Neuroscience最新文献

Brief, discrete sounds such as tone pips or clicks evoke transient, time-locked EEG changes known as evoked responses, revealed through averaging across trials. Steady-state potentials arise from averaging responses to trains of tones or clicks delivered at a specific frequency. Prior modeling and empirical work have suggested that the 40 Hz auditory steady-state response (ASSR) reflects the summation of back-to-back discrete evoked responses. An alternative view proposes that the ASSR represents frequency-specific endogenous entrainment of the oscillating field potential of the brain. Supporting this, only frequencies near the natural resonance of cortical regions reliably entrain oscillations, that emerge gradually over hundreds of milliseconds and often persist beyond stimulus offset. In this study, we used a pharmacological approach to directly compare tone-evoked responses and the 40 Hz ASSR, hypothesizing that if the ASSR simply reflects repeated evoked responses, drug effects should be similar across the two measures. We tested two compounds, MK-801 and clozapine, which are known to modulate the 40 Hz response in opposite directions. While both drugs produced robust effects, these were largely uncorrelated across measures. Our findings suggest that tone-evoked responses and the 40 Hz ASSR engage distinct and partially non-overlapping cortical networks. We further speculate that transient responses such as tone-evoked N1 are primarily driven by rapid feedforward transmission, whereas 40 Hz oscillations emerge from recurrent network activity that builds up gradually. Their established cross-species translational utility and strong but uncorrelated pharmacological responsiveness establish the two measures as largely independent pharmacodynamic biomarkers for drug development.

The inferior colliculus (IC) integrates auditory information through a complex interplay of excitatory and inhibitory neurons, and provides both excitatory and inhibitory inputs to the medial geniculate body (MGB). Although IC projection neurons are predominantly glutamatergic, accumulating evidence suggests that they comprised heterogeneous subpopulations with distinct morphological and functional properties. Somatostatin (SST)-expressing neurons represent one such glutamatergic subpopulation; however, their characteristics and circuit organization remain poorly understood. In this study, we examined the projection domains within the MGB and the local circuits of SST-expressing neurons in the IC. SST-expressing neurons in the central nucleus of the IC (CNIC) project mainly to the ventral division of the MGB (MGv) and posterior limiting nucleus (POL), whereas those in the external (ECIC) and dorsal (DCIC) nuclei primarily target the POL. The SST axon terminals in the MGv were large, formed clusters, and positive for cholecystokinin (CCK), whereas those projecting to the POL were small, non-clustered, and CCK-negative. The local axons of SST-positive neurons in the IC formed vesicular glutamate transporter 2-positive basket-like terminals around large γ-amino butyric acid (GABA)-ergic neurons, a hallmark morphological profile of GABAergic projection neurons to the MGB. This finding indicates that SST-expressing neurons provide strong excitatory input to these inhibitory projection neurons. Collectively, our results show that IC SST-expressing neurons shape thalamic processing not only through direct excitatory inputs to the MGv and POL, but also indirectly via strong excitation of local GABAergic projection neurons, thereby positioning SST neurons as key regulators of IC-MGB communication.

Background: Secondary spinal cord injury (SCI) involves intense neuroinflammation driven by pyroptosis and damage-associated molecular patterns (DAMPs). Targeting NINJ1, an executioner protein for plasma membrane rupture, may break this cycle.

Methods: A mouse contusion SCI model was used, with groups including Sham, Vehicle, Methylprednisolone, and low/high-dose NINJ1 monoclonal antibody (mAb). Functional recovery was assessed by BMS scoring and gait analysis. Histopathology and molecular changes (neuronal survival, pyroptosis proteins GSDMD/NLRP3/Caspase-1, microglial polarization markers, and related pathways) were analyzed at 14 dpi. HMGB1 release was quantified. An in vitro co-culture model of glutamate-injured HT22 neurons and BV2 microglia validated the effects.

Results: NINJ1 mAb treatment significantly improved motor function and reduced pathology versus controls. It enhanced neuronal survival, suppressed pyroptosis executers (GSDMD, while NINJ1 mRNA expression remained unchanged), and decreased HMGB1 release. The treatment shifted microglial polarization from pro-inflammatory M1 to anti-inflammatory M2, correlating with reduced nuclear p-NF-κB p65 and increased p-STAT3. In vitro, NINJ1 mAb directly protected neurons and suppressed microglial M1 polarization and pro-inflammatory cytokine release.

Conclusion: The NINJ1 monoclonal antibody promotes recovery after SCI by inhibiting pyroptotic membrane rupture, reducing DAMP release, and modulating microglia toward an anti-inflammatory phenotype, presenting a novel therapeutic strategy.