The Stewart Lab is focused on understanding how a sex-biased neuronal architecture determines the behavioral consequences of underlying risk factors for mental illness. Though virtually all neuropsychiatric disorders display sex bias in terms of prevalence, age of onset, or specific symptomology, historically, the field of neuroscience has confined investigations into fundamental mechanisms driving disease risk to the exclusive study of male subjects. In support of a biological basis for sex differences in the pathogenesis of mental illness, we have identified engrained region-specific, sex-biased mechanisms modulating release, reuptake, and signaling of the neurotransmitter dopamine (DA), which controls multiple complex behaviors including motor control, motivation, reinforcement learning, attention, and cognition. Two DA synthesizing cell clusters in the midbrain innervate distinct forebrain regions. DA neurons of the substantia nigra pars compacta (SNc) project to the dorsal striatum (dStr), a critical component of the basal ganglia motor loop that subserves aspects of habit formation and decision-making behaviors. DA neurons of the ventral tegmental area (VTA) project to the ventral striatum (vStr), comprised principally of the nucleus accumbens (NAc), modulating circuits linked to reward prediction and response, aversion, and social behavior. The VTA also innervates the pre-frontal cortex (PFC), forming the mesocorticolimbic projection, with activity linked to working memory and goal-driven behavior. Though DA neurons constitute a comparatively small population, dysfunctions in DA signaling have been implicated in several neurologic and neuropsychiatric disorders including Parkinson’s disease, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD) and addiction. Our Lab utilizes a combination of neurochemical, pharmacological, behavioral, and in vivo imaging approaches in genetically modified animals to study the interrelationships between sex, neurophysiology, and behavior.

The primary goals of the lab are to establish:

1) How monoaminergic neurotransmission in the SNc vs VTA and across striatal subregions differs between the sexes.

2) How sex-biased biology leads to differential DA neurotransmission in males vs females including the involvement of genetic (e.g., X vs Y chromosomes) and hormonal factors (e.g., androgen, estrogen, and progestin signaling).

3) How sex modulates the therapeutic actions and abuse potential of drugs targeting the DA system (e.g., psychostimulants and antipsychotics).

4) Whether identification of sex-biased elements of monoaminergic neurotransmission can inform novel or repurposed therapies for psychiatric disorders.