Conditional Human Immunodeficiency Virus Transactivator of Transcription Protein Expression Induces Depression-like Effects and Oxidative Stress.

BACKGROUND: The prevalence of major depression in those with HIV/AIDS is substantially higher than in the general population. Mechanisms underlying this comorbidity are poorly understood. HIV-transactivator of transcription (Tat) protein, produced and excreted by HIV, could be involved. We determined whether conditional Tat protein expression in mice is sufficient to induce depression-like behaviors and oxidative stress. Further, as oxidative stress is associated with depression, we determined whether decreasing or increasing oxidative stress by administering methylsulfonylmethane (MSM) or diethylmaleate (DEM), respectively, altered depression-like behavior. METHODS: GT-tg bigenic mice received intraperitoneal saline or doxycycline (Dox, 25-100 mg/kg/day) to induce Tat expression. G-tg mice, which do not express Tat protein, also received Dox. Depression-like behavior was assessed with the tail suspension test (TST) and the two-bottle saccharin/water consumption task. Reactive oxygen/nitrogen species (ROS/RNS) were assessed ex vivo. Medial frontal cortex (MFC) oxidative stress and temperature were measured in vivo with 9.4-Tesla proton magnetic resonance spectroscopy (MRS). RESULTS: Tat expression increased TST immobility time in an exposure-dependent manner and reduced saccharin consumption. MSM decreased immobility time while DEM increased it in saline-treated GT-tg mice. Tat and MSM behavioral effects persisted for 28 days. Tat and DEM increased while MSM decreased ROS/RNS levels. Tat expression increased MFC glutathione levels and temperature. CONCLUSIONS: Tat expression induced rapid and enduring depression-like behaviors and oxidative stress. Increasing/decreasing oxidative stress increased/decreased, respectively, depression-like behavior. Thus, Tat produced by HIV may contribute to the high depression prevalence among those with HIV. Further, mitigation of oxidative stress could reduce depression severity.

Stress-induced increases in depression-like and cocaine place-conditioned behaviors are reversed by disruption of memories during reconsolidation.

Maladaptive behavioral responses characteristic of post-traumatic stress disorders are notably resistant to treatment. We hypothesized that the pharmacological disruption of memories activated during reconsolidation might reverse established stress-induced increases in depression-like behaviors and cocaine reward. C57BL/6J mice were subjected to repeated social defeat stress (SDS), and examined for time spent immobile in a subsequent forced swim test (FST). An additional set of SDS-exposed mice were place-conditioned with cocaine, and tested for cocaine-conditioned place preference (CPP). All stress-exposed mice were then subjected to a single additional trial of SDS while under the influence of propranolol or cycloheximide to disrupt memory reconsolidation, then given one additional FST or CPP test the next day. Mice subjected to repeated SDS subsequently demonstrated increases in time spent immobile in the FST or in the cocaine-paired chamber. Vehicle-treatment followed by additional SDS exposure did not alter these behaviors, but propranolol or cycloheximide treatment reversed each of the potentiated responses in a dose-dependent manner. Overall, these results demonstrate that while repeated exposure to a social defeat stressor subsequently increased depression-like behavior and cocaine-CPP, disruption of traumatic memories made labile by re-exposure to SDS during reconsolidation may have therapeutic value in the treatment of established post-traumatic stress disorder-related behaviors.

Strain vulnerability and resiliency in the chick anxiety-depression model.

Increasing research is focused on genetic contributions to variability in stress-related endophenotypes in humans and animal model simulations. The current study sought to identify strain vulnerabilities and resiliencies to an isolation-stressor in the chick anxiety-depression model. Nine different strains of socially raised chicks were tested in isolated or non-isolated conditions for 90 min in which distress vocalization (DVoc) rates were collected and then transformed to depression-like phase threshold (@ 25, 50, 75 and 95%) latencies. In general, chicks in the non-isolated condition displayed relatively low DVoc rates throughout the test session, despite some variability in initial rates. Chicks in the isolated condition displayed relatively high DVoc rates in the first 3 min, indicative of an anxiety-like state, which declined by approximately 50% within 10-25 min in all strains and remained stable thereafter, indicative of a depression-like state. Contrast effects revealed that, relative to all other strains, the Black Australorp strain displayed shorter and the Producrain displayed longer depression threshold latencies, respectively. Of the remaining strains, the Silver Laced Wyandotte displayed depression thresholds that best represent an intermediate stress response. These findings identify vulnerable and resilient strains for examining depression-related endophenotypes in the chick anxiety-depression model.

Brain-derived neurotrophic factor response in vulnerable and resilient genetic lines in the chick anxiety-depression model.

Altered BDNF-mediated synaptogenesis is a major contributor to stress-vulnerability and depression. This study sought to determine patterns of hippocampal BDNF expression in stress-vulnerable and -resilient strains in the chick anxiety-depression model. Socially raised Black Australorp and Production Red strains were tested at 5-6 days post hatch under either 30, 60, 90, or 120 min of social separation stress; chicks tested with 2 social companions for 120 min served as controls. Distress vocalizations were recorded throughout the test session and latency to behavioral despair calculated. Following tests, bilateral hippocampal sections were harvested and analyzed via ELISA for BDNF levels. Black Australorps had shorter latencies to behavioral despair than Production Reds reflecting greater stress vulnerability. No differences were detected in BDNF levels between a No-Test and Social group within or between strains. The stress resilient Production Reds showed stable BDNF levels across the isolation test period whereas the vulnerable Black Australorps showed an increase in hippocampal BDNF levels that peaked at 90 min and declined thereafter. These findings fit well with the notion that strain-dependent stress-vulnerability reflects, in part, poor homeostatic mechanisms controlling synaptogenesis.

Pharmacological reversal of cognitive bias in the chick anxiety-depression model.

Cognitive bias presents in clinical populations where anxious individuals adopt a more pessimistic interpretation of ambiguous aversive stimuli and depressed individuals adopt both a more pessimistic interpretation of ambiguous aversive stimuli and a less optimistic interpretation of ambiguous appetitive stimuli. These biases have been reversed by anxiolytics and antidepressants. In the current study, chicks exposed to an isolation stressor of 5-min to induce an anxiety-like state or 60-min to induce a depressive-like state were tested in a straight alley maze to a series of morphed ambiguous appetitive (chick silhouette) to aversive (owl silhouette) cues. Chicks in the depression-like state displayed more pessimistic-like and less optimistic-like approach behavior to ambiguous aversive and appetitive cues, respectively. Both forms of cognitive bias were reversed by 15.0 mg/kg imipramine. Chicks in anxiety-like state displayed more pessimistic-like approach behavior under the ambiguous aversive stimulus cues. However, 0.10 mg/kg clonidine produced modest sedation and thus, was ineffective at reversing this bias. The observation that cognitive biases of more pessimism and less optimism can be reversed in the depression-like phase by imipramine adds to the validity of the chick anxiety-depression model as a neuropsychiatric simulation. This article is part of a Special Issue entitled 'Anxiety and Depression'.

Cognitive bias in the chick anxiety-depression model.

Cognitive bias is a phenomenon that presents in clinical populations where anxious individuals tend to adopt a more pessimistic-like interpretation of ambiguous aversive stimuli whereas depressed individuals tend to adopt a less optimistic-like interpretation of ambiguous appetitive stimuli. To further validate the chick anxiety-depression model as a neuropsychiatric simulation we sought to quantify this cognitive endophenotype. Chicks exposed to an isolation stressor of 5m to induce an anxiety-like or 60 m to induce a depressive-like state were then tested in a straight alley maze to a series of morphed ambiguous appetitive (chick silhouette) to aversive (owl silhouette) cues. In non-isolated controls, runway start and goal latencies generally increased as a function of greater amounts of aversive characteristics in the cues. In chicks in the anxiety-like state, runway latencies were increased to aversive ambiguous cues, reflecting more pessimistic-like behavior. In chicks in the depression-like state, runway latencies were increased to both aversive and appetitive ambiguous cues, reflecting more pessimistic-like and less optimistic-like behavior, respectively.