The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice.

Background: The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN.

Female fertility does not require in suprachiasmatic nucleus neurons expressing arginine vasopressin, vasoactive intestinal peptide, or neuromedin-S.

Disruptions to the circadian system alter reproductive capacity, particularly in females. Mice lacking the core circadian clock gene, , are infertile and have evidence of neuroendocrine disruption including the absence of the preovulatory luteinizing hormone (LH) surge and enhanced responsiveness to exogenous kisspeptin. Here, we explore the role of in suprachiasmatic nucleus (SCN) neuron populations known to project to the neuroendocrine axis.

Deletion of Six3 in post-proliferative neurons produces weakened SCN circadian output, improved metabolic function, and dwarfism in male mice.

Objective: The increasing prevalence of obesity makes it important to increase the understanding of the maturation and function of the neuronal integrators and regulators of metabolic function.

Methods: Behavioral, molecular, and physiological analyses of transgenic mice with Sine oculis 3 (Six3) deleted in mature neurons using the Synapsinallele.

Results: Conditional deletion of the homeodomain transcription factor Six3 in mature neurons causes dwarfism and weakens circadian wheel-running activity rhythms but increases general activity at night, and improves metabolic function, without impacting pubertal onset or fertility in males.

Expanding Perspectives of Element Cycling from 1970 to 2020: The Influence of Stumm and Morgan.

There has been significant advancement in understanding of element cycles over the past 50 years, and the contributions of the three editions of by Stumm and Morgan on the critical role of reactions in the aqueous phase on the global cycles of elements have been substantial. The primary focus of investigation of biogeochemical element cycles has been on the "grand nutrients" carbon, nitrogen, phosphorus, and sulfur. The basic chemistry and chemical systems perspective of helped elucidate the cycles of these elements.

The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice.

The homeodomain transcription factors sine oculis homeobox 3 (Six3) and ventral anterior homeobox 1 (Vax1) are required for brain development. Their expression in specific brain areas is maintained in adulthood, where their functions are poorly understood. To identify the roles of Six3 and Vax1 in neurons, we conditionally deleted each gene using Synapsin , a promoter targeting maturing neurons, and generated Six3 and Vax1 mice.

Naturalistic Intensities of Light at Night: A Review of the Potent Effects of Very Dim Light on Circadian Responses and Considerations for Translational Research.

In this review, we discuss the remarkable potency and potential applications of a form of light that is often overlooked in a circadian context: naturalistic levels of dim light at night (nLAN), equivalent to intensities produced by the moon and stars. It is often assumed that such low levels of light do not produce circadian responses typically associated with brighter light levels. A solid understanding of the impacts of very low light levels is complicated further by the broad use of the somewhat ambiguous term "dim light," which has been used to describe light levels ranging seven orders of magnitude.

Neuronal Activity Regulates Blood-Brain Barrier Efflux Transport through Endothelial Circadian Genes.

The blood vessels in the central nervous system (CNS) have a series of unique properties, termed the blood-brain barrier (BBB), which stringently regulate the entry of molecules into the brain, thus maintaining proper brain homeostasis. We sought to understand whether neuronal activity could regulate BBB properties. Using both chemogenetics and a volitional behavior paradigm, we identified a core set of brain endothelial genes whose expression is regulated by neuronal activity.

Temporal organization of pineal melatonin signaling in mammals.

In mammals, the pineal gland is the sole endocrine source of melatonin, which is secreted according to daily and seasonal patterns. This mini-review synthesizes the established endocrine actions of melatonin in the following temporal contexts. Melatonin is a strictly regulated output of the circadian timing system, but under certain conditions, may also entrain the circadian pacemaker and clocks in peripheral tissues.

Circadian Profile of an Emergency Medicine Department: Scheduling Practices and Their Effects on Sleep and Performance.

Background: Shiftwork causes circadian disruption and is the primary reason for attrition from Emergency Medicine.

Objectives: We aimed to develop concrete recommendations to mitigate negative effects of shiftwork based on measures of work, sleep, alertness, and performance in emergency physicians.

Methods: Thirty-one Emergency Medicine residents were surveyed retrospectively about sleep and alertness on different shifts.

The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function.

The brain's primary circadian pacemaker, the suprachiasmatic nucleus (SCN), is required to translate day-length and circadian rhythms into neuronal, hormonal, and behavioral rhythms. Here, we identify the homeodomain transcription factor ventral anterior homeobox 1 (Vax1) as required for SCN development, vasoactive intestinal peptide expression, and SCN output. Previous work has shown that VAX1 is required for gonadotropin-releasing hormone (GnRH/LHRH) neuron development, a neuronal population controlling reproductive status.

Enhanced Circadian Entrainment in Mice and Its Utility under Human Shiftwork Schedules.

The circadian system is generally considered to be incapable of adjusting to rapid changes in sleep/work demands. In shiftworkers this leads to chronic circadian disruption and sleep loss, which together predict underperformance at work and negative health consequences. Two distinct experimental protocols have been proposed to increase circadian flexibility in rodents using dim light at night: rhythm bifurcation and T-cycle (i.

Physiological, behavioral and environmental factors influence bifurcated circadian entrainment in mice.

Under permissive conditions, mice and hamsters exposed to a polyphasic light regime consisting of two light and two dark phases every 24 h (Light:Dark:Light:Dark; LDLD) can adopt a bifurcated entrainment pattern with roughly equal amounts of running wheel activity in each of the two nights. This rhythm "bifurcation" has significant after-effects on increased circadian adaptability: Mice that have been bifurcated show accelerated rates of re-entrainment after a sudden phase shift and have a markedly expanded range of entrainment. Identifying environmental and physiological factors that facilitate or prevent rhythm bifurcation in LDLD conditions will contribute to an understanding of mechanisms underlying enhanced circadian plasticity.

Photoperiodic Requirements for Induction and Maintenance of Rhythm Bifurcation and Extraordinary Entrainment in Male Mice.

Exposure of mice to a 24 h light:dark:light:dark (LDLD) cycle with dimly illuminated nights induces the circadian timing system to program two intervals of activity and two intervals of rest per 24 h cycle and subsequently allows entrainment to a variety of extraordinary light regimens including 30 h LDLD cycles. Little is known about critical lighting requirements to induce and maintain this non-standard entrainment pattern, termed "bifurcation," and to enhance the range of apparent entrainment. The current study determined the necessary duration of the photophase for animals to bifurcate and assessed whether requirements for maintenance differed from those for induction.

Exceptional Entrainment of Circadian Activity Rhythms With Manipulations of Rhythm Waveform in Male Syrian Hamsters.

The activity/rest rhythm of mammals reflects the output of an endogenous circadian oscillator entrained to the solar day by light. Despite detailed understanding of the neural and molecular bases of mammalian rhythms, we still lack practical tools for achieving rapid and flexible adjustment of clocks to accommodate shift-work, trans-meridian jet travel, or space exploration. Efforts to adapt clocks have focused on resetting the of an otherwise unaltered circadian clock.

Why Should We Abolish Daylight Saving Time?

Local and national governments around the world are currently considering the elimination of the annual switch to and from Daylight Saving Time (DST). As an international organization of scientists dedicated to studying circadian and other biological rhythms, the Society for Research on Biological Rhythms (SRBR) engaged experts in the field to write a Position Paper on the consequences of choosing to live on DST or Standard Time (ST). The authors take the position that, based on comparisons of large populations living in DST or ST or on western versus eastern edges of time zones, the advantages of permanent ST outweigh switching to DST annually or permanently.

Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration.

Mating behavior in males and females is dependent on olfactory cues processed through both the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Signaling through the MOE is critical for the initiation of male mating behavior, and the loss of MOE signaling severely compromises this comportment. Here, we demonstrate that dosage of the homeodomain gene Six3 affects the degree of development of MOE but not the VNO.

Simple Lighting Manipulations Facilitate Behavioral Entrainment of Mice to 18-h Days.

In an invariantly rhythmic world, a robust and stable mammalian circadian clock is presumed to confer fitness advantages. In shift-work or after rapid transmeridian travel, however, a stable clock might be maladaptive and a more flexibly resettable clock may have advantages. The rate at which rodents can adjust to simulated time zone travel and the range of entrainment can be markedly increased through simple light manipulations, namely, by exposing animals to extremely dim light (<0.

Health consequences of electric lighting practices in the modern world: A report on the National Toxicology Program's workshop on shift work at night, artificial light at night, and circadian disruption.

The invention of electric light has facilitated a society in which people work, sleep, eat, and play at all hours of the 24-hour day. Although electric light clearly has benefited humankind, exposures to electric light, especially light at night (LAN), may disrupt sleep and biological processes controlled by endogenous circadian clocks, potentially resulting in adverse health outcomes. Many of the studies evaluating adverse health effects have been conducted among night- and rotating-shift workers, because this scenario gives rise to significant exposure to LAN.

Extraordinary behavioral entrainment following circadian rhythm bifurcation in mice.

The mammalian circadian timing system uses light to synchronize endogenously generated rhythms with the environmental day. Entrainment to schedules that deviate significantly from 24 h (T24) has been viewed as unlikely because the circadian pacemaker appears capable only of small, incremental responses to brief light exposures. Challenging this view, we demonstrate that simple manipulations of light alone induce extreme plasticity in the circadian system of mice.

Circadian waveform bifurcation, but not phase-shifting, leaves cued fear memory intact.

In mammals, memory acquisition and retrieval can be affected by time of day, as well as by manipulations of the light/dark cycle. Under bifurcation, a manipulation of circadian waveform, two subjective days and nights are experimentally induced in rodents. We examined the effect of bifurcation on Pavlovian fear conditioning, a prominent model of learning and memory.

In synch but not in step: Circadian clock circuits regulating plasticity in daily rhythms.

The suprachiasmatic nucleus (SCN) is a network of neural oscillators that program daily rhythms in mammalian behavior and physiology. Over the last decade much has been learned about how SCN clock neurons coordinate together in time and space to form a cohesive population. Despite this insight, much remains unknown about how SCN neurons communicate with one another to produce emergent properties of the network.

Rapid Adjustment of Circadian Clocks to Simulated Travel to Time Zones across the Globe.

Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule-a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths.

Nmf9 Encodes a Highly Conserved Protein Important to Neurological Function in Mice and Flies.

Many protein-coding genes identified by genome sequencing remain without functional annotation or biological context. Here we define a novel protein-coding gene, Nmf9, based on a forward genetic screen for neurological function. ENU-induced and genome-edited null mutations in mice produce deficits in vestibular function, fear learning and circadian behavior, which correlated with Nmf9 expression in inner ear, amygdala, and suprachiasmatic nuclei.

The circadian timing system in ethanol consumption and dependence.

The use of alcohol is an important part of the daily lives of many individuals that may be experienced as a single nightly drink with a meal or a debilitating pattern of intoxication. The circadian timing system imposes a daily temporal order throughout the brain and body. Ethanol, with its complex and broad pharmacology, can thereby alter circadian physiology at multiple levels of organization.