Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

https://science.sciencemag.org/content/sci/311/5762/864.full.pdf

Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress

Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions

High-functioning children with autism were compared with two control groups on measures of anxiety and social worries. Comparison control groups consisted of children with specific language impairment (SLI) and normally developing children. Each group consisted of 15 children between the ages of 8 and 12 years and were matched for age and gender. Children with autism were found to be most anxious on both measures. High anxiety subscale scores for the autism group were separation anxiety and obsessive-compulsive disorder. These findings are discussed within the context of theories of autism and anxiety in the general population of children. Suggestions for future research are made.

Anxiety in high functioning children with autism

Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects

Much of the current understanding about the pathogenesis of altered mood, impaired concentration and neurovegetative symptoms in major depression has come from animal models. However, because of the unique and complex features of human depression, the generation of valid and insightful depression models has been less straightforward than modeling other disabling diseases like cancer or autoimmune conditions. Today’s popular depression models creatively merge ethologically valid behavioral assays with the latest technological advances in molecular biology and automated video-tracking. This chapter reviews depression assays involving acute stress (e.g., forced swim test), models consisting of prolonged physical or social stress (e.g., social defeat), models of secondary depression, genetic models, and experiments designed to elucidate the mechanisms of antidepressant action. These paradigms are critically evaluated in relation to their ease, validity and replicability, the molecular insights that they have provided, and their capacity to offer the next generation of therapeutics for depression.

/pdf/animal-models-of-depression-molecular-perspectives-2xd4cra0xr.pdf

Animal Models of Depression: Molecular Perspectives

Chronic psychoemotional stress induced by negative experience of social defeats in intermale confrontations over a period of 30 days was found to lead to the development of anxious-depressive symptomatology in male mice. Cessation of the psychopathogenic conditions and placing of depressed animals in comfortable conditions for 1–2 weeks with females did not lift the pathological state. Individuals continued to show marked anxiety, a behavioral deficit, decreased communicativeness, and a high level of depressivity, as revealed by a variety of behavioral tests. Persistence of the resulting psychoemotional disturbance in these animals is evidence for the development and persistence of the behavioral pathology requiring drug treatment.

A model of anxious depression: persistence of behavioral pathology.

Repeated aggression is a frequent symptom of many psychiatric and neurological disorders, including obsessive-compulsive and attention deficit hyperactivity disorders, bipolar and post-traumatic stress disorders, epilepsy, autism, schizophrenia and drug abuse. However, repeated aggression is insufficiently studied because there is a lack of adequate models in animals. The sensory contact model (SCM), widely used to study the effects of chronic social defeat stress, can also be used to investigate the effects of repeated aggression. Mice with repeated positive fighting experience in daily agonistic interactions in this model develop pronounced aggressiveness, anxiety and impulsivity, disturbances in motivated and cognitive behaviors, and impairments of sociability; they also demonstrate hyperactivity, attention-deficit behavior, motor dysfunctions and repetitive stereotyped behaviors, such as jerks, rotations and head twitches. In this protocol, we describe how to apply the SCM to study repeated aggression in mice. Severe neuropathology develops in male mice after 20-21 d of agonistic interactions.

Repeated positive fighting experience in male inbred mice

Background 
It is generally recognized that recurrent aggression can be the result of various psychiatric disorders. The aim of our study was to analyze the mRNA levels, in the ventral tegmental area (VTA) of the midbrain, of the genes that may possibly be associated with aggression consistently shown by male mice in special experimental settings.


Methodology/Principal Findings 
The genes were Th, Dat1, Snca and Bdnf; the male mice were a group of animals that had each won 20 daily encounters in succession and a group of animals that had the same winning track record followed by a no-fight period for 14 days. Increased Th, Dat1 and Snca mRNA levels were in the fresh-from-the-fight group as compared to the controls. Increased Th and Dat1 mRNA levels were in the no-fight winners as compared to the controls. Significant positive correlations were found between the level of aggression and Th and Snca mRNA levels.


Conclusions 
Repeated positive fighting experience enhances the expression of the Th, Dat1 and Snca genes, which are associated with brain dopaminergic systems. The expression of the Th and Dat1 genes stays enhanced for a long time.

/pdf/molecular-implications-of-repeated-aggression-th-dat1-snca-4sj003qwrb.pdf

Molecular implications of repeated aggression: Th, Dat1, Snca and Bdnf gene expression in the VTA of victorious male mice.

Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. Most Rps, Rpl, Mprs, and Mprl genes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach may be used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with “ribosomopathies.”

/pdf/dysfunction-in-ribosomal-gene-expression-in-the-hypothalamus-2xtjkjtbcu.pdf

Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq.

Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica (
 http://genoanalytica.ru/
 , Moscow, Russia). Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.

/pdf/altered-slc25-family-gene-expression-as-markers-of-1gl91kzw98.pdf

Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder.

Irina L. Kovalenko

Papers

A model of anxious depression: persistence of behavioral pathology.

Repeated positive fighting experience in male inbred mice

Molecular implications of repeated aggression: Th, Dat1, Snca and Bdnf gene expression in the VTA of victorious male mice.

Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq.

Altered Slc25 family gene expression as markers of mitochondrial dysfunction in brain regions under experimental mixed anxiety/depression-like disorder.