Gavin S Dawe

National University Health System, Singapore

Are you Gavin S Dawe?

Claim your profile

Publications (66)255.84 Total impact

  • Ramamoorthy Rajkumar · You Wu · Usman Farooq · Wei Hao Tan · Gavin S Dawe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The nucleus incertus (NI) is a small brainstem cluster of neurons presumed to play a role in stress responses. We show that swim stress (normal water: 30min and cold water: 20min) and elevation stress robustly induced c-Fos expression in the NI and significantly suppressed long term potentiation (LTP) in the hippocampo-medial prefrontal cortical (HP-mPFC) pathway. To examine whether activation of CRF1 receptors in the NI plays a role in the suppression of HP-mPFC LTP, antalarmin, a specific CRF1 receptor antagonist, was infused directly into the NI either before presentation of (1) elevation stress or (2) high frequency stimulation. As predicted, the intra-NI infusion of antalarmin reversed the elevation stress-induced suppression of LTP in the HP-mPFC pathway. This short report suggests that the CRF1 receptor system in the NI contributes to stress-related impairment in the plasticity of HP-mPFC pathway. The findings suggest that the NI-HP-mPFC is a stress responsive circuit in the rodent brain.
    Brain research bulletin 11/2015; DOI:10.1016/j.brainresbull.2015.10.010 · 2.72 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adaptation of the nervous system to different chemical and physiologic conditions is important for the homeostasis of brain processes and for learning and remembering appropriate responses to challenges. Although processes such as tolerance and dependence to various drugs of abuse have been known for a long time, it was recently discovered that even a single pharmacologically relevant dose of various drugs of abuse induces neuroplasticity in selected neuronal populations, such as the dopamine neurons of the ventral tegmental area, which persist long after the drug has been excreted. Prolonged (self-) administration of drugs induces gene expression, neurochemical, neurophysiological, and structural changes in many brain cell populations. These region-specific changes correlate with addiction, drug intake, and conditioned drugs effects, such as cue- or stress-induced reinstatement of drug seeking. In rodents, adolescent drug exposure often causes significantly more behavioral changes later in adulthood than a corresponding exposure in adults. Clinically the most impairing and devastating effects on the brain are produced by alcohol during fetal development. In adult recreational drug users or in medicated patients, it has been difficult to find persistent functional or behavioral changes, suggesting that heavy exposure to drugs of abuse is needed for neurotoxicity and for persistent emotional and cognitive alterations. This review describes recent advances in this important area of research, which harbors the aim of translating this knowledge to better treatments for addictions and related neuropsychiatric illnesses.
    Pharmacological reviews 09/2015; 67(4):872-1004. DOI:10.1124/pr.115.010967 · 17.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The nucleus incertus (NI), located in the caudal brainstem, mainly consists of GABAergic neurons with widespread projections across the brain. It is the chief source of relaxin-3 in the mammalian brain and densely expresses corticotropin-releasing factor type 1 (CRF1) receptors. Several other neurotransmitters, peptides and receptors are reportedly expressed in the NI. In the present investigation, we show the expression of dopamine type-2 (D2) receptors in the NI by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting (WB) and immunofluorescence (IF). RT-PCR did not show expression of D3 receptors. Cells of the NI co-labelled with D2 receptor short isoform (D2S)-like immunoreactivity and relaxin-3, CRF1/2 receptors and NeuN immunoreactivity. Behavioural effects of D2 receptor activation by intra-NI infusion of quinpirole (a D2/D3 agonist) were evaluated. Hypolocomotion was observed in home cage monitoring system (LABORAS) and novel environment-induced suppression of feeding behavioural paradigms. Thus the D2 receptors expressed in the NI are likely to play a role in locomotion. Based on its strong bidirectional connections to the median raphe and interpeduncular nuclei, the NI was predicted to play a role in modulating behavioural activity [21] and the present results lend support to this hypothesis. This is the first evidence of expression of a catecholamine receptor, D2-like immunoreactivity, in the NI. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 08/2015; 151. DOI:10.1016/j.physbeh.2015.08.024 · 2.98 Impact Factor
  • Wan-Jie Chia · Francis Chee Kuan Tan · Wei-Yi Ong · Gavin S. Dawe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The iron siderophore binding protein lipocalin 2 (LCN2, also known as 24p3, NGAL and siderocalin) may be involved in iron homeostasis, but till date, little is known about expression of its putative receptor, brain-type organic cation transporter (BOCT, also known as BOCT1, 24p3R, NGALR and LCN2R), in the brain during neurodegeneration. The present study was carried out to elucidate the expression of LCN2 and BOCT in hippocampus after excitotoxicity induced by the glutamate analog, kainate (KA) and a possible role of LCN2 in neuronal injury. As reported previously, a rapid and sustained induction in expression of LCN2 was found in the hippocampus after intracerebroventicular injection of KA. BOCT was expressed in neurons of the saline-injected control hippocampus, and immunolabel for BOCT protein was preserved in pyramidal neurons of CA1 at 1 day post-KA injection, likely due to the delayed onset of neurodegeneration after KA injection. At 3 days and 2 weeks after KA injections, loss of immunolabel was observed due to degenerated neurons, although remaining neurons continued to express BOCT, and induction of BOCT was found in OX-42 positive microglia. This resulted in an overall decrease in BOCT mRNA and protein expression after KA treatment. Increased expression of the pro-apoptotic marker, Bim, was found in both neurons and microglia after KA injection, but TUNEL staining indicating apoptosis was found primarily in Bim- expressing neurons, but not microglia. Apo-LCN2 caused no significant differences in neuronal Bim expression or cell survival, whereas holo-LCN2 increased Bim mRNA expression and decreased cell survival. Together, the results suggest that LCN2 and BOCT may have a role in neuronal injury. Copyright © 2015. Published by Elsevier Ltd.
    Neurochemistry International 05/2015; 87. DOI:10.1016/j.neuint.2015.04.009 · 3.09 Impact Factor
  • R Rajkumar · J Fam · E Y M Yeo · G S Dawe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Depression and suicide are known to be intricately entwined but the neurobiological basis underlying this association is yet to be understood. Ketamine is an N-methyl D-aspartate (NMDA) receptor antagonist used for induction and maintenance of general anaesthesia but paradoxically its euphoric effects lead to its classification under drugs of abuse. The serendipitous finding of rapid-onset antidepressant action of subanaesthetic dose ketamine intravenous infusion has sparked many preclinical and clinical investigations. A remarkable suppression of suicidal ideation was also reported in depressed patients. This review focuses on the clinical trials on ketamine that reported remedial effects in suicidal ideation in depression and addresses also the molecular mechanisms underlying the antidepressant and psychotomimetic actions of ketamine. The neuropsychiatric profile of subanaesthetic doses of ketamine encourages its use in the management of suicidal ideation that could avert emergent self-harm or suicide. Finally, the need for neuroimaging studies in suicidal patients to identify the brain region specific and temporal effects of ketamine, and the possibility of employing ketamine as an experimental tool in rodent-based studies to study the mechanisms underlying suicidal behaviour are highlighted. Copyright © 2015. Published by Elsevier Ltd.
    Pharmacological Research 05/2015; 99. DOI:10.1016/j.phrs.2015.05.003 · 4.41 Impact Factor
  • Chao Liu · Francis Chee Kuan Tan · Zhi-Cheng Xiao · Gavin S Dawe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid precursor protein (APP), is commonly associated with Alzheimers disease, but its physiological function remains unknown. Nav1.6 is a key determinant of neuronal excitability in vivo. Since mouse models of gain-of-function and loss-of-function of APP and Nav1.6 share some similar phenotypes, we hypothesized that APP might be a candidate molecule for sodium channel modulation. Here, we report that APP co-localized and interacted with Nav1.6 in mouse cortical neurons. Knocking down APP decreased Nav1.6 sodium channel currents and cell surface expression. APP-induced increases in Nav1.6 cell surface expression were Go protein-dependent and were enhanced by a constitutively active Go-protein mutant and blocked by a dominant negative Go-protein mutant. APP also regulated c-Jun N-terminal kinase (JNK) activity in a Go-protein-dependent manner. JNK inhibition attenuated increases in cell surface expression of Nav1.6 sodium channels induced by overexpression of APP. JNK in turn phosphorylated APP. Nav1.6 sodium channel surface expression was increased by T668E, and decreased by T668A, mutations of APP695 mimicking and preventing T668 phosphorylation, respectively. Phosphorylation of APP695 at T668 enhanced its interaction with Nav1.6. Thus, we show that APP enhances Nav1.6 sodium channel cell surface expression through a Go-coupled JNK pathway. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(19). DOI:10.1074/jbc.M114.617092 · 4.57 Impact Factor
  • Source
    R Shu · W Wong · Q H Ma · Z Z Yang · H Zhu · F J Liu · P Wang · J Ma · S Yan · J M Polo · C C A Bernard · L W Stanton · G S Dawe · Z C Xiao ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid precursor protein (APP) is best known for its involvement in the pathogenesis of Alzheimer's disease. We have previously demonstrated that APP intracellular domain (AICD) regulates neurogenesis; however, the mechanisms underlying AICD-mediated regulation of neuronal differentiation are not yet fully characterized. Using genome-wide chromatin immunoprecipitation approaches, we found that AICD is specifically recruited to the regulatory regions of several microRNA genes, and acts as a transcriptional regulator for miR-663, miR-3648 and miR-3687 in human neural stem cells. Functional assays show that AICD negatively modulates neuronal differentiation through miR-663, a primate-specific microRNA. Microarray data further demonstrate that miR-663 suppresses the expression of multiple genes implicated in neurogenesis, including FBXL18 and CDK6. Our results indicate that AICD has a novel role in suppression of neuronal differentiation via transcriptional regulation of miR-663 in human neural stem cells.
    Cell Death & Disease 02/2015; 6(2):e1651. DOI:10.1038/cddis.2015.10 · 5.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Calcium independent phospholipase A2 (iPLA2) is an 85kDa protein that catalyzes the hydrolysis of the sn-2 acyl ester bond to liberate free fatty acids and lysophospholipids. In this study, we determined the role of constitutive iPLA2β in long term potentiation (LTP) of the hippocampal prefrontal cortex pathway in vivo. We also examined the effect of iPLA2 knockdown using the rewarded alternation in T-maze task, a test of spatial working memory which is dependent on this pathway. Intracortical injection of an inhibitor to iPLA2, bromoenol lactone (BEL) or antisense oligonucleotide to iPLA2β in the prefrontal cortex abolished induction of hippocampal prefrontal cortex LTP. Moreover, iPLA2 inhibition and antisense knockdown resulted in increased errors in the rewarded alternation in T maze task, indicating negative effects on spatial working memory. BEL or antisense injection did not produce DNA fragmentation in the cortex as demonstrated by TUNEL assay. Results confirm a role of constitutive iPLA2β in hippocampal prefrontal cortex synaptic plasticity in vivo, and add to previous observations of a role of iPLA2 in hippocampal LTP in vitro, and long-term memory retrieval. They may be relevant in Alzheimer’s disease, and other neurodegenerative conditions that are associated with changes in iPLA2.
    Neurochemistry International 12/2014; 78. DOI:10.1016/j.neuint.2014.08.006 · 3.09 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we performed gas chromatography time-of-flight mass spectrometry (GC-TOFMS)-based extracellular metabolic profiling on AβPP-transfected CHO cells (CHO-AβPP695) and its wildtype. Orthogonal partial least squares discriminant analysis (OPLS-DA) was then used to identify discriminant metabolites, which gave clues on the effects of AβPP transgene on cellular processes. To confirm the hypotheses generated based on the metabolic data, we performed biochemical assays to gather further evidence to support our findings. The OPLS-DA showed a robust differentiation following 24 h of incubation (Q2(cum) = 0.884) and 15 discriminant metabolites were identified. In contrast, extracellular Aβ42 was identified to increase significantly in CHO-AβPP695 only after incubation for 48 h. The observed 24-h metabolic fluxes were associated with increased mitochondrial AβPP and reduced mitochondrial viabilities, which occurred before extracellular Aβ accumulation. We also investigated the therapeutic potential of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, namely rosiglitazone (RSG) and pioglitazone (PIO), by employing the same approach to characterize the metabolic profiles of CHO-AβPP695 treated with RSG and PIO, with or without their respective receptor blockers. Treatment with PIO was found to reduce the perturbation of the discriminant metabolites in CHO-AβPP695 to a larger extent than treatment with RSG. We also attributed the PIO effects on the lowering of Aβ42, and restoration of mitochondrial activity to PPARγ and PPARα agonism, respectively. Taken together, PIO was demonstrated to be therapeutically superior to RSG. Our findings provide further insights into early disease stages in this AβPP model, and support the advancement of PIO in AD therapy.
    Journal of Alzheimer's disease: JAD 09/2014; 44(1). DOI:10.3233/JAD-140429 · 4.15 Impact Factor
  • Yi Chen · Arindam Basu · Lei Liu · Xiaodan Zou · Ramamoorthy Rajkumar · Gavin Stewart Dawe · Minkyu Je ·
    [Show abstract] [Hide abstract]
    ABSTRACT: A novel signal folding and reconstruction scheme for neural recording applications that exploits the $1/f^{n}$ characteristics of neural signals is described in this paper. The amplified output is ‘folded’ into a predefined range of voltages by using comparison and reset circuits along with the core amplifier. After this output signal is digitized and transmitted, a reconstruction algorithm can be applied in the digital domain to recover the amplified signal from the folded waveform. This scheme enables the use of an analog-to-digital convertor with less number of bits for the same effective dynamic range. It also reduces the transmission data rate of the recording chip. Both of these features allow power and area savings at the system level. Other advantages of the proposed topology are increased reliability due to the removal of pseudo-resistors, lower harmonic distortion and low-voltage operation. An analysis of the reconstruction error introduced by this scheme is presented along with a behavioral model to provide a quick estimate of the post reconstruction dynamic range. Measurement results from two different core amplifier designs in 65 nm and 180 nm CMOS processes are presented to prove the generality of the proposed scheme in the neural recording applications. Operating from a 1 V power supply, the amplifier in 180 nm CMOS has a gain of 54.2 dB, bandwidth of 5.7 kHz, input referred noise of 3.8 $mu V_{rms}$ and power dissipation of 2.52 $mu {rm W}$ leading to a NEF of 3.1 in spike band. It exhibits a dynamic range of 66 dB and maximum SNDR of 43 dB in LFP band. It also reduces system level power (by reducing the number of bits in the ADC by 2) as well as data rate to 80% of a conventional design. In vivo measurements validate the ability of t- is amplifier to simultaneously record spike and LFP signals.
    IEEE Transactions on Biomedical Circuits and Systems 08/2014; 8(4):528-542. DOI:10.1109/TBCAS.2013.2288680 · 2.48 Impact Factor
  • Source
    Liying Corinne Lee · Ramamoorthy Rajkumar · Gavin Stewart Dawe ·

    Brain Research 06/2014; 1568. DOI:10.1016/j.brainres.2014.04.030 · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyloid precursor protein (APP), commonly associated with Alzheimer disease, is upregulated and distributes evenly along the injured axons, and therefore, also known as a marker of demyelinating axonal injury and axonal degeneration. However, the physiological distribution and function of APP along myelinated axons was unknown. We report that APP aggregates at nodes of Ranvier (NOR) in the myelinated central nervous system (CNS) axons but not in the peripheral nervous system (PNS). At CNS NORs, APP expression co-localizes with tenascin-R and is flanked by juxtaparanodal potassium channel expression demonstrating that APP localized to NOR. In APP-knockout (KO) mice, nodal length is significantly increased, while sodium channels are still clustered at NORs. Moreover, APP KO and APP-overexpressing transgenic (APP TG) mice exhibited a decreased and an increased thickness of myelin in spinal cords, respectively, although the changes are limited in comparison to their littermate WT mice. The thickness of myelin in APP KO sciatic nerve also increased in comparison to that in WT mice. Our observations indicate that APP acts as a novel component at CNS NORs, modulating nodal formation and has minor effects in promoting myelination.
    Cell adhesion & migration 04/2014; 8(4). DOI:10.4161/cam.28802 · 4.51 Impact Factor
  • Jared W Young · Anil Ratty · Gavin S Dawe · Mark A Geyer ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia is a prevalent neurodevelopmental psychiatric disorder with poor prognosis and limited understanding of its etiology. This limited etiological understanding renders developing animal models of schizophrenia difficult. Although attempts are made to recreate putative etiologies in models, these models may only enable the generation of treatments targeted at the mechanisms manipulated. Although the chakragati mouse was not created as a result of a specific gene target, reports to date suggest these mice exhibit behavioral abnormalities that are consistent with some observed in patients with schizophrenia. As an initial screen on the relevance of these mice to schizophrenia, we tested the exploration and sensorimotor gating of male and female chakragati mice in the cross-species tests behavioral pattern monitor (BPM) and prepulse inhibition (PPI), respectively. The chakragati mice exhibited hyperactive yet more meandering/circling movements of exploration compared with wildtype (WT) littermates. Moreover, chakragati mice exhibited impaired PPI compared with WT mice, primarily at high prepulse intensity levels. Thus, chakragati mice share some of the abnormal exploratory and PPI behaviors that are observed in patients with schizophrenia. These behaviors can be used to screen for novel antipsychotics which may be based on novel mechanisms of action. The multivariate abnormal exploration of these mice may also yield further information for treatment effects. Further characterization of these mice in tasks with putative links to negative or cognitive symptoms may further advance the utility of these mice as a screen for novel treatments for schizophrenia. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    Behavioral Neuroscience 04/2014; 128(4). DOI:10.1037/a0036425 · 2.73 Impact Factor
  • Dong Han · Yuanjin Zheng · Ramamoorthy Rajkumar · Gavin Stewart Dawe · Minkyu Je ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Neural prosthetics and personal healthcare have increasing need of high channel density low noise low power neural sensor interfaces. The input referred noise and quantization resolution are two essential factors which prevent conventional neural sensor interfaces from simultaneously achieving a good noise efficiency factor and low power consumption. In this paper, a neural recording architecture with dynamic range folding and current reuse techniques is proposed and dedicated to solving the noise and dynamic range trade-off under low voltage low power operation. Measured results from the silicon prototype show that the proposed design achieves 3.2 μVrms input referred noise and 8.27 effective number of bits at only 0.45 V supply and 0.94 μW/channel power consumption.
    IEEE Transactions on Biomedical Circuits and Systems 12/2013; 7(6):735-46. DOI:10.1109/TBCAS.2014.2298860 · 2.48 Impact Factor
  • Source
    Corinne Liying Lee · Ramamoorthy Rajkumar · Gavin Stewart Dawe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: The nucleus incertus (NI), a brainstem nucleus found in the pontine periventricular grey, is the primary source of the neuropeptide relaxin-3 in the mammalian brain. The NI neurons have also been previously reported to express several receptors and neurotransmitters, including corticotropin releasing hormone receptor 1 (CRF1) and gamma-aminobutyric acid (GABA). The NI projects widely to putative neural correlates of stress, anxiety, depression, feeding behaviour, arousal and cognition leading to speculation that it might be involved in several neuropsychiatric conditions. On the premise that relaxin-3 expressing neurons in the NI predominantly co-express CRF1 receptors, a novel method for selective ablation of the rat brain NI neurons using corticotropin releasing factor (CRF)-saporin conjugate is described. In addition to a behavioural deficit in the fear conditioning paradigm, reverse transcriptase polymerase chain reaction (RT-PCR), western blotting (WB) and immunofluorescence labelling (IF) techniques were used to confirm the NI lesion. We observed a selective and significant loss of CRF1 expressing cells, together with a consistent decrease in relaxin-3 and GAD65 expression. The significant ablation of relaxin-3 positive neurons of the NI achieved by this immunolesioning approach is a promising model to explore the neuropsychopharmacological implications of NI/relaxin-3 in behavioural neuroscience.
    Brain research 11/2013; 1543. DOI:10.1016/j.brainres.2013.11.021 · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This paper presents a fully implantable 100-channel neural interface IC for neural activity monitoring. It contains 100-channel analog recording front-ends, 10 multiplexing successive approximation register ADCs, digital control modules and power management circuits. A dual sample-and-hold architecture is proposed, which extends the sampling time of the ADC and reduces the average power per channel by more than 50% compared to the conventional multiplexing neural recording system. A neural amplifier (NA) with current-reuse technique and weak inversion operation is demonstrated, consuming 800 nA under 1-V supply while achieving an input-referred noise of 4.0 μVrms in a 8-kHz bandwidth and a NEF of 1.9 for the whole analog recording chain. The measured frequency response of the analog front-end has a high-pass cutoff frequency from sub-1 Hz to 248 Hz and a low-pass cutoff frequency from 432 Hz to 5.1 kHz, which can be configured to record neural spikes and local field potentials simultaneously or separately. The whole system was fabricated in a 0.18-μm standard CMOS process and operates under 1 V for analog blocks and ADC, and 1.8 V for digital modules. The number of active recording channels is programmable and the digital output data rate changes accordingly, leading to high system power efficiency. The overall 100-channel interface IC consumes 1.16-mW total power, making it the optimum solution for multi-channel neural recording systems.
    Circuits and Systems I: Regular Papers, IEEE Transactions on 10/2013; 60(10):2584-2596. DOI:10.1109/TCSI.2013.2249175 · 2.40 Impact Factor
  • Source
    Ramamoorthy Rajkumar · Sana Suri · Hong Min Deng · Gavin Stewart Dawe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: A priming-challenge schedule of nicotine treatment causes long-lasting potentiation (LLP), a form of synaptic plasticity closely associated with the norepinephrine (NE) neurotransmitter system, at the medial perforant path (MPP)-dentate gyrus (DG) synapse in the rat hippocampus. Previous reports revealed that nicotine activates the locus coeruleus (LC) noradrenergic (NAergic) system and this mechanism may underlie its beta-adrenoceptor sensitive LLP effects. Clozapine, an atypical antipsychotic, is also known to activate the LC. Interactions between nicotine and clozapine are of interest because of the prevalence of smoking in patients with schizophrenia and increasing interest in the use of nicotinic receptor ligands as cognitive enhancers. Rats were subchronically primed with nicotine, clozapine or saline. Twenty one to twenty eight days later, the effects of the nicotine, clozapine or saline challenge on the evoked field excitatory postsynaptic potentials (fEPSP) at the MPP-DG monosynaptic pathway were recorded as a measure of LLP. We confirmed the hypothesis that a challenge dose of either nicotine or clozapine induces LLP exclusively in nicotine- and clozapine-primed rats, and not in saline-primed rats, thus indicating a cross-priming effect. Moreover, unilateral suppression of LC using lidocaine abolished the LLP induced by nicotine in clozapine-primed rats. Furthermore, systemic treatment with clonidine (an α2 adrenoceptor agonist that reduces NAergic activity via autoreceptors) prior to the challenge doses blocked the nicotine/clozapine-induced LLP in nicotine- and clozapine- primed rats. These findings may add to understanding of the cognitive enhancing effects of nicotine. © 2013 Wiley Periodicals, Inc.
    Hippocampus 07/2013; 23(7). DOI:10.1002/hipo.22122 · 4.16 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The medial prefrontal cortex (mPFC) in the rat has been implicated in a variety of cognitive processes, including working memory and expression of fear memory. We investigated the inputs from a brain stem nucleus, the nucleus incertus (NI), to the prelimbic area of the mPFC. This nucleus strongly expresses corticotropin-releasing factor type 1 (CRF1 ) receptors and responds to stress. A retrograde tracer was used to verify connections from the NI to the mPFC. Retrogradely labelled cells in the NI expressed CRF receptors. Electrophysiological manipulation of the NI revealed that stimulation of the NI inhibited spontaneous neuronal firing in the mPFC. Similarly, CRF infusion into the NI, in order to mimic a stressful condition, inhibited neuronal firing and burst firing in the mPFC. The effect of concurrent high-frequency stimulation of the NI on plasticity in the hippocampo-prelimbic medial prefrontal cortical (HP-mPFC) pathway was studied. It was found that electrical stimulation of the NI impaired long-term potentiation in the HP-mPFC pathway. Furthermore, CRF infusion into the NI produced similar results. These findings might account for some of the extra-pituitary functions of CRF and indicate that the NI may play a role in stress-driven modulation of working memory and possibly other cognitive processes subserved by the mPFC.
    European Journal of Neuroscience 05/2013; 38(4). DOI:10.1111/ejn.12242 · 3.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of central nervous system. The present study was designed to investigate the therapeutic effect of ACS84, a hydrogen sulfide-releasing-L-Dopa derivative compound, in a 6-hydroxydopamine (6-OHDA)-induced PD model. ACS84 protected the SH-SY5Y cells against 6-OHDA-induced cell injury and oxidative stress. The protective effect resulted from stimulation of Nrf-2 nuclear translocation and promotion of anti-oxidant enzymes expression. In the 6-OHDA-induced PD rat model, intragastric administration of ACS84 relieved the movement dysfunction of the model animals. Immunofluorescence staining and High-performance liquid chromatography analysis showed that ACS84 alleviated the loss of tyrosine-hydroxylase positive neurons in the substantia nigra and the declined dopamine concentration in the injured striatums of the 6-OHDA-induced PD model. Moreover, ACS84 reversed the elevated malondialdehyde level and the decreased glutathione level in vivo. In conclusion, ACS84 may prevent neurodegeneration via the anti-oxidative mechanism and has potential therapeutic values for Parkinson's disease.
    PLoS ONE 04/2013; 8(4):e60200. DOI:10.1371/journal.pone.0060200 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to hyperexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in the N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than a loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol, and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way toward new therapeutic strategies for AD.
    Journal of Alzheimer's disease: JAD 03/2013; 35(4). DOI:10.3233/JAD-121990 · 4.15 Impact Factor

Publication Stats

1k Citations
255.84 Total Impact Points


  • 2013-2015
    • National University Health System
    • Nanyang Technological University
      • School of Electrical and Electronic Engineering
      Tumasik, Singapore
  • 2009-2014
    • National University of Singapore
      Tumasik, Singapore
    • Clinical Research Center of Moscow
      Moskva, Moscow, Russia
  • 2007
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
  • 2004-2006
    • University of Hamburg
      Hamburg, Hamburg, Germany