Decoding the Testosterone-Anxiety Connection: Elucidating Neurovascular and Mitochondrial Mechanisms in the Nucleus Accumbens
Description: Anxiety, recognized as a crucial risk factor for numerous mental health disorders, including depression, poses a significant public health challenge. Low testosterone (Low-T) conditions, particularly prevalent in aging populations, are associated with increased anxiety and motivational deficits; however, a comprehensive understanding of how peripheral hormones, notably testosterone, modulate anxious states remains elusive. This project builds upon our ongoing investigation into validated anxiety models, where we have identified a crucial link between Low-T levels and alterations in the neurovascular unit and mitochondrial functions within the nucleus accumbens (NAc), uncovering a novel pathway through which testosterone may affect anxiety and related behaviors. This pathway involves the mitochondrial fusion protein Mfn2, which in silico analyses indicate can be regulated by androgen receptors (AR), in astrocytes. Further, along with significant alterations in astrocytic endfeet coverage of the blood-brain barrier (BBB), an associated compromised BBB is observed.Our overarching goal is to unravel the molecular and cellular mechanisms through which low testosterone levels contribute to anxiety-related phenotypes, focusing on the on the NAc as a pivotal neural hub for anxiety and motivation. Central to our investigation is the role of Mfn2 in astrocytes, particularly their connection to the neurovascular unit, exploring their central role in mediating Low-T effects on BBB integrity, neuronal structure, and consequently, behavior related to anxiety.This 18-month project, aimed at complementing our substantial and already acquired set of data, is structured around three aims:1.To investigate how testosterone, acting via AR, influences Mfn2 expression in astrocytes and its subsequent effects on anxiety-related behaviors, BBB integrity, and neuronal morphology.2.To assess the role of astrocytic Mfn2 across various models of Low-T, including aging and chemically-induced hypogonadism, focusing on neurovascular and neuronal implications.3.To compile a comprehensive dataset of molecular mediators altered by Mfn2 manipulation, aiming to identify potential therapeutic targets.We employ an integrative approach, leveraging significant existing work, and combining molecular, cellular, and behavioral analyses. Our methods include AR modulation, Mfn2 expression studies in astrocytes, viral vector-mediated gene manipulation, immunohistochemistry, single-nucleus RNA sequencing, and omics profiling. Despite the project’s short duration, the substantial foundation laid by our ongoing research ensures this study's potential to significantly advance our understanding of testosterone's role in mental health. We expect that our findings will establish a direct mechanistic link between Low-T, astrocytic Mfn2 expression, BBB integrity, and anxiety phenotypes; elucidate the neuroprotective roles of testosterone via AR in brain function; and identify novel, actionable targets for anxiety disorders associated with Low-T.By bridging a significant knowledge gap regarding the neuroendocrine regulation of anxiety, this project promises not only to advance our understanding of anxiety disorders related to Low-T, but also to pave the way for developing more effective, targeted treatments.
Amount: CHF 262,500
Funding type: research
Funder scheme: Project funding
Start date: 2024-10-01
End date: 2026-03-31
Investigator: Sandi Perez, Maria del Carmen
Institution: EPF Lausanne – EPFL
Funded outputs count: 3
Funder award ID: 10003692
OpenAlex ID: G5263218514