Neuroscience bulletin最新文献

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.

Circadian rhythms are present in various species, and circadian rhythm disorder (CRD) affects people of all ages, especially those with age-related neurodegenerative diseases. Gut microbiota, which changes with age, also exhibits circadian rhythms. Disruption of gut microbial balance can trigger neurodegenerative diseases. This study explored the link between aging, CRD, and gut microbes by modeling CRD through light/dark cycle control. We found that aging worsened cognitive and mood disorders, along with gut microbial imbalance, intestinal barrier damage, and systemic inflammation in aged mice with CRD. Abnormal circadian gene expression increased oxidative stress. However, time-restricted feeding (TRF) improved CRD effects in aged mice by boosting Akkermansia muciniphila and inhibiting the NOD-like signaling pathway. This study shows that older mice exhibit increased behavioral and functional issues under CRD-related stress due to complex causes like systemic inflammation from a proinflammatory gut microbiome and oxidative stress from disrupted circadian genes. Maintaining a regular eating schedule significantly alleviates these CRD-induced issues in aged mice.

Schizophrenia (SCZ) is a severe mental illness influenced by gene-environment interactions (GEI). However, little is known about how GEI mediates SCZ. The present study aimed to examine the underlying mechanism of SCZ mediated by GEI. We found that a single environmental factor (two-week adolescent social isolation) or genetic factor (the heterozygous Rims1 knockout mice) did not induce SCZ-like behaviors. Interestingly, two-week adolescent social isolation successfully caused SCZ-like behaviors in heterozygous Rims1 knockout mice, which can be rescued by anti-SCZ drugs. RNA-seq analysis further revealed that synaptic vesicle-related biological processes and target genes were enriched in the hippocampus of GEI animal model mice, which was accompanied by disturbed excitatory synaptic neurotransmission. Finally, the Nrg1 gene was decreased in our RNA-seq analysis, and supplementation of Nrg1 ameliorated SCZ-like behaviors in heterozygous Rims1 socially isolated mice. Our findings establish a novel GEI animal model and offer a potential therapeutic target in the treatment of SCZ.

Effective use of brain-computer interfaces (BCIs) requires the ability to suppress a planned action (volitional inhibition) for adaptable control in real-world scenarios, but their mechanisms are unclear. Here, we used fiber photometry to monitor external globus pallidus (GPe) and subthalamic nucleus (STN) neurons' activity in mice during a volitional stop-signal task (67% GO, 33% NO-GO). GPe/STN neurons (receiving M2 projections) responded to auditory cues, feedback, and rewards in both trials. Importantly, chemogenetic activation of the M2-GPe pathway enhanced volitional inhibition by modulating auditory feedback response, yet inhibited GPe neurons' feedback response. Furthermore, time-locked optogenetic inhibition of M2-projecting GPe neurons at auditory feedback also enhanced volitional inhibition via prolonged GO trial response times. Collectively, these findings identified the M2-GPe pathway for auditory biofeedback to improve volitional control, offering novel avenues for the advancement of neural interfaces for biofeedback and enhancement of BCI efficacy.