- Ginsenoside Rb1 regulates prefrontal cortical GABAergic transmission in MPTP-treated mice. [Journal Article]
- AAging (Albany NY) 2019 Jul 17; 11
- Parkinson's disease (PD) is a common neurodegenerative disease, featured by motor deficits and non-motor symptoms such as cognitive impairment, and malfunction of gamma-aminobutyric acid (GABA) media…
Parkinson's disease (PD) is a common neurodegenerative disease, featured by motor deficits and non-motor symptoms such as cognitive impairment, and malfunction of gamma-aminobutyric acid (GABA) mediated inhibitory transmission plays an important role in PD pathogenesis. The ginsenoside Rb1 molecule, a major constituent of the extract from the Ginseng root, has been demonstrated to ameliorate motor deficits and prevent dopaminergic neuron death in PD. However, whether Rb1 can regulate GABAergic transmission in PD-associated deficits and its underlying mechanisms are still unclear. In this study, we explored the effects of Rb1 on the GABAergic synaptic transmission in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We demonstrated that Rb1 can bind with GABAARα1 and increase its expression in the SH-SY5Y cells and in the prefrontal cortex (PFC) of MPTP model in vitro and in vivo. Furthermore, Rb1 can promote prefrontal cortical GABA level and GABAergic transmission in MPTP-treated mice. We also revealed that Rb1 may suppress presynaptic GABABR1 to enhance GABA release and GABAA receptor-mediated inhibitory transmission. In addition, Rb1 attenuated MPTP-induced dysfunctional gait dynamic and cognitive impairment, and this neuroprotective mechanism possibly involved regulating prefrontal cortical GABAergic transmission. Thus, Rb1 may serve as a potential drug candidate for the treatment of PD.
- Immunomodulatory effects of Calcitriol in acute spinal cord injury in rats. [Journal Article]
- IIInt Immunopharmacol 2019 Jul 02; 74:105726
- Pharmacological therapy options for spinal cord injury (SCI) in acute phase have so far been limited, thus we focused on Calcitriol, FDA-approved biologically active form of vitamin D whose neuroprot…
Pharmacological therapy options for spinal cord injury (SCI) in acute phase have so far been limited, thus we focused on Calcitriol, FDA-approved biologically active form of vitamin D whose neuroprotective effects are increasingly recognized, to ameliorating damage following acute SCI in rats. Calcitriol (1 μg/kg) treatment for 7 consecutive days after SCI was compared SCI control and Sham control rat groups. Calcitriol-treated group had significantly improved outcome in standard functional recovery evaluation test (BBB) 12 weeks after SCI compared to SCI control, which was confirmed by increased ventral horn motor neurons in Calcitriol-treated group. In addition, proliferation test performed on lymphocytes from spleen and lymph nodes one week after SCI showed that calcitriol injection has a significant regulatory effect on Division Index (DI) in response to MBP stimulation compared to control SCI groups, which was associated with significant reduction in IFN-γ and IL-17A secretion and leukocyte infiltration into injury site. Along with confirmation of immunoregulatory aspects of Calcitriol treatment against myelin antigens in SCI, this study has shown that reducing the extent of progressive tissue loss by Calcitriol therapy in acute phase, could result in better recovery after SCI.
- MicroRNA-326 Inhibits Apoptosis and Promotes Proliferation of Dopaminergic Neurons in Parkinson's Disease Through Suppression of KLK7-Mediated MAPK Signaling Pathway. [Journal Article]
- JMJ Mol Neurosci 2019 Jul 03
- Parkinson's disease (PD), one of the motor system disorders, is characterized by the loss of dopamine-producing brain cells. Accumulating evidence has highlighted the involvement of microRNAs (miRs) …
Parkinson's disease (PD), one of the motor system disorders, is characterized by the loss of dopamine-producing brain cells. Accumulating evidence has highlighted the involvement of microRNAs (miRs) in the development and progression of PD. Hence, we aimed at exploring possible effects of miR-326 on the progression of PD in mice in an attempt to elucidate the underlying mechanism associated with the kallikrein-related peptidase 7 (KLK7)-mediated mitogen-activated protein kinase (MAPK) signaling pathway. In order to identify the regulatory relationship between miR-326 and KLK7 and its biological significance in PD, PD mouse models were established and subsequently treated with mimics or inhibitors of miR-326 or siRNA-KLK7. The content of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyrosine (3-MT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA); positive expression of tyrosine hydroxylase (TH) and inducible nitric oxide synthase (iNOS); and the levels of IL-1, IL-6, TNF-α, INF-γ, and MAPK signaling pathway-related genes were determined accordingly. The results obtained indicated that KLK7 was negatively targeted by miR-326, with lower miR-326 and higher KLK7 detected among PD mice. The overexpression of miR-326 or silencing of KLK7 was demonstrated to increase the content of DA, DOPAC, HVA, 3-MT, SOD, GSH-Px, and TH positive expression, while reducing iNOS positive expression, MDA content and cell apoptosis, as well as inhibited levels of IL-1, IL-6, TNF-α, INF-γ, and mRNA and protein levels of p38, ERK, JNK, and caspase-3. Taken together, these results provided evidence suggesting that miR-326 could inhibit iNOS activation and apoptosis of dopaminergic neurons through inhibiting the MAPK signaling pathway and negatively regulating KLK7 in mice with PD. These findings highlight the potential of miR-326 as a novel target for future PD treatment.
- Icariin protects rotenone-induced neurotoxicity through induction of SIRT3. [Journal Article]
- TAToxicol Appl Pharmacol 2019 Jun 25; :114639
- Sirtuin-3 (SIRT3) is a mitochondrial NAD + -dependent deacetylase that is essential in regulating mitochondrial proteins and maintaining cellular antioxidant properties. It has been reported that ica…
Sirtuin-3 (SIRT3) is a mitochondrial NAD + -dependent deacetylase that is essential in regulating mitochondrial proteins and maintaining cellular antioxidant properties. It has been reported that icariin (ICA) is neuroprotective over various neurotoxicant induced oxidative stress. This study aimed to determine whether ICA exerts neuroprotective effects on rotenone (ROT)-induced neurotoxicity through activation of SIRT3. Rats treated with ROT exhibited a marked loss of dopamine (DA) neurons and a decline in motor function, along with a decrease in protein expressions of SIRT3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the substantia nigra (SN). Administration of ICA significantly alleviated the loss of DA neurons, improved behavioral function, and concomitantly enhanced SIRT3 and PGC-1α expressions. The neuroprotective effect of ICA on ROT-induced cytotoxicity was further confirmed in the PC12 cell model, which showed significant improvement in the survival of ROT-treated cells with ICA pretreatment. The cytoprotective effect of ICA was abolished in ROT-treated cells by SIRT3 inhibitor 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP), along with a resultant decrease in PGC-1α expression. In addition, knockdown of PGC-1α by siRNA suppressed ICA-mediated protective effects but did not affect SIRT3 expression, indicating the role of regulation of PGC-1α by SIRT3 in the protective action of ICA. Furthermore, we showed that ICA improved mitochondrial respiration, oxidative status, enhanced antioxidant enzyme SOD activity and GSH/GSSG ratio in cells treated with ROT. However, these protective effects of ICA on ROT-treated cells was markedly abolished by SIRT3 inhibitor 3-TYP. Our findings demonstrate that ICA exerts a neuroprotective role through upregulation of SIRT3.
- Concomitant chest trauma and traumatic brain injury, biomarkers correlate with worse outcomes. [Journal Article]
- JTJ Trauma Acute Care Surg 2019; 87(1S Suppl 1):S146-S151
- CONCLUSIONS: Utilizing biomarkers for early identification of patients with TBI and chest trauma has the capability of modifying adverse factors affecting morbidity and mortality in this subset of TBI patients.
- Reward Expectation Modulates Local Field Potentials, Spiking Activity and Spike-Field Coherence in the Primary Motor Cortex. [Journal Article]
- EeNeuro 2019 May/Jun; 6(3)
- Reward modulation (M1) could be exploited in developing an autonomously updating brain-computer interface (BCI) based on a reinforcement learning (RL) architecture. For an autonomously updating RL-ba…
Reward modulation (M1) could be exploited in developing an autonomously updating brain-computer interface (BCI) based on a reinforcement learning (RL) architecture. For an autonomously updating RL-based BCI system, we would need a reward prediction error, or a state-value representation from the user's neural activity, which the RL-BCI agent could use to update its BCI decoder. In order to understand the multifaceted effects of reward on M1 activity, we investigated how neural spiking, oscillatory activities and their functional interactions are modulated by conditioned stimuli related reward expectation. To do so, local field potentials (LFPs) and single/multi-unit activities were recorded simultaneously and bilaterally from M1 cortices while four non-human primates (NHPs) performed cued center-out reaching or grip force tasks either manually using their right arm/hand or observed passively. We found that reward expectation influenced the strength of α (8-14 Hz) power, α-γ comodulation, α spike-field coherence (SFC), and firing rates (FRs) in general in M1. Furthermore, we found that an increase in α-band power was correlated with a decrease in neural spiking activity, that FRs were highest at the trough of the α-band cycle and lowest at the peak of its cycle. These findings imply that α oscillations modulated by reward expectation have an influence on spike FR and spike timing during both reaching and grasping tasks in M1. These LFP, spike, and spike-field interactions could be used to follow the M1 neural state in order to enhance BCI decoding (An et al., 2018; Zhao et al., 2018).
- Rapsyn facilitates recovery from desensitization in fetal and adult acetylcholine receptors expressed in a muscle cell line. [Journal Article]
- JPJ Physiol 2019; 597(14):3713-3725
- CONCLUSIONS: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied. Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform. Recovery from desensitization is determined by the AChR isoform-specific cytoplasmic M3-M4 domain. The co-expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitization in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering. These effects could be crucial adaptations to motor neuron firing rates, which, in rodents, have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions.
- Routing information flow by separate neural synchrony frequencies allows for "functionally labeled lines" in higher primate cortex. [Journal Article]
- PNProc Natl Acad Sci U S A 2019 Jun 18; 116(25):12506-12515
- Efficient transfer of sensory information to higher (motor or associative) areas in primate visual cortical areas is crucial for transforming sensory input into behavioral actions. Dynamically increa…
Efficient transfer of sensory information to higher (motor or associative) areas in primate visual cortical areas is crucial for transforming sensory input into behavioral actions. Dynamically increasing the level of coordination between single neurons has been suggested as an important contributor to this efficiency. We propose that differences between the functional coordination in different visual pathways might be used to unambiguously identify the source of input to the higher areas, ensuring a proper routing of the information flow. Here we determined the level of coordination between neurons in area MT in macaque visual cortex in a visual attention task via the strength of synchronization between the neurons' spike timing relative to the phase of oscillatory activities in local field potentials. In contrast to reports on the ventral visual pathway, we observed the synchrony of spikes only in the range of high gamma (180 to 220 Hz), rather than gamma (40 to 70 Hz) (as reported previously) to predict the animal's reaction speed. This supports a mechanistic role of the phase of high-gamma oscillatory activity in dynamically modulating the efficiency of neuronal information transfer. In addition, for inputs to higher cortical areas converging from the dorsal and ventral pathway, the distinct frequency bands of these inputs can be leveraged to preserve the identity of the input source. In this way source-specific oscillatory activity in primate cortex can serve to establish and maintain "functionally labeled lines" for dynamically adjusting cortical information transfer and multiplexing converging sensory signals.
- Major Contribution of Somatostatin-Expressing Interneurons and Cannabinoid Receptors to Increased GABA Synaptic Activity in the Striatum of Huntington's Disease Mice. [Journal Article]
- FSFront Synaptic Neurosci 2019; 11:14
- Huntington's disease (HD) is a heritable neurological disorder that affects cognitive and motor performance in patients carrying the mutated huntingtin (HTT) gene. In mouse models of HD, previous rep…
Huntington's disease (HD) is a heritable neurological disorder that affects cognitive and motor performance in patients carrying the mutated huntingtin (HTT) gene. In mouse models of HD, previous reports showed a significant increase in spontaneous GABAA receptor-mediated synaptic activity in striatal spiny projection neurons (SPNs). In this study, using optogenetics and slice electrophysiology, we examined the contribution of γ-aminobutyric acid (GABA)-ergic parvalbumin (PV)- and somatostatin (SOM)-expressing interneurons to the increase in GABA neurotransmission using the Q175 (heterozygote) mouse model of HD. Patch clamp recordings in voltage-clamp mode were performed on SPNs from brain slices of presymptomatic (2 months) and symptomatic (8 and 12 months) Q175 mice and wildtype (WT) littermates. While inhibitory postsynaptic currents (IPSCs) evoked in SPNs following optical activation of PV- and SOM-expressing interneurons differed in amplitude, no genotype-dependent differences were observed at all ages from both interneuron types; however, responses evoked by either type were found to have faster kinetics in symptomatic mice. Since SOM-expressing interneurons are constitutively active in striatal brain slices, we then examined the effects of acutely silencing these neurons in symptomatic mice with enhanced Natronomonas pharaonis halorhodopsin (eNpHR). Optically silencing SOM-expressing interneurons resulted in a greater decrease in the frequency of spontaneous IPSCs (sIPSCs) in a subset of SPNs from Q175 mice compared to WTs, suggesting that SOM-expressing interneurons are the main contributors to the overall increased GABA synaptic activity in HD SPNs. Additionally, the effects of activating GABAB and cannabinoid (CB1) receptors were investigated to determine whether these receptors were involved in modulating interneuron-specific GABA synaptic transmission and if this modulation differed in HD mice. When selectively activating PV- and SOM-expressing interneurons in the presence of the CB1 receptor agonist WIN-55,212, the magnitudes of the evoked IPSCs in SPNs decreased for both interneuron types although this change was less prominent in symptomatic Q175 SPNs during SOM-expressing interneuron activation. Overall, these findings show that dysfunction of SOM-expressing interneurons contributes to the increased GABA synaptic activity found in HD mouse models and that dysregulation of the endocannabinoid system may contribute to this effect.
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- Modulations in Oscillatory Activity of Globus Pallidus Internus Neurons During a Directed Hand Movement Task-A Primary Mechanism for Motor Planning. [Journal Article]
- FSFront Syst Neurosci 2019; 13:15
- Globus pallidus internus (GPi) neurons in the basal ganglia are traditionally thought to play a significant role in the promotion and suppression of movement via a change in firing rates. Here, we hy…
Globus pallidus internus (GPi) neurons in the basal ganglia are traditionally thought to play a significant role in the promotion and suppression of movement via a change in firing rates. Here, we hypothesize that a primary mechanism of movement control by GPi neurons is through specific modulations in their oscillatory patterns. We analyzed neuronal spiking activity of 83 GPi neurons recorded from two healthy nonhuman primates executing a radial center-out motor task. We found that, in directionally tuned neurons, the power in the gamma band is significantly (p < 0.05) greater than that in the beta band (a "cross-over" effect), during the planning stages of movements in their preferred direction. This cross-over effect is not observed in the non-directionally tuned neurons. These data suggest that, during movement planning, information encoding by GPi neurons may be governed by a sudden emergence and suppression of oscillatory activities, rather than simply by a change in average firing rates.