Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

Greenwood, Benjamin N.; Strong, Paul V.; Foley, Teresa E.; Thompson, Robert S.; Fleshner, Monika

doi:10.1016/j.neuroscience.2006.11.007

Cited by 54 publications

(48 citation statements)

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“…This may not be the same for all paradigms as suggested by Greenwood et al, (2007) who showed that behavioral response was independent of hippocampal BDNF levels in their paradigm of learned helplessness where testing occurred in a novel environment. That study did however, show that wheel running protected against suppression of BDNF due to stress and suggested that this could counteract other behavioral consequences of reduced BDNF.…”

Section: Discussionmentioning

confidence: 82%

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice

et al. 2008

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Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment.

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Section: Discussionmentioning

confidence: 82%

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice

et al. 2008

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“…Alternatively or additionally, the impairment of 5-HT 2A receptor signaling may result from mutual interaction between the 5-HT 2A receptor and brain-derived neurotrophic factor (BDNF). Inescapable stress could decrease the BDNF levels in the brain possibly due to high levels of brain glucocorticoids (Vaidya et al, 1997;Xu et al, 2006;Duman and Monteggia, 2006;Greenwood et al, 2007), whereas the function of the 5-HT 2A receptor appears to depend on BDNF as knockout of BDNF severely impairs 5-HT 2A receptor signaling (Rios et al, 2006). Thus, decrease of BDNF by inescapable stress may also participate in the occurrence of the impairment of 5-HT 2A receptor signaling.…”

Section: -Ht 2a Receptor-mediated Serotonergic Facilitation Of Gaba mentioning

confidence: 99%

Stress Impairs 5-HT2A Receptor-Mediated Serotonergic Facilitation of GABA Release in Juvenile Rat Basolateral Amygdala

Jiang

Xing

Yang

et al. 2008

Neuropsychopharmacol

128

123

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The occurrence of stress and anxiety disorders has been closely associated with alterations of the amygdala GABAergic system. In these disorders, dysregulation of the serotonergic system, a very important modulator of the amygdala GABAergic system, is also well recognized. The present study, utilizing a learned helplessness stress rat model, was designed to determine whether stress is capable of altering serotonergic modulation of the amygdala GABAergic system. In control rats, administration of 5-HT or a-methyl-5-HT, a 5-HT 2 receptor agonist, to basolateral amygdala (BLA) slices dramatically enhanced frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). This effect was blocked by selective 5-HT 2A receptor antagonists while a selective 5-HT 2B receptor agonist and a selective 5-HT 2C receptor agonist were without effect on sIPSCs. Double immunofluorescence labeling demonstrated that the 5-HT 2A receptor is primarily localized to parvalbumin-containing BLA interneurons. Thus, serotonin primarily acts via 5-HT 2A receptors to facilitate BLA GABAergic inhibition. In stressed rats, the 5-HT 2A receptor-mediated facilitative actions were severely impaired. Quantitative RT-PCR and western blot analysis showed that the impairment of 5-HT 2A receptor signaling primarily resulted from receptor downregulation. The stress-induced effect appeared to be specific to 5-HT 2A receptors because stress had no significant impact on other serotonin receptors, as well as histamine H 3 receptor and a 2 adrenoceptor signaling in the BLA. This severe impairment of 5-HT 2A receptor-mediated facilitation of BLA GABAergic inhibition might result in an amygdala circuitry with hyperexcitability, and a lower threshold of activation, and thus be an important mechanism underlying the emergence of stress-associated psychiatric symptoms.

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“…The uncontrollable tail shock procedure followed protocols previously used in our laboratory that are known to produce exaggerated shock-elicited freezing and shuttle box escape deficits (Greenwood et al 2003(Greenwood et al , 2007b. Rats were randomly assigned to either be left in their home cages (No Stress) or to be exposed to the uncontrollable stress procedure (Stress).…”

Section: Uncontrollable Stressmentioning

confidence: 99%

“…Electrodes attached to the tail delivered 100 5-s tail shocks (1.5 mA) on a 1-min variable-interval schedule (Coulbourn Instruments, Allentown, PA, USA). This number and intensity of tail shocks were chosen based on prior work using this same stressor procedure (Greenwood et al 2003(Greenwood et al , 2007bMaier 1990) and a titration of the number of tail shocks required to produce escape deficits (Takase et al 2005). Following termination of shock, rats were returned to their home cages.…”

Section: Uncontrollable Stressmentioning

confidence: 99%

“…Behavioral testing procedures were similar to protocols previously used in our laboratory (Greenwood et al 2003(Greenwood et al , 2007b. Fear conditioning and shuttle box escape behavior took place sequentially in shuttle boxes (20″W×10″D×12″H, Coulbourn Instruments, Whitehall, PA, USA) consisting of a grid floor and Plexiglas walls.…”

Section: Behavioral Testingmentioning

confidence: 99%

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Anxiety-like behaviors produced by acute fluoxetine administration in male Fischer 344 rats are prevented by prior exercise

et al. 2008

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Rationale-Although selective 5-HT reuptake inhibitors (SSRIs) can reduce anxiety after chronic treatment, acute SSRI administration is associated with an increase in anxiety consistent with an acute increase in 5-HT neurotransmission. Exercise is anxiolytic in humans, and wheel running prevents anxiety-like behavioral consequences of uncontrollable stress in rats, but the effects of exercise on acute fluoxetine-induced anxiety-like behaviors are unknown.Objectives-The current studies tested the hypothesis that acute administration of the SSRI fluoxetine would produce behaviors in rats resembling those produced by uncontrollable stress and that these behaviors would be blocked by prior wheel running.Results-Adult, male Fisher 344 rats administered moderate (10 mg/kg) or high (20 mg/kg) doses of fluoxetine demonstrated exaggerated shock-elicited freezing and an interference with shuttle box escape compared to rats given either saline or low-dose fluoxetine (2.5 mg/kg). Fluoxetine-induced behaviors were similar to, but smaller in magnitude than, those produced by uncontrollable stress and were blocked by pretreatment with the 5-HT 2C receptor antagonist SB 242084 (1 mg/kg). Rats allowed access to running wheels for 6 weeks were protected against the anxiety-like behaviors produced by a single injection of fluoxetine (10 mg/kg).Conclusions-Behavioral effects of acute fluoxetine administration resemble those produced by uncontrollable stress. Results are consistent with the idea that exercise can produce resistance against the anxiogenic effects of acute increases in 5-HT and suggest that acute behavioral effects of antidepressants can depend on history of physical activity.

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Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

Cited by 54 publications

References 100 publications

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice

Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice

Stress Impairs 5-HT2A Receptor-Mediated Serotonergic Facilitation of GABA Release in Juvenile Rat Basolateral Amygdala

Anxiety-like behaviors produced by acute fluoxetine administration in male Fischer 344 rats are prevented by prior exercise

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