Chronic Stress Effects on Aversion Encoding by D1- and D2- Medium Spiny Neurons in the Nucleus Accumbens - Project Summary Prolonged stressful experiences are unavoidable and often unpredictable aspects of life; however, they are also widely recognized as a major determinant of risk and severity of neuropsychiatric disorders including depression. The range of symptoms across these disorders is diverse, however people who suffer from depression are more sensitive to negative outcomes or perceived failures and report heightened emotional responses to painful and non-painful stimuli. Since stress-induced changes in aversion sensitivity may contribute significantly to the development of many neuropsychiatric disorders, understanding mechanisms that underlie such processes and how they are changed during depressive states is a critical step towards developing effective treatments. The core subdivision of the nucleus accumbens (NAc) is well positioned to process both positive and negative experiences and translate motivation into behavior. Yet, how stress alters the function of this nucleus remains understudied. Importantly, research from our lab has found that neurons in this region uniquely encode positive and negative stimuli. Of the neurons in this region, there are two subpopulations that appear to play opposing roles in this process. Our central hypothesis is that chronic stress causes enhanced, subtype-specific neuronal response to negative stimuli and that this causes heightened aversion sensitivity. Aim 1 will characterize how chronic stress influences the encoding of aversive stimuli and escape behavior. Prior work indicates that NAc neuronal subpopulations are changed by chronic stress, but it is unknown if these are involved in stress-induced changes to aversion sensitivity. Therefore, these studies will use in vivo fiber photometry to measure how stress affects the encoding of negative events by subtypes of NAc neurons. Aim 2 will test how chronic stress produces electrophysiological changes in these neurons. Research from our lab suggests that aversive experiences decrease NAc dopamine and that this corresponds to drug taking and escape behavior. Ex vivo patch-clamp electrophysiology will be used to test how chronic stress influences how NAc neuron populations respond to dopamine. This study will also test how the strength of input to each neuronal subtype may change in a region-specific manner. I have great confidence in the guidance and training that I will receive from Dr. Hearing and Dr. Wheeler to conduct these experiments throughout this fellowship. Dr. Hearing’s expertise in ex vivo electrophysiology, Dr. Wheeler’s expertise in in vivo fiber photometry, and both of their experience with testing the effects of chronic stress will provide the research training needed to obtain a prestigious postdoctoral fellowship. They will also support my professional and intellectual growth to achieve my ultimate career goal of obtaining a faculty position based on the teacher-scholar model. I aim to develop a productive independent research program at an academic institution where I can also teach and mentor skilled scientists.
