Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior

Abstract

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...

In vivo magnetic resonance images reveal neuroanatomical sex differences through the application of voxel-based morphometry in C57BL/6 mice

“…This region has been associated with sexually dimorphic behaviors such as pheromone processing, anxiety, and aggression (Akhmadeev et al, 2016). Developing female rats have been shown to display increased rates of cell proliferation (Krebs-Kraft et al, 2010) in the amygdala, but not much is known about the origin of this difference. We also observed a larger medial amygdala and bed nucleus of the stria terminalis in males, consistent with previous findings (Corre et al, 2014; Hines et al, 1992).…”

Morphological and Functional Features of the Sex Steroid-Responsive Posterodorsal Medial Amygdala of Adult Rats

“…Though strain differences might exist, puberty affect dendritic spines in the rat MePD in both hemispheres. Indeed, this life event has marked influence on MePD morphology and can account for differences between young and adult animals [64,101,102].…”

Sex differences in cannabinoid-regulated biology: A focus on energy homeostasis

“…While this review focused on the most recent advances into our understanding of sex differences in the metabolic fate, abuse liability, as well as the antinociceptive and appetite-stimulating properties of cannabinoids, it should not be misconstrued that this list is by any means comprehensive. Indeed, there are sex differences reported for the endocannabinoid-mediated neonatal development of the amygdala (Krebs-Kraft et al, 2010), the THC-induced impairment of spatial learning during adolescence and adulthood (Cha et al, 2007), as well as a number of behavioral and endocrine disturbances that develop as a result of chronic or subchronic exposure to cannabinoid receptor agonists during adolescence (Viveros et al, 2011b). …”