Talia N. Lerner, Ph.D. - US grants

DESCRIPTION (provided by applicant): Habits allow for the fast, fluid, nearly effortless execution of complex tasks, yet they can also be detrimental, for example in cases where they lead to compulsive behaviors such as in obsessive-compulsive disorder (OCD) or to behavioral patterns of drug abuse and relapse in addiction. Habit formation requires two reciprocally connected brain areas: the striatum, the input nucleus of the Basal Ganglia, and the substantia nigra (SN), which provides modulatory dopaminergic signals to the striatum. Decades of research on humans, monkeys and rodents have shown that different regions of striatum have different roles in habit formation. Initial task acquisition, which is goal-directed, is mediated b the dorsomedial striatum, while habit formation is mediated by the dorsolateral striatum. How can these two regions of striatum, which are very similar in their gross physiology and anatomy, support these two very different behavioral modes? One hypothesis, explored in this proposal, is that the connectivity motifs - the specific relationships between the inputs and the outputs - o the striatum and the SN differ by region. The long-term objective of this research will be to establish a functional input-output connectivity map of SN dopamine neurons that elucidates the diverse projection-specific functions of these neurons as an animal undergoes habit formation. In service of this overarching objective, three specific, immediately achievable aims are proposed, each of which is made possible by a recently developed technological approach. The approaches are (1) TRIO, a rabies-based circuit mapping technology that allows the simultaneous study of the inputs and outputs of a brain region of interest, (2) slice electrophysiology in combination with optogenetics, allowing for functional circuit mapping and (3) in vivo photometry, permitting the detection of calcium indicator fluorescence from subsets of SN dopamine neurons defined by their output in order to measure the activity of specific circuit elements in freely behaving animals. Together, these approaches will yield new insights into the structure and function of striatonigrostriatal circuit elements during the process of habit formation.

² Project Summary/Abstract Adverse childhood experiences (ACEs), such as abuse and neglect, have been strongly and consistently linked to increased risk for a variety of psychiatric diseases, including anxiety disorders, mood disorders, and substance abuse disorders. These diseases extract a massive emotional and economic toll on society, and their combination can be devastating and even deadly in cases of suicide and overdose. The increased risk for psychiatric disease following ACEs can persist for decades, well into adulthood, and combine with adult stressors to provoke the onset of symptoms. Despite the huge burden of psychiatric disease on our nation, and the clear impact of ACEs in producing that burden, we still have little understanding of the underlying neural circuits mediating increased psychiatric risk following adverse childhood experience. Why does stress during a window of early life confer elevated psychiatric disease risk? And why are some individuals nevertheless resilient? I hypothesize that stress during an early-life period of ongoing development in the midbrain dopamine system may alter the structure, and therefore function, of neuromodulation in the adult brain, dysregulating adult stress responses. Furthermore, I propose that individual variation in the dopamine circuit alterations produced by early life stress may explain individual variation in the later development of disease symptoms. This project will elucidate the neural circuit basis of susceptibility to psychiatric disease using mice as a model system. Mice of both sexes will be exposed to varying positive and negative early life conditions, and then tested for susceptibility or resilience to stress in adulthood using a panel of behavioral tests measuring affective function and motivation. Using cutting edge neural circuit imaging techniques, including CLARITY, optogenetics, and fiber photometry, I will ask whether the strength of specific brain connections in each individual subject is predictive of that subject?s susceptibility or resilience to stress. My CLARITY approach will allow me to search broadly and systematically for connections within the dopamine circuitry that are relevant to stress susceptibility, while my optogenetics and fiber photometry approach will allow me to track specific connection strengths in awake behaving animals before, during, and after the onset of behavioral changes. This project represents my vision of harnessing individual variation in behavior to gain insight into core circuit dysfunctions underlying polygenic and heterogeneously presenting psychiatric disorders. Together, the results from these studies will lead to understanding how the dopamine system regulates complex behaviors and will guide translational work to create sophisticated new circuit therapeutics for some of the most difficult problems in psychiatric medicine.