Clues to brain differences between males and females
How male sex steroids play a key role in understanding behavioral development
March 1, 2019
Science Daily/University of Maryland School of Medicine
Researchers at the University of Maryland School of Medicine have discovered a mechanism for how androgens -- male sex steroids -- sculpt brain development. The research, conducted by Margaret M. McCarthy, Ph.D., who Chairs the Department of Pharmacology, could ultimately help researchers understand behavioral development differences between males and females.
The research, published in Neuron, discovered a mechanism for how androgens, male sex steroids, sculpt the brains of male rats to produce behavioral differences, such as more aggression and rougher play behavior. "We already knew that the brains of males and females are different and that testosterone produced during the second trimester in humans and late gestation in rodents contributes to the differences but we did not know how testosterone has these effects" said Dr. McCarthy.
Jonathan Van Ryzin, PhD, a Postdoctoral Fellow, was lead author on this research conducted in Dr. McCarthy's lab.
A key contributor to the differences in play behavior between males and females is a sex-based difference in the number of newborn cells in the part of the brain called the amygdala, which controls emotions and social behaviors. The research showed that males have fewer of these newborn cells, because they are actively eliminated by immune cells.
In females, the newborn cells differentiated into a type of glial cell, the most abundant type of cell in the central nervous system. In males however, testosterone increased signaling at receptors in the brain which bind endocannabinoids, causing immune cells to be activated. The endocannabinoids prompted the immune cells to effectively eliminate the newborn cells in males. Females rats in the study were unaffected, suggesting that the activation of the immune cells by the increased endocannabinoids in males was necessary for cell elimination. In this respect, this research shows that cannabis use, which stimulates endocannabinoids in the brain and nervous system, could impact brain development of the fetus and this impact could differ between male and female fetuses.
This study provides a mechanism for sex-based differences in social behaviors and suggests that differences in androgen and endocannabinoid signaling may contribute to individual differences in brain development and thus behavioral differences among people.
"These discoveries into brain development are critical as we work to tackle brain disorders as early in life as possible, even in pregnancy," said UMSOM Dean E. Albert Reece, MD, PhD, MBA, who is also the Executive Vice President for Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor.
https://www.sciencedaily.com/releases/2019/03/190301160901.htm
Sex, drugs and estradiol: Why cannabis affects women differently
October 26, 2018
Science Daily/Frontiers
Sex differences in cannabis use are beginning to be explained with the aid of brain studies in animals and humans.
Cannabis use is riding high on a decade-long wave of decriminalization, legalization and unregulated synthetic substitutes. As society examines the impact, an interesting disparity has become apparent: the risks are different in females than in males.
A new review of animal studies says that sex differences in response to cannabis are not just socio-cultural, but biological too. Published in Frontiers in Behavioral Neuroscience, it examines the influence of sex hormones like testosterone, estradiol (estrogen) and progesterone on the endocannabinoid system: networks of brain cells which communicate using the same family of chemicals found in cannabis, called 'cannabinoids'.
Animal studies
"It has been pretty hard to get laboratory animals to self-administer cannabinoids like human cannabis users," says study co-author Dr Liana Fattore, Senior Researcher at the National Research Council of Italy and President of the Mediterranean Society of Neuroscience. "However, animal studies on the effects of sex hormones and anabolic steroids on cannabinoid self-administration behavior have contributed a lot to our current understanding of sex differences in response to cannabis."
So how does cannabis affect men and women differently? Besides genetic background and hormonal fluctuations, the paper highlights a number of important sex differences.
Men are up to four times more likely to try cannabis -- and use higher doses, more frequently.
"Male sex steroids increase risk-taking behavior and suppress the brain's reward system, which could explain why males are more likely to try drugs, including cannabis" explains Fattore. "This is true for both natural male sex steroids like testosterone and synthetic steroids like nandrolone."
But despite lower average cannabis use, women go from first hit to habit faster than men. In fact, men and women differ not only in the prevalence and frequency of cannabis use, pattern and reasons of use, but also in the vulnerability to develop cannabis use disorder.
"Females seem to be more vulnerable, at a neurochemical level, in developing addiction to cannabis," explains Fattore.
"Studies in rats show that the female hormone estradiol affects control of movement, social behavior and filtering of sensory input to the brain -- all targets of drug taking -- via modulation of the endocannabinoid system, whose feedback in turn influences estradiol production.
"Specifically, female rats have different levels of endocannabinoids and more sensitive receptors than males in key brain areas related to these functions, with significant changes along the menstrual cycle.
"As a result, the interactions between the endocannabinoid system and the brain level of dopamine -- the neurotransmitter of "pleasure" and "reward" -- are sex-dependent."
Human impact
The inconsistency of conditions in these studies greatly complicates interpretation of an already complex role of sex hormones in the endocannabinoid system and cannabinoid sensitivity.
"The effects varied according the specific cannabinoid studied, as well as the strain of animals tested and duration of hormone exposure," admits Fattore. However, the human data so far are consistent with the idea that estradiol regulates the female response to cannabinoids. As in animals, human males and females are diverse in their genetic and hormonally driven behaviour and they process information differently, perceive emotions in different ways and are differently vulnerable to develop drug addiction.
"Blood levels of enzymes which break down cannabinoids fluctuate across the human menstrual cycle, and imaging studies show that brain levels of cannabinoid receptors increase with aging in females -- mirroring in each case changes in estradiol levels."
Fattore believes that deepening our understanding of the interactions between cannabinoids and sex steroids is crucial in assessing the impact of increasing cannabis use, and tackling the fallout.
"Gender-tailored detoxification treatments and relapse prevention strategies for patients with cannabis addiction are increasingly requested. Optimizing personalized evidence-based prevention and treatment protocols demands further research on the source of sex disparities in cannabis response."
https://www.sciencedaily.com/releases/2018/10/181026102627.htm