Wednesday, May 14, 2025
5/14/2025
Estradiol regulation of an amygdala microcircuit for valence processing - PROJECT SUMMARY Compared to men, women are twice as likely to be diagnosed with post-traumatic stress disorder (PTSD) and also experience higher rates of comorbidity with anxiety disorders and major depression. A common link between these psychiatric illnesses is dysregulation of valence processing that leads to exaggerated responses to negative stimuli, particularly to cues associated with trauma. The amygdala is well-established as the valence processing center of the brain. Converging evidence strongly implicates ovarian hormones in the regulation of both amygdala valence processing and PTSD symptom severity across the menstrual cycle, whereby high physiological levels of estradiol are beneficial. We and others have shown similar regulation of valence processing across the mouse reproductive cycle. When estradiol peaks during proestrus, negative valence behaviors decrease, whereas positive valence behaviors increase. While elegant research over the last decade has revealed populations of amygdala neurons that stably code stimuli conveying positive and negative valence, none of these studies investigated sex differences or hormonal regulation of these processes. The overall objective of this proposal is to bridge this critical gap in knowledge and discover novel cellular mechanisms within the amygdala that drive shifts in valence processing across the reproductive cycle. Based on preliminary data, we focus on local inhibitory connections called microcircuits that regulate activity of a unique principal neuron type that controls negative valence and is genetically defined by expression of R- spondin2 (Rspo2). We find that Rspo2 neurons and parvalbumin-containing inhibitory interneurons are enriched with estrogen receptor beta, which is known to regulate negative valence behavior and constrain amygdala plasticity. We show that both Rspo2 neurons and parvalbumin interneurons exhibit robust transcriptional plasticity across the reproductive cycle. Interestingly, our data suggest downregulation of parvalbumin interneuron neurotransmission in proestrus, leading us to hypothesize that these cells form a disynaptic circuit to inhibit Rspo2 neurons through disinhibition of other interneuron populations when estradiol levels peak. In Aim 1, we will interrogate estradiol-regulated sites of plasticity in this microcircuit with conventional and optogenetic-assisted slice electrophysiology. In Aim 2, we will establish the causal link between activity within this microcircuit and shifts in valence processing across the reproductive cycle with in vivo calcium imaging and closed-loop optogenetics. In Aim 3, we will determine the role of estradiol signaling in this microcircuit in the development of persistent negative valence following an intense acute stress model relevant to PTSD. Successful completion of these experiments will establish the existence and behavioral relevance of a novel inhibitory microcircuit for negative valence processing in the amygdala, as well as elucidate novel cellular mechanisms driving shifts in valence processing across the female reproductive cycle that may confer unique protection against stress experienced under high estradiol states.
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