Effect of Flavonoids in Scutellariae Radix on Depression-Like Behavior and Brain Rewards: Possible in Dopamine System

A series of animal models are used to investigate the anti-depression mechanism of flavonoids in scutellariae radix (SR) in vivo. Depression-like behavior in mice was studied after intraperitoneal administration of SR. The results showed that SR administered to mice by the intraperitoneal route obviously shortened the duration in the tail suspension test and the forced swimming test, aggravated the symptoms of eyelid ptosis, akinesia, and mortality caused by reserpine, prolonged climbing times, affected the conditioned place preference, and increased sugar consumption in mice. However the SR did not affect the head twitches induced by 5-HTP, locomotor activity in mice, the toxicity of yohimbine, and the body temperature decrease caused by high dosage of apomorphine. The tests show that SR has some anti-depression effect related to the dopamine system. Furthermore another anti-depression mechanism was possible that could affect the mechanism of brain reward, bring positive reinforcement, and increase the sensitivity to euphoria in mice.     

The expression of morphine-induced behavioral sensitization depends more on treatment regimen and environmental novelty than on conditioned drug effects

Both conditioned responses (CRs) and sensitized behaviors induced by addictive drugs are considered to reflect drug-seeking motivation. Based on an excitatory conditioning model of behavioral sensitization, this work hypothesizes that conditioned locomotor activity and locomotor sensitization concomitantly occur using different drug treatment regimens. In the present study, conditioned locomotor activity and sensitized locomotion and stereotypy are assessed with pretreatment of two doses of morphine in a familiar or novel environment. When rats are trained with morphine (3 or 5 mg/kg) in an environment to which the animals are habituated, a CR but not contextual sensitization is induced when tested after 1 week of abstinence. When rats receive the 5 mg/kg dose of morphine immediately after placement into a novel environment, the same results are obtained, but when the drug dose is decreased to 3 mg/kg, both the CR and contextual sensitization are observed. Therefore, the sensitized behaviors, rather than the CR produced by morphine pretreatment, appear to be dependent on the drug treatment regimen and environmental novelty, suggesting that different mechanisms may be involved in the expression of the CR and contextual sensitization.     

Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence

Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness. In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicates that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta-arrestins. Using a knockout mouse lacking beta-arrestin-2 (beta arr2-/-), we have assessed the contribution of desensitization of the mu-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.     

Dopamine responses comply with basic assumptions of formal learning theory.

According to contemporary learning theories, the discrepancy, or error, between the actual and predicted reward determines whether learning occurs when a stimulus is paired with a reward. The role of prediction errors is directly demonstrated by the observation that learning is blocked when the stimulus is paired with a fully predicted reward. By using this blocking procedure, we show that the responses of dopamine neurons to conditioned stimuli was governed differentially by the occurrence of reward prediction errors rather than stimulus-reward associations alone, as was the learning of behavioural reactions. Both behavioural and neuronal learning occurred predominantly when dopamine neurons registered a reward prediction error at the time of the reward. Our data indicate that the use of analytical tests derived from formal behavioural learning theory provides a powerful approach for studying the role of single neurons in learning.     

Orientation-specific cortical responses develop in early infancy

Neurones in the visual cortex of higher mammals differ from those elsewhere in the visual pathway in that the majority respond selectively to particular edge or bar orientations in the stimulus. We have developed a visually evoked potential (VEP) technique which isolates the response of orientation-selective mechanisms from that of cortical or sub-cortical neurones which lack orientation selectivity. We are unable to find such orientation-selective responses in newborn human infants within the sensitivity of our method, but repeated longitudinal testing of individual infants shows that measurable responses emerge around 6 weeks of age. This result is consistent with the idea that human cortical visual function is very immature at birth, but develops rapidly in the first two postnatal months.     

海流对潜标系统影响的现场测试

潜标系统作为海洋观测的重要载体,具有其它载体所不具备的优点。一般潜标系统所载测试设备都为高灵敏精密仪器,要求潜标载体自身的振动强度不能过高。海流作用下潜标系统不可避免地会产生动力响应,当响应强度过大时会影响测试设备的正常工作。主要针对某潜标系统在海流作用下动力响应问题,设计并进行海上现场振动测试,探明了潜标体与其系留缆绳间的振动传递特性。     

Distinct functions of the two isoforms of dopamine D2 receptors

Signalling through dopamine D2 receptors governs physiological functions related to locomotion, hormone production and drug abuse. D2 receptors are also known targets of antipsychotic drugs that are used to treat neuropsychiatric disorders such as schizophrenia. By a mechanism of alternative splicing, the D2 receptor gene encodes two molecularly distinct isoforms, D2S and D2L, previously thought to have the same function. Here we show that these receptors have distinct functions in vivo; D2L acts mainly at postsynaptic sites and D2S serves presynaptic autoreceptor functions. The cataleptic effects of the widely used antipsychotic haloperidol are absent in D2L-deficient mice. This suggests that D2L is targeted by haloperidol, with implications for treatment of neuropsychiatric disorders. The absence of D2L reveals that D2S inhibits D1 receptor-mediated functions, uncovering a circuit of signalling interference between dopamine receptors.     

Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation

The RGS proteins are GTPase activating proteins that accelerate the deactivation of G proteins in a variety of signalling pathways in eukaryotes. RGS9 deactivates the G proteins (transducins) in the rod and cone phototransduction cascades. It is anchored to photoreceptor membranes by the transmembrane protein R9AP (RGS9 anchor protein), which enhances RGS9 activity up to 70-fold. If RGS9 is absent or unable to interact with R9AP, there is a substantial delay in the recovery from light responses in mice. We identified five unrelated patients with recessive mutations in the genes encoding either RGS9 or R9AP who reported difficulty adapting to sudden changes in luminance levels mediated by cones. Standard visual acuity was normal to moderately subnormal, but the ability to see moving objects, especially with low-contrast, was severely reduced despite full visual fields; we have termed this condition bradyopsia. To our knowledge, these patients represent the first identified humans with a phenotype associated with reduced RGS activity in any organ.     

Amygdala intercalated neurons are required for expression of fear extinction

Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders. In mammals, repeated presentations of a conditioned stimulus that was previously paired to a noxious stimulus leads to the gradual disappearance of conditioned fear responses. Although much evidence suggests that this extinction process depends on plastic events in the amygdala, the underlying mechanisms remain unclear. Intercalated (ITC) amygdala neurons constitute probable mediators of extinction because they receive information about the conditioned stimulus from the basolateral amygdala (BLA), and contribute inhibitory projections to the central nucleus (CEA), the main output station of the amygdala for conditioned fear responses. Thus, after extinction training, ITC cells could reduce the impact of conditioned-stimulus-related BLA inputs to the CEA by means of feed-forward inhibition. Here we test the hypothesis that ITC neurons mediate extinction by lesioning them with a toxin that selectively targets cells expressing micro-opioid receptors (microORs). Electron microscopic observations revealed that the incidence of microOR-immunoreactive synapses is much higher in ITC cell clusters than in the BLA or CEA and that microORs typically have a post-synaptic location in ITC cells. In keeping with this, bilateral infusions of the microOR agonist dermorphin conjugated to the toxin saporin in the vicinity of ITC neurons caused a 34% reduction in the number of ITC cells but no significant cell loss in surrounding nuclei. Moreover, ITC lesions caused a marked deficit in the expression of extinction that correlated negatively with the number of surviving ITC neurons but not CEA cells. Because ITC cells exhibit an unusual pattern of receptor expression, these findings open new avenues for the treatment of anxiety disorders.     

Adult hippocampal neurogenesis buffers stress responses and depressive behaviour

Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.     

Evolutionary genetics: evolution of mate choice in the wild

Qvarnstr?m et al. test whether the preference of female collared flycatchers (Ficedula albicollis) for males with large forehead patches could have evolved as a by-product of selection acting on male patch size. They find that the crucial genetic correlation between female choice and male patch size is not significant, and conclude that preference for large patches must have been shaped directly by selection. However, their use of the patch size of a female's social partner as a measure of choice is incomplete, and will result in low estimates of the potential for direct selection to shape female preference. Their study is therefore unable to resolve the question of how female preference for large forehead patches has evolved.     

Control of visual cortical signals by prefrontal dopamine

The prefrontal cortex is thought to modulate sensory signals in posterior cortices during top-down attention, but little is known about the underlying neural circuitry. Experimental and clinical evidence indicate that prefrontal dopamine has an important role in cognitive functions, acting predominantly through D1 receptors. Here we show that dopamine D1 receptors mediate prefrontal control of signals in the visual cortex of macaques (Macaca mulatta). We pharmacologically altered D1-receptor-mediated activity in the frontal eye field of the prefrontal cortex and measured the effect on the responses of neurons in area V4 of the visual cortex. This manipulation was sufficient to enhance the magnitude, the orientation selectivity and the reliability of V4 visual responses to an extent comparable with the known effects of top-down attention. The enhancement of V4 signals was restricted to neurons with response fields overlapping the part of visual space affected by the D1 receptor manipulation. Altering either D1- or D2-receptor-mediated frontal eye field activity increased saccadic target selection but the D2 receptor manipulation did not enhance V4 signals. Our results identify a role for D1 receptors in mediating the control of visual cortical signals by the prefrontal cortex and suggest how processing in sensory areas could be altered in mental disorders involving prefrontal dopamine.     

两个封闭群昆明小鼠行为学差异和试验方法信度分析

摘要: 目的 探讨两个封闭群昆明小鼠的行为学差异并评估行为学试验方法检测昆明小鼠行为的可信度。方法 应用小鼠行为学试验检测两个不同封闭群昆明小鼠的行为差异并做试验方法的复测信度检验。两个封闭群昆明 小鼠各取 20 只雄性小鼠分别记为 A 组、B 组,两组小鼠经过适应性饲养 3 d 后进行首次试验,记录体质量( 之后每 天记录体质量并绘制体质量增长趋势图) ,做衣架试验、网屏试验、蔗糖偏嗜度试验、旷场试验和强迫游泳试验等。 相隔 7d 进行复测试验。用 SPSS17. 0 软件处理数据并检验各行为学方法的复测信度。结果 行为学差异检测中 A 组、B 组首测昆明小鼠体质量、蔗糖偏嗜度、旷场试验水平运动、总分、网屏试验各项结果差异具有统计学意义( P ＜ 0. 05) ; 复测试验中体质量、蔗糖偏嗜度、网屏试验差异具有统计学意义( P ＜ 0. 05) ; 复测信度试验中粪便颗粒试验 为不可信( 信度系数为负值) ,衣架试验和旷场试验中垂直运动记分可信度较差,其它试验相关性均为可信( 体质量 为高度可信) 。结论 A、B 两组封闭群昆明小鼠体质量增长速度、蔗糖偏嗜度和网屏试验存在差异; 行为学检测方 法中信度评级为体质量 ＞ 强迫游泳 ＞ 蔗糖偏嗜度 ＞ 水平运动 ＞ 总分 ＞ 网屏试验 ＞ 衣架试验 ＞ 垂直运动。     

Opioids block long-term potentiation of inhibitory synapses

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.     

Rewarding effects of opiates are absent in mice lacking the receptor for substance P

Modulation of substance P activity offers a radical new approach to the management of depression, anxiety and stress. The substance P receptor is highly expressed in areas of the brain that are implicated in these behaviours, but also in other areas such as the nucleus accumbens which mediate the motivational properties of both natural rewards such as food and of drugs of abuse such as opiates. Here we show a loss of the rewarding properties of morphine in mice with a genetic disruption of the substance P receptor. The loss was specific to morphine, as both groups of mice responded when cocaine or food were used as rewards. The physical response to opiate withdrawal was also reduced in substance P receptor knockout mice. We conclude that substance P has an important and specific role in mediating the motivational aspects of opiates and may represent a new pharmacological route for the control of drug abuse.     

Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning

Pavlovian conditioning results when an innocuous stimulus, such as an odour, is paired with a behaviourally relevant stimulus, such as a foot-shock, so that eventually the former stimulus alone will elicit the behavioural response of the latter. The lateral nucleus of the amygdala (LAT) is necessary for the emotional memory formation in this paradigm. Enhanced neuronal firing in LAT to conditioned stimuli emerge in parallel with the behavioural changes and are dependent on local dopamine. To study the changes in neuronal excitability and synaptic drive that contribute to the pavlovian conditioning process, here we used in vivo intracellular recordings to examine LAT neurons during pavlovian conditioning in rats. We found that repeated pairings of an odour with a foot-shock resulted in enhanced post-synaptic potential (PSP) responses to the odour and increased neuronal excitability. However, a non-paired odour displayed PSP decrement. The dopamine antagonist haloperidol blocked the PSP enhancement and associated increased neuronal excitability, without reversing previous conditioning. These results demonstrate that conditioning and habituation processes produce opposite effects on LAT neurons and that dopamine is important in these events, consistent with its role in emotional memory formation.     

SKF83959调节大鼠的自发活动和焦虑行为

为了探讨多巴胺D1类受体激动剂SKF83959在动物自发活动、焦虑情绪和学习记忆方面的作用,将3月龄雄性大鼠随机分为给药组和空白对照组,分别腹腔注射1.0mg/kgSKF83959或等体积PBS缓冲液后,进行行为学测试.实验结果显示,与对照组相比,SKF83959注射后的大鼠在开放场测试中水平方向活动次数和总活动时间显著增加;在高架十字迷宫中给药组大鼠在闭臂区的停留时间更长,总穿臂次数和开臂、闭臂进臂次数也都减少.在恐惧性条件学习中,SKF83959处理组大鼠的记忆能力与对照组大鼠之间没有明显差异.结果提示,SKF83959能够提高大鼠的活动量,增加大鼠的焦虑情绪行为,而对大鼠恐惧记忆没有明显影响.     

居民地方感的尺度偏好与影响因素研究

以南京农业大学学生为被试，通过半结构化的调查问卷，结合定量和质性分析方法，了解现有行政区划体系下居民对地方依附和地方认同的偏好尺度，分析其人口统计学差异，揭示地方感形成机制与居民地方感偏好尺度的关联.研究结果表明:(1)居民地方依附的尺度偏好呈“倒U型曲线”；地方认同的尺度偏好随尺度递减而下降. (2)年龄、独生子女与否、民族、户籍、专业、入学前的住校时间都会影响居民地方感尺度偏好. (3)地方依附和地方认同作为地方感的从属概念，均包含了情感、认知和行为的过程，都可以采用认同领域的指导性理论加以诠释.     

Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice

Although the question of to whom a male directs his mating attempts is a critical one in social interactions, little is known about the molecular and cellular mechanisms controlling mammalian sexual preference. Here we report that the neurotransmitter 5-hydroxytryptamine (5-HT) is required for male sexual preference. Wild-type male mice preferred females over males, but males lacking central serotonergic neurons lost sexual preference although they were not generally defective in olfaction or in pheromone sensing. A role for 5-HT was demonstrated by the phenotype of mice lacking tryptophan hydroxylase 2 (Tph2), which is required for the first step of 5-HT synthesis in the brain. Thirty-five minutes after the injection of the intermediate 5-hydroxytryptophan (5-HTP), which circumvented Tph2 to restore 5-HT to the wild-type level, adult Tph2 knockout mice also preferred females over males. These results indicate that 5-HT and serotonergic neurons in the adult brain regulate mammalian sexual preference.     

Differential modulation of endotoxin responsiveness by human caspase-12 polymorphisms

Caspases mediate essential key proteolytic events in inflammatory cascades and the apoptotic cell death pathway. Human caspases functionally segregate into two distinct subfamilies: those involved in cytokine maturation (caspase-1, -4 and -5) and those involved in cellular apoptosis (caspase-2, -3, -6, -7, -8, -9 and -10). Although caspase-12 is phylogenetically related to the cytokine maturation caspases, in mice it has been proposed as a mediator of apoptosis induced by endoplasmic reticulum stress including amyloid-beta cytotoxicity, suggesting that it might contribute to the pathogenesis of Alzheimer's disease. Here we show that a single nucleotide polymorphism in caspase-12 in humans results in the synthesis of either a truncated protein (Csp12-S) or a full-length caspase proenzyme (Csp12-L). The read-through single nucleotide polymorphism encoding Csp12-L is confined to populations of African descent and confers hypo-responsiveness to lipopolysaccharide-stimulated cytokine production in ex vivo whole blood, but has no significant effect on apoptotic sensitivity. In a preliminary study, we find that the frequency of the Csp12-L allele is increased in African American individuals with severe sepsis. Thus, Csp12-L attenuates the inflammatory and innate immune response to endotoxins and in doing so may constitute a risk factor for developing sepsis.