New research sheds light on how a specific gene influences brain development and behavior. Researchers have discovered that the transient receptor potential cation channel 2 (TRPC2) gene plays a crucial role in shaping the structure of the mouse brain. The findings, published in the Journal of Comparative Neurology, highlight the potential role of environmental signals, such as pheromones, in shaping brain and behavioral sex differences.
While previous research mainly focused on the influence of gonadal hormones on shaping sex differences in brain structure and behavior, recent findings suggested that peripheral factors, particularly the vomeronasal organ (VNO) and its sensory pathways, might also contribute to these distinctions. The VNO is responsible for detecting pheromones in the environment, and TRPC2 plays a vital role in transmitting pheromonal signals from the VNO to the brain’s accessory olfactory bulb (AOB), ultimately affecting the amygdala and hypothalamus, regions linked to sex-specific behaviors.
Past studies demonstrated that mice lacking a functional TRPC2 gene exhibited altered sexual and aggressive behaviors. These behavioral changes were linked to the loss of TRPC2 function and were not observed when the VNO was removed in adulthood, suggesting that TRPC2 might influence brain development. However, the neural basis for these changes in social behavior and whether TRPC2 influences brain morphology in relevant regions were largely unknown. This study aimed to address this gap.
“I find interactions between the environment and brain fascinating,” explained study author Daniel Pfau, a postdoctoral researcher at the University of Michigan, Ann Arbor. “The TRPC2 gene allows mice to respond to chemical cues in their social environment by expressing different sex-typical behaviors, which are thought to rely on anatomical sex differences in the brain.”
“Without the TRPC2 gene, mice lose sex differences in social behaviors. We know hormones and genes associated with sexual development guide brain and behavioral sex differences but TRPC2 loss does not alter sex development. I wanted to know if TRPC2-dependent environmental signals play a role in the appearance of brain sex differences by comparing male and female mice with or without the TRPC2 gene.”
The researchers conducted a meticulous study using laboratory mice as their subjects. They worked with both TRPC2 knockout mice and their wild-type counterparts. These knockout mice had the TRPC2 gene intentionally inactivated to observe how its absence would affect the brain’s development and organization.
The researchers focused their attention on two specific brain regions: the posterodorsal aspect of the medial amygdala (MePD) and the ventromedial nucleus of the hypothalamus (VMHvl). These areas have long been associated with sexual and aggressive behaviors, making them ideal candidates for investigating the impact of the TRPC2 gene. The study’s results indicated that the TRPC2 gene played a crucial role in shaping both regions in the mouse brain.
“We often describe certain characteristics as male or female, implying they are the product of sexual differentiation. However, our data suggest that some brain and behavioral sex differences are decoupled from sexual differentiation and instead rely on unique environmental cues, such as pheromones in mice,” Pfau told PsyPost.
MePD volume was found to vary depending on both sex and genotype. In wild-type mice, there were noticeable sex differences in MePD volume, with males having larger MePD volumes compared to females. However, TRPC2 knockout mice exhibited a disruption in these sex-based differences.
The number of neurons in the MePD was significantly affected by sex and genotype. Male mice, regardless of genotype, had more neurons in this region than females. However, TRPC2 knockout introduced new sex-based differences, reducing neuron numbers in knockout males compared to knockout females.
The size of neuronal somata (cell bodies) was larger in males than females, but it remained unaffected by the presence or absence of the TRPC2 gene. The number of glial cells, which provide support and maintenance to neurons, showed an overall effect of both sex and genotype. Males had more glial cells than females, and knockout mice had fewer glial cells compared to wild-type mice.
Astrocyte counts in the MePD revealed a significant sex difference, with males having more astrocytes than females. However, this sex difference disappeared in knockout mice, primarily due to an increase in astrocyte counts in knockout males.
When examining the complexity of astrocyte arbors (the branching structure of astrocytes), knockout mice showed a reduction in certain parameters, such as the number of nodes and branch endings, suggesting that the TRPC2 gene plays a role in the intricate branching patterns of astrocytes.
The researchers found that VMHvl volume was influenced by both sex and genotype, with TRPC2 knockout introducing a sex difference not present in wild-type mice. VMHvl volume was smaller in knockout males than in knockout females and in wild-type males.
Neuron numbers in the VMHvl were influenced by sex, genotype, and their interaction. Knockout mice exhibited fewer neurons than wild-type mice, and this reduction was more pronounced in males.
The size of neuronal somata in the VMHvl was smaller in TRPC2 knockout mice than in wild-type mice, indicating a main effect of genotype on soma size.
While astrocyte counts in the VMHvl were influenced by both sex and genotype, the significant interaction between these factors revealed that TRPC2 knockout affected astrocyte counts differently in males and females.
Astrocyte complexity was notably impacted in the VMHvl of knockout males, with fewer nodes and branch endings compared to knockout females and wild-type males.
“In my previous examinations, sex differences were often dependent on measures being higher in males compared with females,” Pfau noted. “However, we found that female mice have more astrocytes, a specific type of glia, than males in one region of the hypothalamus. Further, loss of TRPC2 increased the number of astrocytes in male mice.”
“While I initially imagined that the loss of brain sex differences would be marked by reductions in anatomical measures, the sex difference in astrocyte number disappeared because TRPC2 loss increases astrocyte number in males but has no effect on astrocyte number in females.”
As with any scientific study, it’s essential to consider its limitations. Pfau’s research provides valuable insights, but it also raises questions for future exploration. “How TRPC2-dependent brain anatomy appears remains unexamined and a key next step is determining when TRPC2 acts to induce these changes,” Pfau explained. “For example, is it the loss of pheromonal and/or olfactory signals that affects sexual differentiation of the brain?”
The study, “Loss of TRPC2 function in mice alters sex differences in brain regions regulating social behaviors“, was authored by Daniel R. Pfau, Sarah Baribeau, Felix Brown, Niki Khetarpal, S. Marc Breedlove, and Cynthia L. Jordan.
