Highlights • Mast cells (MCs) are brain-resident immune cells that serve both as sensors and effectors in communication among nervous, vascular and immune systems. • MCs lie on the brain side of the ...blood–brain barrier (BBB) and communicate with neurons, glia, blood vessels, and other hematopoietic cells via their neuroactive prestored and newly synthesized chemicals. • Although small in number, MCs exert powerful effects because they are first responders that act as catalysts and recruiters to initiate, amplify, and prolong other immune and nervous responses upon activation. • MCs both promote deleterious outcomes in brain function and contribute to normative behavioral functioning, particularly cognition and emotionality. • New experimental tools enabling isolation of brain MCs, manipulation of MCs or of their products, and measurement of MC products in very small brain volumes present unprecedented opportunities for examining these enigmatic cells, both during development and adulthood.
Background
Steroids are lipid hormones that reach bodily tissues through the systemic circulation, and play a major role in reproduction, metabolism, and homeostasis. All of these functions and ...steroids themselves are under the regulation of the circadian timing system (CTS) and its cellular/molecular underpinnings. In health, cells throughout the body coordinate their daily activities to optimize responses to signals from the CTS and steroids. Misalignment of responses to these signals produces dysfunction and underlies many pathologies.
Questions Addressed
To explore relationships between the CTS and circulating steroids, we examine the brain clock located in the suprachiasmatic nucleus (SCN), the daily fluctuations in plasma steroids, the mechanisms producing regularly recurring fluctuations, and the actions of steroids on their receptors within the SCN. The goal is to understand the relationship between temporal control of steroid secretion and how rhythmic changes in steroids impact the SCN, which in turn modulate behavior and physiology.
Evidence Surveyed
The CTS is a multi-level organization producing recurrent feedback loops that operate on several time scales. We review the evidence showing that the CTS modulates the timing of secretions from the level of the hypothalamus to the steroidogenic gonadal and adrenal glands, and at specific sites within steroidogenic pathways. The SCN determines the timing of steroid hormones that then act on their cognate receptors within the brain clock. In addition, some compartments of the body-wide CTS are impacted by signals derived from food, stress, exercise etc. These in turn act on steroidogenesis to either align or misalign CTS oscillators. Finally this review provides a comprehensive exploration of the broad contribution of steroid receptors in the SCN and how these receptors in turn impact peripheral responses.
Conclusion
The hypothesis emerging from the recognition of steroid receptors in the SCN is that mutual shaping of responses occurs between the brain clock and fluctuating plasma steroid levels.
Circadian rhythms are generated by an endogenously organized timing system that drives daily rhythms in behavior, physiology and metabolism. In mammals, the suprachiasmatic nucleus (SCN) of the ...hypothalamus is the locus of a master circadian clock. The SCN is synchronized to environmental changes in the light:dark cycle by direct, monosynaptic innervation via the retino‐hypothalamic tract. In turn, the SCN coordinates the rhythmic activities of innumerable subordinate clocks in virtually all bodily tissues and organs. The core molecular clockwork is composed of a transcriptional/post‐translational feedback loop in which clock genes and their protein products periodically suppress their own transcription. This primary loop connects to downstream output genes by additional, interlocked transcriptional feedback loops to create tissue‐specific ‘circadian transcriptomes’. Signals from peripheral tissues inform the SCN of the internal state of the organism and the brain's master clock is modified accordingly. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body. This overview examines landmark studies in the history of the study of circadian timing system, and highlights our current understanding of the operation of circadian clocks with a focus on topics of interest to the neuroscience community.
The suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock. The SCN is synchronized to the light‐dark cycle by direct, monosynaptic innervation via the retinohypothalamic tract. In turn, the SCN coordinates rhythmic activities of innumerable subordinate brain clocks via neural efferents and diffusible/paracrine signals which, in turn, modulate activity in the rest of the body. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body.
There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse ...linking the capillary vessels of the brain's clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways.
Increases in arousal and activity in anticipation of a meal, termed "food anticipatory activity" (FAA), depend on circadian food-entrainable oscillators (FEOs), whose locations and output signals ...have long been sought. It is known that ghrelin is secreted in anticipation of a regularly scheduled mealtime. We show here that ghrelin administration increases locomotor activity in nondeprived animals in the absence of food. In mice lacking ghrelin receptors, FAA is significantly reduced. Impressively, the cumulative rise of activity before food presentation closely approximates a Gaussian function (r = 0.99) for both wild-type and ghrelin receptor knockout animals, with the latter having a smaller amplitude. For both groups, once an animal begins its daily anticipatory bout, it keeps running until the usual time of food availability, indicating that ghrelin affects response threshold. Oxyntic cells coexpress ghrelin and the circadian clock proteins PER1 and PER2. The expression of PER1, PER2, and ghrelin is rhythmic in light-dark cycles and in constant darkness with ad libitum food and after 48 h of food deprivation. In behaviorally arrhythmic-clock mutant mice, unlike control animals, there is no evidence of a premeal decrease in oxyntic cell ghrelin. Rhythmic ghrelin and PER expression are synchronized to prior feeding, and not to photic schedules. We conclude that oxyntic gland cells of the stomach contain FEOs, which produce a timed ghrelin output signal that acts widely at both brain and peripheral sites. It is likely that other FEOs also produce humoral signals that modulate FAA.
The prevailing view is that recreational methamphetamine use causes a broad range of severe cognitive deficits, despite the fact that concerns have been raised about interpretations drawn from the ...published literature. This article addresses an important gap in our knowledge by providing a critical review of findings from recent research investigating the impact of recreational methamphetamine use on human cognition. Included in the discussion are findings from studies that have assessed the acute and long-term effects of methamphetamine on several domains of cognition, including visuospatial perception, attention, inhibition, working memory, long-term memory, and learning. In addition, relevant neuroimaging data are reviewed in an effort to better understand neural mechanisms underlying methamphetamine-related effects on cognitive functioning. In general, the data on acute effects show that methamphetamine improves cognitive performance in selected domains, that is, visuospatial perception, attention, and inhibition. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically significant differences between methamphetamine users and control participants have been observed on a minority of measures. More importantly, however, the clinical significance of these findings may be limited because cognitive functioning overwhelmingly falls within the normal range when compared against normative data. In spite of these observations, there seems to be a propensity to interpret any cognitive and/or brain difference(s) as a clinically significant abnormality. The implications of this situation are multiple, with consequences for scientific research, substance-abuse treatment, and public policy.
While much is known about the mechanisms that underlie sleep and circadian rhythms, the investigation into sex differences and gonadal steroid modulation of sleep and biological rhythms is in its ...infancy. There is a growing recognition of sex disparities in sleep and rhythm disorders. Understanding how neuroendocrine mediators and sex differences influence sleep and biological rhythms is central to advancing our understanding of sleep-related disorders. While it is known that ovarian steroids affect circadian rhythms in rodents, the role of androgen is less understood. Surprising findings that androgens, acting via androgen receptors in the master "circadian clock" within the suprachiasmatic nucleus, modulate photic effects on activity in males point to novel mechanisms of circadian control. Work in aromatase-deficient mice suggests that some sex differences in photic responsiveness are independent of gonadal hormone effects during development. In parallel, aspects of sex differences in sleep are also reported to be independent of gonadal steroids and may involve sex chromosome complement. This a summary of recent work illustrating how sex differences and gonadal hormones influence sleep and circadian rhythms that was presented at a Mini-Symposium at the 2011 annual meeting of the Society for Neuroscience.
Daily oscillations in physiology and behavior are regulated by a brain clock located in the suprachiasmatic nucleus (SCN). Individual cells within this nucleus contain an autonomous molecular clock. ...Recent discoveries that make use of new molecular and genetic data and tools highlight the conclusion that the SCN is a heterogeneous network of functionally and phenotypically differentiated cells. Neurons within SCN subregions serve distinctly separate functions in regulating the overall activity of the circadian clock: some cells within the SCN rhythmically express ‘clock’ genes, whereas others exhibit induced expression of these genes after the organism has been exposed to a light pulse. The coordinated interaction of these functionally distinct cells is integral to the coherent functioning of the brain clock.
The suprachiasmatic nucleus (SCN) is the locus of the master circadian clock, setting the daily rhythms in physiology and behavior and synchronizing these responses to the local environment. The most ...important of these phase-setting cues derive from the light-dark cycle and reach the SCN directly via the retinohypothalamic tract (RHT). The SCN contains anatomically and functionally heterogeneous populations of cells. Understanding how these neurons access information about the photic environment so as to set the phase of daily oscillation requires knowledge of SCN innervation by the RHT. While retinal innervation of the SCN has long been a topic of interest, the information is incomplete. In some instances, studies have focused on the caudal aspect of the nucleus, which contains the core region. In other instances, subregions of the nucleus have been delineated based on projections of where specific peptidergic cell types lie, rather than based on double or triple immunochemical staining of distinct populations of cells. Here, we examine the full extent of the mouse SCN using cholera toxin β (CTβ) as a tracer to analyze RHT innervation in triple-labeled sagittal sections. Using specific peptidergic markers to identify clusters of SCN cells, we find 3 distinct patterns. First is an area of dense RHT innervation to the core region, delineated by gastrin-releasing peptide (GRP) and vasoactive intestinal peptide (VIP) immunoreactive cells. Second is an area of moderate RHT fiber clusters, bearing arginine-vasopressin (AVP)–positive cells that lie close to the core. Finally, the outermost, shell, and rostral AVP-containing regions of the SCN have few to no detectable retinal fibers. These results point to a diversity of inputs to individual SCN cell populations and suggest variation in the responses that underlie photic phase resetting.
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