The Experts below are selected from a list of 7491 Experts worldwide ranked by ideXlab platform
Kerry J Ressler - One of the best experts on this subject based on the ideXlab platform.
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bdnf TrkB Receptor regulation of distributed adult neural plasticity memory formation and psychiatric disorders
Progress in Molecular Biology and Translational Science, 2014Co-Authors: Raul Andero, Dennis C Choi, Kerry J ResslerAbstract:Brain-derived neurotrophic factor (BDNF) and its single transmembrane Receptor, tropomysin-related kinase B (TrkB), are essential for adult synaptic plasticity and the formation of memories. However, there are regional and task-dependent differences underlying differential mechanisms of BDNF-TrkB function in the formation of these memories. Additionally, the BDNF pathway has been implicated in several psychiatric disorders including posttraumatic stress disorder, phobia, and panic disorder. Gaining a better understanding of this pathway and the neurobiology of memory through fundamental research may be helpful to identify effective prevention and treatment approaches both for diseases of memory deficit as well as in cases of enhanced aversive memory, such as in anxiety disorders.
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prelimbic bdnf and TrkB signaling regulates consolidation of both appetitive and aversive emotional learning
Translational Psychiatry, 2012Co-Authors: Dennis C Choi, Shannon L Gourley, Kerry J ResslerAbstract: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.
V R King - One of the best experts on this subject based on the ideXlab platform.
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changes in truncated TrkB and p75 Receptor expression in the rat spinal cord following spinal cord hemisection and spinal cord hemisection plus neurotrophin treatment
Experimental Neurology, 2000Co-Authors: V R King, Elizabeth J Bradbury, Stephen B. Mcmahon, John V PriestleyAbstract:Although numerous studies have examined the effects of neurotrophin treatment following spinal cord injury, few have examined the changes that occur in the neurotrophin Receptors following either such damage or neurotrophin treatment. To determine what changes occur in neurotrophin Receptor expression following spinal cord damage, adult rats received a midthoracic spinal cord hemisection alone or in combination with intrathecal application of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). Using immunohistochemical and in situ hybridization techniques, p75, trkA, TrkB, and trkC Receptor expression was examined throughout the spinal cord. Results showed that trkA, full-length TrkB, and trkC Receptors were not present in the lesion site but had a normal expression pattern in uninjured parts of the spinal cord. In contrast, p75 Receptor expression occurred on Schwann cells throughout the lesion site. BDNF and NT-3 (but not saline) applied to the lesion site increased this expression. In addition, the truncated TrkB Receptor was expressed in the border between the lesion and intact spinal cord. Truncated TrkB Receptor expression was also increased throughout the white matter ipsilateral to the lesion and BDNF (but not NT-3 or saline) prevented this increase. The study is the first to show changes in truncated TrkB Receptor expression that extend beyond the site of a spinal cord lesion and is one of the first to show that BDNF and NT-3 affect Schwann cells and/or p75 expression following spinal cord damage. These results indicate that changes in neurotrophin Receptor expression following spinal cord injury could influence the availability of neurotrophins at the lesion site. In addition, neurotrophins may affect their own availability to damaged neurons by altering the expression of the p75 and truncated TrkB Receptor.
Xia Liu - One of the best experts on this subject based on the ideXlab platform.
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TrkB Receptor cleavage by delta secretase abolishes its phosphorylation of app aggravating alzheimer s disease pathologies
Molecular Psychiatry, 2021Co-Authors: Xia Liu, Yiyuan Xia, Zhihao Wang, Pai Liu, Laura E Edgingtonmitchell, Xiaochuan WangAbstract:Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin Receptor kinases. BDNF and its high-affinity Receptor TrkB are reduced in Alzheimer's disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB Receptor binds and phosphorylates APP, reducing amyloid-β production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.
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biochemical and biophysical investigation of the brain derived neurotrophic factor mimetic 7 8 dihydroxyflavone in the binding and activation of the TrkB Receptor
Journal of Biological Chemistry, 2014Co-Authors: Xia Liu, Chi Bun Chan, Obiamaka Obianyo, Junjian Huang, Shenghui Xue, Jenny J Yang, Fanxing Zeng, Mark M GoodmanAbstract:7,8-dihydroxyflavone (7,8-DHF), a newly identified small molecular TrkB Receptor agonist, rapidly activates TrkB in both primary neurons and the rodent brain and mimics the physiological functions of the cognate ligand BDNF. Accumulating evidence supports that 7,8-DHF exerts neurotrophic effects in a TrkB-dependent manner. Nonetheless, the differences between 7,8-DHF and BDNF in activating TrkB remain incompletely understood. Here we show that 7,8-DHF and BDNF exhibit different TrkB activation kinetics in which TrkB maturation may be implicated. Employing two independent biophysical approaches, we confirm that 7,8-DHF interacts robustly with the TrkB extracellular domain, with a Kd of ∼10 nm. Although BDNF transiently activates TrkB, leading to Receptor internalization and ubiquitination/degradation, in contrast, 7,8-DHF-triggered TrkB phosphorylation lasts for hours, and the internalized Receptors are not degraded. Notably, primary neuronal maturation may be required for 7,8-DHF but not for BDNF to elicit the full spectrum of TrkB signaling cascades. Hence, 7,8-DHF interacts robustly with the TrkB Receptor, and its agonistic effect may be mediated by neuronal development and maturation.
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protection of spiral ganglion neurons from degeneration using small molecule TrkB Receptor agonists
The Journal of Neuroscience, 2013Co-Authors: Qing Chang, Xia Liu, Yunfeng Wang, Shusheng Gong, Xi Erick LinAbstract:Neurotrophins (NTs) play essential roles in the development and survival of neurons in PNS and CNS. In the cochlea, NTs [e.g., NT-3, brain-derived neurotrophic factor (BDNF)] are required for the survival of spiral ganglion neurons (SGNs). Preservation of SGNs in the cochlea of patients suffering sensorineural deafness caused by loss of hair cells is needed for the optimal performance of the cochlear implant. Directly applying exogenous BDNF into the cochlea prevents secondary degeneration of SGNs when hair cells are lost. However, a common translational barrier for in vivo applications of BDNF is the poor pharmacokinetics, which severely limits the efficacy. Here we report that 7,8-dihydroxyflavone and 7,8,3′-trihydroxyflavone, both small-molecule agonists of tyrosine Receptor kinase B (TrkB), promoted SGN survival with high potency both in vitro and in vivo. These compounds increased the phosphorylated TrkB and downstream MAPK and protected the SGNs in a TrkB-dependent manner. Their applications in the bulla of conditional connexin26 null mice offered significant protection for SGN survival. The function of survived SGNs was assessed by measuring evoked action potentials (APs) in vitro and electrically evoked auditory brainstem response (eABR) thresholds in vivo. APs were reliably evoked in cultured single SGNs treated with the compounds. In addition, eABR thresholds measured from the treated cochleae were significantly lower than untreated controls. Our findings suggest that these novel small-molecule TrkB agonists are promising in vivo therapeutic agents for preventing degeneration of SGNs.
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o methylated metabolite of 7 8 dihydroxyflavone activates TrkB Receptor and displays antidepressant activity
Pharmacology, 2013Co-Authors: Xia Liu, Ge Xiao, Hongbo R LuoAbstract:7,8-Dihydroxyflavone (7,8-DHF) acts as a TrkB Receptor-specific agonist. It mimics the physiological actions of brain-derived neurotrophic factor (BDNF) and demonstrates remarkable therapeutic efficacy in animal models of various neurological diseases. Nonetheless, its in vivo pharmacokinetic profiles and metabolism remain unclear. Here we report that 7,8-DHF and its O-methylated metabolites distribute in mouse brain after oral administration. Both hydroxy groups can be mono-methylated, and the mono-methylated metabolites activate TrkB in vitro and in vivo. Blocking methylation, using COMT inhibitors, diminishes the agonistic effect of TrkB activation by 7,8-DHF or 4'-dimethylamino-7,8-DHF, supporting the contribution of the methylated metabolite to TrkB activation in mouse brain. Moreover, we have synthesized several methylated metabolite derivatives, and they also potently activate the TrkB Receptor and reduce immobility in both forced swim test and tail suspension test, indicating that these methylated metabolites may possess antidepressant activity. Hence, our data demonstrate that 7,8-DHF is orally bioavailable and can penetrate the brain-blood barrier. The O-methylated metabolites are implicated in TrkB Receptor activation in the brain.
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N-acetylserotonin activates TrkB Receptor in a circadian rhythm
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Sung-wuk Jang, Gianluca Tosini, Xia Liu, Sompol Pradoldej, Qiang Chang, P. Michael IuvoneAbstract:Brain-derived neurotrophic factor (BDNF) is a cognate ligand for the TrkB Receptor. BDNF and serotonin often function in a cooperative manner to regulate neuronal plasticity, neurogenesis, and neuronal survival. Here we show that NAS (N-acetylserotonin) swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. NAS, a precursor of melatonin, is acetylated from serotonin by AANAT (arylalkylamine N-acetyltransferase). NAS rapidly activates TrkB, but not TrkA or TrkC, in a neurotrophin- and MT3 Receptor-independent manner. Administration of NAS activates TrkB in BDNF knockout mice. Furthermore, NAS, but not melatonin, displays a robust antidepressant-like behavioral effect in a TrkB-dependent way. Endogenous TrkB is activated in wild-type C3H/f+/+ mice but not in AANAT-mutated C57BL/6J mice, in a circadian rhythm; TrkB activation is high at night in the dark and low during the day. Hence, our findings support that NAS is more than a melatonin precursor, and that it can potently activate TrkB Receptor.
Harvey J Grill - One of the best experts on this subject based on the ideXlab platform.
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protein tyrosine phosphatase 1b ptp1b is a novel regulator of central brain derived neurotrophic factor and tropomyosin Receptor kinase b TrkB signaling
Journal of Biological Chemistry, 2014Co-Authors: Ceren Ozek, Scott E Kanoski, Harvey J Grill, Zhong Yin Zhang, Kendra K BenceAbstract:Neuronal protein-tyrosine phosphatase 1B (PTP1B) deficiency in mice results in enhanced leptin signaling and protection from diet-induced obesity; however, whether additional signaling pathways in the brain contribute to the metabolic effects of PTP1B deficiency remains unclear. Here, we show that the tropomyosin Receptor kinase B (TrkB) Receptor is a direct PTP1B substrate and implicate PTP1B in the regulation of the central brain-derived neurotrophic factor (BDNF) signaling. PTP1B interacts with activated TrkB Receptor in mouse brain and human SH-SY5Y neuroblastoma cells. PTP1B overexpression reduces TrkB phosphorylation and activation of downstream signaling pathways, whereas PTP1B inhibition augments TrkB signaling. Notably, brains of Ptpn1(-/-) mice exhibit enhanced TrkB phosphorylation, and Ptpn1(-/-) mice are hypersensitive to central BDNF-induced increase in core temperature. Taken together, our findings demonstrate that PTP1B is a novel physiological regulator of TrkB and that enhanced BDNF/TrkB signaling may contribute to the beneficial metabolic effects of PTP1B deficiency.
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TrkB Receptor signaling in the nucleus tractus solitarius mediates the food intake suppressive effects of hindbrain bdnf and leptin
American Journal of Physiology-endocrinology and Metabolism, 2012Co-Authors: Andrea M Spaeth, Scott E Kanoski, Matthew R Hayes, Harvey J GrillAbstract:Brain-derived neurotrophic factor (BDNF) and TrkB Receptor signaling contribute to the central nervous system (CNS) control of energy balance. The role of hindbrain BDNF/TrkB Receptor signaling in energy balance regulation is examined here. Hindbrain ventricular BDNF suppressed body weight through reductions in overall food intake and meal size and by increasing core temperature. To localize the neurons mediating the energy balance effects of hindbrain ventricle-delivered BDNF, ventricle subthreshold doses were delivered directly to medial nucleus tractus solitarius (mNTS). mNTS BDNF administration reduced food intake significantly, and this effect was blocked by preadministration of a highly selective TrkB Receptor antagonist {[N2–2-2-Oxoazepan-3-yl amino]carbonyl phenyl benzo (b)thiophene-2-carboxamide (ANA-12)}, suggesting that TrkB Receptor activation mediates hindbrain BDNF's effect on food intake. Because both BDNF and leptin interact with melanocortin signaling to reduce food intake, we also examined whether the intake inhibitory effects of hindbrain leptin involve hindbrain-specific BDNF/TrkB activation. BDNF protein content within the dorsal vagal complex of the hindbrain was increased significantly by hindbrain leptin delivery. To assess if BDNF/TrkB Receptor signaling acts downstream of leptin signaling in the control of energy balance, leptin and ANA-12 were coadministered into the mNTS. Administration of the TrkB Receptor antagonist attenuated the intake-suppressive effects of leptin, suggesting that mNTS TrkB Receptor activation contributes to the mediation of the anorexigenic effects of hindbrain leptin. Collectively, these results indicate that TrkB-mediated signaling in the mNTS negatively regulates food intake and, in part, the intake inhibitory effects of leptin administered into the NTS.
John V Priestley - One of the best experts on this subject based on the ideXlab platform.
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changes in truncated TrkB and p75 Receptor expression in the rat spinal cord following spinal cord hemisection and spinal cord hemisection plus neurotrophin treatment
Experimental Neurology, 2000Co-Authors: V R King, Elizabeth J Bradbury, Stephen B. Mcmahon, John V PriestleyAbstract:Although numerous studies have examined the effects of neurotrophin treatment following spinal cord injury, few have examined the changes that occur in the neurotrophin Receptors following either such damage or neurotrophin treatment. To determine what changes occur in neurotrophin Receptor expression following spinal cord damage, adult rats received a midthoracic spinal cord hemisection alone or in combination with intrathecal application of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3). Using immunohistochemical and in situ hybridization techniques, p75, trkA, TrkB, and trkC Receptor expression was examined throughout the spinal cord. Results showed that trkA, full-length TrkB, and trkC Receptors were not present in the lesion site but had a normal expression pattern in uninjured parts of the spinal cord. In contrast, p75 Receptor expression occurred on Schwann cells throughout the lesion site. BDNF and NT-3 (but not saline) applied to the lesion site increased this expression. In addition, the truncated TrkB Receptor was expressed in the border between the lesion and intact spinal cord. Truncated TrkB Receptor expression was also increased throughout the white matter ipsilateral to the lesion and BDNF (but not NT-3 or saline) prevented this increase. The study is the first to show changes in truncated TrkB Receptor expression that extend beyond the site of a spinal cord lesion and is one of the first to show that BDNF and NT-3 affect Schwann cells and/or p75 expression following spinal cord damage. These results indicate that changes in neurotrophin Receptor expression following spinal cord injury could influence the availability of neurotrophins at the lesion site. In addition, neurotrophins may affect their own availability to damaged neurons by altering the expression of the p75 and truncated TrkB Receptor.
