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Graduate School of Biomedical Sciences

The Jamie Maguire Lab

Mechanisms mediating Transitions between Network and Behavioral States: Implications for Neurological nd Psychiatric Disorders

Neuropsychiatric disorders are increasingly acknowledged to involve altered brain states. However, understanding how the brain transitions between pathological and healthy brain states is not currently understood. Transitions between brain states in relation to mood may provide insight into the episodic nature of neuropsychiatric disorders and will be informative for developing novel effective treatments. Our work is addressing critical gaps in our knowledge regarding the mechanisms of oscillation generation and physiological, pathological, and pharmacological mechanisms mediating transitions between network and behavioral states:

Context and Experience

Stress is a major risk factor for psychiatric disorders. We are investigating the mechanisms through which stress increases vulnerability to psychiatric illnesses, focusing on hypothalamic-pituitary-adrenal (HPA) axis dysfunction and the ability of stress to corrupt networks implicated in mood.

Pharmacological

Neurosteroids: Neurosteroids exert anxiolytic and antidepressant effects which are thought to be mediated by their ability to act as positive allosteric modulators of GABAA receptors. We are investigating the cell types and brain regions mediating the anxiolytic and antidepressant effects of neurosteroids. We propose that tonic inhibition mediated by these neurosteroid-sensitive GABAARs can modulate the pattern of activity within networks implicated in mood.

Alcohol: The anxiolytic properties of alcohol motivate consumption and contribute to the high comorbidity of alcohol use and anxiety disorders. Further, anxiety is a symptom of alcohol withdrawal, highlighting the interaction between alcohol and anxiety behaviors. We are currently investigating whether alcohol impacts networks implicated in fear and anxiety. These studies are investigating a completely novel mechanism mediating the effects of alcohol in the brain and point to a novel mechanism mediating the relationship between anxiety and alcohol.

Pathological

Our work has discovered a critical role for PV interneurons in controlling network activity in the BLA. We also discovered that there is a loss of PV interneurons in the BLA in chronically epileptic mice, which we propose may be a pathophysiological mechanism mediating the comorbidity of anxiety and epilepsy. These studies will be important for understanding how networks may become corrupted under pathological states and increase vulnerability to mood disorders.

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