Early Life Stress Effects on Ventral Hippocampal Microcircuitry during Emotional Behaviors

I am a physician-scientist in psychiatry studying neural circuits involved in psychiatric illness using animal models that enable us to record and manipulate real-time neuronal activity with single-cell resolution. My career goal is to become an expert on developmental risk factors, microcircuit physiology, and emotional processing. This career development award will support my work to determine the impact of early life stress on ventral hippocampal microcircuitry and how this influences anxiety- and anhedonia-related behaviors in adulthood. Early life stress (ELS) increases the risk of adult psychiatric illnesses, so understanding how ELS affects the neural circuits controlling emotional behaviors would provide a mechanism for this increased vulnerability and point towards therapeutic targets. We can model ELS in rodents by inducing fragmented maternal care in the early postnatal period and then examine neural activity during anxiety-like and reward- seeking behaviors in adulthood. The ventral portion of the hippocampus is directly connected to both fear and reward circuits, and heavily involved in emotional processing. The balance between excitatory pyramidal cells and inhibitory interneurons in the hippocampus is important for controlling the flow of information to and from other regions of these circuits. ELS alters the development of interneurons and decreases excitatory and inhibitory synaptic density in the hippocampus. We do not yet know how ELS affects hippocampal excitatory and inhibitory cell activity in vivo and how these changes relate to observed behavioral differences. This proposal will address these questions through three Specific Aims. In Aim 1, I will test the hypothesis that altered anxiety-like behavior and decreased reward-seeking in adult mice after ELS are correlated with increased pyramidal cell activity in the CA1 output region of the ventral hippocampus (vCA1). In Aim 2, I will determine the effects of ELS on PV neurons in the vCA1 during development and adulthood. First, I will test the hypothesis that ELS decreases vCA1 PV cell activity during anxiety-like and reward behaviors. Then, I will test the hypothesis that precocious expression of PV in the hippocampus after ELS is associated with changes in global hippocampal neural activity in response to positive and negative stimuli. In Aim 3, I will test the hypothesis that inhibition of vCA1 PV cell activity in normally-reared adult mice can alter anxiety- and anhedonia-like behaviors. I will conduct this work within the New York State Psychiatric Institute and Columbia University under the mentorship of Drs. René Hen and Kevin Bath. The training objectives of this K08 are to become an expert in in vivo calcium imaging and optogenetic manipulations in freely moving mice, animal models for ELS and neurodevelopment, computational techniques for examining task-related representations in neural firing, and volume microscopy imaging with immunostaining. Upon completing these scientific aims and training objectives, I will be prepared to transition to the next phase of my career as an independent investigator directing a research group at an academic medical center.