Neuroscience bulletin最新文献

Ultrasound neuromodulation shows promise for treating neurological disorders, but the underlying mechanisms remain unclear. Here, we developed an integrated surface acoustic wave (SAW) ultrasound chip enabling simultaneous electrophysiological recording and Ca²⁺ imaging of cultured hippocampal neurons to investigate neuronal excitability and synaptic transmission during ultrasound stimulation. This study revealed, for the first time, three distinct neuronal response patterns induced by SAW ultrasound: an immediate response showing rapid activation, a delayed response exhibiting facilitation after several minutes, and a non-response maintaining baseline activity. Ultrasound stimulation increased action potential firing, enhanced excitatory postsynaptic currents, and elevated intracellular Ca²⁺ levels. These effects were dependent on extracellular Ca²⁺ influx and primarily dominated by L-type Ca²⁺ channels. Our findings suggest that individual neurons exhibit heterogeneous responses to SAW ultrasound stimulation based on their intracellular Ca²⁺ levels and L-type Ca²⁺ channel activity. This integrated approach provides new insights into the cellular mechanisms of ultrasound neuromodulation while highlighting the potential of SAW technology for precise, cell-type-specific neural control.

Cerebral ischemia restricts cerebral blood flow (CBF), leading to unstable hemodynamics. Past studies of ischemia mainly focused on cortical CBF reduction. However, its impact on hemodynamic changes, especially temporal varying characteristics, remains poorly understood. Here, we collected cortical resting-state CBF in rats with left carotid artery blockage during occlusion-reperfusion, and measured the temporal variability and changes in laterality using a novel state-space method. This method was also applied to stroke EEG datasets to validate its effectiveness. After arterial occlusion, the left marginal motor, sensory, auditory, and visual cortices exhibited severe temporal variability impairments. The laterality analysis indicated that affected left regions showed inferior unilateral mean, inter-hemispheric transition probability, time fraction, and laterality duration, while the right side had a higher laterality time fraction and duration. These impairments recovered partially following blood flow restoration. Besides, the ischemic state-space metrics were positively correlated with the pre-occlusion baseline appearance. Stroke patients exhibited impaired temporal variability in the affected ischemic hemisphere. The state-space analysis revealed damaged CBF temporal variability during cerebral ischemia and predicted baseline-ischemia connections.

Early intervention in neuropathic pain can effectively delay its chronicity. Sigma non-opioid intracellular receptor 1 (SIGMAR1) is upregulated in the spinal dorsal horn during the development of spared nerve injury (SNI)-induced neuropathic pain. Methylated RNA immunoprecipitation confirmed that the SIGMAR1 upregulation was driven by mRNA N⁶-methyladenosine (m⁶A) modification. Intrathecal injection of the SIGMAR1 antagonist or siRNA effectively alleviated mechanical allodynia during the development of neuropathic pain. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) and co-immunoprecipitation experiments revealed that SIGMAR1 directly binds to neuronal pentraxin-1 (NPTX1), promoting its ubiquitin-proteasome degradation. Intraspinal injection of adeno-associated virus (AAV) to specifically overexpress NPTX1 in neurons alleviates SNI-induced neuropathic pain, whereas NPTX1 knockdown reduces the mechanical pain threshold in naive male mice. Furthermore, bioinformatics predicts that NPTX1 binds the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). Downregulation of NPTX1 promoted AMPAR membrane trafficking and central sensitization. Collectively, SIGMAR1, a potential therapeutic target for early-stage neuropathic pain, promotes AMPAR-mediated hyperexcitability of nociceptive neurons through interacting with NPTX1 in male mice.

The basic helix-loop-helix transcription factors, Neurog1 and Neurod1, orchestrate spiral ganglion neuron (SGN) differentiation in the embryonic cochlea. Their knockout leads to profound SGN and hair cell (HC) loss, cochlear truncation, and hearing impairment. To investigate SGN diversification and lineage origins, we generated three knock-in mouse strains: Neurod1-Cre, Neurod1-iCreER, and Neurog1-iCreER. In Neurod1-Cre; Rosa26-LSL-tdTomato (Ai9) mice, in addition to SGNs, tdTomato⁺ HCs and supporting cells were observed, displaying an apical-to-basal gradient. Tamoxifen induction at embryonic day 7.5 (E7.5) also labeled HCs in Neurog1-iCreER/iCreER; Ai9/+ mice at E18.5. Notably, a pure population of SGNs was traced in Neurod1-iCreER/+; Ai9/+ mice with tamoxifen administration from E7.5 to postnatal day 0 (P0). Dose standardization further enabled maximal SGN labeling upon induction at E12.5. These results illuminate the progenitor origins and developmental trajectories of SGNs and HCs, and establish a functional genetic tool for sorting and conditional manipulation of SGNs in auditory research.

The bladder is essential for the body's fluid balance to ensure normal physiological conditions; thus, a non-pathological bladder-that is, one sustaining internal homeostasis-is critical for this function. However, the neuro-network maintaining the bladder's intrinsic homeostasis is much less well-known compared with that for urination. Here, we identified that vagal nodose ganglion-pseudounipolar neurons project down to the bladder, up to the nucleus of the solitary tract, and further to multiple brain regions. The components of this network and those revealed by direct tracing from the bladder with herpes simplex virus (HSV) have significant overlaps and differences. Chemogenetic activation coupled with functional magnetic resonance imaging (fMRI) and c-Fos staining verified that the components in the vagal network were functionally connected. Strikingly, this vagal network did not include the primary motor cortex (M1), suggesting a role distinct from conscious urination control, and a cystitis model therefore revealed its potential role in transmitting bladder inflammation. Taken together, we have identified a non-spinal bladder-brain network not for urination but potentially for homeostasis of the bladder itself.

Neuropathic pain arises from a primary lesion or disease affecting the somatosensory system; however, the brain circuitry underlying the regulation of neuropathic pain remains unclear. The red nucleus (RN) is a critical brain region involved in regulating muscle tension, coordinating movement, and facilitating sensorimotor integration. While some evidence has shown that RN regulates pain, its specific role in neuropathic pain and associated neural circuits remains elusive. In this study, we found that CaMKIIα-positive neurons in the magnocellular red nucleus (RMC^CaMKIIα) were activated following common peroneal nerve (CPN) ligation-induced chronic neuropathic pain in adult male mice. Interestingly, chemogenetic and optogenetic inhibition of these RMC^CaMKIIα neurons alleviated the thermal hyperalgesia and mechanical allodynia in the neuropathic pain model mice, whereas activation of these neurons sufficiently induced the mechanical allodynia and thermal hyperalgesia in naïve mice. Trans-synaptic viral tracing studies further revealed that long-range CaMKIIα⁺ neuron projections from RMC to the dorsal horn (DH) facilitated the neuropathic pain-like behaviors following CPN ligation. DH neurons received direct innervation from RMC^CaMKIIα neurons, and inhibition of RMC^CaMKIIα-DH^CaMKIIα circuits alleviated the neuropathic pain in the ligated mice. Taken together, these results identify a novel long-range excitatory neural circuit from RMC to DH that facilitates the neuropathic pain-like behaviors in adult male mice, providing a new target for neuropathic pain treatment.

Spiral ganglion neurons (SGNs) play a crucial role in auditory signal transmission, and their degeneration is a significant factor in hearing loss. The protection of SGNs remains a central focus in auditory neuropathy treatment, while repairing their surrounding myelin sheaths has often been underestimated. To better simulate the cochlear neural microenvironment and enhance regenerative therapy, we developed a regenerative strategy using mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) combined with a biomimetic 3D cochlear culture system. Our results demonstrate that MSC-sEV significantly promotes Schwann cell migration and proliferation, thereby supporting the structural integrity and trophic environment essential for SGN function. Simultaneously, MSC-sEV treatment markedly enhances SGN survival, axonal outgrowth, and neural network reconstruction within the 3D culture model, mimicking the in vivo cochlear microenvironment. Importantly, in an ouabain-induced auditory neuropathy model, MSC-sEV administration attenuated neuronal loss, preserved SGN-hair cell connectivity, and facilitated functional recovery. By targeting both SGNs and their myelin sheaths, this dual-action strategy effectively reconstructs the neuroglial functional unit, fostering a regenerative microenvironment for auditory circuit repair.

AMPA receptors mediate the majority of excitatory synaptic transmission in the central nervous system, and are essential for LTP/LTD through insertion into/removal from postsynaptic density. Experimental manipulation (pharmacological, genetic) of AMPA receptors affects synaptic plasticity and has important implications for learning and memory and neurological diseases. We found that bilateral expression of the GluA1 C80 peptide in the dorsal hippocampus CA1 region acutely blocked endogenous GluA1 function, significantly affected the synaptic plasticity, which led to impairments in short-term spatial memory but not long-term spatial memory in mice. Mechanistically, our results revealed that the GluA1 C80 peptide might impair LTP and short-term spatial memory through interference of the binding between GluA1 to 4.1N. Our study suggests that the GluA1 C80 peptide could serve as a useful tool for acute manipulation of endogenous AMPA receptors in a brain region-specific manner in vivo.

Working memory (WM) temporarily holds and processes information, with its precision decreasing as load increases. Although retro-cues enhance WM precision by focusing attention on relevant items, neural mechanisms driving this effect across varying loads remain unclear. We recorded electroencephalography (EEG) signals during two experiments where participants performed a retrospective-cue WM task under low and high loads. We found that retro-cues significantly enhanced recall precision and sped response times, with larger precision benefits under high load. Alpha (8-12 Hz) activity showed load-dependent attentional modulation during retention, including later delayed desynchronization (ERD) and prolonged lateralization modulation index (MI) under higher load. Under high load, the retro-cues caused slower theta frequency, suggesting phase coding mechanisms in WM. Inverted encoding model (IEM) results revealed more precise mnemonic representation under low load, supporting less noise and more refined encoding. These findings highlight WM adaptive nature, flexibly adjusting to changing cognitive demands through dynamic attentional control.

Brain state-dependent transcranial magnetic stimulation (TMS) synchronizes with instantaneous power and is a novel time-precise neuroregulation approach. The key to this approach is using instantaneous power to reliably estimate specific cortical excitability. However, the specific influence of instantaneous power, particularly aperiodic brain activity, on corticospinal excitability is not fully understood. In our study, single-pulse TMS stimulated the primary motor cortex at 110% resting motor threshold (RMT) and 120% RMT, and the electroencephalography and motor-evoked potentials (MEP) were recorded simultaneously. We conducted a five-part analysis, including total power, periodic power, aperiodic power, the aperiodic exponent, and offset, to evaluate the power dependence of corticospinal excitability. We found that the higher the alpha and beta power were, the greater the MEP amplitudes were. The aperiodic component plays a more critical role than the periodic component. Furthermore, corticospinal output was less affected by power at 120% RMT than at 110% RMT. Our findings highlight that the aperiodic component is associated with cortical excitability and may be a valuable parameter for optimizing brain-state-dependent TMS approaches.