Partial deletions in the heterochromatin region of the Y chromosome may contribute to increased vulnerability to stress and reduced new neuron formation in mice, according a new study performed by scientists at the Center for Cellular and Molecular Biology (CCMB) and Indian Institute of Chemical Technology (IICT), Hyderabad.
The Y‑chromosome is the male sex determining chromosome in mammals. It is responsible for specifying male body parts in the developing embryo and replenishing the sperm supply in adults. Recent studies have shown that the Y‑chromosome plays an important role in determining the characteristic aggressive behaviour of male mice. While many genes on the Y‑chromosome are expressed in both the testes and the brain, very little is known about the function of most Y‑linked genes in the brain.
“Researchers in this field initially thought that the heterochromatin region of the Y‑chromosome is not functional,” said Rachel Jesudasan, emeritus scientist, CCMB, lead author for the molecular aspects of the study.
Jesudasan’s team was studying the factors involved with infertility using mutant mice with deletions in heterochromatin region of the Y‑chromosome. Surprisingly, in addition to sperm-related defects, they observed certain behavioural alterations in these mutant mice. “We were keen on understanding the neural mechanism and behavioural pattern involved with this activity,” said Jesudasan.
Based on this finding, the researchers conducted a series of experiments to evaluate anxiety and depression-like behaviours in the mutant mice with partial deletions in the Y‑chromosome. They found that the mutant mice reacted more strongly to an acute stressor, showing increased anxiety-like behaviours (when compared to control mice) after being forced to swim in water for 10 minutes.
One probable cause for such changes in stress-induced behaviours could be impaired formation of new neurons in the hippocampus, a brain region involved in the regulation of mood, learning and memory. The researchers found significantly fewer dividing cells in the hippocampi of the mutant male mice, suggesting reduced neurogenesis. They also observed changes in the expression of several genes which mediate the process of neurogenesis.
Interestingly, bioinformatic analysis revealed that the regulatory regions of many of these genes displayed partial homology to regions on the Y‑chromosome, implying that perhaps the expression of these genes can be regulated by transcripts from the Y‑chromosome under normal conditions.
“The behavioural changes observed in the mutant mice can be due to the altered neurogenesis in its hippocampal region making them more susceptible to depression and neuropsychiatric disorders,” said Sumana Chakravarty, Principal scientist at IICT, Hyderabad and lead author for the behavioural aspects of the study.
Commenting on the importance of studying sexual dimorphism in neuropsychiatric disorders, Chakravarty said, “Both males and females exhibit similar phenotype for neurological disorders. But the underlying mechanism involved with the regulation of these neurological pathways is different and we are working on understanding the basics of this.”
“The study results are interesting and suggest a potential new mechanism conferring protection against affective conditions in males,” said William Davies, senior lecturer at Cardiff University at Wales, who was not involved with the study, cautioning, however, “The effect sizes in the study are small and the results need to be replicated in larger experimental cohorts before any firm conclusion is drawn.”
Infertility in males has been considered as an underlying cause for stress and depression. This research hints towards the role of the Y‑heterochromatin region as an alternative pathway for regulating anxiety-related behaviour and stress response in males.