Dataset Information

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

ABSTRACT: Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization-resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC, suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression.

SUBMITTER: Mikics E

PROVIDER: S-EPMC5635971 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

Mikics Éva É Guirado Ramon R Umemori Juzoh J Tóth Máté M Biró László L Miskolczi Christina C Balázsfi Diána D Zelena Dóra D Castrén Eero E Haller József J Karpova Nina N NN

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20170707 2

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-soci ...[more]

PMID: 28685757

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Project description:Morphological alterations in astrocytes are characteristic for post mortem brains of patients affected by major depressive disorder (MDD). Recently, a significant reduction in the coverage of blood vessels (BVs) by aquaporin-4 (AQP-4)-positive astrocyte endfeet has been shown in the prefrontal cortex (PFC) of MDD patients, suggesting that either alterations in the morphology of endfeet or in AQP-4 distribution might be responsible for the disease phenotype or constitute a consequence of its progress. Antidepressant drugs (ADs) regulate the expression of several proteins, including astrocyte-specific ones. Thus, they may target AQP-4 to induce morphological changes in astrocytes and restore their proper shape or relocate AQP-4 to endfeet. Using an animal model of depression, rats selectively bred for high anxiety-like behavior (HAB), we confirmed a reduced coverage of BVs in the adult PFC by AQP-4-immunoreactive (AQP-4-IR) astrocyte processes with respect to non-selected Wistar rats (NAB), thereby validating it for our study. A further evaluation of the morphology of astrocyte in brain slices (ex vivo) and in vitro using an antibody against the astrocyte-specific cytoskeletal protein glial fibrillary acidic protein (GFAP) revealed that HAB astrocytes extended less processes than NAB cells. Furthermore, short-term drug treatment in vitro with the AD fluoxetine (FLX) was sufficient to increase the plasticity of astrocyte processes, enhancing their number in NAB-derived cells and recovering their basal number in HAB-derived cells. This enhanced FLX-dependent plasticity occurred, however, only in the presence of intact AQP-4, as demonstrated by the lack of effect after the downregulation of AQP-4 with RNAi in both NAB and HAB cells. Nonetheless, a similar short-term treatment did neither modulate the coverage of BVs with AQP-4-positive astrocyte endfeet in NAB nor in HAB rats, although dosage and time of treatment were sufficient to fully recover GFAP expression in HAB brains. Thus, we suggest that longer treatment regimes may be needed to properly restore the coverage of BVs or to relocate AQP-4 to astrocyte endfeet. In conclusion, FLX requires AQP-4 to modulate the plasticity of astrocyte processes and this effect might be essential to re-establish a functional glia-vasculature interface necessary for a physiological communication between bloodstream and brain parenchyma.

Project description:BackgroundEarly drug intervention in childhood disorders aims to maximize individual potential in the short- and long-term. Consistently, juvenile exposure to psychostimulants, such as methylphenidate (MPH), reduces risk for substance use in animals and sub-populations of individuals with attention deficit hyperactivity disorder (ADHD). We investigated the effects of MPH on brain plasticity via dopamine receptor D3 (D3R) and brain-derived neurotrophic factor (BDNF) expression in developing rats.MethodsBetween postnatal days 20-35, rat pups were administered saline vehicle (Veh) or MPH (2 mg/kg), the D3R-preferring agonist ±7-OHDPAT, or the antagonist nafadotride (0.05 mg/kg) alone, or in combination with MPH twice a day. In adulthood, subjects were challenged to Veh or cocaine (10 mg/kg for two days). The prefrontal cortex was analyzed for protein and mRNA levels of total BDNF, its splice variants I, IIc, III/IV, and IV/VI, and D3 receptors. A separate group of subjects was assessed for splice variants at 20, 35, 40, and 60 days of age.ResultsAcross age strong correlations were evident between Drd3 and Bdnf mRNA levels (r = 0.65) and a negative relationship between Drd3 and exon IIc after MPH treatment (r = -0.73). BDNF protein levels did not differ between Veh- and MPH subjects at baseline, but were significantly lower in MPH-treated and cocaine challenged subjects (30.3 ± 9.7%). Bdnf mRNA was significantly higher in MPH-treated subjects, and reversed upon exposure to cocaine. This effect was blocked by nafadotride. Furthermore, Bdnf total and Bdnf splice variants I, IIc, III/IV, and IV/VI changed across the transitions between juvenility and late adolescence.ConclusionsThese data suggest a sensitive window of vulnerability to modulation of BDNF expression around adolescence, and that compared to normal animals, juvenile exposure to MPH permanently reduces prefrontal BDNF transcription and translation upon cocaine exposure in adulthood by a D3R-mediated mechanism.

Dataset Information

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

Publications

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

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