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.

Gonadal hormones play a vital role in driving motivated behavior. They not only modulate responses to naturally rewarding stimuli, but also influence responses to drugs of abuse. A commonality between gonadal hormones and drugs of abuse is that they both impact the neurocircuitry of reward, including the regulation of structural plasticity in the nucleus accumbens (NAc). Previous hormonal studies have focused on the mechanisms and behavioral correlates of estradiol-induced dendritic spine changes in the female NAc. Here we sought to determine the effects of androgens on medium spiny neuron (MSN) spine plasticity in the male NAc. Following treatment with the androgen receptor agonist dihydrotestosterone (DHT), MSNs in castrated male rats exhibited a significant decrease in dendritic spine density. This effect was isolated to the shell subregion of the NAc. The effect of DHT was dependent on mGluR5 activity, and local mGluR5 activation and subsequent endocannabinoid signaling produce an analogous NAc shell spine decrease. Somewhat surprisingly, DHT-induced conditioned place preference remained intact following systemic inhibition of mGluR5. These findings indicate that androgens can utilize mGluR signaling, similar to estrogens, to mediate changes in NAc dendritic structure. In addition, there are notable differences in the direction of spine changes, and site specificity of estrogen and androgen action, suggesting sex differences in the hormonal regulation of motivated behaviors.

Asymmetric cell division is critical during development, as it influences processes such as cell fate specification and cell migration. We have characterized FRK-1, a homolog of the mammalian Fer nonreceptor tyrosine kinase, and found it to be required for differentiation and maintenance of epithelial cell types, including the stem cell-like seam cells of the hypodermis. A genomic knockout of frk-1, allele ok760, results in severely uncoordinated larvae that arrest at the L1 stage and have an excess number of lateral hypodermal cells that appear to have lost asymmetry in the stem cell-like divisions of the seam cell lineage. frk-1(ok760) mutants show that there are excess lateral hypodermal cells that are abnormally shaped and smaller in size compared to wild type, a defect that could be rescued only in a manner dependent on the kinase activity of FRK-1. Additionally, we observed a significant change in the expression of heterochronic regulators in frk-1(ok760) mutants. However, frk-1(ok760) mutants do not express late, nonseam hypodermal GFP markers, suggesting the seam cells do not precociously differentiate as adult-hyp7 cells. Finally, our data also demonstrate a clear role for FRK-1 in seam cell proliferation, as eliminating FRK-1 during the L3-L4 transition results in supernumerary seam cell nuclei that are dependent on asymmetric Wnt signaling. Specifically, we observe aberrant POP-1 and WRM-1 localization that is dependent on the presence of FRK-1 and APR-1. Overall, our data suggest a requirement for FRK-1 in maintaining the identity and proliferation of seam cells primarily through an interaction with the asymmetric Wnt pathway. KEYWORDS Wnt; fer; kinase; asymmetry; development A SYMMETRIC division is a critical component of stem cell populations, ranging from organismal development to tissue maintenance during adulthood. Without asymmetric divisions early embryos would not progress toward cellular specification and adult cell types, such as blood, would lose the ability to maintain numbers through self-renewal. Particularly important to stem cell division is the capability to maintain the stem cell population via asymmetric division where one daughter cell is specified to become a certain cell type, while the other daughter cell becomes another stem cell.In the nematode Caenorhabditis elegans a stem cell-like population, called seam cells, exists in the hypodermis and undergoes a series of asymmetric divisions after each larval molt, thus facilitating postembryonic development (Sulston and Horvitz 1977). Seam cells are critical for proper formation of the hypodermis, the secreted cuticle, and other cell types derived from seam cells such as neuroblasts and glial cells. The seam cells consist of three anterior sets, H0, H1, and H2, followed by six V cells and one T cell in the posterior (Figure 1). The V cells undergo unique stem cell-like divisions during postembryonic development that lead to one anterior daughter that fuses with the hypodermal syncytial cell, hyp7, and one posterior daughte...

Low levels of desire and arousal are the primary sexual dysfunctions in women, necessitating neurobiological studies of sexual motivation in female animal models. As the mesocorticolimbic system is a primary neural circuit underlying sexual motivation, the goal of this study was to test the hypothesis that medial prefrontal cortex (mPFC) glutamate mediates sexual behavior activation of the nucleus accumbens. Glutamatergic neurons in the mPFC were activated by sex behavior, and these sex-activated cells shown to project to the nucleus accumbens. During sexual interactions with the male, glutamate transients recorded in the nucleus accumbens of female hamsters were specifically associated with the receipt of intromissions from the male. Further, inhibition of the mPFC during sex significantly decreased nucleus accumbens activation. Glutamatergic medial prefrontal cortical input to the nucleus accumbens mediates the activity in the nucleus accumbens during female sexual behavior. These results offer novel insights into the neurobiology of the motivational control of female sexual behavior and provide attractive avenues for pursuing target-specific and clinically-relevant therapies for sexual dysfunction in women.

Preventing and treating iron deficiency are important components in the nutritional care of female varsity athletes, as these interventions may improve aerobic endurance and athletic performance. We examined the factors associated with ferritin concentration in 30 female varsity athletes (18–30 years) at the University of British Columbia in Vancouver, Canada. Biochemical indicators of iron and inflammation status, dietary intake, supplementation practices, weight, height, and menstrual blood losses were assessed. Iron deficiency prevalence was 20% (n = 6/30; inflammation-adjusted ferritin <15 μg/L). Multiple linear regression was used to assess the associations of a number of independent explanatory variables with log-transformed serum ferritin (μg/L) as the continuous outcome variable. A 1-unit increase in body mass index (BMI; kg/m2) was associated with 22% (95% CI: 9%–37%) higher mean ferritin concentrations, and a 1-point increase in menstrual loss score was associated with 1% (95% CI: 1%–2%) lower ferritin concentrations. Hemoglobin and hepcidin concentrations, inflammation biomarkers, consumption of iron supplements in any form or dose for ≥3 days/week, and age were not significantly associated with ferritin concentrations in the final adjusted model. Novelty Estimated monthly menstrual losses and BMI were associated with serum ferritin concentrations in female athletes in our study. These are easy-to-measure, noninvasive measurements that should be considered in the assessment of risk of iron deficiency in female athletes.