Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure

Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2. © 2013 Falcon et al

Daily rhythms and sex differences in vasoactive intestinal polypeptide, VIPR2 receptor and arginine vasopressin mRNA in the suprachiasmatic nucleus of a diurnal rodent, Arvicanthis niloticus

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73328/1/j.1460-9568.2009.06936.x.pd

Day differences in the cortisol awakening response predict day differences in synaptic plasticity in the brain

The cortisol awakening response (CAR) is the most prominent, dynamic and variable part of the circadian pattern of cortisol secretion. Despite this its precise purpose is unknown. Aberrant patterns of the CAR are associated with impaired physical and mental health and reduced cognitive function, suggesting that it may have a pervasive role or roles. It has been suggested that the CAR primes the brain for the expected demands of the day but the mechanisms underlying this process are unknown. We examined temporal covariation of the CAR and rapid transcranial magnetic stimulation (rTMS)-induced long term depression (LTD)-like responses in the motor cortex. Plasticity was evaluated across 180 measures from 5 time points on 4 sessions across 9 researcher participants, mean age 25 ± 2.5 years. Plasticity estimates were obtained in the afternoon after measurement of the CAR on 4 days, at least 3 days apart. As both CAR magnitude and rTMS-induced responses are variable across days we hypothesised that days with larger than individual average CARs would be associated with a greater than individual average plasticity response. This was confirmed by mixed regression modelling where variation in the CAR predicted variation in rTMS-induced responses (Df: 1, 148.24; F: 10.41; p=0.002). As the magnitude of the CAR is regulated by the ‘master’ circadian CLOCK, and synaptic plasticity is known to be modulated by peripheral ‘slave’ CLOCK genes, we suggest that the CAR may be a mediator between the master and peripheral circadian systems to entrain daily levels of synaptic plasticity

Meta‐Analysis of Genetic Influences on Initial Alcohol Sensitivity

BackgroundPrevious studies indicate that low initial sensitivity to alcohol may be a risk factor for later alcohol misuse. Evidence suggests that initial sensitivity is influenced by genetic factors, but few molecular genetic studies have been reported.MethodsWe conducted a meta-analysis of 2 population-based genome-wide association studies of the Self-Rating of the Effects of Alcohol scale. Our final sample consisted of 7,339 individuals (82.3% of European descent; 59.2% female) who reported having used alcohol at least 5 times. In addition, we estimated single nucleotide polymorphism (SNP)-based heritability and conducted a series of secondary aggregate genetic analyses.ResultsNo individual locus reached genome-wide significance. Gene and set based analyses, both overall and using tissue-specific expression data, yielded largely null results, and genes previously implicated in alcohol problems and consumption were overall not associated with initial sensitivity. Only 1 gene set, related to hormone signaling and including core clock genes, survived correction for multiple testing. A meta-analysis of SNP-based heritability resulted in a modest estimate of hSNP2  = 0.19 (SE = 0.10), though this was driven by 1 sample (N = 3,683, hSNP2  = 0.36, SE = 0.14, p = 0.04). No significant genetic correlations with other relevant outcomes were observed.ConclusionsFindings yielded only modest support for a genetic component underlying initial alcohol sensitivity. Results suggest that its biological underpinnings may diverge somewhat from that of other alcohol outcomes and may be related to core clock genes or other aspects of hormone signaling. Larger samples, ideally of prospectively assessed samples, are likely necessary to improve gene identification efforts and confirm the current findings

Control of the daily melatonin rhythm: a model of time distribution by the biological clock mediated through the autonomic nervous system

Chez les Mammifères, les rythmes circadiens, présentant une rythmicité endogène proche de 24h sont sous le contrôle d’une horloge interne située dans les Noyaux Suprachiasmatiques de l’hypothalamus (NSC). Afin de mieux comprendre la distribution du message temps par les NSC, nous avons étudié spécifiquement le contrôle du rythme journalier de sécrétion de mélatonine, hormone sécrétée de nuit par la glande pinéale partant du postulat selon lequel les NSC contrôleraient ce rythme en utilisant, pendant la journée, un signal inhibiteur de nature GABAergique pour inhiber la voie polysynaptique reliant les Noyaux paraventriculaires de l’hypothalamus (PVN) à la glande pinéale. Nos premiers travaux ont révélé, par lésions thermiques des différents noyaux intéressés, un rôle de simple relais de l’information pour les PVN, ainsi qu’une action inhibitrice des NSC sur la synthèse de mélatonine de jour associée à une action stimulatrice nocturne. A l’aide de la technique de microdialyse intracérébrale multiple, nous avons ensuite pu confirmer, in vivo, que l’activité neuronale nocturne des NSC était cruciale pour une stimulation nocturne de synthèse de mélatonine. De plus, un rôle important du neurotransmetteur glutamate a pu être montré pour cette action stimulatrice. Nous avons également montré que la chute de sécrétion de mélatonine en fin de nuit était due à une augmentation de sécrétion GABAergique par les NSC associée soit à la disparition du signal stimulateur soit à l’apparition d’un second signal inhibiteur. Par ailleurs, en corrélant l’expression neuronale des gènes de l’horloge Per1 et Per2 et la sécrétion de vasopressine par les NSC, nous avons révélé une régionalisation fonctionnelle des NSC. Ensemble, les résultats de cette thèse ont permis de réactualiser le concept du contrôle du rythme journalier de mélatonine par l’horloge biologique, exemple de moyen de distribution du message temps au reste de l’organisme via le système nerveux autonome.In mammals, circadian rhythms, i.e. showing an endogenous rhythmicity close to 24h are under the control of a master biological clock, located in the suprachiasmatic nucleus of the hypothalamus (SCN). In order to further understand the mechanisms of time distribution by the SCN, we specifically studied the control of the daily secretion of melatonin, hormone strictly produced at night by the pineal gland, with the initial hypothesis that the SCN controls the daily rhythm of melatonin synthesis by imposing during daytime an inhibitory signal of GABAergic nature onto the polysynaptic pathway connecting the Paraventricular Nucleus of the hypothalamus (PVN) to the pineal gland. By lesioning or removing it was necessary regarding the literature to first realise a comparison of the role of each of the different nuclei involved in this pathway, Iour first study revealed a simple role of information-relay for the PVN, as well as a combined inhibitory and stimulatory role for the SCN during the day and the night respectively. Using the multiple intracerebral microdialysis technique, we were then able to confirm in vivo that the SCN nocturnal activity is crucial for a nocturnal stimulation of melatonin synthesis and we showed as well that glutamatergic transmission is responsible for such a stimulatory action onto the melatonin synthesis. In addition, we revealed that the early morning drop of melatonin synthesis is due to the association of an increased GABAergic secretion derived by the SCN and either the disappearance of the stimularory signal or the appearance of a second inhibitory signal. Furthermore, correlating the neuronal expression of the clock genes Per1 and Per2 and the SCN vasopressin secretion, we revealed a clear functional compartmentalisation of the SCN. Together these results helped re-actualising the concept of the control of the daily rhythm of melatonin synthesis by the biological clock, which is a great example of time distribution to the rest of the organism via the autonomic nervous system

A network of (autonomic) clock outputs.

The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock that produces a coherent output capable of timing all the different daily changes in behavior and physiology. We investigated which anatomical connections and neurotransmitters are used by the biological clock to control the daily release pattern of a number of hormones. The picture that emerged shows projections contacting target neurons in the medial hypothalamus surrounding the SCN. The activity of these pre-autonomic and neuro-endocrine target neurons is controlled by differentially timed waves of vasopressin, GABA, and glutamate release from SCN terminals, among other factors. Together our data indicate that, with regard to the timing of their main release period within the LD cycle, at least four subpopulations of SCN neurons should be discernible. The different subgroups do not necessarily follow the phenotypic differences among SCN neurons. Thus, different subgroups can be found within neuron populations containing the same neurotransmitter. Remarkably, a similar distinction of four differentially timed subpopulations of SCN neurons was recently also discovered in experiments determining the temporal patterns of rhythmicity in individual SCN neurons by way of the electrophysiology or clock gene expression. Moreover, the specialization of the SCN may go as far as a single body structure, i.e., the SCN seems to contain neurons that specifically target the liver, pineal gland, and adrenal gland.

A network of (autonomic) clock outputs.

The circadian clock in the suprachiasmatic nuclei (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. A major question is still how these individual oscillators are organized into a biological clock that produces a coherent output capable of timing all the different daily changes in behavior and physiology. We investigated which anatomical connections and neurotransmitters are used by the biological clock to control the daily release pattern of a number of hormones. The picture that emerged shows projections contacting target neurons in the medial hypothalamus surrounding the SCN. The activity of these pre-autonomic and neuro-endocrine target neurons is controlled by differentially timed waves of vasopressin, GABA, and glutamate release from SCN terminals, among other factors. Together our data indicate that, with regard to the timing of their main release period within the LD cycle, at least four subpopulations of SCN neurons should be discernible. The different subgroups do not necessarily follow the phenotypic differences among SCN neurons. Thus, different subgroups can be found within neuron populations containing the same neurotransmitter. Remarkably, a similar distinction of four differentially timed subpopulations of SCN neurons was recently also discovered in experiments determining the temporal patterns of rhythmicity in individual SCN neurons by way of the electrophysiology or clock gene expression. Moreover, the specialization of the SCN may go as far as a single body structure, i.e., the SCN seems to contain neurons that specifically target the liver, pineal gland, and adrenal gland

Glutamatergic clock output stimulates melatonin synthesis at night

The rhythm of melatonin synthesis in the rat pineal gland is under the control of the biological clock, which is located in the suprachiasmatic nucleus of the hypothalamus (SCN). Previous studies demonstrated a daytime inhibitory influence of the SCN on melatonin synthesis, by using gamma-aminobutyric acid input to the paraventricular nucleus of the hypothalamus (PVN). Nevertheless, a recent lesion study suggested the presence of a stimulatory clock output in the control of the melatonin rhythm as well. In order to further investigate this output in acute in vivo conditions, we first measured the release of melatonin in the pineal gland before, during and after a temporary shutdown of either SCN or PVN neuronal activity, using multiple microdialysis. For both targets, SCN and PVN, the application of tetrodotoxin by reverse dialysis in the middle of the night decreased melatonin levels. Due to recent evidence of the existence of glutamatergic clock output, we then studied the effect on melatonin release of glutamate antagonist application within the PVN in the middle of the night. Blockade of the glutamatergic input to the PVN significantly decreased melatonin release. These results demonstrate that (i) neuronal activity of both PVN and SCN is necessary to stimulate melatonin synthesis during the dark period and (ii) glutamatergic signalling within the PVN plays an important role in melatonin synthesi