Aggression in non-human vertebrates: Genetic mechanisms and molecular pathways.

Aggression is an adaptive behavioral trait that is important for the establishment of social hierarchies and competition for mating partners, food, and territories. While a certain level of aggression can be beneficial for the survival of an individual or species, abnormal aggression levels can be detrimental. Abnormal aggression is commonly found in human patients with psychiatric disorders. The predisposition to aggression is influenced by a combination of environmental and genetic factors and a large number of genes have been associated with aggression in both human and animal studies. In this review, we compare and contrast aggression studies in zebrafish and mouse. We present gene ontology and pathway analyses of genes linked to aggression and discuss the molecular pathways that underpin agonistic behavior in these species. © 2015 Wiley Periodicals, Inc.

Interaction of NOS1AP with the NOS-I PDZ domain: Implications for schizophrenia-related alterations in dendritic morphology.

Schizophrenia involves morphological brain changes, including changes in synaptic plasticity and altered dendritic development. Amongst the most promising candidate molecules for schizophrenia are neuronal nitric oxide (NO) synthase (NOS-I, also known as nNOS) and its adapter protein NOS1AP (previously named CAPON). However, the precise molecular mechanisms by which NOS-I and NOS1AP affect disease pathology remain to be resolved. Interestingly, overexpression of NOS1AP affects dendritic morphology, possibly through increased association with the NOS-I PDZ domain. To investigate the effect of NOS1AP on dendritic morphology we overexpressed different NOS1AP isoforms, NOS1AP deletion mutants and the aminoterminal 133 amino acids of NOS-I (NOS-IN133) containing an extended PDZ domain. We examined the interaction of the overexpressed constructs with endogenous NOS-I by co-immunoprecipitation and the consequences of increased NOS-I/NOS1AP PDZ interaction in primary cultures of hippocampal and cortical neurons from C57BL/6J mice. Neurons overexpressing NOS1AP isoforms or deletion mutants showed highly altered spine morphology and excessive growth of filopodia-like protrusions. Sholl analysis of immunostained primary cultured neurons revealed that dendritic branching was mildly affected by NOS1AP overexpression. Our results hint towards an involvement of NOS-I/NOS1AP interaction in the regulation of dendritic spine plasticity. As altered dendritic spine development and filopodial outgrowth are important neuropathological features of schizophrenia, our findings may provide insight into part of the molecular mechanisms involved in brain morphology alterations observed in schizophrenia. As the NOS-I/NOS1AP interface can be targeted by small molecules, our findings ultimately might help to develop novel treatment strategies for schizophrenia patients.

Gene-environment interaction influences anxiety-like behavior in ethologically based mouse models.

Ethologically based animal models are widely used; however, results from different laboratories vary significantly which may partly be due to the lack of standardization. Here, we examined the effects of circadian rhythm, lighting condition and mouse strain (BALB/c and C57BL/6, known to differ in measures of avoidance and risk assessment behavior) on two well established behavioral tests in mice: the Elevated Plus Maze (EPM) and the Open Field (OF). Parameters from both paradigms are commonly used as indices of anxiety-like behavior. BALB/c mice and C57BL/6 mice were independently tested in the morning and at night, in regular laboratory lighting and in the dark. We developed a novel method based on infrared lighting from below, coupled to respective video-tracking equipment, which facilitates standard testing of behavior interference-free in complete darkness. The two mouse strains differed in anxiety-related variables for the EPM in the dark, and for the OF in regular laboratory lighting. Moreover, BALB/c displayed greater anxiety-like behavior than C57BL/6 in the OF but less anxiety-like behavior than C57BL/6 in the EPM. Lighting condition has a major influence on both behavioral tests and this to a considerably larger extent than circadian rhythm. In addition, the lighting condition interacts strongly with the genetic background, producing discriminative differences in the anxiety-related variables depending on mouse strain and lighting condition. These results challenge the comparability of not sufficiently standardized tests of anxiety-like behavior and emphasize the need for controlling environmental variables in behavioral phenotyping.

The COGITAT holeboard system as a valuable tool to assess learning, memory and activity in mice.

The comprehensive and stress-free assessment of various aspects of learning and memory is a prerequisite to evaluate mouse models for neuropsychiatric disorders such as Alzheimer's disease or attention deficit/hyperactivity disorder (ADHD). COGITAT is an automated holeboard system allowing simultaneous assessment of spatial working and reference-memory performance which we have adapted in this study to enable its usage with mice. The holeboard apparatus consists of an open-field chamber with a 25-hole floor insert, each hole being monitored by infrared light beams, located on three different levels, allowing the distinction between visits of holes, i.e. the animal reaches the bottom of the hole, or inspections, which means only superficial exploration of the hole. Across trials, animals learn a pattern of five baited holes. Here, we show that C57BL/6 mice readily acquire this task within 5 days when submitted to six trials per day. A number of individual parameters - overall exploratory activity, number of visits into or inspections of holes, number of baited, unbaited, or previously baited holes visited or inspected, reinspections of or revisits into any holes, number of pellets eaten, time to find pellets, and reference and working memory errors-are obtained simultaneously and results are immediately available after the end of each experiment. The muscarinic antagonist scopolamine impaired task performance, while the cognitive enhancer metrifonate (an acetylcholinesterase inhibitor) reduced error rates. Overall, our data indicate that this spatial learning task will be useful to characterize spatial memory in various genetic or pharmacological mouse models.