The amygdala is a sexually dimorphic brain region critical for the regulation of social, cognitive, and emotional behaviors, but both the nature and the source of sex differences in the amygdala are largely unknown. We have identified a unique sex difference in the developing rat medial amygdala (MeA) that is regulated by cannabinoids. Newborn females had higher rates of cell proliferation than males. Treatment of neonates with the cannabinoid receptor agonist, WIN 55,212-2 (WIN), reduced cell proliferation in females to that of males and a wide range of WIN doses had no effect on cell proliferation in males. The effect of WIN on cell proliferation in the MeA was prevented by coinfusions of a CB2 but not CB1 receptor antagonist. Females had higher amygdala content of the endocannabinoid degradation enzymes, fatty acid amid hydrolase, and monoacylglycerol lipase than males, and lower amounts of the endocannabinoids 2-arachidonoylglycerol and N-arachidonylethanolamide (anandamide). Inhibition of the degradation of 2-arachidonoylglycerol in females occluded the sex difference in cell proliferation. Analyses of cell fate revealed that females had significantly more newly generated glial cells but not more newly generated neurons than males, and treatment with WIN significantly decreased glial cell genesis in females but not males. Finally, early exposure to cannabinoids masculinized juvenile play behavior in females but did not alter this behavior in males. Collectively, our findings suggest that sex differences in endocannabinoids mediate a sex difference in glial cell genesis in the developing MeA that impacts sex-specific behaviors in adolescence.sexual differentiation | neurogenesis | development T he medial amygdala (MeA) is a sexually dimorphic nucleus critical for modulating sex differences in juvenile rough-and-tumble play (1), and regulation of adult social behaviors, including mating, parenting, aggression, and territoriality (2). The overall size of the rat MeA is larger in adult males than females (3) and is responsive to steroids in adulthood (4). Most of the well-characterized volumetric sex differences in the brain are the result of differential cell death during a perinatal-sensitive period, with more cells dying in one sex than the other (5).A large body of evidence has accumulated in the last 10 y supporting the important role of cannabinoid receptors and their endogenous ligands in regulation of synaptic strength (6). It is clear, in particular, that endocannabinoid signaling, via CB1 receptor activation, subserves activity-dependent, retrograde signaling in many brain regions. Cannabinoid receptors and endogenous cannabinoid ligands are present and active early in brain development (7), and the tissue contents of the primary endocannabinoids N-arachidonylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) vary substantially throughout brain development. The 2-AG content peaks on the day of birth and dramatically decreases from there, whereas AEA content gradually increases throughout life (8). C...

Prostaglandins are lipid-derived molecules that mediate the generation of fever in the central nervous system. In addition to their proinflammatory role, prostaglandins also impact neuronal development and synaptic plasticity, sometimes in a sex-specific manner. The cerebellum has a high expression of prostaglandin receptors during development, but the role that these molecules play during normal cerebellar maturation is unknown. We demonstrate here that disrupting prostaglandin synthesis with cyclo-oxygenase inhibitors during a time-sensitive window in early postnatal life alters cerebellar Purkinje cell development in rats, resulting in initially increased dendritic growth in both sexes. We show that this results in later cerebellar atrophy in males only, resulting in a sex-specific loss of cerebellar volume. Further, although performance in motor tasks is spared, social interaction and the sensory threshold are altered in males developmentally exposed to cyclo-oxygenase inhibitors. This work demonstrates a previously unknown role for prostaglandins in cerebellar development and emphasizes the role that the cerebellum plays outside motor tasks, in cognitive and sensory domains that may help to explain its connection to complex neurodevelopmental disorders such as autism.

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Blockade of septal hyperpolarization-activated cyclic nucleotide-gated channels (HCN) impairs hippocampal theta, an effect that would be expected to impair memory. To test this hypothesis, the present experiments determined whether septal infusions of the selective HCN channel blocker ZD7288 would impair performance on two memory tasks that involve the septo-hippocampal system: spontaneous alternation (SA) and continuous multiple inhibitory avoidance (CMIA). Fifteen minutes prior to assessing SA or CMIA, different groups of male Sprague-Dawley rats were given septal infusions of saline or ZD7288 (0.2, 0.6 or 1.5 microg/0.5 micro1). Septal infusions of ZD7288 impaired SA in a dose-dependent manner; the same infusions did not affect CMIA acquisition or retention. These results appear to be the first demonstration that HCN channels in the medial septum influence memory. Specifically, they suggest that septal HCN channels play a permissive role in spatial working memory, but do not influence emotional long-term memory. Given that these channels are preferentially located on GABA septo-hippocampal projection neurons, the present data provide further evidence that these projection neurons are involved in memory.

Although septal infusions of glucose typically have positive effects on memory, we have shown repeatedly that this treatment exacerbates memory deficits produced by co-infusions of gamma-aminobutyric acid (GABA) receptor agonists. The present experiments tested whether this negative interaction between glucose and GABA in the medial septum would be observed in the hippocampus, a brain region where glucose typically has positive effects on memory. Specifically, we determined whether hippocampal infusions of glucose would reverse or exacerbate memory deficits produced by hippocampal co-infusions of the GABA receptor agonist muscimol. Fifteen minutes prior to either assessing spontaneous alternation (SA) or continuous multiple trial inhibitory avoidance (CMIA) training, male Sprague-Dawley-derived rats were given bilateral hippocampal infusions of vehicle (phosphate-buffered saline [PBS], 1 microl/2 min), glucose (33 or 50 nmol), muscimol (0.3 or 0.4 microg, SA or 3 microg, CMIA) or muscimol and glucose combined in one solution. The results indicated that hippocampal infusions of muscimol alone decreased SA scores and CMIA retention latencies. More importantly, hippocampal infusions of glucose, at doses that had no effect when infused alone, attenuated (33 nmol) or reversed (50 nmol) the muscimol-induced memory deficits. Thus, although co-infusions of glucose with muscimol into the medial septum impair memory, the present findings show that an opposite effect is observed in the hippocampus. Collectively, these findings suggest that the memory-impairing interaction between glucose and GABA in the medial septum is not a general property of the brain, but rather is brain region-dependent.