Neuron and Glia Remodeling Contribute to Male Behavior

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The social behavior of males and females is different as are the brains of males and females. Brain remodeling occurs not only during embryonic development and early childhood but also at critical periods throughout life, such as during adolescence. Brain cells include neurons and glial cells. The brain also has its own specialized immune cells called microglia. “Pruning,” that is the selective elimination, of neurons is a well known phenomenon.

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Figure 1. Synaptic changes during development. [More details]

Rats are model for studying how these differences in brain structure arise and influence behavior (Figure 1). Female rats tend to perform more behaviors called social exploration (sniffing and grooming); whereas males interact more frequently and perform “rough and tumble” behaviors called social play (nape attacks and supine postures). Recent studies provide insight into how sex-based differences in the brain influence social play behavior.

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Figure 2. Comparison of the anatomy of the human and rat brains. [More details]

A study by Kopec and colleagues found that microglia and proteins in the complement system mediate the selective removal of a particular subtype of dopamine receptor, the D1R, in the nucleus accumbens of adolescent male rats. The D1R-positive neurons are part of the reward circuit, which controls the response to pleasurable or rewarding experiences. The amount of D1R decreases in both male and female rats, but the change occurs at different times during their maturation. Only the reduction in D1R in males involved microglia and complement protein C3.

Microglia are cells that phagocytose (eat) other cells or cellular debris. The protein C3 and its cleavage products serve as tags marking cells or debris that the microglia should phagocytose. Microglia have a receptor, C3R, that recognizes the C3 tag. Social behavior in male rats peaks 30 days after birth and has decreased 8 days later. Blocking this C3-microglia–mediated refinement of the reward circuitry in males increased social behavior at 38 days after birth, and the increase in social behavior required the receptor D1R. In females, blocking the interaction between C3 and its receptor also increased social behaviors. However, in females this change did not involve D1R. Collectively, these data reveal a sex-dependent mechanism for modifying social behavior in rats. In males, the D1R circuit appears to be altered during adolescence through microglial-mediated synapse elimination.

A study by the McCarthy lab also examined the sex-based differences in social play in juvenile rats. According to the first author Jonathan Van Ryzin, Ph.D., “We knew that the brains of males and females are different and that testosterone produced during the second trimester in humans and the third trimester in rodents contributes to the differences. We wanted to determine how testosterone shapes sex-based differences in brain development.”

In contrast to neuronal or synapse elimination, Van Ryzin and colleagues found that testosterone shapes the brains of juvenile male rats by eliminating newborn cells destined to become a type of glial cell called astrocytes. Furthermore, this reduction in astrocytes occurred in the amygdala, a part of the brain that controls emotions and social behavior. The amygdala sends signals to the nucleus accumbens, which was the area of the brain studied by Kopec et al.

McCarthy and her colleagues found that testosterone, the male sex steroid, increased endocannabinoid signaling in the amygdala during the first few days after birth. The increased endocannabinoid signaling activated microglia, which phagocytosed the newborn cells through a process dependent on the complement receptor C3R. Blocking this receptor only increased the number of newborn cells in the male rats and not in the female rats. However, enhancing either androgen signaling or endocannabinoid signaling in the newborn female rats masculinized this part of the brain, as well as their social interactions as young adolescents.

One of the implications from this study is that differences in androgen and endocannabinoid signaling may contribute to individual differences in behaviors by altering brain development. Additionally, this study has implications for the use of cannabis during pregnancy and childhood exposure to the active compounds in cannabis. The active compounds in cannabis stimulate endocannabinoid receptors. Furthermore, these compounds cross the placenta and enter breast milk. Thus, cannabis use during pregnancy and breast feeding would expose the baby’s brain to compounds that can alter brain development and potentially influence behavior throughout life.

Highlighted Articles

J. W. VanRyzin, A. E. Marquardt. K. J. Argue, H. A. Vecchiarelli, S. E. Ashton, S. E. Arambula, M .N. Hill, M. M. McCarthy, Microglial phagocytosis of newborn cells is induced by endocannabinoids and sculpts sex differences in juvenile rat social play. Neuron (28 February 2019) DOI: 10.1016/j.neuron.2019.02.006

A. M. Kopec, C. J. Smith, N. R. Ayre, S. C. Sweat, S. D. Bilbo, Microglial dopamine receptor elmiination defines sex-specific nucleus accumbens development and social behavior in adolescent rats. Nat. Comm. 9, 3769 (2019) DOI: 10.1038/s41467-018-06118-z PubMed

Related Reading

K. Sokolowski, J. G. Corbin, Wired for behaviors: from development to function of innate limbic system circuitry. Front. Mol. Neurosci. (26 April 2012) DOI: 10.3389/fnmol.2012.00055

B. Cornell, Synaptic formation. BioNinja (2016) http://ib.bioninja.com.au/options/option-a-neurobiology-and/a1-neural-development/synaptic-formation.html (accessed 1 March 2019)

J. Morrison,UMSOM Researchers Discover Clues to Brain Differences Between Males and Females. University of Maryland School of Medicine Press Release. (2019) http://www.medschool.umaryland.edu/news/2019/UMSOM-Researchers-Discover-Clues-to-Brain-Differences-Between-Males-and-Females.html

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Cite as: N. R. Gough, Neuron and Glia Remodeling Contribute to Male Behavior. BioSerendipity (2 March 2019)
https://www.bioserendipity.com/neuron-and-glia-remodeling-contribute-to-male-behavior/.

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