Our group studies adult brain homeostasis by investigating the potential for form and function changes in mature brain cells that may allow for adaptation. To this end, we study both neuronal and glial cell biology in independent lines of investigations, that converge onto the larger theme of scope for flexibility within these fully mature adult brain cells. Our goal is to understand how might retained flexibilities enable adaptabilities, as required, during healthy aging and for subverting pathologies during physiological disturbances. Using a suite of high-throughput and high-resolution tools in mouse model, we investigate neurons, microglia, astrocytes, adult neural stem cells and the adult neurogenic program, in independent lines of investigations. Additionally, we seek to understand the logic of transcriptional regulation in adult brain cells by investigating the pleiotropic transcription factor Tcf4, which is implicated in multiple neurological disorders, including schizophrenia.

Under the overarching theme of investigating mechanisms of resilience in the adult brain, the following independent lines of investigations are ongoing in the laboratory:

Dendritic structural plasticity in the adult brain

Dendritic structure changes in healthy adult brain are a poorly studied topic. Although noted in the context of aging and pathology, whether changes in dendritic structures are necessarily detrimental remain to be proven. An alternative hypothesis could be that the seen changes in a terminally pathologic brain could be the remnants of potentially failed adaptive processes. We recently demonstrated that the dendritic tree of adult neurons retains the flexibility to change (Sarkar, D. et al., Translational Psychiatry, 2021). Our study also revealed novel gene networks that underlies the maintenance of the intended structure of the dendritic arbour in adult neurons. Investigating the physiological relevance of proactive maintenance of dendritic structure, we are examining if the structural flexibility in dendritic arbors play a role in neuronal homeostatic plasticity, on the timescale of weeks and months in a lifespan

Microglia diversity and function in health and pathology

Microglia, the brain resident macrophage, plays myriad roles in the brain which can be broadly classified into two categories that supports a)  neuronal functions in normal conditions of a healthy brain, and b) immune functions under conditions of physiological disturbances such as infection, injury, and diseases. The diverse transcriptional states of microglia are well appreciated in the field, especially with revelations from single cell transcriptomics studies. However, what remains unclear is the functional relevance of this diversity. Another important question that remains is whether the varied transcriptional profiles present merely a cellular ‘state’ that is malleable and not hard-wired, or if these varied profiles are in fact, specialized ‘subtypes’ with specific functions. We use brain injury as a model (Sahasrabuddhe, V. et al., Cell Reports, 2022) to investigate diversity of transcriptional states in microglia to gain insights into their functional relevance for neuronal versus immune functions.

Adult neurogenesis and the role of adult neural stem cells in stress resilience

Neural Stem Cells (NSC) make new neurons in specific anatomical locations in the adult brain throughout a lifespan. These newly made neurons in the adult brain participate in specific cognitive processes such as pattern separation, reversal learning and stress resilience. An interesting aspect of adult NSC is that they enhance and reduce neurogenesis depending on the physical and emotional state of an organisms. For instance, physical exercise and heterogenous enriched experiences enhance adult neurogenesis, while stress and isolation dampens it. Interestingly, while adult neurogenesis helps in stress resilience, the production of new neurons is adversely affected by stress, leaving a conundrum as to how exactly adult NSC respond to stress to contribute to stress resilience. We recently demonstrated that the adult NSCs harbour latent potential for making myeloid inflammatory factors, which is kept suppressed through active regulation by Tcf4 (Shariq, M. et al, Science Advances, 2021). Investigating the physiological relevance of the latent inflammatory properties of adult NSC, we are currently investigating if adult NSC mediated inflammation may play a role in stress resilience and the dynamics of the program of adult neurogenesis during stress.

Schizophrenia risk gene Tcf4’s varied functions in adult brain

Tcf4, a bHLH transcription factor, is implicated in Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD), however the functional consequence for Tcf4’s disease risk-association is yet to be elucidated. A large body of work has shown a critical role for Tcf4’s role in brain development, while its functions in the adult brain remained elusive. Work from our laboratory in the last few years revealed that Tcf4 plays critical role in the maintenance of neurons and neural stem cells in the adult brain by regulating distinct gene-networks in a cell-type specific manner, and also targeting vastly different genes in adult brain cells in comparison to during brain development. Intrigued by the unique and indispensable role of Tcf4 in different cell-types in the adult brain, we have recently created novel Crispr-engineered mice that reports for Tcf4 isoforms in real time in vivo, while also allowing for inducible cell-type specific deletion of one or the other isoform. Using these novel mouse-models, we are examining the functional significance Tcf4 isoforms, thereby probing into mechanisms of pleiotropy in transcriptional regulation in adult brain plasticity.

As we go about investigating the above questions gaining insights into mechanisms of brain resilience, more interesting queries keep getting added under our bigger theme, and the branches of each project continue to grow broad and deep. Students get an opportunity to develop ideas and initiate new investigations around these themes. If the topic of brain resilience interests you, join us in solving the mysteries of the brain and uncover its resilience power.