Effects of chronic exposure to bisphenol A in adult female mice on social behavior, vasopressin system, and estrogen membrane receptor (GPER1).

Bisphenol A (BPA), an organic synthetic compound found in some plastics and epoxy resins, is classified as an endocrine disrupting chemical. Exposure to BPA is especially dangerous if it occurs during specific "critical periods" of life, when organisms are more sensitive to hormonal changes (i.e., intrauterine, perinatal, juvenile or puberty periods). In this study, we focused on the effects of chronic exposure to BPA in adult female mice starting during pregnancy. Three months old C57BL/6J females were orally exposed to BPA or to vehicle (corn oil). The treatment (4 µg/kg body weight/day) started the day 0 of pregnancy and continued throughout pregnancy, lactation, and lasted for a total of 20 weeks. BPA-treated dams did not show differences in body weight or food intake, but they showed an altered estrous cycle compared to the controls. In order to evidence alterations in social and sociosexual behaviors, we performed the Three-Chamber test for sociability, and analyzed two hypothalamic circuits (well-known targets of endocrine disruption) particularly involved in the control of social behavior: the vasopressin and the oxytocin systems. The test revealed some alterations in the displaying of social behavior: BPA-treated dams have higher locomotor activity compared to the control dams, probably a signal of high level of anxiety. In addition, BPA-treated dams spent more time interacting with no-tester females than with no-tester males. In brain sections, we observed a decrease of vasopressin immunoreactivity (only in the paraventricular and suprachiasmatic nuclei) of BPA-treated females, while we did not find any alteration of the oxytocin system. In parallel, we have also observed, in the same hypothalamic nuclei, a significant reduction of the membrane estrogen receptor GPER1 expression.

Defining circadian disruption in neurodegenerative disorders.

Neurodegenerative diseases encompass a large group of conditions that are clinically and pathologically diverse yet are linked by a shared pathology of misfolded proteins. The accumulation of insoluble aggregates is accompanied by a progressive loss of vulnerable neurons. For some patients, the symptoms are motor focused (ataxias), while others experience cognitive and psychiatric symptoms (dementias). Among the shared symptoms of neurodegenerative diseases is a disruption of the sleep/wake cycle that occurs early in the trajectory of the disease and may be a risk factor for disease development. In many cases, the disruption in the timing of sleep and other rhythmic physiological markers immediately raises the possibility of neurodegeneration-driven disruption of the circadian timing system. The aim of this Review is to summarize the evidence supporting the hypothesis that circadian disruption is a core symptom within neurodegenerative diseases, including Alzheimer's disease, Huntington's disease, and Parkinson's disease, and to discuss the latest progress in this field. The Review discusses evidence that neurodegenerative processes may disrupt the structure and function of the circadian system and describes circadian-based interventions as well as timed drug treatments that may improve a wide range of symptoms associated with neurodegenerative disorders. It also identifies key gaps in our knowledge.

Assessment of Arterial Configurations of the Suprachiasmatic Region from the Endoscopic Endonasal Perspective: A Cadaveric Anatomical Study.

BACKGROUND: Endoscopic endonasal surgery has proved to offer a practical route to treat suprasellar lesions, including tumors and vascular pathologies. Understanding the different configurations of the anterior cerebral communicating artery (ACoA) complex (ACoA-C) is crucial to properly navigate the suprachiasmatic space and decrease any vascular injury while approaching this region through an endonasal approach. METHODS: An endoscopic endonasal transplanum-transtubercular approach was performed on 36 cadaveric heads (72 sides). The variations of the ACoA-C and feasibility of reaching its different components were analyzed. The surgical area exposure of the lamina terminalis was also quantified before and after mobilization of the ACoA-C. RESULTS: The typical ACoA-C configuration was found in 41.6% of specimens. The following 2 main variations were identified: accessory anterior cerebral artery segment 2 (5, 13.9%) and common trunk of anterior cerebral artery with absence of ACoA (5, 13.9%). Of 101 recurrent arteries of Heubner, 96 (95.0%) were identified within 4 mm proximal or distal to the ACoA. The mean lamina terminalis exposure area was 33.1 ± 16.7 mm2, which increased to 59.9 ± 11.9 mm2 after elevating the ACoA. CONCLUSIONS: A considerable amount of variation of the ACoA-C can be found through an endoscopic endonasal transplanum-transtubercular approach. These configurations determine the feasibility of lamina terminalis exposure and the complexity of reaching the ACoA. Assessment of ACoA morphology and its adjacent structures is crucial while approaching the suprachiasmatic through a transnasal corridor.

Metabolic Profiling of Suprachiasmatic Nucleus Reveals Multifaceted Effects in an Alzheimer's Disease Mouse Model.

BACKGROUND: Circadian rhythm disturbance is commonly observed in Alzheimer's disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood. OBJECTIVE: To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors that couple SCN dysfunction with GABA modulation and inflammation. METHODS: High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1. RESULTS: Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock protein, Bmal1, especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type. CONCLUSION: Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD.

Testosterone works through androgen receptors to modulate neuronal response to anxiogenic stimuli.

Testosterone (T) exerts anxiolytic effects through functional androgen receptors (ARs) in rodents. T treatment of castrated mice reduces anxiety-like behavior in wild-type (WT) males, but not males with a spontaneous mutation that renders AR dysfunctional (testicular feminization mutation, Tfm). Using Cre-LoxP technology we created males carrying induced dysfunctional AR allele (induced TFM; iTfm) to determine the brain regions responsible for T-induced anxiolysis. Adult WT and iTfm mice were castrated and T treated. Castrated WTs given a blank capsule (WT + B) served as additional controls. Mice were later exposed to the anxiogenic light/dark box, sacrificed and their brains processed for immediate early gene cFos immunoreactivity. Analyses revealed that T treatment increased cFos-expressing neurons in the basolateral amygdala (blAMY) of WT males, but not in iTfm males, which did not differ from WT + B mice. In contrast, WT + T males displayed fewer cFos + cells than iTfm + T or WT + B groups in the suprachiasmatic nucleus of the hypothalamus (SCN). No effects of genotype or hormone were seen in cFos expression in the hippocampus, medial prefrontal cortex, paraventricular nucleus of the hypothalamus, oval and anterodorsal bed nucleus of the stria terminalis, or dorsal periaqueductal grey. AR immunohistochemistry indicated that ∼65 % of cells in the blAMY and SCN were AR + in WT males, so AR could act directly within neurons in these regions to modulate the animals' response to anxiogenic stimuli. Because absence of a functional AR did not affect cFos response to mild stress in the other brain regions, they are unlikely to mediate androgen's anxiolytic effects.

Circadian disruption, melatonin rhythm perturbations and their contributions to chaotic physiology.

The aim of this report is to summarize the data documenting the vital nature of well-regulated cellular and organismal circadian rhythms, which are also reflected in a stable melatonin cycle, in supporting optimal health. Cellular fluctuations in physiology exist in most cells of multicellular organisms with their stability relying on the prevailing light:dark cycle, since it regulates, via specialized intrinsically-photoreceptive retinal ganglion cells (ipRGC) and the retinohypothalamic tract, the master circadian oscillator, i.e., the suprachiasmatic nuclei (SCN). The output message of the SCN, as determined by the light:dark cycle, is transferred to peripheral oscillators, so-called slave cellular oscillators, directly via the autonomic nervous system with its limited distribution. and indirectly via the pineal-derived circulating melatonin rhythm, which contacts every cell. Via its regulatory effects on the neuroendocrine system, particularly the hypothalamo-pituitary-adrenal axis, the SCN also has a major influence on the adrenal glucocorticoid rhythm which impacts neurological diseases and psychological behaviors. Moreover, the SCN regulates the circadian production and secretion of melatonin. When the central circadian oscillator is disturbed, such as by light at night, it passes misinformation to all organs in the body. When this occurs the physiology of cells becomes altered and normal cellular functions are compromised. This physiological upheaval is a precursor to pathologies. The deterioration of the SCN/pineal network is often a normal consequence of aging and its related diseases, but in today's societies where manufactured light is becoming progressively more common worldwide, the associated pathologies may also be occurring at an earlier age.

Synaptic Specializations of Melanopsin-Retinal Ganglion Cells in Multiple Brain Regions Revealed by Genetic Label for Light and Electron Microscopy.

The form and synaptic fine structure of melanopsin-expressing retinal ganglion cells, also called intrinsically photosensitive retinal ganglion cells (ipRGCs), were determined using a new membrane-targeted version of a genetic probe for correlated light and electron microscopy (CLEM). ipRGCs project to multiple brain regions, and because the method labels the entire neuron, it was possible to analyze nerve terminals in multiple retinorecipient brain regions, including the suprachiasmatic nucleus (SCN), olivary pretectal nucleus (OPN), and subregions of the lateral geniculate. Although ipRGCs provide the only direct retinal input to the OPN and SCN, ipRGC terminal arbors and boutons were found to be remarkably different in each target region. A network of dendro-dendritic chemical synapses (DDCSs) was also revealed in the SCN, with ipRGC axon terminals preferentially synapsing on the DDCS-linked cells. The methods developed to enable this analysis should propel other CLEM studies of long-distance brain circuits at high resolution.

Investigating the Role of the Hypothalamus in Outcomes to Repetitive Mild Traumatic Brain Injury: Neonatal Monosodium Glutamate Does Not Exacerbate Deficits.

Repetitive mild traumatic brain injury (RmTBI) is a prevalent and costly head injury particularly among adolescents. These injuries may result in long-term consequences, especially during this critical period of development. Insomnia and sleeping difficulties are frequently reported following RmTBI and greatly impair recovery. We sought to develop an animal model of exacerbated deficits following RmTBI by disrupting the hypothalamic circadian system. To accomplish this, we conducted RmTBI on adolescent rats that had received neonatal injections of monosodium glutamate (MSG), a known hypothalamic neurotoxin. We then examined behavioral, circadian, and epigenetic changes. MSG treated rats showed lower anxiety-like behaviors and displayed poor short-term working memory. We also showed changes in the morphology of the circadian clock in the suprachiasmatic nucleus (SCN) vasoactive intestinal polypeptide (VIP) immunostaining. VIP optical density in the SCN increased with MSG but decreased with RmTBI. There were changes in the expression of the clock genes and upregulation of the orexin receptors in response to RmTBI. MSG treated rats had longer telomere lengths than controls. Finally, although both MSG and RmTBI alone produced attenuated circadian amplitudes of activity and body temperature, exacerbated deficits were not identified in animals that received MSG and RmTBI. In sum, both MSG and RmTBI can alter behavior, circadian rhythm amplitude, SCN morphology, and gene expression independently, but the effects do not appear to be additive. Specific damage in the hypothalamus and SCN should be considered when patients experience sleeping problems following RmTBI, as this may improve therapeutic strategies.

Diabetes Alters Diurnal Rhythm of Electroretinogram in db/db Mice.

Diabetic retinopathy (DR) is the most common complications of diabetes and a leading cause of blindness in the United States. The retinal neuronal changes precede the vascular dysfunction observed in DR. The electroretinogram (ERG) determines the electrical activity of retinal neural and non-neuronal cells. The retinal ERG amplitude is reduced gradually on the progression of DR to a more severe form. Circadian rhythms play an important role in the physiological function of the body. While ERG is known to exhibit a diurnal rhythm, it is not known whether a progressive increase in the duration of diabetes affects the physiological rhythm of retinal ERG. To study this, we determined the ERG rhythm of db/db mice, an animal model of type 2 diabetes at 2, 4, and 6 months of diabetes under a regular light-dark cycle and constant dark. Our studies demonstrate that the diurnal rhythm of ERG amplitude for retinal a-wave and b-wave was altered in diabetes. The implicit time was increased in db/db mice while the oscillatory potential was reduced. Moreover, there was a progressive decline in an intrinsic rhythm of ERG upon an increase in the duration of diabetes. In conclusion, our studies provide novel insights into the pathogenic mechanism of DR by showing an altered circadian rhythm of the ERG.

Degeneration of the Suprachiasmatic Nucleus in an Alzheimer's Disease Mouse Model Monitored by in vivo Magnetic Resonance Relaxation Measurements and Immunohistochemistry.

In Alzheimer's disease (AD), disturbances in the circadian rhythm and sleep-wake cycle are frequently observed. Both are controlled by the master clock: the suprachiasmatic nucleus (SCN), which was reported in postmortem studies of AD subjects to be compromised. However, the influence of age and gender on the biophysical integrity and subtle microstructural changes of SCN and mechanistic connections between SCN dysfunction and AD progression in vivo remain to be explored. In the present study, we utilized state-of-the-art in vivo magnetic resonance relaxation measurements in combination with immunohistochemistry to follow microstructural changes in SCN of the Tg2576 mouse model of AD. Longitudinal monitoring of in vivo T2 relaxation with age shows significant shortening of T2 values in the SCN of transgenic mice and more substantially in female transgenic than aged-matched controls. Multiexponential T2 analysis detected a unique long T2 component in SCN of transgenic mice which was absent in wild-type mice. Immunohistochemical examination revealed significantly elevated numbers of activated astrocytes and an increase in the astrocyte to neuron ratio in SCN of transgenic compared to wild-type mice. This increase was more substantial in female than in male transgenic mice. In addition, low GABA production in SCN of transgenic mice was detected. Our results offer a brief appraisal of SCN dysfunction in AD and demonstrate that inflammatory responses may be an underlying perpetrator for the changes in circadian rhythmicity and sleep disturbance in AD and could also be at the root of marked sex disparities observed in AD subjects.

A suprachiasmatic-independent circadian clock(s) in the habenula is affected by Per gene mutations and housing light conditions in mice.

For many years, the suprachiasmatic nucleus (SCN) was considered as the unique circadian pacemaker in the mammalian brain. Currently, it is known that other brain areas are able to oscillate in a circadian manner. However, many of them are dependent on, or synchronized by, the SCN. The Habenula (Hb), localized in the epithalamus, is a key nucleus for the regulation of monoamine activity (dopamine, serotonin) and presents circadian features; nonetheless, the clock properties of the Hb are not fully described. Here, we report, first, circadian expression of clock genes in the lateral habenula (LHb) under constant darkness (DD) condition in wild-type mice which is disturbed in double Per1-/--Per2Brdm1 clock-mutant mice. Second, using Per2::luciferase transgenic mice, we observed a self-sustained oscillatory ability (PER2::LUCIFERASE bioluminescence rhythmicity) in the rostral and caudal part of the Hb of arrhythmic SCN-ablated animals. Finally, in Per2::luciferase mice exposed to different lighting conditions (light-dark, constant darkness or constant light), the period or amplitude of PER2 oscillations, in both the rostral and caudal Hb, were similar. However, under DD condition or from SCN-lesioned mice, these two Hb regions were out of phase, suggesting an uncoupling of two putative Hb oscillators. Altogether, these results suggest that an autonomous clock in the rostral and caudal part of the Hb requires integrity of circadian genes to tick, and light information or SCN innervation to keep synchrony. The relevance of the Hb timing might reside in the regulation of circadian functions linked to motivational (reward) and emotional (mood) processes.

The day/night difference in the circadian clock's response to acute lipopolysaccharide and the rhythmic Stat3 expression in the rat suprachiasmatic nucleus.

The circadian clock in the suprachiasmatic nucleus (SCN) regulates daily rhythms in physiology and behaviour and is an important part of the mammalian homeostatic system. Previously, we have shown that systemic inflammatory stimulation with lipopolysaccharide (LPS) induced the daytime-dependent phosphorylation of STAT3 in the SCN. Here, we demonstrate the LPS-induced Stat3 mRNA expression in the SCN and show also the circadian rhythm in Stat3 expression in the SCN, with high levels during the day. Moreover, we examined the effects of LPS (1mg/kg), applied either during the day or the night, on the rhythm in locomotor activity of male Wistar rats. We observed that recovery of normal locomotor activity patterns took longer when the animals were injected during the night. The clock genes Per1, Per2 and Nr1d1, and phosphorylation of kinases ERK1/2 and GSK3ß are sensitive to external cues and function as the molecular entry for external signals into the circadian clockwork. We also studied the immediate changes in these clock genes expressions and the phosphorylation of ERK1/2 and GSK3ß in the suprachiasmatic nucleus in response to daytime or night-time inflammatory stimulation. We revealed mild and transient changes with respect to the controls. Our data stress the role of STAT3 in the circadian clock response to the LPS and provide further evidence of the interaction between the circadian clock and immune system.

A Histologic Study of the Circadian System in Parkinson Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy.

Importance: Circadian dysfunction may be associated with the symptoms and neurodegeneration in Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP), although the underlying neuroanatomical site of disruption and pathophysiological mechanisms are not fully understood. Objective: To perform a neuropathological analysis of disease-specific inclusions in the key structures of the circadian system in patients with PD, MSA, and PSP. Design, Setting, and Participants: This investigation was a brain bank case-control study assessing neuropathological inclusions in the suprachiasmatic nucleus (SCN) of the hypothalamus and pineal gland in healthy controls, PD (Lewy pathology), MSA (glial cytoplasmic inclusions), and PSP (tau inclusions). The study analyzed 12 healthy control, 28 PD, 11 MSA, and 21 PSP samples from consecutive brain donations (July 1, 2010, to June 30, 2016) to the Queen Square Brain Bank for Neurological Disorders and the Parkinson's UK Brain Bank, London, United Kingdom. Cases were excluded if neither SCN nor pineal tissue was available. Main Outcomes and Measures: Disease-specific neuropathological changes were graded using a standard semiquantitative scoring system (absent, mild, moderate, severe, or very severe) and compared between groups. Results: Because of limited tissue availability, the following total samples were examined in a semiquantitative histologic analysis: 5 SCNs and 7 pineal glands in the control group (6 male; median age at death, 83.8 years; interquartile range [IQR], 78.2-88.0 years), 13 SCNs and 17 pineal glands in the PD group (22 male; median age at death, 78.8 years; IQR, 75.5-83.8 years), 5 SCNs and 6 pineal glands in the MSA group (7 male; median age at death, 69.5 years; IQR, 61.6-77.7 years), and 5 SCNs and 19 pineal glands in the PSP group (13 male; median age at death, 74.3 years; IQR, 69.7-81.1 years). No neuropathological changes were found in either the SCN or pineal gland in healthy controls or MSA cases. Nine PD cases had Lewy pathology in the SCN, and only 2 PD cases had Lewy pathology in the pineal gland. All PSP cases showed inclusions in the SCN, but no PSP cases had pathology in the pineal gland. Conclusions and Relevance: Disease-related neuropathological changes were found in the SCN but not in the pineal gland in PD and PSP, while both structures were preserved in MSA, reflecting different pathophysiological mechanisms that may have important therapeutic implications.

Perinatal Programming of Circadian Clock-Stress Crosstalk.

An intact communication between circadian clocks and the stress system is important for maintaining physiological homeostasis under resting conditions and in response to external stimuli. There is accumulating evidence for a reciprocal interaction between both-from the systemic to the molecular level. Disruption of this interaction by external factors such as shiftwork, jetlag, or chronic stress increases the risk of developing metabolic, immune, or mood disorders. From experiments in rodents, we know that both systems maturate during the perinatal period. During that time, exogenous factors such as stress or alterations in the external photoperiod may critically affect-or program-physiological functions later in life. This developmental programming process has been attributed to maternal stress signals reaching the embryo, which lastingly change gene expression through the induction of epigenetic mechanisms. Despite the well-known function of the adult circadian system in temporal coordination of physiology and behavior, the role of maternal and embryonic circadian clocks during pregnancy and postnatal development is still poorly defined. A better understanding of the circadian-stress crosstalk at different periods of development may help to improve stress resistance and devise preventive and therapeutic strategies against chronic stress-associated disorders.

Effects of a free-choice high-fat high-sugar diet on brain PER2 and BMAL1 protein expression in mice.

The suprachiasmatic nucleus (SCN) times the daily rhythms of behavioral processes including feeding. Beyond the SCN, the hypothalamic arcuate nucleus (ARC), involved in feeding regulation and metabolism, and the epithalamic lateral habenula (LHb), implicated in reward processing, show circadian rhythmic activity. These brain oscillators are functionally coupled to coordinate the daily rhythm of food intake. In rats, a free choice high-fat high-sugar (fcHFHS) diet leads to a rapid increase of calorie intake and body weight gain. Interestingly, under a fcHFHS condition, rats ingest a similar amount of sugar during day time (rest phase) as during night time (active phase), but keep the rhythmic intake of regular chow-food. The out of phase between feeding patterns of regular (chow) and highly rewarding food (sugar) may involve alterations of brain circadian oscillators regulating feeding. Here, we report that the fcHFHS diet is a successful model to induce calorie intake, body weight gain and fat tissue accumulation in mice, extending its effectiveness as previously reported in rats. Moreover, we observed that whereas in the SCN the day-night difference in the PER2 clock protein expression was similar between chow-fed and fcHFHS-fed animals, in the LHb, this day-night difference was altered in fcHFHS-exposed animals compared to control chow mice. These findings confirm previous observations in rats showing disrupted daily patterns of feeding behavior under a fcHFHS diet exposure, and extend our insights on the effects of the diet on circadian gene expression in brain clocks.

Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus.

Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.

Disruption of normal circadian clock function in a mouse model of tauopathy.

Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to ß-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.

Suprachiasmatic Nucleus Interaction with the Arcuate Nucleus; Essential for Organizing Physiological Rhythms.

The suprachiasmatic nucleus (SCN) is generally considered the master clock, independently driving all circadian rhythms. We recently demonstrated the SCN receives metabolic and cardiovascular feedback adeptly altering its neuronal activity. In the present study, we show that microcuts effectively removing SCN-arcuate nucleus (ARC) interconnectivity in Wistar rats result in a loss of rhythmicity in locomotor activity, corticosterone levels, and body temperature in constant dark (DD) conditions. Elimination of these reciprocal connections did not affect SCN clock gene rhythmicity but did cause the ARC to desynchronize. Moreover, unilateral SCN lesions with contralateral retrochiasmatic microcuts resulted in identical arrhythmicity, proving that for the expression of physiological rhythms this reciprocal SCN-ARC interaction is essential. The unaltered SCN c-Fos expression following glucose administration in disconnected animals as compared to a significant decrease in controls demonstrates the importance of the ARC as metabolic modulator of SCN neuronal activity. Together, these results indicate that the SCN is more than an autonomous clock, and forms an essential component of a larger network controlling homeostasis. The present novel findings illustrate how an imbalance between SCN and ARC communication through circadian disruption could be involved in the etiology of metabolic disorders.

Physiological links of circadian clock and biological clock of aging.

Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.

Insulin-regulated aminopeptidase immunoreactivity is abundantly present in human hypothalamus and posterior pituitary gland, with reduced expression in paraventricular and suprachiasmatic neurons in chronic schizophrenia.

The vasopressin- and oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP) is expressed in various organs including the brain. However, knowledge about its presence in human hypothalamus is fragmentary. Functionally, for a number of reasons (genetic linkage, hydrolysis of oxytocin and vasopressin, its role as angiotensin IV receptor in learning and memory and others) IRAP might play a role in schizophrenia. We studied the regional and cellular localization of IRAP in normal human brain with special emphasis on the hypothalamus and determined numerical densities of IRAP-expressing cells in the paraventricular, supraoptic and suprachiasmatic nuclei in schizophrenia patients and controls. By using immunohistochemistry and Western blot analysis, IRAP was immunolocalized in postmortem human brains. Cell countings were performed to estimate numbers and numerical densities of IRAP immunoreactive hypothalamic neurons in schizophrenia patients and control cases. Shape, size and regional distribution of IRAP-expressing cells, as well the lack of co-localization with the glia marker glutamine synthetase, show that IRAP is expressed in neurons. IRAP immunoreactive cells were observed in the hippocampal formation, cerebral cortex, thalamus, amygdala and, abundantly, hypothalamus. Double labeling experiments (IRAP and oxytocin/neurophysin 1, IRAP with vasopressin/neurophysin 2) revealed that IRAP is present in oxytocinergic and in vasopressinergic neurons. In schizophrenia patients, the numerical density of IRAP-expressing neurons in the paraventricular and the suprachiasmatic nuclei is significantly reduced, which might be associated with the reduction in neurophysin-containing neurons in these nuclei in schizophrenia. The pathophysiological role of lowered hypothalamic IRAP expression in schizophrenia remains to be established.