Reward‐related ventral striatum reactivity mediates gender‐specific effects of a galanin remote enhancer haplotype on problem drinking

The neuropeptide galanin has been implicated in the regulation of appetitive and consummatory behaviors. Prior studies have shown that direct injection of galanin into the hypothalamus results in increased release of dopamine (DA) in the nucleus accumbens (NAcc), and parallel increases in food and alcohol consumption. These studies are consistent with a role of hypothalamic galanin in regulating reward system reactivity. In humans, a common functional haplotype (GAL5.1) within a remote enhancer region upstream of the galanin gene (GAL) affects promoter activity and galanin expression in hypothalamic neurons in vitro. Given the effects of hypothalamic galanin on NAcc DA release and the effects of the GAL5.1 haplotype on GAL expression, we examined the impact of this functional genetic variation on human reward‐related ventral striatum (VS) reactivity. Using an imaging genetics strategy in Caucasian individuals (N = 138, 72 women) participating in the ongoing Duke Neurogenetics Study, we report a significant gender‐by‐genotype interaction (right hemisphere: F_1,134 = 8.08, P = 0.005; left hemisphere: F_1,134 = 5.39, P = 0.022), such that homozygosity for the GG haplotype, which predicts greater GAL expression, is associated with relatively increased VS reactivity in women (n = 50, right hemisphere: P = 0.015; left hemisphere: P = 0.060), but not in men (N = 49, P‐values > 0.10). Furthermore, these differences in VS reactivity correlated positively with differences in alcohol use, such that VS reactivity mediated a gender‐specific association between GAL5.1 haplotype and problem drinking. Our current results support those in animal models implicating galanin signaling in neural pathways associated with appetitive and consummatory behaviors of relevance for understanding risk for substance use and abuse.     

Programmed nuclear destruction in yeast

Studies of the budding yeast Saccharomyces cerevisiae have provided many of the most important insights into the mechanisms of autophagy, which are common to all eukaryotes. However, investigation of yeast self-destruction pathways, including autophagy and programmed cell death, has been almost exclusively restricted to cells undergoing vegetative growth, leaving very little exploration of their functions during developmental transitions in the yeast life cycle. We have recently discovered that whole nuclei are subject to programmed destruction during yeast gametogenesis. Programmed nuclear destruction (PND) possesses characteristics of apoptosis in the form of DNA cleavage by endonuclease G, and involves bulk protein turnover through an unusual autophagic pathway involving lysis of the vacuole rather than delivery of components to it through macroautophagy. We thus illuminate an example of developmentally programmed cellular “self-eating” in yeast, which is associated with the rupture of a lytic organelle, reminiscent of programmed cell death mechanisms in plants and animals.     

成年雄性斑胸草雀前脑与中脑对习得性发声控制的侧别差异

成年雄性鸣禽的习得性发声信号——长鸣(long call)和鸣唱(song)是由前脑高级发声中枢启动,以及由前脑最后一级输出核团弓状皮质栎核(robust nucleus of the arcopallium,RA)整合输出.RA投射神经元与位于中脑的基本发声中枢丘间复合体背内侧核(dorsomedial nucleus of the intercollicular,DM)形成突触连接.该文采用电损毁与声谱分析相结合的方法,通过依次损毁成年雄性斑胸草雀(Taeniopygia guttata)单侧RA和DM核团,探讨了前脑和中脑对习得性发声的影响.结果提示,RA核团与DM核团共同参与了对雄性斑胸草雀习得性声音的调控,而且这种控制具有右侧优势.     

THE HUMAN CIRCADIAN CLOCK AND AGING

The suprachiasmatic nucleus (SCN) of the hypothalamus is implicatedin the timing of a wide variety of circadian processes. Since the environmentallight-dark cycle is the main zeitgeber for many of the rhythms, photic informationmay have a synchronizing effect on the endogenous clock of the SCN by inducingperiodic changes in the biological activity of certain groups of neurons.By studying the brains obtained at autopsy of human subjects, marked diurnaloscillations were observed in the neuropeptide content of the SCN. Vasopressin,for example, one of the most abundant peptides in the human SCN, exhibiteda diurnal rhythm, with low values at night and peak values during the earlymorning. However, with advancing age, these diurnal fluctuations deteriorated,leading to a disrupted cycle with a reduced amplitude in elderly people. Thesefindings suggest that the synthesis of some peptides in the human SCN exhibitsan endogenous circadian rhythmicity, and that the temporal organization ofthese rhythms becomes progressively disturbed in senescence. (ChronobiologyInternational, 17(3), 245–259, 2000)     

Modulation of mammalian circadian rhythms by tumor necrosis factor-α

Systemic low doses of the endotoxin lipopolysaccharide (LPS, 100?µg/kg) administered during the early night induce phase-delays of locomotor activity rhythms in mice. Our aim was to evaluate the role of tumor necrosis factor (Tnf)-alpha and its receptor 1/p55 (Tnfr1) in the modulation of LPS-induced circadian effects on the suprachiasmatic nucleus (SCN). We observed that Tnfr1-defective mice (Tnfr1 KO), although exhibiting similar circadian behavior and light response to that of control mice, did not show LPS-induced phase-delays of locomotor activity rhythms, nor LPS-induced cFos and Per2 expression in the SCN and Per1 expression in the paraventricular hypothalamic nucleus (PVN) as compared to wild-type (WT) mice. We also analyzed Tnfr1 expression in the SCN of WT mice, peaking during the early night, when LPS has a circadian effect. Peripheral inoculation of LPS induced an increase in cytokine/chemokine levels (Tnf, Il-6 and Ccl2) in the SCN and in the PVN. In conclusion, in this study, we show that LPS-induced circadian responses are mediated by Tnf. Our results also suggest that this cytokine stimulates the SCN after LPS peripheral inoculation; and the time-related effect of LPS (i.e. phase shifts elicited only at early night) might depend on the increased levels of Tnfr1 expression. We also confirmed that LPS modulates clock gene expression in the SCN and PVN in WT but not in Tnfr1 KO mice.

Highlights: We demonstrate a fundamental role for Tnf and its receptor in circadian modulation by immune stimuli at the level of the SCN biological clock.     

Functional changes of the SCN in spontaneous hypertension but not after the induction of hypertension

ABSTRACT

The present study investigates the circadian behavior of spontaneously hypertensive rats (SHRs) during the pre-hypertensive and hypertensive stage, with the aim to gain insight into whether observed changes in the functionality of suprachiasmatic nucleus (SCN) in the hypertensive state are cause or consequence of hypertension. Four types of animals were used in this study: (1) SHRs which develop hypertension genetically; (2) their normotensive controls, Wistar Kyoto rats (WKYs); (3) Wistar rats whereby hypertension was surgically induced (2 Kidney 1 Clamp (2K1C) method); and (4) sham-operated control Wistar rats. Period length and activity levels and amplitude changes of locomotor and wheel running activity were determined, in constant conditions, as a measure of the functionality of the SCN. Hereto two conditions were used, constant darkness (0 lux) and constant dim (5 lux) light. SHRs showed a shortened period of their locomotor and running wheel activity rhythms in constant darkness during both pre-hypertensive and hypertensive stages and exhibited period lengthening in constant dim light conditions, only during hypertensive stages. Total amount as well as the amplitude of daily running wheel rhythms showed an inverse correlation with the period length, and this relation was significantly different in SHRs compared to WKYs. None of the aforementioned changes in circadian rhythms were observed after the surgical induction of hypertension. The present findings suggest early functional changes of the SCN in the etiology of spontaneous hypertension.     

Organotypic Suprachiasmatic Nuclei Cultures of Adult Voles Reflect Locomotor Behavior: Differences in Number of Vasopressin Cells

This study is the first to demonstrate organotypic culturing of adult suprachiasmatic nuclei (SCN). This approach was used to obtain organotypic SCN cultures from adult vole brain with a previously determined state of behavioral circadian rhythmicity. We examined vasopressin (AVP) immunoreactivity in these organotypic slice cultures. AVP is one of the major neuropeptides produced by the SCN, the main mammalian circadian pacemaker. AVP immunoreactivity in the SCN of adult common voles in vivo has been shown to correlate with the variability in expression of circadian wheel-running behavior. Here, cultures prepared from circadian rhythmic and nonrhythmic voles were processed immunocytochemically for AVP. Whereas in all cultures AVP could be observed, AVP immunoreactivity differed considerably between vole SCN cultures. SCN cultures from rhythmic voles contained significantly lower numbers of AVP immunoreactive (AVPir) cells per surface area than cultures from nonrhythmic voles. The correlation between timing of behavior and AVP immunoreactivity in vitro is similar to the correlation found earlier in vivo. Apparently, such correlation depends on intrinsic AVP regulation mechanisms of SCN tissue, and not on neural or hormonal input from the environment, as present in intact brain.     

Selective Labeling of [3H]2-Deoxy-d-Glucose in the Snake Trigeminal System: Basal and Infrared-Stimulated Conditions

[³H]2-Deoxy-d-glucose (2-DG) and high-resolution autoradiography were employed to investigate labeling patterns of the trigeminal and infrared sensory system in acrotaline snake, the pit viper (Trimeresurus flavoviridis). Following intracardiac injection of 9.25 MBq [³H]2-DG, neurons in the nucleus of the lateral descending trigeminal tract (LTTD), nucleus reticularis caloris (RC), nucleus trigemini mesencephalicus, nucleus trigemini motorius, and trigeminal ganglia were labeled in various degrees after the pit organ had been removed (basal condition). This revealed that a higher rate of glucose utilization occurred in these nuclei than in the common sensory trigeminal nuclei, which lacked labeling entirely. When a pit was stimulated periodically with an infrared stimulus for 45 min, the difference in percentage of labeled cells was ipsilaterally increased by 12.84% in large cells of the LITD and by 7.55% in the RC, as compared with the contralateral, basal-condition side. These slight changes indicate a small increase of glucose consumption during infrared reception. On the other hand, the small cells in the LTTD showed labeling that did not change with stimulation, suggesting that 2-DG uptake in inhibitory interneurons is relatively constant.     

Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca2+ in neurons

Two glutamate receptors, metabotropic glutamate receptor 5 (mGluR5), and ionotropic NMDA receptors (NMDAR), functionally interact with each other to regulate excitatory synaptic transmission in the mammalian brain. In exploring molecular mechanisms underlying their interactions, we found that Ca²⁺/calmodulin‐dependent protein kinase IIα (CaMKIIα) may play a central role. The synapse‐enriched CaMKIIα directly binds to the proximal region of intracellular C terminal tails of mGluR5 in vitro. This binding is state‐dependent: inactive CaMKIIα binds to mGluR5 at a high level whereas the active form of the kinase (following Ca²⁺/calmodulin binding and activation) loses its affinity for the receptor. Ca²⁺ also promotes calmodulin to bind to mGluR5 at a region overlapping with the CaMKIIα‐binding site, resulting in a competitive inhibition of CaMKIIα binding to mGluR5. In rat striatal neurons, inactive CaMKIIα constitutively binds to mGluR5. Activation of mGluR5 Ca²⁺‐dependently dissociates CaMKIIα from the receptor and simultaneously promotes CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα‐sensitive site. Together, the long intracellular C‐terminal tail of mGluR5 seems to serve as a scaffolding domain to recruit and store CaMKIIα within synapses. The mGluR5‐dependent Ca²⁺ transients differentially regulate CaMKIIα interactions with mGluR5 and GluN2B in striatal neurons, which may contribute to cross‐talk between the two receptors.