bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, September 11th, 2025
| Time |
Event |
| 7:45a |
Permethrin elicits chemoreceptive responses on different Anopheles gambiae sensory appendages.
Non-contact detection of pyrethroid insecticides by malaria mosquitoes has been unveiled and may contribute to the evolution of mosquito behavioral modifications against vector control tools. However, the mechanisms underlying this detection are not yet fully understood. It has been hypothesized that the spatial repellency of pyrethroids may be mediated by chemosensory receptors and/or via the activation of voltage-gated sodium channels (VGSCs). This study aimed to explore these two hypotheses by identifying which chemosensory appendages in Anopheles gambiae are involved in the non-contact detection of permethrin, a widely used pyrethroid in malaria control. Behavioral responses to permethrin headspace were recorded in female An. gambiae, in which specific sensory appendages were either removed or coated with resin to impair their chemosensory function. Additionally, electrophysiological recordings were performed on different sensory appendages: antennae, palpi and tarsi, to characterize their electrophysiological activity after permethrin stimulation. The behavioral assays revealed that tarsi were primarily responsible for mediating mosquito takeoff responses after permethrin headspace delivery. This finding was supported by significant electrophysiological tarsal responses to the insecticide. In contrast, removal of the antennae did not alter behavioral responses, although electroantennogram recordings indicated neural activity in response to permethrin. Palps showed neither behavioral nor electrophysiological responses. These findings indicate that permethrin is detected through two distinct sensory appendages, tarsi and antennae, but with varying behavioral output. Such appendage-specific detection favors the hypothesis that permethrin detection and the associated behavioral output is mediated by chemosensory receptors rather than by VGSCs. Nonetheless, further investigations are needed to identify the chemosensory receptors and pathways involved in pyrethroid insecticide detection in malaria mosquitoes. | | 7:45a |
Axon termination of the SAB motor neurons in C. elegans depends on pre- and postsynaptic activity
Axon termination is a critical step in neural circuit formation, but the contribution of activity from postsynaptic targets to this process remains unclear. Using Caenorhabditis elegans SAB neurons as a model system, we showed that inhibition of muscle activity during a critical period of postembryonic development led to axonal overgrowth and ectopic synapse formation. This effect is mediated by a local retrograde signal and requires neuronal voltage-gated calcium channels (VGCCs) acting cell-autonomously to constrain axon growth. Manipulating SAB neuron excitability demonstrated that increased intrinsic neuronal activity drives overgrowth, while reducing activity suppresses it, establishing a functional link between muscle-derived cues and presynaptic excitability. Transcriptomic analysis and genetic studies further implicate the neuropeptides FLP-18 and NLP-12 as essential modulators of this activity-dependent process. Our findings reveal a temporally and spatially restricted retrograde signaling mechanism in motor neurons, where target activity, neuronal calcium dynamics and neuropeptide signaling cooperate to ensure proper axon termination. These results highlight conserved principles of activity-dependent regulation at neuromuscular junctions and provide a framework for understanding how motor circuits integrate target feedback to sculpt precise connectivity. | | 8:16a |
Synchrotron XRF imaging reveals manganese accumulation in the Golgi and post-synapses of neurons and enhanced uptake in astrocytes
Manganese is an essential trace metal for humans, but excessive exposure can cause neurotoxicity, including parkinsonian syndromes, cognitive deficits, and has also been implicated in the pathogenesis of neurodegenerative diseases. Globally, tens of millions of people are exposed to elevated manganese levels through drinking water, exceeding the WHO recommended guideline. Despite its public health significance, the cellular and subcellular mechanisms underlying manganese neurotoxicity remain poorly defined, particularly its distribution across brain cell types and its specific intracellular targets. In this study, we investigated manganese accumulation in primary cultures of hippocampal neurons and astrocytes. Using a correlative imaging approach that combined cryo-fluorescence light microscopy with synchrotron X-ray fluorescence imaging, we mapped and quantified manganese at subcellular resolution. Our analysis revealed that manganese preferentially accumulates in the Golgi apparatus of both neurons and astrocytes. In neurons, manganese was also detected in dendrites at the postsynaptic density, suggesting a role in synaptic vulnerability. Quantitative elemental analysis showed that astrocytes accumulated 3 times more manganese than neurons. Furthermore, when neurons were co-cultured with astrocytes, their manganese uptake was significantly reduced, indicating a possible protective or buffering role of astrocytes. These findings identify key cellular and subcellular targets of manganese and highlight the Golgi apparatus as a major regulator of manganese neurotoxicity. This work provides a foundation for understanding cell type-specific responses to manganese exposure and may inform the development of targeted neuroprotection strategies. | | 10:16a |
Integration of memory and sensory information in skilled sequence production
Sequential movements rely on two information sources: external sensory cues and internal memory representations. Although often both sources jointly drive sequential behavior, previous research has primarily examined them in isolation. To address this, we trained participants to perform sequences of rapid finger presses in response to numerical cues. Sensory influence was measured by varying the number of visible cues, and memory influence by comparing repeating and random sequences. Early in learning, participants integrated sensory and memory information: repeating sequences were performed more quickly when more cues were visible. After learning, when repeating sequences were predictable with certainty, participants relied solely on memory and ignored sensory cues. However, when this certainty was manipulated by introducing occasional violations within repeating sequences, participants reverted to integrating memory with sensory cues. We propose a computational model that successfully predicted both speed and accuracy of individual presses. Critically, this model relied on the assumption that multiple movements are planned independently of each other. This independence assumption was then validated by examining response patterns to isolated violations in repeating sequences. Finally, we provide evidence into how sequence memories can be flexibly deactivated and reactivated in response to these violations. Together, these results reveal how brain dynamically integrates sensory and memory information to produce sequences of movements. | | 10:16a |
Loss of presenilin 2 function age-dependently increases susceptibility to kainate-induced acute seizures and blunts hippocampal kainate-type glutamate receptor expression
Presenilin 2 (PSEN2) gene variants increase the risk of early-onset Alzheimer's disease (AD). AD patients with PSEN2 variants have increased risk of unprovoked seizures versus age-matched healthy controls, yet few studies have interrogated PSEN2 contributions to seizures, and fewer have done so with aging. PSEN2 variant mice also do not exhibit amyloid-{beta} (A{beta}) accumulation, allowing for the assessment of A{beta}-independent contributions to seizure risk in AD. Critically, PSEN proteolytic capacity may regulate hippocampal kainate-type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring KAR agonist that acutely evokes severe seizures in mice. We thus hypothesized that PSEN2 knockout (KO) mice would have reduced latency to acutely evoked seizures and status epilepticus (SE), increased convulsive SE burden, worsened 7-day survival, and altered hippocampal KAR expression vs age-matched wild-type (WT) mice. Using a repeated low-dose systemic KA administration paradigm, we quantified the latency to acute seizures and convulsive SE, then quantified neuropathology in 3-4-month-old and 12-15-month-old male and female PSEN2 KO versus WT mice. GluK2 and GluK5 KAR subunit expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA-SE or sham-SE to define the interaction between PSEN2 loss and acute seizures on hippocampal KARs. Regardless of sex, young PSEN2 KO mice were more susceptible to KA-induced acute seizures than WTs. Young PSEN2 KO mice of both sexes also entered SE sooner than age-matched WT mice. In aged mice, there was no significant difference in latency to first seizure or SE onset between genotypes in either sex. However, regardless of genotype, aged females entered SE sooner than young females and experienced greater mortality. This was not observed in males. Among young animals, there was no difference in KAR expression between genotypes and regardless of treatment group. In both genotypes, hippocampal CA3 astrocytes expressed GluK5 following KA-SE, however, astrocytic GluK2 expression only occurred in WT mice. GluK5 expression was significantly reduced in untreated aged PSEN2 KO mice versus untreated WT mice, while total GluK2 expression did not differ between genotypes or seizure groups. Following KA-SE, astrocytic GluK5 expression was only present in WT animals in CA3, while both genotypes presented with astrocytic GluK5 expression. This study highlights that KARs are an understudied contributor to seizures in aging and AD that warrant further investigation. | | 10:16a |
Spectral envelopes of rhythmic facial movements predict intention and motor cortical representations
Animals, including humans, use coordinated facial movements to sample the environment, ingest nutrients, and communicate. To study these behaviors and the neural signals that underlie them, we introduce face-rhythm, a tool for quantitatively tracking, extracting, and interpreting facial movements. The approach utilizes markerless point tracking, spectral analysis, and tensor component analysis to extract demixed components of behavior from videos of facial movements. Face-rhythm is fully unsupervised and allows for the discovery of uninstructed behaviors; when applied to videos of facial behavior, face-rhythm identifies interpretable behaviors such as whisking, sniffing, and snout movements. Analysis of videos of mice in various behavioral conditions, including a classical conditioning protocol, a brain-machine interface (BMI) task, and natural behaviors outside of a task structure, revealed robust signatures of uninstructed facial movements in all regimes. The expression of these facial movements predicted internal belief states during classical conditioning and was correlated with instructed neural activity when the BMI was activated. Furthermore, facial behaviors identified by face-rhythm were highly represented in face-associated areas of primary motor cortex (M1). We found that M1 neural activity encodes a mixed representation of both the phase of facial movements as well as the phase-invariant spectral envelope of movement patterns, with higher-frequency facial movements being more likely to be represented as phase-invariant. Our results demonstrate that face-rhythm provides a novel and flexible approach for decomposing continuous face movements into natural behavioral motifs that are closely linked to neural activity patterns. | | 10:16a |
CA2 neurons show abnormal responses to social stimuli in a rat model of Fragile X syndrome
Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is highly comorbid with autism spectrum disorders and can cause abnormal social behaviors. The CA2 subregion of the hippocampus is essential for social memory processing and social recognition. A social interaction induces changes in CA2 neuronal firing; however, it is unknown whether these changes are impaired in FXS models. Here, we examined CA2 activity in a rat model of Fragile X Syndrome (Fmr1 knockout rats). In Fmr1 knockout rats, we observed impaired CA2 cell responses to social stimuli, despite similar social behaviors. Further, in CA2 of Fmr1 knockout rats, we found reduced expression of oxytocin receptors and impaired whole cell responses to oxytocin. Together, these results raise the possibility that abnormal CA2 activity contributes to impaired social behavior in FXS and may suggest novel treatment targets for FXS patients. | | 10:47a |
Fractionation of sex differences in human cortical anatomy
Humans show reproducible sex differences in regional cortical volume (CV), but it remains unclear how these arise from underlying sex-biases in the two biologically dissociable determinants of CV: surface area (SA) and cortical thickness (CT). Moreover, limited access to experimental methods in humans has hindered direct studies of the causal drivers of regional sex differences in the human cortex, although rodent models have argued for both chromosomal and gonadal contributions to sex-biased mammalian cortical development. Here, we first use structural neuroimaging data in two independent human cohorts (combined N=1,754; 967 females) to quantify and spatially resolve the differential contributions of SA and CT to observed sex differences in CV. These dissociable facets of sex-biased cortical organization are highly reproducible and align with distinct functional networks and histo-molecular signatures. We then leverage complementary neuroimaging data in clinical case-control cohorts (combined N=313) featuring variations in X and Y chromosome dosage (sex chromosome aneuploidies) and testicular hormone production (isolated GnRH deficiency) to establish that regions of sex-biased CV, SA and CT in humans are enriched for congruent anatomical effects of X-chromosome dosage (e.g., primary sensory and insular cortices) and gonadal hormones (e.g. dorsomedial frontal and temporo-parietal-occipital regions). Taken together, these findings substantially advance both the breadth and granularity of our understanding regarding sex-biased cortical organization in humans - disambiguating sex effects on regional CV, SA and CT and nominating their potential genetic and endocrine causes. | | 10:47a |
Spatiomolecular mapping reveals anatomical organization of heterogeneous cell types in the human nucleus accumbens
The nucleus accumbens (NAc) is a key component of the mesolimbic dopamine system that critically regulates many behaviors related to reward and motivation. The NAc is implicated in several neuropsychiatric disorders, including major depressive disorder, schizophrenia, and substance use disorders. Rodent studies have identified spatial organization of heterogeneous medium spiny neuron (MSN) subtypes across the NAc core and shell, but the extent to which this cellular diversity and spatial organization is conserved in the human brain remains unclear. Here, we generated a spatiomolecular atlas of NAc cell types and spatial domains by integrating spatial transcriptomics and single-nucleus RNA sequencing data from postmortem NAc tissue from 10 neurotypical adult donors. We identified 20 transcriptionally unique cell populations and 8 spatial domains, including specialized D1 islands composed of distinct dopamine receptor 1 (DRD1) MSN subtypes, which were enriched for OPRM1. In contrast to a discrete core vs. shell division, we observed continuous spatial gradients of gene expression across MSN domains, suggesting a more complex organization of DRD1 and DRD2 MSNs. Cross-species comparisons demonstrated conservation of MSN subtypes and spatial features between human, rodent, and nonhuman primate NAc. Genetic enrichment analysis with stratified linkage disequilibrium score regression revealed specific spatial domains associated with risk for psychiatric and addiction-related traits. To investigate this further, we spatially mapped ligand-receptor interactions involving neuropsychiatric risk genes. Finally, we leveraged existing rodent NAc data to identify drug-responsive transcriptional programs and predict their spatial distribution in the human NAc. Collectively, we provide a spatiomolecular framework for understanding the human NAc and its relevance to neuropsychiatric disease. | | 10:47a |
Interneuron theta phase locking controls seizure susceptibility
The timing of neuronal activity is highly precise and often organized by brain-wide oscillations. Many neurons modulate their firing rates at specific phases of theta (known as theta phase locking), creating discrete windows for information processing. Disrupted theta phase locking has been found across several neurological and psychiatric disorders (e.g., epilepsy), but gaps in technology have prevented its causal influence from being tested. Here, we developed PhaSER, a closed-loop optogenetic system designed to control the phase locking of specific interneurons, and demonstrate a causal role for inhibitory phase locking in seizure susceptibility. We first found that parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the dentate gyrus (DG) show distinct theta phase locking profiles and are differentially impacted in a mouse model of chronic temporal lobe epilepsy. In healthy mice, PV+ interneurons have extremely consistent phase-locked firing near the trough of CA1 theta, aligned with excitatory inputs to DG. However, in epileptic mice, PV+ interneuron activity is dispersed across the theta cycle, suggesting that altered inhibitory phase locking could be a causal mediator of seizure susceptibility in epilepsy. To test this hypothesis, we applied PhaSER to directly control the phase locking of DG interneurons during an acute test of seizure susceptibility. In epileptic mice, re-aligning DG PV+ interneuron theta phase locking reduced seizure susceptibility, while in healthy mice, disrupting normal phase locking of PV+ interneurons increased seizure susceptibility. Together, this provides the first causal evidence that inhibitory theta phase locking can directly control network function by shifting seizure susceptibility in the healthy and epileptic brain. | | 10:47a |
Pth4 neurons define a novel hypothalamic circuit that promotes sleep via brainstem monoaminergic neurons
Classical studies identified a critical role for the hypothalamus in regulating sleep and wake states, but few such hypothalamic neuronal populations have been identified. Here we describe a sleep-promoting population of hypothalamic neurons that expresses the neuropeptides QRFP and parathyroid hormone 4 (Pth4) in zebrafish. Optogenetic stimulation of these neurons results in a large increase in sleep that requires pth4 but not qrfp. Noradrenergic locus coeruleus (LC) neurons and serotonergic raphe neurons (RN) in the hindbrain express distinct pth receptors, and genetic epistasis and cell ablation experiments revealed that Pth4 neuron-induced sleep is suppressed in mutants that lack noradrenaline in the LC or lack the serotonergic RN. Pth4 neuron-induced sleep is also suppressed in serine/threonine kinase 32a (stk32a) mutants, possibly via stk32a-expressing neurons in the prethalamus that express pth receptors. These results identify QRFP/Pth4 neurons as a novel hypothalamic sleep-promoting population and support a model in which distinct sleep- and wake-promoting hypothalamic populations act via monoaminergic neurons in the hindbrain to control vigilance state. | | 10:47a |
Interplay of synaptic and backpropagating signals in neurogliaform dendrites
Dendrites in diverse neuronal cell types, including interneurons, are active structures that enhance neuronal computational capabilities. Neurogliaform interneurons exhibit robust synaptic plasticity and supralinear summation of clustered dendritic inputs. However, the principles governing supralinear synaptic integration, its interaction with backpropagating somatic signals, and the interplay of the two in the context of synaptic plasticity, remain incompletely understood. We developed a biophysically realistic, multi-compartmental model of a murine hippocampal neurogliaform interneuron, recapitulating key experimental results on dendritic integration. We simulated diverse synaptic input configurations and action potential backpropagation, generating testable predictions validated through ex vivo patch-clamp electrophysiology and two-photon imaging. We further examined how dendritic supralinear integration interacts with backpropagating action potentials to influence synaptic plasticity. Our results show that while both clustered and dispersed synaptic inputs elicit supralinear responses in neurogliaform interneurons, clustered inputs induce more pronounced local depolarisations and calcium transients. Somatic action potentials backpropagate across the dendritic arbour but are attenuated at branch points. Coincident synaptic input and backpropagating action potentials enhance EPSP amplitude and increase calcium influx along the dendrite, enabling voltage and calcium signal propagation and thereby likely contributing to synaptic plasticity. | | 3:45p |
Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer knock-in mouse phenotypes
Metabolic dysfunction contributes to the risk and progression of Alzheimer's disease (AD) through insulin signaling, but the cellular mechanisms are not fully understood. In this study, we examined the effects of streptozotocin-induced insulin deficiency or a high-fat, high-sugar (HFHS) diet-induced insulin resistance on cognitive function in knock-in AD mouse models expressing human mutant APP and wild-type tau. Both metabolic perturbations caused hyperglycemia, but only the HFHS diet resulted in weight gain and greater learning and memory deficits. The HFHS diet exacerbation occurred without changes in amyloid-{beta} or phospho-tau accumulation and with only subtle alterations in microglial morphology. The basis for functional deficits was explored with single-nucleus transcriptomic analysis. Prominent gene expression changes in glial cells and cerebral cortex Layer 2 inhibitory neurons correlated with the enhanced behavioral deficits. In HFHS-fed AD mice, we observed a shared metabolic impairment in neurodegeneration (MinD) state across multiple glial cell types. Additionally, the HFHS diet, with or without AD pathology, induced selective upregulation of the transcription factor Meis2 in cortical Layer 2 inhibitory neurons, in association with pathways involved in cell excitability. Overall, these findings suggest that HFHS-driven metabolic stress affects brain function and behavior through specific cellular programs distinct from amyloid or tau pathology, and identifies new targets that link diet-induced metabolic stress to cognitive decline in AD. | | 4:15p |
Endogenous suspension and reset of consciousness: 7T fMRI brain mapping of the extended cessation meditative endpoint
Extended cessation (EC), an advanced meditative state in which consciousness is volitionally suspended and later reset with immense mental clarity, equanimity, and peace, offers an endogenous model for investigating the mechanisms of consciousness. Using ultra-high-resolution 7T fMRI with dense within-subject sampling (N=3), we quantified whole-brain activity, functional and effective connectivity, cortical gradients, and eigenmodes, and related them to chemoarchitecture and cognitive maps. EC is marked by increased activity in unimodal regions, down-regulation in transmodal regions, subcortex, and brainstem, an expansion of the principal gradient, and decrease in low-order global eigenmodes. Cognitive decoding linked EC to heightened perceptual clarity and attention, least with mental suffering, and co-varied with histaminergic H receptors topology. These findings challenge predictions of Global Neuronal Workspace and Integrated Information Theory, while supporting the Active Inference Framework. More broadly, EC demonstrates that consciousness can cease without global suppression, suggesting a potential 'reset' mechanism that fosters equanimity and the potential for flourishing. Keywords: advanced meditation, extended cessation, consciousness, subcortical, brainstem, functional connectivity, chemoarchitecture | | 7:50p |
Minimizing the influence of magnetic vestibular stimulation inside MRI-scanners by adjusting head position
Magnetic resonance imaging (MRI) offers detailed diagnostic insights but also unintentionally induces vestibular side effects by its static magnetic field. Magnetic vestibular stimulation (MVS) may cause dizziness and confound behavioral and physiological measures in fMRI by introducing an unavoidable mixture of neural activation in vestibular projection areas, driven both by the signal of interest and by vestibular system activation. This study investigated how different head orientations within a 3T MRI scanner influence the MVS-induced vestibulo-ocular reflex (VOR) in complete darkness, with the goal of identifying a head position that minimizes or eliminates MVS effects. Results revealed a linear relationship between head pitch and the horizontal VOR (Experiment 1), as well as between head roll and the vertical VOR (Experiment 2). Across participants, the horizontal VOR was eliminated at an average forward head pitch of 24.4 degree, while the vertical VOR was nullified at an average roll angle of 15.9 degree towards the right shoulder. A head position combining this forward pitch with this rightward roll effectively minimized both horizontal and vertical VOR components across subjects (Experiment 3). The findings provide a practical solution to reduce the impact of MVS effects in MRI with important implications for improving data quality in neuroscientific fMRI studies and patient comfort during clinical imaging. |
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