Infusion Of Brain-derived Neurotrophic Factor Research Articles

Intracerebroventricular BDNF infusion may reduce cerebral ischemia/reperfusion injury by promoting autophagy and suppressing apoptosis.

Here, it was aimed to investigate the effects of intracerebroventricular (ICV) Brain Derived Neurotrophic Factor (BDNF) infusion for 7 days following cerebral ischemia (CI) on autophagy in neurons in the penumbra. Focal CI was created by the occlusion of the right middle cerebral artery. A total of 60 rats were used and divided into 4 groups as Control, Sham CI, CI and CI + BDNF. During the 7-day reperfusion period, aCSF (vehicle) was infused to Sham CI and CI groups, and BDNF infusion was administered to the CI + BDNF group via an osmotic minipump. By the end of the 7th day of reperfusion, Beclin-1, LC3, p62 and cleaved caspase-3 protein levels in the penumbra area were evaluated using Western blot and immunofluorescence. BDNF treatment for 7 days reduced the infarct area after CI, induced the autophagic proteins Beclin-1, LC3 and p62 and suppressed the apoptotic protein cleaved caspase-3. Furthermore, rotarod and adhesive removal test times of BDNF treatment started to improve from the 4th day, and the neurological deficit score from the 5th day. ICV BDNF treatment following CI reduced the infarct area by inducing autophagic proteins Beclin-1, LC3 and p62 and inhibiting the apoptotic caspase-3 protein while its beneficial effects were apparent in neurological tests from the 4th day.

Detection of Arc/Arg3.1 oligomers in rat brain: constitutive and synaptic activity-evoked dimer expression in vivo.

The immediate early gene product activity-regulated cytoskeleton-associated protein (Arc or Arg3.1) is a major regulator of long-term synaptic plasticity with critical roles in postnatal cortical development and memory formation. However, the molecular basis of Arc function is undefined. Arc is a hub protein with interaction partners in the postsynaptic neuronal compartment and nucleus. Previous in vitro biochemical and biophysical analysis of purified recombinant Arc showed formation of low-order oligomers and larger particles including retrovirus-like capsids. Here, we provide evidence for naturally occurring Arc oligomers in the mammalian brain. Using in situ protein crosslinking to trap weak Arc-Arc interactions, we identified in various preparations a prominent Arc immunoreactive band on SDS-PAGE of molecular mass corresponding to a dimer. While putative trimers, tetramers and heavier Arc species were detected, they were of lower abundance. Stimulus-evoked induction of Arc expression and dimer formation was first demonstrated in SH-SY5Y neuroblastoma cells treated with the muscarinic cholinergic agonist, carbachol, and in primary cortical neuronal cultures treated with brain-derived neurotrophic factor (BDNF). In the dentate gyrus (DG) of adult anesthetized rats, induction of long-term potentiation (LTP) by high-frequency stimulation (HFS) of medial perforant synapses or by brief intrahippocampal infusion of BDNF led to a massive increase in Arc dimer expression. Arc immunoprecipitation of crosslinked DG tissue showed enhanced dimer expression during 4 h of LTP maintenance. Mass spectrometric proteomic analysis of immunoprecipitated, gel-excised bands corroborated detection of Arc dimer. Furthermore, Arc dimer was constitutively expressed in naïve cortical, hippocampal and DG tissue, with the lowest levels in the DG. Taken together the results implicate Arc dimer as the predominant low-oligomeric form in mammalian brain, exhibiting regional differences in its constitutive expression and enhanced synaptic activity-evoked expression in LTP.

Intranasal Administration of Resolvin E1 Produces Antidepressant-Like Effects via BDNF/VEGF-mTORC1 Signaling in the Medial Prefrontal Cortex.

Intracerebroventricular infusion of resolvin E1 (RvE1), a bioactive metabolite derived from eicosapentaenoic acid, exerts antidepressant-like effects in a mouse model of lipopolysaccharide (LPS)-induced depression; these effects are blocked by systemic injection of rapamycin, a mechanistic target of rapamycin complex 1 (mTORC1) inhibitor. Additionally, local infusion of RvE1 into the medial prefrontal cortex (mPFC) or dorsal hippocampal dentate gyrus (DG) produces antidepressant-like effects. To evaluate the potential of RvE1 for clinical use, the present study examined whether treatment with RvE1 via intranasal (i.n.) route, a non-invasive route for effective drug delivery to the brain, produces antidepressant-like effects in LPS-challenged mice using tail suspension and forced swim tests. Intranasal administration of RvE1 significantly attenuated LPS-induced immobility, and these antidepressant-like effects were completely blocked by an AMPA receptor antagonist or L-type voltage-dependent Ca2+ channel blocker. The antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 were blocked by intra-mPFC infusion of a neutralizing antibody (nAb) for brain-derived neurotrophic factor (BDNF) or vascular endothelial growth factor (VEGF). Intra-mPFC infusion of rapamycin completely blocked the antidepressant-like effects of both i.n. and intra-mPFC administrations of RvE1 as well as those of intra-mPFC infusion of BDNF and VEGF. Moreover, i.n. RvE1 produced antidepressant-like effects via mTORC1 activation in the mPFC of a mouse model of repeated prednisolone-induced depression. Intra-dorsal DG infusion of BDNF and VEGF nAbs, but not rapamycin, blocked the antidepressant-like effects of i.n. RvE1. These findings suggest that i.n. administration of RvE1 produces antidepressant-like effects through activity-dependent BDNF/VEGF release in the mPFC and dorsal DG, and mTORC1 activation in the mPFC, but not in the dorsal DG. Thus, RvE1 can be a promising candidate for a novel rapid-acting antidepressant.

Aluminum Oxide Nanoparticles Impair Working Memory and Neuronal Activity through the GSK3β/BDNF Signaling Pathway of Prefrontal Cortex in Rats.

Studies demonstrated that alumina nanoparticles (alumina NPs) impair spatial cognition and hippocampus-dependent synaptic plasticity. Although alumina NPs accumulate in the prefrontal cortex (PFC), their effects on PFC-mediated neuronal and cognitive function have been not yet documented. Here, alumina NPs (10 or 20 μg/kg of body weight) were bilaterally injected into the medial PFC (mPFC) of adult rats, and the levels of glycogen synthase kinase 3β (GSK3β) and the brain-derived neurotrophic factor (BDNF) were detected. The PFC-dependent working memory task with one-minute or three-minute delay time was conducted. Meanwhile, the neuronal correlates of working memory performance were recorded. The specific expression of neuronal BDNF was assessed by colabeled BDNF expression with the neuronal nuclear antigen (NeuN). Whole-cell patch-clamp recordings were employed to detect neuronal excitability. Intra-mPFC alumina NP infusions significantly enhanced the expression of GSK3β but reduced the phosphorylation of GSK3β (pGSK3β) and BDNF levels more severely at a dose of 20 μg/kg. Alumina NPs acted in a dose-dependent manner to impair working memory. The neuronal expression of BDNF in the 20 μg/kg group was markedly declined compared with the 10 μg/kg group. During the delay time, the neuronal frequency of pyramidal cells but not interneurons was significantly weakened. Furthermore, both the frequency and amplitude of the excitatory postsynaptic currents (EPSCs) were descended in the mPFC slices. Additionally, the infusion of GSK3β inhibitor SB216763 or BDNF could effectively attenuate the impairments in neuronal correlate, neuronal activity, and working memory. From the perspective of the identified GSK3β/BDNF pathway, these findings demonstrated for the first time that alumina NPs exposure can be a risk factor for prefrontal neuronal and cognitive functions.

The BDNF-TrkB Pathway Acts Through Nucleus Accumbens D2 Expressing Neurons to Mediate Stress Susceptible Outcomes.

Brain-derived neurotrophic factor (BDNF) has a critical role in stress response including neuropsychiatric disorders that are precipitated by stress, such as major depressive disorder (MDD). BDNF acts through its full-length BDNF receptor tyrosine kinase B (TrkB) to trigger a pro-plasticity effect. In contrast, the truncated isoform of the BDNF receptor (TrkB.t1) triggers an anti-plasticity effect. In stress outcomes, BDNF acting in the hippocampus has a stress resilience effect, and, inversely, in the nucleus accumbens (NAc), BDNF acts as a stress susceptible molecule. It is unknown if BDNF-TrkB acts on a specific NAc projection neuron, i.e., medium spiny neuron (MSN or spiny projection neuron), a subtype in stress outcomes. To determine this, we performed chronic social or vicarious witness defeat stress (CSDS or CWDS) in mice expressing TrkB.t1 in dopamine receptor 1 or 2 containing MSNs (D1- or D2-MSNs). Our results showed that TrkB.t1 overexpression in NAc D2-MSNs prevented the CSDS-induced social avoidance or other stress susceptible behaviors in male and female mice. We further showed that this overexpression in D2-MSNs blocked stress susceptible behavior induced by intra-NAc BDNF infusion. In contrast, our results demonstrate that overexpression of TrkB.t1 on NAc D1-MSNs facilitates the SDS susceptible behaviors. Our study provides enhanced details into the NAc cell subtype role of BDNF-TrkB signaling in stress outcomes.

IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine

Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine. However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine. In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively). The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation. These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.

Brain-derived neurotrophic factor (BDNF) affects the activity of the gonadotrophic axis in sheep

This study aimed to examine the hypothesis that BDNF modulates the activity of the gonadotrophic axis in sheep. Central infusions of BDNF were administered to sexually mature Polish Merino sheep. The sheep were randomly divided into three groups: the control group received intracerebroventricular (ICV) infusions of the vehicle, the BDNF 10 group received ICV infusions of BDNF at 10 μg/480 μL/day, and the BDNF 60 group was infused with BDNF at 60 μg/480 μL/day. A series of four infusions on three consecutive days was performed. Blood samples were collected on days 0 and 3 of the infusions. Immediately after the experiment, all the sheep were slaughtered, and selected structures of the hypothalamus and pituitaries were collected for Real Time RT-qPCR analysis. The collected plasma samples, as well as parts of pituitaries were stored for radioimmunoassay analysis of LH and FSH.Central treatment with exogenous BDNF stimulated GnRH mRNA expression in the preoptic area, as well as GnRH-R mRNA in the pituitary. Furthermore, substantial changes in the KNDy mRNA expression in the mediobasal hypothalamus were observed after the ICV BDNF administration. Additionally, central BDNF infusion caused a decrease in LH concentration and a simultaneous increase in FSH concentration in peripheral blood. Neither pulse amplitude nor pulse frequency for any gonadotrophin was affected in both groups of sheep that received BDNF infusion.Our results revealed that exogenous BDNF affects GnRH and KNDy gene expression and changes in the LH and FSH pituitary cell secretory activities. These findings suggest that BDNF may participate in the mechanism modulating the activity of the gonadotrophic axis at the central level in female sheep.

Consecutive Treatment with Brain-Derived Neurotrophic Factor and Electrical Stimulation Has a Protective Effect on Primary Auditory Neurons.

Degeneration of neurons, such as the inner ear spiral ganglion neurons (SGN), may be decelerated or even stopped by neurotrophic factor treatment, such as brain-derived neurotrophic factor (BDNF), as well as electrical stimulation (ES). In a clinical setting, drug treatment of the SGN could start directly during implantation of a cochlear implant, whereas electrical stimulation begins days to weeks later. The present study was conducted to determine the effects of consecutive BDNF and ES treatments on SGN density and electrical responsiveness. An electrode drug delivery device was implanted in guinea pigs 3 weeks after deafening and five experimental groups were established: two groups received intracochlear infusion of artificial perilymph (AP) or BDNF; two groups were treated with AP respectively BDNF in addition to ES (AP + ES, BDNF + ES); and one group received BDNF from the day of implantation until day 34 followed by ES (BDNF ⇨ ES). Electrically evoked auditory brainstem responses were recorded. After one month of treatment, the tissue was harvested and the SGN density was assessed. The results show that consecutive treatment with BDNF and ES was as successful as the simultaneous combined treatment in terms of enhanced SGN density compared to the untreated contralateral side but not in regard to the numbers of protected cells.

The duration of the antidepressant-like effects of a single infusion of brain-derived neurotrophic factor into the medial prefrontal cortex in mice

Rapid release of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC) plays a critical role in the rapid and sustained antidepressant actions of ketamine, an N-methyl-d-aspartate receptor antagonist. Although our recent studies demonstrated that a single infusion of recombinant BDNF (100 ng/side) into the mPFC produced rapid antidepressant behavioral responses, the duration of the antidepressant-like effects of the single dose is unclear. Herein, we examined the duration of the antidepressant-like effects of intra-mPFC infusion of BDNF using male C57BL/6 J mice in two different behavioral paradigms namely, despair (forced swim test, FST) and motivation/reward (female urine sniffing test, FUST). Intra-mPFC BDNF infusion significantly decreased immobility time in the FST on days 1 and 7, but not 14 after the infusion. Similarly, BDNF significantly increased the time spent sniffing female urine in the FUST on days 3 and 8, but not 15 after the infusion. Intra-mPFC infusion of BDNF did not affect locomotor activity 2 days after the infusion. These results indicate that the antidepressant-like effects of a single intra-mPFC infusion of BDNF last for approximately one week and that this duration is similar to that of the antidepressant actions of ketamine.

Brain-Derived Neurotrophic Factor Affects mRNA and miRNA Expression of the Appetite Regulating Centre in the Sheep Arcuate Nucleus

Abstract The neuromodulatory effects of brain-derived neurotrophic factor (BDNF) on appetite regulation centre peptide gene activity in the sheep hypothalamus have not been examined yet. The aim of this study was to determine whether BDNF participates in modulation of neuropeptide Y (npy), agouti-related peptide (agrp), cocaine and amphetamine regulated transcript (cart), and proopiomelanocortin (pomc) mRNA expression and selected microRNAs in the sheep hypothalamic arcuate (ARC) nucleus. Animals (Polish Merino sheep, n=24) were divided into three groups. The control group received a central infusion of Ringer-Locke solution (480 µl/day) whereas the experimental groups were treated with BDNF in two doses: 10 or 60 μg/480 µl/day. All sheep received four intracerebroventricular infusions (performed from 08:40 a.m. to 01:30 p.m.; infusion scheme: 4 x 50 min infusions with 30 min intervals between them) on each of three consecutive days. Immediately after the last infusion, the sheep were slaughtered, and selected structures of the hypothalamus were frozen for further real-time qPCR analysis. Central infusion of BDNF evoked dose-dependent changes in npy, agrp, cart, pomc and peptidylglicine alpha-amidating monooxygenase (pam) mRNA expression in the sheep ARC nucleus. An increase in npy, agrp and pomc mRNA expression but also a decrease in cart mRNA expression in the ARC nucleus were detected. Moreover, a decrease in pam (gene encoding an enzyme that converts POMC into α-MSH) mRNA expression, was also noted. Furthermore, after central BDNF administration, changes in miRNA-33a-5p, miRNA-33b-5p, miRNA-377-3p, miRNA-214-3p, miRNA-485 and miRNA-488 expression were observed. Based on the presented results, it can be concluded that BDNF may affect the appetite regulating centre activity through modulation of npy, agrp, cart, pomc and pam mRNA expression in the ARC nucleus. It was also revealed that BDNF modulates miRNA expression in the sheep ARC nucleus.

A TrkB agonist and ampakine rescue synaptic plasticity and multiple forms of memory in a mouse model of intellectual disability

Fragile X syndrome (FXS) is associated with deficits in various types of learning, including those that require the hippocampus. Relatedly, hippocampal long-term potentiation (LTP) is impaired in the Fmr1 knockout (KO) mouse model of FXS. Prior research found that infusion of brain-derived neurotrophic factor (BDNF) rescues LTP in the KOs. Here, we tested if, in Fmr1 KO mice, up-regulating BDNF production or treatment with an agonist for BDNF's TrkB receptor restores synaptic plasticity and improves learning. In hippocampal slices, bath infusion of the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) completely restored otherwise impaired hippocampal field CA1 LTP of Fmr1 KOs without effect in wild types (WTs). Similarly, acute, semi-chronic, or chronic treatments with 7,8-DHF rescued a simple hippocampus-dependent form of spatial learning (object location memory: OLM) in Fmr1 KOs without effect in WTs. The agonist also restored object recognition memory, which depends on cortical regions. Semi-chronic, but not acute, treatment with the ampakine CX929, which up-regulates BDNF expression, lowered the training threshold for OLM in WT mice and rescued learning in the KOs. Positive results were also obtained in a test for social recognition. An mGluR5 antagonist did not improve learning. Quantification of synaptic immunolabeling demonstrated that 7,8-DHF and CX929 increase levels of activated TrkB at excitatory synapses. Moreover, CX929 induced a robust synaptic activation of the TrkB effector ERK1/2. These results suggest that enhanced synaptic BDNF signaling constitutes a plausible strategy for treating certain aspects of the cognitive disabilities associated with FXS.

Gadd45b mediates depressive-like role through DNA demethylation

Animal studies using chronic social defeat stress (CSDS) in mice showed that brain-derived neurotrophic factor (BDNF) signaling in the mesolimbic dopamine (DA) circuit is important for the development of social aversion. However, the downstream molecular targets after BDNF release from ventral tegmental area (VTA) DA terminals are unknown. Here, we show that depressive-like behaviors induced by CSDS are mediated in part by Gadd45b downstream of BDNF signaling in the nucleus accumbens (NAc). We show that Gadd45b mRNA levels are increased in susceptible but not resilient mice. Intra-NAc infusion of BDNF or optical stimulation of VTA DA terminals in NAc enhanced Gadd45b expression levels in the NAc. Importantly, Gadd45b downregulation reversed social avoidance in susceptible mice. Together, these data suggest that Gadd45b in NAc contributes to susceptibility to social stress. In addition, we investigated the function of Gadd45b in demethylating CpG islands of representative gene targets, which have been associated with a depressive phenotype in humans and animal models. We found that Gadd45b downregulation changes DNA methylation levels in a phenotype-, gene-, and locus-specific fashion. Together, these results highlight the contribution of Gadd45b and changes in DNA methylation in mediating the effects of social stress in the mesolimbic DA circuit.

Combined brain-derived neurotrophic factor with extinction training alleviate impaired fear extinction in an animal model of post-traumatic stress disorder.

Impaired fear memory extinction (Ext) is one of the hallmark symptoms of post-traumatic stress disorder (PTSD). However, since the precise mechanism of impaired Ext remains unknown, effective interventions have not yet been established. Recently, hippocampal-prefrontal brain-derived neurotrophic factor (BDNF) activity was shown to be crucial for Ext in naïve rats. We therefore examined whether decreased hippocampal-prefrontal BDNF activity is also involved in the Ext of rats subjected to a single prolonged stress (SPS) as a model of PTSD. BDNF levels were measured by enzyme-linked immunosorbent assay (ELISA), and phosphorylation of TrkB was measured by immunohistochemistry in the hippocampus and medial prefrontal cortex (mPFC) of SPS rats. We also examined whether BDNF infusion into the ventral mPFC or hippocampus alleviated the impaired Ext of SPS rats in the contextual fear conditioning paradigm. SPS significantly decreased the levels of BDNF in both the hippocampus and mPFC and TrkB phosphorylation in the ventral mPFC. Infusion of BDNF 24 hours after conditioning in the infralimbic cortex (ILC), but not the prelimbic cortex (PLC) nor hippocampus, alleviated the impairment of Ext. Since amelioration of impaired Ext by BDNF infusion did not occur without extinction training, it seems the two interventions must occur consecutively to alleviate impaired Ext. Additionally, BDNF infusion markedly increased TrkB phosphorylation in the ILC of SPS rats. These findings suggest that decreased BDNF signal transduction might be involved in the impaired Ext of SPS rats, and that activation of the BDNF-TrkB signal might be a novel therapeutic strategy for the impaired Ext by stress.

Increasing Brain-Derived Neurotrophic Factor (BDNF) in medial prefrontal cortex selectively reduces excessive drinking in ethanol dependent mice

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) has been implicated in a number of neuropsychiatric disorders, including alcohol use disorder. Studies have shown that BDNF activity in cortical regions, such as the medial prefrontal cortex (mPFC) mediates various ethanol-related behaviors. We previously reported a significant down-regulation in Bdnf mRNA in mPFC following chronic ethanol exposure compared to control mice. The present study was conducted to extend these findings by examining whether chronic ethanol treatment reduces BDNF protein expression in mPFC and whether reversing this deficit via direct injection of BDNF or viral-mediated overexpression of BDNF in mPFC alters voluntary ethanol consumption in dependent and nondependent mice. Repeated cycles of chronic intermittent ethanol (CIE) exposure was employed to model ethanol dependence, which produces robust escalation of ethanol intake. Results indicated that CIE treatment significantly increased ethanol intake and this was accompanied by a significant decrease in BDNF protein in mPFC that lasted at least 72 h after CIE exposure. In a separate study, once dependence-related increased drinking was established, bilateral infusion of BDNF (0, 0.25, 0.50 μg) into mPFC significantly decreased ethanol intake in a dose-related manner in dependent mice but did not affect moderate drinking in nondependent mice. In a third study, viral-mediated overexpression of BDNF in mPFC prevented escalation of drinking in dependent mice but did not alter intake in nondependent mice. Collectively, these results provide evidence that adaptations in cortical (mPFC) BDNF activity resulting from chronic ethanol exposure play a role in mediating excessive ethanol drinking associated with dependence.

BDNF infusion into the MPN mag is sufficient to restore copulatory behavior in the castrated Syrian hamster

Testosterone plays a key role in the expression of male sex behavior by influencing cellular activity and synapses within the magnocellular medial preoptic nucleus (MPN mag), a sub-nucleus of the medial preoptic area (MPOA) in the Syrian hamster. Although the mechanisms underlying hormonally-induced synaptic plasticity in this region remain elusive, the data suggests that an increase in synaptic density may mediate testosterone's effects on copulation. As brain derived neurotrophic factor (BDNF) plays an integral role in regulating synaptic plasticity and gonadal steroids regulate the levels of BDNF, we hypothesize that BDNF may mediate the effects of gonadal hormones on copulatory behavior. To test this hypothesis, we infused BDNF or controls into the MPN mag of long-term castrates. Our results indicate that BDNF, but not the controls, restored copulatory behavior in castrated male Syrian hamsters. Furthermore, the rise of BDNF expression in the MPOA preceded the rise of synaptophysin following testosterone replacement in castrated males. These data are consistent with our hypothesis, implicating a role for BDNF in mediating testosterone's action on copulation and suggest that the delay in testosterone's restoration of copulation is, in part, due to the delay in the increase of BDNF and synaptophysin.

Activated brain-derived neurotrophic factor/TrkB signaling in rat dorsal and ventral hippocampi following 10-day electroconvulsive seizure treatment

Electroconvulsive therapy (ECT) is still the most effective strategy to treat severe and drug-resistant depressive disorders. Electroconvulsive seizure (ECS), which induces neuroplastic structural alterations and resilient behavioral changes in experimental animals, is the model of the ECT for human depression. ECT is typically administered three times per week for up to 4 weeks, while ECS treatments are administered daily for 10days. The increased expression of hippocampal brain-derived neurotrophic factor (BDNF) induced by antidepressive ECS treatment in experimental animals has been well documented. BDNF executes various neuroplastic functions by phosphorylating its high-affinity receptor, full-length TrkB, which has an intrinsic tyrosine kinase domain. However, the exact activation of BDNF/TrkB signaling following multiple ECS treatments has not been well elucidated. In epileptogenesis, conflicting effects of BDNF have been reported; while acute BDNF administration enhanced neuronal hyperexcitability and induced epileptiform activities, continuous BDNF infusion inhibited epileptogenesis. These conflicting results have been attributed to agonist-induced adaptive response of expressional down-regulation of the BDNF receptor. In the present study, using western blotting, we demonstrated increased phosphorylation as well as decreased expression of the full-length TrkB receptor (145kD) in both dorsal and ventral hippocampal regions of rats after a 10-day ECS treatment. The expression of mature BDNF (14kD) was up-regulated while that of proBDNF (32kD) remained unaltered in both hippocampal regions after the ECS treatment. Our results indicate that the hippocampal BDNF/TrkB signaling pathway is activated by multiple ECS treatments despite the ligand-induced down-regulation of the full-length TrkB receptor.

Brain-derived neurotrophic factor in the infralimbic cortex alleviates inflammatory pain.

In chronic pain, it has been reported that the medial prefrontal cortex (mPFC) takes important regulatory roles, and may change functionally and morphologically in result of chronic pain. Brain-derived neurotrophic factor (BDNF) is well known as a critical modulator of neuronal excitability and synaptic transmission in the central nervous system. The aim of the present study is to investigate the role of BDNF in the infralimbic cortex and the prelimbic cortex of the mPFC in complete Freund's adjuvant (CFA)-induced inflammatory pain. We found that the BDNF level decreased in the infralimbic cortex, but not in the prelimbic cortex, 3days after the CFA induction of the inflammatory pain. BDNF infusion into bilateral infralimbic cortices to activate neuronal activities could alleviate inflammatory pain and accelerate long-term recovery from pain. In conclusion, BDNF in the infralimbic cortex of the mPFC could accelerate recovery from inflammatory pain.

Brain-derived neurotrophic factor downregulates immunoglobulin heavy chain binding protein expression after repeated cocaine administration in the rat dorsal striatum

Brain-derived neurotrophic factor (BDNF) is a key molecule involved in the regulation of glutamatergic neurotransmission in response to chronic stimulation of psychostimulants. This study demonstrated that BDNF in the dorsal striatum regulates the endoplasmic reticulum (ER) stress response after repeated exposure to cocaine. The results showed that unilateral intracaudate infusion of BDNF (0.40, 0.75, or 1.50μg/μL) decreased the repeated cocaine-induced increase in the expression of immunoglobulin heavy chain binding protein (BiP) sensing unfolded or misfolded proteins in a dose-dependent manner. Unilateral intracaudate infusion of BDNF (0.75μg/μL) also decreased the phosphorylation of c-Jun N-terminal kinase (JNK), which had been initially elevated by seven consecutive daily intraperitoneal injections of cocaine (20mg/kg/day). These decreases were reversed by unilateral intracaudate infusion of the specific tropomyosin receptor kinase B (TrkB) antagonist, cyclotraxin B (1ng/μL). These findings suggest that BDNF regulates the unfolded protein response via TrkB-linked JNK inactivation in the dorsal striatum after repeated cocaine administration, thus contributing to the restoration of the ER functions.

Effects of brain-derived neurotrophic factor (BDNF) on the cochlear nucleus in cats deafened as neonates

Many previous studies have shown significant neurotrophic effects of intracochlear delivery of BDNF in preventing degeneration of cochlear spiral ganglion (SG) neurons after deafness in rodents and our laboratory has shown similar results in developing cats deafened prior to hearing onset. This study examined the morphology of the cochlear nucleus (CN) in a group of neonatally deafened cats from a previous study in which infusion of BDNF elicited a significant improvement in survival of the SG neurons. Five cats were deafened by systemic injections of neomycin sulfate (60 mg/kg, SQ, SID) starting one day after birth, and continuing for 16–18 days until auditory brainstem response (ABR) testing demonstrated profound bilateral hearing loss. The animals were implanted unilaterally at about 1 month of age using custom-designed electrodes with a drug-delivery cannula connected to an osmotic pump. BDNF (94 μg/ml; 0.25 μl/hr) was delivered for 10 weeks. The animals were euthanized and studied at 14–23 weeks of age.Consistent with the neurotrophic effects of BDNF on SG survival, the total CN volume in these animals was significantly larger on the BDNF-treated side than on the contralateral side. However, total CN volume, both ipsi- and contralateral to the implants in these deafened juvenile animals, was markedly smaller than the CN in normal adult animals, reflecting the severe effects of deafness on the central auditory system during development. Data from the individual major CN subdivisions (DCN, Dorsal Cochlear Nucleus; PVCN, Posteroventral Cochlear Nucleus; AVCN, Anteroventral Cochlear Nucleus) also were analyzed. A significant difference was observed between the BDNF-treated and control sides only in the AVCN. Measurements of the cross-sectional areas of spherical cells showed that cells were significantly larger in the AVCN ipsilateral to the implant than on the contralateral side. Further, the numerical density of spherical cells was significantly lower in the AVCN ipsilateral to the implant than on the contralateral side, consistent with the larger AVCN volume observed with BDNF treatment. Together, findings indicate significant neurotrophic effects of intracochlear BDNF infusion on the developing CN.

Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking

Cocaine self-administration induces dysfunctional neuroadaptations in the prefrontal cortex that underlie relapse to cocaine-seeking. Cocaine self-administration disturbs glutamatergic transmission in the nucleus accumbens that is prevented by infusion of brain-derived neurotrophic factor (BDNF) into the prelimbic area of the prefrontal cortex. Intra-prelimbic infusion of BDNF decreases cocaine-seeking in a TrkB-ERK MAP kinase-dependent manner. Neuronal activity triggers an interaction between TrkB receptors and NMDA receptors, leading to ERK activation. In the present study, infusion of the GluN2A-containing NMDA receptor antagonist, TCN-201, or the GluN2B-containing NMDA receptor antagonist, Ro-25-6981, into the prelimbic cortex of rats blocked the suppressive effect of BDNF on cocaine-seeking. During early withdrawal from cocaine self-administration, tyrosine phosphorylation of ERK, GluN2A, and GluN2B in the prelimbic cortex was reduced and this reduction of phospho-proteins was prevented by intra-prelimbic BDNF infusion. TCN-201 infusion into the prelimbic cortex inhibited the BDNF-mediated increase in pERK and pGluN2A whereas Ro-25-6981 infusion into the prelimbic cortex blocked BDNF-induced elevation of pERK and pGluN2B, indicating that both GluN2A- and GluN2B-containing NMDA receptors underlie BDNF-induced ERK activation. These data demonstrate that BDNF-mediated activation of GluN2A- and GluN2B-containing NMDA receptors underlies ERK activation in the prelimbic cortex during early withdrawal, preventing subsequent relapse to cocaine-seeking.