Aomine, Y. | bioRxiv Science

bioRxiv2024

Sex-dependant differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice.

1Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, nicotine significantly improved performance in VDR, but not VD, task, while, in female mice, nicotine significantly worsened performance in the VD, but not VDR, task. Next, to investigate the cellular mechanisms that underlie the sex differences in the effects of nicotine on cognition, transcriptomic analyses were performed on prefrontal cortex tissue samples from male and female mice that had undergone VD and VDR tasks. Pathway enrichment analysis and Protein-protein interaction (P-PI) analysis using gene sets with altered gene expression found three types of effects of nicotine: those common to both sexes, those in males only, and those in females only. Decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility.

animal behavior and cognition↗

bioRxiv2024

Importin α4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice.

Importin 4, which is encoded by the Kpna4 gene, is a well characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-{kappa}B. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, deceased social interaction and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-{kappa}B activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-{kappa}B genes and pro-inflammatory cytokines such as TNF, Il1{beta} or Il-6 in the Prefrontal Cortex or Basolateral Amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full-length, but also a nuclear transport deficient truncation mutant of importin 4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult Microglia and Astrocytes and subsequent transcription factor analysis suggested increases in Polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin 4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.

neuroscience↗