Department of Biomedical and Molecular Sciences
Plenary Seminar
Wednesday January 8th, 2025
12:30pm – 1:30pm
School of Medicine, Room 132A
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Jeremy Borniger, PhD
Assistant Professor
Cancer Center & Neuroscience Division
Cold Spring Harbor Laboratory
One Bungtown Road
Cold Spring Harbor, NY
Neuronal mechanism underlying glucocorticoid circadian rhythm dysfunction in breast cancer
Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality. The exact cause of this phenomenon - whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVN CRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVN CRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVN CRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVN CRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVN CRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.
Plenary Coordinator: Sheela Abraham
Host: Sebastien Talbot
Assistant: Kat Brennan-Rowcliffe
Department of Biomedical and Molecular Sciences
Plenary Seminar
Wednesday January 15th, 2025
12:30pm – 1:30pm
School of Medicine, Room 132A
Caroline Menard, PhD
Associate Professor (Professeure agrégée)
Department of Psychiatry and Neuroscience
Faculty of Medicine, Université Laval
CERVO Brain Research Center
Neurovascular Adaptations Underlie Stress Vulnerability vs Resilience in Mice and Human Depression
Our research program aims to shed light on the biological mechanisms underlying stress vulnerability vs resilience, with help of state-of-the-art photonic technology, in order to develop innovative treatments and identify biomarkers of mood disorders. Our multidisciplinary approach combines behavioral experiments to functional, cellular, molecular, and imaging studies and validation of our rodent findings in human samples. We showed that chronic stress exposure promotes blood-brain barrier hyperpermeability leading to passage of circulating inflammatory mediators into the brain and the establishment of depressive behaviors. These changes occur in a sex-specific manner which may contribute to sex differences in depression prevalence, symptoms and treatment responses.
Plenary Coordinator: Sheela Abraham
Host: Faith Brennan
Assistant: Kat Brennan-Rowcliffe