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

Berton, Olivier; McClung, Colleen A.; DiLeone, Ralph J.; Krishnan, Vaishnav; Renthal, William; Russo, Scott J.; Graham, Danielle; Tsankova, Nadia M.; Bolaños, Carlos A.; Rios, Maribel; Monteggia, Lisa M.; Self, David W.; Nestler, Eric J.

doi:10.1126/science.1120972

Cited by 1,883 publications

(1,830 citation statements)

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“…One or a combination of these factors could contribute to increased depression and aggression scores reported in response to n-3 PUFA deprivation in rats. 15,39,[59][60][61][62] As CREB has been implicated in the pathophysiology of depression as well as of bipolar disorder, 33,63,64 n-3 PUFAs' ability to regulate CREB could be related to their effects in these diseases. CREB requires phosphorylation in order to transcribe CREB-regulated genes, including BDNF.…”

Section: Discussionmentioning

confidence: 99%

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

et al. 2006

Mol Psychiatry

258

151

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Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.

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Section: Discussionmentioning

confidence: 99%

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

et al. 2006

Mol Psychiatry

258

151

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“…CSD has been reported to increase expression of fear freezing to context and CS (Yu et al, 2011). As noted in the Introduction, for CSD behavioural effects the major focus to-date has been on passive avoidance by CSD mice of mice from the dominant aggressor CD-1 strain in a social proximity test (Berton et al, 2006;Haque et al, 2012;Krishnan et al, 2007;Savignac et al, 2011a). In terms of helplessness theory, this effect constitutes increased emotional reactivity to the specific stimulus that induced the CSD (Russo et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. AbstractIn neuropsychiatric research, animal studies that demonstrate causal effects of environmental manipulations relevant to human aetiological factors on emotional and cognitive behaviours relevant to human psychopathologies are valuable. Such valid animal models can be useful for improved understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core psychopathology symptoms or features. In the present study we exposed adult male C57BL/6 mice to an environmental manipulation of 15-day psychosocial stress with loss of social control but with minimal physical wounding. One cohort of stressed and control mice was assessed in a novel 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. The socially stressed mice displayed dec...

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“…Conversely, inhibiting BDNFTrkB signaling via viral infection of dominant-negative TrkB-T1 in NAc elicits a dramatic anti-depressive effect (Eisch et al, 2003). Using a social defeat paradigm, Berton et al (2006) recently showed that repeated exposure to aggression results in long-lasting social withdrawal in mice. BDNF gene deletion in the NAc via injection of a Crerecombinase virus to mice carrying a floxed BDNF allele prevents social defeat, mirroring the effect obtained with chronic antidepressant treatment .…”

Section: Bdnfmentioning

confidence: 99%

Interaction between BDNF and Serotonin: Role in Mood Disorders

Martinowich

2007

Neuropsychopharmacol

674

458

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Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are two seemingly distinct signaling systems that play regulatory roles in many neuronal functions including survival, neurogenesis, and synaptic plasticity. A common feature of the two systems is their ability to regulate the development and plasticity of neural circuits involved in mood disorders such as depression and anxiety. BDNF promotes the survival and differentiation of 5-HT neurons. Conversely, administration of antidepressant selective serotonin reuptake inhibitors (SSRIs) enhances BDNF gene expression. There is also evidence for synergism between the two systems in affective behaviors and genetic epitasis between BDNF and the serotonin transporter genes.

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

Cited by 1,883 publications

References 38 publications

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

n-3 Polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Interaction between BDNF and Serotonin: Role in Mood Disorders

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