During my PhD, I worked primarily on four questions:
Exploring the differential effects of physical exercise on hippocampal physiology in two closely-related mouse substrains with underlying anatomical and genetic differences. In this work, we observed distinct anatomical, physiological, and genomic differences between two mouse substrains of common origin (both C57Bl/6N-derived), which were both obtained from Charles River, but at different times (NCrl - 5 years ago, NCrlCri - 40 years ago). When subjected to voluntary physical exercise, only the NCrl mice showed positive effects on the levels of circulating growth factors, hippocampal neurotrophic factor expression, HPC mitochondrial biogenesis/function, as well as adult HPC neurogenesis, whereas these effects were either absent or highly attenuated in the NCrlCri mice. Given the antidepressant-like effects of physical exercise, and the involvement of the aforementioned molecular and cellular hippocampal changes in the behavioural effects, the findings of our study potentially shed light on the molecular mechanisms (physiological/genomic) that are pertinent to the effects of physical exercise on the hippocampus. This work is currently being written and is in the process of submission.
Understanding the implications of activating adult hippocampal progenitors on mood-related behaviour. In this work, we observed that chronic Gq-mediated activation of adult hippocampal progenitors (using chemogenetic activation in bigenic mouse lines) resulted in an increase in adult hippocampal neurogenesis, accompanied by a reduction in anxiety-like behaviour and an enhancement in fear extinction learning. This work has recently been published. (https://www.sciencedirect.com/science/article/pii/S2667242124000022)
Understanding the effects of early life adversity on mitostasis and inflamm-ageing in the rat hippocampus. In this work, we used a rodent model of early life adversity, maternal separation (MS), which is reported to enhance adult anxiety- and depression-like behaviour, and accelerate ageing. We observed that a history of MS was associated with perturbed mitochondrial homeostasis and neuroinflammation in the hippocampus, and cognitive decline in middle-aged rats, which was associated with peripheral inflammatory changes. The cognitive/neuroinflammatory changes in MS-middle-aged rats could be rescued with interventional strategies that target mitochondrial bioenergetics. This work is currently being written and in the process of submission. (https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2022.822917/full)
Investigating the contribution of SIRT1-PGC1a axis in mediating the neurometabolic effects of serotonergic psychedelics on the neocortex. It was previously shown in our laboratory that serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1a axis (Fanibunda et al., 2019, PNAS). We found that DOI (2,5-Dimethoxy-4-iodoamphetamine), a serotonergic psychedelic, induces potent effects on mitochondrial biogenesis in the neocortex within short timescales, and this effect could not be observed in mice with a forebrain loss of function of SIRT1 or PGC1a. Studies to assess the contribution of SIRT1 and PGC1a in the antidepressant-like effects of DOI are underway.