Circadian Implications for Female Reproductive Health
Successful female reproduction requires the precise temporal coordination of estrogen-sensitive neural networks that converge to drive the hypothalamo-pituitary–gonadal (HPG) axis. In mammals, the master pacemaker located in the suprachiasmatic nucleus (SCN) coordinates neuroendocrine events vital for reproductive success. For species with limited fertile windows, circadian regulation ensures that sexual motivation aligns with the timing of ovulation. Conversely, disruptions to these biological rhythms, common in shift work or poor sleep environments, can lead to significant impairments in fecundity across species, including humans. Although the master clock's role is well-established, the specific neural pathways and molecular mechanisms through which it operates remain poorly defined. Current research primarily targets communication between the SCN and the reproductive axis in initiation of the preovulatory luteinizing (LH) surge. However, the same molecular clock machinery found in SCN cells is active within multiple cell phenotypes in this modulatory circuit. Investigating how the master clock synergizes with these subordinate oscillators offers a compelling opportunity to understand endogenous timing in female reproductive health and develop safe and effective strategies to maximize female reproduction in the modern world where circadian disruption is prominent.
Circadian Involvement in Age Related Cognitive Decline
Cognitive decline is pervasive with advancing age, with an estimated 50 million people presently living with dementia worldwide. While this cognitive deterioration is widespread, the mechanisms underlying dementia, its underlying neuropathology, and why some individuals are vulnerable while others are resilient are poorly understood. With advancing age, disruptions to circadian and sleep homeostasis are virtually universal and precede age-related dementia. Likewise, the blood-brain barrier (BBB) is regulated by circadian rhythms and sleep, with disruptions to circadian timing/sleep leading to BBB dysfunction. Because deficits in BBB permeability are linked to age-related cognitive deterioration, our research explores the possibility that age-related deficits in circadian rhythms and sleep lead to BBB degradation and resultant cognitive decline, and that resilience to sleep/circadian degradation is neuroprotective. This work also applies approaches to rescue degraded circadian rhythms and sleep as a strategy for maximizing healthy cognitive aging. Together, this work will enhance our understanding of the mechanisms and underlying neuropathology of age-related cognitive decline, but also have the potential for wide-ranging treatment.
The Influence of Circadian Disruption on Dopamine and Reward Processing in Bipolar Disorder
Circadian/sleep and reward system disturbances are two key risk factors for the onset and course of bipolar disorder (BD). People with BD show a reduction in the typical 24-h activity rhythm, disturbed sleep, and differences in genes regulating circadian function. People with BD also show heightened behavioral and neural responses to reward cues. This ‘reward sensitivity’ predicts the onset and course of mania and intensifies as manic symptoms increase. We connect these two risk factors and examine the hypothesis that a failure to dampen reward sensitivity in the evening is a key feature of BD. We are presently testing this link in a mouse model and people with BD. In mice, we disrupt cellular clocks in targeted regions of the brain and and examine the impact on the BD phenotype. In people with BD and healthy controls (HC), we measure multiple aspects of reward sensitivity across the day, functional brain activity in response to reward, and the impact of variation in regional DA biology. These findings have the potential to identify novel brain and behavioral signatures underlying BD, potentially providing novel biological and psychological treatment targets.
Determining Whether Strategies that Improve Circadian Rhythms Can Influence Symptoms of Bipolar Disorder
Circadian rhythms and sleep are commonly disrupted among people with bipolar disorder (BD). Accordingly, there is a profound need for interventions that can maximize circadian and sleep health in BD. Time-restricted eating (TRE) is an intervention that improves circadian rhythms in animals and humans, but it has not been tested in BD. In collaboration with Dr. Sheri Johnson, we are conducting two studies to examine TRE in BD. First, we are conducting a randomized controlled trial (RCT) to examine efficacy as compared to a control intervention of the Mediterranean diet, and to test the hypothesis that the intervention will be particularly powerful early in the course of BD. Second, to understand mechanism, we will measure how TRE adherence predicts the diurnal amplitude of core circadian clock gene expression and phase and amplitude of melatonin secretion, and how amplitude of clock gene expression predicts changes in symptoms and quality of life. If successful, this work will provide a novel, easily implemented and highly acceptable intervention for BD, and a critically needed test of the circadian rhythm hypothesis of BD.