Accumulating epidemiological evidence shows that life event stressors are major vulnerability factors for psychiatric diseases such as major depression. It is also well known that social isolation in male mice results in aggressive behavior. However, it is not known how social isolation-induced aggression affects anxiety and depressive-like behavior in isolated male mice subjected to unpredictable chronic mild stress (CMS), an animal model of depression. C57/B6 male mice were divided into 3 groups; non-stressed controls, in Group I; isolated mice subjected to the CMS protocol in Group II and aggression by physical contact in socially isolated mice subjected to the CMS protocol in Group III. In the sucrose intake test, ingestion of a 1% sucrose solution by mice in Groups II and III was significantly lower than in Group I. Furthermore, intake of this solution in Group III mice was significantly lower than in Group II mice. In the open field test, mice in Group III, showed reduced locomotor activity and reduced entry and retention time in the central zone, compared to Groups I and II mice. Moreover, the distances moved in 1 hour by Group III mice did not differ between night and morning. In the light/black box test, Groups II and III animals spent significantly less time in the light box compared to Group I animals. In the tail suspension test (TST) and forced swimming test (FST), the immobility times of Group II and Group III mice were significantly longer than in Group I mice. In addition, immobility times in the FST were significantly longer in Group III than in Group II mice. These findings show that social isolation-induced aggression could potentiate anxiety and depressive -like behaviors in isolated male mice subjected to CMS.

Depression is a disturbing psychiatric disease with unsatisfied therapy. Not all patients are sensitive to anti-depressants currently in use, side-effects are unavoidable during therapy and the cases with effectiveness are always accompanied with delayed onset of clinical efficacy. Delivering brain-derived neurotrophic factor (BDNF) to brain seems to be a promising therapy. However, a better approach to delivery is still rudimentary. The purpose of our present work is to look for a rapid-onset and long-lasting therapeutic strategy for major depressive disorder (MDD) by effectively delivering BDNF to brain. BDNF, fused with cell-penetrating peptides (TAT and HA2), was packaged in adenovirus associated virus (AAV) to construct the BDNF-HA2TAT/AAV for intranasally delivering BDNF to central nervous system (CNS) via nose-brain pathway. Intranasal administration of BDNF-HA2TAT/AAV to normal mice displayed anti-depression effect in forced swimming test when the delivery lasted relatively longer. The AAV applied to mice subjected to chronic mild stress (CMS) through intranasal administration for 10 days also alleviated depression-like behaviors. Western-blotting analysis revealed that BDNF-HA2TAT/AAV nasal administration enhanced hippocampal BDNF content. These results indicate intranasal administration of constructed BDNF-HA2TAT/AAV exerts anti-depression effect in CMS mice by increasing hippocampal BDNF, suggesting that this strategy holds a promising therapeutic potential for MDD.

Repeated exposure to addictive drugs elicits long-lasting cellular and molecular changes. It has been reported that the aberrant expression of long non-coding RNAs (lncRNAs) is involved in cocaine and heroin addiction, yet the expression profile of lncRNAs and their potential effects on methamphetamine (METH)-induced locomotor sensitization are largely unknown. Using high-throughput strand-specific complementary DNA sequencing technology (ssRNA-seq), here we examined the alterations in the lncRNAs expression profile in the nucleus accumbens (NAc) of METH-sensitized mice. We found that the expression levels of 6246 known lncRNAs (6215 down-regulated, 31 up-regulated) and 8442 novel lncRNA candidates (8408 down-regulated, 34 up-regulated) were significantly altered in the METH-sensitized mice. Based on characterizations of the genomic contexts of the lncRNAs, we further showed that there were 5139 differentially expressed lncRNAs acted via cis mechanisms, including sense intronic (4295 down-regulated and one up-regulated), overlapping (25 down-regulated and one up-regulated), natural antisense transcripts (NATs, 148 down-regulated and eight up-regulated), long intergenic non-coding RNAs (lincRNAs, 582 down-regulated and five up-regulated), and bidirectional (72 down-regulated and two up-regulated). Moreover, using the program RNAplex, we identified 3994 differentially expressed lncRNAs acted via trans mechanisms. Gene ontology (GO) and KEGG pathway enrichment analyses revealed that the predicted cis- and trans- associated genes were significantly enriched during neuronal development, neuronal plasticity, learning and memory, and reward and addiction. Taken together, our results suggest that METH can elicit global changes in lncRNA expressions in the NAc of sensitized mice that might be involved in METH-induced locomotor sensitization and addiction.