Publications by authors named "Lianyan Huang"

14 Publications

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Learning-Dependent Dendritic Spine Plasticity Is Reduced in the Aged Mouse Cortex.

Front Neural Circuits 2020 26;14:581435. Epub 2020 Nov 26.

Department of Anesthesiology, New York University School of Medicine, New York, NY, United States.

Aging is accompanied by a progressive decrease in learning and memory function. Synaptic loss, one of the hallmarks of normal aging, likely plays an important role in age-related cognitive decline. But little is known about the impact of advanced age on synaptic plasticity and neuronal function . In this study, we examined the structural dynamics of postsynaptic dendritic spines as well as calcium activity of layer 5 pyramidal neurons in the cerebral cortex of young and old mice. Using transcranial two-photon microscopy, we found that in both sensory and motor cortices, the elimination rates of dendritic spines were comparable between young (3-5 months) and mature adults (8-10 months), but seemed higher in old mice (>20 months), contributing to a reduction of total spine number in the old brain. During the process of motor learning, old mice compared to young mice had fewer new spines formed in the primary motor cortex. Motor training-evoked somatic calcium activity in layer 5 pyramidal neurons of the motor cortex was also lower in old than young mice, which was associated with the decline of motor learning ability during aging. Together, these results demonstrate the effects of aging on learning-dependent synapse remodeling and neuronal activity in the living cortex and suggest that synaptic deficits may contribute to age-related learning impairment.
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http://dx.doi.org/10.3389/fncir.2020.581435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726160PMC
November 2020

Reduced Dendritic Spines in the Visual Cortex Contralateral to the Optic Nerve Crush Eye in Adult Mice.

Invest Ophthalmol Vis Sci 2020 08;61(10):55

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China.

Purpose: To determine alteration of dendritic spines and associated changes in the primary visual cortex (V1 region) related to unilateral optic nerve crush (ONC) in adult mice.

Methods: Adult unilateral ONC mice were established. Retinal nerve fiber layer (RNFL) thickness was measured by spectral-domain optical coherence tomography. Visual function was estimated by flash visual evoked potentials (FVEPs). Dendritic spines were observed in the V1 region contralateral to the ONC eye by two-photon imaging in vivo. The neurons, reactive astrocytes, oligodendrocytes, and activated microglia were assessed by NeuN, glial fibrillary acidic protein, CNPase, and CD68 in immunohistochemistry, respectively. Tropomyosin receptor kinase B (TrkB) and the markers in TrkB trafficking were estimated using western blotting and co-immunoprecipitation. Transmission electron microscopy and western blotting were used to evaluate autophagy.

Results: The amplitude and latency of FVEPs were decreased and delayed at 3 days, 1 week, 2 weeks, and 4 weeks after ONC, and RNFL thickness was decreased at 2 and 4 weeks after ONC. Dendritic spines were reduced in the V1 region contralateral to the ONC eye at 2, 3, and 4 weeks after ONC, with an unchanged number of neurons. Reactive astrocyte staining was increased at 2 and 4 weeks after ONC, but oligodendrocyte and activated microglia staining remained unchanged. TrkB was reduced with changes in the major trafficking proteins, and enhanced autophagy was observed in the V1 region contralateral to the ONC eye.

Conclusions: Dendritic spines were reduced in the V1 region contralateral to the ONC eye in adult mice. Reactive astrocytes and decreased TrkB may be associated with the reduced dendritic spines.
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http://dx.doi.org/10.1167/iovs.61.10.55DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463183PMC
August 2020

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Cell 2020 06 2;181(7):1547-1565.e15. Epub 2020 Jun 2.

Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman Medical Center, New York, NY 10016, USA; Center for Neural Science, New York University, New York, NY 10003, USA. Electronic address:

Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca-permeable AMPA receptor upregulation, L-type Ca channel activation, enhanced spine Ca transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
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http://dx.doi.org/10.1016/j.cell.2020.05.013DOI Listing
June 2020

Neuropathic Pain Causes Pyramidal Neuronal Hyperactivity in the Anterior Cingulate Cortex.

Front Cell Neurosci 2018 20;12:107. Epub 2018 Apr 20.

Langone Medical Center, Neuroscience Institute, New York University School of Medicine, New York University, New York, NY, United States.

The anterior cingulate cortex (ACC) is thought to be important for acute pain perception as well as the development of chronic pain after peripheral nerve injury. Nevertheless, how ACC neurons respond to sensory stimulation under chronic pain states is not well understood. Here, we used an two-photon imaging technique to monitor the activity of individual neurons in the ACC of awake, head restrained mice. Calcium imaging in the dorsal ACC revealed robust somatic activity in layer 5 (L5) pyramidal neurons in response to peripheral noxious stimuli, and the degree of evoked activity was correlated with the intensity of noxious stimulation. Furthermore, the activation of ACC neurons occurred bilaterally upon noxious stimulation to either contralateral or ipsilateral hind paws. Notably, with nerve injury-induced neuropathic pain in one limb, L5 pyramidal neurons in both sides of the ACC showed enhanced activity in the absence or presence of pain stimuli. These results reveal hyperactivity of L5 pyramidal neurons in the bilateral ACC during the development of neuropathic pain.
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http://dx.doi.org/10.3389/fncel.2018.00107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919951PMC
April 2018

Composition and Nutrient Value Proposition of Brewers Spent Grain.

J Food Sci 2017 Oct 23;82(10):2232-2242. Epub 2017 Aug 23.

Innovation Center for Food Nutrition and Human Health, China.

Brewer's spent grain (BSG), a major brewing industry byproduct, is generated in large quantities annually. This review summarizes research into the composition and preservation of BSG, different extraction techniques for BSG proteins and phenolic acids, and the bioactivities of these phenolic components. Moreover, this article also highlights BSG integration into foodstuff for human consumption and animal feed supplements. BSG is considered a rich source of fiber, protein, and phenolic compounds. The phenolic acids present in BSG are hydroxycinnamic acids (ferulic, p-coumaric, and caffeic acids), which have many biofunctions, such as antioxidant, anticarcinogenic, antiatherogenic, and antiinflammatory activities. Previously, attempts have been made to integrate BSG into human food, such as ready-to-eat snacks, cookies and bread, to increase fiber and protein contents. The addition of BSG to animal feed leads to increased milk yields, higher fat contents in milk, and is a good source of essential amino acids. Therefore, many studies have concluded that integrating the biofunctional compounds in BSG into human food and animal feed has various health benefits.
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http://dx.doi.org/10.1111/1750-3841.13794DOI Listing
October 2017

Evaluation of the Cellular and Animal Models for the Study of Antioxidant Activity: A Review.

J Food Sci 2017 Feb 24;82(2):278-288. Epub 2017 Jan 24.

Innovation Center for Food Nutrition and Human Health, Beijing Technology & Business Univ. (BTBU), Beijing, 100048, China.

The mechanisms of antioxidant activities of phytochemicals are highly complex, so various methods to study them have been developed. However, the diverse available methods show inconsistent results. Different stressors, cell models, and animal models have been used to evaluate the antioxidant properties of phytochemicals. However, the literature still lacks a summary of the effects of different stressors, cell models, and animal models on the evaluation of antioxidant activities. Therefore, the mechanisms of action of different oxidative stimuli and the characteristics of the available cell models and animal models are summarized in this review.
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http://dx.doi.org/10.1111/1750-3841.13605DOI Listing
February 2017

Long-lasting behavioral effects in neonatal mice with multiple exposures to ketamine-xylazine anesthesia.

Neurotoxicol Teratol 2017 Mar - Apr;60:75-81. Epub 2016 Sep 10.

Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University School of Medicine, New York, NY 10016, USA. Electronic address:

Anesthetic agents are often administered in the neonatal period, a time of rapid brain development and synaptogenesis. Mounting evidence suggests that anesthetics can disrupt neurocognitive development, particularly in cases of multiple or prolonged anesthetic exposure. Previous studies have shown that administering multiple doses of ketamine-xylazine (KX) anesthesia to neonatal mice can induce long-term changes to synaptic plasticity in the cortex, but the effect on neurocognitive function remains unclear. In this study, we exposed neonatal mice to single dose and multiple doses of KX anesthesia in the neonatal period (postnatal days 7, 9, 11), and conducted a series of behavioral tests in young adulthood (1month of age). Mice receiving multiple doses of KX anesthesia showed deficits in novel object recognition, sociability, preference for social novelty and contextual fear response, but no effect on auditory-cued fear response. Single dose of KX anesthesia had no effect on these behaviors except for contextual fear response. We also observed that multiple exposures to KX anesthesia were associated with decreased CaMKII phosphorylation, which is known to play a role in synapse development and long-term potentiation, likely contributing to learning impairment.
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http://dx.doi.org/10.1016/j.ntt.2016.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346063PMC
January 2018

Post-anesthesia AMPA receptor potentiation prevents anesthesia-induced learning and synaptic deficits.

Sci Transl Med 2016 06;8(344):344ra85

Department of Anesthesiology, Perioperative Care, and Pain Medicine, New York University School of Medicine, New York, NY 10016, USA.

Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium imaging in the mouse motor cortex, we show that ketamine anesthesia causes a marked and prolonged reduction in neuronal activity during the period of post-anesthesia recovery. Administration of the AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine] to potentiate AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor activity during emergence from anesthesia in mice enhances neuronal activity and prevents long-term motor learning deficits induced by repeated neonatal anesthesia. In addition, we show that CX546 administration also ameliorates various synaptic deficits induced by anesthesia, including reductions in synaptic expression of NMDA (N-methyl-d-aspartate) and AMPA receptor subunits, motor training-evoked neuronal activity, and dendritic spine remodeling associated with motor learning. Together, our results indicate that pharmacologically enhancing neuronal activity during the post-anesthesia recovery period could effectively reduce the adverse effects of early-life anesthesia.
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http://dx.doi.org/10.1126/scitranslmed.aaf7151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025762PMC
June 2016

MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2.

Oncotarget 2015 Apr;6(11):8914-28

Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Repair and Regeneration of Guangdong, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration, invasion, and drug resistance in several types of cancer. In this study, our aim was to clarify microRNAs (miRNAs)-related mechanisms underlying EMT followed by acquired resistance to chemotherapy in glioblastoma (GBM). We used multiple methods to achieve our goal including microarray analysis, qRT-PCR, western blotting analysis, loss/gain-of-function analysis, luciferase assays, drug sensitivity assays, wound-healing assay and invasion assay. We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87). Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance. SNAI2 was identified as a direct target gene of miR-203. The knockdown of SNAI2 by short hairpin RNA (shRNA) inhibited EMT and drug resistance. In GBM patients, miR-203 expression was inversely related to SNAI2 expression, and those tumors with low expression of miR-203 experienced poorer clinical outcomes. Our findings indicate that re-expression of miR-203 or targeting SNAI2 might serve as potential therapeutic approaches to overcome chemotherapy resistance in GBM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496192PMC
http://dx.doi.org/10.18632/oncotarget.3563DOI Listing
April 2015

Repeated exposure to ketamine-xylazine during early development impairs motor learning-dependent dendritic spine plasticity in adulthood.

Anesthesiology 2015 Apr;122(4):821-31

From the Department of Anesthesiology, New York University Medical Center, New York, New York.

Background: Recent studies in rodents suggest that repeated and prolonged anesthetic exposure at early stages of development leads to cognitive and behavioral impairments later in life. However, the underlying mechanism remains unknown. In this study, we tested whether exposure to general anesthesia during early development will disrupt the maturation of synaptic circuits and compromise learning-related synaptic plasticity later in life.

Methods: Mice received ketamine-xylazine (20/3 mg/kg) anesthesia for one or three times, starting at either early (postnatal day 14 [P14]) or late (P21) stages of development (n = 105). Control mice received saline injections (n = 34). At P30, mice were subjected to rotarod motor training and fear conditioning. Motor learning-induced synaptic remodeling was examined in vivo by repeatedly imaging fluorescently labeled postsynaptic dendritic spines in the primary motor cortex before and after training using two-photon microscopy.

Results: Three exposures to ketamine-xylazine anesthesia between P14 and P18 impair the animals' motor learning and learning-dependent dendritic spine plasticity (new spine formation, 8.4 ± 1.3% [mean ± SD] vs. 13.4 ± 1.8%, P = 0.002) without affecting fear memory and cell apoptosis. One exposure at P14 or three exposures between P21 and P25 has no effects on the animals' motor learning or spine plasticity. Finally, enriched motor experience ameliorates anesthesia-induced motor learning impairment and synaptic deficits.

Conclusions: Our study demonstrates that repeated exposures to ketamine-xylazine during early development impair motor learning and learning-dependent dendritic spine plasticity later in life. The reduction in synaptic structural plasticity may underlie anesthesia-induced behavioral impairment.
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http://dx.doi.org/10.1097/ALN.0000000000000579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366292PMC
April 2015

Mitochondrial KATP Channels Control Glioma Radioresistance by Regulating ROS-Induced ERK Activation.

Mol Neurobiol 2015 Aug 24;52(1):626-37. Epub 2014 Sep 24.

Department of Occupational Health and Occupational Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, 510515, Guangdong, China.

Malignant glioma is the most prevalent form of malignant brain tumor. Although radiotherapy is widely used in glioma treatment, the radioresistance of glioma cells limits the success of the glioma treatment. The lack of effective targets and signaling pathways to reverse glioma radioresistance is the critical obstacle in successful treatment. In this study, we demonstrate that mitochondrial ATP-sensitive potassium channels (mtK(ATP) channels) are overexpressed in glioma cells and are closely related to the malignancy grade and the overall survival of the patients. Importantly, we showed that mtK(ATP) channels could control glioma radioresistance by regulating reactive oxygen species (ROS)-induced ERK activation. The inhibition of mtK(ATP) channels suppresses glioma radioresistance by inhibiting ERK activation both in vitro and in vivo. These findings reveal the important roles of the mitochondria and mtK(ATP) channels as key regulators in the radioresistance of glioma cells, and suggest that mtK(ATP) channel blockers and MAPK/ERK kinase (MEK) inhibitors are potential targets for drug development of glioma treatments.
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http://dx.doi.org/10.1007/s12035-014-8888-1DOI Listing
August 2015

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

Nat Neurosci 2014 Aug 22;17(8):1055-63. Epub 2014 Jun 22.

1] State Key Laboratory of Organ Failure Research, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. [2] Key Laboratory of Neuroplasticity of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou, China.

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca(2+) release, nucleoplasmic Ca(2+) elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca(2+)-sensitive gene expression and promotes dendritic arborization in a nuclear Ca(2+)-dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca(2+) to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity-dependent neuronal functions.
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http://dx.doi.org/10.1038/nn.3744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115017PMC
August 2014

ATP-sensitive potassium channels control glioma cells proliferation by regulating ERK activity.

Carcinogenesis 2009 May 28;30(5):737-44. Epub 2009 Jan 28.

Department of Occupational Health and Occupational medicine, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong 510515, China.

Ion channels are found in a variety of cancer cells and necessary for cell cycle and cell proliferation. The roles of K(+) channels in the process are, however, poorly understood. In the present study, we report that adenosine triphosphate (ATP)-sensitive potassium channel activity plays a critical role in the proliferation of glioma cells. The expression of K(ATP) channels in glioma tissues was greatly increased than that in normal tissues. Treatment of glioma cells with tolbutamide, K(ATP) channels inhibitor, suppressed the proliferation of glioma cells and blocked glioma cell cycle in G(0)/G(1) phase. Similarly, downregulation of K(ATP) channels by small interfering RNA (siRNA) inhibited glioma cell proliferation. On the other hand, K(ATP) channels agonist diazoxide and overexpression of K(ATP) channels promoted the proliferation of glioma cells. Moreover, inhibiting K(ATP) channels slowed the formation of tumor in nude mice generated by injection of glioma cells. Whereas activating K(ATP) channels promoted development of tumor in vivo. The effect of K(ATP) channels activity on glioma cells proliferation is mediated by extracellular signal-regulated kinase (ERK) activation. We found that activating K(ATP) channel triggered ERK activation and inhibiting K(ATP) channel depressed ERK activation. U-0126, the mitogen-activated protein kinase kinase (MAPK kinase) inhibitors blocked ERK activation and cell proliferation induced by diazoxide. Furthermore, constitutively activated MEK plasmids transfection reversed the inhibitory effects of tolbutamide on glioma proliferation, lending further support for a role of ERK in mediating this process. Our results suggest that K(ATP) channels control glioma cell proliferation via regulating ERK pathway. We concluded that K(ATP) channels are important in pathological cell proliferation and open a promising pathway for novel targeted therapies.
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http://dx.doi.org/10.1093/carcin/bgp034DOI Listing
May 2009

Activation of ATP-sensitive K channels protects hippocampal CA1 neurons from hypoxia by suppressing p53 expression.

Neurosci Lett 2006 May 19;398(1-2):34-8. Epub 2006 Jan 19.

School of Public Health and Tropical Medicine, Guangzhou, Guangdong 510515, China.

Oxygen-sensing and responses to changes in oxygen concentration is a fundamental property of cellular physiology. In the central nervous system (CNS), hippocampal CA1 neurons are known to be extremely vulnerable to low oxygen concentrations or anoxia. Understanding the mechanisms governing tolerance to oxygen depletion is vital for developing strategies to protect the brain from hypoxic-ischemic insult. Our current study demonstrates the protective mechanism of KATP channels on hippocampal CA1 neurons subjected to hypoxic or anoxic conditions. Specifically, we show that CA1 neurons undergo apoptosis when depleted of oxygen for 12 or 24 h. A KATP channels agonist diazoxide inhibits the observed apoptosis. The inhibition of apoptosis is mediated through diazoxide's ability to reduce p53 expression. On the other hand, tolbutamide, a KATP channels antagonist which blocks the cellular sulphonylureas receptor, significantly increases p53 expression and apoptosis under hypoxic/anoxic conditions. Trichostatin (TSA), a p53 inhibitor, can block the effects of tolbutamide, lending further support for a role of p53 in mediating this process. These studies demonstrate that KATP channels act as an upstream antagonist of p53 in hippocampal CA1 neurons, and suggests their protective role in cerebral hypoxia.
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http://dx.doi.org/10.1016/j.neulet.2005.12.075DOI Listing
May 2006