The cognitive impact of light: illuminating ipRGC circuit mechanisms.

Ever-present in our environments, light entrains circadian rhythms over long timescales, influencing daily activity patterns, health and performance. Increasing evidence indicates that light also acts independently of the circadian system to directly impact physiology and behaviour, including cognition. Exposure to light stimulates brain areas involved in cognition and appears to improve a broad range of cognitive functions. However, the extent of these effects and their mechanisms are unknown. Intrinsically photosensitive retinal ganglion cells (ipRGCs) have emerged as the primary conduit through which light impacts non-image-forming behaviours and are a prime candidate for mediating the direct effects of light on cognition. Here, we review the current state of understanding of these effects in humans and mice, and the tools available to uncover circuit-level and photoreceptor-specific mechanisms. We also address current barriers to progress in this area. Current and future efforts to unravel the circuits through which light influences cognitive functions may inform the tailoring of lighting landscapes to optimize health and cognitive function.

DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.