bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, June 10th, 2025
| Time |
Event |
| 7:33a |
AAV gene therapy for Cockayne syndrome
Cockayne Syndrome (CS) is an autosomal recessive, progressive developmental and neurodegenerative disease. Approximately 30% of cases are caused by mutations in the ERCC8/CSA gene. Patients with CS present with cutaneous photosensitivity, growth failure, shorter life span and a progressive degeneration of the central nervous system. Loss of function mutations in CSA result in deficiencies in transcription-coupled nucleotide excision repair, regulation of RNA Pol II mediated transcription repair of oxidative DNA damage, and mitochondrial metabolism. Currently there are no available therapies for these patients. AAV gene therapy offers an opportunity to address this unmet need. We designed a new AAV vector encoding human CSA under a CBA promoter. We tested the therapeutic efficacy of this AAV9-CSA vector by neonatal ICV injection in the Csa-/-;Xpa-/- mouse model. Treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, neuropathologic alterations including hypo-myelination, astrocytosis, microgliosis, and likely life limiting transcriptomic alterations in liver at endpoint. Nonetheless, the success of these experiments paves the way for the first in human clinical translation of a gene therapy for CS patients. | | 8:48a |
Lateral hypothalamus directs stress-induced modulation of acute and psoriatic itch
Stress and anxiety are well-known modulators of both physiological and pathological itch. Acute stress suppresses itch, while chronic stress exacerbates it. These effects are mediated by neural circuits within the brain, though the precise mechanisms remain poorly understood. In this study, we investigate the role of neurons in the stress-sensitive lateral hypothalamic area (LHA) in modulating itch. Using neural activity-dependent genetic labeling and chemogenetic tools, we selectively engaged a population of LHA neurons (LHAstress-TRAP neurons) responsive to stress. Transient stimulation of these neurons induced anxiety-like behaviors, conditioned place aversion, and suppressed acute (chloroquine-induced) and chronic (psoriatic) itch. Conversely, the inhibition of the LHAstress-TRAP neurons enhanced acute and chronic itch. Interestingly, LHAstress-TRAP neurons did not respond to acute itch stimuli, but their activity was temporally correlated with scratching episodes in mice with psoriasis. Ex vivo whole-cell patch-clamp recordings revealed that these neurons exhibit heightened excitability in psoriatic animals. Anterograde viral tracing demonstrated that LHAstress-TRAP neurons project to brainstem regions implicated in itch modulation, including the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and lateral parabrachial nucleus (LPBN). Furthermore, chemogenetic activation and optogenetic silencing of LHAstress-TRAP axon terminals revealed that bidirectional modulation of itch is primarily mediated through projections to the PAG. Together, these findings identify a previously unrecognized central mechanism by which stress modulates itch, centered on a specific population of LHA neurons and their downstream brainstem targets. | | 8:48a |
Pupil-linked arousal differentially modulates cell-type-specific sensory processing
Arousal is a ubiquitous influence on the brain that fluctuates during wakefulness and modulates sensation and perception. These fluctuations impact membrane potential, cortical state, and sensory encoding, yet prior studies report inconsistent effects, likely due to averaging across heterogeneous cell types. To resolve this, we combined two-photon calcium imaging and pupillometry in awake mice to examine arousal-related activity in excitatory subpopulations of the auditory cortex: intratelencephalic (IT), extratelencephalic (ET), and corticothalamic (CT) neurons. Pupil-linked arousal modulated all cell types through diverse linear and non-linear response motifs. ET neurons showed significant multiplicative and additive gain modulation, with enhanced response magnitude and encoding but reduced frequency selectivity. CT and L2/3 neurons exhibited inverted-U relationships between arousal and both response strength and decoding accuracy, while IT neurons were minimally affected. These patterns closely tracked changes in population-level reliability, revealing a mechanistic link between internal state and the stability of sensory representations. | | 8:48a |
Altered GluN2A levels reduce the emergence of seizure-like events in a rat model of GRIN2A haploinsufficiency
GluN2A-containing NMDA receptors, encoded by the GRIN2A gene, are critical components of excitatory synaptic transmission and are essential for proper brain development and function. Dysregulation of NMDA receptor activity is strongly implicated in the pathophysiology of epilepsy. While excessive GluN2A-mediated signalling can lead to hyperexcitability and seizure generation, loss-of-function mutations in GRIN2A, which result in reduced GluN2A expression, have also been identified in patients with various forms of epilepsy, including focal epilepsies and epileptic encephalopathies. This paradox highlights the complexity of NMDA receptor contributions to network excitability and suggests that both gain- and loss-of-function mutations can be pathogenic. However, the mechanisms through which reduced GluN2A expression influences seizure susceptibility remains unclear. In this study, we examined the impact of reduced and absence of GluN2A on seizure-like activity using in vitro model system. Hippocampal slices were prepared from wild-type littermate controls (Grin2a+/+), heterozygous (Grin2a+/-) and homozygous (Grin2a-/-) transgenic rats and subjected to pro-convulsant conditions to elicit epileptiform-like events. Specifically, we employed three well established in vitro epilepsy models: (i) 4-aminopyridine (4-AP), (ii) zero-magnesium with elevated potassium (0Mg2+/5K+), and (iii) high-potassium (high-K+). Local field potentials were recorded from the CA1 pyramidal layer to quantify interictal and seizure-like activity, by measuring latency to onset, event frequency, and duration. Spectral analyses were also conducted to assess alterations in network dynamics. Our findings reveal that reduced GluN2A expression alters the susceptibility of hippocampal circuits to seizure-like activity in a model-dependent manner. In the 4-AP model, Grin2a-/- slices exhibited a significantly lower frequency of interictal events and a delayed onset of seizure-like activity relative to both wild-type and heterozygous slices. In the 0Mg2+/5K+ model, both Grin2a+/- and Grin2a-/- slices displayed reduced seizure susceptibility compared to wild-type. Finally, in the high-K+ model, Grin2a-/- slices showed a reduced incidence of seizure-like events compared to wild-type controls when extracellular potassium concentration was increased to 7.5 mM, although this effect was less apparent at higher concentrations (9.5 mM). These results suggest that partial or complete loss of GluN2A-containing NMDA receptors reduces the propensity of hippocampal networks to develop epileptiform activity, potentially by altering intrinsic or synaptic excitability. Our findings provide mechanistic insights into how GRIN2A loss-of-function variants may contribute to epilepsy and highlight the need to consider developmental and circuit-level compensations when interpreting the impact of GluN2A disruption. | | 8:48a |
Intrinsic plasticity underlies malleability of network heterogeneity
Diversity exists throughout biology, playing an important role in maintaining robustness and stability. The same is true of the brain, as has become increasingly apparent in recent years with the accumulation of datasets of unparalleled resolution. These datasets show widespread neural heterogeneity, spanning cells, circuits and system dynamics, marking it as an unavoidable component of the brain's composition. Recent experiments found declines in heterogeneity amongst neurons may accompany pathological states. While heterogeneity has been linked to stability, robustness and increased computational potential, the loss of biophysical diversity was found conducive to the onset of seizure-like activity, suggesting an important functional role. Despite this, how changes in heterogeneity arise remains unknown. Oftentimes considered a static metaparameter resulting from solely genetic disposition, heterogeneity is, in fact, a highly dynamic property of biological networks arising from various sources. Here, we consider this through the lens of intrinsic plasticity, the activity-dependent modulation of neuron biophysical properties, which we propose allows the degree of biophysical diversity to fluctuate in time. Using a network of Poisson neurons endowed with intrinsic plasticity, we combine analytical and numerical approaches to measure the effect of input statistics on the excitability of individual cells, and how this translates into changes in network heterogeneity at the population scale. Our results indicate that, through intrinsic plasticity, diversity in synaptic inputs promotes heterogeneity in cell-to-cell excitability due to changes in the statistics of presynaptic firing rates, and network topology. In contrast, whenever the statistics of synaptic input between cells were too similar, intrinsic plasticity promoted the decline in heterogeneity. Further, we show that changes in heterogeneity can coexist with degeneracy in the firing rate between neurons. Taken together, understanding how input statistics affect neuronal network heterogeneity may provide key insights into brain function resilience and the manipulability of neural diversity through intrinsic plasticity. | | 5:36p |
Hyperpolarization activated cation channel mediated intrinsic plasticity changes underlie the malleability of with-in cell-type electrophysiological heterogeneity
Within cell-type neuronal electrophysiological, morphological, and transcriptomic heterogeneity is the norm in the brain. Although generally considered a fixed property within cell-types, this heterogeneity is malleable and declines in regions of the human brain that generate seizures. Building off this foundational work we hypothesize that such plasticity of cell-type heterogeneity, specifically its decline, arises from the shared history of neuronal activity that drive intrinsic plasticity mechanisms in a concerted fashion. To explore this hypothesis we study neuronal activity in two model systems: human cortical slice cultures from patients with epilepsy as well as slices from the medial prefrontal cortex (mPFC) and subiculum of rodent kainic acid (KA) model of temporal lobe epilepsy. Biophysical properties and spiking dynamics were characterized using whole-cell patch clamp recordings of layer 2 and layer 3 (L2&3) pyramidal neurons in human slice culture as well as deep layer subicular neurons and layer 5 (L5) mPFC of KA mice. We found a significant decline in biophysical heterogeneity and a reduction in information coding in both the KA and slice culture models. In both these models we found a consistent increase in hyperpolarization activated cation current (HCN) dependent electrophysiological properties, the blockade of which restored electrophysiological heterogeneity and information coding. Our findings demonstrate that within cell-type heterogeneity is malleable, and despite being a complex distributed network property, can be tuned by a single ionic current. These findings emphasize the plasticity of within cell-type heterogeneity, suggesting the potential for targeted interventions to restore neuronal heterogeneity changes that accompany epilepsy and potentially other neurological and neuropsychiatric diseases. | | 5:36p |
Unsupervised Phenotyping Reveals Disrupted Neural Firing Characteristics in the Anterior Thalamus and Surrounding Brain Regions Following Third-Trimester Equivalent Alcohol Exposure in Mice
Acute binge-like third-trimester-equivalent alcohol exposure (TTAE) causes apoptosic neurodegeneration in brain regions necessary for spatial learning and memory, such as the anterior thalamus (AT), which encodes context-relevant information, including head direction. While we are beginning to understand the behavioral consequences of this exposure, the neural correlates of spatial cognition deficits are underexplored. Thus, we recorded a mixture of neurons from the AT and surrounding brain regions in mice with TTAE while they freely moved within a controlled environment. To model acute binge-like TTAE, C57BL/6J mice received 2 injections of 2.5 g/kg alcohol (or saline) on post-natal day (PND) 7. Subjects were then left undisturbed until the day of surgery as adults (>PND 60), when they were implanted with silicon or multi-wire arrays. Mice were placed in a circular 40 cm diameter arena under dim red light with 2 LED cues on the walls that rotated on a pseudo-random basis while electrophysiological data was recorded. Following data preprocessing, spike and waveform features were extracted from each putative single spiking unit. These features were reduced utilizing uniform manifold approximation and projection (UMAP). Following dimensionality reduction, we used agglomerative hierarchical clustering to find populations of neurons with similar features. Following this, we compared each feature based on treatment and found the features most important to disambiguate TTAEs impact on neural activity. TTAE was associated with decreases in mean firing rate, peak firing rate, rebound index, and tail decay constant, increases in alpha, peak to trough time, and repolarization time, and bidirectional differences as a function of neuronal subtype in burst index and rebound index. This suggests that TTAE produces long-lasting and fundamental differences in spiking features that can be observed in vivo and are amenable to intervention. Together, this dataset provides further clarifying criteria that can be utilized to diagnose and treat FASD. | | 6:45p |
The link between steady-state EEG and rs-fMRI metrics in healthy young adults: the effect of macrovascular correction
To improve the clinical utility of resting-state fMRI (rs-fMRI), enhancing its interpretability is paramount. Establishing links with electrophysiological activities remains the benchmark for understanding the neuronal basis of rs-fMRI signals. Existing research, while informative, suffers from inconsistencies and a limited scope of rs-fMRI metrics (e.g., seed-based functional connectivity). Phenotypic variables like sex and age are suspected to obscure reliable fMRI-EEG associations. A major contributing factor to these inconsistencies may be the neglect of macrovascular correction in rs-fMRI metrics. Given that macrovascular contributions can inflate rs-fMRI connectivity and power, they may lead to misleading fMRI-EEG associations that do not reflect genuine neuronal underpinnings. In this study, we addressed this by applying macrovascular correction and performing a systematic, inter-participant analysis of multiple rs-fMRI and EEG metrics. Our key findings demonstrate that: 1) Macrovascular correction enhances the relationship between EEG and rs-fMRI metrics and improves model fit in many instances; 2) sex significantly modulates EEG-fMRI associations; 3) EEG complexity is significantly associated with resting-state functional activity (RSFA). This research provides crucial insights into the interplay between rs-fMRI and EEG, ultimately improving the interpretability of rs-fMRI measurements and building upon our prior work linking fMRI and metabolism. | | 6:45p |
Post-Saccadic Disruption of Semantic Category Information in Naturalistic Scenes
During natural vision, people make saccades to efficiently sample visual information from complex scenes. However, a substantial body of evidence has shown impaired visual information processing around the time of a saccade. It remains unclear how saccades affect the processing of high-level visual attributes - such as semantic category information - which are essential for navigating dynamic environments and supporting complex behavioral goals. Here, we investigated whether/how the processing of semantic category information in naturalistic scenes is altered immediately after a saccade. Through both human behavioral and neuroimaging studies, we compared semantic category judgments (Experiments 1A and 1B) and neural representations (Experiment 2) for scene images presented at different time points following saccadic eye movements. In the behavioral experiments, we found a robust reduction in scene categorization accuracy when the scene image was presented within 50 ms after saccade completion. In the neuroimaging experiment, we examined neural correlates of semantic category information in the visual system using fMRI multivoxel pattern analysis (MVPA). We found that scene category representations embedded in the neural activity patterns of the parahippocampal place area (PPA) were degraded for images presented with a short (0-100 ms) compared to a long post-saccadic delay (400-600 ms), despite no corresponding reduction in overall activation levels. Together, these findings reveal that post-saccadic disruption extends beyond basic visual features to high-level visual attributes of naturalistic scenes, highlighting a limitation of visual information processing in the short post-saccadic period before executing the next saccade. | | 6:45p |
FOXP1 differentially regulates the development of murine vasopressin and oxytocin magnocellular neurons
The neuropeptides arginine vasopressin (AVP) and oxytocin (OXT) are closely related. As neurohormones, AVP and OXT are mainly produced in magnocellular neurons (MCNs) located in the hypothalamus. Development of both neuron types requires coordinated expression of transcription factors OTP, SIM1, ARNT2 and POU3F2. However, the exact transcription factors involved in the differential differentiation of the AVP and OXT lineages are yet unknown. We used a publicly available single-cell RNA-sequencing dataset of the developing mouse hypothalamus to identify gene regulatory networks linked to AVP and OXT neuronal differentiation. We identified RORA, EBF3, FOXP1, FOXP2, and BCL11B as transcription factors with possible relevance for Avp and Oxt MCN divergence. We then modeled developmental gene expression dynamics using computational cell fate mapping. This revealed enrichment of EBF3 and BCL11B in the Avp lineage, while FOXP1 and FOXP2 are enriched in the Oxt lineage. Next, in silico analysis of Avp and Oxt promoters found predicted binding sites for FOXP1 and FOXP2 in the Oxt promoter, suggesting a role in Oxt MCN differentiation. Finally, we validated the role of one candidate (FOXP1) with a heterozygous knockout mouse line. Compared to wild-type littermates, we find decreased AVP and OXT neuron abundance, with OXT neurons disproportionally affected. | | 6:45p |
Layer 6 is a hub for cholinergic modulation in the mouse auditory cortex
Basal forebrain cholinergic neurons (BFCNs) densely innervate auditory cortex (ACtx), conveying signals linked to internal brain states and external sensory cues. Several studies have shown that acetylcholine (ACh) rapidly modifies local cortical circuits via nicotinic ACh receptors (nAChRs) on layer 1 (L1) inhibitory neurons. BFCN terminals are also abundant in L6, though the mechanisms and functional consequences of cholinergic modulation in deeper cortical layers has received less attention. Here, we performed multi-plex in situ labeling across cortical layers and cell types and found that L6 pyramidal neurons (L6-PNs) were highly enriched in diverse nAChR subunit and muscarinic ACh receptor (mAChR) transcripts. In vivo optogenetic activation of BFCN axons revealed persistent modulation of regular spiking (RS) units in L2-6 but a rapid phasic activation only in L6. In acute slices, optogenetic activation of BFCN axons elicited fast excitatory post-synaptic potentials via nAChRs in L6-PNs, comparable to responses in L1-INs, and slower inhibitory responses mediated by mAChRs. These findings identify L1 inhibitory neurons and L6 excitatory neurons as two hubs that mediate BFCN modulation of cortical circuits. Transcriptional, synaptic, and local circuit connectivity differences between L1 and L6 hubs may allow BFCN inputs to shape perception and plasticity on distinct timescales. | | 6:45p |
Neural signatures of automatic letter-speech sound integration in literate adults
Automaticity in decoding print is crucial for fluent reading. This process relies on associative memories between letters and speech sounds (LSS) that are overlearned through years of reading practice. While previous neuroimaging studies have identified neural correlates of LSS integration across different stages of reading development, the specific neural signatures underlying automatic LSS integration remain unclear. In the present study, we aimed to isolate neural components specifically associated with automatic LSS integration in literate adults. To this end, we developed an artificial script training paradigm in which adult native Finnish speakers were trained to associate novel foreign letters with familiar Finnish speech sounds. Using magnetoencephalography (MEG), we directly compared the audiovisual processing of newly learned and overlearned LSS associations within the same task, one day after training. Event-related fields (ERFs) and multivariate decoding revealed largely shared neural circuits of audiovisual integration for both types of LSS associations, as evidenced by multisensory interaction and congruency effects. Interestingly, the processing of congruent overlearned audiovisual associations uniquely recruited brain activity in the left parietal cortex during the 235-475 ms time window. Furthermore, temporal generalization analysis of the congruency effects revealed that while both newly learned and overlearned audiovisual associations engaged common neural mechanisms, the newly learned associations were processed systematically more slowly by a few hundred milliseconds. Our study identified the spatiotemporal neural signatures underlying automatized LSS processing, offering insights into neural markers that may help identify levels of reading proficiency. |
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