Neuroscience

AO_SCPLOWBSTRACTC_SCPLOWThe laminins are a family of extracellular matrix proteins that regulate numerous cellular processes, including adhesion, neurite outgrowth, and axon guidance. However, it remains unclear whether laminin regulates axon guidance through local translation. Here, we show that laminin is necessary for local translation in axonal growth cones. Local translation is significantly increased in growth cones of embryonic day 17 mouse cortical neurons, either cultured on or acutely stimulated with soluble laminin 111, in the presence of BDNF. When cultured on laminin isoforms 211 or 221 in the presence of BDNF, there was a remarkable decrease in local translation in growth cones. Using a puromycin-proximity ligation assay to examine newly synthesized {beta}-actin specifically, we find a significant increase in growth cones of neurons cultured on laminin 111 in the presence of BDNF. However, soluble laminin 111 alone results in a significant reduction in nascent {beta}-actin protein synthesis. These results indicate that laminin isoforms can act in multiple ways, including synergistically with guidance cues and independently, to modulate local mRNA translation, thereby differentially influencing axon growth and guidance during development. SO_SCPLOWUMMARYC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWLocal translation in axons is critical for axon guidance. Laminin, a key component of the extracellular matrix, is necessary to induce local translation and thus mediate axon growth and guidance.

Glutamatergic neuronal synapses in the mouse neocortex mature during the first two months after birth. A key event during synaptic maturation is a change in short-term synaptic plasticity (STP), i.e. a switch from strong synaptic depression to a weaker depression or even facilitation. Glutamatergic pyramidal neurons located in the cortical layers II/III, layer V, and layer VI project axons through the corpus callosum where they release glutamate along their shafts and form glutamatergic synapses with oligodendrocyte precursor cells (OPCs). Here, we used single-cell electrophysiological recordings in brain slices to investigate synaptic plasticity at neuron-OPC synapses along axonal shafts in the white matter, and applied computation approaches to pinpoint the mechanisms of this plasticity. We found that during postnatal development of mice, there is a switch from short-term synaptic depression to short-term synaptic facilitation at glutamatergic neuron-OPC synapses in the corpus callosum. Synaptic delay of phasic neuron-OPC excitatory postsynaptic current shortens, and the amount of asynchronous release at neuron-OPC synapses decrease as animals mature, indicating that glutamate release becomes more synchronized. Our computational modelling suggests that both pre- and postsynaptic changes may contribute to the functional development and changes of plasticity at neuron-OPC synapses in the white matter. Taking together, our findings indicate that synaptic release machineries located at different sites along the same axon (i.e. axonal shaft in the white matter vs synaptic boutons in the grey matter) mature in a very similar fashion, STP occurs at both synaptic sites, and STP dynamics represent an important event during brain maturation.

This study investigated the spinal neural mechanisms underlying post-activation potentiation in ten healthy young males (21.9 {+/-} 4.8 years). Participants performed a 10-second maximal isometric plantarflexion, after which we measured twitch torque and assessed spinal excitability using the soleus H-reflex, D1 presynaptic inhibition and heteronymous Ia facilitation (HF). High-density surface EMG was decomposed to track single motor unit responses. The conditioning contraction increased twitch torque by 12.2 Nm (p < 0.001) immediately and returning to baseline within nine minutes. This mechanical potentiation was accompanied by a 29% reduction in H-reflex amplitude (p < 0.001), which recovered within three minutes. Paradoxically, neurophysiological indices of presynaptic inhibition, D1 and HF were significantly increased (D1: p<0.017; HF: p<0.001), resulting in spinal facilitation. Single MU analysis revealed increased discharge probability, particularly in higher-threshold units indicating overall spinal facilitation. These results demonstrate that post-activation potentiation involves a complex dissociation: H-reflex pathway inhibition along with facilitation of presynaptic spinal mechanisms. This paradox can be explained by either post-activation depression (caused by depletion of neurotransmitter at the Ia-motoneuron synapse) or muscle thixotropy, a contraction history-dependent decrease in muscle spindle sensitivity, which reduces the efficacy of the Ia afferent volley independently of spinal inhibitory mechanisms. Our findings highlight a dissociation between spinal presynaptic facilitation and the decreased H-reflex, underscoring the need for future studies to explicitly test the roles of post-activation depression and muscle thixotropy during post-activation potentiation. New & NoteworthyThis study provides evidence that post-activation potentiation reduces the soleus H-reflex amplitude while concurrently facilitating presynaptic spinal mechanisms. By combining global EMG and single motor unit analyses extracted from high-density surface EMG, we reveal a dissociation between spinal disinhibition and reflex depression. These findings suggest that acute post-contraction reflex suppression might be mediated by mechanisms other than presynaptic inhibition, potentially involving post-activation depression spinal mechanisms or changes in muscle spindle sensitivity.

Excitatory glutamatergic synapses in the brain are remarkably plastic. Two forms of plasticity have received the most attention: long-term potentiation (LTP) and synaptic homeostasis. While LTP requires the activation of NMDA receptors, synaptic homeostasis does not. However, both phenomena are mediated by the recruitment of postsynaptic AMPA receptors to the synapses. Recently a new form of plasticity has been described referred to as presynaptic homeostatic plasticity (PHP) (Chipman et al., 2022; Chipman et al., 2025). Pharmacological inhibition of AMPA synaptic responses in CA1 hippocampal pyramidal cells initiates a rapid homeostatic response that results in the recovery of the AMPA responses to normal values in the continued presence of the inhibitor. Accompanying this recovery is a doubling of the NMDA response which is interpreted as an increase in the release of glutamate. This is provocative since it is the first report claiming that a reduction in AMPA responses triggers an enhancement in NMDA responses. Using three different protocols to monitor synaptic responses we fail to observe any recovery of synaptic responses in the presence of an AMPA inhibitor. Furthermore, there was no enhancement in NMDA responses. Thus, we find no evidence for the presence of PHP at CA1 hippocampal synapses.

Cerebellar communication with the prefrontal cortex (PFC) may play a significant role in cognitive functions. Our previous studies found that rule-based (RB) category learning depends on the PFC in humans and rats. The PFC is also crucial for behavioral flexibility following rule-changes in various tasks. Very little is known regarding the role of the cerebellum in RB category learning. The current study was designed to determine whether the cerebellum plays a role in RB category learning, and in categorization following a rule switch. Female and male rats were given bilateral lesions of the lateral cerebellar nuclei (LCN) or a control surgery and trained on an RB category learning task followed by a category rule switch. A subset of rats was trained on a control discrimination task with the same trial procedures as the categorization task. Rats with LCN lesions took significantly longer to learn both the first and second category rules but were not impaired on the control task. Computational modeling revealed less task engagement and increased switching between engaged and non-engaged states in the LCN lesion group. Several measures of task performance indicated that the category learning deficit was not caused by a motor impairment, response bias, or an inability to discriminate the stimuli. The category learning deficits with LCN lesions were related to reduced accuracy of stimulus classification, an inability to maintain task engagement, and loss of flexibility. The results show, for the first time, that the cerebellum plays a crucial role in category learning and category rule-switching.

Voltage-gated sodium channels (VGSCs) are conventionally described as heterotrimers composed of one alpha and two beta subunits. However, the patterns of co-expression of alpha- and beta-subunits in neurons remain unclear. In the present study, we report that alpha- (Nav1.1, Nav1.2, and Nav1.6) and beta- (beta-1 and beta-2) subunits are densely expressed in axon initial segments (AISs) of neurons in the neocortex, hippocampus and cerebellum at postnatal days 14-15 (P14-15) and 8-9 weeks (8-9W). These distributions are largely unique and partially overlapping among brain regions. Notably, in the neocortex and hippocampus, AISs of presumptive parvalbumin-positive inhibitory neurons are positive for Nav1.1 and beta-1, whereas those of excitatory ones are positive for Nav1.2 and beta-2. Similarly, AISs of cerebellar basket cells, which are inhibitory neurons, are positive for Nav1.1 and beta-1, whereas those of granule cells, which are excitatory neurons, are positive for Nav1.2 and beta-2. Nav1.6 is expressed in many of these neurons. Some subunits exhibited distinct distribution patterns at the two postnatal stages analyzed, possibly because of their developmental changes of subcellular localizations. Taken together, these results indicate that combinations of VGSC subunits are largely unique among different neuronal subpopulations. These findings provide a useful reference for understanding the distribution and interactions of VGSC subunits in the brain.

Motor unit (MU) firing is affected by motoneuronal persistent inward currents (PICs), which heavily contribute to gain control of motor output. PICs are highly sensitive to inhibition; for instance, Ia reciprocal inhibition via antagonist muscle vibration drastically reduces discharge rate hysteresis ({Delta}F), an estimate of PIC magnitude. A direct link between sensitivity of PICs to inhibition and voluntary force control, however, has not been established. To determine whether force control is altered with inhibition of PICs, we recorded high-density surface EMG from the tibialis anterior, while 11 participants (5F; 6M) completed and isometric force reproduction task. Tendon vibration was applied to the agonist or antagonist muscle during the first (with visual feedback) or second contraction (without visual feedback) and participants were asked to match percieved effort across contractions, in an attempt to match neural drive to the motor pool. In support of our hypothesis, torque and MU firing rates were reduced when vibration was applied to the antagonist (torque: p < .0001; MU firing rate: p < .0001), but not agonist (torque: p = .9980; MU firing rate: p = .312) muscle tendon in the second contraction, compared to control. Conversely, when vibration was applied during the first contraction, opposite effects were observed. These results suggest that PICs play a role in the proprioceptive sense of force, offering a potential link between PICs and voluntary force control, which may be important for understanding and treatment of motor impairments. KEY POINTSO_LIMotoneuronal persistent inward currents amplify synaptic currents and therefore heavily contribute to motor output, however they are extremely sensitive to Ia reciprocal inhibition induced by muscle tendon vibration. C_LIO_LIWe show that modulation of PICs severely impacts human force sense using an effort-based force reproduction paradigm which enabled us to manipulate combinations of tendon vibration and visual feedback. C_LIO_LIThese findings provide a link between PICs and functional motor output, which may be important for understanding neurological impairments and informing rehabilitation strategies. C_LI

Reward can enhance motor performance. However, its potential to counteract motor fatigability, a reduction in motor performance during sustained movements, remains underinvestigated. This could be particularly relevant in neurological conditions such as multiple sclerosis, where increased motor fatigability is a prominent symptom. One form of motor fatigability is motor slowing, a decline in movement speed over time evoked by fast, repetitive movements. In this study, we investigated whether the possibility to earn reward attenuates motor slowing, and examined associated changes in muscle activity and pupil size, a putative marker of physical effort. Participants performed a wrist tapping task at maximal voluntary speed with or without the possibility of earning a reward. We found that wrist tapping induced motor slowing and that slowing was significantly reduced by reward. Over time, tapping became more costly as indicated by higher muscle activity and coactivation per tap. This was accompanied by a sustained pupil dilation, which could not solely be explained by tapping speed. These findings suggest that, rather than restoring efficient motor control, reward attenuates motor slowing by allowing participants to access a performance reserve and invest more resources into the task, reflected by increased muscle activation per tap and sustained pupil dilation.

Concentrations of estradiol (E2) and progesterone (P4), the main female sex hormones, exhibit large fluctuations across the menstrual cycle. Due to their receptors throughout the central nervous system, both hormones have the potential to influence motor function by influencing ionotropic and metabotropic inputs to motor pools, which can be estimated through the neural codes extracted from motor unit discharge patterns. To address key methodological limitations in prior menstrual cycle research on motor output, we established the Motor Units and Sex Hormones (MUSH) collaboration. The objective of this multi-site investigation was to determine whether endogenous fluctuations in estradiol and progesterone influence human motor unit activity. We hypothesized that motor unit discharge rates and persistent inward current (PIC)-related contributions to discharge would be greatest during the late follicular phase, when estradiol concentrations were highest. Fifty females completed a comprehensive protocol involving menstrual cycle and ovulation tracking, serum hormone measurement, and high-density surface electromyographic recordings during isometric contractions to quantify motor unit activity in the early follicular, late follicular, and mid luteal phases. After exclusion of 10 females with either atypical hormone concentration profiles or insufficient motor unit yield, 40 remained in the final analysis. There were significant changes in several motor unit discharge variables between menstrual cycle phases and significant associations with hormone concentrations. Increased estradiol was associated with higher peak discharge rates and ascending discharge rate nonlinearity, while increased progesterone was associated with higher peak discharge rates, more discharge rate hysteresis and ascending discharge rate nonlinearity. Despite reaching statistical significance, the magnitudes of these effects (i.e., effect sizes) were small. Overall, these findings indicate that fluctuations in sex hormones influence motor unit behavior, but the effects are subtle, highlighting the need for well-powered and methodologically rigorous menstrual cycle research. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/699975v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@2eb2c0org.highwire.dtl.DTLVardef@1d98359org.highwire.dtl.DTLVardef@13e772borg.highwire.dtl.DTLVardef@1bb27_HPS_FORMAT_FIGEXP M_FIG C_FIG KEY POINTSO_LIThere are small but detectable differences in motor unit discharge rates between menstrual cycle phases, which are predicted by within-participant fluctuations in estradiol and progesterone. C_LIO_LIDischarge rate patterns that provide estimates of neuromodulatory and inhibitory input suggest that estradiol and progesterone can influence spinal cord circuitry differently than has previously been documented in the brain, highlighting an understudied aspect of female neurophysiology. C_LIO_LIVariability in menstrual cycles and associate hormones makes large-scale, rigorous studies especially valuable in female neuromuscular research. C_LI

Effective speech analysis involves deconstructing the acoustic signal into identifiable linguistic units, which depends on the ability to recognize and anticipate temporal patterns within the speech stream. However, these processes may be less efficient in individuals with dyslexia. This study investigated the effects of temporal context and related temporal predictions in dyslexic adult participants and matched control participants, using an auditory oddball task with non-verbal stimuli. Pure tones were presented in sequences, and participants were requested to discriminate the pitch of target stimuli. The temporal intervals between the sounds varied in regularity across the sequences, thereby creating contexts with different levels of temporal predictability. At the end of each sequence, participants were prompted to evaluate the perceived rhythmicity of the sequence and to assess their own performance in the auditory discrimination task. Dyslexic participants demonstrated overall lower accuracy in discriminating target sounds than controls. They also showed reduced influence of the temporal context of the sequences on response times, while controls responded faster in sequences that were temporally more regular and predictable. Additionally, individuals with dyslexia perceived the rhythmicity of sound sequences less accurately, overestimating the temporal regularity in irregular sequences and underestimating it in regular sequences. They also reported lower overall confidence in their ability to perform the task compared to control participants. Altogether, these findings provide converging evidence for altered temporal prediction abilities in dyslexia, which may impact auditory perception and then impair language processing.

The aim of this study was to improve our understanding of muscle contractions in the arm as a function of hand orientation for grasp. While there have been several reports on arm kinematics for reach and grasp movements, little has been done at the muscular level. To this end, we analyzed the modulation of shoulder, elbow and hand muscles for a reach and grasp task involving a target in either horizontal or vertical orientation. We hypothesized that unlike what has been observed for kinematics, at the muscular level we would see less correlation between the three muscle groups. A decoding approach with Machine Learning revealed adaptation patterns that were not visible using classical methods. Reach-and-grasp has traditionally been treated as being made of two components - the reach and the grasp components. Our dynamic decoding approach revealed a more complex picture with very different dynamics in the shoulder and elbow muscle groups during reach. All muscle groups showed peak capacity for predicting hand orientation before the start of grasp and followed the ubiquitous proximo-distal organization. The patterns of muscular modulation for hand orientation were strongly perturbed by the eyes closed and slow movement conditions, potentially decreasing the available degrees of freedom for adaptation.

Dopamine (DA) neurons of the midbrain project throughout the striatum, including the nucleus accumbens core (NAc) and are thought to co-release ATP with DA from vesicles. The mechanisms of evoked NAc ATP release and clearance and their relationship to exocytotic DA transmission are largely unexplored and the focus of the present work. Using fast scan cyclic voltammetry (FSCV), we measured simultaneous ATP and DA transmission in response to pharmacological manipulations of release and reuptake cellular machinery. ATP transmission is tightly coupled to that of DA, though ATP release concentrations are typically smaller. Manipulations that increase DA transmission (increased release via 4-aminopyridine Kv channel blockade or decreased uptake via cocaine) also increase ATP transmission, though to a smaller extent. Blocking DA vesicular packaging (reserpine) or action potentials (lidocaine), results in attenuated DA and ATP release. Interestingly, reserpine or lidocaine can result in completely abolished DA release, but not a complete prevention in ATP release, suggesting a secondary source for ATP transmission thats not dependent on DA terminals. Both transmitters were reduced to a similar extent following nAChR blockade, demonstrating that nAChR activation regulates ATP in addition to DA. Surprisingly, cocaine inhibition of DATs reduced clearance for both ATP and DA, which correlated with one another when cocaine concentration was highest. There was also a strong relationship between the effect of cocaine on release of ATP and DA. As the first FSCV study to examine evoked NAc ATP release, this paper bridges prior work to confirm the strong association between ATP and DA in the mesolimbic circuit and identifies unexpected overlap in mechanisms regulating their transmission. Our results contribute novel evidence of both vesicular and non-vesicular ATP release in the NAc and demonstrate that extracellular ATP is a modulator of DA terminal function.

Torpor is a hypometabolic state employed by many mammalian and non-mammalian species to cope with harsh environments. When exposed to a short photoperiod, Djungarian hamsters (Phodopus sungorus) enter daily torpor with body temperatures dropping to as low as 15{degrees}C. Despite the widely-held notion that torpor is a form of deep sleep, torpid animals are not completely inactive but exhibit occasional movements reflected in an increase in EMG tone. Little is known about these EMG events during torpor and whether they have a functional role during the torpid state. We here analysed EEG, EMG, and brain temperature data from Djungarian hamsters, and used an automatic detection algorithm to identify periods of EMG activation during spontaneous daily torpor. The hamsters exhibited regular periods of motility that were invariably initiated during a decline in brain temperature and were followed by a brain temperature increase. The frequency of EMG events exhibited a negative correlation with brain temperature, such that lower brain temperature was associated with a higher frequency of EMG events. In addition, EMG events were associated with a pronounced increase in EEG power, especially between 9.5-15.5 Hz, which often started with an EEG pattern similar to an evoked potential preceding the increase in the EMG activity. On the contrary, micro-arousals during normothermic NREM sleep were associated with a decrease in EEG power, a decrease in brain temperature and were of shorter duration than torpor EMG events, indicating that the two phenomena may serve different purposes. We speculate that periodic motility associated with increased brain activity during torpor may play a role in thermoregulation, and help retain vigilance to potentially mitigate predation risk during this hypometabolic state.

Tourette syndrome (TS) is a neurological disorder characterised by the occurrence of vocal and motor tics. Rhythmic median nerve stimulation (MNS) at 10Hz has been shown to cause a substantial reduction in tic frequency in individuals with Tourette Syndrome. The mechanism of action is currently unknown but has been hypothesised to involve entrainment of cortical oscillations within the sensorimotor cortex linked to the initiation of movement. An important methodological detail of these studies is that MNS is delivered at or above threshold (i.e., the minimum stimulation level required to elicit a visible muscle twitch). This is important issue as it means that the observed effects of rMNS could be driven primarily by afferent signals in response to stimulation, the re-afferent signals arising from the muscle, or a combination of these signals. To examine this further, we used electroencephalography (EEG) to investigate the effect of delivering 1s trains of sub-threshold rhythmic 10Hz MNS in a group of 15 adults with TS compared to a matched group of 20 neurotypical control participants. The results demonstrate that the EEG response (somatosensory evoked potential (SEP) to rMNS increased linearly with increasing stimulation amplitude. This was paralleled by substantially increased inter-trial coherence (ITC) during rMNS. Importantly, the duration of increased ITC was reduced for the TS group compared to controls. Importantly, these results were largely similar when analyses were restricted only to sub-threshold trials in which no visible muscle twitch was elicited by MNS. These results confirm that sub-threshold rhythmic MNS is sufficient to modulate somatosensory physiology and may also be sufficient to elicit the clinical benefits previously observed for MNS.

Drug addiction is an acquired motivational-behavioral state that begins with drug taking, which is comprised of a series of phases, including initial acquisition, stabilization, habituation, and maintenance. In rodent models of cocaine self-administration, the forebrain region nucleus accumbens (NAc) has been critically implicated in the acquisition-maintenance process of drug taking and seeking behaviors. However, it remains unknown how NAc neurons shift their activity patterns in response to these phasic transitions during cocaine taking. To examine this, we used GCaMP6m-based in vivo Ca2+ imaging to monitor activities of principal medium spiny neurons (MSNs) in the NAc across eleven days of cocaine self-administration. Behaviorally, mice exhibited progressive stabilization of operant responding and locomotion across 11 days of cocaine self-administration. During the early training days, we detected a portion of NAc neurons--a potential neuronal ensemble--that exhibited increased activities temporally contingent to the lever-press for cocaine. The number of NAc neurons exhibiting contingent activity increased progressively over the first three training days and then decreased gradually during the later training days, exhibiting expansion-refinement dynamics that may correspond to the acquisition and subsequent stabilization/maintenance of cocaine self-administration. Using a neuron-tracking technique, we found that the lever-press-contingent NAc ensemble exhibited substantial compositional dynamics, with neurons dropping into and out across training days. These activity features of lever-press-contingent neurons may represent key circuit dynamics of the NAc that transition the acquisition toward the maintenance of cocaine-taking behavior.

The macaque lateral intraparietal area (LIP) is known for its role in visually guided saccades as well as in higher cognitive functions. However, its contribution to more basic visuomotor processes remains unclear. Here, we investigated whether neural activity in area LIP is also related to involuntary reflexive eye movements, specifically the fast phases of optokinetic nystagmus (OKN). To address this question, we compared spiking activity and local field potentials (LFPs) in area LIP of two male macaque monkeys during visually guided saccades and during kinematically similar OKN fast phases. Neurons exhibiting robust perisaccadic activation during voluntary saccades showed markedly reduced or no activity around the time of OKN fast phases and were not modulated by fast-phase amplitude or frequency. Using a Generalized Linear Model, we found that during OKN slow phases, area LIP reliably encoded gaze position and the direction of visual motion driving the reflexive eye movement. LFP analyses further revealed that beta-band power differed between voluntary saccades and OKN fast phases, whereas theta-band phase coherence increased following both types of fast eye movements, suggesting distinct local processing but shared post-movement network coordination. Our results reinforce the view of area LIP as a key area for integrating sensory and cognitive signals relevant for goal-directed action rather than a generic oculomotor controller.

Transcutaneous spinal cord stimulation (tSCS) of the cervical spinal cord has been thought to modulate lumbar networks, leading to the hypothesis that leg muscle recruitment may occur via recruitment of long-range spinal connections between cervical and lumbar circuits. To directly test this hypothesis, we compared arm and leg muscle responses elicited in unimpaired participants (N = 12) by cervical tSCS with the anodes placed over the iliac crests, with the anodes placed over the clavicles, and with lumbar tSCS as a control for leg muscle recruitment via the posterior root-muscle reflex. The idea of tSCS targeting cervico-lumbar connectivity would suggest that cervical stimulation could evoke responses in leg muscles. However, in our experiments, leg responses via cervical tSCS were only observed when the anodes were placed over the iliac crests, but not over the clavicles. These leg muscle responses had shorter latencies than those with lumbar tSCS and showed minimal post-activation depression, indicating efferent rather than afferent recruitment. Therefore, changes in leg muscle excitability by cervical-iliac tSCS previously attributed to descending cervical circuits could instead be explained by direct recruitment of efferent fibers near the iliac anodes. These findings suggest that cervical tSCS alone does not engage leg muscle motoneurons via long-range spinal or bidirectional pathways. Therefore, our study highlights the need to carefully consider electrode configuration when interpreting cervical tSCS mechanisms and additional or unexpected rehabilitative effects that extend caudally from the cervical spinal cord.

Traumatic brain injury (TBI) induces a series of neuropathological changes in the brain including neurogenesis, an important cellular response involved in brain repair and regeneration. TBI-enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus is of particular importance due its contribution to learning and memory functions. In the neurogenic process, proliferation and differentiation of neural stem cells (NSCs) follow a well-characterized sequence controlled by many factors including Notch1, which plays essential roles in regulating NSC fate determination under physiological conditions in both developing and adult brains. Following TBI, the dynamic changes of NSCs and the involvement of Notch1 on their development at different stages post-injury are not fully characterized. In the current study, we examined the impact of TBI and Notch1 on NSCs proliferation, survival and neuronal differentiation. Utilizing transgenic mice with tamoxifen-induced GFP expression and Notch1 knock-out in nestin+ NSCs, we examined DG neurogenic response at acute, subacute and chronic stages following a moderate lateral fluid percussion injury. We found that TBI enhanced a proliferative response in the DG at the acute stage following injury; however, this injury response was abolished when Notch1 was conditionally deleted from nestin+ NSCs. We also found that injury and Notch1 deletion drove NSCs committing fate choice towards neuronal differentiation. The results of this study provides further knowledge regarding TBI-induced neurogenic response and Notch1 as the key regulating mechanism.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the leading monogenic cause of autism, resulting from mutations in the Fmr1 gene. While extensive research points to widespread circuit hyperexcitability across cortical and subcortical circuits, the contribution of the spinal cord circuits in the motor phenotypes associated with FXS remains largely unexplored. Given that Fmr1 is expressed in both dorsal and ventral spinal cord, including motoneurons, the possibility exists that loss of its protein product, FMRP, disrupts locomotor circuitry. Here, we investigate whether Fmr1 deletion alters the function of the spinal central pattern generator (CPG) networks and gait-related motor output. Using isolated neonatal spinal cord preparations from Fmr1 knockout (Fmr1 KO) mice, we assessed the ability of spinal circuits to generate coordinated fictive locomotor activity in vitro. In parallel, we quantified the gait parameters and motor performance in freely moving adult mice during unskilled and skill-demanding tasks. Our findings indicate that, despite the absence of FMRP in spinal neurons, neonatal Fmr1 KO spinal cords generated robust and coordinated locomotor rhythms compared to controls. Consistently, adult Fmr1 KO mice exhibited normal gait metrics under baseline conditions. However, these mice displayed hyperactivity and performance deficits during more challenging motor tasks demanding higher coordination. These findings suggest that the fundamental locomotor circuitry is preserved in FXS, likely through compensatory mechanisms. Consequently, motor impairments in FXS may arise primarily from supraspinal or integrative circuit dysfunction, rather than intrinsic deficits in spinal CPG function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=148 SRC="FIGDIR/small/704392v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@19a64cborg.highwire.dtl.DTLVardef@14f8ad2org.highwire.dtl.DTLVardef@1230cbforg.highwire.dtl.DTLVardef@19fd51_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINeonatal Fmr1 KO spinal cords generated robust, coordinated locomotor rhythms similar to controls. C_LIO_LIAdult Fmr1 KO mice exhibited normal gait metrics during baseline, unskilled locomotion. C_LIO_LIFmr1 KO mice displayed hyperactivity and performance deficits during skill-demanding motor tasks. C_LIO_LIFXS motor impairments may arise primarily from supraspinal or integrative circuit dysfunction C_LIO_LISpinal cord circuitry appears to compensate for the fundamental loss of Fmr1 function. C_LI

Oligodendrocyte precursor cells (OPCs) are unique glial cells that communicate bidirectionally with neurons. Neuronal inputs drive various OPC behaviors, including proliferation and differentiation, immunomodulation, blood brain barrier regulation, synapse engulfment and axonal remodeling. OPCs are implicated in numerous stress and pain conditions, where their involvement is likely driven by neuronal activity (ie. neurotransmitter and neuropeptide signaling). One neuropeptide causally involved in chronic pain and stress conditions is calcitonin gene-related peptide (CGRP). Here, we tested the hypothesis that OPCs receive direct inputs from CGRP-containing neurons in the adult brain. Using RNAscope, immunofluorescence and analysis of single-cell datasets, we find that OPCs express receptors for CGRP and we identify close spatial contacts between CGRP and OPCs, with nearly half of CGRP puncta occurring within 1 {micro}m of an OPC. Some of these contacts appear to be synaptic, with CGRP-OPC contacts colocalizing with the presynaptic protein Bassoon and the postsynaptic protein PSD-95. This work suggests the presence of both diffuse and more direct forms of CGRP signaling to OPCs, raising the importance of future experiments to identify both the mode of CGRP release onto OPCs and the functional effects of these different contact types.