Neuronal Activity Research Articles

Local changes in potassium ions regulate input integration in active dendrites.

During neuronal activity, the extracellular concentration of potassium ions ([K+]o) increases substantially above resting levels, yet it remains unclear what role these [K+]o changes play in the dendritic integration of synaptic inputs. We here used mathematical formulations and biophysical modeling to explore the role of synaptic activity-dependent K+ changes in dendritic segments of a visual cortex pyramidal neuron, receiving inputs tuned to stimulus orientation. We found that the spatial arrangement of inputs dictates the magnitude of [K+]o changes in the dendrites: Dendritic segments receiving similarly tuned inputs can attain substantially higher [K+]o increases than segments receiving diversely tuned inputs. These [K+]o elevations in turn increase dendritic excitability, leading to more robust and prolonged dendritic spikes. Ultimately, these local effects amplify the gain of neuronal input-output transformations, causing higher orientation-tuned somatic firing rates without compromising orientation selectivity. Our results suggest that local, activity-dependent [K+]o changes in dendrites may act as a "volume knob" that determines the impact of synaptic inputs on feature-tuned neuronal firing.

KATP channel–dependent electrical signaling links capillary pericytes to arterioles during neurovascular coupling

The brain has evolved mechanisms to dynamically modify blood flow, enabling the timely delivery of energy substrates in response to local metabolic demands. Several such neurovascular coupling (NVC) mechanisms have been identified, but the vascular signal transduction and transmission mechanisms that enable dilation of penetrating arterioles (PAs) remote from sites of increased neuronal activity are unclear. Given the exponential relationship between vessel diameter and blood flow, tight control of arteriole membrane potential and diameter is a crucial aspect of NVC. Recent evidence suggests that capillaries play a major role in sensing neural activity and transmitting signals to modify the diameter of upstream vessels. Thin-strand pericyte cell bodies and processes cover around 90% of the capillary bed, and here we show that these cells play a central role in sensing neural activity and generating and relaying electrical signals to arterioles. We identify a KATP channel-dependent neurovascular signaling pathway that is explained by the recruitment of thin-strand pericytes and we deploy vascular optogenetics to show that currents generated in individual thin-strand pericytes are sent over long distances to upstream arterioles to cause dilations in vivo. Genetic disruption of vascular KATP channels reduces the arteriole diameter response to neural activity and laser ablation of thin-strand pericytes eliminates the KATP-dependent component of NVC. Together, our findings indicate that thin-strand pericytes sense neural activity and transform this into KATP channel-dependent electrometabolic signals that inform upstream arterioles of local energy needs, promoting spatiotemporally precise energy distribution.

Robust self-supervised denoising of voltage imaging data using CellMincer

Voltage imaging is a powerful technique for studying neuronal activity, but its effectiveness is often constrained by low signal-to-noise ratios (SNR). Traditional denoising methods, such as matrix factorization, impose rigid assumptions about noise and signal structures, while existing deep learning approaches fail to fully capture the rapid dynamics and complex dependencies inherent in voltage imaging data. Here, we introduce CellMincer, a novel self-supervised deep learning method specifically developed for denoising voltage imaging datasets. CellMincer operates by masking and predicting sparse pixel sets across short temporal windows and conditions the denoiser on precomputed spatiotemporal auto-correlations to effectively model long-range dependencies without large temporal contexts. We developed and utilized a physics-based simulation framework to generate realistic synthetic datasets, enabling rigorous hyperparameter optimization and ablation studies. This approach highlighted the critical role of conditioning on spatiotemporal auto-correlations, resulting in an additional 3-fold SNR gain. Comprehensive benchmarking on both simulated and real datasets, including those validated with patch-clamp electrophysiology (EP), demonstrates CellMincer’s state-of-the-art performance, with substantial noise reduction across the frequency spectrum, enhanced subthreshold event detection, and high-fidelity recovery of EP signals. CellMincer consistently outperforms existing methods in SNR gain (0.5–2.9 dB) and reduces SNR variability by 17–55%. Incorporating CellMincer into standard workflows significantly improves neuronal segmentation, peak detection, and functional phenotype identification, consistently surpassing current methods in both SNR gain and consistency.

Effects of the therapeutic correction of U1 snRNP complex on Alzheimer’s disease

The U1 snRNP complex recognizes pre-mRNA splicing sites in the early stages of spliceosome assembly and suppresses premature cleavage and polyadenylation. Its dysfunction may precede Alzheimer’s disease (AD) hallmarks. Here we evaluated the effects of a synthetic single-stranded cDNA (APT20TTMG) that interacts with U1 snRNP, in iPSC-derived neurons from a donor diagnosed with AD and in the SAMP8 mouse model. APT20TTMG effectively binds to U1 snRNP, specifically decreasing TAU in AD neurons, without changing mitochondrial activity or glutamate. Treatment enhanced neuronal electrical activity, promoted an enrichment of differentially expressed genes related to key processes affected by AD. In SAMP8 mice, APT20TTMG reduced insoluble pTAU in the hippocampus, amyloid-beta and GFAP in the cortex, and U1-70 K in both brain regions, without cognitive changes. This study highlights the correction of the U1 snRNP complex as a new target for AD.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

The temporal specificity of BOLD fMRI is systematically related to anatomical and vascular features of the human brain

Abstract The ability to detect fast responses with functional MRI depends on the speed of hemodynamic responses to neural activity, because hemodynamic responses act as a temporal low-pass filter which blurs rapid changes. However, the shape and timing of hemodynamic responses are highly variable across the brain and across stimuli. This heterogeneity of responses implies that the temporal specificity of fMRI signals, or the ability of fMRI to preserve fast information, could also vary substantially across the cortex. In this work we investigated how local differences in hemodynamic response timing affect the temporal specificity of fMRI. We used ultra-high field (7T) fMRI at high spatiotemporal resolution, studying the primary visual cortex (V1) as a model area for investigation. We used visual stimuli oscillating at slow and fast frequencies to probe the temporal specificity of individual voxels. As expected, we identified substantial variability in temporal specificity, with some voxels preserving their responses to fast neural activity more effectively than others. We investigated which voxels had the highest temporal specificity, and tested whether voxel timing was related to anatomical and vascular features. We found that low temporal specificity is only weakly explained by the presence of large veins or cerebral cortical depth. Notably, however, temporal specificity depended strongly on a voxel’s position along the anterior-posterior anatomical axis of V1, with voxels within the calcarine sulcus being capable of preserving close to 25% of their amplitude as the frequency of stimulation increased from 0.05Hz to 0.20Hz, and voxels nearest to the occipital pole preserving less than 18%. These results indicate that detection biases in high-resolution fMRI will depend on the anatomical and vascular features of the area being imaged, and that these biases will differ depending on the timing of the underlying neuronal activity. While we attribute this variance primarily to hemodynamic effects, neuronal nonlinearities may also influence response timing. Importantly, this spatial heterogeneity of temporal specificity suggests that it could be exploited to achieve higher specificity in some locations, and that tailored data analysis strategies may help improve the detection and interpretation of fast fMRI responses.

Non-contact confocal calcium imaging of in vivo murine corneal nerves

Abnormal corneal nerve function and associated disease is a significant public health concern. It is associated with prevalent ocular surface diseases, including dry eye disease. Corneal nerve dysfunction is also a common side effect of refractive surgeries, as well as a symptom of diseases that cause peripheral neuropathies. Here, we demonstrate in vivo calcium imaging of mouse corneal nerves expressing GCaMP6f, a genetically encoded calcium indicator. A custom fluorescence imaging and stereotactic system was designed, allowing for non-contact imaging of the mouse cornea with an air objective. Dynamic imaging of neuronal activity is demonstrated in the various layers of the cornea and in response to local anesthetic administration. This approach demonstrates a less invasive means of assessing corneal nerve function than has been previously used, and has significant potential for studying the effects of ocular diseases, refractive surgeries, and peripheral neuropathies on corneal nerve function, as well as the effectiveness of various therapies to treat corneal nerve dysfunction.

Chronic silencing of subsets of cortical layer 5 pyramidal neurons has a long-term influence on the laminar distribution of parvalbumin interneurons and the perineuronal nets.

Neural networks are established throughout cortical development, which require the right ratios of glutamatergic and GABAergic neurons. Developmental disturbances in pyramidal neuron number and function can impede the development of GABAergic neurons, which can have long-lasting consequences on inhibitory networks. However, the role of deep-layer pyramidal neurons in instructing the development and distribution of GABAergic neurons is still unclear. To unravel the role of deep-layer pyramidal neuron activity in orchestrating the spatial and laminar distribution of parvalbumin neurons, we selectively manipulated subsets of layer 5 projection neurons. By deleting Snap25 selectively from Rbp4-Cre + pyramidal neurons, we abolished regulated vesicle release from subsets of cortical layer 5 projection neurons. Our findings revealed that chronically silencing subsets of layer 5 projection neurons did not change the number and distribution of parvalbumin neurons in the developing brain. However, it did have a long-term impact on the laminar distribution of parvalbumin neurons and their perineuronal nets in the adult primary motor and somatosensory cortices. The laminar positioning of parvalbumin neurons was altered in layer 4 of the primary somatosensory cortex in the adult Snap25 cKO mice. We discovered that the absence of layer 5 activity only had a transient effect on the soma morphology of striatal PV neurons during the third week of postnatal development. We also showed that the relationship between parvalbumin neurons and the perineuronal nets varied across different cortical layers and regions; therefore, their relationship is far more complex than previously described. The current study will help us better understand the bidirectional interaction between deep-layer pyramidal cells and GABAergic neurons, as well as the long-term impact of interrupting pyramidal neuron activity on inhibitory network formation.

Distinct Roles of Astrocytes and GABAergic Neurons in the Paraventricular Thalamic Nucleus in Modulating Diabetic Neuropathic Pain

Diabetic neuropathic pain (DNP) is a common chronic complication of diabetes mellitus and a clinically common form of neuropathic pain (NP). The thalamus is an important center for the conduction and modulation of nociceptive signals. The paraventricular thalamic nucleus (PVT) is an important midline nucleus of the thalamus involved in sensory processing, but the specific role of PVT astrocytes and GABAergic neurons in DNP remains unclear. Here, we examined the activity of PVT astrocytes and neurons at various time points during the development of DNP by fluorescence immunohistochemistry and found that the activity of PVT astrocytes was significantly increased while that of PVT neurons was significantly decreased 14 days after streptozotocin (STZ) injection in male rats. The inhibition of PVT astrocytes by chemogenetic manipulation relieved mechanical allodynia in male DNP model rats, whereas the activation of PVT astrocytes induced mechanical allodynia in normal male rats. Interestingly, chemogenetic activation of GABAergic neurons in the PVT alleviated mechanical allodynia in male DNP model rats, whereas chemogenetic inhibition of GABAergic neurons in the PVT induced mechanical allodynia in normal male rats. These data demonstrate the distinct roles of PVT astrocytes and GABAergic neurons in modulating DNP, revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.Significance StatementSome studies have focused on the role of paraventricular thalamic nucleus (PVT) glutamatergic neurons in neuropathic pain (NP) and anxiety. However, the role of PVT astrocytes and GABAergic neurons in diabetic neuropathic pain (DNP) has not been studied. We used chemogenetic techniques to bidirectionally regulate the activity of PVT astrocytes or GABAergic neurons and found that PVT astrocyte activation promotes NP, while PVT GABAergic neuron activation may mediate antinociceptive effects. These findings clarify the critical roles of PVT astrocytes and GABAergic neurons in modulating DNP, providing insight for the development of new strategies for the prevention and treatment of DNP and revealing the mechanism of DNP pathogenesis and the role of the PVT in pain modulation.

Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus

AbstractAstrocytes of the suprachiasmatic nucleus (SCN) can regulate sleep-wake cycles in mammals. However, the nature of the information provided by astrocytes to control circadian patterns of behavior is unclear. Neuronal circadian activity across the SCN is organized into spatiotemporal waves that govern seasonal adaptations and timely engagement of behavioral outputs. Here, we show that astrocytes across the mouse SCN exhibit instead a highly uniform, pulse-like nighttime activity. We find that rhythmic astrocytic GABA production via polyamine degradation provides an inhibitory nighttime tone required for SCN circuit synchrony, thereby acting as an internal astrocyte zeitgeber (or “astrozeit”). We further identify synaptic GABA and astrocytic GABA as two key players underpinning coherent spatiotemporal circadian patterns of SCN neuronal activity. In describing a new mechanism by which astrocytes contribute to circadian timekeeping, our work provides a general blueprint for understanding how astrocytes encode temporal information underlying complex behaviors in mammals.

Recording Cortical and Subcortical Neuronal Activity Using Electrode Systems

Recording Cortical and Subcortical Neuronal Activity Using Electrode Systems

Recording Cortical and Subcortical Neuronal Activity Using Electrode Systems

Recording Cortical and Subcortical Neuronal Activity Using Electrode Systems

Hesperidin produces antidepressant effects by activating AMPA receptor: enhancing synaptic proteins to promote hippocampal neuronal activities.

Hesperidin treatments reduce depressive symptoms in mouse models of depression, but the mechanism that mediates its antidepressant effects is unclear. This study shows that hesperidin exerts its antidepressant effects by activating α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor to promote synaptic and neuronal function in the hippocampus. The optimal dose of hesperidin (10 mg/kg) for the antidepressant potential was determined after 7 consecutive days of treatments, demonstrating decreased latency to eat and increased food consumption in novelty suppressed feeding, and decreased immobility time in tail suspension test (TST). Moreover, the optimal dose also reversed the depressive phenotypes of Institute of Cancer Research mice exposed to chronic unpredictable mild stress (CUMS), including reduced immobility time in the TST and increased sucrose preference in the sucrose preference test. In addition, hesperidin increased the expression of AMPA receptor protein (Glur1) and synaptic proteins (BDNF, PSD95, synapsin1) in the hippocampus of CUMS-exposed mice. Furthermore, inhibition of AMPA receptor activity by NBQX blocked the effect of hesperidin in reversing the depressive phenotypes, upregulated the expression of synaptic proteins (BDNF, PSD95, synapsin1) and cFOS-positive cells in the hippocampus, and increased the number of Ki67-positive cells in the dentate gyrus of the hippocampus of CUMS-exposed mice. These results help to further understand the antidepressant mechanism of hesperidin and provide new ideas for the future development of antidepressant drugs.

Histaminergic Innervation of the Ventral Anterior Thalamic Nucleus Alleviates Motor Deficits in a 6-OHDA-Induced Rat Model of Parkinson’s Disease

AbstractThe ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson’s disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K+ channels, or Ca2+-activated K+ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.

Neurochemical dynamics during two hypnotic states evidenced by magnetic resonance spectroscopy

This study explores neurochemical changes in the brain during hypnosis, targeting the parieto-occipital (PO) and posterior superior temporal gyrus (pSTG) regions using proton magnetic resonance spectroscopy (MRS). We examined 52 healthy, hypnosis experienced participants to investigate how two different hypnotic states of varying depth impacted brain neurochemistry in comparison to each other and to their respective non-hypnagogic control conditions. Alongside neurochemical assessments, we recorded respiration and heart rate variability (HRV) to further explore possible associations between physiological correlates of hypnotic depth. Significant changes in myo-Inositol concentration relative to total creatine were observed in the PO region during the deeper hypnosis state, possibly indicating reduced neuronal activity. No significant neurochemical shifts were detected in the pSTG region. Additionally, our findings revealed notable physiological changes during hypnosis. Respiratory rates were significantly slowed in both hypnotic states compared to the respective controls, with more pronounced slowing in the deeper hypnotic state. This study contributes a first-time insight into neurochemical responses during hypnotic states. We hope offering a foundation for further research in understanding the neurobiological correlates of hypnosis in both, basic science and—down the line—clinical applications.

D2 receptor antagonist raclopride regulates glutamatergic neuronal activity in the pedunculopontine nucleus in a rat model of Parkinson's disease

Parkinson disease (PD) is defined by the loss of dopamine (DA). Changes in the pedunculopontine nucleus (PPN), particularly in local field potential (LFP), can be attributed to deficits in DA and DA receptor expression levels. PPN is a heterogeneous nucleus consisting of cholinergic, γ-aminobutyric acid (GABAergic), and glutamatergic neurons. However, it is unclear whether low levels of DA receptors affect the activity of different PPN neuron types. We record the neuronal activity of PPN by administering the selective dopamine D1 and D2 receptor antagonists, SCH23390 and Raclopride, respectively. This study discover that the firing rates of glutamatergic neurons could be normalized, and their firing patterns were more consistent in lesioned rats treated with raclopride. Raclopride administration could correct the increased coherence and phase locking between glutamatergic spikes and beta-band oscillatory activity in lesioned rats. Raclopride administration correct the increased coherence and phase locking between glutamatergic spikes and beta-band oscillatory activity in lesioned rats.

TRPM8 Mutations Associated With Persistent Pain After Surgical Injury of Corneal Trigeminal Axons.

Despite extensive efforts, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain following corneal refractive surgery offers a valuable human model for investigating trigeminal axonal injury because laser-assisted in situ keratomileusis (LASIK) severs axons of trigeminal ganglion neurons innervating the cornea. While the majority of patients are pain-free shortly after surgery, a minority endure persistent postoperative ocular pain. Through genomic analysis of patients experiencing persistent postoperative ocular pain, we identified rare variants in genes encoding ion channels and receptors, including TRPM8, which codes for the menthol-sensitive and cold-sensing transient receptor potential cation channel. We conducted a profiling of 2 TRPM8 mutant variants, D665N and V915M, which were identified in patients suffering from persistent pain after LASIK surgery. We used patch-clamp and multielectrode array (MEA) recordings to investigate the biophysical and pharmacologic properties of mutant vs wild-type (WT) channels. Patch-clamp analysis shows that these mutations shift the activation curves of TRPM8 in a hyperpolarized direction, with this effect being significantly different between WT and D665N channels. In addition, both mutations significantly increase channel sensitivity to the canonical ligand, menthol. MEA recordings from transfected rat trigeminal ganglion neurons indicate that expression of D665N and V915M mutant channels increases spontaneous activity compared with WT channels. Consistent with patch-clamp results, neuronal activity in MEA recordings was increased on exposure to menthol. Collectively, our findings suggest that proexcitatory mutations of TRPM8, in the context of axonal injury within the cornea, can produce trigeminal ganglion neuron hyperexcitability that contributes to persistent postoperative ocular pain. In addition to providing additional evidence for a role of TRPM8 in human pain, our results suggest that inhibitors of this channel merit future study.

Neuronal activity features of the subthalamic nucleus associated with optimal deep brain stimulation electrode insertion path in Parkinson's disease

AbstractDeep brain stimulation (DBS) of the subthalamic nucleus (STN) is a standard treatment for advanced Parkinson's disease (PD). The precise positioning of the electrode can significantly influence the results of DBS and the overall improvement in the quality of life for PD patients receiving this therapy. We hypothesize that single unit activity (SUA) features can serve as a valid marker of the optimal DBS‐electrode insertion trajectory, leading to the most favorable outcome of STN‐DBS surgery. We analyzed spontaneous SUA data recorded during microelectrode recording (MER) for 21 patients with PD who underwent DBS surgery. We compared 29 linear and six nonlinear characteristics of the STN neural activity recorded along different microelectrode insertion paths to determine features corresponding to favorable stimulation outcomes. Our research indicated that the SUA features of pause neurons in a dorsal STN region significantly affected stimulation outcomes. For the trajectories chosen for lead insertion, firing rate, burst rate and oscillatory activity at 8–12 and 12–20 bands were significantly decreased. Moreover, nonlinear feature analysis showed a significant increase in mutual information for the chosen trajectories. Our findings highlight the significance of specific indicators, such as the activity of pause neurons in the dorsal region and numerous linear SUA characteristics, in determining the optimal lead installation trajectory. Furthermore, our findings emphasize the importance of investigating paths rejected during test stimulation to understand motor impairment in Parkinson's disease and its treatment mechanisms.

Complex dynamic behavioral transitions in auditory neurons induced by chaotic activity

Chaotic sequences are widely used in secure communication due to their high randomness. Chaotic resonance (CR) refers to the resonant response of a system to weak signals induced by chaotic activity, but its practical application remains limited. This study designs a simplified FitzHugh-Nagumo (FHN) auditory neuron model by simulating the physiological activities of auditory neurons and considering the combined stimulation of chaotic activity and sound signals. It is found that the neuron dynamics depend on both external sound stimuli and chaotic current intensity. Chaotic currents induce spikes in the neuron output sequence through CR, and the spikes become more frequent with increasing current intensity, eventually leading to a chaotic state regardless of the initial state. However, the sensitivity of the initial value of this chaotic sequence shifts to the chaotic current excitation system. The injection of chaotic currents can reduce the system's average Hamiltonian energy under certain conditions. By measuring the complexity of the generated sequences, we find that the addition of chaotic currents can enhance the complexity of the original sequences, and the enhancement ability increases with the intensity. This provides a new approach to enhance the complexity of original chaotic sequences. Moreover, different chaotic currents can induce different chaotic sequences with varying abilities to enhance the complexity of the original sequences. We hope our work can contribute to secure communication.