Project Portugal 2030

Summary

MDD is characterized by multiple debilitating symptoms that include lack of motivation, social deficits, and anhedonia. Evidence shows that the NAc is dysfunctional in various animal models of depression and in depressed patients. Yet, the precise genetic and functional features of ensembles involved in the disease are not known. We HYPOTHESIZE that genetically and functionally distinct NAc ensembles are differentially affected in the depressed brain, which can underlie individual heterogeneity in symptom severity and can differentially contribute for disease manifestation and progression. Here, we will use previous snRNA-seq data and a sophisticated and innovative approach, to understand with unprecedent detail, the anatomical, genetic, and functional maps of neuronal ensembles relevant for depressive symptoms in a clinically relevant model of depression (males and females) (ANNEX1; Fig.5). We aim to: 1. Characterize the neuronal maps of genetically identified NAc neuronal ensembles in the context of the depression, using a high throughput molecular profiling method: spatial transcriptomics; 2. Evaluate the activity of distinct NAc neuronal sub-populations during the establishment of the depressive phenotype, both in susceptible and resilient mice using calcium imaging recordings coupled with miniaturized microscopes; 3. Determine the causal relationships between NAc neuronal function and behavior deficits of the CSDS mouse model, through temporally controlled manipulation of neuronal activity during behavior using optogenetics or chemogenetics. CHALLENGES ADDRESSED The proposed research addresses important challenges in MDD research, ranging from the heterogeneity of symptoms and inadequacy of classical markers to the need for a more profound understanding of neural circuits and the translation of findings into potential therapeutic strategies. By employing advanced techniques, we will identify which neuronal subpopulations are dysfunctional, providing a more profound understanding of the diversity within D1- and D2-MSNs. This will also contribute to bridging the gap between disruptions in specific NAc sub-populations and circuits and depressive symptoms. The use of the CSDS model, mimicking chronic psychosocial stress and presenting anhedonia and social deficits, adds clinical relevance to the study, allowing for the exploration of susceptibility and resilience, mirroring the variability observed in human depression. NOVELTY The outlined objectives show ambition beyond state-of-the-art by merging novel concepts and approaches, employing advanced technologies, integrating a multidisciplinary team, and aiming for a level of precision that surpasses conventional practices in neuroscience and depression research fields. To our knowledge, there are no studies focusing on the evaluation of genetically distinct NAc populations during the emergence of depressive symptoms in both susceptible and resilient mice. Contribution for scientific excellency: production of high impact papers for the community; development of toolset for evaluation and manipulation of activity of genetically distinct neurons; drawing of an anatomical and functional profile of NAc ensembles involved in the pathobiology of depression; providing seeds for other future projects focusing in developing new targeted therapeutic strategies (e.g. new small molecules based on genetic features of neurons; optogenetically-inspired DBS) in animal models of depression.