brain function, we will examine baseline neural activity patterns in a population of neurons during normal behavior, follow the evolution of these patterns in this same population of neurons during the induction and maintenance of a depression-like state, determine whether antidepressant therapies bring the network back to a baseline state or an alternate state, and attempt to normalize these pathological neural dynamics with fast, circuit-based, optogenetic intervention. Specifically, we will record the neural activity of genetically or topologically identified network of neurons using the genetically encoded calcium indicator GCaMP6f and a fluorescence microendoscope designed for use during free behavior. Neural activity will be monitored before, during, and after the induction of a depression-like state (with chronic mild stress) during behaviors that probe processes relevant to depression and during the resting state. Neuronal population data will be analyzed to identify network states associated with depression. We will then use targeted optogenetic stimulation to move the network dynamics back towards the baseline patterns seen before the induction of depression, a novel application of simultaneous optical control and readout. The research proposed here is extremely well suited to the goals of the New Innovator program. New technological approaches will be developed and used to ask questions about disease-related changes in neural circuit function that are not possible to address with existing methods, and new approaches to the circuit-specific treatment of depression will be tested with an eye towards translation to human patients. My scientific background in systems neurophysiology, computational neuroscience, and optogenetics combined with my demonstrated productivity in the field of depression research is the precise combination of skills and interests needed to execute this paradigm-shifting work.

Project Summary/Abstract This project is aimed at understanding the neural mechanisms of learning and memory. An extensive literature has documented the role of the hippocampus, retrosplenial cingulate cortex and anterior thalamus in memory functions. Damage to these brain regions is a primary cause of the memory impairments seen in Alzheimer's disease, age-related memory decline, and various human amnesic syndromes and learning disabilities. Abnormalities in these structures have also been implicated in depression, anxiety and schizophrenia. Understanding the function of these systems is crucial for the development of treatment strategies for patients with these conditions. The memory role of the hippocampus has been well documented and, although they have not been studied as extensively, the retrosplenial cortex and anterior thalamus are also known to play a critical role in learning and memory. However, the precise contribution of each of these brain regions to the learning process remains unclear. Recent findings suggest that these closely interconnected structures form a functional circuit which mediates spatial and contextual memory. The proposed experiments are focused on understanding how memory-related information is represented by neurons in the retrosplenial cortex, and how interactions of the retrosplenial cortex, hippocampus and anterior thalamus support memory functions. In order to investigate this, neuronal activity will be recorded in these brain regions as rats perform various spatial and contextual memory tasks. Optogenetic, chemogenetic and neurochemical methods will be used to suppress neuronal activity in various components of this circuit in order to assess their contributions to functioning in the broader memory circuit. By monitoring neuronal responses as subjects learn and the effects of temporary inactivation within the circuit, it will be possible to determine how memory related information is processed and how memory may fail when damage occurs within the circuit.

Project Summary How do we decide whether to continue pursuing a goal or abandon the quest? Survival requires both the ability to persist in behavior directed toward a goal and the ability to determine when it is time to stop, a finely-tuned balance of perseverance and disengagement. The optimal balance between goal-directed and disengaged behavior differs depending on internal state and the environment, and sensitive, context-appropriate regulation of this balance is both essential and challenging. Excessive or insufficient goal-directed behavior is associated with psychiatric dysfunction ranging from attention deficit hyperactivity disorder to obsessive compulsive disorder to addiction. Disengagement from goal pursuit is an essential process, and it can be elicited by factors with either negative or positive valence. For example, an animal might stop attempting to obtain water because its actions to obtain water have failed, because it has already consumed enough water, or because it needs to quickly respond to an imminent threat to survival. Are the circuits that suppress goal-directed behavior in response to action failure the same as those that suppress goal-directed behavior after satisfying homeostatic needs or in response to threats? The LHb is a major conduit of information from the forebrain to brainstem neuromodulatory centers, and LHb neural activity suppresses midbrain dopamine neural activity via the GABAergic rostromedial tegmental nucleus (RMTg). LHb neurons fire when animals don?t receive expected rewards and when they receive punishments, and stimulation of LHb neurons and glutamatergic inputs to the LHb promotes behavioral avoidance. The objective of this study is to systematically probe the functional role of lateral habenula (LHb) circuits in regulating disengagement from goals in response to action failure, homeostatic resolution, and threat. We will use optical methods to monitor and control LHb neural circuits in order to characterize the long-timescale dynamics and functional role of LHb neurons in regulating the balance between goal-directed and disengaged behavioral states.