Sex and circadian influences on olfactory behavior and neurophysiology - Project Summary A growing scientific literature concerning the influence of olfaction on cognitive health shows that olfactory dysfunction is involved in a myriad of diseases, including depression and dementia. Smell deficits are often the first symptom of Alzheimer’s Disease and other types of dementia. Many of these diseases exhibit sex differences in incidence and/or clinical presentation along with striking time-of-day dependent changes in symptom severity. Therefore, how biological factors (sex) and environmental cues (light, time-of-day information) affect olfactory system function will inform understanding of cognitive health. Despite mandates to include sexes equally in biomedical research, few studies address sex differences in primary olfactory function relevant to non-sexual odors. Likewise, circadian function is largely ignored in olfactory research. The majority of behavioral testing occurs during the light phase, even though lab rodents are typically nocturnal, and behavior and physiology vary strikingly across the day. This proposed work will examine cognitive and physiological factors underlying sex differences in olfactory behavior and interactions between time of day and sex in odor processing in rats. Preliminary data indicate that female rats sample odors as much as 40% longer than males when they are rewarded to learn an odor discrimination task, but this sex difference is reversed when rats learn new odors without any reinforcement, suggesting that odor sampling is not simply dictated by sex, but instead the sex difference depends on what is being learned. Moreover, these sex differences in behavioral strategy fluctuated based on the time of day. Preliminary neurophysiological recordings show that females produce lower amplitude fast cortical oscillations than males when sniffing odors, and that female and male brains show different olfactory-hippocampal network configurations when performing an odor discrimination task. Here we will test the hypotheses (1) that females and males utilize distinct behavioral and neurophysiological mechanisms to solve olfactory learning tasks, and (2) that olfactory cognitive skills vary over the circadian cycle. Aim 1 examines sex differences in olfactory behavior and neurophysiology, using odor habituation and two operant associative odor discrimination tasks; these studies will identify interactions among sex, task difficulty, and the cognitive structure of the task itself. Studies will also define the role of circulating sex hormones in driving sex differences. Aim 2 interrogates how circadian time affects olfactory cognition; these studies will characterize how behavior and neurophysiology vary when rats are tested across multiple phases of the light and dark cycle. Male and female rats will be included in equal numbers in all experiments. To permit analysis of neural signals from olfactory and hippocampal regions, electrophysiology will be performed in a smaller group of rats as they learn odors and perform tasks. Sex and time-of-day currently contribute an unknown degree of variance to research in olfactory neuroscience. These innovative experiments will quantify these sources of variance and thereby enhance rigor and reproducibility in research on odor perception and olfactory neurophysiology. The outcomes will inform basic questions about how sex and time affect the brain and will serve as a foundation for future practices in olfactory neuroscience research.
