Maternal Separation Early in Life Alters the Expression of Genes Npas4 and Nr1d1 in Adult Female Mice: Correlation with Social Behavior

Abstract

Early-life stress affects neuronal plasticity of the brain regions participating in the implementation of social behavior. Our previous studies have shown that brief and prolonged separation of pups from their mothers leads to enhanced social behavior in adult female mice. The goal of the present study was to characterize the expression of genes (which are engaged in synaptic plasticity) Egr1, Npas4, Arc, and Homer1 in the prefrontal cortex and dorsal hippocampus of adult female mice with a history of early-life stress. In addition, we evaluated the expression of stress-related genes: glucocorticoid and mineralocorticoid receptors (Nr3c1 and Nr3c2) and Nr1d1, which encodes a transcription factor (also known as REVERBα) modulating sociability and anxiety-related behavior. C57Bl/6 mice were exposed to either maternal separation (MS, 3 h once a day) or handling (HD, 15 min once a day) on postnatal days 2 through 14. In adulthood, the behavior of female mice was analyzed by some behavioral tests, and on the day after the testing of social behavior, we measured the gene expression. We found increased Npas4 expression only in the prefrontal cortex and higher Nr1d1 expression in both the prefrontal cortex and dorsal hippocampus of adult female mice with a history of MS. The expression of the studied genes did not change in HD female mice. The expression of stress-related genes Nr3c1 and Nr3c2 was unaltered in both groups. We propose that the upregulation of Npas4 and Nr1d1 in females with a history of early-life stress and the corresponding enhancement of social behavior may be regarded as an adaptation mechanism reversing possible aberrations caused by early-life stress.

The Role of Stress-Induced Changes of Homer1 Expression in Stress Susceptibility

“…Our research on models of early postnatal stress has shown that either chronic separation of pups from their mothers during the first 2 weeks of life (3 h/d) or single separation on the 9th postnatal day (24 h) does not change expression levels of Homer1 and Homer1a, Homer1b, and Homer1c transcripts in the prefrontal cortex of male mice on the 15th postnatal day; however, in adulthood, there is a decrease in total mRNA expression of Homer1 without the change in the ratio of short to long transcripts (unpub lished data, NCBI BioProject PRJNA649640). Taken together, our results obtained in mouse models also indi cate that the delayed effects of early postnatal stress are present only in males [74]. Diminished total expression of the gene in question could be evidence of the epigenetic changes that occurred in its regulatory regions or in the genes whose protein products are regulators of Homer1 expression.…”

Sociability as a personality trait in animals: methods, causes and consequences

“…After birth, experience during and after the period of parental care may also play a role in generating variation among individuals in their social tendency. Separation from the mother during critical stages of development is associated with reduced sociability in pig‐tailed macaques Macaca nemestrina (Caine, Earle & Reite, 1983), but in female mice is associated with enhanced social behaviour that corresponds with altered gene expression (Ryabushkina, Reshetnikov & Bondar, 2020). A lack of social interactions directly after weaning in rats had a negative effect on social activity that extended into adulthood, but this effect was not seen with isolation later in life, suggesting that certain periods during development can be critical in determining social tendencies (Hol et al ., 1999).…”

Essential Functions of the Transcription Factor Npas4 in Neural Circuit Development, Plasticity, and Diseases

“…Npas4 expression levels were reduced in mice and rats exposed to different forms of stress, including conditioned fear (Wang et al, 2018;Unno et al, 2020), sleep deprivation (Orozco-Solis et al, 2017), and anxiogenic environments (Jaehne et al, 2015). For instance, impaired neurogenesis and hippocampusdependent fear memory in mice (Yun et al, 2010), contextual fear exposure in adolescent Long Evans rats (Heroux et al, 2018), and altered adult female behavior due to early maternal separation (Ryabushkina et al, 2020) have been reported to be associated with altered expression of Npas4. Npas4 knock-out mice also exhibited higher levels of the pro-inflammatory cytokines IL-6 and TNF-α post-stroke (Choy et al, 2016), and stroke-induced upregulation of Npas4 was found in brain regions linked to emotion and cognition (Leong et al, 2013).…”