Melanocortin 4 receptor signaling in Sim1 neurons permits sexual receptivity in female mice.

Introduction: Female sexual dysfunction affects approximately 40% of women in the United States, yet few therapeutic options exist for these patients. The melanocortin system is a new treatment target for hypoactive sexual desire disorder (HSDD), but the neuronal pathways involved are unclear. Methods: In this study, the sexual behavior of female MC4R knockout mice lacking melanocortin 4 receptors (MC4Rs) was examined. The mice were then bred to express MC4Rs exclusively on Sim1 neurons (tbMC4RSim1 mice) or on oxytocin neurons (tbMC4ROxt mice) to examine the effect on sexual responsiveness. Results: MC4R knockout mice were found to approach males less and have reduced receptivity to copulation, as indicated by a low lordosis quotient. These changes were independent of body weight. Lordosis behavior was normalized in tbMC4RSim1 mice and improved in tbMC4ROxt mice. In contrast, approach behavior was unchanged in tbMC4RSim1 mice but greatly increased in tbMC4ROxt animals. The changes were independent of melanocortin-driven metabolic effects. Discussion: These results implicate MC4R signaling in Oxt neurons in appetitive behaviors and MC4R signaling in Sim1 neurons in female sexual receptivity, while suggesting melanocortin-driven sexual function does not rely on metabolic neural circuits.

Reductions in regional theta power and fronto-parietal theta-gamma phase-amplitude coupling during gaze processing in bipolar disorder.

Impaired social cognition is common in bipolar disorder (BD) and predicts poor functional outcomes. A critical determinant of social cognition is the ability to discriminate others' gaze direction, and its alteration may contribute to functional impairment in BD. However, the neural mechanisms underlying gaze processing in BD are unclear. Because neural oscillations are crucial neurobiological mechanisms supporting cognition, we aimed to understand their role in gaze processing in BD. Using electroencephalography (EEG) data recorded during a gaze discrimination task for 38 BD and 34 controls (HC), we examined: theta and gamma power over bilateral posterior and midline anterior locations associated with early face processing and higher-level cognitive processing, and theta-gamma phase-amplitude coupling (PAC) between locations. Compared to HC, BD showed reduced midline-anterior and left-posterior theta power, and diminished bottom-up/top-down theta-gamma PAC between anterior/posterior sites. Reduced theta power and theta-gamma PAC related to slower response times. These findings suggest that altered theta oscillations and anterior-posterior cross-frequency coupling between areas associated with higher-level cognition and early face processing may underlie impaired gaze processing in BD. This is a crucial step towards translational research that may inform novel social cognitive interventions (e.g., neuromodulation to target specific oscillatory dynamics) to improve functioning in BD.

Oxytocin Neurons Enable Melanocortin Regulation of Male Sexual Function in Mice.

The melanocortin pathway has been implicated in both metabolism and sexual function. When the melanocortin 4 receptor (MC4R) is knocked out globally, male mice display obesity, low sexual desire, and copulatory difficulties; however, it is unclear whether these phenotypes are interdependent. To elucidate the neuronal circuitry involved in sexual dysfunction in MC4R knockouts, we re-expressed the MC4R in these mice exclusively on Sim1 neurons (tbMC4RSim1 mice) or on a subset of Sim1 neurons, namely oxytocin neurons (tbMC4Roxt mice). The groups were matched at young ages to control for the effects of obesity. Interestingly, young MC4R null mice had no deficits in sexual motivation or erectile function. However, MC4R null mice were found to have an increased latency to reach ejaculation compared to control mice, which was restored in both tbMC4RSim1 and tbMC4Roxt mice. These results indicate that melanocortin signaling via the MC4R on oxytocin neurons is important for normal ejaculation independent of the male's metabolic health.

Sim1 Neurons Are Sufficient for MC4R-Mediated Sexual Function in Male Mice.

Sexual dysfunction is a poorly understood condition that affects up to one-third of men around the world. Existing treatments that target the periphery do not work for all men. Previous studies have shown that central melanocortins, which are released by pro-opiomelanocortin neurons in the arcuate nucleus of the hypothalamus, can lead to male erection and increased libido. Several studies specifically implicate the melanocortin 4 receptor (MC4R) in the central control of sexual function, but the specific neural circuitry involved is unknown. We hypothesized that single-minded homolog 1 (Sim1) neurons play an important role in the melanocortin-mediated regulation of male sexual behavior. To test this hypothesis, we examined the sexual behavior of mice expressing MC4R only on Sim1-positive neurons (tbMC4Rsim1 mice) in comparison with tbMC4R null mice and wild-type controls. In tbMC4Rsim1 mice, MC4R reexpression was found in the medial amygdala and paraventricular nucleus of the hypothalamus. These mice were paired with sexually experienced females, and their sexual function and behavior was scored based on mounting, intromission, and ejaculation. tbMC4R null mice showed a longer latency to mount, a reduced intromission efficiency, and an inability to reach ejaculation. Expression of MC4R only on Sim1 neurons reversed the sexual deficits seen in tbMC4R null mice. This study implicates melanocortin signaling via the MC4R on Sim1 neurons in the central control of male sexual behavior.

Utilization of behavioral therapy services long-term after traumatic brain injury in young children.

OBJECTIVE: To examine associations of clinical need, defined by elevated parent ratings of child behavior problems and utilization of behavioral health services in young children with traumatic brain injury (TBI) and an orthopedic injury (OI) comparison group. DESIGN: Parents completed outcome measures 18 months after injury and at an extended follow-up conducted an average of 38 months postinjury. SETTING: Children's hospitals and a general hospital. PARTICIPANTS: Participants included parents of 3 groups of children injured between 3 and 7 years of age (N=139): 47 children with complicated mild to moderate TBI, 18 with severe TBI, and 74 with OI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Parents completed ratings of child behavior, mental health symptomology, and family functioning at both visits; at the extended follow-up, they reported utilization of behavior therapy or counseling services since the 18-month follow-up visit. RESULTS: Children with TBI had more behavior problems than those with OI. Although clinical need at both follow-ups was associated with greater service utilization at the extended follow-up, all groups had unmet needs as defined by a clinical need in the absence of services. Lower socioeconomic status was associated with higher rates of unmet need across groups. CONCLUSIONS: The results document unmet long-term behavioral health needs after both TBI and OI in children and underscore the importance of monitoring and treatment of postinjury behavior problems.