Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia

Molteni, Raffaella; Lipska, Barbara K.; Weinberger, Daniel R.; Racagni, Giorgio; Riva, Marco A.

doi:10.1038/sj.mp.4000865

Cited by 70 publications

(45 citation statements)

References 61 publications

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“…Accumulating data on the behavioral and neurobiological effects of NVHLs indicate that the adult syndrome entails changes in medial PfC regions that normally receive direct ventral hippocampal projections Carr and Sesack 1996). For example, N-acetylaspartate concentrations, taken as markers of neuronal integrity (Bertolino et al 2002) and stress-induced expression of brain derived neurotrophic factor (BDNF) mRNA expression, as a mediator of synaptic plasticity, are reduced in the medial PfC of NVHL rats (Molteni et al 2001). Both major excitatory and inhibitory transmitter systems in the PfC also appear to be altered by NVHLs, as evidenced by alterations in splice variants of AMPA glutamate receptor mRNA (Stine et al 2001), increased glutamate binding (Schroeder et al 1999), decreased concentrations of the γ-aminobutyric acid (GABA) production enzyme GAD-67 mRNA (Lipska et al 2003) and decreased pyramidal cell dendritic length and spine density .…”

Section: Discussionmentioning

confidence: 99%

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

et al. 2004

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Rational-Psychostimulant injections in rats have been shown to alter future performance in natural reward conditioning. These effects may represent a persistent impact of drugs on neurocircuits that interface cognitive and motivational processes, which may be further altered in neuropsychiatric conditions that entail increased addiction vulnerability.Objective-This study investigated whether a rat model of schizophrenia with cocaine addiction vulnerability shows altered natural reward conditioning with or without prior cocaine exposure.Methods-Adult rats with SHAM or neonatal ventral hippocampal lesions were given cocaine (15 mg/kg per day for 5 days) or saline injections, followed 7 days later by natural reward-conditioned learning. Over ten daily sessions, water-restricted rats were assessed for durations of head entries into a magazine during random water presentations, a conditioning stimulus phase predictive of the water reward, and an "inappropriate" phase when conditioning stimuli were absent and reward presentation would be delayed.Results-Over repeated sessions, lesioned and SHAM rats showed similar reductions in total magazine entry durations, with similar increases in the allocations of entry times during the water presentation. However, lesioned rats, especially those exposed to cocaine, demonstrated reduced allocations of magazine entry times during the conditioning stimulus phase, and increased allocations during the inappropriate phase.Conclusions-Intact natural reward motivation accompanied by deficient learning of complex contingencies to guide efficient reward approach may represent a form of impulsivity as an addiction vulnerability trait marker in an animal model of schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

et al. 2004

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“…Restraint (Molteni et al, 2001), immobilization (Lee et al, 2006), and IS all rapidly (within 1 hour) increase BDNF mRNA in the PFC. Here we report that IS can also increase BDNF protein in the PFC.…”

Section: The Role Of Bdnf In Lhmentioning

confidence: 99%

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

et al. 2007

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Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein.The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/ kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 hours later. Finally, bilateral injections of BDNF (1 μg) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats.These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

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“…We found no significant change in baseline prepubertal or adult levels of BDNF mRNA but a trend for a reduction in BDNF mRNA in the rodent prefrontal cortex after developmental damage to the ventral hippocampus. 45,91 In the rodent prefrontal cortex, BDNF mRNA that is normally induced by stress was deficient in young adult rats, which had experienced an early lesion of the ventral hippocampus. 91 These data support the notion that an early alteration in the developing brain may alter the ability of the frontal cortex to upregulate BDNF in response to environmental or hormonal demands later in life.…”

Section: Evaluation Of the Evidence For Model 1fepiphenomenamentioning

confidence: 99%

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia

et al. 2003

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Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean = 23%) and protein (mean = 40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder.

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Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia

Cited by 70 publications

References 61 publications

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

Natural reward-related learning in rats with neonatal ventral hippocampal lesions and prior cocaine exposure

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

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia

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