Brain Research

Curcumin is a phenolic compound derived from turmeric, one of the main ingredients of curry powder, which is widely used for its antioxidant, anti-inflammatory and immunomodulatory effects. Curcumin has been reported to help relieve pain, such as neuropathic pain caused by injury or disease, but the specific mechanism of its antinociceptive effect on pathological pain is unclear. Cyclin-dependent kinase 5 (Cdk5) is a key control point for the release of neurotransmitters from presynaptic vesicles. Cdk5 and its activator p35 couple to regulate key signaling cascades, thereby participating in the pain process. In this study, we established a NP model by chronic constriction injury (CCI) of the bilateral sciatic nerve in rats and evaluated behavioral hyperalgesia using mechanical and hot and cold tests. Protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that Iba-1 and Cdk5/p35 were co-localized in the dorsal horn and dorsal root ganglia, respectively. After CCI, the expression of Cdk5 and p35 was upregulated in the dorsal horn and dorsal root ganglia, while intraperitoneal injection of curcumin significantly reversed the activation of Cdk5/p35 protein and alleviated the hyperalgesia in rats. In addition, the injection of curcumin reduced the co-localization expression of Iba-1 and Cdk5/p35, indicating that curcumin inhibited the activation of Cdk5/p35 protein in the dorsal horn and dorsal root ganglia, thereby affecting the activation of microglia, thereby having a destructive effect on the neuronal cell plasticity and synaptic structure remodeling in the development of NP. Our study provides new evidence that Cdk5/p35 in the dorsal horn and dorsal root ganglia is related to the occurrence of NP, introduces microglia as the basis for the long-term maintenance of NP, and provides insights into the molecular mechanisms involved in the analgesic effect of curcumin. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/623498v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@125fc20org.highwire.dtl.DTLVardef@cba7d3org.highwire.dtl.DTLVardef@772291org.highwire.dtl.DTLVardef@17e87e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

ObjectiveElectroacupuncture has demonstrated beneficial effects in post-stroke motor dysfunction, yet the molecular mechanisms underlying its therapeutic efficacy remain incompletely understood. This study aims to investigate whether electroacupuncture promotes post-stroke motor function recovery by modulating the interaction between miR-124-3p and the NRG1/ErbB4 signaling pathway, specifically exploring whether miR-124-3p directly targets NRG1 to regulate neural plasticity in a focal cerebral ischemia rat model. MethodsThe ischemic stroke model was established by middle cerebral artery occlusion/reperfusion (MCAO/R) in adult rats. These rats were randomly divided into sham, model, electroacupuncture and model plus miR-124-3p inhibitor groups. The model group, electroacupuncture group and model plus miR-124-3p inhibitor group received EA intervention 24 h after modelling for 7 consecutive days. Behavioural function was assessed by Zea Longa score and mechanical pain rating. Hippocampal damage was detected by HE staining and neuronal apoptosis was observed by TUNEL staining. IL-1{beta} and IL-18 levels were measured by ELISA. PCR and Western blotting were used to detect the expression of miR-124-3p and inflammatory pathway proteins. The interaction between miR-124-3p and TLR4 was verified by dual-luciferase reporter assay. ResultsElectroacupuncture improved motor function in rat model of MCAO/R, as evidenced by improved Zea Longa scores and decreased mechanical withdrawal thresholds. Electroacupuncture significantly attenuated neuronal damage and also inhibited the inflammatory response by decreasing IL-18 and IL-1{beta} levels (P < 0.001). Notably, electroacupuncture upregulated miR-124-3p expression (P < 0.0001) and activated the NRG1/ErbB4 signaling pathway in the hippocampus. When miR-124-3p was inhibited, NRG1 protein expression decreased while GABA expression tended to increase. Dual-luciferase reporter assays confirmed that miR-124-3p directly targets the 3UTR of NRG1 mRNA and regulates its expression at the translational level. These findings suggest that electroacupuncture may alleviate neuronal and axonal damage by modulating miR-124-3p/NRG1/ErbB4 signalling and regulating GABA release. ConclusionElectroacupuncture can ameliorate motor dysfunction induced after brain I/R injury by targeting and modulating the NRG1-ErbB4 signaling pathway via miR-124-3p. These data are expected to provide new insights into the mechanisms of electroacupuncture for the prevention of potential targets for the recovery of motor dysfunction after stroke.

The brain plays a major role in controlling the desire to eat. This meta-analysis aimed to assess the association between dopamine receptor (DR) availability, measured using positron emission tomography, and obesity. We performed a systematic search of MEDLINE (from inception to June 2019) and EMBASE (from inception to June 2019) for articles published in English using the keywords "dopamine receptor," "obesity," and "neuroimaging." Fitting a locally weighted estimated scatterplot smoothing curve for binding potential (BPND) of the ventral striatum measured by 11C-raclopride was performed. Five studies involving 119 subjects were included in this analysis. 11C-raclopride was used in four studies, regardless of the ROIs included. The curve of BPND of the ventral striatum went up and down at BMI of 20-30 kg/m2 and became flat after a BMI of >40 kg/m2. Linear regression analysis was performed with BPND of the striatum from two studies (n = 20). The BPND of the striatum was negatively associated with BMI. In conclusion, dopamine plays a major role in the reward system with regard to obesity. Compared to normal-weight subjects, overweight and obese subjects had decreased DR availability. However, this tendency should be interpreted carefully with regard to radiopharmaceuticals and ROIs.

The traditional medicinal mushroom Hericium erinaceus has long been known for enhancing the peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. It was also reported to protect against ageing-dependent cognitive decline in wildtype and in Alzheimers disease mouse models suggesting a yet to be defined action on neurons of the central nervous system. Here, we purified and identified biologically active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom together with its hydrophobic derivative hericene A, were highly potent in inducing extensive axon outgrowth and neurite branching in the absence of serum demonstrating high neurotropic activity. NDPIH also induced enlarged growth cones suggestive of a brain-derived neurotrophic factor (BDNF)-like activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA12 prevented NDPIH-induced neurotrophic activity providing evidence that NDPIH acts via TrkB receptors to mediate its neurotrophic effect in central neurons. Finally, in vivo treatment with H. erinaceus crude extract and hericene A significantly increased BDNF and downstream pathway and enhanced learning and memory in the novel object recognition memory test. Our results suggest that hericene A can promote BDNF-like activity in neurons in vitro and in vivo thereby enhancing recognition memory.

Acute aerobic exercise (AEX) can enhance motor learning and promote neuroplasticity. However, the effect of AEX intensity on primary motor cortex (M1) excitability has not been systematically examined. Hence, the dose-response relationship between AEX intensity and M1 excitability modulation remains unclear. This study investigated the impact of AEX intensity on distinct M1 circuits using transcranial magnetic stimulation (TMS). Thirty right-handed adults underwent four experimental sessions: rest (control), light (LIIT), moderate (MIIT), and high-intensity interval training (HIIT) AEX. AEX intensity was prescribed with the heart rate reserve (HRR) method, and the interval cycling sessions consisted of alternating between 3 min at the target intensity (LIIT: 35% HRR; MIIT: 55% HRR; HIIT: 80% HRR) and 2 min of active recovery (25% HRR) for 20 min total. We performed TMS measures before (Pre), immediately post (Post0), and 20 min post (Post20) AEX/rest to assess modulation of corticospinal excitability and GABAergic inhibition as measured by short interval-intracortical inhibition (SICI). This study found that: (1) HIIT and MIIT increased corticospinal excitability, with HIIT eliciting a sustained increase; and (2) all AEX intensities (LIIT, MIIT and HIIT) decreased SICI, with the greatest sustained reduction following MIIT. Also, there was a greater reduction in GABAergic inhibition when measured with anterior-posterior than posterior-anterior TMS current following MIIT. Collectively, our results demonstrate the impact of HIIT and MIIT to enhance corticospinal excitability and reduce GABAergic inhibition in M1. This study provides evidence for a dose-response effect of AEX intensity on the modulation of distinct motor cortical circuits. KEY POINTS SUMMARYO_LIAcute aerobic exercise (AEX) is known to modulate primary motor cortex (M1) excitability, but the effect of AEX intensity is unclear. C_LIO_LIThis study examined the impact of light-, moderate-, and high-intensity interval training (LIIT, MIIT, HIIT) AEX and rest (non-AEX, control) on distinct M1 cortical circuits using transcranial magnetic stimulation (TMS). C_LIO_LIHIIT induced a sustained increase in M1 output excitability, MIIT induced a transient increase, and LIIT showed no effect. C_LIO_LIAll exercise intensities (LIIT, MIIT and HIIT) decreased GABAergic inhibition, as measured by short-interval intracortical inhibition (SICI), with MIIT showing a sustained decrease. C_LIO_LISICI measured with an anterior-to-posterior TMS current demonstrated greater GABAergic disinhibition compared to posterior-to-anterior TMS current following MIIT. C_LIO_LIThis study demonstrates a nuanced dose-response impact of AEX intensity on distinct M1 cortical circuits. C_LI

Multipotent mesenchymal stem cells (MSCs) including bone marrow stromal cells (BMSCs) have shown analgesic efficacy in recent years. Studies suggested that the therapeutic effect of MSCs was mediated by their secreted small extracellular vesicles (sEVs) mainly exosomes. The present study evaluated the antihyperalgesic effect of BMSC-related sEVs in a mouse model of neuropathic pain involving chronic constriction injury of the infraorbital nerve (CCI-ION). Our separation protocol generated EV particles mostly sized in the range of exosomes (30-170 nm) and express exosome marker proteins CD9, CD81, and Tsg101, suggesting their endosome origin. We show that intravenous injection of BMSC-related sEVs attenuated pain hypersensitivity induced by CCI-ION as indicated by decreased mechanical hypersensitivity (von Frey test) and reduced aversion to noxious stimulation (conditioned place avoidance test). The antihyperalgesic effect of sEVs was observed in both female and male animals, and the effect was dose-dependent. sEVs from NAIVE serum-treated BMSC cultures produced short-lasting antihyperalgesia in male but not female mice, suggesting a subtle sex difference. The antihyperalgesia of sEVs from BMSC culture was blocked by the pretreatment of the culture with GM4869, the antagonist of exosome secretion, suggesting that the effect was not related to other co-isolated soluble mediators but mediated by MSC-derived exosomes. Interestingly, the prior injury condition in which sEVs were isolated favors the pain-relieving effect of sEVs. sEVs isolated from the serum of BMSC-treated animals receiving tendon ligation (TL) injury attenuated hyperalgesia for 24 h, while sEVs from the serum of BMSC-treated NAIVE animals only attenuated hyperalgesia at 3 h after injection. sEVs from the BMSC culture treated with the serum of TL rats were antihyperalgesic, but sEVs from the BMSC culture treated with the serum of naive animals were ineffective. Our results indicate that BMSC-related sEVs produced antihyperalgesia similar to that produced by BMSCs. The results suggest that the interactions between BMSCs and injury conditions are crucially important for producing efficacious sEVs/exosomes and support that the effect of sEVs could be optimized by priming BMSCs with injury-related conditions.

In order to explore the mechanism of general anesthesia emergence, based on the common clinical phenomenon-delayed emergence, we explore the role of 5-hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus in promoting awakening from sevoflurane anesthesia in mice model. In this study, C57BL/6J male mice were selected to specifically activate or inhibit 5-HT neurons in the dorsal raphe nucleus (DRN) and different 5-HT receptors by intraperitoneal, lateral ventricle, intranuclear or DRN injection of agonists/antagonists and optogenetics during the sevoflurane anesthesia to record and observe the anesthesia induction and emergence time of mice. Through intraventricular infusion and intranuclear microinjection of 5-HT and the agonists or antagonists of different 5-HT receptors, our data showed that 5-HT and 5-HT1A and 2A/C receptors, especially 5-HT1A receptor, are involved in the regulation of delayed awakening mediated by DRN 5-HT neurons. This can provide a reliable theoretical basis as well as potential targets for clinical intervention to prevent delayed emergence and some postoperative risks. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/492958v2_ufig1.gif" ALT="Figure 1"> View larger version (68K): org.highwire.dtl.DTLVardef@ff4f7forg.highwire.dtl.DTLVardef@1bc56dborg.highwire.dtl.DTLVardef@1ea5737org.highwire.dtl.DTLVardef@41548_HPS_FORMAT_FIGEXP M_FIG C_FIG

General anesthesia, widely employed for its capacity to induce unconsciousness during surgical and diagnostic procedures, frequently results in postoperative recovery delays, a common complication. The precise mechanisms underpinning this delayed emergence from anesthesia remain not fully understood. Prior research has established a strong association between sleep-wake neural circuits and the anesthetic effects of general anesthetics, with serotonin (5-HT) playing a pivotal role in the regulation of anesthesia emergence. Extensive projections exist between the amygdala and the medial prefrontal cortex (mPFC). In this study, we utilized pharmacological, chemogenetic, and optogenetic techniques to explore the relationship between the 5-HT neural circuitry within the central amygdala (CeA)-mPFC pathway and the process of awakening from general anesthesia. Our findings reveal that modulating the 5-HT system in both the CeA and mPFC, via endogenous and exogenous means, can effectively reverse delayed emergence. This suggests that the 5-HT-ergic pathway within the CeA-mPFC circuit is instrumental in regulating the awakening process from sevoflurane anesthesia. These insights may inform future clinical interventions designed to prevent delayed emergence and reduce postoperative risks.

Methotrexate carried in lipid core nanoparticles (LDE-MTX) is a low toxicity compound effective in reducing inflammation and secondary damage in experimental models of arthritis, atherosclerosis, myocardial infarction, cardiac allograft vasculopathy and other pathological conditions. Nevertheless, whether it is neuroprotective after stroke is unknown. Here, we explored whether LDE-MTX could cross blood brain barrier (BBB) to exert anti-inflammatory and neuroprotecive effects after experimental cortical stroke in rats. Tissue uptake was assessed by injecting radioactively labeled-LDE through the caudal vein into both sham (n=18) and adult Wistar rats submitted to endothelin-1 (ET-1)-induced cortical stroke (n=11). To address possible neuroprotective effects of LDE-MTX after stroke, 10 adult male Wistar rats were randomly allocated in two groups: animals treated with LDE-MTX (1 mg/kg, i.v., n=5) or LDE-alone (i.v., n=5) at 4 hours after stroke induction. Animals were perfused with 0.9% saline and 4% paraformaldehyde at 7 days post-injury. Histopathology was assessed by cresyl violet staining. Mature neuronal bodies (anti-NeuN), astrocytes (anti-GFAP) and microglia (anti-Iba1) were immunolabeled by immunohistochemistry. Scintigraphy technique revealed accumulation of tritiated LDE in different brain regions and in non-neural organs without overt toxicity in both sham and ischemic rats. LDE-MTX treatment induced a 10-fold (1000%) reduction in microglial activation in the ischemic cortex and afforded a 319% increase in neuronal preservation in the ischemic periinfarct region compared to LDE-alone group. There was no effect of LDE-MTX treatment on primary infarct area and astrocytosis. The results suggest that LDE-MTX formulation must be considered a very promising neuroprotective agent for ischemic stroke. Future studies using different concentrations and longer survival times are needed before assessing the suitability of LDE-MTX as a neuroprotective agent for human stroke.

Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT2 receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT2 antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 {+/-} 4 years old) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT2 antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs) and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). Compared to placebo, 5-HT2 antagonism reduced maximal elbow flexion torque (p = 0.004), unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033), and conditioned MEP amplitude during contractions (p = 0.020). 5-HT2 antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT2 antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT2 receptors to regulate motoneurone excitability but not intracortical circuits. Significance statementCellular and animal preparations have revealed that somatodendritic 5-HT2 receptors on motoneurones can modulate motoneurone excitability. However, it is mostly unknown how 5-HT2 receptors modulate motor cortical and motoneurone activity to generate muscle contractions in humans. Here we show that antagonism of 5-HT2 receptors reduced muscle responses to motor cortical stimulation only when the muscle was at rest, or when voluntary motor activity was interrupted by a conditioning TMS stimulus. In contrast, antagonism of 5-HT2 receptors increased the muscle response to cervicomedullary electrical stimulation, but only when descending drive to motoneurones was present. These findings not only suggest that 5-HT2 receptors modulate intracortical and motoneurone activity, but sustained synaptic excitation of motoneurones is required for serotonergic mechanisms to modulate motoneurones.

Brain injury after intracerebral hemorrhage is extremely complicated, and the exact mechanism remains puzzling. Piezo1, a novel mammalian mechanosensitive ion channel, has been identified to play important roles in several pathologic and physiologic procedures that involve cellular mechanotransduction. However, the role of Piezo1 in hematoma compression after intracerebral hemorrhage is still unclear. In the present study, we established a balloon-inflated rat brain model mimicking the pure mechanical compression of a hematoma and detected balloon compression in the basal ganglia region of the brain, resulting in abnormal behaviors and a significant increase in the expression of Piezo1 and proinflammatory cytokines. These effects were reversed by GsMTx4, an antagonist of Piezo1. Additionally, the balloon deflation time affected behavioral function and the levels of Piezo1 and proinflammatory cytokines. These results establish the first in vivo evidence for the role of Piezo1 in blood-brain neuroinflammation after hematoma compression. Piezo1 may therefore be a potential therapeutic target for the treatment of intracerebral hemorrhage.

Although some advancements concerning the arousal involved in mediating the delayed emergency from general anesthesia, which will lead to the serious complications, had been made, the role by arousal in modulating in delayed emergency still remains to be unclear. In our models, based on our previous working that activation of the 5-Hydroxytryptamine (5-HT) neurons in the dorsal raphe nucleus (DRN) by optogenetics can significantly reduce the emergency time by activating arousal pathway, we further test whether the serotonergic neural circuit between the DRN and the basolateral amygdala (BLA) is implicated in modulating the arousal from the sevoflurane anesthesia and the emergency time of sevoflurane anesthesia by the pharmacological, optogenetics and fiber photometry. Our findings showed that whether the serotonergic neural circuit between the DRN and the basolateral amygdala (BLA) plays a key role in modulating the arousal from the sevoflurane anesthesia and the emergency time of sevoflurane anesthesia. Based on the serotonergic neural circuit, the 5-HT 1 A receptor is of great significance to mediate the arousal and the emergency time of the sevoflurane anesthesia. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/511924v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@34621eorg.highwire.dtl.DTLVardef@115ae09org.highwire.dtl.DTLVardef@54eb12org.highwire.dtl.DTLVardef@11515ff_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure1C_FLOATNO C_FIG

Intracerebral hemorrhage (ICH) is an acute cerebrovascular disease with high disability and mortality rates. Recombinant tissue plasminogen activator (rtPA) is commonly applied for hematoma evacuation in minimally invasive surgery (MIS) after ICH. However, rtPA may contact directly with brain tissue during MIS procedure, which makes it necessary to discuss the safety of rtPA. We found that, in the in vivo ICH model induced by VII-type collagenase, rtPA treatment improved the neurological function of ICH mice, alleviated the pathological damage and decreased the apoptosis and autophagy level of the peri-hematoma tissue. In the in-vitro model of ICH induced by hemin, the administration of rtPA down-regulated neuronal apoptosis, autophagy, and endoplasmic reticulum stress of neurons. Transcriptome sequencing analysis showed that rtPA treatment upregulated the PI3K/AKT/mTOR pathway in neurons, and PI3K inhibitor (LY294002) can reverse the protective effects of rtPA in inhibiting excessive apoptosis, autophagy and ER-stress. Epidermal growth factor receptor inhibitor (AG-1487) reversed the effect of rtPA on PI3K/AKT/mTOR pathway, which might indicate that the EGF domain played an important role in the activation of PI3K/AKT/mTOR pathway.

The incretin system is an emerging new field that might provide valuable contributions to the research of both pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the role of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain as well as on the levels of these incretins, insulin and glucose, by inhibiting the central incretins receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimers disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in the brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.

Abnormal amyloid-{beta} (A{beta}) abnormal accumulation and oxidative stress play important roles in Alzheimers disease (AD). Quercetin has been reported to possess antioxidant and anti-inflammatory properties, and thus of therapeutic interests for neurodegenerative disorders. In the present study, we aimed to characterize the mechanisms by which quercetin exerts neuroprotective effects in murine neuroblastoma N2a cells stably expressing human Swedishh mutant amyloid precursor protein (APP). Quercetin treatment exhibited low cytoxicity, attenuated APP expression and APP-induced oxidative neurotoxicity in N2a/APP cells. We found that quercetin effected via the down-regulation of phospho-extracellular signal{square}regulated protein kinase (p-ERK1/2) pathway and up-regulation of phospho-protein kinase B (p-AKT) pathway in N2a/APP cells. In addition, quercetin ameliorated the elevated levels of reactive oxygen species using DCFH-DA flow-cytometry in N2a/APP cells, lipid peroxidation using (4-HNE), and DNA oxidation (8-OHdG assays). Quercetin ameliorated the loss of mitochondrial membrane potential using JC-1 fluorescence assay in N2a/APP cells in a dose-dependent mannor. In conclusion, we domenstrated the neuroprotective effects of quercetin against the APP expression induced oxidative neurotoxicity, impairment of mitochondrial function and oxidative stress through inactivation of the ERK1/2 signaling pathway and activation of AKT signaling pathways.

The effects of spinal epidural stimulation (ES) in regaining various physiological functions after a spinal cord injury (SCI) are well documented. Spinal evoked motor responses (SEMR) are commonly utilized experimental outcomes in longitudinal pre-clinical and human studies to reflect the in-vivo physiological changes in neural networks secondary to a neurological insult or neuro-rehabilitative treatments utilizing ES. However, it remains unknown if the repeated exposure to ES during SEMRs testing itself modulates the spinal cord physiology and hence the SEMRs characteristics. To address this issue, cervical ES was delivered to the healthy adult rats cervical cord using standard stimulation paradigms during multiple sessions ([~]17 hours that spanned across 100 days). Cervical SEMR and electromyography (EMG) activity from forelimb muscles during a reaching & grasping task were collected before and after 100 days. We noted persistent increase in the cervical SEMR and forelimb muscle activity during reaching & grasping task relative to baseline at the end of the stimulation period indicating increased spinal and cortical excitability. Findings from the present work suggests that cervical SEMRs are amenable to modulation by routine ES testing protocols, with prominent changes in the mono and poly synaptic component of evoked responses. Additionally, since multiple testing sessions of cervical ES alone increases the excitability of the intact spinal cord, we suggest that SEMR data be used with caution to infer the physiological status of the spinal circuitry in longitudinal studies involving multiple SEMR testing sessions. Our findings also recommend involving appropriate control groups, motor behavior correlates, and practicing caution while utilizing normalization methods to allow meaningful functional interpretation of SEMR profiles following a SCI.

Breathing results from the interaction of two distinct oscillators: the preBotzinger Complex (preBotC) driving inspiration and the lateral parafacial region (pFRG) driving active expiration. The pFRG is silent during resting and become rhythmically active during high metabolic demand such as hypoxia. Catecholaminergic C1 cells are activated by hypoxia, which is a strong stimulus for active expiration. We hypothesized that the C1 cells and pFRG may constitute functionally distinct but interacting populations in order to contributes to control expiratory activity during hypoxia. We found that: a) C1 neurons are activated by hypoxia and project to pFRG region; b) active expiration elicited by hypoxia was blunted after blockade of ionotropic glutamatergic antagonist at the level of pFRG and c) selective depletion of C1 neurons eliminated the active expiration elicited by hypoxia. The results suggest that C1 cells may regulate the respiratory cycle including the active expiration under hypoxic condition.

The surge in demand for experimental monkeys has led to a rapid increase in their associated costs. Consequently, there is a growing need for the development of a cost-effective model for Parkinsons disease (PD) that exhibits all core clinical and pathological phenotypes of PD. Evolutionarily, tree shrews (Tupaia belangeri) are much closer to primates in comparison to rodents and share more similar PD-related brain structures and movement ability with monkeys. As such, tree shrews represent an ideal small animal species for modeling PD. To develop a tree shrew PD model, we used the 1-Methyl-4-phenylpyridinium (MPP+) metabolite, derived from the well-established PD modeling drug 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to induce lesions in the dopaminergic neurons of the unilateral substantia nigra. After determining the optimal modeling dosage, the tree shrews consistently exhibited and maintained all classic clinical manifestations of PD for a 5-month period. The symptoms closely resembled the ones observed in PD monkeys and included bradykinesia, rest tremor, postural instability, and apomorphine-induced rotations, a classic phenotype of unilateral PD models. Immunostaining showed a significant loss of dopaminergic neurons (approximately 95%) in the substantia nigra on the lesioned side of the brain, a crucial pathological marker of PD. Further cytomorphological analysis revealed that the size of nigral dopaminergic neurons in tree shrews exceeded that of rodents and more closely approximated that of macaques. Based on the principle that structure determines function, the morphological similarity between tree shrews and monkeys may be an important structural basis for the manifestation of the highly similar phenotypes between monkey and tree shrew PD models. Collectively, this study successfully developed a PD model in a small animal species that faithfully recapitulated the classical clinical symptoms and key pathological indicators of PD monkeys. In addition to the well-recognized monkey models, the tree shrew model provides a novel avenue for the evaluation of PD treatments and underlying mechanisms.

This study investigated the causal effect of transcranial photobiomodulation (tPBM) over the left prefrontal cortex (LPFC) on syntactically complex Mandarin Chinese first language (L1) and second language (L2) sentence processing performances. Two (L1 and L2) groups of participants (thirty per group) were recruited to receive the double-blind, sham-controlled tPBM intervention, followed by the sentence processing, the verbal working memory (WM), and the visual WM tasks. Results revealed a consistent pattern for both groups: (a) tPBM enhanced sentence processing performance but not verbal WM and visual WM performance; (b) Participants with lower sentence processing performances under sham tPBM benefited more from active tPBM. Taken together, the current study substantiated that tPBM enhanced L1 and L2 sentence processing ability directly without verbal WM interference, and would serve as a promising and cost-effective noninvasive brain stimulation (NIBS) tool for future applications on upregulating the human language faculty. HighlightsO_LIThe first study that applies tPBM to (complex) sentence processing. C_LIO_LItPBM enhances sentence processing performances in both Mandarin L1 & L2 speakers. C_LIO_LItPBM directly enhances sentence processing without the interference of verbal WM. C_LIO_LIA causal role of LPFC for sentence processing through active tPBM. C_LIO_LIOpening up the promising application prospect for tPBM on sentence processing. C_LI

The progressive decline of dopamine neurons in the substantia nigra is the main pathogenic change in Parkinsons disease (PD). Studies have found that excessive excitement of glutamatergic neurons causes intracellular calcium overload and induces autophagy impairment, which is one of the main mechanisms of dopamine neuron damage. The neuroprotective effect of Ifenprodil against 6-OHDA-injured mice was studied in this study. Ifenprodil was administered intraperitoneally (i.p.) or intracerebrally to rats who had a nigral-striatum pathway lesioned by 6-OHDA stereotactic brain injection. The ability to move was evaluated. The survival of dopamine neurons in the nigral was determined using HE staining, while TH-positive expression was measured using immunohistochemistry. Western Blot was used to examine the expression of CaM protein and light chain 3 (LC3), Beclin-1, BNIP3LNix, and p62. The results revealed that Ifenprodil improves motor function in 6-OHDA rats, and intracerebral injection is more effective than systemic administration. The same results also found in HE and IHC. Ifenprodil enhanced LC3II, BNIP3LNix, and Beclin-1 while decreasing p62, p-CaMKII, and {beta}-Ca expression. In addition, Ifenprodil reduced the activation of microglia caused by 6-OHDA. Overall, the findings imply that Ifenprodil intracerebrally may protect against Parkinsons disease via modulating autophagy-related proteins during 6-OHDA-induced toxicity.