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Investigating brain circuit dysfunction in mental health disorders linked to childhood adversities

Supervisors: Dr Naresh Hanchate, Professor Mehul Dattani

Mental illness is one of the significant challenges afflicting societies across the globe (1).
Depression alone affects around 300 million individuals, and recent epidemiological studies
estimate the global prevalence of psychiatric disorders is rising at an alarming rate, particularly
among adolescents and young adults. There is an urgent need to make rapid advances to
fully understand the brain circuitry and the underlying mechanism through which the brain
regulates stress and the pathological changes occurring in chronic stress, and the
mechanisms underlying stress susceptibility and resilience to ultimately develop effective
treatments.

In mammals, the physiological responses to internal and external dangers (or stressors) are
mediated by the hypothalamic CRHNs (corticotropin-releasing hormone neurons) (2). Given
the pivotal role of hypothalamic CRHNs in governing responses to stress, they provide an
excellent entry point to genetically access the circuitry throughout the brain that transmits
various signals, such as sensory, homeostatic, emotional, social, and others, to CRHNs. It is
well established that chronic social stressors, such as isolation or physical and emotional
abuse, can lead to affective disorders and physiological abnormalities, including dysfunctional
stress responses. In this project, the student will use experimental rodent models of two
distinct dimensions of early life social adversities (neglect and threat). We hypothesize that
chronic stress could impair molecularly identifiable neural circuit components in specific brain
areas containing neurons that send inputs to CRHNs. To trace upstream circuitry and define
their molecular identities and transcriptomes, we recently developed powerful
neurotechnologies, Connect-seq/Nuc-Connect-seq, enabling molecular mapping of brain
circuitry and transcriptome analyses of circuit components at single-cell resolution (3-5). Using
these new tools combined with viral tracing, single-cell transcriptomics, computational
methods, and behavioural and physiological studies in experimental rodent models, the
student shall:

1) Uncover stress susceptible and resilient subsets of hypothalamic CRHNs.
2) Determine the neural substrates with structural and functional abnormalities potentially
mediating maladaptive stress responses induced by chronic adolescent stress.
3) Investigate brain neurocircuit components that are susceptible and resilient to chronic
adolescent adversities.

This opportunity will allow the student to learn and gain expertise in cutting-edge
multidisciplinary approaches, including single-cell genomics, computational biology, neural
circuitry, and fundamental principles of behavioural and physiological neuroscience.

References (max. 5):
1. Murray, C.J.L. et al. Global burden of 87 risk factors in 204 countries and territories, 1990-
2019: a systematic analysis for the Global Burden of Disease Study 2019, The Lancet
396, 1223-1249 (2020).
2. Ulrich-Lai, Y.M. et al. Neural regulation of endocrine and autonomic stress responses, Nat
Rev Neurosci 10, 397-409 (2009).
3. Hanchate, N.K*, Lee, E.J* et al. Connect-seq to superimpose molecular on anatomical
neural circuit maps, Proc Natl Acad Sci U S A (2020).
4. Lee, E.J.*, Hanchate, N.K* et al. A psychological stressor conveyed by appetite-linked
neurons, Science Advances 6, eaay5366 (2020).
5. Hanchate, N.K. et al. Single-cell transcriptomics reveals receptor transformations during
olfactory neurogenesis, Science 350, 1251-5 (2015)