How does the brain transform ?feeling? into ?doing?? The answer to this question has profound implications for understanding the pathophysiology of psychiatric diseases such as depression and anxiety disorders, where the complex relationship between emotion, motivation, and action is disrupted. Broadly, this proposal seeks to reveal neural mechanisms that link ?feeling? with ?doing? in the healthy brain in order to generate mechanistic insights that will inform future translational studies. The amygdala and midbrain dopamine neurons are crucial mediators of emotion and motivated movement, respectively. Thus, communication points between these key systems undoubtedly represent an essential part of the neural substrate that links emotion, motivation and action. Accordingly, many studies have focused on the ventromedial striatum because of its converging inputs from the basolateral amygdala (BLA) and ventral tegmental area dopamine neurons. However, there is also a robust direct link from the central amygdala (CeA) to the substantia nigra pars lateralis (SNL). SNL dopamine neurons in turn project to the posterior dorsolateral striatum (pDLS). Thus, the BLA and CeA contact opposite poles of midbrain and striatal ventromedial-to-dorsolateral anatomical gradients. Although multiple clues suggest that CeA-SNL-pDLS circuits play important and unique roles in shaping emotional behavior, little is known about their organization or function. The objective of this proposal is to determine how emotion-related CeA signals are transformed within the SNL, and subsequently the pDLS, to influence action selection. Our preliminary data indicate that CeA-SNL projections encode a salience signal corresponding to the ?arousal? dimension of emotion. Furthermore, we find that CeA-SNL signals are capable of engaging strong motivational drives to guide action selection, an effect that requires dopamine release in pDLS. These intriguing data suggest that CeA-SNL-pDLS circuits link emotion, motivation and action but do not resolve the underlying mechanisms. The proposed research will address this knowledge gap while enhancing the candidate's core expertise in behavioral neuroscience with critical training in ex vivo electrophysiology and combinatorial optogenetics/photometry in world-class labs at Stanford. Her technical training will be supplemented with high-quality didactic and professional training via frequent mentor interactions, targeted coursework, and other career and intellectual growth opportunities.
In Aim 1, the candidate will determine how GABAergic CeA inputs impact activity in SNL dopamine and GABA neurons in parallel ex vivo and in vivo experiments under mentored supervision in the Malenka and Deisseroth labs to define the net effect of CeA signals on SNL output. After securing a tenure-track position, the candidate will apply this training in Aim 2 to determine how SNL inputs impact activity in pDLS D1 and D2 neurons. Collectively the proposed research will yield fundamental insights into neural circuits that transform ?feeling? into ?doing,? and promise to open up fruitful new directions that will define a unique research niche and launch the candidate's independent career.
Psychiatric disorders such as depression are thought to involve dysfunction of complex brain circuits that link emotional state with voluntary action; our limited understanding of how these circuits normally operate has hampered efforts to develop much-needed treatments. The goal of this proposal is to determine how the neural pathway connecting the central amygdala, substantia nigra and dorsal striatum transforms emotion-related signals into motivational drives that influence action selection in the healthy brain. The proposed research will reveal biological mechanisms that link ?feeling? with ?doing,? offering insights that can be leveraged in future translational studies that examine amygdalo-nigro-striatal circuit function in preclinical models of mental illness.
