Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

Abstract

Sex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis. Significance Statement Previously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer's disease and depression.

Life-long brain compensatory responses to galactic cosmic radiation exposure

“…Importantly, we found that the lowest dose of exposure significantly impaired neurogenesis in females, but only moderately in males, suggesting female mice may be more prone to HZE-induced insult to neurogenesis. Given that male rodents have been shown to develop greater maladaptive responses to HZE-exposure than females 38 and are generally more vulnerable to brain injury than females 39 , our results showing higher sensitivity in females is unexpected and may be reflective of a lower rate of baseline neurogenesis in female rodents 40 , 41 , which is also evident in our data. Remarkably though, the population of newly born neurons in both female and male mice, regardless of radiation dose, rebounded to significantly higher levels than sham-irradiated control levels when assayed later, at 12 months post-exposure.…”

The unique plasticity of hippocampal adult‐born neurons: Contributing to a heterogeneous dentate

“…There may also be dorsal-ventral differences in rates of maturation that are sex-dependent. Adult-born neurons in the dorsal and ventral DG acquired mature neuronal markers faster in males than in females, but adult-born neurons in only the dorsal DG acquired mature morphology faster in males than in females (Yagi et al, 2020).…”

“…Moreover, most studies have solely used male animals to characterize maturational profiles, but recent work in rats suggests that these results do not generalize to females. For example, although the overall density of mature adult‐born neurons in male and female rats does not differ, multiple studies suggest that male rats exhibit significantly higher levels of proliferation (Barha, Brummelte, Lieblich, & Galea, 2011; Brummelte & Galea, 2010; Hillerer, Neumann, Couillard‐Després, Aigner, & Slattery, 2013; Lagace et al, 2007; Spritzer et al, 2017) and attrition than the female rats, and adult‐born neurons of male rats acquire mature neuronal markers and morphology significantly faster than those of female rats (Yagi et al, 2020), suggesting an accelerated developmental trajectory.…”

“…The higher spine density in adult‐born neurons is consistent with reports of a subpopulation of DG neurons with twice the density of spines as the rest of the population (Williams & Matthysse, 1983; sex unstated). Given that at least one study has found some indicators of faster rates of maturation in males than in females (Yagi et al, 2020), more research is needed to look at long‐term spine changes in females. These findings have major implications for functional connectivity and the roles played by adult‐versus developmentally born neurons within the DG.…”

Tau Pathology and Adult Hippocampal Neurogenesis: What Tau Mouse Models Tell us?

“…Distinct time point of analysis could lead to data variation ( 98 ). A remarkable sex difference was observed in AHN of rodent brains ( 75 , 99 ). Furthermore, data variability may be caused by the sensitivities of antibodies used for detection ( 29 ).…”