FWF

Cellular diversity in the developing hypothalamus

The mammalian hypothalamus exhibits the undoubtedly largest heterogeneity of neurons in the brain. The diversity of hypothalamic neurons is tailored to their multimodal functions, interfacing the periphery and the nervous system. Therefore, some hundred-to-thousand neurons (Romanov et al., 2017) and their interplay with neighboring glia can drive fundamental neuroendocrine output along the life-span of an individual. Nevertheless, the molecular mechanisms that shape neuronal identity, determine and synchronize hormonal (endocrine motor) and synaptic connectivity and output during fetal and postnatal development remain largely unknown. This graduate program will rely on single-cell RNA-seq (also correlated with electrophysiology; “Patch-seq”; Fuzik et al., 2016), mouse genetics, developmental biology and imaging in optially-cleared intact tissues in mouse and human (Romanov et al., 2017) to describe organizational principles of the developing hypothalamus including: i) the temporal dynamics of neuronal diversification encomassing the spatial segregation of progenitors and their migratory routes, ii) the emergence of neuropeptide and hormonal heterogeneity and redundancy, their transitions and final lay-out across neuronal cohorts, and their role in neuronal function determination, and iii) guidance mechanisms of axonal patterning to specify neuroendocrine vs. synaptic sites along axon collaterals of identified neurons. iv) the selective ablation of neuronal subtypes that exhibit gender bias (e.g. galanin/AVP neuroendocrine cells) will be causally linked to one of the predicted behavioral outputs: sexual preference, offspring nursing, bodily metabolism or endocrine illnesses. Thus, a unifying concept on the molecular and cellular enrichment of the developing hypothalamus will emerge and serve as a blueprint for functional analysis in conjunction with projects by Margot Ernst and Daniela Pollak. International collaborators are Tomas Hökfelt (Karolinska Institutet) and Tamas L. Horvath (Yale) on the organization and function of the hypothalamic circuitry.