| dcterms.abstract | Schizophrenia, Parkinson's disease, depression, and anxiety, though very different disorders, all feature deficits in the executive functions of the prefrontal cortex. These deficits share properties of greatly reducing quality of life and being poorly responsive to available therapeutics. These cognitive problems also stem at least in part from an imbalance in dopamine control over the prefrontal cortex. Normally, the prefrontal cortex requires dopamine to be held at functionally optimal levels and when dopamine either rises above or falls below this range, prefrontal executive functions become impaired. The disorders in which executive cognitive domains are at risk thus comprise two groups - those that feature too much dopamine, or hyperdopaminergia and those where dopamine levels are deficient, i.e., hypodopaminergia. Strikingly, disorders resulting from prefrontal hypodopaminergia, such as schizophrenia, tend to affect men more than women, whereas women are more vulnerable to hyperdopaminergic disorders, e.g., anxiety. This dissertation explores the neurobiological basis for sex differences in executive operations of the prefrontal cortex, and what makes men and women differentially vulnerable to executive dysfunction in disease. Using adult rats as animal models, my work directly compares male, female, and hormone-manipulated subjects on behavioral, neurochemical, and electrophysiological levels. This work reveals novel mechanisms through which gonadal hormones influence the ways that the male and female prefrontal cortices maintain functionally optimal prefrontal dopamine levels. More specifically, it shows that the relevant gonadal hormone impact is levied against intracortical, dopamine-regulating glutamatergic and GABAergic circuits in the prefrontal cortex itself, rather than its dopamine afferents. As current methods of treating cognitive symptoms in the executive domain are less than optimal, understanding how biological sex and sex hormones modulate these functions could yield an important advance. It is possible that the neurobiological differences that shape sex-specific vulnerability to prefrontal cognitive dysfunction in disease may lead the way to the development of more effective treatments for what are often disabling, treatment-resistant cognitive problems. | |
