Heterozygous loss of epilepsy gene KCNQ2 alters social,repetitive and exploratory behaviors

KCNQ/K_v7 channels conduct voltage‐dependent outward potassium currents that potently decrease neuronal excitability. Heterozygous inherited mutations in their principle subunits K_v7.2/KCNQ2 and K_v7.3/KCNQ3 cause benign familial neonatal epilepsy whereas patients with de novo heterozygous K_v7.2 mutations are associated with early‐onset epileptic encephalopathy and neurodevelopmental disorders characterized by intellectual disability, developmental delay and autism. However, the role of K_v7.2‐containing K_v7 channels in behaviors especially autism‐associated behaviors has not been described. Because pathogenic K_v7.2 mutations in patients are typically heterozygous loss‐of‐function mutations, we investigated the contributions of K_v7.2 to exploratory, social, repetitive and compulsive‐like behaviors by behavioral phenotyping of both male and female KCNQ2^+/? mice that were heterozygous null for the KCNQ2 gene. Compared with their wild‐type littermates, male and female KCNQ2^+/? mice displayed increased locomotor activity in their home cage during the light phase but not the dark phase and showed no difference in motor coordination, suggesting hyperactivity during the inactive light phase. In the dark phase, KCNQ2^+/? group showed enhanced exploratory behaviors, and repetitive grooming but decreased sociability with sex differences in the degree of these behaviors. While male KCNQ2^+/? mice displayed enhanced compulsive‐like behavior and social dominance, female KCNQ2^+/? mice did not. In addition to elevated seizure susceptibility, our findings together indicate that heterozygous loss of K_v7.2 induces behavioral abnormalities including autism‐associated behaviors such as reduced sociability and enhanced repetitive behaviors. Therefore, our study is the first to provide a tangible link between loss‐of‐function K_v7.2 mutations and the behavioral comorbidities of K_v7.2‐associated epilepsy.     

The effects of tamoxifen on mouse behavior

The CreER^T2 recombinase system is an advanced method to temporally control site‐specific mutagenesis in adult rodents. In this process, tamoxifen is injected to induce Cre recombinase expression, and then, Cre recombinase can excise LoxP‐flanked DNA. However, tamoxifen is a nonselective estrogen receptor antagonist that may influence behavioral alterations. Therefore, we designed five different protocols (acute effects, chronic effects, chronic effects after social defeat model, chronic effects after learned helplessness model, chronic effects after isolation models) to explore whether tamoxifen affects mouse behavior. Researching the acute/chronic effects of tamoxifen, we found that tamoxifen could influence locomotor activity, anxiety and immobility time in the forced swimming test. Researching the chronic effects of tamoxifen after social defeat/learned helplessness/isolation models, we found that tamoxifen could also influence locomotor activity, social interaction and anxiety. Therefore, the effects of tamoxifen are more complex than previously reported. Our results show, for the first time, that tamoxifen affects behavior in mouse models. Meanwhile, we compare the effects of tamoxifen in different protocols. These results will provide important information when designing similar experiments.     

Neuropeptide‐S‐receptor deficiency affects sex‐specific modulation of safety learning by pre‐exposure to electric stimuli

Neuropeptide S (NPS) is a neuropeptide involved in the regulation of fear. Because safety learning is impaired in patients suffering from anxiety‐related psychiatric disorders, and polymorphisms of the human neuropeptide S receptor (NPSR) gene have also been associated with anxiety disorders, we wanted to investigate whether NPSR‐deficiency interferes with safety learning, and how prior stress would affect this type of learning. We first investigated the effect of pre‐exposure to two different types of stressors (electric stimuli or immobilization) on safety learning in female and male C57Bl/6 mice, and found that while stress induced by electric stimuli enhanced safety learning in males, there were no differences in safety learning following immobilization stress. To further investigate the role of the NPS system in stress‐induced modulation of safety learning, we exposed NPSR‐deficient mice to stress induced by electric stimuli 10 days before safety learning. In nonstressed male mice, NPSR‐deficiency enhanced safety learning. As in male C57Bl/6 mice, pre‐exposure to electric stimuli increased safety learning in male NPSR +/+ mice. This pre‐exposure effect was blocked in NPSR‐deficient male mice showing impaired, but still intact, safety learning in comparison to their NPSR +/+ and NPSR +/? littermates. There was neither a pre‐exposure nor a genotype effect in female mice. Our findings provide evidence that pre‐exposure to stress induced by electric stimuli enhances safety learning in male mice, and that NPSR‐deficiency prevents the beneficial effect of stress exposure on safety learning. We propose an inverted U‐shape relationship between stress and safety learning.     

The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta‐analysis of direct comparisons

Although psychotherapy and antidepressant medication are efficacious in the treatment of depressive and anxiety disorders, it is not known whether they are equally efficacious for all types of disorders, and whether all types of psychotherapy and antidepressants are equally efficacious for each disorder. We conducted a meta-analysis of studies in which psychotherapy and antidepressant medication were directly compared in the treatment of depressive and anxiety disorders. Systematic searches in bibliographical databases resulted in 67 randomized trials, including 5,993 patients that met inclusion criteria, 40 studies focusing on depressive disorders and 27 focusing on anxiety disorders. The overall effect size indicating the difference between psychotherapy and pharmacotherapy after treatment in all disorders was g=0.02 (95% CI: −0.07 to 0.10), which was not statistically significant. Pharmacotherapy was significantly more efficacious than psychotherapy in dysthymia (g=0.30), and psychotherapy was significantly more efficacious than pharmacotherapy in obsessive-compulsive disorder (g=0.64). Furthermore, pharmacotherapy was significantly more efficacious than non-directive counseling (g=0.33), and psychotherapy was significantly more efficacious than pharmacotherapy with tricyclic antidepressants (g=0.21). These results remained significant when we controlled for other characteristics of the studies in multivariate meta-regression analysis, except for the differential effects in dysthymia, which were no longer statistically significant.     

Physiological and psychological effects of walking on young males in urban parks in winter

Background

Interaction with nature has a relaxing effect on humans. Increasing attention has been focused on the therapeutic effects of urban green space; however, there is a lack of evidence-based field research. This study provided scientific evidence supporting the physiological and psychological effects of walking on young males in urban parks in winter.

Findings

Subjects (13 males aged 22.5 ± 3.1 years) were instructed to walk predetermined 15-minute courses in an urban park (test) and in the city area (control). Heart rate and heart rate variability (HRV) were measured to assess physiological responses. The semantic differential (SD) method, Profile of Mood States (POMS), and State-Trait Anxiety Inventory (STAI) were used to determine psychological responses.Heart rate was significantly lower and the natural logarithm of the high frequency component of HRV was significantly higher when walking through the urban park than through the city area. The results of three questionnaires indicated that walking in the urban park improved mood and decreased negative feelings and anxiety.

Conclusions

Physiological and psychological data from this field experiment provide important scientific evidence regarding the health benefits of walking in an urban park. The results support the premise that walking in an urban park has relaxing effects even in winter.     

Male Wistar rats are more susceptible to lasting social anxiety than Wild-type Groningen rats following social defeat stress during adolescence

Adolescence is an important period for the development of adult social competences. Social stress during adolescence may contribute not only to an inadequate social development but also to adult vulnerability to social anxiety. There seems to be a clear individual differentiation, however, in the vulnerability to the long-term negative consequences of social stress. The current study further explores this individual vulnerability and is aimed at the influence of social stress during adolescence on adult social anxiety and its context specificity. Rats from different strains (Wistar and Wild-type Groningen rats) were exposed to the resident-intruder paradigm five times during 10 min each in the period between postnatal day 45 and 58. Three and 7 weeks later, the animals were re-exposed to the context in the presence of either a dominant male or an anestrous female behind a wire mesh screen. Wistar rats that were socially defeated spent less time exploring the social stimulus in comparison with socially defeated Wild-type rats and their non-defeated controls. We conclude that the stressed Wistar rat shows signs of generalized social anxiety indicating that the Wistar rat can be considered as a vulnerable phenotype to effects of adolescent social stress.     

年轻小鼠咀嚼刺激长期改变对焦虑和认知的影响

建立长期增加或减少年轻小鼠切牙的咀嚼刺激模型.通过形态学的观察,研究小鼠下颌骨和咬肌的变化以及大脑皮层和海马的厚度改变;通过行为学实验(旷场实验、高架十字迷宫、新异物体识别和Morris水迷宫实验)观察小鼠认知能力和焦虑情绪的变化;通过高效液相色谱(HPLC)检测小鼠皮层、海马中4种单胺类神经递质(去甲肾上腺素(NE)、肾上腺素(E)、多巴胺(DA)和5-羟色胺(5-HT))的变化,以探讨小鼠焦虑情绪改变的机理;通过荧光实时定量PCR检测小鼠皮层和海马与认知紧密相关的4种基因(BDNF、Synapsin I、NR2B和CREB)的mRNA表达,以研究小鼠认知能力改变的机理.形态学结果显示:各组小鼠下颌骨和咬肌纤维的形态没有影响,各组小鼠皮层和海马的厚度也没有差异.行为学实验结果显示:咀嚼增加组小鼠焦虑倾向低于对照组和咀嚼减少组,各组小鼠短期记忆能力没有统计学差异,咀嚼增加组小鼠空间认知能力优于咀嚼减少组.高效液相色谱结果显示,咀嚼减少组小鼠与咀嚼增加组和对照组相比,去甲肾上腺素在皮层中明显升高(P<0.05).mRNA检测结果显示,咀嚼减少组小鼠4种与认知相关基因的表达量与咀嚼增加组相比都明显下调(P<0.05).上述结果提示,切牙咀嚼刺激的长期增加可以提高小鼠的自主运动能力,降低焦虑程度,提高空间认知能力,上调海马中认知相关基因的表达.切牙咀嚼刺激的长期减少,会降低小鼠的自主运动能力,下调认知相关的基因表达,增加大脑皮层中去甲肾上腺素的含量.     

Moderate anxiety, whether acute or chronic, is not associated with ovarian suppression in healthy, well-nourished, Western women

The relationship between psychological stress and reduced fecundity has been a matter of speculation and investigation for decades. Most previous studies have been compromised, however, by a number of problems including ambiguous direction of causation, poorly operationalized variables, and the confounding of psychological with energetic stress. We present a two-part study of the relationship between moderate anxiety, both acute and chronic, and daily measures of ovarian steroid and corticosteroid levels in saliva. Anxiety, as a particular form of psychosocial stress, was measured by the Spielberger Stait-Trait Anxiety Inventory as well as by a self-reported daily stress score. In the first part, 23 college juniors taking the Medical College Admissions Test (MCAT) were studied the month before and the month after the test, and again several months later, and compared at the same time points with 27 controls. In the second part, chronic anxiety levels were assessed in 95 women between 27 and 41 years of age and analyzed in relation to daily levels of salivary ovarian and corticosteroids over one menstrual cycle. The sample sizes are sufficient to allow for confidence in negative results. No statistically significant differences in ovarian or corticosteroid levels were observed whether between the MCAT and control subjects in part one, between the MCAT subjects before and after the MCAT test in part one, or between high and low anxiety subjects in part two. The results indicate that moderate levels of anxiety, whether acute or chronic, are not associated with suppressed ovarian function in healthy women.     

Synaptotagmin 1基因敲除对小鼠行为的影响*

目的: 研究Synaptotagmin 1基因敲除(Syt1^+/-)对小鼠情绪行为的影响并初步探讨其可能机制。方法: 选取8周龄雄性Syt1^+/-小鼠及同窝野生型(WT)小鼠各5只,采用免疫荧光染色方法观察小鼠前额叶皮层、海马、杏仁核、伏隔核、纹状体和腹侧被盖区等6个脑区中Syt1的表达;选用8周龄雄性Syt1^+/-小鼠9只,以及WT小鼠10只为对照,通过旷场实验、高架十字迷宫实验和强迫游泳实验检测比较成年Syt1^+/-小鼠和WT小鼠的焦虑样行为;另选用8周龄雄性Syt1^+/-小鼠及WT小鼠各5只,检测小鼠前额叶皮层、海马和杏仁核的谷氨酸含量。结果: 与WT小鼠相比,Syt1^+/-小鼠在前额叶皮层、海马、杏仁核、伏隔核、纹状体和腹侧被盖区Syt1阳性细胞数目显著减少(P＜0.01);Syt1^+/-小鼠在旷场中总移动距离显著减少(P＜0.01),并更偏爱在外周区域活动(P＜0.01),对中心区域的探索欲望显著下降(P＜0.01);Syt1^+/-小鼠更偏好待在封闭安全环境中(P＜0.01),开臂探索次数(P＜0.05)和在其中运动的时间显著减少(P＜0.01);Syt1^+/-小鼠在强迫游泳实验中不动时间明显增加(P＜0.01);同时,Syt1^+/-小鼠杏仁核中谷氨酸的含量显著增加(P＜0.01)。结论: Syt1基因敲除可以引起小鼠显著的焦虑样行为,推测与杏仁核中谷氨酸含量增加有关。