Neuroscience

Vesicular glutamate transporters 1 and 2 (VGluT1 and VGluT2) exhibit largely complementary distributions and have been proposed as molecular markers of descending modulatory and ascending driver-like pathways, respectively. However, this correspondence has rarely been tested directly in anatomically identified projections. We combined anterograde Phaseolus vulgaris leucoagglutinin tracing with simultaneous VGluT1 and VGluT2 immunofluorescence to characterize glutamatergic boutons arising from the primary and secondary visual cortices, lateral geniculate nucleus, lateral posterior thalamic nucleus, and superior colliculus in adult mice. Among 2,178 singly labelled boutons, VGluT1 predominated in corticothalamic, corticopontine, corticotectal, corticostriatal, and corticocortical feedback projections. Conversely, thalamocortical, tectothalamic, thalamostriatal, and tectopontine projections were almost exclusively VGluT2-positive. Projection direction did not fully predict transporter phenotype: ascending corticocortical projections remained predominantly VGluT1-positive, whereas the descending tectopontine projection was exclusively VGluT2-positive. Only 12 of 2,190 VGluT-immunoreactive boutons exhibited detectable VGluT1/VGluT2 colocalization. Morphometric analyses further revealed an interaction between VGluT isoform and projection direction. Within ascending projections, VGluT2-positive boutons and puncta were larger than their VGluT1-positive counterparts, whereas no isoform-related difference in bouton area was detected within descending projections. These findings demonstrate an association between VGluT phenotype and projection class in the mouse visual system. VGluT isoforms therefore provide informative markers of pathway organization, but neither transporter identity nor terminal size alone constitutes an invariant molecular indicator of projection direction or driver-modulator function.

We recently reported that rats performed better at a task distance of 2 m than at 0 m in a T-maze delayed alternation paradigm using a movable home cage in the longer-delay condition (Takita & Ichitani, 2026). We simultaneously recorded local field potentials from the bilateral prefrontal cortex, intermediate hippocampus, and ventral hippocampus. Across task epochs, coherence and two cross-frequency measures (phase-locking value and modulation index [MI]) revealed differences between correct and error trials in prefrontal interactions with hippocampal subregions. Among these measures, only MI was affected by task distance during the pre-task delay epoch. MI was highest in 2-m error trials and lowest in correct trials. In 0-m error trials, MI transiently increased during arm entry to levels comparable to those in 2-m error trials before declining toward the levels observed in correct trials during the later post-task delay. These MI dynamics appeared to be consistent with distance-dependent differences in behavioral performance. In addition, normalized Correct-Error Indices calculated for each electrophysiological measure revealed differential contributions of prefrontal coupling with the intermediate and ventral hippocampus across task distances. These findings suggest the existence of distinct near and far working memory states underlying distance-dependent behavioral differences, with distinct yet complementary contributions of the intermediate and ventral hippocampus to prefrontal interactions.

REV-ERB{beta} is a transcriptional repressor of nuclear receptors that regulates the circadian rhythm and plays an important role in regulation of the proliferation, differentiation, and maturation of neurons. Dysregulation of the circadian rhythm has been associated with neuropsychiatric disorders, and activation of REV-ERBs can induce anxiolytic behavior in mice. Furthermore, hippocampal neurogenesis is important in the effects of antidepressants. However, the role of REV-ERB{beta} in adult hippocampal neurogenesis in vivo at the single-cell level is not known. In this study, protein localization of REV-ERB{beta} in the subgranular zone of the hippocampal dentate gyrus (DG) was mainly shown in NeuN-positive neurons, and the effect of expressing a dominant negative form of REV-ERB{beta} lacking the C-terminal region on newborn neurons in the hippocampal DG of adult mice was examined to investigate the role of REV-ERB{beta} in neurogenesis. A retroviral vector containing the dominant negative REV-ERB{beta} or a control vector was injected into the mouse DG. At 4 weeks after injection, the morphology of dendrites and dendritic spines of newborn neurons labeled by the virus was examined. Expression of the dominant negative form of REV-ERB{beta} inhibited dendrite outgrowth and branching and decreased dendritic spine formation in newborn neurons in the adult mouse hippocampal DG. This study revealed a new role for REV-ERB&{beta} in adult hippocampal neurogenesis at the single cell level, and the results will provide insight into neurogenesis in the adult brain and its relationship with psychiatric disorders.

Axonal action potential propagation critically depends on tightly regulated intra and extracellular electrolyte concentrations and acid base homeostasis. Experimental studies have demonstrated that changes in extracellular sodium, potassium, and calcium concentrations alter axonal excitability and conduction properties. However, it remains unknown whether small variations in electrolyte concentrations within the physiological range are associated with measurable changes in nerve conduction velocity in humans. In this study, data from neurologically healthy children who underwent both nerve conduction studies and blood gas analysis were analyzed to investigate the relationship between electrolyte concentrations and median motor nerve conduction velocity. Nerve conduction velocity was significantly negatively correlated with ionized calcium concentration and positively correlated with sodium concentration, whereas no significant correlation was observed for potassium. In an a priori defined multiple linear regression model, ionized calcium, sodium, and bicarbonate remained significantly associated with nerve conduction velocity after correction for multiple testing. These findings indicate that even small variations in electrolyte concentrations within the physiological range are associated with measurable differences in peripheral nerve conduction velocity and suggest an additional contribution of acid base status to nerve conduction.

The ventral motor and the centromedian (CM) nuclei receive prominent GABAergic inputs from the basal ganglia, massive glutamatergic projections from motor cortices and significant GABAergic afferents from the reticular thalamic nucleus. There is strong evidence that disrupted processing of information through these connections may contribute to the pathophysiology of the basal ganglia-thalamocortical loop in Parkinson's disease (PD). To further assess potential ultrastructural changes in synaptic connectivity and mitochondrial integrity that may contribute to these network dysfunctions, we used a 3D electron microscopic approach to determine whether the pattern of synaptic innervation and morphological integrity of dendritic mitochondria are altered in the basal ganglia-receiving parvocellular ventral anterior nucleus (VApc) and CM neurons of MPTP-treated parkinsonian monkeys. Three main conclusions can be drawn from our findings: (1) Although the overall pattern of synaptic innervation of VApc and CM neurons is not altered in parkinsonian monkeys, the volume of putative corticothalamic terminals is significantly increased in both nuclei, (2) the prevalence of corticothalamic terminals in contact with distal dendrites is several orders of magnitude higher in VApc than CM in both control and parkinsonian monkeys, (3) the complexity and ultrastructural integrity of dendritic mitochondria is altered in CM, but not in the VApc, of parkinsonian monkeys. These findings lay the foundation for future studies of changes in cortical neuromodulation of VApc and CM neurons in parkinsonism and suggest that mitochondrial defects may contribute to the degeneration of CM neurons in PD.

Amacrine cells (ACs) are the most diverse neuron in the retina, with more than sixty different subtypes, each contributing to the detection of specific visual features. Despite their importance in visual feature detection, the genetic basis for this diversity is still not well understood. Recent single-cell transcriptomic datasets have identified several potential genes that may regulate cellular diversity, but the underlying mechanisms have not been investigated. For example, the transcription factor Meis2 is selectively expressed in the GABAergic subclass of ACs. In this study, we focused on how Meis2 regulates the development of GABAergic ACs. We hypothesized that Meis2 is required for specification and survival of GABAergic ACs. To test this, we used the Meis2 conditional knockout mouse (Meis2-CKO) where Meis2 was deleted from either the entire retina or specifically from AC precursor cells. The deletion of Meis2 led to a ~60% reduction in total GABAergic ACs in the retina. This loss of GABAergic ACs occurred only after postnatal day 5 (P5), suggesting Meis2 is not required for early specification but may be required for survival. To further investigate cell death and survival, we quantified cleaved caspase-3 positive cells in the retina at several developmental timepoints. In Meis2-CKO mice, we found an increase in cleaved caspase-3 immunolabeling at P5 and P6 timepoints coinciding with the reduction of GABAergic ACs. Further analysis of GABAergic AC subtypes demonstrated a subtype-specific cell death in Meis2-CKO retinas. For example, the total number of dopaminergic (TH) ACs were significantly reduced, whereas starburst (ChAT) ACs remained unchanged. These findings suggest that Meis2 is important for the survival of a subset of GABAergic AC subtypes in the mammalian retina. In addition, Meis2 may control the expression of specific survival factors that prevent apoptosis during developmental cell death in the retina.

Abstract Background: Long COVID frequently includes post-exertional malaise, neuromuscular fatigue, internal vibrations, tremor-like symptoms, orthostatic intolerance, sleep disturbance, cognitive dysfunction, and autonomic instability. Neuroimaging studies in Long COVID and post-infectious ME/CFS have identified abnormalities across limbic, thalamic, mesiotemporal, brainstem, cerebellar, and white-matter systems, but no single established circuit accounts for this clinical phenotype. We examined whether abnormalities cluster at the mammillary body-fornix-superior tuberal hypothalamic interface and within connected brainstem-cerebellar pathways. Methods: Structural MRI and diffusion tensor imaging were analysed in 88 participants with clinician-diagnosed Long COVID and 34 healthy controls (total N = 122). Thirty-three patients were classified as bedridden. Volumetric and diffusion analyses focused on the mammillary bodies, superior tuberal hypothalamic region, fornix, dorsal and median raphe, midbrain reticular formation, and cerebellar peduncles. Fractional anisotropy was used as an index of white-matter microstructural organisation. Exploratory clinical associations included motor impairment, proprioceptive dysfunction, autonomic symptoms, fatigue, internal vibrations, and tremor-like symptoms. Results: Three mammillary-body volume phenotypes were identified: reduced, enlarged, and control-range. Left and right mammillary-body volumes differed across groups, with large effect estimates. Segmentation showed narrowing or loss of a visible internal passage at the superior tuberal-mammillary interface, while the fornix showed altered diffusion measures and reduced tract coherence in the hypothesised gate region. Additional findings included lower superior cerebellar peduncle volume, lower middle cerebellar peduncle fractional anisotropy, and lower dorsal raphe and midbrain reticular formation volumes in Long COVID. Conclusions: The findings support an exploratory mammillary body-fornix gate model in which a vulnerable periventricular hypothalamic-limbic interface may contribute to network dysfunction in a subgroup of patients with severe Long COVID. The data do not establish direct viral invasion, a coronavirus entry route, axonal destruction, or a single causal pathway. Prospective replication with standardised acquisition, preregistered regions of interest, correction for multiple comparisons, objective movement and autonomic measures, and longitudinal follow-up is required. Keywords: Long COVID; post-COVID condition; ME/CFS; mammillary body; fornix; hypothalamus; diffusion tensor imaging; internal vibrations; tremor-like symptoms; neuromuscular fatigue; dysautonomia; brainstem

Axonal projections and precise synapse formation are essential for the establishment of functional neural circuits, and their dysregulation contributes to various psychiatric and neurodegenerative disorders. Although numerous extracellular cues secreted from surrounding tissues regulate axon guidance and synapse formation, the mechanisms by which neurons locally regulate terminal patterning within their projection fields remain poorly understood. Bone morphogenetic protein 4 (BMP4) is a classical morphogen that is involved in early neural tube patterning during development. However, its postnatal function remains unclear. Previous in vitro studies using hippocampal glutamatergic neurons demonstrated that BMP4 can act locally on axons to suppress synapse formation, raising the possibility that BMP4 regulates terminal differentiation after target innervation. Here, we investigated the role of BMP4 in postnatal cholinergic circuit development using cholinergic neuron-specific Bmp4 conditional knockout (Bmp4 cKO) mice, with adult analyses performed in males. Basal forebrain cholinergic neurons project extensively throughout the neocortex and are essential for higher brain functions, including arousal and attention. Bmp4 cKO mice exhibited increased cholinergic axon terminals in the neocortex, hippocampus, and amygdala, as well as increased axonal ramification in the neocortex without affecting cytoarchitectonic organization or cholinergic neuron numbers in the basal forebrain. These findings demonstrate that BMP4 functions as a negative regulator of cholinergic terminal formation and axonal arborization, suggesting that BMP4 may act locally to restrict cholinergic axonal expansion during neural circuit maturation.

Stress-related experiences alter glutamatergic signaling and neuronal excitability, but the mechanisms that couple experience to dentate granule cell function remain incompletely understood. Here, we examined how protein kinase N1a (PKN1a), a protein kinase C-like serine/threonine kinase, and repeated swim exposure regulate mouse hippocampal dentate granule cell excitability, with a focus on the neuronal glutamate transporter excitatory amino acid transporter 3 (EAAT3) and group I metabotropic glutamate receptors (mGluRs). Five days of repeated swim exposure increased spike firing in mature dentate granule cells from wild-type mice. PKN1a knockout produced a similar increase, and repeated swim did not further enhance firing in knockout mice. The enhanced firing observed after repeated swim exposure and in PKN1a knockout mice was reduced by co-application of an mGluR1 antagonist (LY367385) and an mGluR5 antagonist (MPEP). Inhibition of glutamate transporters with DL-TBOA increased granule cell firing in control wild-type mice but did not further increase firing in repeated-swim wild-type or PKN1a knockout mice, suggesting occlusion of transporter-dependent regulation of excitability. Repeated swim exposure and PKN1a knockout also reduced total and surface expression of EAAT3 in the hippocampus, whereas expression of the glial glutamate transporter EAAT2 was not significantly altered. Finally, PKN1a knockout and repeated swim exposure reduced anxiety-related behavior in the elevated plus maze test. Thus, PKN1a-dependent regulation of EAAT3 may restrain group I mGluR-dependent excitability in dentate granule cells, whereas repeated swim exposure and PKN1a knockout shift this system toward a lower-EAAT3, higher-excitability state accompanied by reduced anxiety-related behavior.

Astrocytes play an important role in neuronal health. A critical function of astrocytes is to clear excess extracellular glutamate and prevent excitotoxicity. STAT3 is a transcription factor that promotes astrocyte development and astrocyte reactivity in neurodegenerative diseases and following central nervous system injury. To determine the innate molecular and behavioral functions of adult astrocyte-expressed STAT3 in a non-pathological state, we created conditional Stat3 astrocyte knockout mice (Stat3 aKO) using Stat3flox and the tamoxifen-activated Cre line, Aldh1l1-Cre/ERT2. We measured transcript levels of Gfap, a known STAT3 target gene, and glutamate transporter genes in the medial prefrontal cortex (PFC) of Stat3 aKO. Gfap, Slc1a2 and Slc17a8 transcripts were decreased in the PFC of Stat3 aKO of both sexes. GLT-1 protein, encoded by Slc1a2, was also reduced in the PFC of male Stat3 aKO. We recorded spontaneous excitatory post-synaptic currents (sEPSCs) in male Stat3 aKO and control prelimbic pyramidal neurons and found increased sEPSC amplitude, consistent with a hyper-glutamatergic state due to impaired glutamate clearance. To determine the behavioral consequences of STAT3 depletion in astrocytes, Stat3 aKO were tested for locomotor activity, anxiety-like behavior and binge ethanol consumption, behaviors linked to dysregulation of glutamate homeostasis. Stat3 aKO mice did not differ in locomotor activity or anxiety-like behavior; however, male Stat3 aKO mice consumed significantly less ethanol than controls. These results indicate that STAT3 in adult astrocytes is crucial for maintaining glutamate transporter levels in the adult brain and that astrocytic STAT3 promotes ethanol consumption in male mice. Main pointsO_LIGfap, Slc1a2 and Slc17a8 expression are lower in the cortex of Stat3 astrocyte knockout mice (Stat3 aKO) C_LIO_LIGLT-1 protein is decreased and glutamate neurotransmission is elevated in the cortex of male Stat3 aKO C_LIO_LIMale Stat3 aKO consume less ethanol C_LI

Long-latency stretch reflex and corticospinal excitability in the tibialis anterior muscle (TA) are facilitated when balance is threatened, even without background TA activity, suggesting supraspinal modulation as preparatory tuning for ankle stabilization. However, it remains unclear whether such tuning is evident at the spinal level and specific to the TA among lower-limb muscles. We therefore examined the effects of height-induced postural threat on multi-segmental monosynaptic spinal reflexes (MMR) in lower-limb muscles during quiet standing. Seventeen healthy young males performed 90-s standing tasks under three postural threat conditions, created by combining real and virtual reality (VR) heights: (1) Low-threat (real ground & VR ground), (2) Medium-threat (real table & VR ground), and (3) High-threat (real table & VR bridge). During each condition, transcutaneous spinal cord stimulation (tSCS) was applied to the lumbar spine to elicit MMR in lower-limb muscles. Electromyograms (EMG) were recorded from six muscles of the right leg: vastus medialis (VM), biceps femoris (BF), TA, soleus (SOL), medial (MG), and lateral gastrocnemius (LG). MMR excitability was quantified as peak-to-peak EMG amplitude. Fear ratings and electrodermal activity were higher in High-threat than Low-threat (all p < 0.05), confirming successful threat induction. Peak-to-peak EMG amplitude in the TA was significantly higher in High-threat than Low-threat (17.1% increase, p = 0.0393), whereas background TA activity remained absent across conditions. These results indicate that TA has unique function to facilitate spinal excitability as a preparatory tuning for ankle stabilization. Key pointsO_LIPrevious studies have shown the supraspinal facilitation of the tibialis anterior muscle without background muscle activation as a preparatory tuning for ankle stabilization. C_LIO_LITo test the hypothesis that such tuning is also evident at the spinal level and specific to the tibialis anterior muscle, this study examined whether height-induced postural threat modulates multi-segmental monosynaptic reflex excitability in lower-limb muscles using transcutaneous spinal cord stimulation. C_LIO_LIElectrodermal activity and fear ratings increased under height-induced postural threat, confirming the successful induction of postural threat. C_LIO_LIUnder height-induced postural threat, the multi-segmental monosynaptic reflex was selectively facilitated in the tibialis anterior muscle, while its background activity remained absent. C_LIO_LIOur findings demonstrate selective facilitation of spinal excitability in the tibialis anterior muscle, which may serve as preparatory tuning for ankle stabilization under threat to balance. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=147 SRC="FIGDIR/small/742625v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@ca21f3org.highwire.dtl.DTLVardef@7b1679org.highwire.dtl.DTLVardef@1007191org.highwire.dtl.DTLVardef@1ff88a_HPS_FORMAT_FIGEXP M_FIG C_FIG Abstract figure legendWhen balance is threatened, corticospinal excitability and long-latency stretch reflex in the tibialis anterior muscle (TA) are facilitated even in the absence of background TA activity, suggesting supraspinal preparatory tuning for ankle stabilization. This study tested the hypothesis that such facilitation is also expressed at the spinal level and is specific to the TA. Participants completed 90-s quiet standing trials under three different height-induced postural threat conditions. During each trial, transcutaneous spinal cord stimulation was delivered over the lumbar spine to elicit multi-segmental monosynaptic reflexes (MMR) in multiple lower-limb muscles. High-threat condition increased fear ratings and electrodermal activity, indicating successful threat induction. Moreover, MMR excitability was selectively increased in the TA under High-threat condition despite the absence of background TA activity. These findings suggest that spinal facilitation is selectively expressed in the TA and may reflect preparatory tuning for ankle stabilization under threat to balance.

Tourette Syndrome (TS) is a neurodevelopmental hyperkinetic disorder characterised by involuntary tics. These tics are thought to arise due to hyperexcitability of the motor cortex due to disinhibition within the cortico-striato-thalamo-cortical pathway. Given the involvement of motor circuits in this disorder, we explored whether there is a difference in the oscillatory dynamics of voluntary movements in people with tic disorders. We recorded optically pumped magnetometer magnetoencephalography during cued voluntary finger abductions in individuals with tic disorders and age- and sex-matched neurotypical controls. We analysed the data both using conventional time frequency analysis and using hidden Markov modelling to explore the difference in beta burst characteristics and dynamics. Whilst no differences were seen between groups during conventional analysis, we demonstrated an increase in beta burst duration during the post-movement beta rebound within the contralateral motor cortex in individuals with TS suggestive of increased inhibition following movement. We also show evidence of increased contralateral sensorimotor functional connectivity and reduced connectivity from and between frontal regions, as measured using coincident beta bursts. This is suggestive of disrupted functional connectivity within frontal control networks in individuals with TS.

Unipolar brush cells (UBCs) are excitatory interneurons that have a characteristic dendritic brush that amplifies and extends incoming signals in the cerebellum. UBCs transform synaptic input through their ionotropic and metabotropic glutamate receptors. Differential regulation of receptor subunits is a critical developmental process, but how the expression of glutamatergic receptors changes in UBCs as they develop is unclear. NMDA-type glutamate receptors (NMDARs) are particularly important for development and plasticity. We examined the expression of NMDAR subunits during development and tested whether signaling through these receptors is necessary for the development of the elaborate dendritic structure and unusual synaptic function of UBCs. Whole-cell patch clamp recordings from UBCs in acute brain slices revealed tonic and synaptic NMDAR-mediated currents in early postnatal UBCs that decrease during development. RNAscope in situ hybridization revealed differential developmental regulation of GluN2C/D subunits. Cell-type specific constitutive NMDAR knockout had no apparent effect on dendritic brush development, but increased UBC number in adulthood, suggesting a role in programmed cell death. Both pharmacological blockade or genetic deletion of NMDARs produced a paradoxical increase in excitability, which was calcium dependent and was occluded by inhibition of calcium activated potassium channels. Thus, NMDA receptors are dispensable for migration and dendritic development but may be involved in cell death pathways. Their functional roles include synaptic signaling as well as providing a tonic calcium flux that dampens excitability in developing UBCs and may influence transformations of vestibular signals essential for smooth movements and balance.

Preventing object slippage requires the central nervous system to control and coordinate the muscle groups while adapting to the variations in the slip characteristics. Our study investigates how slip characteristics, such as slip direction, slip distance, and slip speed, affect the modulation of muscle synergies as a manifestation of object slippage. Our results reveal that there are shared synergies existing in the upward and downward slip emulation, and that these shared synergies are dependent on slip characteristics. However, there were no specific synergies found to exist in the upward and downward slip conditions. Our results also indicate the existence of combined synergies, as the motor modules in the upward slip direction were found to have shared synergies with multiple motor modules in the downward slip direction. We also observed that the number of shared synergies varied depending on the slip distance and slip speed. Together, these findings suggest that the CNS flexibly reconfigures a limited set of muscle synergies to accommodate varying slip dynamics, balancing control stability with adaptability.

The cerebellar nuclei (CN) has demonstrated its influence on cognitive behavior via the cerebello-cortico circuit, yet the role of CN critical period mechanisms and how they may influence cognitive behavior, such as parvalbumin (PV) expressing interneurons enwrapped by perineuronal nets (PNNs), is still unclear. Therefore, we investigated the role of the lateral CN (LCN) PV cell calcium activity while animals performed a visual discrimination touchscreen cognitive task. All animals received the PV cell calcium indicator GCaMP6f at postnatal day 21 (P21). We targeted the LCN critical period by manipulating neural activity in male mice using the inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) from postnatal day 21 to 35 or by injecting an Hapln1-AAV vector to selectively target LCN PNN development. After animals completed the visual discrimination task, cerebellar tissue was collected for viral recovery and antibody staining for PNN components, Hapln1 and aggrecan. Results revealed DREADD animals showed improved reversal learning, an increase in calcium response to learning-related activity and altered PNN expression (Hapln1 and aggrecan). Hapln1 treated animals displayed a decrease in final day acquisition performance, lower reversal performance compared to DREADD groups, a decrease in reversal calcium learning-related activity, and an increase in PNN expression (Hapln1). Together, these data provide further evidence of LCN mechanisms associated with learning as well as the importance of understanding region-specific critical periods of plasticity.

Beat perception, the ability to perceive and anticipate a regular pulse in music, is thought to depend on the basal ganglia. Dopaminergic signaling is a candidate mechanism given its prominence in basal ganglia circuitry and established function in encoding temporal predictions. Parkinson's disease (PD) provides a model for studying dopaminergic contributions to beat perception. To test the hypothesis that higher dopaminergic tone is associated with better beat perception, we conducted a study in PD patients (n=55) and matched controls (n=53). Participants performed a musical beat perception task, the Beat Drop Alignment Test (BDAT). They also completed a non-timing control task measuring musical pitch perception, the Mistuning Perception Test (MPT). We identified a double dissociation in PD patients: daily dopamine dose was associated with beat perception (r=.37, p=.005) but not pitch perception (r=.12, p=.397), while musical background was associated with pitch perception (r=.55, p<.001) but not beat perception (r=.16, p=.236). Results remained consistent when controlling for disease duration and age. This dissociation suggests the effect of dopamine is specific to beat perception and not reflective of a general improvement in auditory processing. High-dopamine patients outperformed both low-dopamine patients and age-matched controls, and this difference was driven by better detection of on-beat than off-beat events. Together, these results suggest that dopamine is associated with enhanced beat perception, potentially through modulation of temporal attention to expected beat times.

The cerebellum supports a wide range of motor and non-motor behaviors, yet the specific cerebellar regions and neuronal populations underlying this functional diversity remain poorly understood. Here, we mapped patterns of immediate early gene activation in the cerebellar cortex during the accelerating rotarod task, an established form of cerebellum-dependent motor learning. Using the immediate early gene c-Fos to identify cells active during the task, we found significantly greater activation throughout the vermis and in crus I of the hemispheres, specifically within the molecular and granule cell layers, compared to naive controls. However, a second control group, which was exposed to the rotarod apparatus but not placed on the rotating rod, revealed similar patterns of c-Fos expression, suggesting that novelty contributed substantially to the observed activation. To separate this potential novelty signal from the motor component of the task, mice were habituated to the apparatus prior to testing. This habituation resulted in an overall decrease in c-Fos expression across cerebellar lobules, with significant motor activity-related differences found in the anterior vermis. Finally, to determine how learning influences c-Fos expression patterns, mice were subjected to a multi-day motor learning paradigm in which genetic tagging of c-Fos-expressing neurons was performed on day 1, followed by c-Fos immunostaining on day 5. We found that, in mice that had learned the task, there was no significant increase in c-Fos signal above naive controls, indicating that rotarod task performance no longer recruited the same level of cerebellar cortical activity, consistent with a potentially reduced role for the cerebellar cortex once the task is well learned. Overall, these findings reveal distinct patterns of activation associated with novelty, motor behaviour, and learning, providing a framework for linking behavior to regional cerebellar function.

The sodium leak channel NALCN regulates resting membrane potential and spontaneous firing in neurons and can be modulated by G-protein coupled receptors (GPCRs). Whether metabotropic glutamate receptors (mGluRs) modulate NALCN is unknown and would represent a novel mechanism through which glutamate could affect neuronal excitability. Here we examine NALCN function and modulation by mGluRs in cerebellar unipolar brush cells (UBCs) in mouse brain slices. Activation of group II mGluRs inhibited the NALCN current through a G protein-dependent mechanism, as the effect was abolished by intracellular GDP-{beta}-S and by NALCN deletion. The OFF UBC subtype that is inhibited by glutamate had a larger NALCN current than the ON UBC subtype that is excited by glutamate. OFF UBCs also had a tonic NALCN current that was absent in ON UBCs. Genetic deletion of NALCN converted the regular spontaneous firing pattern of OFF UBCs, to an irregular pattern similar to that of ON UBCs, suggesting that a tonic NALCN current may be a general mechanism to promote regular firing. Additionally, we identify the presence of group III mGluRs in OFF UBCs and GABA-B receptors in ON UBCs and show that neither inhibit NALCN, demonstrating that different GPCRs engage distinct downstream ion channels. These findings identify a previously unrecognized form of glutamatergic synaptic inhibition that is selectively initiated by group II mGluRs, but not other Gi/o-coupled GPCRs, within the same neurons.

Background: Detecting environmental regularities is a sophisticated cognitive skill, but its neural basis remains unclear. We tested whether corticospinal excitability tracks stimulus predictability, prediction errors, and task progression while the participants played the Goalkeeper Game. Methods: Sixteen right-handed males (24.4 +/- 6.8 years) saved penalty kicks using index, middle, or ring fingers (left, center, right). Kick sequences were generated by a context tree model, in which contexts represent the minimum recent history required to predict the next event. Participants completed 1,200 trials (6 blocks x 200 trials each). Transcranial magnetic stimulation (TMS) delivered 400 ms before the go signal elicited motor evoked potentials (MEPs) in the first dorsal interosseous (FDI) and flexor digitorum superficialis (FDS) muscles during blocks 2, 4, and 6. Contexts were classified as unpredictable (1, 10) or predictable (2, 20, 00); prediction errors were defined for non-deterministic transitions after context 1. Log-MEPs were analyzed using mixed-effects models. Results: In FDI, a Predictability x Previous-Error x Block interaction emerged (F(2,8997)=6.89, p=.001), confined to the final block. Predictability increased MEP amplitudes after successful transitions (+6.3%; p=0.006) but decreased MEP amplitudes after failed transitions (-7.0%; p=0.007). For FDS, unpredictable trials elicited larger MEPs (+7.2%; p=0.002), and MEPs increased from block 2 to 6 (+16.8%; p=0.003). Conclusions: FDS MEP responses were broadly associated with uncertainty and task progression, whereas FDI MEP responses showed context-specific, error-dependent modulation after extended exposure, suggesting fine-grained predictive coding in goal-executing effectors.

The functioning of neuronal networks critically depends on the coordinated interaction between excitation and inhibition. The properties of glutamatergic and GABAergic synapses are finely tuned by network activity, and the heterosynaptic nature of inhibitory plasticity further emphasizes their functional coupling. Although the dependence of glutamatergic plasticity on protein synthesis is well established, the role of translation in inhibitory plasticity remains unclear. Herein, we investigated how protein synthesis supports the concurrent plasticity at inhibitory and excitatory inputs onto CA1 pyramidal neurons. To this end, we applied a high-frequency stimulation protocol of CA3-CA1 input combined with prolonged postsynaptic depolarization of principal cells. This induced both glutamatergic long-term potentiation (LTP) and inhibitory LTP (iLTP) at synapses formed by somatostatin-expressing interneurons onto pyramidal neurons. Although LTP was observed in slices from both juvenile ([&le;]45 days) and adult (>45 days) mice, iLTP was only present in the adult group, revealing an unusual developmental profile. Moreover, in adult animals, excitatory LTP was required for the induction of iLTP but did not determine its magnitude. We found that bath application of translation inhibitor cycloheximide (CHX) strongly attenuated LTP and converted co-occurring iLTP into iLTD. However, when CHX was restricted to the recorded postsynaptic neuron, the initial phase of iLTP proceeded normally, but GABAergic currents gradually returned to baseline levels, indicating intact induction but impaired maintenance. In contrast, postsynaptic CHX left excitatory LTP unaffected. Together, these findings identify two distinct translational mechanisms: a postsynaptic one necessary for strengthening inhibition and a non-postsynaptic process required to potentiate excitation.