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Results for “temporal single-cell analysis”

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PubMed2026

Interpretable data integration for single-cell and spatial multi-omics.

Integrating single-cell or spatial transcriptomic and epigenomic data enables scrutinizing the transcriptional regulatory mechanisms controlling cell fate. Current integration methods usually align multi-omics data into a shared latent space but fail to reveal the underlying connections between genes and regulatory elements. The correlation- or regression-based regulatory inference methods cannot dissect different transcriptional regulation codes for cells under different spatial and temporal states. To address both problems, we develop a feature-guided optimal transport (FGOT) method, which simultaneously uncovers cellular heterogeneity and their associated transcriptional regulatory links. FGOT also provides post hoc interpretability for existing integration methods. FGOT is applicable for paired/unpaired single-cell multi-omics data and paired spatial multi-omics data. Benchmarking and validating via histone modification data or three-dimensional (3D) genomics data show good robustness and accuracy in integration and inference of regulatory links. The method allows systematic screening of cell-state and spatial-location-specific regulatory elements in diseases at the single-cell level. A record of this paper's transparent peer review process is included in the supplemental information.

Single-Cell Analysis↗

PubMed1997

Activation of protein kinase C after fertilization is required for remodeling the mouse egg into the zygote.

Fertilization of the mammalian egg initiates numerous biochemical and structural changes which remodel the egg into a single-celled zygote. To date, the most extensively studied phenomenon of fertilization in virtually all species has been the relationship between sperm penetration and the induction of the initial rise in intracellular-free calcium ([Ca2+]i) concentration within the egg. In contrast, relatively few studies have focused on the biochemical events following this rise in calcium, and even fewer studies have directly linked the biochemical events to the structural changes which must ensue for proper development of the embryo. In this study, we exploited recently developed technologies to investigate the action of protein kinase C (PKC), a presumed downstream transducer of the initial rise in [Ca2+]i, during fertilization and artificial activation with calcium ionophore or phorbol 12-myristate 13-acetate (PMA). The newly developed myristoylated PKC pseudosubstrate (myrPKC psi) was used to specifically inhibit PKC, thereby averting the trauma of injecting the egg with nonmyristoylated PKC psi. Following fertilization, eggs which were pretreated with myr-PKC psi were not capable of forming a second polar body and pronuclear formation was significantly inhibited. Spatial and temporal localization of PKC using confocal microscopy to visualize the PKC reporter dye, Rim-1, demonstrated localization of PKC to the lateral aspects of the forming second polar body after fertilization, or after artificial activation with calcium ionophore or PMA. In vivo biochemical analysis of eggs which were fertilized or artificially activated demonstrated that PKC activity rose at the same time (40 min) as the second polar body formed and then subsided over the next 5 hr post activation. From these data, we conclude that PKC plays an integral role in directing the transformation from egg to embryo.

Animals↗

PubMed2026

Single-cell sequencing reveals synovial fluid γδ T-cell expansion in equine experimental osteoarthritis.

OBJECTIVE: Define temporal cellular changes following joint injury using single-cell RNA sequencing in experimental equine posttraumatic osteoarthritis (PTOA). METHODS: PTOA was induced in 4 Quarter Horses (3 to 5 years) via carpal osteochondral fragmentation and high-speed treadmill exercise. Synovial fluid (SF) cells and synovium were sampled over 18 weeks (November 2023 to April 2024). Single-cell suspensions were processed (10x Genomics Chromium iX), then aligned to the equine genome (Cell Ranger). Downstream analysis was completed in the R Seurat package. Differential gene expression (log2[fold change] > 1; P < .05) and differential abundance analyses were performed (P < .1). RESULTS: Cartilage injury had a modest impact on gene expression changes and cell abundance shifts in SF. Integrated analysis of 90,323 SF cells across 4 time points revealed 9 distinct cell types, primarily T cells (73 ± 19%) followed by myeloid cells (20 ± 13%). Subcluster analysis of T cells revealed 9 transcriptomically distinct subtypes (3 CD8, 2 CD4, 3 γδ, and 1 cycling). Differential abundance analyses of temporal changes identified increased γδ T and decreased CD4+ T-cell subsets in joints over time. Expanded populations of IL-23 receptor-positive γδ T cells exhibited increased T-helper 17 signatures. CONCLUSIONS: IL-23 receptor-positive γδ T-cell expansion, associated with joint inflammation, occurred in PTOA. Limitations include small sample size and individual heterogeneity; further investigation over extended timeframe is necessary to confirm whether later stages of the experimental model reflect natural chronic OA. CLINICAL RELEVANCE: Cellular immunotherapy targeting γδ T cells and IL-23/IL-17 blockade may warrant investigation to mitigate equine OA progression.

equine↗

PubMed2026

Spatially guided in vivo single-cell functional genomics of postnatal heart.

Understanding how spatial organization and cell-cell interactions shape gene regulatory programs is central to decoding tissue development and function. The transition at birth, marked by increased circulatory demands and rapid tissue growth, requires precise spatiotemporal coordination of cardiac maturation. In this study, we generated a high-resolution spatial and temporal atlas of the postnatal mouse heart by integrating single-nucleus RNA sequencing with image-based spatial transcriptomics. This framework revealed dynamic cellular interactions, niche-specific signaling and transcriptional programs guiding cardiomyocyte maturation. To functionally test prioritized regulators in vivo and at scale, we developed PIP-seq (probe-based indel-detectable Perturb-seq), a high-throughput platform that detects single guide RNA identity, infers gene editing and profiles transcription from fixed nuclei. Applying PIP-seq to the developing postnatal heart, we identified 21 previously uncharacterized regulators of cardiomyocyte maturation, including genes essential for sarcomere assembly, metabolic reprogramming and electrophysiological transitions. Together, our findings define how microenvironmental signals and intrinsic gene programs cooperate to guide heart maturation and establish a broadly applicable framework for functional genomics in complex tissues.

Animals↗

PubMed2026

Network methods for diagonal integration of unpaired single-cell multiomics data: a review.

MOTIVATION: Advances in single-cell sequencing have enabled multiomics profiling at unprecedented resolution; however, mass spectrometry-based single-cell proteomics (scMS) remains inherently destructive, precluding simultaneous transcriptomic capture. Unlike antibody-based methods such as CITE-seq, which permit paired profiling but are restricted to targeted protein panels, scMS provides unbiased, genome-scale coverage of the intracellular proteome yet necessitates post hoc integration of unpaired datasets. This diagonal integration challenge, where transcriptomes and proteomes are measured in separate cells lacking shared anchors, remains underserved by existing reviews, which focus predominantly on vertical integration strategies enabled by non-destructive assays. RESULTS: We survey the complete computational pipeline for constructing mechanistic proteogenomic networks from unpaired single-cell data, covering: (i) unimodal network inference such as knowledge-based approaches, probabilistic graphical models, temporal directionality inference, and generative and foundation model strategies that establish the transcriptomic scaffold; (ii) cross-modal integration architectures such as network propagation, graph neural networks (scMRDR, scmFormer, scCotag), and consensus frameworks designed explicitly for the unpaired proteomics setting; and (iii) benchmarking paradigms spanning network reconstruction (BEELINE, GRETA, CausalBench) and multi-task integration evaluation (scMultiBench, SCMMIB), with guidance on metric selection under network sparsity and class imbalance. We identify three principal axes of future development: generative proteomic translation from transcriptomic precursors, inductive prior embedding in next-generation architectures, and perturbation-based causal benchmarking. AVAILABILITY AND IMPLEMENTATION: This is a review article; no novel software is distributed. A curated benchmark resource table, methods starter guide, and per-method bottleneck annotations are provided in the Supplementary Material.

Multiomics↗

PubMed1998

Adenosine 5'-triphosphate, uridine 5'-triphosphate, bradykinin, and lysophosphatidic acid induce different patterns of calcium responses by human articular chondrocytes.

Small calcium-mobilizing inflammatory mediators have been implicated in joint pathology. Here we demonstrate that bradykinin, adenosine 5'-triphosphate, uridine 5'-triphosphate, and lysophosphatidic acid raise the intracellular calcium concentration ([Ca2+]i) in human articular chondrocytes. Heterologous cross-desensitization experiments showed that the uridine 5'-triphosphate response was abolished by prior treatment with adenosine 5'-triphosphate and, conversely, that the adenosine 5'-triphosphate response was abolished by prior treatment with uridine 5'-triphosphate; this indicated competition for the same receptor site, whereas bradykinin and lysophosphatidic acid did not compete with other ligands. Pretreatment with thapsigargin abolished ligand-mediated Ca2+ responses but not vice versa; this confirmed that Ca2+ release occurred from intracellular stores. Single-cell analysis of Fura-2 acetoxymethyl ester loaded chondrocytes showed mediator-dependent patterns of oscillatory Ca2+ changes in a subset of cells when challenged with submaximal concentrations of bradykinin, adenosine 5'-triphosphate, or uridine 5'-triphosphate in the presence of extracellular Ca2+. However, no oscillatory responses were seen after a challenge with lysophosphatidic acid. Therefore, although a number of different Ca2+-mobilizing ligands activate chondrocytes, the differences that occur in the temporal patterning of Ca2+ responses may result in unique mediator-dependent changes in cellular activity.

Adenosine Triphosphate↗

PubMed1989

Graphical and statistical approaches to data analysis for in situ hybridization.

Quantification of gene expression in a morphological context is an invaluable tool for neurobiological investigation. The ability to measure the quantity of specific mRNA molecules at the level of the single neuron permits one to monitor the modulation of complex cell synthetic activity of intact neuron populations. The cells of interest can be contiguous or dispersed in functionally significant patterns throughout a broad anatomical region of the brain. The application of quantitative in situ hybridization is technically difficult and labor intensive. Nevertheless, it has great utility for investigating gene expression from a structural perspective. (1) In situ hybridization permits one to ask questions concerning the anatomical pattern of neuronal gene expression. (2) It permits analyses concerning the initiation of expression, cell location, cell type, and alterations of level of expression within a spatial and temporal context. (3) In cases where blotting methods suggest a message exists at low copy, in situ hybridization permits queries at the single-cell level. For example, in situ hybridization can determine if very few cells are expressing the gene product or if many neurons dispersed throughout a brain region exhibit low mRNA copy number/cell. Quantitative analyses also allow detailed investigation of cell response to physiologically meaningful stimulation. Our application of statistical and numerical methods is a demonstration of the utility of probabilistic models; the mixture distribution accounted for data from both labeled and unlabeled sources. In agreement with many previous investigations, grain density over an unlabeled uniform source (oxytocinergic cells) was suitably described by the Poisson distribution. The population of labeled vasopressinergic cells, however, was best described by the negative binomial distribution. Previous investigations from different fields of biology show that the negative binomial can be used to describe many biological phenomena, and this distribution was considered in at least two previous investigations to evaluate autoradiographic data which did not fit the Poisson function. From a theoretical perspective, the probabilistic relationship between beta-particle decay (a Poisson function) and the distribution of message levels among individual neurons in a cell group (gamma distribution) prompts consideration of the negative binomial. For both data sets the observed variances were larger than the mean, and the labeled portion of the data sets exhibited positive skewness.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Correlation and spectral analysis of relations between single unit discharge and muscle activities.

Correlation and spectral analysis was used to study functional linkages between single-cell discharge in the magnocellular red nucleus and the electromyographic activity of several limb muscles. Long sequences of unit discharge and EMG activity were recorded while feline subjects performed a food retrieval task. Unit discharge and muscle activity were patterned in bursts that corresponded to different phases of the task. There was sufficient variability in the parameters of these bursts to regard the signals as pseudorandom variables, thus facilitating a correlation analysis. Cross-correlation functions computed between unit discharge and each muscle EMG served to characterize the strength and reliability of linkages between a single unit and various limb muscles. Auto-correlation and auto-spectral density functions provided summary measures of the temporal and frequency characteristics of the signals. Power in the signals was concentrated in a behaviorally relevant range (0.2-8 Hz). Coherence functions showed peaks that indicated which frequency components were well correlated with unit discharge. Two-sided impulse responses served to characterize the dynamic properties of the linkages. These methods are shown to be valuable in characterizing noncausal, as well as causal, linkages through multisynaptic pathways in the nervous system.

Action Potentials↗

PubMed1997

Synchronicity of nociceptive and non-nociceptive adjacent neurons in the spinal dorsal horn of the rat: stimulus-induced plasticity.

Current knowledge of spinal processing of sensory information is largely based on single-cell recordings; however, temporal correlation of multiple cell discharges may play an important role in sensory encoding, and single electrode recordings of several neurons may provide insights into the functions of a neuronal network. The technique was applied to the lumbar spinal dorsal horn of pentobarbital-anaesthetized rats during background activity, steady-state noxious heat stimulation (48 degrees C, 100 s), cold block spinalization or radiant heat-induced inflammation of the skin, and the recordings were evaluated by means of auto-correlation, autospectral and cross-correlation analysis. Background patterns obtained by these three methods were extremely stable in time. Autocorrelation with short lag peaks was observed in 72.2% of neurons (n = 223). Background correlated discharges were found in 83.6% of the neuron pairs (n = 134). Cross-correlation with a central peak, suggestive of common input to the recorded cells, was the most common pattern observed in almost all laminae and was associated with high incidence (91.8%) of overlapping receptive fields and with neurons with initial peak autocorrelation pattern. Cross-correlations with central trough were associated with increase autocorrelation patterns. Bilateral peaks in cross-correlation, suggestive of reverberating circuitry, were observed only for pairs of neurons located in laminae IV and V and were associated with rhythmic discharges in one or in both simultaneously-recorded neurons. Lagged peaks or troughs were observed in 4.6% and 2.2% of neuronal pairs, respectively. Long-lasting skin heating induced qualitative changes (pattern changes) in the cross-correlation of 21.6% of the neuron pairs and quantitative changes in 85.7% of them. During skin inflammation qualitative changes in the cross-correlation pattern were observed in 30.8% of the neuron pairs, and quantitative changes (strength and/or synchronization time) in about 57.7% of them. Spinalization induced quantitative changes in cross-correlation in the vast majority of neuron pairs. The results of the present study suggest that discharges of neighbouring spinal dorsal horn neurons are strongly synchronized probably by propriospinal and primary afferent sources. The existence of functional reverberating circuitry was also evidenced. Finally, the functional synchronicity in the spinal dorsal horn presents stimulus-induced plasticity which consists mainly of changes on the strength and/or time of the synchronization and rarely of activation of new connectivities.

Animals↗

PubMedDate not supplied

Fine structure analysis of temporal patterns in the light response of cells in the lateral geniculate nucleus of cat.

This study focuses on the analysis of temporal patterns in the spike train of cells in the lateral geniculate nucleus (LGN) of cat. Two-hundred eighty-three units have been recorded extracellularly in anesthetized animals during visual stimulation with flashing spot stimuli of different size. We used a novel method of temporally local computed interval distributions (intervalogram; Funke & Wörgötter, 1995) to visualize the statistical distribution of interspike intervals during different phases of the visual response. Multimodal interval distributions were observed mainly in X- and Y-ON cells, reflecting the tendency of these cells to fire with preferred intervals during the sustained light response. The shortest preferred interval is called the fundamental interval and the longer ones (higher-order intervals) are, in general, multiples thereof. During increasing surround inhibition a redistribution of the intervals towards the higher orders was observed. We regarded the different in the interval distributions as different components of possible temporal spike sequences and performed a pattern search up to the level of five subsequent intervals. While it is obvious, that the dominant peak is most strongly represented in any interval sequence, we also show that a significant overrepresentation of short sequences of similar intervals exists. The repetition rate is rather small (4-5 intervals) and, therefore, no long-lasting oscillatory pattern was observed in the autocorrelograms. Power spectral analysis of the peristimulus-time histograms, however, revealed that the sequential firing pattern is strongly stimulus locked at least for the majority of sweeps in the records. The mean firing rate of an LGN cell decreases with increasing stimulus size as well as with decreasing contrast. Therefore, the mean rate cannot be used to distinguish between these situations. While in the whole network this tradeoff can be resolved by the combined activity of multiple cells, our findings additionally suggest that contrast and size can be distinguished already at the single-cell level using different temporal patterns.

Animals↗

PubMed1998

Laser-micropipet combination for single-cell analysis.

Due to its potential for exquisite mass detection limits and resolving power, capillary electrophoresis is used for biochemical measurements on single cells; however, accurate measurements of many physiological parameters require sampling strategies that are considerably faster than those presently available. We have developed a laser-based technique to lyse single, adherent, mammalian cells on millisecond time scales. The cellular contents are then introduced into a capillary where electrophoretic separation and detection are performed. Improved temporal resolution of biological measurements results from the extremely rapid lysis made possible by this method. Additionally, the cell is not perturbed by mechanical or electrical stresses prior to sampling. Such disturbances can alter cellular physiology, resulting in inaccurate measurements. The fast cell lysis, the absence of cellular stresses prior to lysis, and the application to adherent mammalian cells are significant refinements to CE-based measurements on single cells. With this laser-micropipet combination, it will be possible to measure the intracellular concentration of molecules that change on subsecond to second time scales, for example, substrates of many cellular enzymes.

Animals↗

PubMed2021

Epigenetically regulated digital signaling defines epithelial innate immunity at the tissue level.

To prevent damage to the host or its commensal microbiota, epithelial tissues must match the intensity of the immune response to the severity of a biological threat. Toll-like receptors allow epithelial cells to identify microbe associated molecular patterns. However, the mechanisms that mitigate biological noise in single cells to ensure quantitatively appropriate responses remain unclear. Here we address this question using single cell and single molecule approaches in mammary epithelial cells and primary organoids. We find that epithelial tissues respond to bacterial microbe associated molecular patterns by activating a subset of cells in an all-or-nothing (i.e. digital) manner. The maximum fraction of responsive cells is regulated by a bimodal epigenetic switch that licenses the TLR2 promoter for transcription across multiple generations. This mechanism confers a flexible memory of inflammatory events as well as unique spatio-temporal control of epithelial tissue-level immune responses. We propose that epigenetic licensing in individual cells allows for long-term, quantitative fine-tuning of population-level responses.

Animals↗

PubMed1998

Cardiac arrest in rodents: maximal duration compatible with a recovery of neuronal activity.

We report here that during a permanent cardiac arrest, rodent brain tissue is "physiologically" preserved in situ in a particular quiescent state. This state is characterized by the absence of electrical activity and by a critical period of 5-6 hr during which brain tissue can be reactivated upon restoration of a simple energy (glucose/oxygen) supply. In rat brain slices prepared 1-6 hr after cardiac arrest and maintained in vitro for several hours, cells with normal morphological features, intrinsic membrane properties, and spontaneous synaptic activity were recorded from various brain regions. In addition to functional membrane channels, these neurons expressed mRNA, as revealed by single-cell reverse transcription-PCR, and could synthesize proteins de novo. Slices prepared after longer delays did not recover. In a guinea pig isolated whole-brain preparation that was cannulated and perfused with oxygenated saline 1-2 hr after cardiac arrest, cell activity and functional long-range synaptic connections could be restored although the electroencephalogram remained isoelectric. Perfusion of the isolated brain with the gamma-aminobutyric acid A receptor antagonist picrotoxin, however, could induce self-sustained temporal lobe epilepsy. Thus, in rodents, the duration of cardiac arrest compatible with a short-term recovery of neuronal activity is much longer than previously expected. The analysis of the parameters that regulate this duration may bring new insights into the prevention of postischemic damages.

Animals↗

PubMedDate not supplied

Correlation of unit recordings with regional cell counts in epileptogenic human temporal lobe.

The previously reported diminished incidence of neuronal activity recorded from areas ipsilateral to a seizure focus may result from either cell loss or pathophysiologic changes in hippocampus and related structures. We examined records of single-cell discharge from 471 electrode bundles in 62 patients who later had cell counts taken from samples of resected tissue. Analysis of variance showed that amygdala and parahippocampal gyrus had more activity than hippocampus and the subicular complex and that the resected side had less activity overall. Only the posterior subicular complex showed more high-amplitude (> 50 microV) activity on the epileptogenic side; all other areas showed more activity contralaterally. Activity between 25 and 50 microV did not differ across sides or structures. Percentage of maximal cell count was correlated with the number of electrodes with high-amplitude activity only in the subicular complex. Low-amplitude activity in nonresected hippocampus, however, was strongly negatively correlated with cell counts on the resected side, perhaps owing to compensatory mechanisms. Cell counts in hippocampus correlated negatively with high-amplitude unit activity in resected amygdala, suggesting reciprocity between these areas. These results suggest that the amount of cell activity recorded from mesiotemporal structures involves bilateral factors more complex than simple cell loss.

Amygdala↗

PubMed1991

Acute electrophysiological responses of bradykinin-stimulated human fibroblasts.

1. Acute responses to bradykinin in human dermal fibroblasts were studied at 20-24 degrees C using both the patch-clamp technique to monitor ion currents and Fura-2 fluorescence to monitor [Ca2+]i. 2. During subconfluent culture, human dermal fibroblasts can express a diversity of ion channels as described in the preceding paper. 3. When GTP (1 mM) was included in the pipette solution, two additional ion channel populations were transiently augmented in response to bradykinin stimulation. 4. The first is a component of outwardly rectifying current which reached maximal induction within 10-15 s after bradykinin addition (1 microM) and then decayed back to near baseline over 60 s. 5. Ion substitution experiments combined with tail current analysis indicate that the outward current is carried predominantly by K+. 6. Video imaging of single-cell Fura-2 fluorescence from both intact cells and patch-clamped cells showed temporal correlation of the K+ current modulation and the Ca2+ transients in response to bradykinin stimulation. 7. The calcium ionophore, ionomycin, caused both an increase in intracellular calcium and the augmentation of the outward K+ current. The amount of additional K+ current was correlated with [Ca2+]i levels and could be elicited even without the presence of GTP in the pipette. 8. Apamin, a blocker of Ca(2+)-activated K+ channels, inhibited (at 1 microM) the ionomycin-induced modulation of K+ current. 9. In addition, an inward current was transiently induced in response to bradykinin. This current was strictly dependent on the presence of GTP in the pipette solution. This current showed little voltage dependence, as evidenced by a linear current vs. voltage relation, and a reversal potential near but measurably more positive than 0 mV. 10. This current could be decoupled from the Ca2+ transient and be irreversibly induced by including GTP gamma S (100 microM) in the pipette solution. 11. Ion substitution experiments show that this is a non-specific cation channel. This current prefers monovalents but exhibits a small permeability to divalents. 12. GTP gamma S-induced single channels from isolated outside-out patches showed similar ion selectivity and voltage dependence. These channels are 32 pS in size with an estimated reversal potential of 17 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Bradykinin↗

PubMed1994

Receptive-field maps of correlated discharge between pairs of neurons in the cat's visual cortex.

1. To investigate the functional significance of temporally correlated discharge between nearby cells in the visual cortex, we obtained receptive-field maps of correlated discharge for 68 cell pairs in kittens and cats. Discharge from cell pairs was measured by a single extracellular electrode. A reverse correlation procedure was used to relate neural discharge to particular stimuli within a random sequence of briefly flashed bright and dark bars. Bicellular receptive fields (BRFs) were mapped by applying reverse correlation to approximately synchronous discharge from two cells. Unicellular receptive fields (URFs) were simultaneously mapped by separately applying reverse correlation to the discharge of each cell. 2. The receptive fields of the two neurons within each pair were initially studied by varying the orientation and spatial frequency of drifting sinusoidal gratings. After these tests a random sequence of appropriately oriented bars was used to evoke discharge suitable for reverse correlation analysis. For most cell pairs, the temporal pattern or strength of correlated discharge produced by such stimulation is different from that observed with stimulation by sinusoidal gratings. This indicates that visually evoked correlated discharge between nearby cells is stimulus dependent. 3. BRFs were classified according to their pattern of spatial sensitivity into three groups that roughly correspond to the single-cell receptive-field types of the lateral geniculate nucleus (LGN; center-surround) and visual cortex (simple and complex). These classifications were compared with the receptive-field types of the single cells within each pair. LGN-type and simple-type BRFs were only seen for pairs in which at least one of the cells was simple. Conversely, complex-type BRFs were only seen for pairs in which at least one of the cells was complex. 4. Because the reverse correlation procedure can be used to characterize the spatiotemporal receptive-field structure of simple cells, we were able to compare both the spatial and temporal properties associated with the URFs and BRFs of simple cell pairs. The spatiotemporal structure of the BRF of a simple-cell pair can largely be predicted on the basis of the two URFs. Although this prediction suggests the possibility that BRFs are stimulus artifacts, a shuffle procedure, in which multiple repetitions of random sequences were presented, verifies the neural origin of BRFs. BRFs emerge from specific neural pathways and are not simply a consequence of unicellular response preferences. 5. Five measures were derived from the reverse correlation analysis of simple-cell receptive fields: width, duration, optimal spatial and temporal frequency, and optimal velocity.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗

PubMed1999

In vivo intracellular analysis of granule cell axon reorganization in epileptic rats.

In vivo intracellular recording and labeling in kainate-induced epileptic rats was used to address questions about granule cell axon reorganization in temporal lobe epilepsy. Individually labeled granule cells were reconstructed three dimensionally and in their entirety. Compared with controls, granule cells in epileptic rats had longer average axon length per cell; the difference was significant in all strata of the dentate gyrus including the hilus. In epileptic rats, at least one-third of the granule cells extended an aberrant axon collateral into the molecular layer. Axon projections into the molecular layer had an average summed length of 1 mm per cell and spanned 600 microm of the septotemporal axis of the hippocampus-a distance within the normal span of granule cell axon collaterals. These findings in vivo confirm results from previous in vitro studies. Surprisingly, 12% of the granule cells in epileptic rats, and none in controls, extended a basal dendrite into the hilus, providing another route for recurrent excitation. Consistent with recurrent excitation, many granule cells (56%) in epileptic rats displayed a long-latency depolarization superimposed on a normal inhibitory postsynaptic potential. These findings demonstrate changes, occurring at the single-cell level after an epileptogenic hippocampal injury, that could result in novel, local, recurrent circuits.

Action Potentials↗

PubMed2026

Single-cell transcriptomic atlas of Alzheimer's disease middle temporal gyrus reveals region, cell type, and sex specificity of gene expression with novel genetic risk for MERTK in female.

BackgroundAlzheimer's disease (AD), the most common age-related neurodegenerative disease, is closely associated with both amyloid-β plaque and neuroinflammation. Two thirds of AD patients are female, and they have a higher disease risk; women with AD have more extensive brain histological changes than men along with more severe cognitive symptoms and neurodegeneration.ObjectiveThis study aimed to determine how sex difference induces structural brain changes and molecular cell vulnerabilities in AD, with a focus on identifying sex-specific transcriptional alterations and genetic risk factors.MethodsWe performed single nucleus RNA sequencing on postmortem brains from individuals with AD and age- and sex-matched controls, focusing on the middle temporal gyrus, a cortical brain region strongly affected by the disease, and integrated single nucleus RNA sequencing results with genome-wide association study (GWAS) data using cell type-specific enrichment and generalized gene-set analysis approaches. The analysis pipeline is provided with threshold information.ResultsWe identified a selectively vulnerable subpopulation of layer 2/3 excitatory neurons that were RORB-negative and CDH9-expressing in both males and females. Disease-associated, but sex-independent, reactive astrocyte signatures were also present. In clear contrast, the microglia signatures of AD brains differed between males and females. Integrating single cell transcriptomic data with results from GWAS, we identified MERTK genetic variation as a candidate novel risk factor for AD selectively in females.ConclusionsTaken together, our single cell atlas of middle temporal gyrus revealed a unique cellular-level view of sex-specific transcriptional changes in AD, illuminating GWAS identification of sex-specific AD genes. These data serve as a rich resource for interrogation of the molecular and cellular basis of AD.

Alzheimer's disease↗