bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, March 20th, 2025
| Time |
Event |
| 3:30a |
Serotonergic signaling governs C. elegans sensory response to conflicting olfactory stimuli
Neural circuits that consolidate sensory cues are essential for neurological functioning. Neural circuits that perform sensory integration can vary greatly because the sensory processing regions of the brain employ various neural motifs. Here, we investigate a neural circuit that mediates the response to conflicting olfactory stimuli in C. elegans. We concurrently expose animals to an aversive dispersal pheromone, osas#9, and an attractive bacterial extract. While worms usually avoid osas#9 alone, they suppress this avoidance behavior in the presence of a bacterial extract. Loss-of-function mutants and cell-specific rescues reveal that serotonergic signaling from the ADF neuron is essential for bacterial extract-induced osas#9 avoidance attenuation. The inhibitory serotonin receptor, MOD-1, which is widely expressed on interneurons and motor neurons, is required for this sensory integration, suggesting that serotonin acts in an inhibitory manner. By performing calcium imaging on the ADF neurons in synaptic signaling (unc-13) and peptidergic (unc-31) signaling mutant backgrounds, we show that the ADF neurons require input from other neurons, likely the ASK neurons, to respond to food extracts. We reveal a cue integration neural circuit in which serotonergic signaling at the sensory neuron level silences an aversive neural signal. | | 3:30a |
An entropic measure of diverse specialisation highlights multifunctional neurons in annotated connectomes
The creation and curation of synaptic-level neuronal networks, or connectomes, enables the study of the relationship between structure and function of these networks. Topological characteristics of neuronal networks have been studied extensively. Separately there have been considerable efforts to classify the morphology, cell types, and lineages of neurons. Here we introduce a network metric that combines topological analysis with node metadata. This entropic quantity measures the diversity of incoming or outgoing connections to a node in terms of the metadata distribution. We find that in emph{C. elegans}, the top-scoring neurons in terms of this metric have known functions that integrate and disseminate multimodal information involved in sensorimotor functions. In the nerve cord of emph{Drosophila melanogaster}, we find that the top-scoring neurons are located in the abdominal neuropil, where sensorimotor coordination is required for complex innate behaviour such as mating. | | 3:30a |
Functional Connectivity Alterations in Spinocerebellar Ataxia Type 10: Insights from Gray Matter Atrophy
Spinocerebellar ataxia type 10 (SCA10) is a rare, inherited neurological disorder caused by an expansion of the non-coding ATTCT pentanucleotide repeat in the ATAXIN 10 gene. It is characterized by cerebellar ataxia and epilepsy. Previous research has demonstrated extensive white and gray matter degeneration, particularly in the cerebellum. However, the impact of the SCA10 mutation on functional connectivity (FC) remains unexplored. This study aimed to characterize intrinsic FC changes in SCA10 patients and their relationship to clinical manifestations. Structural and resting-state MRIs were obtained from 26 SCA10 patients and 26 control subjects. Voxel-based morphometry (VBM) and seed-ROI and Independent Components Analysis (ICA) were performed to identify cerebral atrophy and FC changes respectively. Additionally, correlation analyses were conducted between FC changes and scores from the Scale for the Assessment and Rating of Ataxia (SARA) and the Montreal Cognitive Assessment (MoCA). In SCA10 patients, VBM analysis revealed extensive gray matter loss in motor cortices and the cerebellum. FC analysis identified significant FC changes originating from seed-ROIs in the right cerebellar VI and left precentral gyrus. Furthermore, group comparison using ICA components showed that SCA10 patients exhibited higher FC in the sensorimotor and cerebellar functional networks. Moreover, the average BOLD signal within the cerebellar network negatively correlated with MoCA scores. In summary, SCA10 patients exhibited enhanced FC in brain regions that displayed gray matter atrophy, underscoring the impact of SCA10 degeneration on resting state networks and induction of potential maladaptive FC compensatory mechanisms. | | 4:37a |
Preferred spatial frequency covaries with cortical magnification in human primary visual cortex
A comprehensive description of the organizational principles of human primary visual cortex (V1) requires an understanding of how V1 neural properties covary across the cortical map. We used fMRI to quantify V1 preferred spatial frequency and cortical magnification as a function of both eccentricity and polar angle, and across individual observers (n=40). We found that the two measurements: (1) declined proportionally with eccentricity; (2) covaried systematically with polar angle, but with variation in cortical magnification double that of preferred spatial frequency; and (3) covaried across individuals. These data reveal a link between V1 preferred spatial frequency and cortical magnification within observers -as a function of visual field location- and between observers -when summed over visual field location. These results suggest that to a large degree, these two measurements of cortex develop in a coordinated manner, consistent with the hypothesis of a canonical cortical circuit. | | 4:37a |
Pre- and postsynaptic mechanisms of neuronal inhibition assessed through biochemically detailed modelling of GABAB receptor signalling
GABAB receptors (GABABRs) are an important building block in neural activity. Despite their widely hypothesized role in many basic neuronal functions and mental disorder symptomatology, there is a lack of biophysically and biochemically detailed models of these receptors and the way they mediate neuronal inhibition. Here, we developed a computational model for the activation of GABABRs and its effects on the activation of G protein-coupled inwardly rectifying potassium (GIRK) channels as well as inhibition of voltage-gated Ca2+ channels. To ensure the generality of our modelling framework, we fit our model to electrophysiological data including patch-clamp and intracellular recordings that described both pre- and postsynaptic effects of the receptor activation. We validated our model using data on postsynaptic effects of GABABRs on layer V pyramidal cell firing activity ex vivo and in vivo and confirmed the strong impact of dendritic GIRK channel activation on the neuron output. Finally, we reproduced and dissected the effects of a knockout of RGS7 (a G protein signalling protein) on CA1 pyramidal cell electrophysiological properties, which shows the potential of our model in generating insights on genetic manipulations of the GABABR system and related genetic variants. Our model thus provides a flexible tool for biochemically and biophysically detailed simulations of different aspects of GABABR activation that can reveal both foundational principles of neuronal dynamics and brain disorder-associated traits and treatment options. | | 6:18a |
Structural Connectivity Correlates of Response to Electroconvulsive Therapy in Treatment-Resistant Depression
Background: Electroconvulsive therapy (ECT) is the most effective option for treatment resistant depression (TRD). In this study, we sought to explore if structural connectivity of limbic networks has an association with response to ECT. Methods: We studied 23 patients with TRD who underwent a course of bifrontal ECT, employing probabilistic tractography at baseline to assess structural connectivity between the thalamus (THA), posterior (PCC), subgenual cingulate cortices, anterior insula (aINS), amygdala and orbitofrontal and ventrolateral prefrontal cortices, hypothesizing that these hubs participate in the formation and refractoriness of depression symptoms. We also include 21 healthy subject as controls group (HC). Results: Connectivity between left THA and left PCC was related to both baseline depression severity (R=0.504; p= 0.017) and clinical response (R=0.452; p=0.004). Right aINS-prefrontal connectivity was associated with less clinical response. Structural connectivity was globally higher in patients than in HC (F=2.488; p=0.007). Conclusions: The association of ECT response with stronger structural connectivity between hubs supporting self-referential bodily experience as well as autobiographical memory encoding and retrieval deserves exploration as a predictor in persons with TRD. In turn, the right aINS is a major hub for the salience network and is involved in repetitive negative mentation. Stronger structural connectivity of this region may be a heuristically valid biomarker for refractory TRD. We discuss the potential of the present findings for the design of anatomically precise neuromodulation interventions that would be useful to treat TRD while circumventing cognitive side effects of ECT. | | 6:18a |
The cognitive and neural bases of creative thought: a cross-domain meta-analysis of transcranial direct current stimulation studies
Creative thought enables humans to flexibly generate, evaluate and select novel and adaptive ideas according to different contexts. Decades of creativity research indicates that it involves at least two aspects: retrieval of previously acquired knowledge and manipulation of that knowledge. However, the cognitive processes underpinning these two aspects of creative thought remain underspecified. The broader clinical-cognitive neuroscience literature suggests that retrieval and manipulation of knowledge is underpinned by general purpose cognitive mechanisms supporting semantic cognition, controlled episodic memory retrieval, and executive mechanisms. To identify commonalities from converging evidence that points towards a unifying theory for the neurocognitive bases of creative thought, we reviewed and meta-analysed 152 studies from creativity and the relevant parallel cognitive neuroscience literature using transcranial direct current stimulation (tDCS). The results revealed three things: 1) current tDCS studies are heavily biased towards the frontal cortex (459/591 effect sizes; 77.7%); 2) only anodal tDCS over the left lateral frontal cortex promotes creativity (p <.01); and 3) anodal tDCS stimulation over the same region also promotes improvement in many other cognitive processes. The latter includes more efficient processing of semantic knowledge (p <.05), more accurate episodic memory retrieval (p <.05), better and more efficient manipulation of buffered knowledge (all p <.001), and more efficient response selection amongst competing options (i.e., task-setting; p <.01). By merging these previously separate literatures, tDCS studies support the notion that creative thought arises from general purpose cognitive mechanisms including controlled retrieval and temporary storage of semantic and episodic information, as well as executive mechanisms. | | 8:18a |
Structural Determinants of Signal Speed: A Multimodal Investigation of Face Processing in Autism Spectrum Disorder
Face perception is fundamental to social cognition and often disrupted in autism. However, the neurological basis for this disrupted face perception and the mechanisms underlying altered electrophysiological signaling in autism, such as increased latency of the N170-an electrophysiological marker of face processing, remain unknown. Here, we leverage multimodal neuroimaging in autistic adolescents to establish a link between MRI-measured axonal microstructure within the face processing network and EEG-measured N170 latency. We demonstrate that a novel metric of axonal signal transit time derived from axonal diameter, myelination, and length-estimated axonal latency (EAL)-predicts N170 latency during face processing. Moreover, we demonstrate that individuals with and without autism rely upon different pathways, providing a structural account for autism-related face processing differences. By establishing this relationship between EEG-based electrical function and MRI-based axonal microstructure, we provide a non-invasive, spatially-detailed estimate of neuronal processing speed that can inform understanding of brain function, development, and disorder. | | 2:46p |
Serial dependence during visuomotor integration is robust to the passage of time and interference from intervening tasks
When intercepting a moving target, responses are systematically biased toward the time of impact from the previous trial. This phenomenon, known as serial dependence, relies on a memory mechanism that remains poorly understood. In interceptive tasks, multiple stimulus features - such as speed, time, or motor responses - can guide behavior on the current trial and may be stored to influence subsequent trials. Here, we examined how memory decays over short inter-trial intervals (Experiment 1, N = 23) and whether interleaved tasks influence serial dependence (Experiment 2, N = 28). Participants performed either a temporal reproduction task or a speed judgment task, designed to compete for temporal and speed-processing resources, respectively. Our findings reveal that serial dependence persists across all inter-trial durations and remains unaffected by intervening tasks. While serial dependence was neither reduced nor eliminated, variations in responses were partially influenced by prior temporal reproductions from the interfering task. These results suggest that serial dependence in visuomotor tasks is robust to both the passage of time and external interference, though task responses may be subtly modulated by preceding temporal reproductions. | | 3:21p |
Normative high-frequency oscillation phase-amplitude coupling and effective connectivity under sevoflurane
Resective surgery for pediatric drug-resistant focal epilepsy often requires extraoperative intracranial electroencephalography recording to accurately localize the epileptogenic zone. This procedure entails multiple neurosurgeries, intracranial electrode implantation and explantation, and days of invasive inpatient evaluation. There is a need for methods to reduce diagnostic burden and introduce objective epilepsy biomarkers. Our preliminary studies aimed to address these issues by using sevoflurane anesthesia to rapidly and reversibly activate intraoperative phase-amplitude coupling between delta and high-frequency activities, as well as high-frequency activity-based effective connectivity. Phase-amplitude coupling can serve as a proxy for spike-and-wave discharges, and effective connectivity describes the spatiotemporal dynamics of neural information flow among regions. Notably, sevoflurane activated these interictal electrocorticography biomarkers most robustly in areas whose resection led to seizure freedom. However, they were also increased in normative brain regions that did not require removal for seizure control. Before using these electrocorticography biomarkers prospectively to guide resection, we should understand their endogenous distribution and propagation pathways, at different anesthetic stages. In the current study, we highlighted the normative distribution of delta and high-frequency activity phase-amplitude coupling and effective connectivity under sevoflurane. Normative data was derived from nineteen patients, whose ages ranged from four to eighteen years and included eleven males. All achieved seizure control following focal resection. Electrocorticography was recorded at an isoflurane baseline, during stepwise increases in sevoflurane concentration, and also during extraoperative slow-wave sleep without anesthesia. Normative electrode sites were then mapped onto a standard cortical surface for anatomical visualization. Dynamic tractography traced white matter pathways that connected sites with significantly augmented biomarkers. Finally, we analyzed all sites -regardless of normal or abnormal status - to determine whether sevoflurane-enhanced biomarker values could intraoperatively localize the epileptogenic sites. We found that normative electrocorticography biomarkers increased as a function of sevoflurane concentration, especially in bilateral frontal and parietal lobe regions (Bonferroni-corrected p-values <0.05). Callosal fibers directly connected homotopic Rolandic regions exhibiting elevated phase-amplitude coupling. The superior longitudinal fasciculus linked frontal and parietal association cortices showing augmented effective connectivity. Higher biomarker values, particularly at three to four volume percent sevoflurane, characterized epileptogenicity and seizure-onset zone status (Bonferroni-corrected p-values <0.05). Supplementary analysis showed that epileptogenic sites exhibited less augmentation in delta-based effective connectivity. This study helps clarify the normative distribution of, and plausible propagation pathways supporting, sevoflurane enhanced electrocorticographic biomarkers. Future work should confirm that sevoflurane-activated electrocorticography biomarkers can predict postoperative seizure outcomes in larger cohorts, to establish their clinical utility. | | 5:17p |
Oxytocin Receptor Expression and Activation in Parasympathetic Brainstem Cardiac Vagal Neurons
Autonomic imbalance, particularly reduced activity from brainstem parasympathetic cardiac vagal neurons (CVNs) is a major characteristic of many cardiorespiratory diseases. Therapeutic approaches to selectively increase CVN activity have been limited by lack of identified selective translational targets. Recent work has shown that there is an important excitatory synaptic pathway from oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVN) to brainstem CVNs, and that OXT could provide a key selective excitation of CVNs. In clinical studies, intranasal OXT increases parasympathetic cardiac activity, autonomic balance, and reduces obstructive event durations and oxygen desaturations in obstructive sleep apnea patients. However, the mechanisms by which activation of hypothalamic OXT neurons, or intranasal OXT, increases brainstem parasympathetic cardiac activity is poorly understood. CVNs are located in two cholinergic brainstem nuclei: the nucleus ambiguus (NA) and dorsal motor nucleus of the vagus (DMNX). In this study we characterize the co-localization of OXT receptors in CVNs (OXTR), as well as non-CVN cholinergic neurons, located in the NA and DMNX nuclei. Selective chemogenetic excitation of OXTR+ CVNs was performed by expressing DREADDs with a combination of Cre and flp dependent viruses. We found that OXT receptors are highly expressed in CVNs in the DMNX and OXT increases DMNX CVN activity, but the receptors and responses are absent in CVNs in the NA. Selective chemogenetic activation of OXTR+ CVNs in the DMNX evoked a rapid and sustained bradycardia. | | 6:31p |
Two Axes of White Matter Development
Despite decades of neuroimaging research, how white matter develops along the length of major tracts in humans remains unknown. Here, we identify fundamental patterns of white matter maturation by examining developmental variation along major, long-range cortico-cortical tracts in youth ages 5-23 years using diffusion MRI from three large-scale, cross-sectional datasets (total N = 2,710). Across datasets, we delineate two replicable axes of human white matter development. First, we find a deep-to-superficial axis, in which superficial tract regions near the cortical surface exhibit greater age-related change than deep tract regions. Second, we demonstrate that the development of superficial tract regions aligns with the cortical hierarchy defined by the sensorimotor-association axis, with tract ends adjacent to sensorimotor cortices maturing earlier than those adjacent to association cortices. These results reveal developmental variation along tracts that conventional tract-average analyses have previously obscured, challenging the implicit assumption that white matter tracts mature uniformly along their length. Such developmental variation along tracts may have functional implications, including mitigating ephaptic coupling in densely packed deep tract regions and tuning neural synchrony through hierarchical development in superficial tract regions - ultimately refining neural transmission in youth. | | 6:31p |
The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
Traumatic brain injury (TBI) is a major risk factor for neurodegenerative diseases, including Alzheimers disease (AD), yet the mechanistic link remains unclear. Here, we integrated human patient-derived transcriptomics with a 3D in vitro brain injury model to dissect cell-specific mitochondrial dysfunction as a driver of neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a one-of-a-kind cell-specific mitochondria tracking system, we demonstrate prolonged neuronal mitochondrial fragmentation, bioenergetic failure, and metabolic instability, coinciding with the emergence of AD markers, including pTau, APP, and Abeta 42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes failing to maintain metabolic support and microglia sustaining chronic inflammation. These findings establish neuronal mitochondrial failure as an early trigger of injury-induced neurodegeneration, reinforcing mitochondrial dysfunction as a therapeutic target for preventing TBI-driven AD pathology. | | 6:31p |
Benchmarking overlapping community detection methods for applications in human connectomics
Brain networks exhibit non-trivial modular organization, with groups of densely connected areas participating in specialized functions. Traditional community detection algorithms assign each node to one module, but this representation cannot capture integrative, multi-functional nodes that span multiple communities. Despite the increasing availability of overlapping community detection algorithms (OCDAs) to capture such integrative nodes, there is no objective procedure for selecting the most appropriate method and its parameters for a given problem. Here we overcome this limitation by introducing a datadriven method for selecting an OCDA and its parameters from performance on a tailored ensemble of generated benchmark networks, assessing 22 unique algorithms and parameter settings. Applied to the human structural connectome, we find that the Order Statistics Local Optimization Method (OSLOM) best identifies ground-truth overlapping structure in the benchmark ensemble and yields a seven-network decomposition of the human cortex. These modules are bridged by fifteen overlapping regions that generally sit at the apex of the putative cortical hierarchy--suggesting integrative, higher-order function-- with network participation increasing along the cortical hierarchy, a finding not supported using a non-overlapping modular decomposition. This data-driven approach to selecting OCDAs is applicable across domains, opening new avenues to detecting and quantifying informative structures in complex real-world networks. |
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