The Role of TrkB and BDNF in Governing the Steroid-Mediated Regulation of Male Copulatory Behavior in the Syrian hamster (Mesocricetus auratus).

Gonadal steroids have profound effects on the regulation of many social behaviors. For example, castration (i.e. removal of the gonadal hormones) eliminates copulatory behavior in a variety of rodent species and systemic treatment with testosterone restores these behaviors. However, there are some “clarifications” which must be addressed, as the expression of male-typical sex behavior requires an interaction between pheromonal cues and gonadal steroids acting on its receptors in particular brain areas. One such brain area, the medial preoptic area (MPOA), plays a critical role in the regulation of male sex behavior in many species. There exists a sub-nucleus of the MPOA found only in the Syrian hamster (Mesocricetus auratus), the magnocellular medial preoptic area (MPN mag), which has been demonstrated to mediate copulation in male Syrian hamsters. Neurons in the male MPN mag contain high levels of steroid receptors and are stimulated in the presence of pheromonal cues, indicating this region is highly specific to the integration of these signals. Several studies from our lab have indicated that testosterone facilitates synaptic changes in the MPN mag leading to a male copulatory phenotype, but the underlying mechanisms of testosterones action to influence copulation are not fully understood.The neurotrophins brain derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) are likely candidates to mediate testosterones action on the MPN mag. TrkB and BDNF produce a neurotrophin complex integral for neuronal growth, differentiation, and maintenance of synaptic connections. In a variety of species, gonadal hormones influence the expression of BDNF and TrkB in many regions of brain. For example, testosterone and BDNF are required for the development and maintenance of the sexually dimorphic avian song control system and they work in concert to promote synaptic growth to facilitate communication. It stands to reason that testosterone could upregulate TrkB/BDNF in neurons of the MPNmag; giving rise to stable synapses for enhanced communication.The experiments presented here use the Syrian hamster to test the hypothesis that BDNF and TrkB play a role in the steroid-mediated regulation of copulation. I first established there is a sexual dimorphism in the MPOA for BDNF, TrkB, and a truncated isoform of TrkB (TrkB-T1), indicating an inverse, sex-specific relationship between the two TrkB receptors. This dimorphism could be the underlying mechanism forming sex-behavior circuits in male and female Syrian hamsters. Taking this one step further, I then found that testosterone regulates neurotrophins in the MPOA, a key finding in the pursuit of a steroid-mediated molecule that could regulate synapses to influence copulation. I then used a short-interfering ribonucleic acid to prevent the transcription of the TrkB gene in vivo and examine the effects on copulatory behavior in intact males. Knocking down TrkB in the MPN mag completely eliminated male copulatory behavior, consistent with the idea that TrkB is necessary for male sex behavior. To determine if BDNF is sufficient to restore copulation in castrated male hamsters, I infused BDNF into the MPN mag and restored copulation. These results are at least partially consistent with a role for BDNF and TrkB in control of sex behavior, but manipulation of BDNF anf TrkB had far more rapid effects on behavior than castration or treatment with testosterone. Direct application of BDNF might recruit synapses more rapidly than the natural increases in BDNF that result from increases in androgen action, or alternatively, BDNF and TrkB might act on neural circuity that controls sex behavior independent of the effects of testosterone. As gonadal steroids have profound effects on a variety of social behaviors, future studies are warranted to determine if this mechanism is involved in other steroid-mediated behaviors, such as circadian rhythms, aggression, learning, memory, anxiety, and parenting.The results of these experiments shed light on a novel molecular mechanism that influences male sex behavior in the Syrian hamster