Social Isolation-Induced Territorial Aggression in Male Offspring Is Enhanced by Exposure to Diesel Exhaust during Pregnancy

Diesel exhaust particles are a major component of ambient particulate matter, and concern about the health effects of exposure to ambient particulate matter is growing. Previously, we found that in utero exposure to diesel exhaust affected locomotor activity and motor coordination, but there are also indications that such exposure may contribute to increased aggression in offspring. Therefore, the aim of the present study was to test the effects of prenatal diesel exhaust exposure on social isolation-induced territorial aggression. Pregnant mice were exposed to low concentrations of diesel exhaust (DE; mass concentration of 90 μg/m³: DE group: n = 15) or clean air (control group: n = 15) for 8 h/day during gestation. Basal locomotion of male offspring was measured at 10 weeks of age. Thereafter, male offspring were individually housed for 2 weeks and subsequently assessed for aggression using the resident−intruder test at 12 weeks of age, and blood and brain tissue were collected from the male offspring on the following day for measuring serum testosterone levels and neurochemical analysis. There were no significant differences in locomotion between control and DE-exposed mice. However, DE-exposed mice showed significantly greater social isolation-induced territorial aggressive behavior than control mice. Additionally, socially-isolated DE-exposed mice expressed significantly higher concentrations of serum testosterone levels than control mice. Neurochemical analysis revealed that dopamine levels in the prefrontal cortex and nucleus accumbens were higher in socially isolated DE-exposed mice. Serotonin levels in the nucleus accumbens, amygdala, and hypothalamus were also lower in the socially isolated DE-exposed mice than in control mice. Thus, even at low doses, prenatal exposure to DE increased aggression and serum testosterone levels, and caused neurochemical changes in male socially isolated mice. These results may have serious implications for pregnant women living in regions with high levels of traffic-related air pollution.     

Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension

Williams-Beuren syndrome (WBS), caused by a heterozygous deletion at 7q11.23, represents a model for studying hypertension, the leading risk factor for mortality worldwide, in a genetically determined disorder. Haploinsufficiency at the elastin gene is known to lead to the vascular stenoses in WBS and is also thought to predispose to hypertension, present in approximately 50% of patients. Detailed clinical and molecular characterization of 96 patients with WBS was performed to explore clinical-molecular correlations. Deletion breakpoints were precisely defined and were found to result in variability at two genes, NCF1 and GTF2IRD2. Hypertension was significantly less prevalent in patients with WBS who had the deletion that included NCF1 (P=.02), a gene coding for the p47(phox) subunit of the NADPH oxidase. Decreased p47(phox) protein levels, decreased superoxide anion production, and lower protein nitrotyrosination were all observed in cell lines from patients hemizygous at NCF1. Our results indicate that the loss of a functional copy of NCF1 protects a proportion of patients with WBS against hypertension, likely through a lifelong reduced angiotensin II-mediated oxidative stress. Therefore, antioxidant therapy that reduces NADPH oxidase activity might have a potential benefit in identifiable patients with WBS in whom serious complications related to hypertension have been reported, as well as in forms of essential hypertension mediated by a similar pathogenic mechanism.     

Deletion of glutamate delta-1 receptor in mouse leads to aberrant emotional and social behaviors

The delta family of ionotropic glutamate receptors consists of glutamate δ1 (GluD1) and glutamate δ2 (GluD2) receptors. While the role of GluD2 in the regulation of cerebellar physiology is well understood, the function of GluD1 in the central nervous system remains elusive. We demonstrate for the first time that deletion of GluD1 leads to abnormal emotional and social behaviors. We found that GluD1 knockout mice (GluD1 KO) were hyperactive, manifested lower anxiety-like behavior, depression-like behavior in a forced swim test and robust aggression in the resident-intruder test. Chronic lithium rescued the depression-like behavior in GluD1 KO. GluD1 KO mice also manifested deficits in social interaction. In the sociability test, GluD1 KO mice spent more time interacting with an inanimate object compared to a conspecific mouse. D-Cycloserine (DCS) administration was able to rescue social interaction deficits observed in GluD1 KO mice. At a molecular level synaptoneurosome preparations revealed lower GluA1 and GluA2 subunit expression in the prefrontal cortex and higher GluA1, GluK2 and PSD95 expression in the amygdala of GluD1 KO. Moreover, DCS normalized the lower GluA1 expression in prefrontal cortex of GluD1 KO. We propose that deletion of GluD1 leads to aberrant circuitry in prefrontal cortex and amygdala owing to its potential role in presynaptic differentiation and synapse formation. Furthermore, these findings are in agreement with the human genetic studies suggesting a strong association of GRID1 gene with several neuropsychiatric disorders including schizophrenia, bipolar disorder, autism spectrum disorders and major depressive disorder.     

转录因子Egr-1参与长期性恐惧记忆和焦虑

锌指转录因子点Egr-1在将细胞外信号和胞内基因表达的变化相耦联过程中发挥重要的作用。海马和杏仁体是记忆形成和储存的两个主要的脑区。在海马和杏仁体中,Egr-1可被长时程增强（long-term potentiation,LTP）和学习过程上调。在Egr-1敲除小鼠上观察到晚时相声音恐惧记忆受损,而短时的痕迹和场景记忆却不受影响;另外,在Egr-1敲除小鼠上,用theta burst刺激杏仁体和听觉皮层所引起的突触增强被明显减弱或完全阻断。因此,我们的研究表明,转录因子Egr-1选择性地在晚时相听觉恐惧记忆中发挥作用。     

Mapping Genetically Controlled Neural Circuits of Social Behavior and Visuo-Motor Integration by a Preliminary Examination of Atypical Deletions with Williams Syndrome

In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.     

Peptides of love and fear: vasopressin and oxytocin modulate the integration of information in the amygdala

Neuropeptides vasopressin and oxytocin regulate a variety of behaviors ranging from maternal and pair bonding to aggression and fear. Their role in modulating fear responses has been widely recognized, but not yet well understood. Animal and human studies indicate the major role of the amygdala in controlling fear and anxiety. The amygdala is involved in detecting threat stimuli and linking them to defensive behaviors. This is accomplished by projections connecting the central nucleus of the amygdala (CeA) to the brain stem and to hypothalamic structures, which organize fear responses. A recent study by Huber et al demonstrates that vasopressin and oxytocin modulate the excitatory inputs into the CeA in opposite manners. Therefore this finding elucidates the mechanisms through which these neuropeptides may control the expression of fear.     

Deletion of Glutamate Delta-1 Receptor in Mouse Leads to Enhanced Working Memory and Deficit in Fear Conditioning

Glutamate delta-1 (GluD1) receptors are expressed throughout the forebrain during development with high levels in the hippocampus during adulthood. We have recently shown that deletion of GluD1 receptor results in aberrant emotional and social behaviors such as hyperaggression and depression-like behaviors and social interaction deficits. Additionally, abnormal expression of synaptic proteins was observed in amygdala and prefrontal cortex of GluD1 knockout mice (GluD1 KO). However the role of GluD1 in learning and memory paradigms remains unknown. In the present study we evaluated GluD1 KO in learning and memory tests. In the eight-arm radial maze GluD1 KO mice committed fewer working memory errors compared to wildtype mice but had normal reference memory. Enhanced working memory in GluD1 KO was also evident by greater percent alternation in the spontaneous Y-maze test. No difference was observed in object recognition memory in the GluD1 KO mice. In the Morris water maze test GluD1 KO mice showed no difference in acquisition but had longer latency to find the platform in the reversal learning task. GluD1 KO mice showed a deficit in contextual and cue fear conditioning but had normal latent inhibition. The deficit in contextual fear conditioning was reversed by D-Cycloserine (DCS) treatment. GluD1 KO mice were also found to be more sensitive to foot-shock compared to wildtype. We further studied molecular changes in the hippocampus, where we found lower levels of GluA1, GluA2 and GluK2 subunits while a contrasting higher level of GluN2B in GluD1 KO. Additionally, we found higher postsynaptic density protein 95 (PSD95) and lower glutamate decarboxylase 67 (GAD67) expression in GluD1 KO. We propose that GluD1 is crucial for normal functioning of synapses and absence of GluD1 leads to specific abnormalities in learning and memory. These findings provide novel insights into the role of GluD1 receptors in the central nervous system.     

Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development

The gene GTF2IRD1 is localized within the critical region on chromosome 7 that is deleted in Williams syndrome patients. Genotype-phenotype comparisons of patients carrying variable deletions within this region have implicated GTF2IRD1 and a closely related homolog, GTF2I, as prime candidates for the causation of the principal symptoms of Williams syndrome. We have generated mice with an nls-LacZ knockin mutation of the Gtf2ird1 allele to study its functional role and examine its expression profile. In adults, expression is most prominent in neurons of the central and peripheral nervous system, the retina of the eye, the olfactory epithelium, the spiral ganglion of the cochlea, brown fat adipocytes and to a lesser degree myocytes of the heart and smooth muscle. During development, a dynamic pattern of expression is found predominantly in musculoskeletal tissues, the pituitary, craniofacial tissues, the eyes and tooth buds. Expression of Gtf2ird1 in these tissues correlates with the manifestation of some of the clinical features of Williams syndrome.     

Estrogen involvement in social behavior in rodents: Rapid and long-term actions

This article is part of a Special Issue (“Estradiol and cognition”).Estrogens have repeatedly been shown to influence a wide array of social behaviors, which in rodents are predominantly olfactory-mediated. Estrogens are involved in social behavior at multiple levels of processing, from the detection and integration of socially relevant olfactory information to more complex social behaviors, including social preferences, aggression and dominance, and learning and memory for social stimuli (e.g. social recognition and social learning). Three estrogen receptors (ERs), ERα, ERβ, and the G protein-coupled ER 1 (GPER1), differently affect these behaviors. Social recognition, territorial aggression, and sexual preferences and mate choice, all requiring the integration of socially related olfactory information, seem to primarily involve ERα, with ERβ playing a lesser, modulatory role. In contrast, social learning consistently responds differently to estrogen manipulations than other social behaviors. This suggests differential ER involvement in brain regions important for specific social behaviors, such as the ventromedial and medial preoptic nuclei of the hypothalamus in social preferences and aggression, the medial amygdala and hippocampus in social recognition, and the prefrontal cortex and hippocampus in social learning. While the long-term effects of ERα and ERβ on social behavior have been extensively investigated, our knowledge of the rapid, non-genomic, effects of estrogens is more limited and suggests that they may mediate some social behaviors (e.g. social learning) differently from long-term effects. Further research is required to compare ER involvement in regulating social behavior in male and female animals, and to further elucidate the roles of the more recently described G protein-coupled ERs, both the GPER1 and the Gq-mER.     

Abnormal social behaviors in mice lacking Fgf17

The fibroblast growth factor family of secreted signaling molecules is essential for patterning in the central nervous system. Fibroblast growth factor 17 (Fgf17) has been shown to contribute to regionalization of the rodent frontal cortex. To determine how Fgf17 signaling modulates behavior, both during development and in adulthood, we studied mice lacking one or two copies of the Fgf17 gene. Fgf17-deficient mice showed no abnormalities in overall physical growth, activity level, exploration, anxiety-like behaviors, motor co-ordination, motor learning, acoustic startle, prepulse inhibition, feeding, fear conditioning, aggression and olfactory exploration. However, they displayed striking deficits in several behaviors involving specific social interactions. Fgf17-deficient pups vocalized less than wild-type controls when separated from their mother and siblings. Elimination of Fgf17 also decreased the interaction of adult males with a novel ovariectomized female in a social recognition test and reduced the amount of time opposite-sex pairs spent engaged in prolonged, affiliative interactions during exploration of a novel environment. After social exploration of a novel environment, Fgf17-deficient mice showed less activation of the immediate-early gene Fos in the frontal cortex than wild-type controls. Our findings show that Fgf17 is required for several complex social behaviors and suggest that disturbances in Fgf17 signaling may contribute to neuropsychiatric diseases that affect such behaviors.