Gender-distinct circuit for depression identified in mice.

Depression is the leading cause of disability worldwide, affecting more than 300 million people globally, characterized by persistent sadness and a loss of interest in activities, accompanied by an inability to carry out daily tasks, for at least two weeks. Depression is a complex condition with various contributing factors including biological, psychological or social pathology. Researchers have also found clear gender differences in the prevalence of depressive disorders with studies indicating women are affected nearly twice as often as men, however, the neurobiological underpinnings of this discrepancy remains unclear. Now, a study from researchers at Michigan State University identifies a gender-specific circuit in mice which activates during stress and is controlled by testosterone. The team state they focused on the activity between neurons in the ventral hippocampus, which become active under stress and emotion, and their activation of nucleus accumbens neurons, a critical region in reward and motivation. The study is published in the journal Biological Psychiatry.

Previous studies show distinct gender differences in prevalence rates of certain mental health problems, with females more likely to present with internalizing disorders such as depression and anxiety, and men more likely to present with externalizing conditions such as antisocial personality disorder or substance abuse. Preclinical studies in male mice suggest that the activity of ventral hippocampus neurons projecting to the nucleus accumbens regulates depression in response to stress. The current study characterizes this hippocampus-accumbens circuit in male and female genders to investigate its role in potential sex differences in models of depression.

The current study utilises a subchronic variable stress model, the rodent representation of depression, to investigate male and female gender differences in models of this mood-based disorder. Results show increased hippocampus-accumbens circuit activity in female brains which quietened when testosterone is introduced. Data findings show the female mice also become resistant to depression-like behaviours when testosterone was introduced to their system.

Results in males show hippocampus-accumbens circuit activity in male brains during stress was significantly lower than in females, and this requires testosterone. Data findings show, conversely, when testosterone is removed from their system the male mice begin to express depression-like behaviours. The group states this is the first circuit to be identified which drives gender-specific behaviour in depression and stress. They go on to add that researchers can now use this data to identify new therapeutic targets in humans.

The team surmise they have identified a new circuit involved in depression and confirm how it drives different behaviours in males and females. For the future, the researchers state as chemogenetic tools were used to manipulate neuronal circuitry in this study, these results may enable genetic medicine for the treatment of human diseases.

Source: Michigan State University

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