Genetic Programs of Hypothalamic Development and how Changes in these Programs Might Underlie the Etiology of Neurodevelopmental Disorders

The fundamental goal of my laboratory is to understand how hypothalamic nuclear structures develop, with the long-term objective to link in utero challenges and associated behavioral outcomes with specific changes in hypothalamic specification and/or organization. Despite having considerable knowledge about how layered regions of the brain develop (e.g., the cortex), very little is known about how clusters of neurons form. My lab uses mice and zebrafish to understand the genetic programs that guide hypothalamic neuronal specification and migration into a functional nuclear structure. The hypothalamus is a small but powerful brain region known to control a wide variety of physiologies, including obesity and reproduction.

As we learn more about the basic science underlying nuclei formation, we can also begin to ask questions about how the environment might be perturbing these processes. Given the rise of neuroendocrine disorders in our society, there is urgency to understand how prenatal environmental exposures (e.g., pesticides) or maternal health (e.g., obesity) – during key windows of development – might adversely affect brain development. Here, I discuss one of these projects: the effects of Bisphenol A on hypothalamic neurogenesis. In humans, in utero exposure to Bisphenol A (BPA) during the second trimester has been linked to a hyperactive phenotype later in life. To better understand the molecular changes in brain cytoarchitecture that might explain this behavioural dysregulation, we turned to the increasingly popular model organism – zebrafish - to study how environmentally-relevant levels of BPA might alter the onset and duration of neuronal birth. We show that BPA affects the timing of neurogenesis of the hypothalamus. In addition, this shift in neural development also leads to hyperactive phenotype in exposed zebrafish larvae. We also demonstrate that Bisphenol S, which has largely replaced BPA in plastics, similarly affects brain development and behavior. Finally, to understand the mechanistic underpinnings linking BPA to behavioural changes, we show that mitochondrial bioenergetics is altered following exposure to BPA. Combined, these data serve to link BPA to changes in fundamental steps in neural development, and suggest that regulation of progenitor maintenance may be a key factor underlying a variety of neurodevelopmental disorders.