Scientists find gender-distinct circuit for depression

Summary: A circuit-specific gender difference in ventral hippocamps to nucleus accumbens (vHPC-NAc) neurons is dependent on testosterone and causes more susceptibility to stress in females.

Source: Michigan State University

Depression affects women nearly twice as much as men, but unraveling the brain’s blueprint that regulates this behavior, let alone identifying specific molecular differences between sexes, has proven difficult.

Michigan State University researchers, however, have found and flipped a switch in the brain, revealing a single circuit in mice that activates during stress and is controlled by testosterone. The results, published in Biological Psychiatry, focus on the activity between neurons in the ventral hippocampus, which become active under stress and emotion, and their activation of nucleus accumbens neurons, critical players in reward and motivation.

“What makes these findings stand out is not only identifying this new circuit,” said A.J. Robison, MSU physiologist and lead author of the study, “but also observing and confirming how it drives different behaviors in males and females.”

Oddly enough, many circuit-specific animal model studies involving depression-related behaviors don’t include female subjects. This gap exists despite sex differences in several depression-related brain regions, including the hippocampus, Robison added.

To help close this void, Robison and a team of MSU scientists focused on this hippocampus-accumbens circuit and saw that the activity in male brains during stress was significantly lower than in females, and this required testosterone. When they removed testosterone, however, the male mice began expressing depression-like behaviors.

Conversely, the team observed increased circuit activity in female brains, but when testosterone was introduced, the neurons quieted, and the female mice became resistant to the depression-like behaviors.

This shows hippocampal neurons
MSU researchers have found a gender-distinct circuit for depression that activates during stress and is controlled by testosterone. The image is credited to MSU.

“Even with our best antidepressants, such as Prozac, we don’t know exactly how they work,” Robison said. “This is the first time we’ve found a circuit that drives this sexually different behavior; other scientists can now explore how this could translate to identifying new therapeutic targets in humans.”

Robison’s group used chemogenetic tools to manipulate specific circuit activity in the mouse brain in this study. Such tools may inform the development of “genetic medicine” for the treatment of human diseases in the future.

Funding: This research was funded in part by the National Institutes of Mental Health, the National Institutes of Neurological Disease and Stroke, the National Institutes of Drug Abuse and the Avielle Foundation.

Additional MSU scientists who contributed to this research include: Elizabeth Williams, Claire Manning, Andrew Eagle, Ashlyn Swift-Gallant (now at Memorial University of Newfoundland), Natalia Duque-Wilckens, Sadhana Chinnusamy, Adam Moeser, Cynthia Jordan and Gina Leinninger.

About this neuroscience research article

Michigan State University
Media Contacts:
Layne Cameron – Michigan State University
Image Source:
The image is credited to MSU.

Original Research: Closed access
“Androgen-Dependent Excitability of Mouse Ventral Hippocampal Afferents to Nucleus Accumbens Underlies Sex-Specific Susceptibility to Stress”. A.J. Robison et al.
Biological Psychiatry doi:10.1016/j.biopsych.2019.08.006.


Androgen-Dependent Excitability of Mouse Ventral Hippocampal Afferents to Nucleus Accumbens Underlies Sex-Specific Susceptibility to Stress

Depression affects women nearly twice as often as men, but the neurobiological underpinnings of this discrepancy are unclear. Preclinical studies in male mice suggest that activity of ventral hippocampus (vHPC) neurons projecting to the nucleus accumbens (NAc) regulates mood-related behavioral responses to stress. We sought to characterize this circuit in both sexes and to investigate its role in potential sex differences in models of depression.

We used male and female adult C57BL/6J mice in the subchronic variable stress model to precipitate female-specific reduction in sucrose preference and performed gonadectomies to test the contributions of gonadal hormones to this stress response. In addition, ex vivo slice electrophysiology of transgenic Cre-inducible Rosa-eGFP-L10a mice in combination with retrograde viral tracing to identify circuits was used to test contributions of gonadal hormones to sex differences in vHPC afferents. Finally, we used an intersecting viral DREADD (designer receptor exclusively activated by designer drugs) strategy to manipulate vHPC-NAc excitability directly in awake behaving mice.

We show a testosterone-dependent lower excitability in male versus female vHPC-NAc neurons and corresponding testosterone-dependent male resilience to reduced sucrose preference after subchronic variable stress. Importantly, we show that long-term DREADD stimulation of vHPC-NAc neurons causes decreased sucrose preference in male mice after subchronic variable stress, whereas DREADD inhibition of this circuit prevents this effect in female mice.

We demonstrate a circuit-specific sex difference in vHPC-NAc neurons that is dependent on testosterone and causes susceptibility to stress in female mice. These data provide a substantive mechanism linking gonadal hormones to cellular excitability and anhedonia—a key feature in depressive states.

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