Austin Avery Coley
David Geffen School of Medicine
University of California, Los Angeles
A critical issue within the mental health field is the lack of granularity in diagnostic practices. We speculate the key to developing effective antidepressants that work for everyone is to first identify a strategy to differentiate between heterogeneous conditions. Anhedonia, a condition identified in multiple neuropsychiatric disorders, is described as the inability to experience pleasure and is linked to anomalous medial prefrontal cortex (mPFC) activity. The mPFC is responsible for higher order functions, such as valence processing; however, it remains unknown how mPFC valence-specific neuronal population activity is affected during anhedonic conditions. To test this, we implemented the unpredictable chronic mild stress (CMS) protocol in rodents and examined hedonic behaviors following stress and ketamine treatment. We used unsupervised clustering to delineate individual variability in hedonic values in response to stress. We then performed in vivo 2-photon calcium imaging to longitudinally track mPFC valence-specific neuronal population activity and dynamics during Pavlovian conditioning tasks. We observed reductions in mPFC valence processing neurons within anhedonic mice. Using dimensionality reduction analysis, we identified a critical time point that shows an imbalance in mPFC dynamics that predicts resiliency to chronic mild stress, and rebounds following ketamine treatment. Also, we utilized behavioral pose-estimation tracking systems to detect a reduction in specific facial features during Pavlovian conditioning tasks during anhedonia. Lastly, we applied a linear classifier to decode resiliency prior to stress based on mPFC valence-encoding properties. Altogether, these experiments point to the need for identifying factors that decode the induction conditions of stress-induced anhedonia.
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