Changes In Excitability Research Articles

A distinct impact of repeated morphine exposure on synaptic plasticity at Schaffer collateral-CA1, temporoammonic-CA1, and perforant pathway-dentate gyrus synapses along the longitudinal axis of the hippocampus.

We aimed to study how morphine affects synaptic transmission in the dentate gyrus and CA1 regions along the hippocampal long axis. For this, recording and measuring of field excitatory postsynaptic potentials (fEPSPs) were utilized to test the effects of repeated morphine exposure on paired-pulse evoked responses and long-term potentiation (LTP) at Schaffer collateral-CA1 (Sch-CA1), temporoammonic-CA1 (TA-CA1) and perforant pathway-dentate gyrus (PP-DG) synapses in transverse slices from the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus in adult male rats. After repeated morphine exposure, the expression of opioid receptors and the α1 and α5 GABAA subunits were also examined. We found that repeated morphine exposure blunt the difference between the DH and the VH in their basal levels of synaptic transmission at Sch-CA1 synapses that were seen in the control groups. Significant paired-pulse facilitation of excitatory synaptic transmission was observed at Sch-CA1 synapses in slices taken from all three hippocampal segments as well as at PP-DG synapses in slices taken from the VH segment in the morphine-treated groups as compared to the control groups. Interestingly, significant paired-pulse inhibition of excitatory synaptic transmission was observed at TA-CA1 synapses in the DH slices from the morphine-treated group as compared to the control group. While primed-burst stimulation (a protocol reflecting normal neuronal firing) induced a robust LTP in hippocampal subfields in all control groups, resulting in a decaying LTP at TA-CA1 synapses in the VH slices and at PP-DG synapses in both the IH and VH slices taken from the morphine-treated rats. In the DH of morphine-treated rats, we found increased levels of the mRNAs encoding the α1 and α5 GABAA subunits as compared to the control group. Taken together, these findings suggest the potential mechanisms through which repeated morphine exposure causes differential changes in circuit excitability and synaptic plasticity in the dentate gyrus and CA1 regions along the hippocampal long axis.

The interaction between metaplastic neuromodulation and fatigue in multiple sclerosis

Background and objectiveNeuromuscular fatigue contributes to decrements in quality of life in Multiple Sclerosis (MS), yet available treatments demonstrate limited efficacy. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique which presents promise in managing fatigue, possibly related to its capacity to modulate corticospinal excitability. There is evidence for capitalising on metaplasticity using tDCS for improving outcomes. However, this remains to be explored with fatigue in people with MS (pwMS). We investigated cathodal tDCS (ctDCS) priming on anodal tDCS (atDCS)-induced corticospinal excitability and fatigue modulation in pwMS. Methods15 pwMS and 15 healthy controls completed fatiguing exercise whilst receiving either ctDCS or sham (stDCS) primed atDCS to the motor cortex. We assessed change in contraction force and motor evoked potential (MEP) amplitude across time to represent changes in fatigue and corticospinal excitability. Results and conclusionctDCS primed atDCS induced MEP elevation in healthy participants but not in pwMS, possibly indicating impaired metaplasticity in pwMS. No tDCS-mediated change in the magnitude of fatigue was observed, implying that development of fatigue may not rely on changes in corticospinal excitability. SignificanceThese findings expand understanding of tDCS effects in pwMS, highlighting differences that may be relevant in the disease pathophysiology.

Analysis of Lewis number effects on dynamic response of laminar premixed flames

The dynamic response of premixed flames with different fuel Lewis numbers is crucial to understand for the design of safe combustion chambers with wide operating range. Due to preferential diffusion effects associated with fuel Lewis number for lean mixtures, a premixed flame responds differently to flame stretch. These responses could manifest in the flame’s response to small perturbations. In order to investigate this effect, in this study, lean premixed hydrogen, methane and propane flames at the same adiabatic unstretched flame speed are studied using numerical simulations. Steady unperturbed flames show significant differences in flame stand-off distances, flame height, flame stabilization limits, burner temperature and recirculation zone length. Flames are perturbed using a step function excitation and noticeable changes in the gain and phase of the flame transfer function are found even when the flame burning velocity and the inlet flow speed are kept the same. Maximum gain of the response is found to increase with the mixture Lewis number and is shown to be directly dependent on the flame tip burning strong or weak. Phase difference at low frequencies is found to depend on the average of the time scales of the recirculation vortex which in turn depends on the flame burning stronger or weaker under the influence of positive stretch at the flame base, axial convective wave and perturbation travelling along the flame front. Time for the flame to settle to a new position after the step excitation is found to correlate well with the sum of time scales of vortex, flame tangential speed and flame tip speed. Overall, it is found that hydrogen flame responds the fastest to the perturbations and exhibits smaller increase in gain compared to methane and propane.

Assessing Corticospinal Excitability During Goal-Directed Reaching Behavior.

Reaching is a widely studied behavior in motor physiology and neuroscience research. While reaching has been examined using a variety of behavioral manipulations, there remain significant gaps in the understanding of the neural processes involved in reach planning, execution, and control. The novel approach described here combines a two-dimensional reaching task with transcranial magnetic stimulation (TMS) and concurrent electromyography (EMG) recording from multiple muscles. This method allows for the noninvasive detection of corticospinal activity at precise time points during the unfolding of reaching movements. The example task code includes a delayed response reaching task with two possible targets displayed ± 45° off the midline. Single pulse TMS is delivered on the majority of task trials, either at the onset of the preparatory cue (baseline) or 100 ms prior to the imperative cue (delay). This sample design is suitable for investigating changes in corticospinal excitability during reach preparation. The sample code also includes a visuomotor perturbation (i.e., cursor rotation of ± 20°) to investigate the effects of adaptation on corticospinal excitability during reach preparation. The task parameters and TMS delivery can be adjusted to address specific hypotheses about the state of the motor system during reaching behavior. In the initial implementation, motor evoked potentials (MEPs) were successfully elicited on 83% of TMS trials, and reach trajectories were recorded on all trials.

Hippocampal mossy cells exhibit some of the earliest signs of increased excitability in the Tg2576 model of Alzheimer’s disease neuropathology

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative illness characterized by progressive accumulation of amyloid beta (Aβ) and neurofibrillary tangles, with cognitive impairment and altered neural activity. Hyperexcitability in the early stages of AD contribute to Aβ accumulation and cognitive impairment, aggravating the progression of AD. However, the hyperexcitability origin is not clear. This study aimed to test whether mossy cells (MCs), an excitatory cell of the hippocampal dentate gyrus, show increased excitability at early stages of AD and contribute to the increased network excitability generation. Indeed, alterations of MCs contribute to hyperexcitability and cognitive impairment in epilepsy. However, the role of MCs in AD has not been substantially explored.MethodsIntrinsic and synaptic properties of MCs and granule cells (GCs) from WT and Tg2576 mice at early ages (1‐2 m.o.) were characterized by whole‐cell patch‐clamp recordings. Synaptic properties included the frequency and amplitude of spontaneous excitatory postsynaptic potentials (EPSPs) and excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs). Deterioration in MCs morphology was evaluated using Nissl staining and GluR2/3 labeling by light‐ and confocal microscopy. Aβ deposition was evaluated using the McSA1 antibody.ResultsTg2576 GCs did not have any significant difference in their intrinsic properties, as we shown previously in mice ∼3 m.o. However, an enhanced excitatory and inhibitory input to GCs, depicted by augmented IPSC (7.16 vs 14.04 events/s) and NMDA‐mediated EPSC frequencies (0.81 vs 1.41 events/s) were found. Interestingly, Tg2576 MCs had an augmented EPSP frequency (5.75 vs 9.44 events/s), and their intrinsic properties showed a depolarized RMP (‐72.88 vs ‐58.36 mV), and reduced rheobase (145.56 vs 47.14 pA), AP amplitude (98.14 vs 76.66 mV), time‐to‐peak (552.75 vs 266.16 ms) and maximum rise (171.44 vs 88.68 mV/ms) and decay slopes (‐61.17 vs ‐42.38 mV/ms). The correlation between #APs and current injected showed Tg2576 MCs fired significantly more APs (SEZD = 0.34; z = 2.48). Tg2576 MCs showed robust intracellular Aβ aggregation without any significant morphological change.ConclusionsMCs changes in excitability and early accumulation of Aβ suggest that MCs could be the cause of increased excitability occurring later in GCs. In this manner, MCs could be an important contributor to AD.

Postnatal development of electrophysiological and morphological properties in layer 2/3 and layer 5 pyramidal neurons in the mouse primary visual cortex.

Eye-opening is a critical point for laminar maturation of pyramidal neurons (PNs) in primary visual cortex. Knowing both the intrinsic properties and morphology of PNs from the visual cortex during development is crucial to contextualize the integration of visual inputs at different age stages. Few studies have reported changes in intrinsic excitability in these neurons but were restricted to only one layer or one stage of cortical development. Here, we used in vitro whole-cell patch-clamp to investigate the developmental impact on electrophysiological properties of layer 2/3 and layer 5 PNs in mouse visual cortex. Additionally, we evaluated the morphological changes before and after eye-opening and compared these in adult mice. Overall, we found a decrease in intrinsic excitability in both layers after eye-opening which remained stable between juvenile and adult mice. The basal dendritic length increased in layer 5 neurons, whereas spine density increased in layer 2/3 neurons after eye-opening. These data show increased number of synapses after onset of sensory input paralleled with a reduced excitability, presumably as homeostatic mechanism. Altogether, we provide a database of the properties of PNs in mouse visual cortex by considering the layer- and time-specific changes of these neurons during sensory development.

Diagnostics of a nanosecond atmospheric plasma jet. Electron and ro-vibrational excitation dynamics

Atmospheric repetitive He discharge with 10 ns current peak width and V s−1 voltage front rise working in jet geometry is studied. The first part of the study is devoted to electrical and optical discharge characterization including voltage-current behavior, emission dynamics, as well as ro-vibrational dynamics of N2, N and OH molecules. It is found that He atoms get excited at the very early stage, as a result of ionization wave formation. This process follows by excitation of O, N2 and N. It is also shown that a rather small (0.1%–1%) air admixtures facilitate gas breakdown, as revealed by shortening of the discharge current risetime. The rotational excitation of N always overtakes He excitation by about 5 ns, with rotational temperature peaking at about 650 K and decaying afterwards, whereas rotational temperature of N2 always remains constant equal to about 300 K. This value is associated with gas kinetic temperature since the electron-rotational (e-R) excitation process is too slow, so it cannot be activated during the plasma phase and no additional change in rotational excitation of N2 happens. Nitrogen molecules remain vibrationally excited in the discharge, post-discharge and jet areas after the plasma pulse which is likely a result of ionization wave propagation. Upon water vapor injection the apparent OH rotational distributions reveal double Boltzmann slope representing thermalized and non-thermalized OH groups. Rotational temperature of the thermalized group correlates with the one of N showing, however, much longer relaxation time, whereas for the non-thermalized group it remains above 1 eV at all conditions. The obtained results confirm that the studied ns- discharge is a good candidate for temperature-sensitive applications, such as the bio-sample treatment. Further analysis related to the ionization waves, electron density and electric field behavior is undertaken in the second part.

Structural plasticity of axon initial segment in spinal cord neurons underlies inflammatory pain.

Physiological or pathology-mediated changes in neuronal activity trigger structural plasticity of the action potential generation site-the axon initial segment (AIS). These changes affect intrinsic neuronal excitability, thus tuning neuronal and overall network output. Using behavioral, immunohistochemical, electrophysiological, and computational approaches, we characterized inflammation-related AIS plasticity in rat's superficial (lamina II) spinal cord dorsal horn (SDH) neurons and established how AIS plasticity regulates the activity of SDH neurons, thus contributing to pain hypersensitivity. We show that in naive conditions, AIS in SDH inhibitory neurons is located closer to the soma than in excitatory neurons. Shortly after inducing inflammation, when the inflammatory hyperalgesia is at its peak, AIS in inhibitory neurons is shifted distally away from the soma. The shift in AIS location is accompanied by the decrease in excitability of SDH inhibitory neurons. These AIS location and excitability changes are selective for inhibitory neurons and reversible. We show that AIS shift back close to the soma, and SDH inhibitory neurons' excitability increases to baseline levels following recovery from inflammatory hyperalgesia. The computational model of SDH inhibitory neurons predicts that the distal shift of AIS is sufficient to decrease the intrinsic excitability of these neurons. Our results provide evidence of inflammatory pain-mediated AIS plasticity in the central nervous system, which differentially affects the excitability of inhibitory SDH neurons and contributes to inflammatory hyperalgesia.

Difference between the Effects of Peripheral Sensory Nerve Electrical Stimulation on the Excitability of the Primary Motor Cortex: Examination of the Combinations of Stimulus Frequency and Duration.

Peripheral sensory nerve electrical stimulation (PES) excites the primary motor cortex and is expected to improve motor dysfunction post-stroke. However, previous studies have reported a variety of stimulus frequencies and stimulus duration settings, and the effects of these different combinations on primary motor cortex excitability are not clear. We aimed to clarify the effects of different combinations of stimulus frequency and stimulus duration of PES on the excitation of primary motor cortex. Twenty-one healthy individuals (aged > 18 years, right-handed, and without a history of neurological or orthopedic disorders) were included. Each participant experienced three different stimulation frequencies (1, 10 and 50 Hz) and durations (20, 40 and 60 min). Motor-evoked potentials (MEPs) were recorded pre- and post-PES. The outcome measure was the change in primary motor cortex excitability using the MEP ratio. We used a D-optimal design of experiments and response surface analysis to define the optimal combination within nine different settings inducing more satisfying responses. The combination of stimulation frequency and stimulation time that maximized the desirability value was 10 Hz and 40 min, respectively. The results of this study may provide fundamental data for more minimally invasive and effective implementation of PES in patients with stroke.

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury

BackgroundTraumatic brain injury (TBI) is characterized by massive changes in neuronal excitation, from acute excitotoxicity to chronic hyper- or hypoexcitability. Nuclear calcium signaling pathways are involved in translating changes in synaptic inputs and neuronal activity into discrete transcriptional programs which not only affect neuronal survival and synaptic integrity, but also the crosstalk between neurons and glial cells. Here, we report the effects of blunting neuronal nuclear calcium signals in the context of TBI.MethodsWe used AAV vectors to express the genetically encoded and nuclear-targeted calcium buffer parvalbumin (PV.NLS.mCherry) or the calcium/calmodulin buffer CaMBP4.mCherry in neurons only. Upon TBI, the extent of neuroinflammation, neuronal death and synaptic loss were assessed by immunohistochemistry and targeted transcriptome analysis. Modulation of the overall level of neuronal activity was achieved by PSAM/PSEM chemogenetics targeted to parvalbumin interneurons. The functional impact of neuronal nuclear calcium buffering in TBI was assessed by quantification of spontaneous whisking.ResultsBuffering neuronal nuclear calcium unexpectedly resulted in a massive and long-lasting increase in the recruitment of reactive microglia to the injury site, which was characterized by a disease-associated and phagocytic phenotype. This effect was accompanied by a substantial surge in synaptic loss and significantly reduced whisking activity. Transcriptome analysis revealed a complex effect of TBI in the context of neuronal nuclear calcium buffering, with upregulation of complement factors, chemokines and interferon-response genes, as well as the downregulation of synaptic genes and epigenetic regulators compared to control conditions. Notably, nuclear calcium buffering led to a substantial loss in neuronal osteoprotegerin (OPG), whereas stimulation of neuronal firing induced OPG expression. Viral re-expression of OPG resulted in decreased microglial recruitment and synaptic loss. OPG upregulation was also observed in the CSF of human TBI patients, underscoring its translational value.ConclusionNeuronal nuclear calcium signals regulate the degree of microglial recruitment and reactivity upon TBI via, among others, osteoprotegerin signals. Our findings support a model whereby neuronal activity altered after TBI exerts a powerful impact on the neuroinflammatory cascade, which in turn contributes to the overall loss of synapses and functional impairment.

Creation of Neuronal Ensembles and Cell-Specific Homeostatic Plasticity through Chronic Sparse Optogenetic Stimulation.

Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles in ex vivo cortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations.SIGNIFICANCE STATEMENT The connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used an ex vivo approach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms of their correlated activity and functional connectivity. The absence of feedback between different brain areas and full control of external input allowed for a tractable system to study the underlying mechanisms and development of a computational model. Results show that differential stimulation of subpopulations of neurons significantly reshapes cortical circuits and forms subnetworks referred to as neuronal ensembles.

Excitability changes induced in the human auditory cortex by transcranial alternating current stimulation

Transcranial alternating current stimulation (tACS) has been widely studied for its ability to regulate motor, perceptual, and cognitive functions. Given the unique frequency specificity of tACS, it is expected to directly target rhythmic activity in the typical electroencephalogram (EEG) range. After tACS stimulation, changes in stimulation-induced and evoked activities can be inspected. Detecting changes in auditory evoked activity after different frequencies of tACS stimulation will be helpful for further revealing the influence of tACS on the excitation/inhibition of γ activity in the auditory cortex. Using a randomized repeated measures design, this study assessed the effects of alpha(α)-tACS and gamma(γ)-tACS on the auditory steady-state response (ASSR) in 11 normal-hearing participants. Participants attended four sessions held at least one week apart, receiving tACS or sham treatment. The results indicated that α-tACS had an inhibitory effect on 40-Hz ASSR compared to both γ-tACS and sham tACS, which occurred 30 min after stimulation. Taken together, these findings contribute to the understanding of tACS-induced excitability changes in the human auditory cortex, helping reveal the neurophysiological changes after tACS.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n=14; 61 ± 7yrs) or abnormally enlarged (hyperechogenic; n=9; 60 ± 6yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p=.005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Neural correlates of spatial attention bias: Changes in functional connectivity in attention networks associated with tDCS

The prevailing theory concerning the pathophysiology of unilateral spatial neglect is that it is caused by an interhemispheric imbalance in attention networks. Previous studies have demonstrated that repetitive transcranial magnetic stimulation or transcranial direct current stimulation (tDCS) delivered over the right posterior parietal cortex can induce transitory neglect-like deficits in healthy individuals. We examined whether right cathodal and left anodal tDCS delivered over the posterior parietal cortex could produce neglect-like deficits and change the resting-state functional connectivity (rsFC) of attention networks. We found that the reaction time for targets in the left hemifield was significantly prolonged during two different types of visual search tasks, and rsFC of the attention networks was altered by tDCS. Furthermore, the change in the reaction times for the left visual target in the two different tasks significantly correlated with the change in the rsFC of either the right dorsal attention network (DAN) or right ventral attention network (VAN) based on the tasks. These results suggest that tDCS delivered to the posterior parietal cortex bilaterally induced neglect-like deficits by altering the connectivity of the attentional networks through excitability changes in the cortical area under the electrode. The results of this study are consistent with the hypothesis that the cause of neglect is the interhemispheric imbalance of attention networks. This is the first study to demonstrate that local cortical stimulation can induce changes not only in the local brain function but also in the cortical networks in healthy individuals.

A cognitive task, deep breathing, and static stretching reduce variability of motor evoked potentials during subsequent transcranial magnetic stimulation

BackgroundMotor evoked potentials (MEPs) induced via transcranial magnetic stimulation (TMS) demonstrate trial-to-trial variability limiting detection and interpretation of changes in corticomotor excitability. This study examined whether performing a cognitive task, voluntary breathing, or static stretching before TMS could reduce MEP variability. Methods20 healthy young adults performed no-task, a cognitive task (Stroop test), deep breathing, and static stretching before TMS in a randomized order. MEPs were collected in the non-dominant tibialis anterior muscle at 130% active motor threshold. Variability of MEP amplitude was quantified as coefficient of variation (CV). ResultsMEP CV was greater after no-task (25.4 ± 7.0) than after cognitive task (23.3 ± 7.2; p < 0.05), deep breathing (20.1 ± 6.3; p < 0.001), and static stretching (20.9 ± 6.0; p = 0.004). MEP CV was greater after cognitive task than after deep breathing (p = 0.007) and static stretching (p = 0.01). There was no effect of condition on MEP amplitude. ConclusionsPerforming brief cognitive, voluntary breathing, and stretching tasks before TMS can reduce MEP variability with no effect on MEP amplitude in the tibialis anterior of healthy, young adults. Similar tasks could be incorporated into research and clinical settings to improve detection of changes, normative data, and clinical predictions.

Using evoked compound action potentials to quantify differential neural activation with burst and conventional, 40 Hz spinal cord stimulation in ovines.

We implanted 7 sheep with a dorsal stimulation lead at T9/T10, a dorsal ECAP sensing lead at T6/T7, and a lead also at T9/T10 but adjacent to the anterolateral system (ALS). Both burst and conventional SCS with stimulation amplitudes up to the visual motor threshold (vMT) were delivered to 3 different dorsal spinal locations, and ECAP thresholds (ECAPTs) were calculated for all combinations. Then, changes in ALS activation were assessed with both types of SCS. Evoked compound action potential thresholds and vMTs were significantly higher (P < 0.05) with conventional vs burst SCS, with no statistical difference (P > 0.05) among stimulation sites. However, the vMT-ECAPT window (a proxy for the useable therapeutic dosing range) was significantly wider (P < 0.05) with conventional vs burst SCS. No significant difference (P > 0.05) in ALS activation was noted between conventional and burst SCS. When dosed equivalently, no differentially unique change in ALS activation results with burst SCS vs conventional SCS; in addition, sub-ECAPT burst SCS results in no discernable excitability changes in the neural pathways feeding pain relevant supraspinal sites.

GnRH Neuron Excitability and Action Potential Properties Change with Development But Are Not Affected by Prenatal Androgen Exposure.

Gonadotropin-releasing hormone (GnRH) neurons produce the final output from the brain to control pituitary gonadotropin secretion and thus regulate reproduction. Disruptions to gonadotropin secretion contribute to infertility, including polycystic ovary syndrome (PCOS) and idiopathic hypogonadotropic hypogonadism. PCOS is the leading cause of infertility in women and symptoms resembling PCOS are observed in girls at or near the time of pubertal onset, suggesting that alterations to the system likely occurred by that developmental period. Prenatally androgenized (PNA) female mice recapitulate many of the neuroendocrine phenotypes observed in PCOS, including altered time of puberty, disrupted reproductive cycles, increased circulating levels of testosterone, and altered gonadotropin secretion patterns. We tested the hypotheses that the intrinsic properties of GnRH neurons change with puberty and with PNA treatment. Whole-cell current-clamp recordings were made from GnRH neurons in brain slices from control and PNA females before puberty at three weeks of age and in adulthood to measure GnRH neuron excitability and action potential (AP) properties. GnRH neurons from adult females were more excitable and required less current to initiate action potential firing compared with three-week-old females. Further, the afterhyperpolarization (AHP) potential of the first spike was larger and its peak was delayed in adulthood. These results indicate development, not PNA, is a primary driver of changes to GnRH neuron intrinsic properties and suggest there may be developmentally-induced changes to voltage-gated ion channels in GnRH neurons that alter how these cells respond to synaptic input.

The RNA-Binding Protein HuR Is Integral to the Function of Nociceptors in Mice and Humans.

HuR is an RNA-binding protein implicated in RNA processing, stability, and translation. Previously, we examined protein synthesis in dorsal root ganglion (DRG) neurons treated with inflammatory mediators using ribosome profiling. We found that the HuR consensus binding element was enriched in transcripts with elevated translation. HuR is expressed in the soma of nociceptors and their axons. Pharmacologic inhibition of HuR with the small molecule CMLD-2 reduced the activity of mouse and human sensory neurons. Peripheral administration of CMLD-2 in the paw or genetic elimination of HuR from sensory neurons diminished behavioral responses associated with NGF- and IL-6-induced allodynia in male and female mice. Genetic disruption of HuR altered the proximity of mRNA decay factors near a key neurotrophic factor (TrkA). Collectively, the data suggest that HuR is required for local control of mRNA stability and reveals a new biological function for a broadly conserved post-transcriptional regulatory factor.SIGNIFICANCE STATEMENT Nociceptors undergo long-lived changes in excitability, which may contribute to chronic pain. Noxious cues that promote pain lead to rapid induction of protein synthesis. The underlying mechanisms that confer specificity to mRNA control in nociceptors are unclear. Here, we identify a conserved RNA-binding protein called HuR as a key regulatory factor in sensory neurons. Using a combination of genetics and pharmacology, we demonstrate that HuR is required for signaling in nociceptors. In doing so, we report an important mechanism of mRNA control in sensory neurons that ensures appropriate nociceptive responses to inflammatory mediators.

Effect of standardized training in combination with masseter sensitization on corticomotor excitability in bruxer and control individuals: a proof of concept study

Recently, it has been proposed that bruxism could represent an overlearned behavior due to the absence of corticomotor plasticity following a relevant tooth-clenching task (TCT). This study assessed the modulatory effects of a nerve growth factor (NGF) injection on masseter muscle corticomotor excitability, jaw motor performance, pain, and limitation in bruxer and control participants following a TCT. Participants characterized as definitive bruxers or controls were randomly assigned to have injected into the right masseter muscle either NGF or isotonic saline (IS), resulting in a study with 4 arms: IS_Control (n = 7), IS_Bruxer (n = 7); NGF_Control (n = 6), and NGF_Bruxer (n = 8). The primary outcome was the masseter motor evoked potential (MEP) amplitude measured at baseline and after a TCT. After the interventions, significantly higher and lower MEP amplitude and corticomotor map area were observed, respectively, in the IS_Control and NGF_Control groups (P < 0.05). Precision and accuracy depended on the series and target force level with significant between-group differences (P < 0.01). NGF‐induced masseter muscle sensitization, in combination with a training-induced effect, can significantly impact the corticomotor excitability of the masseter muscle in control participants indicating substantial changes in corticomotor excitability, which are not observed in bruxers. These preliminary findings may have therapeuthic implications for the potential to “detrain” and manage bruxism, but further studies with larger sample sizes will be needed to test this new concept.

Motoneuron excitability dysfunction in ALS: Pseudo-mystery or authentic conundrum?

In amyotrophic lateral sclerosis (ALS), abnormalities in motoneuronal excitability are seen in early pathogenesis and throughout disease progression. Fully understanding motoneuron excitability dysfunction may lead to more effective treatments. Yet decades of research have not produced consensus on the nature, role or underlying mechanisms of motoneuron excitability dysfunction in ALS. For example, contrary to Ca excitotoxicity theory, predictions of motoneuronal hyper-excitability, normal and hypo-excitability have also been seen at various disease stages and in multiple ALS lines. Accordingly, motoneuron excitability dysfunction in ALS is a disputed topic in the field. Specifically, the form (hyper, hypo or unchanged) and what role excitability dysfunction plays in the disease (pathogenic or downstream of other pathologies; neuroprotective or detrimental) are currently unclear. Although several motoneuron properties that determine cellular excitability change in the disease, some of these changes are pro-excitable, whereas others are anti-excitable, making dynamic fluctuations in overall 'net' excitability highly probable. Because various studies assess excitability via differing methods and at differing disease stages, the conflicting reports in the literature are not surprising. Hence, the overarching process of excitability degradation and motoneuron degeneration is not fully understood. Consequently, the discrepancies on motoneuron excitability dysfunction in the literature represent a substantial barrier to our understanding of the disease. Emerging studies suggest that biological variables, variations in experimental protocols, issues of rigor and sampling/analysis strategies are key factors that may underlie conflicting data in the literature. This review highlights potential confounding factors for researchers to consider and also offers ideas on avoiding pitfalls and improving robustness of data.