Background Escalated aggression is a behavioral sign of numerous psychiatric disorders characterized by a loss of control. The neurobiology underlying escalated aggression is unknown and is particularly understudied in females. Research in our laboratory demonstrated that repeated aggressive experience in female hamsters resulted in an escalated response to future aggressive encounters and an increase in dendritic spine density on NAc neurons. We hypothesized that the activation of group I metabotropic glutamate receptors signaling though the Fragile X Mental Retardation Protein (FMRP) pathway may underlie synaptic plasticity associated with aggression escalation. Methods Female hamsters were given 5 daily aggression tests with or without prior treatment with the mGluR5 antagonist MPEP. Following aggression testing, mRNA expression and protein levels were measured in the nucleus accumbens for PSD-95 and SAPAP-3, as well as the levels of phosphorylated FMRP. Results Experience-dependent escalation of aggression in female hamsters depends on activation of mGluR5 receptors. Furthermore, aggressive experience decreases phosphorylation of FMRP in the NAc which is coupled to a long-term increase in the expression of the synaptic scaffolding proteins, PSD-95 and SAPAP-3. Finally, the experience-dependent increase in PSD-95 is prevented by antagonism of the mGluR5 receptor. Conclusions Activation of the FMRP pathway by group I metabotropic glutamate receptors is involved in regulating synaptic plasticity following aggressive experience. The NAc is a novel target for preclinical studies of the treatment of escalated aggression, with the added benefit that emerging therapeutic approaches are likely to be effective in treating pathological aggression in both females and males.

In Syrian hamsters (Mesocricetus auratus), the expression of reproductive behavior requires the perception of social odors. The behavioral response to these odors is mediated by a network of ventral forebrain nuclei, including the posterior bed nucleus of the stria terminalis (pBNST). Previous studies have tested the role of pBNST in reproductive behavior, but the use of large, fiber-damaging lesions in these studies make it difficult to attribute post-lesion deficits to pBNST specifically. Thus, the current study used discrete, excitotoxic lesions of pBNST to test the role of pBNST in opposite-sex odor preference and copulatory behavior in both sexually-naïve and sexually-experienced males. Lesions of pBNST decreased sexually-naïve males' investigation of volatile female odors, resulting in an elimination of opposite-sex odor preference. This elimination of preference was not due to a sensory deficit, as males with pBNST lesions were able to discriminate between odors. When, however, subjects were given sexual experience prior to pBNST lesions, their preference for volatile opposite-sex odors remained intact post-lesion. Similarly, when sexually-naïve or sexually-experienced subjects were allowed to contact the social odors during the preference test, lesions of pBNST decreased males' investigation of female odors, but did not eliminate preference for opposite-sex odors, regardless of sexual experience. Finally, lesions of pBNST delayed the copulatory sequence in sexually-naïve, but not sexuallyexperienced, males such that they took longer to mount, intromit, ejaculate, and display long intromissions. Together, these results demonstrate that pBNST plays a unique and critical role in both appetitive and consummatory aspects of male reproductive behaviors.

In many rodent species, including Syrian hamsters, the expression of appropriate social behavior depends critically on the perception and identification of conspecific odors. The behavioral response to these odors is mediated by a network of steroid-sensitive ventral forebrain nuclei including the medial amygdala (Me), posterior bed nucleus of the stria terminalis (BNST) and medial preoptic area (MPOA). Although it is well-known that Me, BNST, and MPOA are densely interconnected and each uniquely modulates odor-guided social behaviors, the degree to which conspecific odor information and steroid hormone cues are directly relayed between these nuclei is unknown. To answer this question, we injected the retrograde tracer, cholera toxin B (CTB), into the BNST or MPOA of male subjects and identified whether retrogradely-labeled cells in Me and BNST 1) expressed immediate early genes (IEGs) following exposure to male and/or female odors or 2) expressed androgen receptor (AR). Although few retrogradely-labeled cells co-localized with IEGs, a higher percentage of BNST-and MPOA-projecting cells in the posterior Me (MeP) expressed IEGs in response to female odors than to male odors. The percentage of retrogradelylabeled cells that expressed IEGs did not, however, differ between and female-and male-odorexposed groups in the anterior Me (MeA), posterointermediate BNST (BNSTpi), or posteromedial BNST (BNSTpm). Many retrogradely-labeled cells co-localized with AR, and a higher percentage of retrogradely-labeled MeP and BNSTpm cells expressed AR than retrogradely-labeled MeA and BNSTpi cells, respectively. Together, these data demonstrate that Me, BNST, and MPOA interact as a functional circuit to process sex-specific odor cues and hormone information in male Syrian hamsters.

In Syrian hamsters (Mesocricetus Auratus), the expression of reproductive behavior requires the perception and discrimination of sexual odors. The behavioral response to these odors is mediated by a network of ventral forebrain nuclei, including the medial preoptic area (MPOA). The role of MPOA in male copulatory behavior has been well-studied, but less is known about the role of MPOA in appetitive aspects of male reproductive behavior. Furthermore, many previous studies that examined the role of MPOA in reproductive behavior have used large lesions that damaged other nuclei near MPOA or fibers of passage within MPOA, making it difficult to attribute postlesion deficits in reproductive behavior to MPOA specifically. Thus, the current study used discrete, excitotoxic lesions of MPOA to test the role of this nucleus in opposite-sex odor preference and copulatory behavior in both sexually-naïve and sexually-experienced males. Lesions of MPOA eliminated preference for volatile, opposite-sex odors in sexually-naïve, but not sexually-experienced, males. When, however, males were allowed to contact the sexual odors, preference for female odors remained intact. Surprisingly, lesions of MPOA caused severe copulatory deficits only in sexually-naïve males, suggesting previous reports of copulatory deficits following MPOA lesions in sexually-experienced males were not due to damage to MPOA itself.Together, these results demonstrate that the role of MPOA in appetitive and consummatory aspects of reproductive behavior depends on the type of access to sexual odors and the sexual experience of the male. KeywordsOlfaction; Reproduction; Pheromone; Odor Preference In many rodent species, including Syrian hamsters, male reproductive behavior depends critically on the perception of odor cues from the environment (Johnston 1990). Volatile odor cues are processed primarily by the main olfactory system (MOS), whereas nonvolatile odor cues are processed primarily by the accessory olfactory system (AOS) (Breer 2003). Together, these two systems have been shown to mediate both appetitive and consummatory aspects of reproductive behavior in Syrian hamsters, including males'Corresponding Author: Laura E. Been,. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2011 November 10. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript attraction to female vaginal secretion (Powers et al. 1979) and copulatory behavior (Murphy and Schneider 1970;Powers and Winans 1975).The behavioral response to...

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