HUNTING GHOST NEURONS IN THE NEUROENDOCRINE HYPOTHALAMUS (Ghostbuster)

The hypothalamus contains heterogeneous neurons that dictate behaviours and physiological functions through cross-talk mechanisms with peripheral hormones.

Neuronal diversity is the key to enabling hypothalamic functions and, according to the neuroscience dogma, is mainly preset during embryonic life. But what if this model is incorrect? Can neuronal heterogeneity be plastically modulated throughout adult life as well?

Here, based on my published work and solid preliminary results, I propose that special 'Ghost' neurons in the hypothalamus display plastic mechanisms of cell-identity reprogramming to accommodate neuroendocrine functions in adult life under physiological conditions. Such identity plasticity can become maladaptive and contribute to neuroendocrine disorders such as obesity.

My central hypothesis is that atypical 'Ghost' neurons are hidden within mature populations of neuroendocrine brain neurons. The Ghostbuster project will hunt down these brain cells and uncover their role in physiology and metabolic disease.

A multidisciplinary approach will be used toward this goal, uniting lineage tracing strategies, nutritional interventions, single-cell profiling of hypothalamic neurons, bioinformatic analyses, and viral-based tools for targeting Ghost cell-related genes.

These strategies will be combined with behavioural, metabolic and hormonal assessments of mice models of Ghost neuron loss or gain of function.

The project will overturn the dogma that post-mitotic neurons have negligible cell-reprogramming capacity and revolutionise our understanding of how brain functions are plastically regulated throughout life.

We will shed light on key molecular targets that allow the reprogramming of neuronal functional identity for therapeutic use and provide a novel framework for understanding the fundamental biological mechanisms that cause neuroendocrine disorders such as obesity, infertility, and beyond.