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.

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.

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.

Melatonin deficiency in Parkinson's disease (PD) patients correlates with impaired glymphatic function as measured by diffusion tensor imaging along the perivascular space (DTI-ALPS) index, suggesting circadian-regulated waste clearance as a therapeutic target. Unlike previous studies focusing on agomelatine's (AGM) antidepressant and sleep-regulating properties, we demonstrate its novel mechanism in PD treatment through glymphatic enhancement. Retrospective clinical analysis of PD patients revealed that AGM administration restored glymphatic function and improved motor performance. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) PD models, AGM alleviated glymphatic dysfunction and anxiety-like behaviors while reducing PD pathology. Crucially, AGM promoted aquaporin-4 (AQP4) polarization at astrocytic endfeet, as evidenced by RNA sequencing showing enhanced gap junction-related gene expression. The brain and muscle ARNT-like 1 (BMAL1)-mediated transcriptional regulation emerged as the key pathway underlying these effects. Our findings establish AGM as the first melatoninergic agent targeting the glymphatic-AQP4 axis in PD, shifting therapeutic strategies from symptomatic relief to disease modification. This provides clinical rationale for repurposing circadian regulators to decelerate PD progression through enhanced protein clearance.

The hippocampal dorsal CA2 subregion (dCA2) is critical for social memory; however, its contribution to other types of hippocampus-dependent memories is not well understood. Here, we performed dCA2-specific circuit tracing, single-neuron projectome analysis, photometric Ca imaging, and optogenetic manipulations to study the physiological roles of dCA2 neurons and their axon projections in behavioral paradigms for novel object recognition, novel location recognition, and contextual fear memory. We found that dCA2 neurons sent their strongest axon projections to the dorsal portion of ventral CA1 (vCA1d) and showed object and location-specific Ca responses. Notably, the dCA2-vCA1d projection contributed to the memory formation of object location but not identity. Furthermore, optogenetic inhibition of the dCA2-vCA1d axon terminals reduced fear responses to foot shocks and impaired contextual memory formation. Collectively, our study reveals critical roles of the dCA2-vCA1d circuit in spatial and context-dependent memories, providing new insights into the function of CA2 neurons.

The prelimbic cortex (PL) plays a critical role in processing both the sensory and affective components of pain. However, the underlying molecular mechanisms remain poorly understood. In this study, we observed a reduction in hyperpolarization-activated cation current (I) in layer V pyramidal neurons of the contralateral PL in a mouse model of spared nerve injury (SNI). The expression of hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) channels was also decreased in the contralateral PL. Conversely, microinjection of fisetin, a partial agonist of HCN2, produced both analgesic and anxiolytic effects. Additionally, we found that cyclin-dependent kinase 5 (CDK5) was activated in the contralateral PL, where it formed a complex with HCN2 and phosphorylated its C-terminus. Knockdown of CDK5 restored HCN2 expression and alleviated both pain hypersensitivity and anxiety-like behaviors. Collectively, these results indicate that CDK5-mediated dysfunction of HCN2 in the PL underlies nerve injury-induced mechanical hypersensitivity and anxiety.

Non-invasive infrared (IR) modulation requires IR photons to penetrate multi-layered cranial barriers, including skin, skull bone, and dura mater. However, the wavelength-dependent transmittance profiles and the modulatory effect of IR light on neural signals remain poorly understood. Using synchrotron radiation Fourier-transform infrared (SR-FTIR) microspectroscopy, we systematically mapped transmittance spectra of freshly isolated cranial tissue layers and brain tissues (gray matter and white matter) obtained from adult mice. The viability of brain tissue was maintained through microfluidic and oxygenated artificial cerebrospinal fluid (ACSF) perfusion during spectral acquisition. We identified two IR windows with relatively high transmittance through cranial tissues: a near-infrared (NIR) window (wavelength: 1.5-3.0 μm) and a mid-infrared (MIR) window (3.5-6.0 μm). Notably, the MIR sub-band ranging from 5.2 to 5.7 μm exhibited a relatively higher transmittance through neural tissue, particularly in axon bundles, compared to the surrounding bath solution. Further electrophysiological experiments revealed that MIR with a wavelength of 5.6 μm substantially decreased the amplitude and duration of both somatic and axonal action potentials, while simultaneously facilitating their conduction velocity along both myelinated and unmyelinated axons. Together, these results identify specific IR bands that can penetrate the cranial tissue layers and reveal a wavelength-specific modulation of neural signals, providing a promising non-invasive strategy for IR neuromodulation.

There is a vicious cycle between brain metabolism and epileptic seizures that compounds the deleterious consequences of seizures. Human epilepsy samples implicate cholesterol 25-hydroxylase (CH25H) in linking lipid metabolism and immunity. CH25H expression increased in microglia after status epilepticus, with its product 25-hydroxycholesterol (25-HC) accumulating in the hippocampus and blood. Thus, we generated microglia-specific CH25H knockdown mice to study the role of CH25H specifically in epilepsy. CH25H knockdown inhibited the assembly and activation of NLRP3 inflammasome and restrained the loss of neurons in the hippocampal area in epileptic mice. More importantly, CH25H knockdown reduced the number of recurrent seizures and time in seizure by electroencephalogram recording, which was partly reversed after 25-HC treatment. Untargeted metabolomics showed that another lipid metabolite, arachidonic acid, might be a potential biomarker of CH25H-mediated epilepsy. These findings suggest that microglial CH25H regulated the status epilepticus in a hydroxylase-dependent mechanism.

Neuropathic pain is frequently comorbidity with cognitive deficits. Neuralized1 (Neurl1)-mediated ubiquitination of CPEB3 in the hippocampus is critical in learning and memory. However, the role of Neurl1 in the cognitive impairment in neuropathic pain remains elusive. Herein, we found that lumbar 5 spinal nerve ligation (SNL) in male rat-induced neuropathic pain was followed by learning and memory deficits and LTP impairment in the hippocampus. The Neurl1 expression in the hippocampal CA1 was decreased after SNL. And this decrease paralleled the reduction of ubiquitinated-CPEB3 level and reduced production of GluA1 and GluA2. Overexpression of Neurl1 in the CA1 rescued cognitive deficits and LTP impairment, and reversed the reduction of ubiquitinated-CPEB3 level and the decrease of GluA1 and GluA2 production following SNL. Specific knockdown of Neurl1 or CPEB3 in bilateral hippocampal CA1 in naïve rats resulted in cognitive deficits and impairment of synaptic plasticity. The rescued cognitive function and synaptic plasticity by the treatment of overexpression of Neurl1 before SNL were counteracted by the knockdown of CPEB3 in the CA1. Collectively, the above results suggest that the downregulation of Neurl1 through reducing CPEB3 ubiquitination and, in turn, repressing GluA1 and GluA2 production and mediating synaptic plasticity impairment in hippocampal CA1 leads to the genesis of cognitive deficits in neuropathic pain.

The anterior cingulate cortex (ACC) has recently been proposed as a key player in the representation of itch stimuli. However, to date, little is known about the contribution of specific ACC interneuron populations to itch processing. Using c-Fos immunolabeling and in vivo Ca imaging, we reported that both histamine and chloroquine stimuli-induced acute itch caused a marked enhancement of vasoactive intestinal peptide (VIP)-expressing interneuron activity in the ACC. Behavioral data indicated that optogenetic and chemogenetic activation of these neurons reduced scratching responses related to histaminergic and non-histaminergic acute itch. Similar neural activity and modulatory role of these neurons were seen in mice with chronic itch induced by contact dermatitis. Together, this study highlights the importance of ACC VIP neurons in modulating itch-related affect and behavior, which may help us to develop novel mechanism-based strategies to treat refractory chronic itch in the clinic.

Bayesian integration is posited as a fundamental computational mechanism underlying multisensory integration, and feedforward neural networks have been proposed to instantiate optimal Bayesian integration (OBI). However, empirical and theoretical research highlights the prevalence of neural feedback projections, raising questions about how recurrent neural networks might contribute to multisensory OBI. We simulated a two-layer neural circuit computational model with reciprocal projections performing a perceptual discrimination task, in which sensory inputs comprise single or dual modalities. The model with reciprocal projections between sensory and decision-making modules can match, underperform, or outperform OBI, depending on feedforward-feedback interplay. This model performance variability accords with prior experimental data. In addition, our theoretical analysis reveals the importance of non-linear interactions within neuronal assemblies in mediating such multisensory integration behaviors. Our work suggests that sensory modalities can be entangled through top-down feedback, challenging the traditional view of their independence, while explaining deviations from OBI.