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Depression is a recurrent disorder, with about 50% of patients experiencing relapse. Exposure to stressful events may have an adverse impact on the long-term course of the disorder and may alter the response to a subsequent stressor. Indeed, not all the systems impaired by stress may normalize during symptoms remission, facilitating the relapse to the pathology. Hence, we investigated the long-lasting effects of chronic restraint stress (CRS) and its influence on the modifications induced by the exposure to a second hit on brain-derived neurotrophic factor (BDNF) signaling in the prefrontal cortex (PFC). We exposed adult male Sprague Dawley rats to 4 weeks of CRS, we left them undisturbed for the subsequent 3 weeks, and then we exposed animals to one hour of acute restraint stress (ARS). We found that CRS influenced the release of corticosterone induced by ARS and inhibited the ability of ARS to activate mature BDNF, its receptor Tropomyosin receptor kinase B (TRKB), and their associated intracellular cascades: the TRKB-PI3K-AKT), the MEK-MAPK/ERK, and the Phospholipase C γ (PLCγ) pathways, positively modulated by ARS in non-stressed animals. These results suggest that CRS induces protracted and detrimental consequences that interfere with the ability of PFC to cope with a challenging situation.

Although activity-dependent transcription represents a crucial mechanism for long-lasting experience-dependent changes in the hippocampus, limited data exist on its contribution to pathological conditions. We aim to investigate the influence of chronic stress on the activity-dependent transcription of brain-derived neurotrophic factor (BDNF). The ex vivo methodology of acute stimulation of hippocampal slices obtained from rats exposed to chronic mild stress (CMS) was used to evaluate whether the adverse experience may alter activity-dependent BDNF gene expression. CMS reduces BDNF expression and that acute depolarization significantly upregulates total BDNF mRNA levels only in control animals, showing that CMS exposure may alter BDNF transcription under basal conditions and during neuronal activation. Moreover, while the basal effect of CMS on total BDNF reflects parallel modulations of all the transcripts examined, isoform-specific changes were found after depolarization. This different effect was also observed in the activation of intracellular signaling pathways related to the neurotrophin. In conclusion, our study discloses a functional alteration of BDNF transcription as a consequence of stress. Being the activity-regulated transcription a critical process in synaptic and neuronal plasticity, the different regulation of individual BDNF promoters may contribute to long-lasting changes, which are fundamental for the vulnerability of the hippocampus to stress-related diseases.

Serotonin (5-HT) and brain-derived neurotrophin factor (BDNF) are known to modulate behavioral responses to stress and to mediate the therapeutic efficacy of antidepressant agents through neuroplastic and epigenetic mechanisms. While the two systems interact at several levels, this scenario is complicated by a number of variants including brain region specificity, 5-HT receptor selectivity and timing. Based on recent insights obtained using 5-HT transporter (5-HTT) knockout rats we here set-out and discuss the crucial role of neurodevelopmental mechanisms and the contribution of transcription factors and epigenetic modifications to this interaction and its variants. 5-HTT knockout in rats, as well as the low activity short allelic variant of the serotonin transporter human polymorphism, consistently show reduced BDNF mRNA and protein levels in the hippocampus and in the prefrontal cortex. This starts during the second postnatal week, is preceded by DNA hypermethylation during the first postnatal week, and it is developmentally paralleled by reduced expression of key transcription factors. The reduced BDNF levels, in turn, affect 5-HT1A receptor-mediated intracellular signaling and thereby the serotonergic phenotype of the neurons. We propose that such a negative spiral of modifications may affect brain development and reduce its resiliency to environmental challenges during critical time windows, which may lead to phenotypic alterations that persist for the entire life. The characterization of 5-HT-BDNF interactions will eventually increase the understanding of mental illness etiology and, possibly, lead to the identification of novel molecular targets for drug development., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Experimental evidence in mice indicates that environmental conditions affect females and males differently. However, in a recent study analyzing the heterozygous mutation of brain-derived neurotrophic factor (BDNF), both sexes presented a similar emotional phenotype, which became obvious only under impoverished, but not in enriched conditions suggesting an "enrichment-induced" rescue. To investigate the basis of this behavioral "rescue" effect, we analyzed neurochemical changes (BDNF expression, serotonergic changes, and corticosterone) in the hippocampus, frontal cortex and hypothalamus of animals housed under respective conditions. In male mice, enrichment induced an increase of BDNF expression in the hippocampus of both BDNF heterozygous (BDNF(+/-)) and wild-types. Notably, in enriched-reared BDNF(+/-) mice BDNF mRNA and protein increased to levels comparable to those of wild-types in impoverished environment. In the frontal cortex of males, only wild-types presented an enrichment-induced increase of BDNF mRNA, while no effect of environment could be detected in BDNF protein levels of the male hypothalamus. A further male-specific effect of "environment" is the significant reduction of hypothalamic 5-hydroxyindoleacetic acid in enriched-housed wild-types. In female mice, environmental enrichment did not affect BDNF expression in the hippocampus and hypothalamus. However, comparable to males, an enrichment-induced increase of BDNF mRNA was detected in the frontal cortex of wild-types only. In contrast to males, no influence of environment on serotonergic parameters was observed. Male and female corticosterone levels were neither affected by "genotype" nor by "environment". In conclusion, we propose that the rescue of the emotional phenotype by environmental enrichment in BDNF(+/-) mice is directed by distinct mechanisms in males and females. Only in male BDNF(+/-) mice the rescue is related to an increase in hippocampal BDNF expression suggesting that enrichment triggers different neuronal systems in a gender-specific manner., (Copyright © 2012. Published by Elsevier Ltd.)

Objectives: Alterations of BDNF signalling in major depression (MD) are supported by studies demonstrating decreased levels of the neurotrophin serum and plasma content in MD patients. We conducted a replication study and we performed two meta-analyses on studies analysing serum and plasma BDNF levels in MD patients., Methods: The samples were composed by 489 patients/483 controls for the meta-analysis on serum and by 161 patients/211 controls for that on plasma levels. We performed also subgroup analyses to examine whether the decrease in BDNF levels in MD was influenced by gender., Results: In the replication study we found decreased serum BDNF levels in MD patients (P<0.01) and we demonstrated that is down-regulated the mature form of the neurotrophin (mBDNF). No significant difference was evidenced for plasma BDNF levels. The meta-analyses showed a reduction of both BDNF serum (P<0.0001) and plasma levels (P=0.02) in MD. No difference in the effect size on serum BDNF was observed between males and females (P=0.18)., Conclusions: In conclusion, our results provide evidence of peripheral BDNF alteration in MD and support the rationale for further investigation aiming to the identification of biomarkers for differential diagnosis and personalization of therapies in this disorder.

Dysfunction of the serotonergic system is implicated in the etiology of many psychiatric disorders, including major depression. Major vulnerability genes for mood disorders are also related to the serotonergic system: one of these genes encodes for the serotonin transporter (SERT), which represent a major target for the action of antidepressant drugs. We have demonstrated recently that SERT knockout (KO) rats, generated by N-ethyl-N-nitrosourea-induced mutagenesis, show reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in the hippocampus and prefrontal cortex, suggesting that depression vulnerability can be associated with impaired neuronal plasticity. In the present study, we demonstrate that chronic treatment with the antidepressant duloxetine (DLX) was able to normalize the expression of BDNF mRNA-coding exon (IX) in the hippocampus and prefrontal cortex of SERT KO rats through the modulation of selected neurotrophin transcripts, whose expression was up-regulated by DLX only in SERT KO rats. On the other hand, the modulation of BDNF protein by DLX in frontal cortex was abolished in mutant rats. These data suggest that animals with a genetic defect of the serotonin transporter maintain the ability to show neuroplastic changes in response to antidepressant drugs. Because these animals show depression-like behavior, the region and isoform-specific increase of BDNF levels may be a mechanism activated by long-term antidepressant treatment to restore normal plasticity that is defective under genetic dysfunction of the serotonin transporter.

Increasing evidence suggests that depression is characterised by impaired brain plasticity that might originate from the interaction between genetic and environmental risk factors. Hence, the aim of this study was to investigate changes in neuroplasticity following exposure to stress, an environmental condition highly relevant to psychiatric disorders, in glucocorticoid receptor-deficient mice (GR(+/-)), a genetic model of predisposition to depression. Specifically, we have analysed the neurotrophin brain-derived neurotrophic factor (BDNF) and the immediate-early gene activity-regulated cytoskeletal-associated protein (Arc), two closely related molecules that can contribute to neuroplastic and morphological changes observed in depression. We found a region-specific influence of the GR-genotype on BDNF levels both under basal and stress conditions. Steady-state levels of BDNF mRNA were unchanged in hippocampus while up-regulated in frontal lobe of GR(+/-) mice. Following exposure to an acute stress, increased processing from pro- to mature BDNF was observed in hippocampal synaptosomes of wild-type mice, but not in GR mutants. Furthermore, the stress-dependent modulation of Arc was impaired in the hippocampus of GR(+/-) mice. These results indicate that GR(+/-) mice show overt differences in the stress-induced modulation of neuroplastic proteins, which may contribute to pathologic conditions that may originate following gene x environment interaction.

In order to identify the molecular mechanisms that may contribute to the enhanced susceptibility to depression under serotonin transporter (SERT) dysfunction, we analyzed the expression of brain-derived neurotrophic factor (BDNF), a key player in neuronal plasticity, which is implicated in the etiology and treatment of depression. We found that BDNF levels were significantly reduced in the hippocampus and prefrontal cortex of SERT knockout rats, through transcriptional changes that affect different neurotrophin isoforms. The reduction of BDNF gene expression observed in prefrontal cortex is due, at least in part, to epigenetic changes that affect the promoter regions of exons IV and VI. Moreover, BDNF gene expression is also significantly reduced in leukocytes from healthy subjects carrying the S allele of the 5-HTTLPR, suggesting that the changes observed in SERT mutant rats may also be present in humans and may confer enhanced vulnerability to mood disorders., (2009 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the acute modulation of the neurotrophin Brain-derived neurotrophic factor (BDNF) by the novel antidepressant agomelatine and the relative contribution of its melatonergic and serotonergic receptor components., Methods: BDNF mRNA levels were measured in rat hippocampus and prefrontal cortex after acute administration of agomelatine, melatonin or the 5-HT(2C) antagonist S32006., Results: BDNF expression was significantly increased 16 h after acute agomelatine administration, an effect that follows a specific temporal profile, is limited to the prefrontal cortex and it is due to changes of specific neurotrophin transcripts. Moreover, the acute up-regulation of BDNF mRNA levels appears to be the result of a synergistic effect between the melatonergic properties of agomelatine as MT1/MT2 agonist and its serotonergic 5-HT(2C) antagonism, since either melatonin or the 5-HT(2C) antagonist S32006 does not mimic the effects of agomelatine., Conclusions: These data provide evidence that acute agomelatine treatment modulates the expression of BDNF through a functional interaction between melatonergic MT1/MT2 and serotonergic 5-HT(2C) receptors, supporting the notion that intracellular events can be regulated via a synergistic activity of different neuromodulatory systems.

Although stress represents the major environmental element of susceptibility for mood disorders, the relationship between stress and disease remains to be fully established. In the present article we review the evidence in support for a role of neuronal plasticity, and in particular of neurotrophic factors. Even though decreased levels of norepinephrine and serotonin may underlie depressive symptoms, compelling evidence now suggests that mood disorders are characterized by reduced neuronal plasticity, which can be brought about by exposure to stress at different stages of life. Indeed the expression of neurotrophic molecules, such as the neurotrophin BDNF, is reduced in depressed subjects as well as in experimental animals exposed to adverse experience at early stages of life or at adulthood. These changes show an anatomical specificity and might be sustained by epigenetic mechanisms. Pharmacological intervention may normalize such defects and improve neuronal function through the modulation of the same factors that are defective in depression. Several studies have demonstrated that chronic, but not acute, antidepressant treatment increases the expression of BDNF and may enhance its localization at synaptic level. Antidepressant treatment can normalize deficits in neurotrophin expression produced by chronic stress paradigms, but may also alter the modulation of BDNF under acute stressful conditions. In summary, there is good agreement in considering neuronal plasticity, and the expression of key proteins such as the neurotrophin BDNF, as a central player for the effects of stress on brain function and its implication for psychopathology. Accordingly, effective treatments should not limit their effects to the control of neurotransmitter and hormonal dysfunctions, but should be able to normalize defective mechanisms that sustain the impairment of neuronal plasticity.

Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.

There is growing evidence that brain-derived neurotrophic factor (BDNF) can be relevant to mood disorders and that modulation of its biosynthesis following prolonged antidepressant treatment may contribute to neuroplastic changes required for clinical response. In the present study, we investigated the effects of the novel antidepressant duloxetine on BDNF in the rat brain. Duloxetine is a serotonin-norepinephrine reuptake inhibitor that differs from other antidepressants by virtue of its balanced potency on both neurotransmitter systems. We found that chronic, but not acute, treatment with duloxetine produces a robust increase of exon V BDNF mRNA levels in frontal cortex when the animals were killed 1 or 24 h after the last administration. The expression of the neurotrophin was also increased in other cortical subregions, but not in the hippocampus. We also found that the increased expression of BDNF in frontal cortex was mainly sustained by enhanced mRNA levels for exons I and III, whereas the expression of exon IV was reduced. Protein analysis in different subcellular fractions showed that chronic treatment with duloxetine, but not with the prototypical SSRI fluoxetine, reduced mature BDNF in the cytosol, but markedly increased its levels in the crude synaptosomal fraction. Our data suggest that chronic treatment with the novel antidepressant duloxetine not only produces a marked upregulation of BDNF mRNA and protein, but may also affect the subcellular redistribution of the neurotrophin. These changes might improve synaptic plasticity and cognitive function that are defective in depressed subjects.

During the last few years several studies have highlighted the possibility that major depression can be characterized by a general reduction in brain plasticity and an increased vulnerability under challenging situations. Such dysfunction may be the consequence of reduced expression and function of proteins important for neuroplasticity such as brain-derived neurotrophic factor (BDNF). On this basis, by using a sensitive non-radioactive in-situ hybridization, we evaluated the effects of a chronic treatment with fluoxetine on BDNF expression within rat dopaminergic regions. In fact, besides the well-established role of the hippocampus, increasing evidence indicates that other brain regions may be involved in the pathophysiology of depression and consequently be relevant for the therapeutic action of antidepressant drugs. Our results indicate that 3 wk of fluoxetine administration up-regulates BDNF mRNA levels selectively within structures belonging to the meso-cortico-limbic pathway. The expression of the neurotrophin is significantly increased in the ventral tegmental area, prefrontal cortex, and shell region of the nucleus accumbens, whereas no changes were detected in the substantia nigra and striatum. Moreover, in agreement with previous studies, fluoxetine increased BDNF mRNA levels in the hippocampus, an effect that was limited to the cell bodies without any change in its dendritic targeting. These data show that chronic treatment with fluoxetine increases BDNF gene expression not only in limbic areas but also in dopaminergic regions, suggesting that such an effect may contribute to improve the function of the dopaminergic system in depressed subjects.

Fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) are trophic factors, widely distributed in the adult brain, whose expression can be modulated by psychoactive drugs. Administration of the atypical antipsychotic quetiapine resulted in a marked elevation of FGF-2 and BDNF mRNA levels in the rat hippocampus, but only under conditions of reduced NMDA receptor activity. These effects were drug-specific, given that they were not observed with the conventional antipsychotic haloperidol; and anatomically defined, since no similar effect was observed in striatum, prefrontal or frontal cortex. These results suggest that quetiapine may promote neuroplasticity via the up-regulation of neurotrophic factors when NMDA-mediated transmission is perturbed.

Voluntary exercise leads to an upregulation of brain-derived neurotrophic factor (BDNF) and associated proteins involved in synaptic function. Activity-induced enhancement of neuroplasticity may be considered for the treatment of traumatic brain injury (TBI). Given that during the first postinjury week the brain is undergoing dynamic restorative processes and energetic changes that may influence the outcome of exercise, we evaluated the effects of acute and delayed exercise following experimental TBI. Male Sprague-Dawley rats underwent either sham or lateral fluid-percussion injury (FPI) and were housed with or without access to a running wheel (RW) from postinjury days 0-6 (acute) or 14-20 (delayed). FPI alone resulted in significantly elevated levels of hippocampal phosphorylated synapsin I and phosphorylated cyclic AMP response element-binding-protein (CREB) at postinjury day 7, of which phosphorylated CREB remained elevated at postinjury day 21. Sham and delayed FPI-RW rats showed increased levels of BDNF, following exercise. Exercise also increased phosphorylated synapsin I and CREB in sham rats. In contrast to shams, the acutely exercised FPI rats failed to show activity-dependent BDNF upregulation and had significant decreases of phosphorylated synapsin I and total CREB. Additional rats were cognitively assessed (learning acquisition and memory) by utilizing the Morris water maze after acute or delayed RW exposure. Shams and delayed FPI-RW animals benefited from exercise, as indicated by a significant decrease in the number of trials to criterion (ability to locate the platform in 7 s or less for four consecutive trials), compared with the delayed FPI-sedentary rats. In contrast, cognitive performance in the acute FPI-RW rats was significantly impaired compared with all the other groups. These results suggest that voluntary exercise can endogenously upregulate BDNF and enhance recovery when it is delayed after TBI. However, when exercise is administered to soon after TBI, the molecular response to exercise is disrupted and recovery may be delayed.

A diet high in total fat (HF) reduces hippocampal levels of brain-derived neurotrophic factor (BDNF), a crucial modulator of synaptic plasticity, and a predictor of learning efficacy. We have evaluated the capacity of voluntary exercise to interact with the effects of diet at the molecular level. Animal groups were exposed to the HF diet for 2 months with and without access to voluntary wheel running. Exercise reversed the decrease in BDNF and its downstream effectors on plasticity such as synapsin I, a molecule with a key role in the modulation of neurotransmitter release by BDNF, and the transcription factor cyclic AMP response element binding protein (CREB), important for learning and memory. Furthermore, we found that exercise influenced the activational state of synapsin as well as of CREB, by increasing the phosphorylation of these molecules. In addition, exercise prevented the deficit in spatial learning induced by the diet, tested in the Morris water maze. Furthermore, levels of reactive oxygen species increased by the effects of the diet were decreased by exercise. Results indicate that exercise interacts with the same molecular systems disrupted by the HF diet, reversing their effects on neural function. Reactive oxygen species, and BDNF in conjunction with its downstream effectors on synaptic and neuronal plasticity, are common molecular targets for the action of the diet and exercise. Results unveil a possible molecular mechanism by which lifestyle factors can interact at a molecular level, and provide information for potential therapeutic applications to decrease the risk imposed by certain lifestyles.

Brain-derived neurotrophic factor (BDNF) promotes a variety of neuromodulatory processes during development as well as in adulthood. This neurotrophin has been associated with synaptic plasticity, suggesting that its regulation may represent one of the mechanisms through which psychotropic drugs alter brain function. Because reduced glutamatergic function represents a major feature of schizophrenia, we investigated the effects of the concomitant administration of haloperidol or olanzapine with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 on BDNF expression. MK-801 reduces the hippocampal expression of the neurotrophin; this effect was exacerbated by haloperidol, but it was normalized by olanzapine. Our data reveal a fine tuning of BDNF biosynthesis and a differential modulation by antipsychotic drugs when NMDA-mediated transmission is reduced, suggesting that haloperidol and olanzapine can produce different effects on brain plasticity through the modulation of BDNF expression., (Copyright 2003 Wiley-Liss, Inc.)

We have conducted studies to determine the potential of dietary factors to affect the capacity of the brain to compensate for insult. Rats were fed with a high-fat sucrose (HFS) diet, a popularly consumed diet in industrialized western societies, for 4 weeks before a mild fluid percussion injury (FPI) or sham surgery was performed. FPI impaired spatial learning capacity in the Morris water maze, and these effects were aggravated by previous exposure of the rats to the action of the HFS diet. Learning performance decreased according to levels of brain-derived neurotrophic factor (BDNF) in individual rats, such that rats with the worst learning efficacy showed the lowest levels of BDNF in the hippocampus. BDNF immunohistochemistry localized the decreases in BDNF to the CA3 and dentate gyrus of the hippocampal formation. BDNF has a strong effect on synaptic plasticity via the action of synapsin I and cAMP-response element-binding protein (CREB), therefore, we assessed changes in synapsin I and CREB in conjunction with BDNF. Levels of synapsin I and CREB decreased in relation to decreases in BDNF levels. The combination of FPI and the HFS diet had more dramatic effects on the active state (phosphorylated) of synapsin I and CREB. There were no signs of neurodegeneration in the hippocampus of any rat group assessed with Fluoro-Jade B staining. The results suggest that FPI and diet impose a risk factor to the molecular machinery in charge of maintaining neuronal function under homeostatic and challenging situations.

We have investigated potential mechanisms by which exercise can promote changes in neuronal plasticity via modulation of neurotrophins. Rodents were exposed to voluntary wheel running for 3 or 7 days, and their lumbar spinal cord and soleus muscle were assessed for changes in brain-derived neurotrophic factor (BDNF), its signal transduction receptor (trkB), and downstream effectors for the action of BDNF on synaptic plasticity. Exercise increased the expression of BDNF and its receptor, synapsin I (mRNA and phosphorylated protein), growth-associated protein (GAP-43) mRNA, and cyclic AMP response element-binding (CREB) mRNA in the lumbar spinal cord. Synapsin I, a synaptic mediator for the action of BDNF on neurotransmitter release, increased in proportion to GAP-43 and trkB mRNA levels. CREB mRNA levels increased in proportion to BDNF mRNA levels. In separate experiments, the soleus muscle was paralyzed unilaterally via intramuscular botulinum toxin type A (BTX-A) injection to determine the effects of reducing the neuromechanical output of a single muscle on the neurotrophin response to motor activity. In sedentary BTX-A-treated rats, BDNF and synapsin I mRNAs were reduced below control levels in the spinal cord and soleus muscle. Exercise did not change the BDNF mRNA levels in the spinal cord of BTX-A-treated rats but further reduced the BDNF mRNA levels in the paralyzed soleus relative to the levels in sedentary BTX-A-treated rats. Exercise also restored synapsin I to near control levels in the spinal cord. These results indicate that basal levels of neuromuscular activity are required to maintain normal levels of BDNF in the neuromuscular system and the potential for neuroplasticity.

Brain-derived neurotrophic factor (BDNF), its signal transduction receptor trkB, and its downstream effector, synapsin I, were measured in the hippocampus and occipital cortex of young animals after fluid-percussion brain injury (FPI). Isofluorane anaesthetized postnatal day 19 rats were subjected to a mild lateral FPI or sham injury. Rats were sacrificed at 24 h, 7 days, or 14 days after injury in order to determine mRNA expression. Additional animals were sacrificed at 7 and 14 days after injury for protein analysis. Only FPI animals exhibited hemispheric differences in BDNF levels. These animals exhibited a contralateral increase, ranging from 40% to 75%, in BDNF mRNA within both the hippocampus and occipital cortex at 24 h and 7 days after injury. The increase in message within the occipital cortex was accompanied by an increase in BDNF protein at 7 and 14 days after injury. However, hippocampal BDNF protein increased in both hemispheres at postinjury day 7 and was restricted to the ipsilateral hippocampus at postinjury day 14. At postinjury day 7, both trkB and synapsin I mRNA expression increased ipsilaterally and decreased contralaterally in the occipital cortex. In addition, synapsin I phosphorylation was increased by 20% in the ipsilateral cortex and by 30% in the hippocampus on this day. These results indicate that the developing brain responds to a mild injury by modifying factors related to synaptic plasticity and suggest that regions remote from the site of injury express neurotrophic signals potentially needed for compensatory responses.

We have investigated a potential mechanism by which a diet, similar in composition to the typical diet of most industrialized western societies rich in saturated fat and refined sugar (HFS), can influence brain structure and function via regulation of neurotrophins. We show that animals that learn a spatial memory task faster have more brain-derived neurotrophic factor (BDNF) mRNA and protein in the hippocampus. Two months on the HFS diet were sufficient to reduce hippocampal level of BDNF and spatial learning performance. Consequent to the action of BDNF on synaptic function, downstream effectors for the action of BDNF on synaptic plasticity were reduced proportionally to BDNF levels, in the hippocampus of rats maintained on the HFS diet between 2 and 24 months. In particular, animals maintained on the HFS diet showed a decrease in levels of: (i) synapsin I mRNA and protein (total and phosphorylated), important for neurotransmitter release; (ii) cyclic AMP-response element-binding protein (CREB) mRNA and protein (total and phosphorylated); CREB is required for various forms of memory and is under regulatory control of BDNF; (iii) growth-associated protein 43 mRNA, important for neurite outgrowth, neurotransmitter release, and learning and memory. Diet-related changes were specific for the hippocampus consequent to its role in memory formation, and did not involve neurotrophin-3, another member of the neurotrophin family. Our results indicate that a popularly consumed diet can influence crucial aspects of neuronal and behavioral plasticity associated with the function of BDNF.

The neonatal (PND 7) lesion of the ventral hippocampus (VH) with ibotenic acid represents a well-established experimental paradigm that recapitulates many schizophrenia-like phenomena. In order to investigate molecular changes that could contribute to long lasting consequences on brain function, we have investigated the effects of the VH lesion on the expression for the trophic factors FGF-2 and BDNF. We used RNase protection assay to measure their mRNA levels in cortical regions of prepubertal (PND 35) and young adult (PND 56) animals, both under basal condition as well as in response to an acute restraint stress. The expression of BDNF was not altered by the VH lesion in prefrontal (PFC) and frontal cortex (FC) of PND 35 or PND 56 rats. An acute restraint stress at PND 35 produced a significant increase of the neurotrophin expression in PFC of sham as well as lesioned animals. However in young adult animals a significant elevation of BDNF expression was observed only in sham rats. We also found that the VH lesion produced a significant reduction of basal BDNF mRNA levels in the cingulate cortex of young adult, but not prepubertal rats. This effect was not accompanied by changes in the acute modulation of the neurotrophin, which was up-regulated by stress in both experimental groups. Conversely the expression of FGF-2 at PND 35 and PND 56 was not altered by early postnatal VH lesion, and there were no major differences between sham and lesioned animals in response to the acute stress. The changes in trophic factor expression may be relevant for the long-term effects of VH lesion on synaptic plasticity and may determine an increased vulnerability of the brain under challenging situations.

Neurotrophic factors (NTF) play important roles in the developing and in the adult brain. NTF involvement in neuronal plasticity is suggested by the modulation of NTF expression patterns in different physiological and pathological situations and by the effects they produce in the adult brain (e.g. axonal sprouting induction and neuroprotection). We used the RNAase protection assay to investigate the expression patterns of some NTFs during amygdala kindling, an animal model of epilepsy in which 'pathological' neuronal plasticity appears to occur. After a single kindling stimulation, fibroblast growth factor-2 (FGF-2) mRNA levels were increased in the hippocampus, the cortex and the hypothalamus, whereas they were not significantly altered in the thalamus and the striatum. A single stimulation did not alter fibroblast growth factor-1 (FGF-1) and brain-derived neurotrophic factor (BDNF) gene expression. Fully kindled animals, left unstimulated for a week, did not exhibit any alteration in the mRNA levels for any of the NTFs examined. However, in contrast with the effect of a single stimulation, amygdala stimulation of kindled animals (evoking a generalized tonic-clonic seizure) produced a great increase in hippocampal and cortical BDNF mRNA levels, but FGF-1 mRNA levels were not altered, and FGF-2 mRNA levels were significantly increased only in the cortex. These results suggest that different NTFs can be recruited at different stages of kindling epileptogenesis and, accordingly, may play different parts in the adaptive changes taking place in this experimental paradigm.