Neural circuits of sex-specific responses to stress

Anxiety disorders affect women twice as often as men; symptom profile and response to treatment are also different depending on biological sex. This sex difference in anxiety disorders – and mood disorders in general – is well documented, yet, we still have an incomplete understanding of the neurobiological mechanisms at play. Recent work in my laboratory identified a brain circuit that modulates anxiety levels selectively in females. We used optogenetics, a method allowing for light-driven activation of neurons, to show that activation of neurons using the neurotransmitter serotonin, and that send projections to the ventral hippocampus, increases anxiety levels only in females. We also uncovered a striking difference in the baseline excitability of these neurons: in females, raphe-ventral hippocampus neurons were hyperexcitable. These results, funded by our previous Brain Canada grant, provide evidence that baseline activity of serotonergic neurons varies with biological sex. Building on these results, we now propose to compare encoding of emotion-related stimuli by raphe serotonergic neurons and elucidate the mechanisms underlying sex-specific effects of serotonin in the ventral hippocampus. We propose to answer two key

questions:

1- Are there sex differences in the response of serotonergic neurons to different types of stimuli? We will use optogenetics to identify serotonergic neurons in mice, and record their responses to salient stimuli and to intrinsically aversive or appetitive stimuli. We will also determine if the female neuron hyperexcitability observed in vitro is also present in freely behaving mice.

2- How does serotonin act on ventral hippocampus circuits, in male and female mice? We will uncover these mechanisms at the molecular, cellular and circuit levels using a combination of cutting-edge neuroscience tools.

Taken together, this research will clarify some of the sex-related differences in response to stress and open new avenues to treat anxiety disorders in men and women.