eNeuro最新文献

Vestibular dysfunction constitutes a major medical concern, and regeneration of hair cells (HC) is a primary target of gene therapy aimed at restoring vestibular functions. Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded variable and partial results, and the functional identity and quantity of HCs required to restore minimal or normal vestibular function remain undefined. Indeed, direct comparisons between structural pathology and quantitative assessments of vestibular dysfunctions are lacking in humans and are rather limited in animal models, representing a significant gap in current knowledge. Here, we present an innovative methodology to bridge the gap between HC integrity and functional vestibular loss in individual mice of either sex. Gradual vestibular deficits were induced through a dose-dependent ototoxic lesion, quantified with canal or utricular-specific vestibulo-ocular reflex tests, and were then correlated in all individuals with the loss of type I and type II HCs in different regions of ampulla and macula. Our findings reveal that the structure-function relationship is nonlinear, with lower bound of approximately 50% of HCs necessary to retain minimal vestibular function, and threshold exceeding 80% to preserve normal function, thus shedding light on population coding mechanisms for vestibular response. Our data further support the decisive role of type I, rather than type II, HC in the tested VOR functions.Significance Statement: Vestibular dysfunction poses a major medical challenge, with significant consequences for balance, spatial orientation, and quality of life. While regenerative therapies targeting hair cell (HC) repair offer promise, the minimal structural requirements for restoring normal vestibular functions remain unclear. Through an innovative methodology that combines precise vestibulo-ocular reflex (VOR) quantification and region-specific analyses of HC loss in mice, we demonstrate a nonlinear relationship between structural integrity and functional recovery. Our findings establish critical thresholds of HC preservation, approximately 50% for minimal vestibular function and over 80% for normal function. These insights provide valuable benchmarks for translational research, refining therapeutic strategies for vestibular pathologies and advancing our understanding of population-coding mechanisms.

Dementia-causing diseases, including Alzheimer's disease (AD), are one of the greatest health concerns facing the aging world population. A key feature of AD is excessive accumulation of amyloid-beta, leading to synapse and cell loss in brain structures, such as the hippocampus. This neurodegeneration is preceded by impaired neuron function, notably reduced synaptic inhibition. Metabotropic GABA_B receptors (GABA_BRs) may be modulated by amyloid precursor protein (APP) and are reported to be progressively lost from neuronal membranes of hippocampal pyramidal neurons. However, it remains unknown whether functional GABA_BR-mediated signaling changes over aging and whether or not pharmacological intervention can prevent receptor loss. In this study, we combine electrophysiological and biochemical analysis of hippocampal neurons in the Amyloid Precursor Protein/Presenilin-1 (APP/PS1) mouse model of AD from acute brain slices and organotypic slice cultures prepared from male and female mice to determine if functional GABA_BRs are lost and the effect of pharmacological modulation. Overall, we found that GABA_BR expression decreased with age, independent of genotype, with no evidence for postsynaptic GABA_BR loss in CA1 pyramidal cells at any age. We did observe a genotype-dependent reorganization of postsynaptic GABA_BR-mediated IPSCs, which was independent of age. Presynaptic GABA_BR-mediated inhibition was impaired in APP/PS1 mice, also independent of age. We observed that chronic GABA_BR modulation differentially regulated function but was independent of genotype. Overall, our data show that functional GABA_BR signaling is altered in APP/PS1 mice, independent of age, increasing our understanding of amyloidopathy-induced dysfunction.

Galanin-expressing neurons in the ventrolateral preoptic area (VLPO^galanin) are active during sleep and play an important role regulating non-rapid eye movement (NREM) sleep. It is generally believed that VLPO^galanin neurons promote sleep via inhibitory actions in arousal promoting regions of the brain. Histaminergic neurons are a population of wake-active neurons that receive strong projections from the sleep-active VLPO^galanin neurons. However, the ability of galanin to influence the activity of histaminergic neurons has received limited attention. Here, using whole-cell patch clamp electrophysiological recordings from genetically identified histaminergic neurons in male mice, we explore the mechanisms by which galanin influences histaminergic neuron electrical excitability. Our results reveal that galanin is a powerful inhibitor of histaminergic neuron activity and demonstrate that the inhibitory effects of galanin are mediated by galanin receptor 1 (GALR1) and the subsequent opening of G protein-coupled inwardly rectifying (GIRK) and large conductance calcium-activated potassium (BK) channels. Furthermore, we identify that histaminergic neurons highly express Galr1 mRNA and show that the GALR1-mediated hyperpolarization of histaminergic neurons is largely independent of action potential-dependent synaptic transmission, or fast excitatory or inhibitory neurotransmitters. Together, these results suggest that direct post-synaptic activation of GALR1 expressed on histaminergic neurons mediates the inhibitory effects of galanin on these neurons. This data also supports the notion that the sleep-promoting effects of VLPO^galanin neuron activation may occur via the ability of galanin to inhibit the arousal-promoting histaminergic neurons.Significance Statement The "flip-flop switch" model of sleep and wakefulness proposes that sleep-active galanin-expressing neurons in the ventrolateral preoptic area (VLPO) promote sleep via inhibitory actions on arousal promoting neurons, such as the histaminergic neurons. However, the molecular mechanisms surrounding this theory are lacking. Here, we report that histaminergic neurons are strongly inhibited by galanin, an effect that occurs via galanin receptor 1 (GALR1) mediated opening of potassium channels. The GALR1-induced inhibition persisted in blockers of synaptic transmission and Galr1 mRNA was expressed in histaminergic neurons. Together, these results suggest galanin inhibits histaminergic neurons via GALR1 expressed on histaminergic neurons and supports the notion that galanin-expressing VLPO neurons could silence the wake-active histaminergic neurons to promote sleep.

The dorsomedial striatum (DMS) is critical for both motivating and inhibiting behavioral responses. The region integrates inputs from the cortex, thalamus, and other subcortical structures including midbrain dopamine neurons. Though less studied, serotonin neurons from the dorsal raphe nucleus also richly innervate the DMS, which expresses nearly all 14 serotonin receptor subtypes. Slice electrophysiology shows that the serotonin 1B receptor (5-HT1BR) impacts DMS physiology and plasticity, and behavioral experiments show that 5-HT1BR expression modulates impulsivity and other DMS-dependent reward-related behaviors. In these studies, our goal was to investigate the effects of 5-HT1BR on the DMS in vivo. Using a genetic 5-HT1BR loss-of-function mouse model, we examined calcium activity of individual medium spiny neurons (MSNs) in the DMS of both males and females during operant tasks focusing on responses to actions, reward, and waiting. We found that knock-out of 5-HT1BRs resulted in different effects on MSN calcium activity depending on behavioral state. Specifically, mice lacking 5-HT1BRs showed significantly more inhibition of MSN calcium activity during the rewards, but more cells with excitatory calcium responses during the delay period of the trial. This suggests that serotonin, acting via 5-HT1BRs, may recruit MSN activity in response to reward but inhibit MSN activity during waiting. These results highlight the importance of in vivo studies for understanding the functional role of DMS serotonin in reward-related behavior. Overall our results demonstrate that serotonin can modulate the DMS in a behavioral state-specific manner, potentially providing a mechanism for how serotonin effects on behavior are context dependent.

Gamma oscillations (40-140 Hz) play a fundamental role in neural coordination and cognitive functions in the medial entorhinal cortex (mEC). While previous studies suggest that pyramidal-interneuron network gamma (PING) and interneuron network gamma (ING) mechanisms contribute to these oscillations, the precise role of inhibitory circuits remains unclear. Using optogenetic stimulation and whole-cell electrophysiology in acute mouse brain slices, we examined synaptic input and spike timing in neurons across layer II/III mEC. We found that fast-spiking interneurons exhibited robust gamma-frequency firing, while excitatory neurons engaged in gamma cycle skipping. Stellate and pyramidal cells received minimal recurrent excitation, whereas fast-spiking interneurons received strong excitatory input. Both excitatory neurons and fast-spiking interneurons received gamma-frequency inhibition, emphasizing the role of recurrent inhibition in gamma rhythms. Gamma activity was reduced but persisted after AMPA/kainate receptor blockade, indicating that interneurons can sustain oscillations via an ING mechanism. Selective activation of PV+ interneurons confirmed their ability to sustain fast gamma inhibition autonomously. To further assess the interplay of excitation and inhibition, we developed computational network models constrained by our experimental data. Simulations revealed that weak excitatory input to interneurons supports fast ING-dominated rhythms (∼100-140 Hz) while strengthening excitatory drive induces a transition to slower PING-dominated oscillations (60-100 Hz), although this regime shift was not observed consistently after AMPA/kainate receptor block. These findings highlight the dominant role of inhibitory circuits in sustaining gamma rhythms, demonstrate how excitation strength tunes the oscillatory regime, and refine models of entorhinal gamma oscillations critical for spatial memory processing.

Age-related vascular changes accompany or precede the development of Alzheimer's disease (AD) pathology. The comorbidity of AD and arterial stiffening suggests that vascular changes have a pathogenic role. Carotid artery mechanics and hemodynamics have been associated with age-related cognitive decline. However, the impact of hemodynamics and vascular mechanics on regional vulnerability within the brain has not been thoroughly explored. Compared with the arterial system, brain venous circulation in cognitive impairment is less understood despite the venous system's role in transport. To study vasculature impact on biochemistry in AD models, we must first establish the differences in vasculature mechanics and hemodynamics in a common AD model compared with healthy controls. With this baseline data, future studies on manipulating vasculature integrity in mice become feasible. Young and aged female 3xTg mice and age-matched controls were imaged using a combination of ultrasound and mass spectrometry. Wall shear stress varied across age and AD models. Mean velocity and pulsatility index varied across age and AD. Liquid chromatography-mass spectrometry of brain tissue revealed several lipids that were statistically different between age and AD, and matrix-assisted laser desorption/ionization MS imaging revealed region-specific differences between groups. Combining both ultrasound and mass spectrometry, we were able to detect significant changes in the vascular biomechanics of neck vasculature prior to observing significant changes in the brain biochemistry. Our work revealed significant vascular differences in the 3xTg compared with controls and, to our knowledge, is the first to study vascular biomechanics via ultrasound in the 3xTg AD mouse model.

The cerebellum is well established in subsecond motor timing, but its role in suprasecond interval timing remains unclear. Here, we investigated how cerebellar output influences time estimation over longer timescales. Male rats performed a nose-poke interval timing task in which reward availability could be predicted either from a fixed 2.5 s auditory cue (cued trials) or had to be estimated internally during uncued 3.5 s trials that demanded self-timing. Chemogenetic inhibition of the lateral cerebellar nucleus (LCN) produced bidirectional effects: delayed action initiation in predictable trials and premature (∼100-160 ms) responses when self-timing was required. Despite a slowing of movement, overall task success rates remained unchanged. Because motor slowing is likely to lead to later, not earlier, action initiation, these results implicate the LCN in computing internal time estimates. These findings demonstrate that the cerebellum integrates motor and cognitive processes for suprasecond timing, with differential effects on externally guided and self-generated timing.

Auditory-evoked EEG signals contain rich temporal and cognitive features that reflect both the identity of individuals and their neural response to external stimuli. Traditional unimodal approaches often fail to fully leverage this multidimensional information fully, limiting their effectiveness in real-world biometric and neurocognitive applications. This study aims to develop a unified deep learning model capable of jointly performing biometric identification, auditory stimulus language classification, and device modality recognition, thereby exploiting both physiological and cognitive dimensions of auditory-evoked EEG. We introduce TriNet-MTL (Triple-Task Neural Transformer for Multitask Learning), a multi-branch deep learning framework composed of a shared temporal encoder and a transformer-based sequence modeling unit, trained and validated on auditory-evoked EEG data from 20 human participants (16 males and 4 females). The architecture is designed to simultaneously learn task-specific features via three dedicated output heads, each addressing one of the following: user identity (biometric), stimulus language (native vs. non-native), and stimulus delivery mode (in-ear vs. bone-conduction). The model is trained using a sliding window approach and optimized through joint cross-entropy loss across tasks. TriNet-MTL demonstrates robust performance across all three classification tasks, achieving high accuracy in biometric identification (>93%) and strong generalization in cognitive state inference. Multi-task training further improves representation learning, reducing inter-task interference while enhancing task synergy. The proposed TriNet-MTL framework effectively captures both user-specific and cognitively informative patterns from auditory-evoked EEG, establishing a promising direction for integrated EEG-based biometric authentication and cognitive state monitoring in real-world systems.Significance Statement Understanding how the brain responds to sound offers new ways to identify individuals and assess their cognitive state. This study introduces a deep learning model that can simultaneously recognize a person, determine whether the sound they heard was in their native language, and identify how the sound was delivered. By combining all three tasks, the system learns richer patterns from brain signals, making it more accurate and reliable. Our results show that this approach can improve the performance of brain-based identification systems while also tracking how people process sounds. This work opens new possibilities for secure, brain-driven authentication and real-time cognitive monitoring.

Neurite outgrowth is essential for neural circuit formation and is tightly regulated by secreted factors and their receptors. The secreted extracellular domain of the amyloid precursor protein (sAPPα) has been shown to modulate neurite outgrowth. Recently, the gamma amino butyric acid receptor type-B subunit 1a (GABA_BR1a) was identified as an sAPPα binding partner that mediates its effects on synaptic transmission. Here, we investigated whether this interaction also regulates neurite outgrowth. In mouse primary hippocampal neurons of either sex, the GABA_BR agonist baclofen reduced axon length; whereas, its antagonist CGP54626 increased axon length in primary hippocampal neurons. Moreover, GABA_BR1a knockout increased axon length and abolished the effect of baclofen. Application of sAPPα reduced axon length, an effect that required the presence of both GABA_BR1a and the extension domain of sAPPα, which mediates its binding to GABA_BR1a. Similarly, the APP 17mer peptide, which is sufficient to bind GABA_BR1a and mimic the effects of sAPP on synaptic transmission, reduced axon outgrowth in wildtype but not in GABA_BR1a-deficient neurons. Together, these findings indicate that the 1a isoform contributes to GABA_BR-dependent suppression of neurite outgrowth and mediates the inhibitory effect of sAPPα on neurite outgrowth.Significance Statement Amyloid precursor protein (APP) plays a central role in Alzheimer's disease, yet its normal functions are not fully understood. In this study, we uncover a previously unrecognized role of the GABA B Receptor in mediating the inhibitory effects of sAPPα on neurite outgrowth. These findings provide mechanistic insight into how disruptions in APP signaling could influence both normal brain development and pathological processes in neurodevelopmental disorders and Alzheimer's disease.