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GnRH-II is the most evolutionarily conserved member of the GnRH peptide family. In mammals, GnRH-II has been shown to regulate reproductive and feeding behaviors. In female musk shrews, GnRH-II treatment increases mating behaviors and decreases food intake. Although GnRH-II-containing neurons are known to reside in the midbrain, the neural sites of GnRH-II action are undetermined, as is the degree to which GnRH-II is regulated by energy availability. To determine whether GnRH-II function is affected by changes in food intake, we analyzed the levels of GnRH-II mRNA in the midbrain and GnRH-II protein in numerous target regions. Adult musk shrews were ad libitum fed, food restricted, or food restricted and refed for varying durations. Compared with ad libitum levels, food restriction decreased, and 90 min of refeeding reinstated, GnRH-II mRNA levels in midbrain and GnRH-II peptide in several target areas including the medial habenula and ventromedial nucleus. Refeeding for 90 min also reinstated female sexual behavior in underfed shrews. In male shrews, abundant GnRH-II peptide was present in all sites assayed, including the preoptic area, a region with only low GnRH-II in females. In contrast to females, food restriction did not affect GnRH-II protein in male brains or inhibit their mating behavior. Our results further define the relationship between GnRH-II, energy balance, and reproduction, and suggest that food restriction may inhibit female reproduction by reducing GnRH-II output to several brain nuclei. We postulate that this highly conserved neuropeptide functions similarly in other mammals, including humans, to fine-tune reproductive efforts with periods of sufficient energy resources.

Gonadotrophin-releasing hormone (GnRH) is a regulatory neuropeptide of which there are multiple structural variants. In mammals, a hypothalamic form (GnRH-I) controls gonadotrophin secretion whereas a midbrain form (GnRH-II) appears to have a neuromodulatory role affecting feeding and reproduction. In female musk shrews and mice, central administration of GnRH-II reinstates mating behaviour previously inhibited by food restriction. In addition, GnRH-II treatment also decreases short-term food intake in musk shrews. GnRH-II can bind two different mammalian GnRH receptors (type-1 and type-2), and thus it is unclear which receptor subtype mediates the behavioural effects of this peptide. Adult female musk shrews implanted with i.c.v. cannula were food restricted or fed ad lib and then tested for sexual behaviour or food intake. One hour before testing, animals were pretreated with vehicle or Antide, a potent type-1 GnRH receptor antagonist (at a dose that blocks GnRH-I or -II mediated ovulation). Twenty minutes before testing, females were infused a second time with either GnRH-II or vehicle. Additional females were tested after an infusion of 135-18, a type-1 receptor antagonist that displays agonist actions at the primate type-2 receptor. GnRH-II treatment increased sexual behaviour in underfed female shrews; pretreatment with Antide did not block this action, suggesting that the effects of GnRH-II are not mediated via the type-1 receptor. Similarly, the inhibitory effects of GnRH-II on short-term food intake were not prevented by pretreatment with Antide. The behavioural effects of the type-2 receptor agonist 135-18 were similar to those seen in GnRH-II-treated females, with 135-18 promoting sexual behaviour and decreasing food intake. Collectively, these results indicate that GnRH-II does not act via the type-1 GnRH receptor to regulate mammalian behaviour but likely activates the type-2 GnRH receptor.

Across human cultures and mammalian species, sex differences can be found in the expression of aggression and parental nurturing behaviors: males are typically more aggressive and less parental than females. These sex differences are primarily attributed to steroid hormone differences during development and/or adulthood, especially the higher levels of androgens experienced by males, which are caused ultimately by the presence of the testis-determining geneSryon the Y chromosome. The potential for sex differences arising from the different complements of sex-linked genes in male and female cells has received little research attention. To directly test the hypothesis that social behaviors are influenced by differences in sex chromosome complement other thanSry, we used a transgenic mouse model in which gonadal sex and sex chromosome complement are uncoupled. We find that latency to exhibit aggression and one form of parental behavior, pup retrieval, can be influenced by both gonadal sex and sex chromosome complement. For both behaviors, females but not males with XX sex chromosomes differ from XY. We also measured vasopressin immunoreactivity in the lateral septum, which was higher in gonadal males than females, but also differed according to sex chromosome complement. These results imply that a gene(s) on the sex chromosomes (other thanSry) affects sex differences in brain and behavior. Identifying the specific X and/or Y genes involved will increase our understanding of normal and abnormal aggression and parental behavior, including behavioral abnormalities associated with mental illness.

High doses of estradiol (E(2)) can impair spatial learning in the Morris water maze, in ovariectomized mice, but the same dose has no effect on adult castrated males. Here, we test the hypothesis that this sex difference is caused by neonatal actions of E(2). In Experiment 1, C57BL/6J pups were given daily estradiol benzoate (EB) or oil injections from the day of birth until postnatal Day 3. Adults were gonadectomized and received EB (s.c.) or oil 28 h before the first day of training, and 4 h before each of four daily training sessions on the Morris water maze. Females given oil as neonates, and EB prior to training displayed the poorest performance. Females that received EB as neonates and EB prior to training were insensitive to the deleterious effects of adult EB and performed better than males given the same hormone treatments. We conducted a second experiment using aromatase enzyme knockout (ArKO) mice. Adult male and female ArKO and wild-type (WT) littermates were gonadectomized and received either injections of oil or EB prior to and during water maze training (as described above). Hormone treatment failed to affect performance, yet, female but not male ArKO mice showed impaired learning compared to WT littermates. Thus, exposure to estradiol during neonatal development can counteract the deleterious effects of EB on adult spatial learning.