Neuroscience

Rat pinealocytes receive noradrenergic innervation that stimulates melatonin synthesis in a cAMP-mediated manner. In addition to melatonin, we showed previously that pinealocytes secrete L-glutamate through an exocytic mechanism. The released glutamate inhibits norepinephrine (NE)-dependent melatonin synthesis. Consistent with this observation, specific agonists of class II metabotropic glutamate receptors (mGluRs), including 1-(1S,3R)aminocyclopentane-1,3-dicarboxylic acid (tACPD), inhibited NEdependent melatonin synthesis, whereas agonists for other types of glutamate receptors did not. Furthermore, reverse transcription-PCR, Northern blotting, and immunohistochemistry analyses indicated expression of class II mGluR3 in pinealocytes. Inhibitory guanine nucleotide-binding protein (G i ) was also detected in pinealocytes. L-Glutamate or agonists of class II receptors decreased NE-or forskolin-dependent increase of cAMP and serotonin-N-acetyltransferase activities to similar extents. These effects were blocked by pertussis toxin or dibutyryl cAMP. These results indicate that the inhibitory cAMP cascade is involved in the glutamate-evoked inhibition of melatonin synthesis. We propose that the glutaminergic system negatively regulates NE-dependent melatonin synthesis in rat pinealocytes.

Myotonic dystrophy type 1 (DM1) is a genetic disorder that causes muscle weakness and myotonia. In DM1 patients, cardiac electrical manifestations include conduction defects and atrial fibrillation. DM1 results in the expansion of a CTG transcribed into CUG-containing transcripts that accumulate in the nucleus as RNA foci and alter the activity of several splicing regulators. The underlying pathological mechanism involves two key RNA-binding proteins (MBNL and CELF) with expanded CUG repeats that sequester MBNL and alter the activity of CELF resulting in spliceopathy and abnormal electrical activity. In the present study, we identified two DM1 patients with heart conduction abnormalities and characterized their hiPSC lines. Two differentiation protocols were used to investigate both the ventricular and the atrial electrophysiological aspects of DM1 and unveil the impact of the mutation on voltage-gated ion channels, electrical activity, and calcium homeostasis in DM1 cardiomyocytes derived from hiPSCs. Our analysis revealed the presence of molecular hallmarks of DM1, including the accumulation of RNA foci and sequestration of MBNL1 in DM1 hiPSC-CMs. We also observed mis-splicing of SCN5A and haploinsufficiency of DMPK. Furthermore, we conducted separate characterizations of atrial and ventricular electrical activity, conduction properties, and calcium homeostasis. Both DM1 cell lines exhibited reduced density of sodium and calcium currents, prolonged action potential duration, slower conduction velocity, and impaired calcium transient propagation in both ventricular and atrial cardiomyocytes. Notably, arrhythmogenic events were recorded, including both ventricular and atrial arrhythmias were observed in the two DM1 cell lines. These findings enhance our comprehension of the molecular mechanisms underlying DM1 and provide valuable insights into the pathophysiology of ventricular and atrial involvement.

Voltage gated sodium channels (Na v channels) play an important role in nociceptive transmission. They are intimately tied to the genesis and transmission of neuronal firing. Five different isoforms (Na v 1.3, Na v 1.6, Na v 1.7, Na v 1.8, and Na v 1.9) have been linked to nociceptive responses. A change in the biophysical properties of these channels or in their expression levels occurs in different pathological pain states. However, the precise involvement of the isoforms in the genesis and transmission of nociceptive responses is unknown. The aim of the present study was to investigate the synergy between the different populations of Na v channels that give individual neurons a unique electrophysical profile. We used the patch-clamp technique in the whole-cell configuration to record Na v currents and action potentials from acutely dissociated small diameter DRG neurons (<30 μm) from adult rats. We also performed single cell qPCR on the same neurons. Our results revealed that there is a strong correlation between Na v currents and mRNA transcripts in individual neurons. A cluster analysis showed that subgroups formed by Na v channel transcripts by mRNA quantification have different biophysical properties. In addition, the firing frequency of the neurons was not affected by the relative populations of Na v channel. The synergy between populations of Na v channel in individual small diameter DRG neurons gives each neuron a unique electrophysiological profile. The Na v channel remodeling that occurs in different pathological pain states may be responsible for the sensitization of the neurons.

occurs during ischemic events, may alter the interaction between ranolazine and the channel. In this study, we performed whole-cell patch clamp experiments with extracellular solution titrated to pH 7.4 or pH 6.0 using HEK cells expressing NaV1.5 and CHO cells expressing NaV1.2. We found that ranolazine modulates these sodium channels with onset/recovery kinetics and voltage-dependence resembling slow inactivation. In this way, ranolazine increases use-dependent inactivation of the channel and decreases window currents. At pH 6.0, ranolazine interaction with the sodium channel is slowed approximately 4-5 fold in both NaV1.2 and NaV1.5. Despite the slowed kinetics, ranolazine remains effective at steady-state during acidic conditions. At low extracellular pH ranolazine rescues the voltage-dependence of slow inactivation at a therapeutically relevant concentration (10mM). Our results suggest that, at pH 6.0, ranolazine compensates for proton-induced impaired slow inactivation and remains effective at reducing persistent currents.

Synaptic and axonal glutamatergic signaling to NG2 glia in white matter is critical for the cells' differentiation and activity dependent myelination. However, in gray matter the impact of neuron-to-NG2 glia signaling is still elusive, because most of these cells keep their non-myelinating phenotype throughout live. Early in postnatal development, hippocampal NG2 glia express AMPA receptors with a significant Ca 2+ permeability allowing for plasticity of the neuron-glia synapses, but whether this property changes by adulthood is not known. Moreover, it is unclear whether NG2 glia express auxiliary transmembrane AMPA receptor related proteins (TARPs), which modify AMPA receptor properties, including their Ca 2+ permeability. Through combined molecular and functional analyses, here we show that hippocampal NG2 glia abundantly express TARPs γ4, γ7, and γ8 as well as cornichon (CNIH)-2. TARP γ8 undergoes profound downregulation during development. Receptors of adult NG2 glia showed an increased sensitivity to blockers of Ca 2+ permeable AMPA receptors, but this increase mainly concerned receptors located close to the soma. Evoked synaptic currents of NG2 glia were also sensitive to blockers of Ca 2+ permeable AMPA receptors. The presence of AMPA receptors with varying Ca 2+ permeability during postnatal maturation may be important for the cells' ability to sense and respond to local glutamatergic activity and for regulating process motility, differentiation, and proliferation.

Highlights d In the thalamus, astrocytes and oligodendrocytes form large coupled networks d These panglial networks are essential for energy supply to neurons d Oligodendrocytes assist astrocytes in metabolite transfer to postsynapses Authors

P2X receptors are ligand-gated ion channels which are activated by excitatory neurotransmitter ATP. Despite considerable evidence of signaling by extracellular nucleotides in other sensory systems, P2X receptors in the visual system have only rarely been studied, and almost nothing is known about their functional significance in the retina. To determine whether ATP plays a role in the modulation of vertical retinal signal pathways, we examined the expression of P2X receptor mRNA in freshly isolated bipolar cells of the rat retina Ž . Brown Norway, P25 using the single-cell RT-PCR technique. Positive amplification signals were found in about 33% of the bipolar cells for P2X , P2X and P2X but not for P2X mRNA. We conclude that at least a subpopulation of bipolar cells in the rat retina 3 4 5 7 expresses ionotropic P2 receptors of the P2X type and that these possibly exert a neuromodulatory influence on information processing in the retina.

Since animal models are inevitable for medical research, information on species differences in glial cell properties is critical for successful translational research. Here, we review current knowledge about morphological and functional properties of human astrocytes and NG2 glial cells and compare these data with those obtained for the comparable cells in rodents. Morphological analyses of astrocytes in the neocortex of rodents versus humans have demonstrated clear differences. In contrast, the functional properties of astrocytes or NG2 glial cells in these species are surprisingly similar. However, these findings should be interpreted with caution, as so far functional analyses of human cells are only available from neocortex and hippocampus, and it is known from rodent studies that the properties of astrocytes in different brain regions may vary considerably. Moreover, technical challenges render astrocyte electrophysiological measurements in situ unreliable, and human cell properties may be affected by medications. Nevertheless, based on the limited data currently available, there is substantial similarity between human and rodent astrocytes with regard to those functional properties studied to date. The unique morphological characteristics of astrocytes in human neocortex call for further physiological analysis. The basic properties for NG2 glia are even less completely evaluated with regard to the question of species differences but no glaring differences have been reported so far. In conclusion, it remains justifiable to employ mouse or rat models to investigate the etiology of human CNS diseases that might involve astrocytes or NG2 glia.

NG2 cells are equipped with transmitter receptors and receive direct synaptic input from glutamatergic and GABAergic neurons. The functional impact of these neuron-glia synapses is still unclear. Here, we combined functional and molecular techniques to analyze properties of GABA A receptors in NG2 cells of the juvenile mouse hippocampus. GABA activated slowly desensitizing responses in NG2 cells, which were mimicked by muscimol and inhibited by bicuculline. To elucidate the subunit composition of the receptors we tested its pharmacological properties. Coapplication of pentobarbital, benzodiazepines, and zolpidem all significantly increased the GABA-evoked responses. The presence of small tonic currents indicated the presence of extrasynaptic GABA A receptors. To further analyze the subunit expression, single cell transcript analysis was performed subsequent to functional characterization of NG2 cells. The subunits ␣1, ␣2, ␤3, ␥1, and ␥2 were most abundantly expressed, matching properties resulting from pharmacological characterization. Importantly, lack of the ␥2-subunit conferred a high Zn 2ϩ sensitivity to the GABA A receptors of NG2 cells. Judging from the zolpidem sensitivity, postsynaptic GABA A receptors in NG2 cells contain the ␥2-subunit, in contrast to extrasynaptic receptors, which were not modulated by zolpidem. To determine the effect of GABA A receptor activation on membrane potential, perforated patch recordings were obtained from NG2 cells. In the current-clamp mode, GABA depolarized the cells to approximately Ϫ30 mV, indicating a higher intracellular Cl Ϫ concentration (ϳ50 mM) than previously reported. GABA-induced depolarization in NG2 cells might trigger Ca 2ϩ influx through voltage-activated Ca 2ϩ channels.

Astrocytes and oligodendrocytes in different brain regions form panglial networks and the topography of such networks can correlate with neuronal topography and function. Astrocyte-oligodendrocyte networks in the lateral superior olive (LSO)-an auditory brainstem nucleus-were found to be anisotropic with a preferred orientation orthogonally to the tonotopic axis. We hypothesized that such a specialization might be present in other tonotopically organized brainstem nuclei, too. Thus, we analyzed gap junctional coupling in the center of the inferior colliculus (IC)-another nucleus of the auditory brainstem that exhibits tonotopic organization. In acute brainstem slices obtained from mice, IC networks were traced employing whole-cell patch-clamp recordings of single sulforhodamine (SR) 101-identified astrocytes and concomitant intracellular loading of the gap junction-permeable tracer neurobiotin. The majority of dye-coupled networks exhibited an oval topography, which was preferentially oriented orthogonal to the tonotopic axis. Astrocyte processes showed preferentially the same orientation indicating a correlation between astrocyte and network topography. In addition to SR101-positive astrocytes, IC networks contained oligodendrocytes. Using Na + imaging, we analyzed the capability of IC networks to redistribute small ions. Na + bi-directionally diffused between SR101-positive astrocytes and SR101-negative cells-presumably oligodendrocytes-showing the functionality of IC networks. Taken together, our results demonstrate that IC astrocytes and IC oligodendrocytes form functional anisotropic panglial networks that are preferentially oriented orthogonal to the tonotopic axis. Thus, our data indicate that the topographic specialization of glial networks seen in IC and LSO might be a general feature of tonotopically organized auditory brainstem nuclei.

NG2 glia receive synaptic input from neurons, but the functional impact of this glial innervation is not well understood. In the developing cerebellum and somatosensory cortex the GABAergic input might regulate NG2 glia differentiation and myelination, and a switch from synaptic to extrasynaptic neuron–glia signaling was reported in the latter region. Myelination in the hippocampus is sparse, and most NG2 glia retain their phenotype throughout adulthood, raising the question of the properties and function of neuron-NG2 glia synapses in that brain region. Here, we compared spontaneous and evoked GABAA receptor-mediated currents of NG2 glia in juvenile and adult hippocampi of mice of either sex and assessed the mode of interneuron–glial signaling changes during development. With patch-clamp and pharmacological analyses, we found a decrease in innervation of hippocampal NG2 glia between postnatal days 10 and 60. At the adult stage, enhanced activation of extrasynaptic receptors occurre...

Copy number variations at 7q11.23 cause neurodevelopmental disorders with shared and opposite manifestations. Deletion causes Williams-Beuren syndrome (WBS), while duplication causes 7q11.23 microduplication syndrome (7Dup). Converging evidence indicates GTF2I, from the 7q11.23 locus, is a key mediator of the cognitive-behavioral phenotypes associated with WBS and 7Dup. Here we integrate molecular profiling of patient-derived cortical organoids (COs) and transgenic mouse models to dissect 7q11.23 disease mechanisms. Proteomic and transcriptomic profiling of COs revealed opposite dynamics of neural progenitor proliferation and transcriptional imbalances, leading to precocious excitatory neuron production in 7Dup. The accelerated excitatory neuron production in 7Dup COs could be rescued by GTF2I knockdown. Transgenic mice with Gtf2i duplication recapitulated early neuronal differentiation defects and ASD-like behaviors. Remarkably, inhibition of LSD1, a downstream effector of GTF2I, was sufficient to rescue ASD-like phenotypes. We propose that the GTF2I-LSD1 axis constitutes a molecular pathway amenable to therapeutic intervention.

While prior noninvasive (e.g., electroencephalographic) studies suggest that the human primary motor cortex (M1) is active during gait processes, the limitations of noninvasive recordings make it impossible to determine whether M1 is involved in high-level motor control (e.g., obstacle avoidance, walking speed), low-level motor control (e.g., coordinated muscle activation), or only nonmotor processes (e.g., integrating/relaying sensory information). This study represents the first invasive electroneurophysiological characterization of the human leg M1 during walking. Two subjects with an electrocorticographic grid over the interhemispheric M1 area were recruited. Both exhibited generalized γ-band (40-200 Hz) synchronization across M1 during treadmill walking, as well as periodic γ-band changes within each stride (across multiple walking speeds). Additionally, these changes appeared to be of motor, rather than sensory, origin. However, M1 activity during walking shared few features with M1 activity during individual leg muscle movements, and was not highly correlated with lower limb trajectories on a single channel basis. These findings suggest that M1 primarily encodes highlevel gait motor control (i.e., walking duration and speed) instead of the low-level patterns of leg muscle activation or movement trajectories. Therefore, M1 likely interacts with subcortical/spinal networks, which are responsible for low-level motor control, to produce normal human walking.

Background: Clinical treatments with typical antipsychotic drugs (APDs) are accompanied by extrapyramidal motor sideeffects (EPS) such as hypokinesia and catalepsy. As little is known about electrophysiological substrates of such motor disturbances, we investigated the effects of a typical APD, a-flupentixol, on the motor behavior and the neuronal activity of the whole basal ganglia nuclei in the rat. The motor behavior was examined by the open field actimeter and the neuronal activity of basal ganglia nuclei was investigated using extracellular single unit recordings on urethane anesthetized rats. We show that aflupentixol induced EPS paralleled by a decrease in the firing rate and a disorganization of the firing pattern in both substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN). Furthermore, a-flupentixol induced an increase in the firing rate of globus pallidus (GP) neurons. In the striatum, we recorded two populations of medium spiny neurons (MSNs) after their antidromic identification. At basal level, both striato-pallidal and striato-nigral MSNs were found to be unaffected by a-flupentixol. However, during electrical cortico-striatal activation only striato-pallidal, but not striato-nigral, MSNs were found to be inhibited by a-flupentixol. Together, our results suggest that the changes in STN and SNr neuronal activity are a consequence of increased neuronal activity of globus pallidus (GP). Indeed, after selective GP lesion, a-flupentixol failed to induce EPS and to alter STN neuronal activity. Our study reports strong evidence to show that hypokinesia and catalepsy induced by a-flupentixol are triggered by dramatic changes occurring in basal ganglia network. We provide new insight into the key role of GP in the pathophysiology of APD-induced EPS suggesting that the GP can be considered as a potential target for the treatment of EPS.

Although, historically, the norepinephrine system has attracted the majority of attention in the study of the stress response, the dopamine system has also been consistently implicated. It has long been established that stress plays a crucial role in the pathogenesis of psychiatric disorders. However, the neurobiological mechanisms that mediate the stress response and its effect in psychiatric diseases are not well understood. The dopamine system can play distinct roles in stress and psychiatric disorders. It is hypothesized that, even though the dopamine (DA) system forms the basis for a number of psychiatric disorders, the pathology is likely to originate in the afferent structures that are inducing dysregulation of the DA system. This review explores the current knowledge of afferent modulation of the stress/DA circuitry, and presents recent data focusing on the effect of stress on the DA system and its relevance to psychiatric disorders.

Optogenetics is an innovative technique for optical control of cells. This field has exploded over the past decade or so and has given rise to great advances in neuroscience. A variety of applications both from the basic and applied research have emerged, turning the early ideas into a powerful paradigm for cell biology, neuroscience and medical research. This review aims at highlighting the basic concepts that are essential for a comprehensive understanding of optogenetics and some important biological/biomedical applications. Further, emphasis is placed on advancement in optogenetics-associated light-based methods for controlling gene expression, spatially-controlled optogenetic stimulation and detection of cellular activities.

Dystrophin is an important protein within the central nervous system. The absence of dystrophin, characterizing Duchenne muscular dystrophy (DMD), is associated with brain related comorbidities such as neurodevelopmental (e.g., cognitive and behavioural) deficits and epilepsy. Especially mutations in the downstream part of the DMD gene affecting the dystrophin isoforms Dp140 and Dp71 are found to be associated with cognitive deficits. However, the function of Dp140 is currently not well understood and its expression pattern has previously been implicated to be developmentally regulated. Therefore, we evaluated Dp140 and Dp71 expression in human hippocampi in relation to cognitive functioning in patients with drug-resistant temporal lobe epilepsy (TLE) and post-mortem controls. Hippocampal samples obtained as part of epilepsy surgery were quantitatively analyzed by Western blot and correlations with neuropsychological test results (i.e., memory and intelligence) were examined. First, we demonstrated that the expression of Dp140 does not appear to differ across different ages throughout adulthood. Second, we identified an inverse correlation between memory loss (i.e., verbal and visual memory), but not intelligence (i.e., neither verbal nor performance), and hippocampal Dp140 expression. Finally, patients with TLE appeared to have similar Dp140 expression levels compared to post-mortem controls without neurological disease. Dp140 may thus have a function in normal cognitive (i.e., episodic memory) processes.

Young adults are less likely to seek professional help even though they are most likely to experience mental health problems. The aim of the present study was to investigate young adults’ attitudes towards mental illness and self-stigma of help-seeking, identify possible determinants of attitudes and self-stigma, and examine the association between attitudes towards mental illness and self-stigma of help-seeking. The sample consisted of 485 Greek young adults (24.5% men, 75.5% women) aged 18–25 years (M = 19.54, SD = 1.83) who completed the Attitudes towards Severe Mental Illness (ASMI) and the Self-Stigma of Seeking Help Scale (SSOSH). The results indicated that Greek young adults hold mostly positive attitudes towards severe mental illness and help-seeking, while their unfavorable attitudes are mainly related to difficulties with viewing people with a severe mental disorder as similar to other people, and fear that by seeking professional help a person’s worth will be diminished. ...

Background and purposeActivation of astrocytes contributes to synaptic remodeling, tissue repair and neuronal survival following traumatic brain injury (TBI). However, the mechanisms by which these cells interact to infiltrated inflammatory cells to rewire neuronal networks and repair brain functions remain poorly understood. Here, we explored how TLR4-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI.Experimental approachWe used pharmacological and genetic approaches to determine how functional astrocyte alterations induced by activation of TLR4-pathway in inflammatory cells regulate synapses and neurovascular unit after TBI. For that, we used calcium imaging, immunofluorescence, flow cytometry, blood-brain barrier (BBB) integrity assessment and molecular and behavioral tools.Key resultsShortly after a TBI there is a recruitment of excitable and reactive astrocytes mediated by TLR4-pathway activation with detrimental effects on PSD-95/VGlut1...

Hyperglycemia is common in patients with acute stroke, even in those without preexisting diabetes, and denotes a bad outcome. However, the mechanisms underlying the detrimental effects of hyperglycemia are largely unclear. In a mouse model of ischemic stroke, we found that hyperglycemia increased the infarct volume and decreased the number of protective noninflammatory monocytes/macrophages in the ischemic brain. Ablation of peripheral monocytes blocked the detrimental effect of hyperglycemia, suggesting that monocytes are required. In hyperglycemic mice, α-dicarbonyl glucose metabolites, the precursors for advanced glycation end products, were significantly elevated in plasma and ischemic brain tissue. The receptor of advanced glycation end products, AGER (previously known as RAGE), interfered with polarization of macrophages to a noninflammatory phenotype. When Ager was deleted, hyperglycemia did not aggravate ischemic brain damage any longer. Independently of AGER, methylglyoxal ...

Oligodendrocyte precursor cells (OPCs) originate in specific areas of the developing central nervous system (CNS). Once generated, they migrate towards their destinations where they differentiate into mature oligodendrocytes. In the adult, 5-8% of all cells in the CNS are OPCs, cells that retain the capacity to proliferate, migrate, and differentiate into oligodendrocytes. Indeed, these endogenous OPCs react to damage in demyelinating diseases, like multiple sclerosis (MS), representing a key element in spontaneous remyelination. In the present work, we review the specific interactions between OPCs and other glial cells (astrocytes, microglia) during CNS development and in the pathological scenario of MS. We focus on: (i) the role of astrocytes in maintaining the homeostasis and spatial distribution of different secreted cues that determine OPC proliferation, migration, and differentiation during CNS development; (ii) the role of microglia and astrocytes in the redistribution of iron, which is crucial for myelin synthesis during CNS development and for myelin repair in MS; (iii) how microglia secrete different molecules, e.g., growth factors, that favor the recruitment of OPCs in acute phases of MS lesions; and (iv) how astrocytes modify the extracellular matrix in MS lesions, affecting the ability of OPCs to attempt spontaneous remyelination. Together, these issues demonstrate how both astroglia and microglia influence OPCs in physiological and pathological situations, reinforcing the concept that both development and neural repair are complex and global phenomena. Understanding the molecular and cellular mechanisms that control OPC survival, proliferation, migration, and differentiation during development, as well as in the mature CNS, may open new opportunities in the search for reparative therapies in demyelinating diseases like MS.

Multiple sclerosis is a demyelinating disease that affects ∼2,000,000 people worldwide. In the advanced stages of the disease, endogenous oligodendrocyte precursors cannot colonize the lesions or differentiate into myelinating oligodendrocytes. During development, both FGF-2 and Anosmin-1 participate in oligodendrocyte precursor cell migration, acting via the FGF receptor 1 (FGFR1). Hence, we performed a histopathological and molecular analysis of these developmental modulators in postmortem tissue blocks from multiple sclerosis patients. Accordingly, we demonstrate that the distribution of FGF-2 and Anosmin-1 varies between the different types of multiple sclerosis lesions: FGF-2 is expressed only within active lesions and in the periplaque of chronic lesions, whereas Anosmin-1 is upregulated within chronic lesions and is totally absent in active lesions. We show that the endogenous oligodendrocyte precursor cells recruited toward chronic-active lesions express FGFR1, possibly in r...

Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS). However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB1and CB2receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB1and CB2receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB1receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB1receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-α, respectively. CB1receptors were also present in macrop...

Brain microvessels possess the unique properties of a blood-brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and

One of the challenges in halal is the acceptance among non-Muslims of the values, due to their lack of appreciation in understanding its concept. Media bias, culture, personal beliefs, racism and Islamophobia are some of the common causes. Past studies concluded that the concept of misjudgment could be realigned to a positive attitude by providing the appropriate information and education. Therefore, the study was conducted with the aim, of assessing how the provision of halal knowledge through the concept of a student exchange program could change a group of non-Muslims’ attitude, acceptance and behavior towards halal. A research experiment was administered that involved a group of university students from a private university in South Korea, who voluntarily took part in a 7-day halal program in Malaysia. The study involved 1) a pre-test assessment, 2) participation in the student exchange heutagogy program and 3) a post-test assessment. Based on the paired sample test results, ove...

AU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly: Ocular light exposure has important influences on human health and well-being through modulation of circadian rhythms and sleep, as well as neuroendocrine and cognitive functions. Prevailing patterns of light exposure do not optimally engage these actions for many individuals, but advances in our understanding of the underpinning mechanisms and emerging lighting technologies now present opportunities to adjust lighting to promote optimal physical and mental health and performance. A newly developed, international standard provides a SI-compliant way of quantifying the influence of light on the intrinsically photosensitive, melanopsin-expressing, retinal neurons that mediate these effects. The present

Ocular light exposure has important influences on human health and well-being through modulation of circadian rhythms and sleep, as well as neuroendocrine and cognitive functions. Current patterns of light exposure do not optimally engage these actions for many individuals, but advances in our understanding of the underpinning mechanisms and emerging lighting technologies now present opportunities to adjust lighting to promote optimal physical and mental health and performance. A newly developed, SI-compliant standard provides a way of quantifying the influence of light on the intrinsically photosensitive, melanopsin-expressing, retinal neurons that mediate these effects. The present report provides recommendations for lighting, based on an expert-scientific consensus and expressed according to this new measurement standard. These recommendations are supported by a comprehensive analysis of the sensitivity of human ‘non-visual’ responses to ocular light, are centred on an easily mea...

During the past 50 years, converging evidence reveals that the fundamental properties of the human circadian system are shared in common with those of other organisms. Concurrent data from multiple physiological rhythms in humans revealed that under some conditions, rhythms oscillated at different periods within the same individuals and led to the conclusion 30 years ago that the human circadian system was composed of multiple oscillators organized hierarchically; this inference has recently been confirmed using molecular techniques in species ranging from unicellular marine organisms to mammals. Although humans were once thought to be insensitive to the resetting effects of light, light is now recognized as the principal circadian synchronizer in humans, capable of eliciting weak (Type 1) or strong (Type 0) resetting, depending on stimulus strength and timing. Realization that circadian photoreception could be maintained in the absence of sight was first recognized in blind humans, as was the property of adaptation of the sensitivity of circadian photoreception to prior light history. In sighted humans, the intrinsic circadian period is very tightly distributed around approximately 24.2 hours and exhibits aftereffects of prior entrainment. Phase angle of entrainment is dependent on circadian period, at least in young adults. Circadian pacemakers in humans drive daily variations in many physiologic and behavioral variables, including circadian rhythms in alertness and sleep propensity. Under entrained conditions, these rhythms interact with homeostatic regulation of the sleep/wake cycle to determine the ability to sustain vigilance during the day and to sleep at night. Quantitative understanding of the fundamental properties of the multioscillator circadian system in humans and their interaction with sleep/wake homeostasis has many applications to health and disease, including the development of treatments for circadian rhythm and sleep disorders.

Parkinson&#39;s disease is the second most common neurodegenerative disorder, leading to the progressive decline of motor control due to the loss of dopaminergic neurons in the substantia nigra pars compacta. At the molecular level, Parkinson&#39;s disease share common molecular signatures with most neurodegenerative diseases including the accumulation of misfolded proteins in the brain. Alteration in the buffering capacity of the proteostasis network during aging is proposed as one of the triggering steps leading to abnormal protein aggregation in this disease, highlighting disturbances in the function of the endoplasmic reticulum (ER). The ER is the main subcellular compartment involved in protein folding and quality control. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which aims restoring proteostasis through the induction of adaptive programs or the activation of cell death pathways when damage is chronic and cannot be repaired. Here, w...

Parkinson’s disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum. Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in vivo, d...

Significance The selective loss of dopaminergic neurons is characteristic of Parkinson disease (PD). Protein folding stress is a salient feature of PD. This study uncovers a previously undefined function of a major unfolded protein response (UPR) transcription factor (XBP1) in supporting the survival of nigral dopaminergic neurons at basal levels and under pathological conditions. Our results reveal an important role for a canonical UPR pathway in the maintenance of dopaminergic neuron proteostasis, which also could be relevant to understand the selective neuronal vulnerability observed in Parkinson disease.

Canonical transient receptor potential (TRPC) non-selective cation channels are broadly expressed by neurons, glia and the microvasculature of the brain. In neurons and astrocytes, these ion channels are coupled to group I metabotropic glutamate receptors via Gαq-phospholipase C signal transduction. In the mouse cerebellar Purkinje neurons, TRPC channels assembled as tetramers of TRPC3 subunits exclusively mediate this glutamatergic signalling mechanism and regulation of alternative splicing results in dominance of a high Ca 2+ conducting TRPC3c isoform. This regional control of TRPC3 transcript type likely has physiological and pathophysiological sequelae. The current study provides a quantitative comparison of the TRPC3c splice variant and the TRPC3b full-length isoform expression across seven regions of the human brain. This shows that the cerebellum has the highest expression level of both isoforms and that regulation of alternative splicing results in a higher propensity of the TRPC3c isoform in the cerebellum relative to the TRPC3b isoform (in a 1:3 ratio). This compares with the other regions (motor cortex, hippocampus, midbrain subregions, pons and medulla) where the prevalence of TRPC3c relative to TRPC3b is typically less than half as abundant. The finding here of a bias in the high-conductance TRPC3c isoform in the cerebellum is consistent with the enhanced vulnerability of the cerebellum to ischaemic injury.

Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory nerve output. Recent research has revealed a number of mechanisms that contribute to noiseinduced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation.

Deafness is the most common form of sensory impairment in the human population and is frequently caused by recessive mutations. To obtain animal models for recessive forms of deafness and to identify genes that control the development and function of the auditory sense organs, we performed a forward genetics screen in mice. We identified 13 mouse lines with defects in auditory function and six lines with auditory and vestibular defects. We mapped several of the affected genetic loci and identified point mutations in four genes. Interestingly, all identified genes are expressed in mechanosensory hair cells and required for their function. One mutation maps to thepejvakingene, which encodes a new member of the gasdermin protein family. Previous studies have described two missense mutations in the humanpejvakingene that cause nonsyndromic recessive deafness (DFNB59) by affecting the function of auditory neurons. In contrast, thepejvakinallele described here introduces a premature stop ...

L1, a neural cell adhesion molecule of the immunoglobulin superfamily, is widely expressed in the nervous system and important in axonal outgrowth, guidance, synapse formation, and signaling. Gene deletion studies emphasize the significance of L1 during development of the central nervous system and L1 is crucial for the topographic targeting of retinal axons. In contrast to the brain and retina, the role of L1 in the inner ear is largely unknown. While previous studies have localized L1 in the developing inner ear of the chicken and mouse, its function during the innervation of the cochlea still remains largely unclear. We therefore investigated the functional role of L1 in the mammalian inner ear. Our aim was to determine whether or not L1 can modulate type I and/or type II spiral ganglion neuron outgrowth using an in vitro alternate choice assay. We found that L1, presented in stripe micropatterns, provide directional cues to neonatal rodent type I but not type II inner ear spiral ganglion neurites. The results suggest that L1 may play a role in axonal pathfinding of type I spiral ganglion dendrites toward their inner hair cell targets, but not of type II toward the outer hair cells.

The adult mammalian cochlea receives dual afferent innervation: the inner sensory hair cells are innervated exclusively by type I spiral ganglion neurons (SGN), whereas the sensory outer hair cells are innervated by type II SGN. We have characterized the spatiotemporal reorganization of the dual afferent innervation pattern as it is established in the developing mouse cochlea. This reorganization occurs during the first postnatal week just before the onset of hearing. Our data reveal three distinct phases in the development of the afferent innervation of the organ of Corti: (1) neurite growth and extension of both classes of afferents to all hair cells (E18-P0);(2) neurite refinement, with formation of the outer spiral bundles innervating outer hair cells (P0-P3); (3) neurite retraction and synaptic pruning to eliminate type I SGN innervation of outer hair cells, while retaining their innervation of inner hair cells (P3-P6). The characterization of this developmental innervation pat...

Previous research suggests that meaning-laden gestures, even when produced in the absence of language (i.e., pantomimed gestures), influence lexical retrieval. Yet, little is known about the neural mechanisms that underlie this process. Based on embodied cognition theories, many studies have demonstrated motor cortex involvement in the representation of action verbs and in the understanding of actions. The present study aimed to investigate whether the motor system plays a critical role in the behavioral influence of pantomimed gestures on action naming. Continuous theta burst stimulation (cTBS) was applied over the hand area of the left primary motor cortex and to a control site (occipital cortex). An action-picture naming task followed cTBS. In the naming task, participants named action pictures that were preceded by videos of congruent pantomimed gestures, unrelated pantomimed gestures or a control video with no movement (as a neutral, non-gestural condition). In addition to behavioral measures of performance, cTBS-induced changes in corticospinal activity were assessed. We replicated previous finding that exposure to congruent pantomimed gestures facilitates word production, compared to unrelated or neutral primes. However, we found no evidence that the left primary motor area is crucially involved in the mechanism underlying behavioral facilitation effects of gesture on verb production. Although, at the group level, cTBS induced motor cortex suppression, at the individual level we found remarkable variability of cTBS effects on the motor cortex. We found cTBS induction of both inhibition of corticospinal activity (with slower behavioral of responses) and enhancement (with faster behavioral responses). Our findings cast doubt on assumptions that the motor cortex is causally involved in the impact of gestures on action-word processing. Our results also highlight the importance of careful consideration of interindividual variability for the interpretation of cTBS effects.

The acute effects of two GABA B receptor antagonists (phaclofen and CGP-35348) were studied in two types of epileptogenic activity: that produced by intracortical injections of baclofen and that appearing after withdrawal of chronic intracerebral GABA infusion (the GABA-withdrawal syndrome, GWS). Intracortical baclofen induced two types of electrographic paroxysmal discharges: one consisting of single spike-and-wave (pattern I) and another of polyspike-and-wave patterns (pattern II). Both patterns showed similar latencies and temporal evolution of spike frequency discharges. Phaclofen, applied directly into the baclofen-induced epileptogenic focus, suppressed pattern I1 but was ineffective in modifying both pattern I and the GWS. CGP-35348, administered systemically, inhibited both patterns l and I1. Intracortical microinjection of baclofen or phaclofen in rats showing a GWS had no effect, nor the systemically given CGP 35348. These results indicate a differential participation of GABA ~ receptors in GABA-related epileptic syndromes of cortical origin.

Overexpression of PMP22 is responsible for the most common form of inherited neuropathy, Charcot-Marie-Tooth disease (CMT) type 1A. The PMP22-transgenic rat (CMT rat) is an animal model of CMT1A, and its peripheral nerves show the characteristic features of ongoing demyelination and remyelination that is also seen in CMT1A patients. Since Schwann cell proliferation is a prominent feature of peripheral nerves in inherited peripheral neuropathies, we examined proliferation and the expression of cyclin D1 in CMT rats. D-type cyclins are required for the initial steps in cell division and nuclear import is crucial for the function of cyclin D1 in promoting cell proliferation. Like normal myelinating Schwann cells in wild-type rats, remyelinating Schwann cells in CMT rats show perinuclear cyclin D1 expression. Schwann cells with nuclear cyclin D1 expression, as well as proliferating Schwann cells, were both associated with demyelinated axonal segments. Supernumerary onion bulb Schwann cells, however, do not express cyclin D1 and were not proliferating. Thus, cyclin D1 expression and its subcellular localization correlate directly with distinct physiological states of Schwann cells in this animal model of CMT1A.

This article aims to investigate the nutritional behavior of dairy cattle, aiming to comprehend their dietary requirements and eating habits. In this regard, an effort has been made to scrutinize dietary patterns by analyzing sound recordings captured from the cows' jaws during the chewing process. The paper outlines the methodology for developing various models to discern nutritional patterns in dairy cattle, employing six well-known classifiers. Understanding nutritional behavior and dietary patterns in dairy cattle is crucial for livestock managers and animal welfare. By comprehending the dietary requirements and eating habits of dairy cattle, managers can ensure that the cows are receiving the appropriate nutrients to maintain their health and productivity. This information can also help managers identify any potential health issues or deficiencies in the cows' diets, allowing for early intervention and prevention of further health problems. Additionally, understanding the nutritional behavior of dairy cattle can lead to more efficient feeding practices, reducing waste and costs associated with overfeeding or underfeeding. Ultimately, establishing an appropriate pattern for evaluating the nutrition of dairy cattle can serve as a valuable guide for livestock managers to ensure the well-being and welfare of the cows while also improving the overall productivity and profitability of the dairy farm.