A Seasonal Switch: Alternative Neuroendocrine Mechanisms Regulating Aggression - Aggression is a complex, adaptive suite of behaviors conserved across mammals that has evolved to allow individuals to compete for limited resources and is critical for survival. Pathological aggression and violence, however, are associated with several psychiatric disorders, including mood disorders, anxiety, post-traumatic stress disorder, autism, and attention deficit hyperactivity disorder. We lack a fundamental understanding of the mechanisms underlying pathological aggression because we lack a full understanding of the complex mechanisms regulating variation in typical aggressive behavior. This knowledge is relevant to the NIH’s mission of understanding the biobehavioral and neurobiological mechanisms underlying aggressive behavior. This grant proposes to use an integrative approach, drawing upon environmental biology, neuroendocrinology, pharmacology, and molecular neuroscience to understand how the pineal hormone melatonin orchestrates increased aggressive behavior in males and females through actions on adrenal DHEA, its conversion to bioactive steroids, and direct actions on aggression circuits within the brain. It is widely accepted that there is a robust relationship between gonadal testosterone and aggression. This notion is based on studies of male-male aggression in highly domesticated species. These correlations are weak or absent in other species, including humans. Our data support our hypothesis of a “seasonal switch” from gonadal to adrenal and melatonin regulation of aggression. This is a novel alternative endocrine mechanism regulating aggressive behaviors. Siberian hamsters are an ideal model to address our hypothesis because males and females display high levels of aggression independent of reproduction, allowing the relationship between gonadal steroids and aggression to be uncoupled. Likewise, growing evidence exists for a strong direct relationship between high DHEA and aggressive or violent behaviors in humans. Thus, the similarities between hamsters and human adrenals make hamsters an excellent model system to experimentally test the link between DHEA and human aggression. By employing neuroendocrine and molecular genetic approaches, we will test the hypothesis that melatonin acts directly on the adrenals to regulate DHEA synthesis, conversion to active metabolites, and ultimately aggressive behavior (Specific Aim 1). We will also test the hypothesis that melatonin acts directly within the canonical aggression circuit in the brain at the level of the periaqueductal gray regulating aggression through the conversion of testosterone to estradiol and on estrogen receptor expression (Specific Aim 2). The proposed studies address this key gap in the literature and will determine how melatonin orchestrates aggression in males and females. This is critically important, especially in females, because they are rarely examined for aggression; thus, we are well-positioned to elucidate novel mechanisms controlling aggression. Furthermore, these findings will provide unique insights into violent human behavior that is associated with mental illness.
