I opportunity to use my imagination in designing experiments

I love doodling, an art form where we create a design by harmoniously arranging random patterns. This extends to scientific research which gives me an opportunity to use my imagination in designing experiments and arranging all the data and facts together to answer certain important questions. Working on a single problem to provide a breakthrough, with all its uncertainties and possibilities of making a difference is an engaging idea and motivates me towards a career in research.During my bachelors, I was involved in organising public outreach programme, ‘Brain Awareness Week’, aimed at creating awareness about various mental disorders and understanding how the brain functions through simple demonstrations. This experience made me realise that there is a social stigma associated with patients suffering from mental disorders, as lot is unknown about the pathophysiology of diseases like autism, depression, schizophrenia etc. Moreover a recent World Health Organisation (WHO) report suggests that “one in four people in the world will be affected by mental or neurological disorders at some point in their lives” yet only one-third of the people seek help from a health professional. Thus pursuing research in the area of Neuroscience intrigued me and reading books by Oliver Sacks helped me appreciate the intricacies of the brain, how synapses shape themselves to form neural networks, taking cues from sensory and cognitive experiences, resulting in complex behavioural patterns in organisms.I believe that this is an era where we all are trying to understand the molecular mechanisms of various neuropsychiatric disorders, with depression and anxiety disorders being some of the most common and proliferating health problems worldwide. Stress is an aspect of our daily lives and conversations, and when a situation is perceived as stressful, the brain activates many neuronal circuits linking centres involved in sensory, motor, autonomic, neuroendocrine, cognitive, and emotional functions in order to adapt to the demand. The developing brain is extremely sensitive to environmental cues and early-life experiences, especially those occurring during elevated periods of brain plasticity. Epigenetics, thus provides a plausible mechanism by which adverse environmental stimuli can result in persistent changes in expression and function of a gene without altering the DNA sequence. Hence they are modifiable and potentially heritable. Studies suggest that chemical modifications such as DNA methylation, histone acetylation and micro RNA may play a pivotal role in understanding how early life adverse experiences may lead to long lasting alterations in behaviour.The first study that reported that the epigenome is responsive to environmental influences beyond embryonic development showed that DNA methylation and histone acetylation patterns of the glucocorticoid receptor (GR) gene in the hippocampus of adult male rats were influenced by the type of maternal care that they had received during infancy. Adult rats raised in poor maternal care showed aberrant features such as DNA hypermethylation in GR genes and less histone acetylation which decreased hippocampal GR expression. This led to less moderate stress response and fear like behaviour in adult rats. Similarly rats exposed to maternal separation in early critical period showed hypermethylation of 12 CG dinucleotides in exon IV of Brain Derived Neurotropic factor (BDNF) gene (needed for brain development and plasticity) which led to reduced levels of both mRNA and protein in the prefrontal cortex, amygdala, and hippocampus as compared to an adult rat raised in presence of maternal care. Even pre natal stress given to mothers led to abnormal alteration in corticotropin releasing factor (CRF) gene expression due its hypomethylation. (Mueller and Bale, 2008).┬áInfant rats are subjected number of assays such as forced swim test, presence of predator, elevated plus maze test, maladaptive maternal care etc. during their critical development period to model anxiety and fear related situations followed by next-generation sequencing and single cell sequencing technologies to identify the stress-induced epigenetic modifications in DNA from neuronal cell types. In addition to this we can also use neuroimaging techniques to map the regions of the brain followed by cellular and physiological assays to confirm expression pattern of the proteins. Employing these techniques I would like to understand whether these epigenetic changes are cell specific for example GRs are present in almost all cell types so is the epigenetic alterations confined to neuronal cells only or are other cells of the body equally affected. Another thing which is intriguing is that CRF may play an important role in progression of other neurodegenerative diseases such as Alzheimer’s, so can epigenetic changes in CRF induced at an early developmental stage lead to disease phenotypes of both Depression and Alzheimer’s, how can one differentiate between the pathophysiology of the two if the same receptor is involved, and what cellular mechanism is similar to both? Can we then say that different neurological disorders may have a common genetic etiology? These epigenetic changes being reversible in nature can act as biomarkers for therapeutics and understating their mechanisms can provide a new breakthrough in the field of treating neurological disorders.I have been keen to take up any opportunity to enrich my knowledge about the subject and its peripherals, along with maintaining a good track record in my coursework. Through my investments in the extra-curricular and previous research projects, I have put in a directed effort that will help me contribute significantly to a project in my field of interest. The challenges and developments during the experiences have only strengthened my motivation towards research in mentioned topic. A lot of labs in US universities work on neuropsychiatric diseases and employ a number of interdisciplinary approaches by collaborating with many medical centres to focus on the translational output of their research. Thus, the Khorana programme will be one of the best opportunities to experience the required collaborative and impactful research needed in this field and would help me develop the required skills to pursue research in Neuropsychiatric disorders. In future, this experience would cater to my scientific endeavours in bringing about a holistic change in the society that will not only be confined to finding better treatment possibilities but also involve spreading awareness.

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