Jessie Muir and Eshaan Sriram Iyer, McGill University
Jessie Muir, Eshaan S. Iyer, Yiu-Chung Tse, Julian Sorensen, Serena Wu, Rand S. Eid, Vedrana Cvetkovska, Karen Wassef, Sarah Gostlin, Peter Vitaro, Nick J. Spencer & Rosemary C. Bagot Sex-biased neural encoding of threat discrimination in nucleus accumbens afferents drives suppression of reward behavior. Nature Neuroscience 27, 1966–1976 (2024). https://doi.org/10.1038/s41593-024-01748-7
Links
https://doi.org/10.1038/s41593-024-01748-7
https://drive.google.com/file/d/1db9LN4imv4euwAUUBGJkYNvzdiXMK6Oc/view?usp=sharing
Discovery of differences in encoding threat discrimination in the brain of males and females
Learning to predict threat is essential, but equally important—yet often overlooked—is learning about the absence of threat. This study by Drs. Jessie Muir and Eshaan Sriram Iyer, working in the laboratory of Dr. Rosemary Bagot at McGill University, looks at mechanisms of threat encoding and discrimination in pathways relevant to depressive-like symptoms in mice. They identified sex differences in the circuits and mechanisms responsible for recognizing threats and suggest they may reflect differences in behavioral strategies that can be relevant for understanding sex differences in risk of psychiatric disorders.
Depression is currently the leading cause of disability worldwide yet current antidepressant treatments remain ineffective in around 50% of the population. Women are twice as likely to develop depression compared to men. Given most pre-clinical studies have looked exclusively at males, there is a large gap in knowledge in the mechanisms underlying the disorder in females. Depression involves a disruption in many adaptive behavioral processes including discriminating aversive from neutral events.
In terms of behaviour, the researchers saw very subtle differences in threat discrimination in males and females, which many would assume meant similar mechanisms underlying the behavior. However, by studying signals in circuits projecting to the nucleus accumbens, a brain region that integrates threat and reward information to drive motivated behaviour, Muir and colleagues revealed sex-differences in encoding of threat discrimination. They found very similar behaviours to be driven by completely different circuits in males and females.
There are marked sex differences in incidence, symptom profiles and treatment response in anxiety and depression in humans. Understanding the neural mechanisms by which negative experiences are encoded and exert behavioral control in males and females is essential to develop effective, sex-informed intervention strategies.
About Jessie Muir & Eshaan Sriram Iyer
Jessie designed the experiments and wrote the manuscript with her PhD supervisor Dr. Rosemary Bagot at McGill University. Jessie performed most of the data collection and analysis with help from co-authors. Of note, Eshaan performed the review experiments, Dr. Yiu-Chung Tse performed the electrophysiology experiments and Dr. Julien Sorensen performed the analyses of pathway synchrony.
Jessie was awarded her PhD in 2023 and is now a post-doctoral researcher at Princeton University in Dr. Christina Kim’s lab while Eshaan was awarded his PhD in April 2025 and is starting his post-doc at Harvard with Dr. Naoshige Uchida.
Source of funding
This work was supported by funding from the Ludmer Centre for Neuroinformatics and Mental Health and a Canadian Institutes of Health Research Project grant , a Canadian Institutes of Health Research graduate scholarship (to J.M.) and a Canadian Institutes of Health Research Post-doctoral Fellowship.
