In today's modern world, the average person spends most of their time indoors due to the nature of their profession and their associated lifestyle. With artificial lighting being substantially less intense than natural sunlight and seasonal variations of daylight intensity being a significant factor, this leaves the average human being consistently lacking exposure to bright lighting. Environmental lighting conditions have shown to play a significant role in cognitive function in a diverse array of human subjects. Longitudinal studies have found that bright light therapy can improve several aspects of cognition in healthy and clinical populations of varying ages. Moreover, fMRI studies in humans have demonstrated that bright light consisting mainly of shorter wavelengths activates the hippocampus (HPC) at a higher rate than dim or longer wavelength light. However, the neural mechanisms for how light impacts cognitive function is still unclear. To expand our understanding, the experiments within this dissertation attempt to address this knowledge gap by utilizing the diurnal Nile grass rat (Arvicanthis niloticus) as a preclinical research model. The grass rat's activity patterns are like that of the average human, with much of its activity being circumscribed to the presence of light (i.e., subjective day) which makes it a suitable animal model for studying light's effect on cognition. Specifically, the work presented here will look at how light modulates HPC-dependent learning and memory. In the first set of experiments, the levels of long-term daylight illumination were associated with the retention of a spatial navigational task known as the Morris Water Maze (MWM). Grass rats that were housed for four weeks in a 12:12hr bright light-dark (brLD) cycle exhibited superior MWM performance over animals housed in a 12:12hr dim light-dark (dimLD) cycle. Deficits in MWM performance shown by the dimLD group were rescued with subsequent exposure to brLD conditions. Additionally, reduced levels of brain-derived neurotrophic factor (BDNF) and a decrease in CA1 dendritic spines were associated with dimLD conditions. These results suggest that chronic daytime light deficiency impacts HPC-dependent learning and memory by dampening hippocampal synaptic plasticity. Subsequent experiments revealed that HPC-dependent learning and memory deficits were further pronounced in female grass rats. Although morphometric analyses revealed reduced CA1 dendritic spine density, like in males, BDNF expression was not impacted, which suggests that light may modulate hippocampal function in female grass rats through distinct neural pathways. Previous studies done in grass rats have revealed that dimLD conditions negatively impact the expression orexin-A (OXA) in the hypothalamus. Based on those findings, the last set of experiments tested the hypothesis that in diurnal mammals, light modulates hippocampal function via the orexinergic system. Intranasal administration of OXA to grass rats in dimLD conditions during MWM training revealed optimal MWM performance, which suggests that these deficits were due to reduced OXA input. Viral vector-mediated knockdown of orexin-1 receptors (OX1R) in the hippocampus of grass rats housed in brLD conditions negatively impacted MWM performance. These results suggest that bright lighting supports HPC-dependent learning and memory through enhanced OXA-OX1R signaling within the HPC. Overall, the present work provides a better understanding of the neurobiological underpinnings of light-modulated learning and memory by identifying and examining molecular pathways linked to synaptic plasticity.
Read
