Deletion Of Bdnf Research Articles

BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury.

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNFPax2-KO) versus the auditory cortex and hippocampus (BDNFTrkC-KO). We demonstrate that BDNFPax2-KO but not BDNFTrkC-KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNFPax2 mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNFPax2-KO, but not of BDNFTrkC-KO mice. Also, BDNFPax2-WT but not BDNFPax2-KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.

Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and Energy Expenditure

Brain-derived neurotrophic factor (BDNF) is a key regulator of energy balance; however, its underlying mechanism remains unknown. By analyzing BDNF-expressing neurons in paraventricular hypothalamus (PVH), we have uncovered neural circuits that control energy balance. The Bdnf gene in the PVH was mostly expressed in previously undefined neurons, and its deletion caused hyperphagia, reduced locomotor activity, impaired thermogenesis, and severe obesity. Hyperphagia and reduced locomotor activity were associated with Bdnf deletion in anterior PVH, whereas BDNF neurons in medial and posterior PVH drive thermogenesis by projecting to spinal cord and forming polysynaptic connections to brown adipose tissues. Furthermore, BDNF expression in the PVH was increased in response to cold exposure, and its ablation caused atrophy of sympathetic preganglionic neurons. Thus, BDNF neurons in anterior PVH control energy intake and locomotor activity, whereas those in medial and posterior PVH promote thermogenesis by releasing BDNF into spinal cord to boost sympathetic outflow.

The paraventricular thalamus controls a central amygdala fear circuit.

Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behavior. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors1-3. However, the role of PVT in the establishment of adaptive behavioral responses remains unclear. Here we show in mice that PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression4,5. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM+) CeL neurons, which has previously been shown to store fear memory6. Consistently, we found that PVT neurons preferentially innervate SOM+ neurons in the CeL, and stimulation of PVT afferents facilitated SOM+ neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression5,6. Notably, PVT modulation of SOM+ CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in PVT or Trkb in SOM+ CeL neurons impaired fear conditioning, while infusion of BDNF into CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT–CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behavior.

Astrocyte-derived BDNF supports myelin protein synthesis after cuprizone-induced demyelination.

It is well established that BDNF may enhance oligodendrocyte differentiation following a demyelinating lesion, however, the endogenous sources of BDNF that may be harnessed to reverse deficits associated with such lesions are poorly defined. Here, we investigate roles of astrocytes in synthesizing and releasing BDNF. These cells are known to express BDNF following injury in vivo. In culture, they increase BDNF synthesis and release in response to glutamate metabotropic stimulation. Following cuprizone-elicited demyelination in mice, astrocytes contain BDNF and increase levels of metabotropic receptors. The metabotropic agonist, trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD), was therefore injected into the demyelinating lesion. Increases in BDNF, as well as myelin proteins, were observed. Effects of ACPD were eliminated by coinjection of trkB-Fc to locally deplete BDNF and by deletion of astrocyte-derived BDNF. The data indicate that astrocyte-derived BDNF may be a source of trophic support that can be used to reverse deficits elicited following demyelination.

Correction: Heldt et al., Bdnf Deletion or TrkB Impairment in Amygdala Inhibits Both Appetitive and Aversive Learning

Correction: Heldt et al., Bdnf Deletion or TrkB Impairment in Amygdala Inhibits Both Appetitive and Aversive Learning

BDNF deletion or TrkB impairment in amygdala inhibits both appetitive and aversive learning.

Brain-derived neurotrophic factor (BDNF) is known to have an integral role in establishing stable memories after learning events. The neuroplasticity induced by Pavlovian fear conditioning has likewise been shown to rely on interactions between BDNF and its principal receptor, tyrosine kinase receptor B (TrkB), in the amygdala after training. Although the necessity of amygdala bdnf expression and TrkB activation for associative learning within aversive contexts has been explored, it is unclear to what extent this interaction is involved in appetitive learning. It is also unclear whether the noted increases in amygdala BDNF after fear conditioning are due to local gene transcription and translation or anterograde transmission from cortical regions. To address both of these questions, we used two lentiviral approaches in mice, using both fear conditioning and cocaine-conditioned place preference (CPP), during acquisition and extinction. First, we decreased expression of bdnf mRNA in the amygdala of homozygous floxed mice with a Cre-expressing virus. In a second set of studies, we infused a virus that expressed a dominant-negative TrkB isoform into the same region. These approaches significantly impaired consolidation of fear conditioning and cocaine-CPP, as well as extinction of CPP. Together, these data suggest that BDNF-TrkB signaling is critical for amygdala-dependent learning of both appetitive and aversive emotional memories.

Prelimbic BDNF and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning

The medial prefrontal cortex (mPFC) is known to regulate executive decisions and the expression of emotional memories. More specifically, the prelimbic cortex (PL) of the mPFC is implicated in driving emotional responses via downstream targets including the nucleus accumbens and amygdala, but mechanisms are yet to be fully understood. Therefore, we investigated whether prelimbic cortical brain-derived neurotrophic factor (BDNF) signaling through the high-affinity tyrosine kinase receptor B (TrkB) receptor may serve as a molecular mechanism underlying emotional memory encoding. Here, we utilized viral-mediated inducible bdnf deletion within the PL, as well as TrkBF616A mutant mice, wherein TrkB receptor point mutation results in its being highly sensitive to inhibition by small PP1-derivative molecules, serving as a specific TrkB inhibitor. The site-specific TrkB antagonism and viral-mediated bdnf deletion within the PL resulted in deficits in both cocaine-dependent associative learning and fear expression. Deficiencies were rescued by the novel TrkB agonist 7,8-dihydroxyflavone, indicating that PL BDNF expression and downstream signaling through the TrkB receptor are required for memory formation in both appetitive and aversive domains.

New Insights Into BDNF Signaling: Relevance to Major Depression and Antidepressant Action

Major depressive disorder is a serious multifactorial mental illness that is characterized by disruptions in multiple symptom domains, including affect, reward, suicidality, cognition, and homeostasis (1). According to the National Institute of Mental Health, it is the leading cause of disability for individuals 15–44 years old, affecting 18.4 million Americans (or 6.7% of the adult population) each year (2). Its prevalence is higher in women, who often report more severe symptoms and longer illness duration. Only 36.8% of patients achieve remission in response to first-line treatment, and a cumulative total of 67% achieve remission following multiple treatment trials that may take several months or years (3). Given its burden of disease, it is imperative that we improve our understanding of the pathophysiology of major depression, with the hope of developing more efficacious treatments.

CD4+ T cell-mediated neuroprotection is independent of T cell-derived BDNF in a mouse facial nerve axotomy model

The production of neurotrophic factors, such as BDNF, has generally been considered an important mechanism of immune-mediated neuroprotection. However, the ability of T cells to produce BDNF remains controversial. In the present study, we examined mRNA and protein of BDNF using RT-PCR and western blot, respectively, in purified and reactivated CD4(+) T cells. In addition, to determine the role of BDNF derived from CD4(+) T cells, the BDNF gene was specifically deleted in T cells using the Cre-lox mouse model system. Our results indicate that while both mRNA expression and protein secretion of BDNF in reactivated T cells were detected at 24 h, only protein could be detected at 72 h after reactivation. The results suggest a transient up-regulation of BDNF mRNA in reactivated T cells. Furthermore, in contrast to our hypothesis that the BDNF expression is necessary for CD4(+) T cells to mediate neuroprotection, mice with CD4(+) T cells lacking BDNF expression demonstrated a similar level of facial motoneuron survival compared to their littermates that expressed BDNF, and both levels were comparable to wild-type. The results suggest that the deletion of BDNF did not impair CD4(+) T cell-mediated neuroprotection. Collectively, while CD4(+) T cells are a potential source of BDNF after nerve injury, production of BDNF is not necessary for CD4(+) T cells to mediate their neuroprotective effects.

Effect of Tie-2 conditional deletion of BDNF on atherosclerosis in the ApoE null mutant mouse

The reduced expression (haplodeficiency) of the main brain derived neurotrophic factor receptor, namely TrkB is associated with reduced atherosclerosis, smooth muscle cells accumulation and collagen content in the lesion. These data support the concept that brain derived neurotrophic factor of vascular origin may contribute to atherosclerosis. However, to date, no experimental approach was possible to investigate this issue due to the lethality of brain derived neurotrophic factor null mice. To overcome these limitations, we generated a mouse model with a conditional deletion of brain derived neurotrophic factor in endothelial cells (Tie-2 Cre recombinase) on an atherosclerotic prone background (apolipoprotein E knock out) and investigated the effect of conditional brain derived neurotrophic factor deficiency on atherosclerosis. Despite brain derived neurotrophic factor reduction in the vascular wall, mice with conditional deletion of brain derived neurotrophic factor did not develop larger atherosclerotic lesion compared to controls. Smooth muscle cell content as well as the distribution of total and fibrillar collagen was similar in the atherosclerotic lesions from mice with brain derived neurotrophic factor conditional deficiency compared to controls. Finally an extended gene expression analysis failed to identify pro-atherogenic gene expression patterns among the animal with brain derived neurotrophic factor deficiency. In spite of the reduced brain derived neurotrophic factor expression, similar atherosclerosis development was observed in the brain derived neurotrophic factor conditional deficient mouse compared to controls. These pieces of evidence indicate that endothelial derived-brain derived neurotrophic factor is not a pro-atherogenic factor and would rather suggest to investigate the role of other TrkB activators on atherosclerosis.

New Insights into the Mechanisms Underlying the Effects of BDNF on Eating Behavior

Food intake is a complex behavior resulting from interactions between homeostatic and hedonic regulatory mechanisms acting in the energy balance and reward centers of the brain. Alterations in feeding behavior are often pervasive and can lead to obesity and its associated medical complications, including metabolic and cardiovascular disorders and psychological distress. A compelling body of evidence emerged recently, indicating a pivotal role of brain-derived neurotrophic factor (BDNF) in pathological processes leading to abnormal food intake and excessive weight gain. BDNF signals through the TrkB receptor to promote neuronal survival, differentiation, and synaptic plasticity. Perturbing central BDNF signaling in mice results in hyperphagic behavior and obesity (Xu et al, 2003; Unger et al, 2007). In humans, BDNF haploinsufficiency was linked to elevated food intake and severe weight gain (Han et al, 2008). These findings have significant clinical implications, as the BdnfVal66Met allele, which impedes regulated BDNF secretion, is highly prevalent in humans (Shimizu et al, 2004). Previous work indicated that hypothalamic BDNF participates in homeostatic processes that preserve energy levels essential for survival. Recently, we demonstrated an intimate involvement of BDNF in the regulation of hedonic feeding via the positive modulation of the mesolimbic dopamine pathway (Cordeira et al, 2010). This neural circuit mediates motivated and reward-seeking behaviors, including consumption of palatable food, and has well-established roles in drug addiction. Mice with selective deletion of Bdnf in the ventral tegmental area (VTA), a principal source of mesolimbic BDNF, consumed significantly more palatable high-fat food than control mice, while exhibiting normal intake of standard chow. Furthermore, evoked release of dopamine by mesolimbic fibers in the nucleus accumbens was diminished in mice lacking central BDNF, suggesting decreased VTA dopamine neuron activity and concomitant reductions in neurotransmitter release. It was proposed previously that hypoactivity of the mesolimbic system might result in reward deficiency syndrome and, behaviorally, in compensatory overeating to enhance a deficient dopaminergic system. In support of this model, hyperphagic leptin-deficient mice were also reported to have reduced evoked dopamine release in the nucleus accumbens (Fulton et al, 2006). Moreover, we found that administration of a dopamine-1 receptor agonist abrogated overeating in BDNF mutant mice. The results argue strongly that BDNF is a natural modulator of hedonic food intake and that dysregulation of BDNF signaling in the reward circuitry increases the drive to eat in the absence of a homeostatic requirement. BDNF facilitates synaptic sensitization of VTA dopamine neurons following cocaine withdrawal, which might represent a mechanism mediating cue-associated drug craving and relapse (Pu et al, 2006). Many questions remain regarding the effects of BDNF on excitability within the VTA during food reward-related processes. For example, does BDNF facilitate forms of synaptic plasticity in the VTA necessary for food reward learning? Does deficient BDNF signal affect the firing rate of dopamine neurons and impede transitions to burst firing and subsequent dopamine release during food reward-related processes? A better understanding of the cellular and molecular mechanisms underlying the anorexigenic effects of this pleiotropic neurotrophin will facilitate the development of novel therapies for appetitive disorders.

Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity.

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are expressed in several hypothalamic and hindbrain nuclei involved in regulating energy homeostasis, developmentally and in the adult animal. Their depletion during the fetal or early postnatal periods when developmental processes are still ongoing elicits hyperphagic behavior and obesity in mice. Whether BDNF is a chief element in appetite control in the mature brain remains controversial. The required sources of this neurotrophin are also unknown. We show that glucose administration rapidly induced BDNF mRNA expression, mediated by Bdnf promoter 1, and TrkB transcription in the ventromedial hypothalamus (VMH) of adult mice, consistent with a role of this pathway in satiety. Using viral-mediated selective knock-down of BDNF in the VMH and dorsomedial hypothalamus (DMH) of adult mice, we were able to elucidate the physiological relevance of BDNF in energy balance regulation. Site-specific mutants exhibited hyperphagic behavior and obesity but normal energy expenditure. Furthermore, intracerebroventricular administration of BDNF triggered an immediate neuronal response in multiple hypothalamic nuclei in wild-type mice, suggesting that its anorexigenic actions involve short-term mechanisms. Locomotor, aggressive, and depressive-like behaviors, all of which are associated with neural circuits involving the VMH, were not altered in VMH/DMH-specific BDNF mutants. These findings demonstrate that BDNF is an integral component of central mechanisms mediating satiety in the adult mouse and, moreover, that its synthesis in the VMH and/or DMH is required for the suppression of appetite.

The Disease Progression of Mecp2 Mutant Mice Is Affected by the Level of BDNF Expression

Mutations in the MECP2 gene cause Rett syndrome (RTT). Bdnf is a MeCP2 target gene; however, its role in RTT pathogenesis is unknown. We examined Bdnf conditional mutant mice for RTT-relevant pathologies and observed that loss of BDNF caused smaller brain size, smaller CA2 neurons, smaller glomerulus size, and a characteristic hindlimb-clasping phenotype. BDNF protein level was reduced in Mecp2 mutant mice, and deletion of Bdnf in Mecp2 mutants caused an earlier onset of RTT-like symptoms. To assess whether this interaction was functional and potentially therapeutically relevant, we increased BDNF expression in the Mecp2 mutant brain with a conditional Bdnf transgene. BDNF overexpression extended the lifespan, rescued a locomotor defect, and reversed an electrophysiological deficit observed in Mecp2 mutants. Our results provide in vivo evidence for a functional interaction between Mecp2 and Bdnf and demonstrate the physiological significance of altered BDNF expression/signaling in RTT disease progression.

Lithium and antidepressants: Potential agents for the treatment of Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder occurring almost exclusively in females. It is caused by mutations in gene encoding methyl-CpG-binding protein 2 (MECP2) in the majority of cases. MECP2 was originally thought to be a global transcriptional repressor, but recent evidence from studies of animals suggests that it may have a role in regulating neuronal activity-dependent expression of specific genes such as Bdnf. A recent report demonstrated that deletion of Bdnf in Mecp2 mutants caused earlier onset/accelerated disease progression, whereas BDNF overexpression in the Mecp2 mutant brain led to later onset/slower disease progression, suggesting that manipulation of BDNF expression/signaling in the brain could be therapeutic for this disease. Lithium and antidepressants have been demonstrated to increase central BDNF levels or signaling in human as well as animal studies. Thus, it is proposed that these agents could have therapeutic potential for RTT subjects. Several points regarding the use of these agents in RTT are discussed. Further evaluation of the therapeutic effects of these drugs in RTT animal models is needed before clinical trials can begin.

Brain-derived neurotrophic factor is essential for opiate-induced plasticity of noradrenergic neurons.

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.

Brain-Derived Neurotrophic Factor Is Essential for Opiate-Induced Plasticity of Noradrenergic Neurons

Chronic opiate exposure induces numerous neurochemical adaptations in the noradrenergic system, including upregulation of the cAMP-signaling pathway and increased expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. These adaptations are thought to compensate for opiate-mediated neuronal inhibition but also contribute to physical dependence, including withdrawal after abrupt cessation of drug exposure. Little is known about molecules that regulate the noradrenergic response to opiates. Here we report that noradrenergic locus ceruleus (LC) neurons of mice with a conditional deletion of BDNF in postnatal brain respond to chronic morphine treatment with a paradoxical downregulation of cAMP-mediated excitation and lack of dynamic regulation of TH expression. This was accompanied by a threefold reduction in opiate withdrawal symptoms despite normal antinociceptive tolerance in the BDNF-deficient mice. Although expression of TrkB, the receptor for BDNF, was high in the LC, endogenous BDNF expression was absent there and in the large majority of other noradrenergic neurons. Therefore, a BDNF-signaling pathway originating from non-noradrenergic sources is essential for opiate-induced molecular adaptations of the noradrenergic system.