Changes In Brain-derived Neurotrophic Factor Expression Research Articles

Abstract P205: Age-dependent Alteration in Expression of Brain-derived Neurotrophic Factor and its Receptors in Central Nervous System of Spontaneously Hypertensive Rats.

Background and Aim: Essential hypertension is a cause unknown disease leading to heart disease, stroke and renal failure. Spontaneously hypertensive rats (SHR) are animal model of human essential hypertension and develop hypertension at 7-15-week-old. Several studies reported expression pattern of brain-derived neurotrophic factor (BDNF) changes in central nervous system (CNS) in SHR, suggesting that BDNF and its receptors might be related to increased blood pressure. However, age-dependent change in BDNF and receptors (TrkB and p75NTR) remains to be elucidated. This study aimed to clarify it. Method: Isolated brain tissues from SHR and control Wistar Kyoto Rats (WKY) at 4-, 7- and 15-week-old were dissected into five regions (cerebral cortex: CC; cerebellum: CB; brainstem: BS; hypothalamus: HT; hippocampus: HC). Protein and mRNA expression of BDNF, TrkB isoforms (FL, T1 and T2) and p75NTR as well as an inflammatory marker NOX-2 was examined by Western blotting and real-time PCR. Results: The following data showed significant difference in SHR compared with WKY (n = 4): pro-BDNF protein was lower by 49.9% (4-week, p < 0.05) and 38.2% (7-week, p < 0.05) in HT, while mature BDNF protein was lower by 21.9% in HC (15-week, p < 0.05). TrkB FL mRNA was higher by 32.5% in CB (7-week, p < 0.05) and 43.1% in BS (7-week, p < 0.05), while TrkB FL protein was higher by 51.4% in BS (15-week, p < 0.05). TrkB T1 mRNA was higher by 22.8% in BS (7-week, p < 0.05) and 17.2% in HT (15-week, p < 0.05), while TrkB T1 protein was higher by 56.1% in BS (4-week, p < 0.01). p75NTR protein was higher by 46.9% in CB (7-week, p < 0.05). NOX-2 mRNA was higher by 29.1% (4-week, p < 0.01), 104.2% (7-week, p < 0.01) and 75.8% (15-week, p < 0.05) in CC, 27.0% in CB (15-week, p < 0.05), 34.6% in BS (4-week, p < 0.05), 326.1% in HT (15-week, p < 0.01) and 29.8% in HC (7-week, p < 0.05). Conclusion: We for the first time revealed age-dependent changes in expression of BDNF and its receptors in CNS of SHR. Specifically, our results suggest that alteration of BDNF and TrkB expression is already occurred at juvenile before a stable blood pressure increase. The upregulation of NOX-2 was also identified. Further detailed study might identify whether and how BDNF-receptor-oxidative stress axis is related to pathogenesis of essential hypertension.

Long-term Administration of Salicylate-induced Changes in BDNF Expression and CREB Phosphorylation in the Auditory Cortex of Rats.

Hypothesis:We investigated whether salicylate induces tinnitus through alteration of the expression levels of brain-derived neurotrophic factor (BDNF), proBDNF, tyrosine kinase receptor B (TrkB), cAMP-responsive element-binding protein (CREB), and phosphorylated CREB (p-CREB) in the auditory cortex (AC).Background:Salicylate medication is frequently used for long-term treatment in clinical settings, but it may cause reversible tinnitus. Salicylate-induced tinnitus is associated with changes related to central auditory neuroplasticity. Our previous studies revealed enhanced neural activity and ultrastructural synaptic changes in the central auditory system after long-term salicylate administration. However, the underlying mechanisms remained unclear.Methods:Salicylate-induced tinnitus-like behavior in rats was confirmed using gap prepulse inhibition of acoustic startle and prepulse inhibition testing, followed by comparison of the expression levels of BDNF, proBDNF, TrkB, CREB, and p-CREB. Synaptic ultrastructure was observed under a transmission electron microscope.Results:BDNF and p-CREB were upregulated along with ultrastructural changes at the synapses in the AC of rats treated chronically with salicylate (p < 0.05, compared with control group). These changes returned to normal after 14 days of recovery (p > 0.05).Conclusion:Long-term administration of salicylate increased BDNF expression and CREB activation, upregulated synaptic efficacy, and changed synaptic ultrastructure in the AC. There may be a relationship between these factors and the mechanism of tinnitus.

Repeated cocaine exposure dysregulates BDNF expression and signaling in the mesocorticolimbic pathway of the adolescent rat

Objectives: Long-term abstinence following cocaine exposure up-regulates brain-derived neurotrophic factor (BDNF) expression in the mesocorticolimbic pathway. Given the increased vulnerability to drug abuse typical of adolescence, we hypothesized that changes in BDNF expression may become manifest early after the end of cocaine treatment in the adolescent brain.Methods: Rats received cocaine injections from postnatal day 28 (PND28) to PND42 and the mesocorticolimbic expression of BDNF was measured by real-time PCR and Western blotting at PND43.Results: In the ventral tegmental area, BDNF-tropomyosin receptor kinase B (TrΚB) expression and phosphorylation are enhanced while the intracellular signaling is unaltered. In the nucleus accumbens (NAc) shell and core, BDNF and its signaling were down-regulated. In the prelimbic (PL) cortex, we found reduced BDNF expression and increased phosphoprylation of TrΚB, ERK and AKT. In the infralimbic (IL) cortex, increased BDNF expression was coupled with reduced activity and expression of its downstream targets. To evaluate the role of glutamate on BDNF-independent changes, we investigated the expression of the transporter GLT-1 and the activation of the NMDA receptor subunit GluN2B, which were both increased in the PL cortex while reduced in the IL cortex.Conclusions: Our results show that adolescent cocaine exposure modulates BDNF system early after treatment in the mesocorticolimbic pathway, identifying a complex but specific set of changes that could provide clues for treatment.

Brain-Derived Neurotrophic Factor Expression in Individuals With Schizophrenia and Healthy Aging: Testing the Accelerated Aging Hypothesis of Schizophrenia

Schizophrenia has been hypothesized to be a syndrome of accelerated aging. Brain plasticity is vulnerable to the normal aging process and affected in schizophrenia: brain-derived neurotrophic factor (BDNF) is an important neuroplasticity molecule. The present review explores the accelerated aging hypothesis of schizophrenia by comparing changes in BDNF expression in schizophrenia with aging-associated changes. Individuals with schizophrenia show patterns of increased overall mortality, metabolic abnormalities, and cognitive decline normally observed later in life in the healthy population. An overall decrease is observed in BDNF expression in schizophrenia compared to healthy controls and in older individuals compared to a younger cohort. There is a marked decrease in BDNF levels in the frontal regions and in the periphery among older individuals and those with schizophrenia; however, data for BDNF expression in the occipital, parietal, and temporal cortices and the hippocampus is inconclusive. Accelerated aging hypothesis is supported based on frontal regions and peripheral studies; however, further studies are needed in other brain regions.

The BDNF Val66Met polymorphism is associated with structural neuroanatomical differences in young children

The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with individual differences in brain structure and function, and cognition. Research on BDNF's influence on brain and cognition has largely been limited to adults, and little is known about the association of this gene, and specifically the Val66Met polymorphism, with developing brain structure and emerging cognitive functions in children.We performed a targeted genetic association analysis on cortical thickness, surface area, and subcortical volume in 78 children (ages 6–10) who were Val homozygotes (homozygous Val/Val carriers) or Met carriers (Val/Met, Met/Met) for the Val66Met locus using Atlas-based brain segmentation. We observed greater cortical thickness for Val homozygotes in regions supporting declarative memory systems (anterior temporal pole/entorhinal cortex), consistent with adult findings. Met carriers had greater surface area in the prefrontal and parietal cortices and greater cortical thickness in lateral occipital/parietal cortex in contrast to prior adult findings that may relate to performance on cognitive tasks supported by these regions in Met carriers. Finally, we found larger right hippocampal volume in Met carriers, although inconsistent with adult findings (generally reports larger volumes for Val homozygotes), is consistent with a recent finding in children.Gene expression levels vary across different brain regions and across development and our findings highlight the need to consider this developmental change in explorations of BDNF-brain relationships. The impact of the BDNF Val66Met polymorphism on the structure of the developing brain therefore reflects regionally-specific developmental changes in BDNF expression and cortical maturation trajectories.

Auditory deprivation modifies the expression of brain-derived neurotrophic factor and tropomyosin receptor kinase B in the rat auditory cortex

The development and plasticity of central auditory system can be influenced by the change of peripheral neuronal activity. However, the molecular mechanism participating in the process remains elusive. Brain-derived neurotrophic factor (BDNF) binding with its functional receptor tropomyosin receptor kinase B (TrkB) has multiple effects on neurons. Here we used a rat model of auditory deprivation by bilateral cochlear ablation, to investigate the changes in expression of BDNF and TrkB in the auditory cortex after auditory deprivation that occurred during the critical period for the development of central auditory system. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry methods were adopted to detect the mRNA and protein expression levels of BDNF and TrkB in the auditory cortex at 2, 4, 6 and 8 weeks after surgery, respectively. The change in the expression of BDNF and TrkB mRNAs and proteins followed similar trend. In the bilateral cochlear ablation groups, the BDNF-TrkB expression level initially decreased at 2 weeks but increased at 4 weeks followed by the reduction at 6 and 8 weeks after cochlear removal, as compared to the age-matched sham control groups. In conclusion, the BDNF-TrkB signaling is involved in the plasticity of auditory cortex in an activity-dependent manner.

Effects of learning on mTOR pathway gene expression in the brain of zebrafish (Danio rerio) of different ages

Target of rapamycin (TOR) is a protein kinase involved in the modulation of mRNA translation and, therefore, in the regulation of protein synthesis. In neurons, the role of TOR is particularly important in the consolidation of long-term memory (LTM). One of the modulators of TOR is brain-derived neurotrophic factor (BDNF), which activates the TOR signaling pathway to promote protein synthesis, synapse strengthening, and the creation of new neural networks. We investigated the gene expression pattern of this pathway during memory consolidation in zebrafish of different ages. Our findings demonstrate that TOR activation in old animals occurs in the early phase of consolidation, and follows a pattern identical to that of BDNF expression. In younger animals, this increase in activation did not occur, and changes in BDNF expression were also not so remarkable. Furthermore, the expression of the main proteins regulated by the synthesis of TOR (i.e., 4EBP and p70S6K) remained identical to that of TOR in all age groups.

The effects of repetitive transcranial magnetic stimulation in an animal model of tinnitus.

Tinnitus (phantom auditory perception associated with hearing loss) can seriously affect wellbeing. Its neural substrate is unknown however it has been linked with abnormal activity in auditory pathways. Though no cure currently exists, repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce tinnitus in some patients, possibly via induction of cortical plasticity involving brain derived neurotrophic factor (BDNF). We examined whether low intensity rTMS (LI-rTMS) alleviates signs of tinnitus in a guinea pig model and whether this involves changes in BDNF expression and hyperactivity in inferior colliculus. Acoustic trauma was used to evoke hearing loss, central hyperactivity and tinnitus. When animals developed tinnitus, treatment commenced (10 sessions of 10 minutes 1 Hz LI-rTMS or sham over auditory cortex over 14 days). After treatment ceased animals were tested for tinnitus, underwent single-neuron recordings in inferior colliculus to assess hyperactivity and samples from cortex and inferior colliculus were taken for BDNF ELISA. Analysis revealed a significant reduction of tinnitus after LI-rTMS compared to sham, without a statistical significant effect on BDNF levels or hyperactivity. This suggests that LI-rTMS alleviates behavioural signs of tinnitus by a mechanism independent of inferior colliculus hyperactivity and BDNF levels and opens novel therapeutic avenues for tinnitus treatment.

POSSIBLE INVOLVEMENT OF BRAIN-DERIVED NEUROTROPHIC FACTOR IN MALE INFERTILITY

Brain-derived neurotrophic factor (BDNF) plays a role in the development of various non-neuronal tissues, as the reproductive system. BDNF transcript and protein has been detected in testis and sperms. The present work aimed to assess the possible involvement of BDNF mRNA expression in sperm functions, hormonal profile and oxidative stress in male infertility. Semen samples from 106 individuals attended the Andrology Outpatient Clinic, Mansoura University Hospital were included in the present study. They were grouped into normozoospermia (n= 31), asthenozoospermia (n= 24), astheno-teratozoospermia (n= 25) and Oligo-astheno-teratozoospermia (n= 26). Reverse transcription-PCR (RT-PCR) for brain-derived neurotrophic factor (BDNF) mRNA expression was done for semen samples. The present study demonstrated that BDNF mRNA expression was significantly decreased in the infertile samples compared with the normozoospermic group. BDNF mRNA expression was significantly positively correlated to testosterone levels (r= 0.337, p= 0.0004) while, negatively correlated to folliclestimulating hormone (FSH) (r= - 0.5, p 0.0001) and malondialdehyde (MDA) /sperm levels (r= - 0.735, p0.0001). Also, the study showed significant positive correlation (p<0.0001) between BDNF mRNA expression and sperm motility, velocity, linear velocity and linearity index. Stepwise multiple regression analysis showed that sperm morphology and alpha glucosidase may be possible determinants that influence changes of BDNF expression. BDNF mRNA may directly affect sperm functions and may be implicated in the pathophysiology of infertility. Furthermore, BDNF may have protection against oxidative stress. Keywords : Brain-Derived Neurotropic Factor (BDNF) mRNA expression, Infertility, Sperm function, Oxidative stress.

APOEε4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: A pilot study

Possession of the Apolipoprotein E (APOE) gene ε4 allele is the most prevalent genetic risk factor for late onset Alzheimer's disease (AD). Recent evidence suggests that APOE genotype differentially affects the expression of brain-derived neurotrophic factor (BDNF). Notably, aerobic exercise-induced upregulation of BDNF is well documented; and exercise has been shown to improve cognitive function. As BDNF is known for its role in neuroplasticity and survival, its upregulation is a proposed mechanism for the neuroprotective effects of physical exercise. In this pilot study designed to analyze exercise-induced BDNF upregulation in an understudied population, we examined the effects of APOEε4 (ε4) carrier status on changes in BDNF expression after a standardized exercise program. African Americans, age 55years and older, diagnosed with mild cognitive impairment participated in a six-month, supervised program of either stretch (control treatment) or aerobic (experimental treatment) exercise. An exercise-induced increase in VO2Max was detected only in male participants. BDNF levels in serum were measured using ELISA. Age, screening MMSE scores and baseline measures of BMI, VO2Max, and BDNF did not differ between ε4 carriers and non-ε4 carriers. A significant association between ε4 status and serum BDNF levels was detected. Non-ε4 carriers showed a significant increase in BDNF levels at the 6month time point while ε4 carriers did not. We believe we have identified a relationship between the ε4 allele and BDNF response to physiologic adaptation which likely impacts the extent of neuroprotective benefit gained from engagement in physical exercise. Replication of our results with inclusion of diverse racial cohorts, and a no-exercise control group will be necessary to determine the scope of this association in the general population.

Changes in expression of BDNF and its receptors TrkB and p75NTR in the hippocampus of a dog model of chronic alcoholism and abstinence.

Chronic ethanol consumption can produce learning and memory deficits. Brain-derived neurotrophic factor (BDNF) and its receptors affect the pathogenesis of alcoholism. In this study, we examined the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR) in the hippocampus of a dog model of chronic alcoholism and abstinence. Twenty domestic dogs (9-10 months old, 15-20 kg; 10 males and 10 females) were obtained from Harbin Medical University. A stable alcoholism model was established through ad libitum feeding, and anti-alcohol drug treatment (Zhong Yao Jie Jiu Ling, the main ingredient was the stems of watermelon; developed in our laboratory), at low- and high-doses, was carried out. The Zhong Yao Jie Jiu Ling was effective for the alcoholism in dogs. The morphology of hippocampal neurons was evaluated using hematoxylin-eosin staining. The number and morphological features of BDNF, TrkB and p75NTR-positive neurons in the dentate gyrus (DG), and the CA1, CA3 and CA4 regions of the hippocampus were observed using immunohistochemistry. One-way ANOVA was used to determine differences in BDNF, TrkB and p75NTR expression. BDNF, TrkB and p75NTR-positive cells were mainly localized in the granular cell layer of the DG and in the pyramidal cell layer of the CA1, CA3 and CA4 regions (DG>CA1>CA3>CA4). Expression levels of both BDNF and TrkB were decreased in chronic alcoholism, and increased after abstinence. The CA4 region appeared to show the greatest differences. Changes in p75NTR expression were the opposite of those of BDNF and TrkB, with the greatest differences observed in the DG and CA4 regions.

β‐Alanine Ingestion Improves Behavioral Responses to a Predator Scent Stress

β‐alanine (BA) has been proposed to reduce depression and anxiety‐like behavior. The purpose of this study was to investigate 30‐days of BA ingestion (100g•kg‐1) on the behavioral and neuroendocrine response of post‐traumatic stress disorder (PTSD) in a murine model. Following supplementation animals were exposed to a predator‐scent stress (PSS), which has been validated in an animal model stimulating PTSD‐like behavior. Behaviors were evaluated with the elevated plus maze and acoustic startle response (ASR)7 days following exposure. Immunohistochemical technique was used to detect expression of corticosterone (CS) and brain‐derived neurotrophic factor (BDNF). Animals exposed to PSS and not provided BA spent significantly less time in the open arms and more time in the closed arms of the maze than animals exposed to PSS but provided BA, or to unexposed animals. Rodents exposed, but provided BA had comparable scores to rodents unexposed and consumed BA. Anxiety index was higher (p&lt;0.05) in animals exposed to PSS and not provided BA compared to animals exposed and consumed BA or were unexposed. The ASR and freezing was greater (p&lt;0.05) in animals exposed to PSS compared to animals unexposed. CS expression was higher (p&lt;0.05) in animals exposed to PSS compared to unexposed animals. BDNF expression in the CA1 and DG subregions of the hippocampus was greater (p&lt;0.05) in animals unexposed, or animals exposed and provided BA compared to animals exposed and were not provided with BA. Results suggest that BA provides a reduction in the symptoms of PTSD‐like behavior, which may be mediated in part by changes of BDNF expression in the brain.

Prenatal Stress as a Risk Factor for Major Depression: an Investigation On Therapeutic Intervention with Antipsychotics and the Role of Social Stimuli During Periadolescence

Introduction Children exposed to adverse psychosocial experiences, or early parental loss, are at an increased risk for later depression. Preclinical data indicate that epigenetic regulation of gene expression mediates the effects of early life stress (ELS) on adult behavior and health. In addition to stress-responsive systems (glucocorticoids), the expression of neurotrophic factors in the brain may be regulated epigenetically in the context of ELS contributing to mental health, or systemic disease at adulthood. Objectives In order to investigate epigenetic changes in target genes involved in the long-term effects of early adversity on psychopathology, we have set up an animal model (rat) of prenatal stress. Results show that ELS leads to a long-term down-regulation in the expression of target genes, such as the receptor for glucocorticoids and Brain derived neurotrophic factor (BDNF), thus mimicking adult conditions characterizing increased risk for psychopathology. Behavioral and neuroendocrine changes accompanying these differences in gene expression suggest increased stress responsivity, as well as impaired social behavior. Chronic treatment with the antipsychotic lurasidone during adolescence was able to counteract the changes in BDNF expression produced by ELS, preventing the down-regulation of long 3’-UTR BDNF levels that occurred from late adolescence into young adulthood. Furthermore, interaction with a non-stressed rat conspecific ameliorated behavioural dysfunction. Overall data indicate potential therapeutic targets to counteract prenatal stress and suggest that the perinatal environment can act as a potential buffer for stressful conditions occurring around birth. Support: ERA net-NEURON 'Poseidon” and Fondazione Cariplo 2012.

Sex differences in depression-like behavior after nerve injury are associated with differential changes in brain-derived neurotrophic factor levels in mice subjected to early life stress

We recently demonstrated that exposure to early life stress exacerbates nerve injury-induced thermal and mechanical hypersensitivity in adult male and female mice. Accumulating evidence suggests that chronic pain causes emotional dysfunction, such as anxiety and depression. In the present study, we investigated the impact of early life stress on depression-like behavior after nerve injury in mice. In addition, we examined the expression of brain-derived neurotrophic factor (BDNF), which is known to be involved in the pathogenesis of depression. Early life stress was induced by maternal separation between 2 and 3 weeks of age combined with social isolation after weaning (MSSI). At 9 weeks of age, the sciatic nerve was partially ligated to elicit neuropathic pain. Depression-like behavior was evaluated using the forced swim test at 12 weeks of age. Tissue samples from different regions of the brain were collected at the end of maternal separation (3 weeks of age) or after the forced swim test (12 weeks of age). At 12 weeks of age, immobility time in the forced swim test was increased only in MSSI-stressed female mice with nerve injury. BDNF expression was increased in male, but not female, MSSI-stressed mice at 3 weeks of age. However, MSSI stress did not impact BDNF expression in male or female mice at 12 weeks of age. Our findings suggest that exposure to early life stress exacerbates emotional dysfunction induced by neuropathic pain in a sex-dependent manner. Changes in BDNF expression after early life stress may be associated with neuropathic pain-induced depression-like behavior in adulthood. Furthermore, sex differences in BDNF expression after exposure to early life stress may contribute to sex-specific susceptibility to neuropathic pain-induced emotional dysfunction.

Furin mediates brain-derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen-glucose deprivation.

This study investigated the changes in brain-derived neurotrophic factor (BDNF) expression and the role of furin in BDNF maturation in reactive astrocytes from rats exposed to oxygen-glucose deprivation (OGD). Furin, a proprotein convertase, is upregulated and cleaves certain substrates during hypoxia in cancer cells. In addition, during hypoxia in the central nervous system, astrocytes become reactive and release BDNF to protect neurons. Maturation of BDNF in astrocytes requires furin-mediated endoproteolytic processing of the precursor protein pro-BDNF to BDNF. To expand our knowledge about the role of furin in BDNF maturation in astrocytes, these cells were exposed to OGD, and expression of furin and BDNF was detected by Western blot analysis. Changes in BDNF expression were observed when furin activity was inhibited by furin prosegment. We found that protein expression of BDNF and furin was upregulated, and this upregulation correlated with OGD stimulation. Furin inhibition reduced BDNF maturation and secretion. These results indicate that furin mediates the upregulation of BDNF in reactive astrocytes exposed to OGD and that furin may impact the biological effect of reactive astrocytes.

Up-regulation of brain-derived neurotrophic factor in the dorsal root ganglion of the rat bone cancer pain model.

Metastatic bone cancer causes severe pain, but current treatments often provide insufficient pain relief. One of the reasons is that mechanisms underlying bone cancer pain are not solved completely. Our previous studies have shown that brain-derived neurotrophic factor (BDNF), known as a member of the neurotrophic family, is an important molecule in the pathological pain state in some pain models. We hypothesized that expression changes of BDNF may be one of the factors related to bone cancer pain; in this study, we investigated changes of BDNF expression in dorsal root ganglia in a rat bone cancer pain model. As we expected, BDNF mRNA (messenger ribonucleic acid) and protein were significantly increased in L3 dorsal root ganglia after intra-tibial inoculation of MRMT-1 rat breast cancer cells. Among the eleven splice-variants of BDNF mRNA, exon 1–9 variant increased predominantly. Interestingly, the up-regulation of BDNF is localized in small neurons (mostly nociceptive neurons) but not in medium or large neurons (non-nociceptive neurons). Further, expression of nerve growth factor (NGF), which is known as a specific promoter of BDNF exon 1–9 variant, was significantly increased in tibial bone marrow. Our findings suggest that BDNF is a key molecule in bone cancer pain, and NGF-BDNF cascade possibly develops bone cancer pain.

Housing environment modulates physiological and behavioral responses to anxiogenic stimuli in trait anxiety male rats

Environmental enrichment can modulate mild and chronic stress, responses to anxiogenic stimuli as well as drug vulnerability in a number of animal models. The current study was designed to examine the impact of postnatal environmental enrichment on selectively bred 4th generation high- (HAn) and low-anxiety (LAn) male rats. After weaning, animals were placed in isolated (IE), social (SE) and enriched environments (EE) (e.g., toys, wheels, ropes, changed weekly). We measured anxiety-like behavior (ALB) on the elevated plus maze (EPM; trial 1 at postnatal day (PND) 46, trial 2 at PND 63), amphetamine (AMPH) (0.5mg/kg, IP)-induced locomotor behavior, basal and post anxiogenic stimuli changes in (1) plasma corticosterone, (2) blood pressure and (3) core body temperature. Initially, animals showed consistent trait differences on EPM with HAn showing more ALB but after 40days in select housing, HAn rats reared in an EE showed less ALB and diminished AMPH-induced activity compared to HAn animals housed in IE and SE. In the physiological tests, animals housed in EE showed elevated adrenocortical responses to forced novel object exposure but decreased body temperature and blood pressure changes after an air puff stressor. All animals reared in EE and SE had elevated brain-derived neurotrophic factor (BDNF)-positive cells in the central amygdala (CeA), CA1 and CA2 hippocampal regions and the caudate putamen, but these differences were most pronounced in HAn rats for CeA, CA1 and CA2. Overall, these findings suggest that environmental enrichment offers benefits for trait anxiety rats including a reduction in behavioral and physiological responses to anxiogenic stimuli and AMPH sensitivity, and these responses correlate with changes in BDNF expression in the central amygdala, hippocampus and the caudate putamen.

Neotrofin reverses the effects of chronic unpredictable mild stress on behavior via regulating BDNF, PSD-95 and synaptophysin expression in rat

Depression is one of the most common neuropsychiatric disorders and has been associated with a wide range of neuronal structural changes in brain regions. Neotrofin, a neurotrophin agonist, has been demonstrated to exhibit neuroprotection in various in vivo and in vitro studies. The present study aimed to investigate the neuroprotective and ameliorating effects of neotrofin treatment in a rat model of chronic unpredictable mild stress (CUMS) induced depression. The results showed that CUMS was effective in producing depression-like behavior in rats as indicated by decreased responses in the sucrose preference test, and locomotor activity in the open-field test. Moreover, the expression of brain-derived neurotrophic factor (BDNF), PSD-95 and synaptophysin were decreased in the amygdala of CUMS rats. Chronic administration of neotrofin (60mg/kg, i.p., 5 weeks) significantly ameliorated all these behavioral and biochemical alterations associated with CUMS induced depression, which demonstrated that the expression changes of BDNF, PSD-95 and synaptophysin were correlated with the depression-like behaviors of CUMS rats. Taken together, the results of the present study highlight that neotrofin exhibits neuroprotective and antidepressant-like effects against CUMS induced depression, and suggest a possible mechanism for this protection via changes in synaptic plasticity within the amygdala. These findings reveal the therapeutic potential of neotrofin for use in clinical trials in the treatment of neuronal deterioration in depression.

Altered Brain-Derived Neurotrophic Factor Expression in the Ventral Tegmental Area, but not in the Hippocampus, Is Essential for Antidepressant-Like Effects of Electroconvulsive Therapy

Impaired neuronal plasticity and, specifically, altered expression of brain-derived neurotrophic factor (BDNF) were shown to play a critical role in depressive behavior and the mechanism of various antidepressant treatments including electroconvulsive therapy (ECT). Interestingly, opposing roles were suggested for BDNF in the hippocampus and the ventral tegmental area (VTA), while interactions between these regions were shown on various levels. Here, we evaluated whether BDNF plays an essential role in the antidepressant-like effects of ECT and performed a direct comparison between BDNF manipulations in the VTA and the hippocampus. Knockdown or overexpression of BDNF was induced in hippocampus or VTA of rats by microinjection of specific lentiviral vectors. The effects of these manipulations on antidepressant outcomes of ECT were evaluated by the forced swim test and by sucrose preference measurements, and BDNF expression levels were assessed in other reward-related brain regions. Here, we show that whereas ECT increased hippocampal BDNF expression, induction of hippocampal BDNF knockdown did not block its antidepressant-like effect. Importantly, we found that ECT caused a robust reduction in VTA BDNF levels. Moreover, VTA BDNF knockdown alone was sufficient to induce an antidepressant-like effect, and VTA BDNF overexpression blocked the antidepressant-like effect of ECT. While neuroplastic alterations, as expressed by changes in BDNF expression within different brain regions, are induced by ECT, the antidepressant-like effect of ECT in an animal model depends on reduction of VTA BDNF expression but not on the elevation of hippocampal BDNF expression.

The dopamine D1 but not D3 receptor plays a fundamental role in spatial working memory and BDNF expression in prefrontal cortex of mice

Although dopamine within the prefrontal cortex has been implicated in working memory, how different dopamine receptor subtypes contribute to this process need to be further characterized. Previous studies have suggest the importance of dopamine receptors signaling in regulating the brain-derived neurotrophic factor (BDNF) function that is associated with synaptic plasticity underlying normal memory formation. Changes in BDNF expression through the dopamine receptors within the prefrontal cortex may accompany and mediate the spatial working memory. To test the possibility, dopamine D1 and D3 receptor mutant mice were tested in Morris water maze for spatial working memory. We found that trial-dependent, matching-to-sample, learning of the platform location, an index of short-term spatial working memory in mice, was significantly impaired in D1 receptor knockout mice compared to wild-type mice, and regular performance of D3 receptor mutants was observed in the similar working memory task. BDNF protein was significantly decreased in prefrontal cortex, though not in hippocampus, of the D1 receptor knockout mice, whereas no changes were found in both prefrontal cortex and hippocampus of D3 receptor knockout mice. These data suggest that dopamine D1 but not D3 receptors are critical for prefrontal cortex BDNF expression which may be related to spatial working memory processes.