Grant: Discovery Grants Program - Individual

The long-term goal of our Research Program is to define the neurobiological mechanisms underlying the stress response. With this Discovery Grant, we propose a comprehensive molecular and cellular characterization of hypothalamic stress-regulatory neurons in primates, an area that has been predominantly explored in rodents. The neuroendocrine stress response is evolutionarily ancient and mediated by the hypothalamic-pituitary-adrenal (HPA) axis. The apex of this axis consists of a group of neuroendocrine neurons in the paraventricular nucleus of the hypothalamus (PVN), which release corticotropin-releasing hormone (CRH). This implies that CRH-secreting PVN neurons integrate diverse stress-related neural signals and translate them into hormonal outputs. The characterizations of the molecular, biophysical, and morphological properties of these neurons have primarily been conducted in rodents. However, studies in primate CRHPVN neurons remain scarce, due in part to the difficulties in obtaining viable primate hypothalamic tissues. It is possible that the complex social lives and highly expanded neocortex of primates have exposed CRHPVN neurons to different stressors and stress-related neural signals, leading to the evolution of new features under evolutionary pressures. Similarities may represent fundamental operating principles of the key regulators of the conserved stress response, while differences could illuminate the limits of initially oversimplified theories about their functions. At Western University, my group has established a unique collaboration with non-human primate researchers conducting marmoset-based in vivo studies. When their research reaches its endpoint, we collect the brains of their animals for subsequent ex vivo experiments, maximizing scientific insights derived from each animal. To date, we have collected a rich dataset encompassing the electrophysiological profiling of over 200 PVN neurons from a substantial cohort of marmosets (14 males and 15 females). A subset of these neurons has been morphologically reconstructed and identified for their neurochemical profiles (e.g., CRH expression) using immunohistochemistry. We discovered that marmoset CRHPVN neurons exhibit a unique biophysical feature, which is absent in mice and mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. In this Discovery Grant, we aim to investigate the contributions of HCN channels to the functions of CRHPVN neurons in marmosets. Furthermore, leveraging our unique access to viable marmoset brains for ex vivo investigations-a rarity in Canada and globally-we will expand our initiative with comprehensive profiling of PVN neurons. This will involve combining single-cell transcriptomics with existing morpho-electrophysiological characterizations. We plan to disseminate our valuable datasets through an Open Science database, providing ample opportunities for future discoveries in the field.