bioRxiv Subject Collection: Neuroscience's Journal
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Saturday, June 28th, 2025
| Time |
Event |
| 1:31a |
The Ventral Tectal Longitudinal Column: A Midbrain Nucleus for Modulation of Auditory Processing in the Cochlear Nucleus, Superior Olivary Complex and Inferior Colliculus
A ventral tectal longitudinal column (TLCv) has been described in rats and is hypothesized to provide multisensory modulation of acoustic processing in the superior olivary complex (Saldana et al., 2007, J Neurosci 27, 13108-16). The TLCv is a column of cells in the dorsomedial tectum extending rostro-caudally through the inferior and superior colliculi. It receives ascending auditory input and projects to the superior olivary complex. Further insight into TLCv function has been hampered by limited information on its connections. Here, we provide evidence that a TLCv is recognizable in mice and that it has more extensive connections than previously believed. Deposit of retrograde tracer into the superior olivary complex labels cells bilaterally in the TLCv, comparable to results seen in rats. Viral labeling of neuronal projections demonstrate input to the TLCv from the superior olivary complex and from the inferior colliculus. Thus, the TLCv in mice has inputs and outputs similar to those described in rats. Additional experiments with retrograde tracers revealed more extensive outputs from the TLCv. Neurons in the TLCv are labeled after deposit of retrograde tracers into the cochlear nucleus or into the inferior colliculus. The projections from the TLCv to these targets, like those to the superior olivary complex, are bilateral. These projections are much broader than those described previously. The results suggest that the TLCv could exert modulation over a wide expanse of the auditory brainstem, from the cochlear nucleus through the inferior colliculus. | | 2:47a |
CaV1.2-dependent excitation-transcription coupling modulates nociception
Peripheral nociceptive sensory neurons integrate various noxious inputs, resulting in local depolarization that triggers the firing of action potentials and thus the sensation of pain. We recently reported that nociceptor depolarization itself initiates signaling by the calcium channel CaV1.2 causing acute hyperalgesia in vivo. However, whether this mechanism initiates excitation-transcription (E-T) coupling and thereby leads to long-lasting modulation of nociceptor activity remains poorly understood. Using high content imaging of dorsal root ganglion (DRG) neurons, we here found that depolarization of nociceptors induces phosphorylation of the transcription factor (TF) cAMP-response element binding protein (CREB), which was affected by inhibition of protein kinase A (PKA) and calcineurin, but not Ca2+/calmodulin-dependent protein kinases. Genetic deletion or pharmacological inhibition of CaV1.2 confirmed its role in calcium-dependent kinase signaling and CREB phosphorylation after depolarization. In line with this, pharmacological modulation of CaV1 channels affected the expression of a subset of depolarization-regulated immediate early genes known to orchestrate a broader transcriptional response. Indeed, RNA-Seq analysis of DRG neurons from mice with a tissue-specific deletion of CaV1.2 in nociceptive sensory neurons (SNS-Cacna1c-/- mice) revealed downregulation of multiple calcium and potassium channel subunits as well as proteins involved in synaptic vesicle release and cell adhesion. Furthermore, repetitive firing of action potentials and release of the neuropeptide CGRP was impaired in CaV1.2-deficient sensory neurons. SNS-Cacna1c-/- mice showed increased sensitivity to noxious heat and exacerbated inflammatory but not neuropathic pain. In conclusion, our data suggest a CaV1.2-dependent E-T coupling mechanism in nociceptors that counteracts nociception in vivo. | | 2:47a |
Interoception vs. Exteroception: Cardiac interoception competes with tactile perception, yet also facilitates self-relevance encoding
Internal bodily signals, notably the heartbeat, influence our perception of the external world - but the nature of this influence remains unclear. One line of evidence (Competition) indicates that interoceptive and exteroceptive inputs compete for neural resources. Another line (Self-related Facilitation) shows a link between interoceptive and self-related processing, that might also include computing the self-relevance of exteroceptive inputs. We tested these seemingly opposing views within a single experimental task. Measuring heartbeat-evoked potentials (HEPs, a measure of cardiac interoception) with EEG, we manipulated the self-relevance of an audio-tactile stimulus by placing the audio source either inside or outside the peripersonal space immediately around the body. This design ensured that Competition and Self-related Facilitation accounts yielded contrasting predictions. On the one hand, pre-stimulus HEP amplitudes over somatosensory cortex were linked to slower reaction times, and affected audio-tactile stimulus-evoked responses in the same area, indicating competition for shared neural resources. On the other hand, pre-stimulus HEPs over integrative sensorimotor and default-mode network regions facilitated subsequent self-relevance encoding, both in reaction times and audio-tactile stimulus evoked responses. Importantly, Competition and Facilitation effects were spatially and statistically independent from each other. We thereby reconcile the two views by showing the co-existence of two independent mechanisms: one that allocates neural resources to either internal bodily signals or the external world, and another by which interoception and exteroception are combined to determine the self-relevance of external signals. Our results highlight the multi-dimensionality of HEPs as neurophysiological markers, and thus of internal states more generally. | | 2:47a |
BELIEFS: A Hierarchical Theory of Mind Model based on StrategyInference
Theory of Mind (ToM) refers to the capacity to infer others' latent mental states, such as intentions, beliefs, and strategies, and use these inferences to predict behavior. A defining characteristic of ToM is its recursive nature: individuals reason not only about what others are thinking, but also about what others think about them. Most computational models of ToM adopt a hierarchical structure in which Level-0 (L0) agents are assumed to follow simple, fixed heuristics (e.g., Win-Stay-Lose-Shift, WSLS) without mentalizing. However, this assumption overlooks the diversity of non-mentalizing strategies exhibited in human behavior, such as imitation or tit-for-tat, which do not conform to WSLS yet require no recursive reasoning. To address this limitation, we introduce a novel ToM framework (BELIEFS) that flexibly infers latent L0 strategies from behavior rather than relying on predefined heuristics. We evaluated the model in four classic dyadic games: Matching Pennies, Prisoner's Dilemma, Bach or Stravinsky, and Stag Hunt, manipulating model's learning rates and the volatility of L0 strategy switching. Predictive accuracy was assessed using cumulative negative log-likelihood (NLL) of opponent's next choice and compared against both a ToM model that assumes only WSLS at L0 and chance-level performance. Our model outperformed both baselines, particularly under low-volatility conditions and at intermediate learning rate. Moreover, to evaluate strategy inference, we computed trial-wise confusion matrices and Cohen's k; between inferred and true L0 strategies, reaching significantly above-chance classification. We further tested the model's ability to distinguish between action sequences generated by the opponent's true Theory of Mind (ToM) level (L0 vs. L1) and those generated using an incorrect ToM level. The model assigned lower negative log-likelihoods (NLLs) to sequences from the true level, suggesting an indirect method for identifying the opponent's actual ToM level. Finally, we assessed whether the model effectively tracks behaviorally distinguishable action probabilities across ToM levels. Using Fisher-transformed correlations between model-generated action probabilities at L0, L1, and L2, we found significant dissimilarities, especially in competitive games. In summary, our model introduces a flexible, probabilistic approach to Theory of Mind that captures both surface-level strategy use and recursive reasoning depth. By jointly tracking dynamic beliefs over L0 strategies and ToM levels, the model adapts to behavioral shifts and outperforms static heuristics. These advances provide a powerful framework for modeling human behavior in interactive contexts, with implications for both human-human and human-machine interaction research. | | 2:47a |
Independent directional tuning of the human triceps surae muscles during standing postural control
The triceps surae, composed of the soleus (SOL) and medial (MG) and lateral (LG) gastrocnemii, are anatomically-derived synergists which act as a functional unit to plantarflex the ankle. However, anatomical differences suggest that each muscle is capable of generating distinct torques at the ankle, raising the possibility that each can be independently controlled to suit the needs of a given task. This possibility was explored by investigating the activation patterns of the triceps surae during two balance tasks that use different neuromechanical control strategies to maintain equilibrium. High-density surface EMG was recorded from the triceps surae of 14 healthy young adults during multiple trials of dual- and single-legged standing. Newly developed analyses examined how each muscle tuned its activity with center of pressure (COP) movement throughout 2-D space. During dual-legged standing, only the SOL and MG were active and both tuned their activity uniformly with anteroposterior COP movement. By contrast, during single-legged standing, each muscle showed robust activation and significantly different directional tuning, with the LG most active before medial COP movement, while SOL and MG were most active before lateral COP movement. Further analyses demonstrated the LG could be activated entirely independent of the SOL and MG, and vice versa, with independent activation of each muscle causing different angular deflections of the COP during single-, but not dual-legged standing. These observations reveal a sophisticated level of neural control, whereby the nervous system exploits subtle differences between highly similar muscles to tune balance corrective adjustments in a task-dependent manner. | | 7:49a |
HILIC-Enabled Mass Spectrometric Discovery of Novel Endogenous and Glycosylated Neuropeptides in the American Lobster Nervous System
Neuropeptides are a highly conserved and diverse class of intercellular signaling molecules that regulate a broad range of neural and hormonal processes across animal phyla. The American lobster, Homarus americanus, has long served as a powerful invertebrate model for the discovery and functional investigation of neuropeptides. Among common post-translational modifications (PTMs) found in neuropeptides, glycosylation remains underexplored due to the inherently low in vivo abundance and intrinsically complex structural heterogeneity. In this study, we employed hydrophilic interaction liquid chromatography (HILIC) enrichment coupled with oxonium-ion triggered EThcD fragmentation strategy to simultaneously profile novel endogenous and glycosylated neuropeptides across eight distinct neural tissues and neuroendocrine organs of Homarus americanus. This integrative mass spectrometry-based approach led to the identification of 154 endogenous neuropeptides derived from 25 families, approximately one-third of which are newly reported, and uncovered 28 O-linked glycosylated neuropeptides in this species for the first time. These peptides exhibit strong tissue-specific expression, distinct proteolytic cleavage patterns, and confidently localized glycosylation sites. Our results highlight the utility of integrated sampling enrichment and hybrid fragmentation strategies for deep neuropeptidomic profiling and provide a valuable resource for future studies on the functional roles of newly identified neuropeptides and glycosylation in crustacean neuromodulation and peptidergic signaling. | | 7:49a |
Cerebellum and Plasma Metabolomics Identify Sepsis Biomarkers and MSC-sEV-Mediated Rescue
Septic encephalopathy (SE) is a devastating complication of sepsis, marked by neuroinflammation and metabolic dysfunction, with the cerebellum being among the most affected brain regions. Progress in the field has been hindered by: (1) the incomplete characterization of cerebellar metabolic disruption in SE, (2) the limited understanding of the therapeutic mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicle (sEV) treatments in SE, and (3) the absence of reliable biomarkers for detecting SE. To address these gaps, we employed a murine sepsis model and performed metabolomic analyses of cerebellar tissue and plasma with and without MSC-sEV treatment. Sepsis induced profound cerebellar metabolic dysfunction, suppression of oxidative energy metabolism, and redox imbalance. MSC-sEVs mitigated these effects through their cargo, restoring cellular energetics and rebalancing antioxidant pathways. Cross-compartment analyses identified six plasma metabolites with strong diagnostic potential. These findings define key cerebellar metabolic mechanisms of SE and MSC-sEV treatment and propose plasma biomarkers for SE diagnostics. | | 9:48a |
Post-biting behavioral reprogramming underlies reproductive efficiency in Aedes aegypti mosquitoes
The global spread and increasing populations of disease vector mosquitoes expose hundreds of millions of people to mosquito-borne illnesses each year. Female Aedes aegypti mosquitoes, global vectors of dengue, require protein from host blood to support egg development and undergo repeated cycles of blood-feeding and egg-laying. After biting, females temporarily alter their behavioral state and suppress host-seeking while using blood-derived nutrients to develop eggs. Host-seeking suppression ends once eggs are laid. While this period has generally been thought of as one of behavioral inactivity, we reveal that it instead reflects behavioral reprogramming, during which females transition from post-blood-meal inactivity into active searching for egg-laying sites. Females with mature eggs show a distinct behavioral state characterized by increased locomotor activity and a shift in circadian behavioral timing, leading to nocturnal humidity-seeking and egg-laying in an otherwise diurnal species. We show that the circadian clock gene cycle is critical for regulating this transition; its absence disrupts the timing of oviposition behaviors, leading to poor site selection and reduced predicted offspring survival. These findings suggest that during egg development, circadian clock-dependent behavioral reprogramming triggers nocturnal hyperactivity and oviposition site search, an essential process for mosquito reproduction and population viability. | | 9:48a |
Information Spillover in Resting Memory and Working Memory
Our fMRI study investigates dependencies between brain areas during resting and working memory states using directed spillover indices estimated from vector autoregressive models that recognize dynamics in the network. A dorsolateral prefrontal centered system (DLPFC) demonstrates spillover memory capacity at rest, labeled resting memory, which facilitates self-referential thinking. Resting memory contains roughly 9 times more neurocognitive dependencies (spillover) as the difference in spillover between working and resting brains, suggesting that resting brains are highly active. The transitioning from resting memory to working memory is initiated by a right inferior fontal (IFG) centered system which connects to the DLPFC centered system when relevant information is detected in the outside world and also inhibits self-referential feedback in parietal cortices. Spillover between the IFG and DLPFC centered systems facilitate a smooth transition in attention from events that take place outside the brain to (sustained) representations of external events within the brain. | | 9:48a |
Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation
Astrocytes adapt to injury and disease by entering a reactive state defined by transcriptomic, morphological, and functional changes. Using a combination of human cortical organoids (hCOs) and primary fetal brain tissue, we investigated the plasticity of human astrocyte reactivity. We observed robust inflammatory transcriptomic and chromatin signatures following cytokine exposure, which varied with duration. To assess reversibility, we withdrew cytokines after acute or chronic exposure. In both cases, astrocytes returned to a quiescent genomic state within days. Chronic exposure induced MHC class II gene ex-pression, normally restricted to professional antigen-presenting cells. We validated MHCII protein in primary tissue and hCOs and used co-immunoprecipitation and mass spectrometry to identify candidate antigens. Finally, we showed that exogenous peptides from fetal neurons could be presented by astrocytic MHCII. | | 10:16a |
Frontal cortex organization supporting audiovisual processing during naturalistic viewing
Our brains dynamically adapt to a multisensory world by orchestrating diverse inputs across sensory streams. This process engages multiple brain regions, but it remains unclear how audiovisual stimuli are represented and evolve over time, especially in naturalistic scenarios. Here, we employed movie-watching to explore this question. We recorded intracranial electrocorticography (iEEG) to measure brain activity in 19 participants watching a short multilingual movie. Using unsupervised clustering and supervised encoding models, we identified a robust modality-specific gradient in the frontal cortex, wherein the ventral division primarily processes auditory information and the dorsal division processes visual inputs. Further, we found that this cortical organization dynamically changed, adapting to different movie contexts. This result potentially reflects flexible audiovisual-resource assignment to construct a coherent percept of the movie. Leveraging behavioral ratings, we found that the frontal cortex is the primary site in this modality assignment process. Together, our findings shed new light on the functional architecture of the frontal cortex underlying flexible multisensory representation and integration in natural contexts. | | 10:16a |
Chemogenetic inhibition of amygdala to ventrolateral prefrontal cortex communication selectively impacts contingent learning
Contingent learning, the process by which specific courses of action become associated with subsequent outcomes, is dependent on the amygdala and ventrolateral prefrontal cortex (vlPFC). The amygdala and vlPFC are bidirectionally connected but it is unclear what the contribution of individual feedforward and feedback pathways is to contingent learning. Here we tested the role of amygdala projections to vlPFC in mediating two key components of contingent learning: signaling the outcome (reward/no reward) that follows a choice and maintaining representation of the choice that was made prior to outcome delivery. To test for these two aspects of contingent learning, we trained macaques to perform a probabilistic reward learning task where for separate stimulus pairs reward was either delivered immediately or after a trace interval. Inhibiting vlPFC-projecting amygdala neurons impacted contingent learning irrespective of whether there was a trace interval or not, and this effect was primarily driven by maladaptive learning on unrewarded trials. Notably, deficits in contingent learning caused by manipulating activity in the amygdala-vlPFC pathway were distinct from impairments in motivation and the ability to update the value of specific rewards in a reinforcer devaluation task. Thus, vlPFC-projecting amygdala neurons appear to play a specific role in contingent learning through signaling the outcomes of a choice, but not in maintaining a memory of the prior choice. | | 10:16a |
Minimally verbal children with autism may see the point, but do not (always) point to what they see:A behavioral and eye-tracking study in visual perceptual processing
During typical development, non social visual object recognition emerges in the first year of life, engaging both low level cues (e.g., color, orientation) and higher level mechanisms involving inference and prior knowledge. Little is known about how these processes function in minimally verbal children with autism (mvASD). We studied 22 children with mvASD using touchscreen based oddball and contour detection tasks, targeting low level (e.g., shape, orientation) and mid level (e.g., Kanizsa figures, 3D shapes) visual stimuli, measuring both pointing and eye gaze responses. All children detected the oddball in the easiest condition with faint distractors, and approximately half succeeded across all low level tasks. Notably, some high performers showed reduced accuracy under mid level conditions with greater stimulus complexity. Strikingly, and not originally anticipated, several low performers who failed to point correctly nonetheless fixated on the correct target. In the Kanizsa oddball task, several mvASD participants, unlike typically developing (TD) peers, consistently pointed to local inducers rather than to the center of the illusory triangle. While the overall deterioration in performance with increased visual complexity suggests that mvASD visual perception may rely on low level representations with attenuated inference based processing, the dissociation between gaze and pointing, along with atypical local pointing behavior, indicates that performance depends not only on what is perceived, but also on how they use the visual signal to drive their behavior. They may, see the point, but not point to what they see. | | 3:16p |
Amyloid pathology reduces dynamic range and disrupts neural coding in a mouse model of Alzheimer's Disease
Alzheimer's Disease (AD) disrupts neural circuits vital for memory and cognition. We used two-photon microscopy to investigate these disruptions in behaving mice, focusing on the link between amyloid plaques - a hallmark of AD - and aberrant neural activity. Using the 5xFAD mouse model, we observed significant changes in hippocampal neurons, including elevated baseline activity and reduced locomotion-driven firing, leading to a diminished neuronal dynamic range. These abnormalities were more pronounced near amyloid plaques. We also found degraded spatial coding, reduced synchrony, and increased variability in neuronal responses. Furthermore, place fields emerged more slowly in both familiar and novel environments, indicative of recall and learning impairments respectively. By showing a specific link between plaque vicinity and neural coding deficits including reduced dynamic range in mice performing spatial tasks, our study offers new insights into the circuit basis of progressive cognitive degradation in AD. | | 6:46p |
Four neurons pattern brain-wide developmental activity through neuropeptide signaling.
In both vertebrates and invertebrates, the developing brain becomes electrically active before it is ready to process sensory input. During neural circuit maturation, developmental activity is thought to refine synaptic connections by driving neuronal co-activation in rhythmic patterns. Here we describe cellular interactions that shape brainwide developmental activity and their molecular basis. In Drosophila, patterned stimulus independent neural activity (PSINA) engages the entire brain in highly stereotyped, globally coordinated cycles of activity. A molecularly-defined population of ~2,000 neurons (Transient Receptor Potential Gamma, Trp{gamma}+ neurons) act as an activity template for PSINA. We show that this activity template is patterned by four neurons expressing the neuropeptide SIFamide (SIFa). Signaling through the SIFa Receptor, SIFa modulates the activity of both SIFa and Trp{gamma}+ neurons to establish the brainwide activity cycles of PSINA. In turn, Trp{gamma}+ neurons sustain SIFa neuron activity through a recurrent interaction. Neuropeptides modulate neuronal activity through synapse-free, or wireless, signaling; a fitting mode of communication for a process tasked with refining on-going synapse formation. By placing neuropeptide signaling at the core of developmental activity, this work highlights the rich neurophysiological potential of the chemical connectome in shaping the developing brain. |
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