Friday, May 3, 2024
5/3/2024
Fear is the human emotion that is elicited when danger or threat are perceived or recognized. Maladaptive fear patterns are common in anxiety disorders. Fear responses are orchestrated by the activation of stimulus-specific neural circuits that converge in the periaqueductal gray (PAG). Drugs targeting the serotonin (5-HT) system decrease anxiety and increasing 5-HT levels attenuates fear responses in animals. Yet, how 5-HT exerts its effects on fear behavior is not well understood. To study fear-like responses in mice I have developed a behavioral assay, in which a predator odor is presented in a chamber that allows for fast on- and off-set of the stimulus. I use deep learning algorithms to analyze behavior. Using projection-specific optogenetics, I already found that 5-HT neurons projecting to the PAG ameliorate fear-like behavior. In Aim 1 and Aim 2 I will now determine the role of endogenous 5-HT signaling in the PAG during normal behavioral response to threat. A risk factor for adult anxiety-like behavior is increased 5-HT during early life that causes enduring changes in 5-HT function. Yet, how specific circuits are affected is not understood. I found that chemogenetic or pharmacologic increases in 5-HT signaling during postnatal (P) day 2 to 11 lead to exacerbated fear responses in the adult. Functional imaging (fMRI) in this mouse model furthermore revealed robust PAG hyperactivity in response to predator odor. These data suggest that developmentally elevated 5-HT signaling produces long-lasting changes in adult 5-HT input into the dlPAG resulting in increased innate fear-like behaviors. I will test this hypothesis in Aim 3. Aim 1 uses genetically encoded 5-HT and Ca2+ sensors to simultaneously monitor 5-HT input and glutamatergic or GABAergic output in the dlPAG during behavior via fiber photometry. Aim 2 uses Cre- dependent inhibitory Archaerhodopsin to optogenetically inhibit 5-HT input into the dlPAG. Aim 3 uses Ca2+ and 5-HT sensors to monitor 5-HT input and neuronal output in the dlPAG during fear behavior after developmentally elevated 5-HTergic activity. Lastly, Aim 3 also uses my established DR(5-HT)-to-dlPAG pathway specific optogenetic protocol to enhance 5-HT signaling in dlPAG in an attempt to rescue increased fear-like responses. Together my Aims will uncover fundamental principles that govern the modulation of the PAG by 5-HT, which will provide insight into pathophysiology and etiology of anxiety disorders. Throughout my training I will work towards translational discoveries targeting developmentally disrupted neural circuits such that maladaptive behaviors can be reversed, with the overall goal of developing new therapeutic strategies. My career development plan capitalizes on my prior experience in molecular and developmental neurophysiology and adds expertise in circuit and behavioral neuroscience. I have engaged a strong mentoring team to guide my scientific efforts and my growth as an independent scientist. I believe that this K01 proposal combines pivotal technical, intellectual, and career development guidance to help me address my scientific aims and promote my transition towards establishing an independent research program.
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