NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.

Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge.

The preovulatory LH surge is triggered when the circadian pacemaker, the bilateral suprachiasmatic nucleus (SCN), stimulates the GnRH system in the presence of high estrogen concentrations (positive feedback). Importantly, during the remainder of the estrous cycle, estradiol inhibits LH release via negative feedback. We have recently documented the presence of a novel mammalian RFamide-related peptide (RFRP), a putative gonadotropin-inhibitory hormone (GnIH), that presumably acts upstream of GnRH to modulate the negative feedback effects of estrogen. The present series of studies used female Syrian hamsters to examine the possibility that, in addition to driving the LH surge positively, the SCN concomitantly coordinates the removal of steroid-mediated RFRP inhibition of the gonadotropic axis to permit the surge. We found that the SCN forms close appositions with RFRP cells, suggesting the possibility for direct temporal control of RFRP activity. During the time of the LH surge, immediate-early gene expression is reduced in RFRP cells, and this temporal regulation is estrogen dependent. To determine whether projections from the SCN regulate the timed reduction in activation of the RFRP system, we exploited the phenomenon of splitting. In split animals in which the SCN are active in antiphase, activation of the RFRP system is asymmetrical. Importantly, this asymmetry is opposite to the state of the GnRH system. Together, these findings point to novel circadian control of the RFRP system and potential participation in the circuitry controlling ovulatory function.

RFamide-related Peptide-3 and the Trade-off between Reproductive and Ingestive Behavior.

Ingestive and sex behaviors are important for individual survival and reproductive success, but when environmental energy availability is limited, individuals of many different species make a trade-off, forfeiting sex for ingestive behavior. For example, food-deprived female Syrian hamsters (Mesocricetus auratus) forego vaginal scent marking and lordosis (sex behaviors) in favor of foraging, hoarding, and eating food (ingestive behavior). Reproductive processes tend to be energetically costly, and individual survival requires homeostasis in metabolic energy. Thus, during energetic challenges, the chances of survival are enhanced by decreasing the energy expended on reproductive processes. The entire hypothalamic-pituitary-gonadal (HPG) system is inhibited by severe energetic challenges, but comparatively little is known about the effects of mild energetic challenges. We hypothesized that (1) a trade-off is made between sex and ingestive behavior even when the level of food restriction is insufficient to inhibit the HPG system; (2) mild energetic challenges force a trade-off between appetitive ingestive and sex behaviors, but not consummatory versions of the same behaviors; and (3) the trade-off is orchestrated by ovarian steroid modulation of RFamide-related peptide 3 (RFRP-3). In other species, RFRP-3, an ortholog of avian gonadotropin-inhibitory hormone, is implicated in control of behavior in response to energetic challenges and stressful stimuli. In support of our three hypotheses, there is a "dose-response" effect of food restriction and re-feeding on the activation of RFRP-3-immunoreactive cells in the dorsomedial hypothalamus and on appetitive behaviors (food hoarding and sexual motivation), but not on consummatory behaviors (food intake and lordosis), with no significant effect on circulating levels of estradiol or progesterone. The effect of food restriction on the activation of RFRP-3 cells is modulated at the time of estrus in gonadally-intact females and in ovariectomized females treated with progesterone alone or with estradiol plus progesterone. Intracerebral treatment with RFRP-3 results in significant decreases in sexual motivation and results in significant but small increases in food hoarding in hamsters fed ad libitum. These and other results are consistent with the idea that ovarian steroids and RFRP-3 are part of a system that orchestrates trade-offs in appetitive behaviors in environments where energy availability fluctuates.

Comparative Review of Approved Melatonin Agonists for the Treatment of Circadian Rhythm Sleep-Wake Disorders.

Circadian rhythm sleep-wake disorders (CRSWDs) are characterized by persistent or recurrent patterns of sleep disturbance related primarily to alterations of the circadian rhythm system or the misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. These disorders collectively represent a significant unmet medical need, with a total prevalence in the millions, a substantial negative impact on quality of life, and a lack of studied treatments for most of these disorders. Activation of the endogenous melatonin receptors appears to play an important role in setting the circadian clock in the suprachiasmatic nucleus of the hypothalamus. Therefore, melatonin agonists, which may be able to shift and/or stabilize the circadian phase, have been identified as potential therapeutic candidates for the treatment of CRSWDs. Currently, only one melatonin receptor agonist, tasimelteon, is approved for the treatment of a CRSWD: non-24-hour sleep-wake disorder (or non-24). However, three additional commercially available melatonin receptor agonists-agomelatine, prolonged-release melatonin, and ramelteon-have been investigated for potential use for treatment of CRSWDs. Data indicate that these melatonin receptor agonists have distinct pharmacologic profiles that may help clarify their clinical use in CRSWDs. We review the pharmacokinetic and pharmacodynamic properties of these melatonin agonists and summarize their efficacy profiles when used for the treatment of CRSWDs. Further studies are needed to determine the therapeutic potential of these melatonin agonists for most CRSWDs.

Circadian rhythms and addiction: mechanistic insights and future directions.

Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug-induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction.

Circadian control of neuroendocrine circuits regulating female reproductive function.

Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG) axis functioning. In mammals, the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus coordinates reproductively relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene) lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the gonadotropin-releasing hormone (GnRH) system in control of the preovulatory luteinizing hormone (LH) surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.

Circadian control of kisspeptin and a gated GnRH response mediate the preovulatory luteinizing hormone surge.

In spontaneously ovulating rodents, the preovulatory LH surge is initiated on the day of proestrus by a timed, stimulatory signal originating from the circadian clock in the suprachiasmatic nucleus (SCN). The present studies explored whether kisspeptin is part of the essential neural circuit linking the SCN to the GnRH system to stimulate ovulation in Syrian hamsters (Mesocricetus auratus). Kisspeptin neurons exhibit an estrogen-dependent, daily pattern of cellular activity consistent with a role in the circadian control of the LH surge. The SCN targets kisspeptin neurons via vasopressinergic (AVP), but not vasoactive intestinal polypeptide-ergic, projections. Because AVP administration can only stimulate the LH surge during a restricted time of day, we examined the possibility that the response to AVP is gated at the level of kisspeptin and/or GnRH neurons. Kisspeptin and GnRH activation were assessed after the administration of AVP during the morning (when AVP is incapable of initiating the LH surge) and the afternoon (when AVP injections stimulate the LH surge). Kisspeptin, but not GnRH, cellular activity was up-regulated after morning injections of AVP, suggesting that time-dependent sensitivity to SCN signaling is gated within GnRH but not kisspeptin neurons. In support of this possibility, we found that the GnRH system exhibits pronounced daily changes in sensitivity to kisspeptin stimulation, with maximal sensitivity in the afternoon. Together these studies reveal a novel mechanism of ovulatory control with interactions among the circadian system, kisspeptin signaling, and a GnRH gating mechanism of control.

Food Restriction-Induced Changes in Gonadotropin-Inhibiting Hormone Cells are Associated with Changes in Sexual Motivation and Food Hoarding, but not Sexual Performance and Food Intake.

We hypothesized that putative anorectic and orexigenic peptides control the motivation to engage in either ingestive or sex behaviors, and these peptides function to optimize reproductive success in environments where energy fluctuates. Here, the putative orexigenic peptide, gonadotropin-inhibiting hormone (GnIH, also known as RFamide-related peptide-3), and the putative anorectic hormones leptin, insulin, and estradiol were examined during the course of food restriction. Groups of female Syrian hamsters were restricted to 75% of their ad libitum food intake or fed ad libitum for 4, 8, or 12 days. Two other groups were food-restricted for 12 days and then re-fed ad libitum for 4 or 8 days. After testing for sex and ingestive behavior, blood was sampled and assayed for peripheral hormones. Brains were immunohistochemically double-labeled for GnIH and the protein product of the immediate early gene, c-fos, a marker of cellular activation. Food hoarding, the number of double-labeled cells, and the percent of GnIH-Ir cells labeled with Fos-Ir were significantly increased at 8 and 12 days after the start of food restriction. Vaginal scent marking and GnIH-Ir cell number significantly decreased after the same duration of restriction. Food hoarding, but not food intake, was significantly positively correlated with cellular activation in GnIH-Ir cells. Vaginal scent marking was significantly negatively correlated with cellular activation in GnIH-Ir cells. There were no significant effects of food restriction on plasma insulin, leptin, estradiol, or progesterone concentrations. In the dorsomedial hypothalamus (DMH) of energetically challenged females, strong projections from NPY-Ir cells were found in close apposition to GnIH-Ir cells. Together these results are consistent with the idea that metabolic signals influence sexual and ingestive motivation via NPY fibers that project to GnIH cells in the DMH.

Aging in the circadian system: considerations for health, disease prevention and longevity.

The circadian system orchestrates internal physiology on a daily schedule to promote optimal health and maximize disease prevention. Chronic disruptions in circadian function are associated with an increase in a variety of disease states including, heart disease, ulcers and diabetes. With advanced age, the genes regulating circadian function at the cellular level become disorganized and the ability of the brain clock to entrain to local time diminishes. As a result, aged individuals exhibit a loss of temporal coordination among bodily systems, leading to deficits in homeostasis and sub-optimal functioning. Such disruptions in the circadian system appear to accelerate the aging process and contribute to senescence, with some systems being more vulnerable than others. This review explores aging-associated changes in circadian function and examines evidence linking such alterations to adverse health consequences in late life and promotion of the aging process.

Proximate mechanisms driving circadian control of neuroendocrine function: Lessons from the young and old.

Circadian rhythms impact a variety of behavioral and physiological functions contributing to longevity and successful reproduction. In their natural environments, individuals of a species are faced with a multitude of challenges and the coordination of internal processes and behavior with external pressures has been hypothesized to be an important target of natural selection. Several lines of evidence from cyanobacteria, Drosophila, and plants provide strong support for an important role of the circadian clock in survival and reproductive success. Similarly in mammals, disruptions in circadian function markedly impact reproduction and lifespan. The present review discusses research outlining the proximate and ultimate mechanisms responsible for the central and peripheral control of the reproductive axis. Because precise temporal coordination of the endocrine system is particularly crucial for reproduction by females, the present overview focuses on the role of circadian timing in this sex.