Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus

Abstract

Chronic stress produces structural changes and neuronal damage especially in the hippocampus. Because neurotrophic factors affect neuron survival, we questioned whether they might be relevant to the heightened vulnerability of hippocampal neurons following stress. To begin investigating this possibility, we examined the effects of immobilization stress (2 hr/d) on the expression of neurotrophic factors in rat brains using in situ hybridization. We found that single or repeated immobilization markedly reduced brain-derived neurotrophic factor (BDNF) mRNA levels in the dentate gyrus and hippocampus. In contrast, NT-3 mRNA levels were increased in the dentate gyrus and hippocampus in response to repeated but not acute stress. Stress did not affect the expression of neurotrophin-4, or tyrosine receptor kinases (trkB or C). Corticosterone negative feedback may have contributed in part to the stress-induced decreases in BDNF mRNA levels, but stress still decreased BDNF in the dentate gyrus in adrenalectomized rats suggesting that additional components of the stress response must also contribute to the observed changes in BDNF. However, corticosterone-mediated increases in NT-3 mRNA expression appeared to be primarily responsible for the effects of stress on NT-3. These findings demonstrate that BDNF and NT-3 are stress-responsive genes and raise the possibility that alterations in the expression of these or other growth factors might be important in producing some of the physiological and pathophysiological effects of stress in the hippocampus.

BDNF in schizophrenia, depression and corresponding animal models

“…20 However, there were no differences in baseline BDNF mRNA levels comparing two other strains of rats, one bred for helplessness in response to stress (cLH) and the other based on selection for resistance (cNLH). 99 These results are not consistent with the findings of other researchers using models of stress-induced depression, 17,21,22 where decreased central BDNF was demonstrated. Unchanged or increased BDNF levels in animal models of depression compared to controls would seem to be at variance with the assumed decreased CNS BDNF in human depression.…”

“…A genetic link between neurotrophins and schizophrenia is supported by the evidence that polymorphisms of the NT-3 and BDNF genes are associated with schizophrenia. [7][8][9] Lastly, findings that BDNF is decreased by factors correlated with first episode onset, such as stress 59,21 and estrogen withdrawal, 60 are also consistent with the putative BDNF role in schizophrenia. Interestingly, these stress-induced decreases in BDNF are blocked by 5-HT2 receptor antagonists, a receptor binding property of many neuroleptics.…”

“…Chronic administration of antidepressants increases BDNF expression in the hippocampus 17,18 BDNF has antidepressant-like activity in learned helplessness paradigms and the forced swim test 19 Environmental stressors decrease central BDNF mRNA 8 Higher BDNF levels in the frontal cortex, occipital cortex, and hypothalamus of the 'depressed' FSL animals relative to the FRL controls 20 Decreased central BDNF in models of stress-induced depression 17,21,22 Downregulation of the Trk-B signaling pathway in the genetic animal models of depression 23 ECS, used as an ECT model, increases BDNF in the hippocampus, striatum, and occipital cortex 24 Lithium increases the expression of BDNF in the hippocampus and cortex of rats 25 BDNF in schizophrenia and depression F Angelucci et al tissue from schizophrenic subjects and MRI data in vivo suggest ongoing specific neurodegeneration. 43 There is also strong evidence suggesting that nonheritable factors in the pathogenesis of schizophrenia are associated with abnormalities during prenatal development.…”

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…Further implicating a role for BDNF signaling in depression and anxiety, it has been shown that decreases in hippocampal BDNF levels are correlated with stressinduced depressive behaviors (Nibuya et al, 1995;Smith et al, 1995;Vaidya et al, 1997;Duman, 2004;Duman and Monteggia, 2006), and that antidepressant treatment enhances the expression of BDNF (Nibuya et al, 1995;Russo-Neustadt et al, 1999;Duman and Monteggia, 2006). Moreover, the BDNF gene as well as the Val66Met polymorphism have been associated with increased risk for a number of neuropsychiatric disorders (Neves-Pereira et al, 2002;Sklar et al, 2002;Schumacher et al, 2005;Strauss et al, 2005;Okada et al, 2006).…”

Maintenance Treatment with Fluoxetine is Necessary to Sustain Normal Levels of Synaptic Markers in an Experimental Model of Depression: Correlation with Behavioral Response

“…This factor has been found diminished in the rat hippocampus after acute and chronic stress (Smith et al, 1995;Scaccianoce et al, 2003) and has proved to possess antidepressant action in different models of depression (Shirayama et al, 2002). Moreover, chronic treatment with FLX promotes BDNF expression in the rat hippocampus (De Foubert et al, 2004) that in turn leads to activation of genes and biochemical pathways involved in plasticity and survival (Mattson et al, 2004).…”