Behavioral impacts of intracortical androgen signaling in the rat prefrontal cortex

State University New York Stony Brook, Stony Brook NY

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Abstract

Data from humans and animals show potent androgen effects on the cells, circuits and behaviors of the adult prefrontal cortex (PFC). However, in addition to acting on brain, gonadal hormones also influence the body's peripheral organs that can in turn affect the CNS. Understanding how androgens modulate cognition thus requires separate knowledge of these processes. Resolving specific actions of androgens in the adult PFC may also be important for the deficits in cognitive PFC-dependent functions that more often and more severely affect males in disorders including schizophrenia and Parkinson's disease. These deficits are disabling and resistant to available treatments. Thus, it is not surprising that clinical trials showing benefits of testosterone augmentation for mood, memory and cognition in schizophrenia, Parkinson's disease and others generate excitement. However, testosterone augmentation induces cardiovascular and other serious side effects that could be avoided if means were available to modulate hormone signaling specifically in the brain. This adds to our motivation for developing tools that isolate and allow for long-term, selective manipulation and study of androgen receptor-mediated signaling in the adult brain and PFC. There are many ways that androgen actions can be studied, including androgen receptor knockouts and rat strains harboring functional androgen receptor mutations. However, none meet the sum of desired criteria for temporally specific, long-lasting, site-directed knockdown of receptor-mediated function in adult rat brain regions of interest. We will thus develop adeno- associated viruses that are engineered to deliver two distinct methods of gene perturbation (CRISPR and TALE based strategies) to achieve these characteristics. We will validate these using the bulbocavernosus /spinal nucleus of the bulbocavernosus system in male rats and the androgen receptor-enriched PFC in adult male and female rats as comprehensive, complimentary frameworks. By targeting receptor function, these tools will avoid uncertainties including those arising from the complex pathways involved in steroidogenesis and hormone metabolism, and issues regarding the dose, delivery and specificity/potency of hormone receptor agonist or antagonist drugs. We will use these tools here to test hypotheses about the biobehavioral effects of CNS-specific, AR-mediated signaling on the PFC in adult male and female rats and in future studies that will focus on preclinical rat models of PD, AD and aging. Our studies will also provide additional proof of principle for the utility of viral-directed gene editing/silencing for flexibly investigating the adult rat and mouse brain. .