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opencc-zeroNov 2022View details →

Precise and stable edge orientation signaling by human first-order tactile neurons

Fast-adapting type 1 (FA-1) and slow-adapting type 1 (SA-1) first-order neurons in the human tactile system have distal axons that branch in the skin and form many transduction sites, yielding receptive fields with many highly sensitive zones or 'subfields'. We previously demonstrated that this arrangement allows FA-1 and SA-1 neurons to signal the geometric features of touched objects, specifically the orientation of raised edges scanned with the fingertips. Here we show that such signaling operates for fine edge orientation differences (5–20°) and is stable across a broad range of scanning speeds (15–180 mm/s); that is, under conditions relevant for real-world hand use. We found that both FA-1 and SA-1 neurons weakly signal fine edge orientation differences via the intensity of their spiking responses and only when considering a single scanning speed. Both neuron types showed much stronger edge orientation signaling in the sequential structure of the evoked spike trains and FA-1 neurons performed better than SA-1 neurons. Represented in the spatial domain, the sequential structure was strikingly invariant across scanning speeds, especially those naturally used in tactile spatial discrimination tasks. This speed invariance suggests that neurons' responses are structured via sequential stimulation of their subfields and thus links this capacity to their terminal organization in the skin. Indeed, the spatial precision of elicited action potentials rationally matched spatial acuity of subfield arrangements, which corresponds to a spatial period similar to the dimensions of individual fingertip ridges.

opencc-zeroDec 2022View details →

Clonally related, Notch-differentiated spinal neurons integrate into distinct circuits EPhys raw data

Shared lineage has diverse effects on patterns of neuronal connectivity. In mammalian cortex, excitatory sister neurons assemble into shared microcircuits, whereas throughout the Drosophila nervous system, Notch-differentiated sister neurons diverge into distinct circuits. Notch-differentiated sister neurons have been observed in vertebrate spinal cord and cerebellum, but whether they integrate into shared or distinct circuits remains unknown. Here we evaluate the connectivity between sister V2a/b neurons in the zebrafish spinal cord. Using an in vivo labeling approach, we identified pairs of sister V2a/b neurons born from individual Vsx1+ progenitors and observed that they have similar axonal trajectories and proximal somata. However, paired whole-cell electrophysiology and optogenetics revealed that sister V2a/b neurons receive input from distinct presynaptic sources, do not communicate with each other, and connect to largely distinct targets. These results resemble the divergent connectivity in Drosophila and represent the first evidence of Notch-differentiated circuit integration in a vertebrate system.

Data for: Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn

Spinally-projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on pain perception. Our tracing experiments revealed an unexpected high selectivity of serotonergic neurons of the LPGi for transduction with spinally injected AAV2retro vectors while medial hindbrain serotonergic neurons were largely resistant to AAV2retro transduction. Taking advantage of this selectivity, we employed intersectional chemogenetic approaches to demonstrate that activation of the LPGi serotonergic projections decreases thermal sensitivity, whereas activation of medial serotonergic neurons increases sensitivity to mechanical von Frey stimulation. Together these results suggest that there are functionally distinct classes of serotonergic hindbrain neurons that differ in their anatomical location in the hindbrain, their postsynaptic targets in the spinal cord, and impact on nociceptive sensitivity. At least the LPGi neurons give rise to rather global and bilateral projections throughout the rostrocaudal extent of the spinal cord suggesting that they contribute to widespread systemic pain control.

Data from: No evidence for sex differences in the electrophysiological properties and excitatory synaptic input onto nucleus accumbens shell medium spiny neurons

Sex differences exist in how the brain regulates motivated behavior and reward, both in normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the dorsal striatum and nucleus accumbens core and shell. These investigations yield accumulating evidence of sexually different electrophysiological properties, excitatory synaptic input, and sensitivity to neuromodulator/hormone action in select striatal regions both before and after puberty. It is unknown whether the electrical properties of neurons in the nucleus accumbens shell differ by sex and whether sex differences in excitatory synaptic input are present before puberty. To test the hypothesis that these properties differ by sex, we performed whole-cell patch-clamp recordings on male and female medium spiny neurons (MSNs) in acute brain slices obtained from prepubertal rat nucleus accumbens shell. We analyzed passive and active electrophysiological properties, and miniature EPSCs (mEPSCs). No sex differences were detected; this includes those properties, such as intrinsic excitability, action potential after hyperpolarization, threshold, and mEPSC frequency, that have been found to differ by sex in other striatal regions and/or developmental periods. These findings indicate that, unlike other striatal brain regions, the electrophysiological properties of nucleus accumbens shell MSNs do not differ by sex. Overall, it appears that sex differences in striatal function, including motivated behavior and reward, are likely mediated by other factors and striatal regions.

SUMOylation of NaV1.2 channels regulates the velocity of backpropagating action potentials in cortical pyramidal neurons

Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and backpropagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes backpropagation of APs to the soma. Here, we show the Small Ubiquitin-like Modifier (SUMO) pathway modulates persistent sodium current (INaP) generation at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.

opencc-by-4.0Feb 2023View details →

Dataset related to article "MASSIVE IRON ACCUMULATION IN PKAN-DERIVED NEURONS AND ASTROCYTES: LIGHT ON THE HUMAN PATHOLOGICAL PHENOTYPE"

The database contains the microxygraphy data included in the article at title

Data from: Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies

The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate-limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain-neutral lipids (the core component of lipid droplets), and whole head metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

opencc-zeroMar 2023View details →

A custom-made AAV1 variant (AAV1-T593K) enables efficient transduction of Japanese quail neurons in vitro and in vivo

The widespread use of rodents in neuroscience has prompted the development of optimized viral variants for transduction of brain cells, in vivo. However, many of the viruses developed are less efficient in other model organisms, with birds being among the most resistant to transduction by current viral tools. Resultantly, the use of genetically-encoded tools and methods in avian species is markedly lower than in rodents; likely holding the field back. We sought to bridge this gap by developing custom viruses towards the transduction of brain cells of the Japanese quail. We first develop a protocol for culturing primary neurons and glia from quail embryos, followed by characterization of cultures via immunostaining, single-cell mRNA sequencing, patch clamp electrophysiology and calcium imaging. We then leverage the cultures for the rapid screening of various viruses, only to find that all yielded poor to no infection of cells in vitro. However, few infected neurons were obtained by AAV1 and AAV2. Scrutiny of the sequence of the AAV receptor found in quails led us to rationally design a custom-made AAV variant (AAV1-T593K; AAV1*) that exhibits improved transduction efficiencies in vitro and in vivo (eight- and five-fold, respectively). Together, we present a unique culturing method, transcriptomic profiles of quail's brain cells and a custom-tailored AAV1 for transduction of quail neurons in vitro and in vivo.

opencc-zeroMar 2023View details →

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion

Structural, functional, and molecular reorganization of denervated neural networks is often observed in neurological conditions. The loss of input is accompanied by homeostatic synaptic adaptations, which can affect the reorganization process. A major challenge of denervation-induced homeostatic plasticity operating in complex neural networks is the specialization of neuronal inputs. It remains unclear whether neurons respond similarly to the loss of distinct inputs. Here, we used in vitro entorhinal cortex lesion (ECL) and Schaffer collateral lesion (SCL) in mouse organotypic entorhino-hippocampal tissue cultures to study denervation-induced plasticity of CA1 pyramidal neurons. We observed microglia accumulation, presynaptic bouton degeneration, and a reduction in dendritic spine numbers in the denervated layers three days after SCL and ECL. Transcriptome analysis of the CA1 region revealed complex changes in differential gene expression following SCL and ECL compared to non-lesioned controls with a specific enrichment of differentially expressed synapse-related genes observed after ECL. Consistent with this finding, denervation-induced homeostatic plasticity of excitatory synapses was observed three days after ECL but not after SCL. Chemogenetic silencing of the EC but not CA3 confirmed the pathway-specific induction of homeostatic synaptic plasticity in CA1. Additionally, increased RNA oxidation was observed after SCL and ECL. These results reveal important commonalities and differences between distinct pathway lesions and demonstrate a pathway-specific induction of denervation-induced homeostatic synaptic plasticity.

opencc-by-4.0Mar 2023View details →

Plasticity of neuronal dynamics in the lateral habenula for cue-punishment associative learning.

The brain’s ability to associate threats with external stimuli is vital to execute essential behaviours including avoidance. Disruption of this process contributes instead to the emergence of pathological traits which are common in addiction and depression. However, the mechanisms and neural dynamics at the single-cell resolution underlying the encoding of associative learning remain elusive. Here, employing a Pavlovian discrimination task in mice we investigate how neuronal populations in the lateral habenula (LHb), a subcortical nucleus whose excitation underlies negative affect, encode the association between conditioned stimuli and a punishment (unconditioned stimulus).

opencc-by-4.0Apr 2023View details →

Xenon's sedative effect is at least partly mediated by interaction with the cyclic nucleotide-binding domain (CNBD) of HCN2 channels expressed by thalamocortical neurons of the ventrobasal nucleus in mice

Xenon (70%xenon, 30%O2) application in the last 10 min of the open field test manage to sedate wild-type mice but not HCN2EA. Wild-type mice in the xenon_wild-type video can be seen moving freely in the early minutes but the general activity starts to decrease sharply in the last 2 minutes and is absent between min 9 and 10 while HCN2EA mice in the xenon_HCN2EA can be seen moving throughout the entire time of the xenon gas mixture application.

opencc-zeroApr 2023View details →

Neuronal activation in the geomagnetic responsive region Cluster N covaries with nocturnal migratory restlessness in white-throated sparrows

Cluster N is a region of the visual forebrain of nocturnally migrating songbirds that supports the geomagnetic compass of nocturnal migrants. Cluster N expresses immediate-early genes (ZENK), indicating neuronal activation. This neuronal activity has only been recorded at night during the migratory season. Night-to-night variation in Cluster N activity in relation to migratory behaviour has not been previously examined. We tested whether Cluster N is activated only when birds are motivated to migrate and presumably engage their magnetic compass. We measured immediate-early gene activation in Cluster N of white-throated sparrows (Zonotrichia albicollis) in three conditions: daytime, nighttime migratory restless, and nighttime resting. Birds in the nighttime migratory restlessness group had significantly greater numbers of ZENK-labelled cells in Cluster N compared to both the daytime and the nighttime resting groups. Additionally, the degree of migratory restlessness was positively correlated with the number of ZENK-labelled cells in the nighttime migratory restless group. Our study adds to the number of species observed to have neural activation in Cluster N and demonstrates for the first time that immediate early gene activation in Cluster N is correlated with the amount of active migratory behaviour displayed across sampled individuals. We conclude that Cluster N is facultatively regulated by the motivation to migrate, together with nocturnal activity, rather than obligatorily active during the migration season.

opencc-by-4.0Jun 2023View details →

Hindbrain modules differentially transform activity of single collicular neurons to coordinate movements

Seemingly simple behaviors such as swatting a mosquito or glancing at a signpost involve the precise coordination of multiple body parts. Neural control of coordinated movements is widely thought to entail transforming a desired overall displacement into displacements for each body part. Here we reveal a different logic implemented in the mouse gaze system. Stimulating superior colliculus (SC) elicits head movements with stereotyped displacements but eye movements with stereotyped endpoints. This is achieved by individual SC neurons whose branched axons innervate modules in medulla and pons that drive head movements with stereotyped displacements and eye movements with stereotyped endpoints, respectively. Thus, single neurons specify a mixture of endpoints and displacements for different body parts, not overall displacement, with displacements for different body parts computed at distinct anatomical stages. Our study establishes an approach for unraveling motor hierarchies and identifies a logic for coordinating movements and the resulting pose.

Data for: Isolation of targeted hypothalamic neurons for studies of hormonal, metabolic, and electrical regulation

All original data used in the study published in the Journal of Visualized Experiments entitled: "Isolation of Targeted Hypothalamic Neurons for Studies of Hormonal, Metabolic, and Electrical Regulation" by Kathera-Ibarra-Forzisi et al. are provided in this dataset. Data are organized in sub-folders containing either confocal or bright-field images of primary hypothalamic neurons. The dataset does not contain analyses or measurements. For each figure of the paper, the data are organized in sub-folders corresponding to a specific experimental condition. The sub-folders are labeled with the corresponding figure number and the salient experimental conditions. For example, the sub-folder labeled "confocal images figure 3" contains all the original confocal images from which the representative images of the figure were chosen from. Likewise, the folder "LepR+ figure 3" contains all the images of neurons immunolabeled with LepR antibody. Data can be used by a third party for verification purposes but cannot be used for publication. Abstract of the study: The hypothalamus regulates fundamental metabolic processes by controlling functions as varied as food intake, body temperature, and hormone release. As the functions of the hypothalamus are controlled by specific subsets of neuronal populations, the ability to isolate them provides a major tool for studying metabolic mechanisms. In this regard, the neuronal complexity of the hypothalamus poses exceptional challenges. For these reasons, new techniques, such as Magnetic-Activated Cell Sorting (MACS), have been explored. This paper describes a new application of magnetic-activated cell sorting (MACS) using microbead technology to isolate a targeted neuronal population from prenatal mice brains. The technique is simple and guarantees a highly pure and viable primary hypothalamic neuron culture with high reproducibility. The hypothalamus is gently dissociated, neurons are selectively isolated and separated from glial cells, and finally, using a specific antibody for a cell surface marker, the population of interest is selected. Once isolated, targeted neurons can be used to investigate their morphological, electrical, and endocrine characteristics and their responses in normal or pathological conditions. Furthermore, given the variegated roles of the hypothalamus in regulating feeding, metabolism, stress, sleep, and motivation, a closer look at targeted and region-specific neurons may provide insight into their tasks in this complex environment.

opencc-by-4.0Jul 2023View details →

NEATmap: a high-efficiency deep learning approach for whole mouse brain neuronal activity trace mapping

Here are some demo datasets for validating the NEATmap pipeline for high-efficiency whole brain c-Fos+ cell automated segmentation and quantitative analysis, including: <ol> <li>BrainImage_group.zip.001-007: Validation of NEATmap for automated segmentation and quantitative analysis of mouse whole-brain c-Fos activity images (in Forced Swimming Test).</li> <li>Segmentation_result.zip: Figure 1a, Supplementary Videos 1 and 2 show dual-channel brain slices and segmentation results. They can be merged using Imaris to validate the segmentation results of NEATmap.</li> <li>RawImage_example.zip: High-resolution 3D images of mouse brain slices showing c-Fos+ cells in Figure 1e.</li> </ol> Due to the total size of the mouse whole-brain image datasets (both raw and processed) included in all the tests exceeding 10 Terabytes, uploading it to a public data repository is impractical. In this work, we provide a dataset of dual-channel (c-Fos+ channel and autofluorescence channel in forced swimming test experimental group) whole-brain images of mouse for the validation of NEATmap automated segmentation method.

Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification, and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs. SST-positive interneurons. We find that there are robust molecular differences in synapse-associated genes between these neuron types, and that individual presynaptic pyramidal neurons evoke postsynaptic responses with heterogeneous synaptic dynamics in different postsynaptic cell types. Using molecular identification with FISH and classifiers based on transcriptomically identified PVALB neurons analyzed by Patch-seq, we find that PVALB neurons typically show depressing synaptic characteristics, whereas other interneuron types including SST-positive neurons show facilitating characteristics. Together, these data support the existence of target cell-specific synaptic properties in human cortex that are similar to rodents, thereby indicating evolutionary conservation of local circuit connectivity motifs from excitatory to inhibitory neurons and their synaptic dynamics.

The neuronal implementation of representational geometry in primate prefrontal cortex

Modern neuroscience has seen the rise of a population-doctrine that represents cognitive variables using geometrical structures in activity space. Representational geometry does not, however, account for how individual neurons implement these representations. Here, leveraging the principle of sparse coding, we present a framework to dissect representational geometry into biologically interpretable components that retain links to single neurons. Applied to extracellular recordings from the primate prefrontal cortex in a working memory task with interference, the identified components revealed disentangled and sequential memory representations including the recovery of memory content after distraction, signals hidden to conventional analyses. Remarkably, each component was contributed by small subpopulations of neurons with distinct electrophysiological properties and response dynamics. Modelling showed that such sparse implementations are supported by recurrently connected circuits as in prefrontal cortex. The perspective of neuronal implementation links representational geometries to their cellular constituents, providing mechanistic insights into how neural systems encode and process information.

Motor cortex analogue neurons in songbirds utilize Kv3 subunits to generate ultranarrow spikes

Complex motor skills in vertebrates require specialized upper motor neurons with precise action potential (AP) firing. To examine how diverse populations of upper motor neurons subserve distinct functions and the specific repertoire of ion channels involved, we conducted a thorough study of the excitability of upper motor neurons controlling somatic motor function in the zebra finch. We found that robustus arcopallialis projection neurons (RAPNs), key command neurons for song production, exhibit ultranarrow spikes and higher firing rates compared to neurons controlling non-vocal somatic motor functions (AId neurons). Pharmacological and molecular data indicate that this striking difference is associated with the higher expression in RAPNs of high threshold, fast-activating voltage-gated Kv3 channels likely containing Kv3.1 subunits. The spike waveform and Kv3.1 expression in RAPNs mirror properties of Betz cells, specialized upper motor neurons involved in fine digit control in humans and other primates but absent in rodents. Our study thus provides evidence that songbirds and primates have convergently evolved the use of Kv3.1 to ensure precise, rapid AP firing in upper motor neurons controlling fast and complex motor skills.

opencc-by-4.0Jul 2023View details →

Ca2+ imaging data for: A rigidity transition of MEC-2/Stomatin condensates controls neuronal mechanotransduction during touch sensing

Calcium imaging data from Sanfeliu et al, NCB, 2023. Project contains fluorescence data to characterize the activity of the touch receptor neurons (TRNs) - which are mechanically activated upon touch – in the model organism Caenorhabditis elegans. The set of data includes wild-type animals as a reference and two different mutants to understand their role during touch sensation: MEC-2(R385H) and UNC-89 knock-out.