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The combined use of two or more different drugs can better promote nerve recovery and its prognosis for treatment of stroke. Salvianolate lyophilized injection (SLI) made from the aqueous extraction of salvia miltiorrhiza and Xueshuantong injection (lyophilized) (XST) made from the Panax Notoginseng extraction are two herbal standardized preparations that have been widely used in China for the treatment of ischemic stroke. In this study, we investigated the neuroprotective effects of XST combined with SLI in the recovery stage of middle cerebral artery occlusion / reperfusion (MCAO/R) injury rat. Wistar rats were subjects to MCAO/R, then were treated with SLI or XST alone, or with their combination (1X1S) via tail injection daily for 14 days. The pathological status of the brain was detected by neurological deficit scores, TTC, regional cerebral blood flow and Nissl staining. Golgi-Cox staining was used to assess dendritic, axonal and synaptic remodeling. The expression of MAP-2, β-Tubulin, PSD95, SYN, BDNF and VEGF were analyzed by western blotting and immunofluorescence. The results showed that administration of 1X1S not only significantly decreased neurological scores and infarct volumes, but also increased regional cerebral blood flow, strengthened dendritic and synaptic remodeling compared with XST, SLI used alone. And the mechanism of combined of 1X1S to exert neuroprotection may be associated with PI3K/ AKT/ mTOR and RhoA/ROCK2 pathways. Overall, these findings suggest that combination of XST and SLI promotes dendritic spine density and synaptic plasticity via upregulation of the PI3K/ AKT/ mTOR pathways and inhabitation the RhoA/ROCK2 signaling pathway in rat with MCAO/R, showing its multiple-action-multiple-target efficacy and suggest a potential new strategy for ischemia.

Movement imagery (MI) is a cognitive process wherein an individual simulates themselves performing a movement in the absence of physical movement. The current paper reports an examination of the relationship between behavioural indexes of MI ability and the magnitude of corticospinal adaptation following MI training. Behavioural indexes of MI ability included data from a questionnaire (MIQ-3), a mental chronometry task, and a hand laterality judgment task. For the measure of corticospinal adaptation, single-pulse transcranial magnetic stimulation (TMS) was administered to elicit thumb movements to determine the representation of thumb movements before and after MI training. MI training involved participants imagining themselves moving their thumb in the opposite direction to the dominant direction of the TMS-evoked movements prior to training. Pre/post-training changes in the direction and velocity of TMS-evoked thumb movements indicated the magnitude of adaptation following MI training. The two main findings were: 1) a positive relationship was found between the MIQ-3 and the pre/post-training changes in the direction of TMS-evoked thumb movements; and 2) a negative relationship between the mental chronometry measure and both measures of corticospinal adaptation following MI training. These results indicate that both ease of imagery and timing of imagery could predict the magnitude of neuroplastic adaptation following MI training. Thus, both these measures may be considered when assessing imagery ability and determining who might benefit from MI interventions.

This study is aimed to investigate the mechanism of miR-146a/KLF4 axis regarding epilepsy seizure and synaptic plasticity.Pentylenetetrazol (PTZ)-kindling mouse model of epilepsy was established and evaluated by Racine's scale. PTZ-treated mice were subjected to stereotactic injection of miR-146a antagomir and pre-KLF4 to verify the role of miR-146a and KLF4 in mice. Primary hippocampal neurons from fetal mouse were isolated and identified through immunofluorescence for microtubule-associated protein (MAP)-2. Cellular models of epilepsy were prepared using magnesium-free extracellular fluid and then the neurons were transfected with miR-146a antagomir, miR-146a agomir, miR-146a agomir + pre-KLF4, AG490 (an inhibitor of STAT3 signal pathway) or miR-146a agomir + AG490. The binding site between miR-146a and KLF4 was predicted and identified. The expression levels of miR-146a, KLF4, CREB, Synaptotagmin-11 (SYT11), and STAT3-related proteins were measured in addition to the morphology of neurons and length of neurite. The severity of synaptic plasticity was assessed according to the levels of CREB and SYT11.The expression of miR-146a was elevated and KLF4 expression was decreased in epileptic mice. Stereotactic injection of miR-146a antagomir and pre-KLF4 reduced the seizure scores of epileptic mice. Transfection of miR-146a antagomir or pre-KLF4 could attenuate synaptic plasticity in epileptic mice and epileptic cellular models. miR-146a can negatively regulate KLF4 in epileptic cellular models to mediate synaptic plasticity. Epilepsy was attenuated in AG490 and miR-146a agomir + AG490 groups compared with that in Model group.miR-146a inhibits KLF4 to activate STAT3, thus promoting synaptic plasticity in epileptic mice.

Methamphetamine (Meth) produces a variety of epigenetic effects in the brain, which are seminal to establish long-lasting alterations in neuronal activity. However, most epigenetic changes were described by measuring the rough amount of either histone acetylation and methylation or direct DNA methylation, without focusing on a specific DNA sequence. This point is key to comprehend Meth-induced phenotypic changes, brain plasticity, addiction and neurodegeneration. In this research paper we analyze the persistence of Meth-induced striatal synucleinopathy at a prolonged time interval of Meth withdrawal. At the same time, Meth-induced alterations, specifically within alpha-synuclein gene (SNCA) or its promoter, were evaluated. We found that exposure to high and/or prolonged doses of Meth, apart from producing nigro-striatal toxicity, determines a long-lasting increase in striatal alpha-synuclein levels. This is consistent along immune-blotting, immune-histochemistry, and electron microscopy. This was neither associated with an increase of SNCA copy number nor with alterations within SNCA sequence. However, we documented persistently demethylation within SNCA promoter, which matches the increase in alpha-synuclein protein. The amount of the native protein, which was measured stoichiometrically within striatal neurons, surpasses the increase reported following SNCA multiplications. Demethylation was remarkable (ten-fold of controls) and steady, even at prolonged time intervals being tested so far (up to 21 days of Meth withdrawal). Similarly alpha-synuclein protein assayed stoichiometrically steadily increased roughly ten-fold of controls. Meth-induced increase of alpha-synuclein was also described within limbic areas. These findings are discussed in the light of Meth-induced epigenetic changes, Meth-induced phenotype alterations, and Meth-induced neurodegeneration.

Fast spiking interneurons (FSINs) have an important role in neuronal network dynamics. Although plasticity of synaptic properties is known to affect network synchrony, the role of plasticity of FSINs’ intrinsic excitability on network dynamics remain elusive. Using computational approaches in an excitatory-FSIN model network (EI) based on previously established hippocampal neuronal models we show that altered FSIN intrinsic excitability robustly affects the coherence and frequency of network firing monotonically in the connected excitatory network. Surprisingly, the effect of FSIN excitability was dependent on the mechanisms associated with changes in intrinsic excitability rather than on the direction of the change. Decreasing FSIN excitability by decreasing the membrane specific resistance (Rm), increasing peak HCN conductance (gihbar) increased the excitatory network coherence while increased peak delayed potassium conductance (gKDbar) decreased the coherence. However, the perturbations affected the excitatory network frequency in a similar manner. Further, in an isolated FSIN all-to-all network (II), decreasing FSIN excitability caused significant decrease in the network steady-state frequency due to any of the alterations. However, II network coherence remained unaltered with change in FSIN Rm but increased with higher gihbar and lower gKDbar. Interestingly, decreased FSIN Rin could partially rescue the decreasing EI network coherence with increasing gKDbar. The phenomenon of FSIN Rm, gihbar and gKDbar dependent EI network coherence alterations was robust for different proportions of plastic FSINs. Our results indicate that plasticity of intrinsic excitability in FSINs can regulate network dynamics and thus serve as an important network strategy during different physiological states.

The direct and indirect pathway striatal medium spiny neurons (dMSNs and iMSNs) have long been linked to action selection, but the precise roles of these neurons in this process remain unclear. Here, we review different models of striatal pathway function, focusing on the classic “go/no-go” model which posits that dMSNs facilitate movement while iMSNs inhibit movement, and the “complementary” model, which argues that dMSNs facilitate the selection of specific actions while iMSNs inhibit potentially conflicting actions. We discuss the merits and shortcomings of these models and propose a new “competitive” model to explain the contribution of these two pathways to behavior. The “competitive” model argues that rather than inhibiting conflicting actions, iMSNs are tuned to the same actions that dMSNs facilitate, and the two populations “compete” to determine the animal’s behavioral response. This model provides a theoretical explanation for how these pathways work together to select actions. In addition, it provides a link between action selection and behavioral reinforcement, via modulating synaptic strength at inputs onto dMSNs and iMSNs. Finally, this model makes predictions about how imbalances in the activity of these pathways may underlie behavioral traits associated with psychiatric disorders. Understanding the roles of these striatal pathways in action selection may help to clarify the neuronal mechanisms of decision-making under normal and pathological conditions.

Neuromodulatory facilitation of long-term synaptic plasticity is important in learning, memory, and experience-dependent cortical plasticity. Although muscarinic-induced long-term depression (mLTD) in the visual cortex is well known, its cellular mechanisms are not fully understood yet. Since endocannabinoid signaling mediates presynaptic expression of LTD in various brain areas including the primary visual cortex of rats, we investigated the involvement of endocannabinoids in the induction of mLTD in different dendritic compartments of layer 2/3 pyramidal neurons. With an unloading experiment of FM1-43 as an indicator of synaptic vesicle recycling, we confirmed that layer 1 and layer 4 stimulations mainly activated distal apical (in layer 1) and perisomatic (in layer 2/3) dendritic compartments, respectively. Bath application of muscarine (10 min) induced LTD in synaptic inputs activated by stimulation of layers 1 (L1-mLTD) and 4 (L2/3-mLTD). Both mLTDs were blocked by intracellular Ca2+ chelator BAPTA and bath application of NMDA receptor antagonist d -AP5. However, only L2/3-mLTD exhibited an increase in paired-pulse ratio. In addition, only L2/3-mLTD was blocked by treatment with CB1 receptor antagonist AM251. Both mLTDs were blocked by intracellular NMDA receptor antagonist MK801, but not by glia-specific metabolic inhibitor fluoroacetate, implying that neither presynaptic NMDA receptors nor astrocytes are involved in mLTD. These results suggest that L2/3-mLTD is expressed presynaptically via retrograde endocannabinoid signaling while L1-mLTD is endocannabinoid independent in layer 2/3 pyramidal neurons of the visual cortex. Therefore, layer-specific involvement of endocannabinoids in the induction of mLTD might play an important role in cortical development and information processing in the neocortex.

Brain-Derived Neurotrophic Factor (BDNF) signaling through TrkB receptors has important roles in synapse formation, synaptic plasticity, learning, and specific diseases. However, it is challenging to relate BDNF-TrkB synapses to circuit physiology or learning, as BDNF-TrkB synapses are embedded in complex circuits that contain numerous neuron and synapse types. Thus, analyzing the physiology of neurons connected by BDNF-TrkB synapses would be advanced by a technology to deliver different genes into presynaptic and postsynaptic neurons, connected by a BDNF-TrkB synapse. Here, we report selective gene transfer across BDNF-TrkB synapses: The model system was the large projection from rat postrhinal to perirhinal cortex. The first gene transfer, into presynaptic neurons in postrhinal cortex, used a virus vector and standard gene transfer procedures. This vector expresses a synthetic peptide neurotransmitter composed of three domains, a dense core vesicle sorting domain, BDNF, and the His tag. Upon release, this peptide neurotransmitter binds to TrkB receptors on postsynaptic neurons. The second gene transfer, into connected postsynaptic neurons in perirhinal cortex, uses antibody-mediated, targeted gene transfer and an anti-His tag antibody, as the synthetic peptide neurotransmitter contains the His tag. Confocal microscope images showed that using untargeted gene transfer, only 10–15% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. But using targeted gene transfer, ∼70% of the transduced presynaptic axons were proximal to a transduced postsynaptic dendrite. This technology may support studies on the roles of neurons connected by BDNF-TrkB synapses in circuit physiology and learning.

Functional targeting with anodal high-definition transcranial direct current stimulation (HD-atDCS) of involved brain areas during performance of a motor task (online) may facilitate sensorimotor cortex neuroplasticity compared to performing the motor task after HD-atDCS (offline). The aim of this study was to employ functional near-infrared spectroscopy to compare the time course of motor task-related changes in sensorimotor cortex activation between online and offline HD-atDCS. We hypothesized that online HD-atDCS would have a greater effect on task-related sensorimotor cortex activation than offline HD-atDCS. In a within-subject sham controlled and randomized study design, 9 healthy participants underwent 3 HD-atDCS sessions (online, offline and sham) targeting the left sensorimotor cortex separated by 1 week. Functional near-infrared spectroscopy hemodynamic changes were measured from the left sensorimotor cortex during a simple finger opposition motor task before (Pre), immediately (T1) and 30 min after (T2) each session. The movement rates were not different between (online, offline, sham) or within (Pre, T1, T2) sessions. At T2, online HD-atDCS was associated with a significant increase (large effect size) in sensorimotor cortex activation (Hedges g = 1.01, p 0.001) when compared to sham; there was a nonsignificant trend to increase activation between offline and sham (Hedges g = 0.52, p = 0.05) and between online and offline (Hedges g = 0.53, p = 0.06). Concurrent application of HD-atDCS during a motor task may produce larger sensorimotor cortex activation than sequential application.

Cux1 and Cux2 are the vertebrate members of a family of homeodomain transcription factors (TF) containing Cut repeat DNA-binding sequences. Perturbation of their expression has been implicated in a wide variety of diseases and disorders, ranging from cancer to autism spectrum disorder (ASD). Within the nervous system, both genes are expressed during neurogenesis and in specific neuronal subpopulations. Their role during development and circuit specification is discussed here, with a particular focus on the cortex where their restricted expression in pyramidal neurons of the upper layers appears to be responsible for many of the specialized functions of these cells, and where their functions have been extensively investigated. Finally, we discuss how Cux TF represent a promising avenue for manipulating neuronal function and for reprogramming., L.A.W. is funded by the PCIN-2015-176-C02-02/ERA-Net Neuron (Era-Net, MINECO). M.N. research is funded by grants from the Secretaría de Estado de Investigación, Desarrollo e Innovación (MINECO), (SAF2011-23735, BFU2016-81887-REDT/AEI, PCIN2015-176-C02-02/ERA-Net Neuron) and an institutional grant from the Ramón Areces Foundation.

Sensory input for hearing plays a significant role in the development of human brain. Absence of an early auditory input leads to the alteration of important neural regions, which in turn results in a complex process known as cross-modal neuroplasticity. Previous studies related to the structural brain alteration of adult deaf individuals have shown inconsistent results. To address this issue, we investigated the brain morphology in 50 prelingual adult deaf individuals and compared it with the same number of individuals with normal hearing, using structural magnetic resonance imaging and three inter-related but completely distinct analysis methods namely univariate approach (voxel based morphometry), multivariate approach (source based morphometry), and projection based cortical thickness. The findings from all these inter-related analyses suggest alterations in important neural regions such as bilateral superior temporal gyrus, bilateral inferior temporal, bilateral fusiform gyrus, and bilateral middle frontal. These findings also justify a strong ventral visual pathway in the deaf group. We suggest that these morphological alterations in important brain regions are due to the compensatory cross-modal reorganization.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory decline and impaired hippocampal synaptic plasticity. The serotonin 5-HT4 receptor is involved in learning and memory processes. This study explored the effects of chronic stimulation of 5-HT4R on cognition, memory, long-term potentiation (LTP), paired-pulse ratio (PPR), and neuronal apoptosis in a rat model of amyloid-beta (Aβ)-induced AD. Thirty-five male Wistar rats were randomly divided into three groups as follows: the sham, Aβ, and Aβ + BIMU8 groups. Aβ (6 µg/µl) was administrated by intracerebroventricular (icv) injection. The animals were treated with BIMU8 (1 μg/μL, ICV) as a 5-HT4R agonist for 30 days. Memory and behavioral changes were assessed by the passive avoidance learning, novel object recognition, open field, and elevated plus maze tests. Hippocampal synaptic plasticity was evaluated in the dentate gyrus (DG) in response to the stimulation applied to the perforant pathway. Furthermore, neuronal apoptosis was measured in the hippocampus. Data were analyzed by SPSS version 19 using one-way ANOVA, followed by Tukey’s post hoc test. Aβ induced memory deficits and neuronal loss and inhibited LTP induction. Aβ also increased the normalized PPR. BIMU8 enhanced the slope of the field excitatory postsynaptic potential in LTP and improved cognition behavior. Paired-pulse inhibition or facilitation was not affected by LTP induction in Aβ animals receiving the BIMU8. It can be concluded that the stimulation of the 5-HT4 receptor modulated the Aβ-induced cognition and memory deficits, probably via a decrease in the hippocampal apoptotic neurons and an improvement in the hippocampal synaptic functions without involving its inhibitory interneurons.

Intracerebral hemorrhage (ICH) is a subtype of stroke that causes major motor impairments. Brain-derived neurotrophic factor (BDNF) is known to have important roles in neuroplasticity and beneficially contributes to stroke recovery. This study aimed to characterize BDNF expression in the motor cortex after ICH and investigate the relationship between cortical BDNF expression and behavioral outcomes using an ICH rat model. Wistar rats were divided into two groups: a SHAM group (n = 7) and an ICH group (n = 8). ICH was induced by the injection of collagenase into the left striatum near the internal capsule. For behavioral assessments, the cylinder test and open field test were performed before surgery and 3 days, 1 week, 2 weeks, and 4 weeks after surgery. Following the behavioral assessments at 4 weeks, BDNF expression in the ipsilateral and contralateral motor cortex was assayed using RT-PCR and ELISA methods. There was no significant difference in either cortical BDNF mRNA or protein expression levels between the SHAM and ICH groups. However, the asymmetry index of BDNF mRNA expression between the ipsilateral and contralateral hemispheres shifted to the ipsilateral hemisphere after ICH. Furthermore, the ipsilateral cortical BDNF mRNA expression level positively correlated with motor function in the affected forelimb after ICH. This study describes for the first time that cortical BDNF mRNA expression is related to post-ICH motor impairment. These results highlight the importance of assessing the interhemispheric laterality of BDNF expression and could help develop novel treatment strategies for BDNF-dependent recovery after ICH.

Vagus nerve stimulation (VNS) paired with motor rehabilitation enhances recovery of function after neurological injury in rats and humans. This effect is ascribed to VNS-dependent facilitation of plasticity in motor networks. Previous studies document an inverted-U relationship between VNS intensity and cortical plasticity, such that moderate intensities increase plasticity, while low or high intensity VNS does not. We tested the interaction of moderate and high intensity VNS trains to probe the mechanisms that may underlie VNS-dependent plasticity. Rats performed a behavioral task where VNS was paired with jaw movement during chewing. For five days, subjects received 100 pairings of moderate intensity VNS (Standard VNS), 100 pairings alternating between moderate and high intensity VNS (Interleaved VNS), or 50 pairings of moderate intensity VNS (Short VNS) approximately every 8 seconds. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate movement representations in motor cortex. 100 pairings of moderate intensity VNS enhanced motor cortex plasticity. Replacing half of moderate intensity stimulation with high intensity VNS blocked this enhancement of plasticity. Removing high intensity stimulation, leaving only 50 pairings of moderate intensity VNS, reinstated plasticity. These results demonstrate that there is a period for at least 8 seconds after high intensity stimulation in which moderate intensity VNS is not able to engage mechanisms required for synaptic reorganization. More importantly, this study demonstrates that changes in stimulation parameters are a critical determinant of the magnitude of plasticity and likely the efficacy of VNS-enhanced recovery.

Traumatic brain injury (TBI) frequently causes cardiac autonomic dysfunction (CAD), irrespective of its severity, which is associated with an increased morbidity and mortality in patients. Despite the significance of probing the cellular mechanism underlying TBI-induced CAD, animal studies on this mechanism are lacking. In the current study, we tested whether TBI-induced CAD is associated with functional plasticity in cardiac efferent neurons. In this regard, TBI was induced by a controlled cortical impact in rats. Assessment of heart rate variability and baroreflex sensitivity indicated that CAD was developed in the sub-acute period after moderate and severe TBI. The cell excitability was increased in the stellate ganglion (SG) neurons and decreased in the intracardiac ganglion (ICG) neurons in TBI rats, compared with the sham-operated rats. The transient A-type K+ (KA) currents, but not the delayed rectifying K+ currents were significantly decreased in SG neurons in TBI rats, compared with sham-operated rats. Consistent with these electrophysiological data, the transcripts encoding the Kv4 α subunits were significantly downregulated in SG neurons in TBI rats, compared with sham-operated rats. TBI causes downregulation and upregulation of M-type K+ (KM) currents and the KCNQ2 mRNA transcripts, which may contribute to the hyperexcitability of the SG neurons and the hypoexcitability of the ICG neurons, respectively. In conclusion, the key cellular mechanism underlying the TBI-induced CAD may be the functional plasticity of the cardiac efferent neurons, which is caused by the regulation of the KA and/or KM currents.

Neuropathic pain (NP) is related to the presence of hyperalgesia, allodynia, and spontaneous pain, affecting 7%–10% of the general population. Repetitive transcranial magnetic stimulation (rTMS) is applied for NP relief, especially in patients with refractory pain. As NP response to existing treatments is often insufficient, we aimed to evaluate rTMS treatment on the nociceptive response of rats submitted to an NP model and its effect on pro-and anti-neuroinflammatory cytokine and neurotrophin levels. A total of 106 adult male Wistar rats (60 days old) were divided into nine experimental groups: control, control + sham rTMS, control + rTMS, sham NP, sham neuropathic pain + sham rTMS, sham neuropathic pain + rTMS, NP, neuropathic pain + sham rTMS, and neuropathic pain + rTMS. NP establishment was achieved 14 days after the surgery to establish chronic constriction injury (CCI) of the sciatic nerve. Rats were treated with 5 min daily sessions of rTMS for eight consecutive days. Nociceptive behavior was assessed using von Frey and hot plate tests at baseline, after NP establishment, and post-treatment. Biochemical assays to assess the levels of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-α), and interleukin (IL)-10, were performed in the prefrontal cortex (PFC) and spinal cord tissue homogenates. rTMS treatment promoted a partial reversal of mechanical allodynia and total reversal of thermal hyperalgesia induced by CCI. Moreover, rTMS increased the levels of BDNF, TNF-α, and IL-10 in the PFC. rTMS may be a promising tool for the treatment of NP. The alterations induced by rTMS on neurochemical parameters may have contributed to the analgesic effect presented.

Currently, there is no efficacious pharmacological treatment for traumatic brain injury (TBI). Previous studies revealed that L-lactate preconditioning has shown rich neuroprotective effects against cerebral ischemia, and therefore has the potential to improve neurological outcomes after TBI. L-lactate played a neuroprotective role by activating GPR81 in diseases of the central nervous system (CNS) such as TBI and cerebral ischemia. In this study we investigated the effects of L-lactate preconditioning on TBI and explored the underlying mechanisms. In this study, the mNSS test revealed that L-lactate preconditioning alleviates the neurological deficit caused by TBI in rats. L-lactate preconditioning significantly increased the expression of GPR81, PSD95, GAP43, BDNF, and MCT2 24 h after TBI in the cortex and hippocampus compared with the sham group. Taken together, these data suggested that L-lactate preconditioning is an effective method with which to recover neurological function after TBI. This reveals the mechanism of L-lactate preconditioning on TBI and provides a potential therapeutic method for TBI in humans.

Circular RNAs (circRNAs) play key roles in various pathogenic and biological processes in human disease. However, the effect of circRNAs on the development of diabetic encephalopathy (DE) remains largely unknown. Therefore, the aim of this study was to investigate changes in the expression of circRNAs and their potential mechanism in DE formation. Compared with db/m mice, spatial learning/memory, dendritic spines, and synaptic plasticity were all impaired in the hippocampus of the db/db mice. In addition, the dendritic spine density of neurons was significantly decreased after treatment with advanced glycation end-products (AGEs). We used high-throughput RNA sequencing (RNA-Seq) to detect circRNA expression in DE, and the results revealed that 183 circRNAs were significantly altered in primary hippocampal neurons treated with AGEs. Three circRNAs were chosen for detection using quantitative real-time polymerase chain reaction (qRT-PCR), including circ-Smox (chr2: 131511984-131516443), circ-Nbea (mmu-chr3: 56079859-56091120), and circ-Setbp1 (chr18: 79086551-79087180), and circ-Nbea expression was significantly decreased. According to the bioinformatics prediction and detection using qRT-PCR and double luciferase assays, circ-Nbea sponges miR-128-3p. Based on these results, we speculated that a newly identified circRNA, circ-Nbea, may play an important role in the development of DE, and the mechanism is mediated by sponging miR-128-3p. This study provides new insight into the treatment of DE.

In the central nervous system (CNS), extracellular matrix (ECM) molecules comprise more than 20% of the volume and are involved in neuronal plasticity, synaptic transmission, and differentiation. Perineuronal nets (PNNs) are ECM molecules that highly accumulate around the soma of neurons. The components of the ECM in the CNS include proteins, proteoglycans, and glycosaminoglycans. Although hyaluronic acid (HA) is considered a constituent element of PNNs, the distribution of HA in the cortex has not been clarified. To elucidate the cortical region-specific distribution of HA, we quantitatively analyzed HA binding protein (HABP)-positive PNNs in the mature mouse cerebral cortex. Our findings revealed that HABP-positive PNNs are present throughout the mouse cortex. The distribution of many HABP-positive PNNs differed from that of Wisteria floribunda agglutinin-positive PNNs. Furthermore, we observed granular-like HABP-positive PNNs in layer 1 of the cortex. These findings indicate that PNNs in the mouse cortex show region-dependent differences in composition. HABP-positive PNNs in layer 1 of the cortex may have different functions such as neuronal differentiation, proliferation, and migration unlike what has been reported for PNNs so far.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na(+), K(+)-ATPase activity (NKA), an excess of Fxyd1 may reduce NKA activity and contribute to the neuronal phenotype of Mecp2 deficient (KO) mice. To determine if Fxyd1 can rescue these RTT deficits, we studied the male progeny of Fxyd1 null males bred to heterozygous Mecp2 female mice. Maximal NKA enzymatic activity was not altered by the loss of MeCP2, but it increased in mice lacking one Fxyd1 allele, suggesting that NKA activity is under Fxyd1 inhibitory control. Deletion of one Fxyd1 allele also prevented the increased extracellular potassium (K(+)) accumulation observed in cerebro-cortical neurons from Mecp2 KO animals in response to the NKA inhibitor ouabain, and rescued the loss of dendritic arborization observed in FC neurons of Mecp2 KO mice. These effects were gene-dose dependent, because the absence of Fxyd1 failed to rescue the MeCP2-dependent deficits, and mimicked the effect of MeCP2 deficiency in wild-type animals. These results indicate that excess of Fxyd1 in the absence of MeCP2 results in deregulation of endogenous K(+) conductances functionally associated with NKA and leads to stunted neuronal growth.

The mechanisms involved in the anti-seizure effects of low-frequency stimulation (LFS) have not been completely determined. However, G

The Dorsal Raphe (DR) is the primary source of serotonergic input in the brain and a center for the homeostatic maintenance of the serotonergic tone. Under repeated stimulation, it can undergo adaptive modifications that alter serotonergic neurotransmission, which can lead to behavioral dysfunction. Post-transcriptional regulation by microRNAs is implicated in these adaptations. However, a global microRNA/target network effect on the DR neuroplasticity has yet to be elucidated. Here we investigate the microRNAs/mRNAs regulatory activity in the mouse DR after a chronic stress experience. First, we assessed the behavioral consequences of repeated restraint stress exposure and the functional adaptations of the DR by measuring the change in acute stress-induced serotonin release. Then, through next generation RNA-Seq of Argonaute2-bound RNA (RISC-Seq) we identified microRNAs and their targets that are associated to the RISC complex of the DR in unstressed and stressed mice. We mapped the potential microRNA/mRNA network within the stress-altered transcripts, uncovering new interactions that contribute to the chronic stress-induced DR modifications.

Sensory neurons of the vagus nerve receive many different peripheral signals that can change rapidly and frequently throughout the day. The ability of these neurons to convey the vast array of nuanced information to the brain requires neuronal adaptability. In this review we discuss evidence for neural plasticity in vagal afferent neurons as a mechanism for conveying nuanced information to the brain important for the control of feeding behavior. We provide evidence that synaptic plasticity, changes in membrane conductance, and neuropeptide specification are mechanisms that allow flexibility in response to metabolic cues that can be disrupted by chronic intake of energy dense diets.

Mutations in the nuclear localization signal of the RNA binding protein FUS cause both Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). These mutations result in a loss of FUS from the nucleus and the formation of FUS-containing cytoplasmic aggregates in patients. To better understand the role of cytoplasmic FUS mislocalization in the pathogenesis of ALS, we identified a population of cholinergic neurons in Drosophila that recapitulate these pathologic hallmarks. Expression of mutant FUS or the Drosophila homolog, Cabeza (Caz), in class IV dendritic arborization neurons results in cytoplasmic mislocalization and axonal transport to presynaptic terminals. Interestingly, overexpression of FUS or Caz causes the progressive loss of neuronal projections, reduction of synaptic mitochondria, and the appearance of large calcium transients within the synapse. Additionally, we find that overexpression of mutant but not wild type FUS results in a reduction in presynaptic Synaptotagmin, an integral component of the neurotransmitter release machinery, and mutant Caz specifically disrupts axonal transport and induces hyperexcitability. These results suggest that FUS/Caz overexpression disrupts neuronal function through multiple mechanisms, and that ALS-causing mutations impair the transport of synaptic vesicle proteins and induce hyperexcitability.

The midbrain is a subcortical area involved in central functions such as integrating sensory modalities, movement initiation and bottom-up and top-down attention. In chicken, the midbrain roof is termed optic tectum (TeO) and consists of 15 layers with distinct in- and output regions. Visual input targets the superficial layers, while auditory input terminates in deeper layers. It has been shown that ablation of sensory epithelia leads to changes in the cellular patterning and structural organization of the sensory pathways. For the tectum, ablation of the eye anlagen was shown to affect retinorecipient neurons. While the gross morphology remained intact after enucleation, the shape of dendritic endings was changed presumably due to missing presynaptic input during synaptic pruning. We investigated the effect of deafferentation in a multisensory cell type, the Shepherd's crook neuron (SCN) in the TeO. SCNs have distinct dendritic branches in retinorecipient layers (superficial layers 1 to 5 and 7) and in layers where auditory input terminates. To assess whether removal of a single sensory input only affects the dendrites recipient for that input, we removed the eye anlagen and retrogradely labeled SCNs later in embryogenesis to visualize the morphology in lesioned and non-lesioned embryos. We found no changes in the gross morphology or in the basal dendrites, but an altered growth of the fine structures at the apical dendrite of SCNs in the retinorecipient layers. Our data indicate that the neuronal morphology of SCNs is mostly predefined before retinal innervation affect the fine structure.

Functional recovery after a stroke is important for patients' quality of life. Not only medical care during the acute phase, but also rehabilitation during the chronic phase after a stroke is important. However, the mechanisms underlying functional recovery, particularly the chronic phase after stroke, are still not fully understood. Thus, further basic study on brain after focal stroke is necessary. In this study, we found that the concentration of dopamine (DA) increased during first week after a stroke in the hemisphere contralateral in the site of stroke by in vivo microdialysis. When we applied haloperidol (HPD), a potent DA receptor blocker, functional recovery was inhibited. Interestingly, administration of aripiprazole (ARP), a novel partial agonist of the DA receptor, during the chronic phase improved the remodeling of neuronal circuits in somatosensory cortex (SSC). These findings indicate that the DAergic system play a critical role in functional compensation by the non-infarcted hemisphere after a focal stroke in SSC. It is also revealed that administration of HPD/ARP to stroke patients affects functional recovery after a stroke, and stimulation of the DAergic system during the chronic phase of stroke potentially benefits stroke patients.

In Alzheimer's disease (AD), dementia severity correlates most strongly with decreased synapse density in the hippocampus and cerebral cortex. Although studies in rodents have established that hippocampal long-term potentiation (LTP) is inhibited by soluble oligomers of beta-amyloid (Aβ), the synaptic mechanisms remain unclear. Here, field excitatory postsynaptic potentials (fEPSP) recordings were made in the CA1 region of mouse hippocampal slices. The medium of APP-expressing CHO cells, which contain soluble forms of Aβ including small oligomers, inhibited LTP and facilitated long-term depression (LTD), thus making the LTP/LTD curve shift toward the right. This phenomenon could be mimicked by the non-selective glutamate transporter inhibitor, DL-TBOA. More specifically, the Aβ impaired LTP and facilitated LTD were occluded by the selective astrocytic glutamate transporter inhibitors, TFB-TBOA. In cultured astrocytes, the Aβ oligomers also decrease astrocytic glutamate transporters (EAAT1, EAAT2) expression. We conclude that soluble Aβ oligomers decrease the activation of astrocytic glutamate transporters, thereby impairing synaptic plasticity.

Cerebral infarction causes motor, sensory, and cognitive impairments. Although rehabilitation enhances recovery of activities of daily living after cerebral infarction, its mechanism remains elusive due to the lack of reproducibility and low survival rate of brain ischemic model animals. Here, to investigate the relationship between rehabilitative intervention, motor function, and pathophysiological remodeling of the tissue in the ipsilateral hemisphere after cerebral infarction, we took advantage of a highly reproducible model of cerebral infarction using C.B-17/Icr-+/+Jcl mice. In this model, we confirmed that voluntary running exercise improved functional recovery after ischemia. Exercise did not alter the volume of infarction or survived cortex, or the number of NeuN-labeled cells in the peri-infarct cortex. In mice who did not exercise, the number of basal dendritic spines of layer 5 pyramidal cells decreased in the peri-infarct motor cortex, whereas in mice who exercised it remained at the normal level. The voluntary exercise intervention maintained basal dendritic spine density within the peri-infarct area, which may reflect an adaptive remodeling of the surviving neural circuitry that might contribute to promoting the recovery of activities of daily living.

Lead (Pb) exposure damages synaptic structural plasticity that results in cognitive impairment. Resveratrol, a natural polyphenolic compound, is one of the most potent agonists of silencing information regulator 1 (SIRT1) discovered to date. However, the effects of SIRT1 on synaptic functional plasticity in early life Pb exposure are not well studied. Herein, the purpose of this study is to investigate the expression of synaptic markers and SIRT1 in rats exposed to Pb and to evaluate the regulatory effect of resveratrol during this process. The Pb exposed male SD pups were treated with resveratrol (50 mg/kg/d) or EDTA (150 mg/kg/d) followed by hippocampal and blood sampling for analysis at postnatal day 21 (PND21). In the Morrris water maze test, resveratrol treatement protected the rats against Pb-induced impairment of learning and memory (P0.05). Resveratrol also enhanced the expression of brain-derived neurotrophic factor (BDNF, P 0.001 vs 0.2% Pb group), and reversed the effects of Pb exposure on SIRT1(P 0.001 vs 0.2% Pb group). The DG, CA1 and CA3 regions of the hippocampus showed a considerable increase in the expression of pre- and postsynaptic proteins (P 0.001 vs 0.2% Pb group). In conclusion, our study demonstrated that resveratrol, through the activation of SIRT1, played a protective role against Pb-induced defects in synaptic plasticity, and suggested a new potential adjuvant treatment for Pb poisoning.

Approximately one-third of Persian Gulf War veterans are afflicted by Gulf War Illness (GWI), a chronic multisymptom condition that fundamentally presents with cognitive deficits (i.e., learning and memory impairments) and neuroimmune dysfunction (i.e., inflammation). Factors associated with GWI include overexposures to neurotoxic pesticides and nerve agent prophylactics such as permethrin (PM) and pyridostigmine bromide (PB), respectively. GWI-related neurological impairments associated with PB-PM overexposures have been recapitulated in animal models; however, there is a paucity of studies assessing PB-PM-related aberrations in hippocampal synaptic plasticity and transmission that may underlie behavioral impairments. Importantly, FDA-approved neuroactive treatments are currently unavailable for GWI. In the present study, we assessed the efficacy of an immunomodulatory therapeutic, lacto-N-fucopentaose-III (LNFPIII), on ameliorating acute effects of in vivo PB-PM exposure on synaptic plasticity and transmission as well as trophic factor/cytokine expression along the hippocampal dorsoventral axis. PB-PM exposure resulted in hippocampal synaptic transmission deficits 48 h post-exposure, a response that was ameliorated by LNFPIII coadministration, particularly in the dorsal hippocampus (dH). LNFPIII coadministration also enhanced synaptic transmission in the dH and the ventral hippocampus (vH). Notably, LNFPIII coadministration elevated long-term potentiation in the dH. Further, PB-PM exposure and LNFPIII coadministration uniquely altered key inflammatory cytokine and trophic factor production in the dH and the vH. Collectively, these findings demonstrate that PB-PM exposure impaired hippocampal synaptic responses 48 h post-exposure, impairments that differentially manifested along the dorsoventral axis. Importantly, LNFPIII ameliorated GWI-related electrophysiological deficits, a beneficial effect indicating the potential efficacy of LNFPIII for treating GWI.

The Inhibitory effect of electrical low-frequency stimulation (LFS) on neuronal excitability and seizure occurrence has been indicated in experimental models, but the precise mechanism has not established. This investigation was intended to figure out the role of α1 and α2 adrenergic receptors in LFS' inhibitory effect on neuronal excitability. Epileptiform activity induced in an in vitro rat hippocampal slice preparation by high K+ ACSF and LFS (900 square wave pulses at 1 Hz) was administered at the beginning of epileptiform activity to the Schaffer collaterals. In CA1 pyramidal neurons, the electrophysiological properties were measured at the baseline, before high K+ ACSF washout, and at 15 min after high K+ ACSF washout using whole-cell, patch-clamp recording. Results indicated that after high K+ ACSF washout, prazosine (10 µM; α1 adrenergic receptor antagonist) and yohimbine (5 µM; α2 adrenergic receptor antagonist) suppressed the LFS’ effect of reducing rheobase current and utilization time following depolarizing ramp current, the latency to the first spike following a depolarizing current and latency to the first rebound action potential following hyperpolarizing current pulses. Thus, it may be proposed that LFS’ inhibitory action on the neuronal hyperexcitability, in some way, is mediated by α1 and α2 adrenergic receptors.

The cortico-thalamocortical network is relevant to music performance in that the network can regulate sensitivity to afferent input or sound, mediate the integration of multimodal information required for the performance, and play a role in skilled performance control. We, therefore, predicted that this network would be reorganized via musical training-induced neuroplasticity. To test this hypothesis, we analyzed resting-state functional connectivity of the thalamocortical network in musicians (n=35) and nonmusicians (n=35). The seed-to-voxel functional connectivity analysis of the left thalamus seed showed enhanced connectivity voxels in the precuneus/posterior cingulate cortex (PCC) in musicians compared with nonmusicians. Region of interest (ROI)-to-ROI functional connectivity analysis showed that the auditory areas were also more strongly connected with the left thalamus in musicians. Discriminant analysis using the ROI-to-ROI functional connectivity data of the precuneus/PCC and auditory areas as predictors yielded an 87% correct discrimination of musicians from nonmusicians. Therefore, we can conclude that, as a consequence of long-term musical training, musicians have a characteristically organized thalamocortical network. The precuneus and PCC are principal nodes of the default mode network and play a pivotal role in the manipulation of mental imagery. We propose that the reorganized thalamocortical network in musicians contributes not only to higher sensitivity to sound but also to the integration of mental imagery with sound, which are both presumed to be important for better music performance.