bioRxiv Subject Collection: Neuroscience's Journal
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Sunday, July 6th, 2025
| Time |
Event |
| 1:51a |
Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity
The unfolded protein response sensor PERK exists in haplotypes A and B. PERK-B confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tauopathy remain unknown. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. However, a careful examination employing puromycin-based proteomics revealed that a subset of mRNA translation events were permissible under PERK-B, but not PERK-A, dependent UPR. One of the targets that escaped PERK-B suppression was the transcription factor DLX1, which is genetically linked to PSP risk. We found that DLX1 solubility shifted in human PSP brain tissue. Furthermore, silencing the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets. | | 2:18a |
Electrocorticographic Detection of Speech Networks in Glioma-infiltrated Cortex
Direct cortical stimulation (DCS) is the clinical gold standard for identifying functional cortex in the human brain, which is essential for the safe removal of brain lesions. Defining the electro-physiological properties of DCS-positive cortical regions may facilitate the identification of critical language regions, thereby permitting safe glioma resections in communities without access. Leveraging a multicenter electrophysiologic dataset of DCS-positive language regions spatially matched with subdural arrays, we analyzed regions identified as functionally critical (DCS+) versus functionally non-critical (DCS-) during intraoperative language mapping. In IDH-mutant gliomas, DCS+ regions exhibited significantly greater speech-related neural activity and enhanced encoding and decoding of linguistic and semantic features. We demonstrate that resting-state classifiers distinguish DCS+ from DCS- regions in IDH-mutant tumors. Task-based and resting-state electrophysiologic distinctions were pathology-specific and not present in IDH-wildtype glioblastomas. These findings may accelerate DCS mapping by guiding surgeons to priority regions, improving efficiency, and patient outcomes. | | 2:18a |
The c-Src inhibitor eCF506 diminishes opioid tolerance creating bias against β-arrestin2 recruitment
Opioids reduce severe pain, but persistent use is compromised by tolerance, attenuated by either {beta}-arrestin2 depletion, prompting development of biased opioids limited by partial efficacy, or c-Src kinase inhibitors, potentially acting through off-target effects. We tested eCF506, a conformationally selective c-Src inhibitor, on morphine antinociception and examined its effect on receptor signaling and {beta}-arrestin2 recruitment. Oral eCF506 inhibited morphine tolerance in C57BL/6J mice. Exposure of PathHunter CHO cells to eCF506 did not affect inhibition of cAMP accumulation by the agonist, DAMGO, but reduced {beta}-arrestin2 recruitment. This effect, mimicked by targeted degradation of c-Src, occurred through inhibition of c-Src catalytic function as evidenced by its diminution by the catalytically inactive Src250-536(K298M) construct. This mutant also restricted the effect of c-Src inhibitors on {beta}-arrestin2 recruitment. eCF506 additionally increased surface expression of receptors and limited their internalization by endomorphin-2 but did not alter DAMGO-evoked GRK-mediated receptor phosphorylation. These findings suggest that eCF506 prolongs opioid antinociception by inducing signalling bias, diminishing {beta}-arrestin2-mediated receptor regulation. | | 2:18a |
Differential encoding of social identity, valence and unfamiliarity in the amygdala and piriform cortex
To appropriately respond to social situations, animals must rapidly identify conspecifics as individuals, gauge their familiarity and recall any good or bad associations. In previous work (Mazuski & OKeefe, 2022), we characterized populations of neurons in the basolateral amygdala complex (BLA) that were strongly tuned to social conspecifics. In this current study, we asked whether these or other populations in the BLA encode properties necessary for social interaction: individual recognition, familiarity detection and reward association. In addition to cells in the rat lateral amygdala (LA) and basolateral amygdala (BLA), we recorded from cells in the anatomically-related piriform cortex (PIR) to see how much of the amygdala response was inherited from this input. Here, we show that these three interrelated areas encode distinct features of social conspecifics at the population and single neuron level. We recorded from large populations of neurons using 4-shank Neuropixels probes while rats learned a social discrimination task, where one male conspecific was paired with a food reward (S+) and the other its absence (S-). For comparison, two unfamiliar animals were presented on occasional probe trials. After successful discrimination learning, we looked for transfer effects to our previously studied task where implanted rats freely interacted with all four conspecifics in an open-field environment. The LA dynamically encoded social reward learning. Initially, LA neuronal population activity could not distinguish between the S+ and S- conspecifics, but after learning distinct representations emerged. In contrast, the PIR showed no effect of social reward learning. Single PIR units encoded social identity with strong tuning to individual conspecifics both before and after learning. The BLA encoded both reward learning and social identity suggesting this is where the PIR and LA information streams converge. Unexpectedly, the BLA and LA strongly coded for the unfamiliarity of the rat - single neurons responded to the probe trial animals with firing rates 2-5x higher than to the task animals. This cross-region encoding of identity, reward and unfamiliarity was reactivated during social interaction in the new open-field environment, demonstrating that the learning was not context specific. The results throw light on how distinct neural circuits contribute to social recognition and memory and how they interact with each other. | | 3:31a |
Dissociating the Effects of Light at Night from Circadian Misalignment in a Neurodevelopmental Disorder Mouse Model Using Ultradian Light-Dark Cycles.
Individuals with neurodevelopmental disorders (NDDs) often experience sleep disturbances and are frequently exposed to light during nighttime hours. Our previous studies using the Cntnap2 knockout (KO) mouse model of NDDs demonstrated that nighttime light exposure increases behaviors such as excessive grooming, reduces social interactions, and disrupts daily locomotor rhythms. To further evaluate the effects of nighttime light exposure, we exposed wild-type (WT) and Cntnap2 KO mice to an ultradian lighting cycle (T7), which alternates 3.5 hours of light and 3.5 hours of darkness. Circadian rhythms in activity, corticosterone levels, and clock gene expression are maintained under T7 lighting despite the presence of light during the usual night phase, whilst animals display increased depressive-like behaviors and reduce performance on the novel object recognition test. Based on these observations, we hypothesized that T7 lighting would mimic the impact of nighttime light exposure seen in standard light-dark cycles with dim light at night (DLaN). However, in this study, adult WT and Cntnap2 KO mice held under the T7 cycle did not show the increased grooming behavior or reduced social interaction observed in Cntnap2 KO mice exposed to DLaN. Regarding locomotor activity rhythms, the T7 cycle lengthened the circadian period and weakened the rhythm amplitude but did not abolish rhythmicity in either genotype. Finally, opposite to DLaN, neither the T7 cycle nor constant darkness (DD) elicited an increase in cFos expression in the basolateral amygdala in WT and KO mice. These results demonstrate that the adverse behavioral and neurobiological effects of nighttime light exposure in a model of a neurodevelopmental disorder depend on circadian disruption rather than light exposure alone, highlighting the importance of circadian stability as a protective factor in NDDS. | | 3:31a |
Reframing Sleep Architecture: A Compositional and Temporal Approach to Sleep Data Analysis
Significant progress has been made in developing sleep staging methodologies; however, less attention has been devoted to the analysis of sleep architecture. Two critical aspects remain underexplored: the choice of binning window (i.e., grouping data into time intervals) and the statistical treatment of the interdependencies among sleep phases. While one-hour bins are commonly used, this choice is often based on convention rather than empirical justification. Additionally, sleep architecture data are typically expressed as proportions of time spent in each sleep phase, forming compositional datasets, non-negative values that represent parts of a whole and are constrained by a constant sum (e.g., 100%). Such data violate the assumptions of traditional statistical methods, yet their compositional nature is often overlooked, compromising analytical validity. In this study, we address two key methodological challenges in sleep architecture analysis: (1) determining the optimal binning window through a data-driven approach that balances information retention and noise reduction, and (2) applying isometric log-ratio (ILR) transformation to account for the compositional structure of the data, enabling the use of conventional statistical tests. By addressing these issues, we propose a more rigorous and interpretable framework for analyzing sleep architecture, aiming to enhance the accuracy and reproducibility of findings in sleep research. | | 4:42a |
Realistic coupling enables flexible macroscopic traveling waves in the mouse cortex
Traveling waves are ubiquitous in neuronal systems across different spatial scales. While microscopic and mesoscopic waves are relatively well studied, the mechanisms underlying the emergence of macroscopic traveling waves remain less understood. Here, by modeling the mouse cortex using spatial transcriptomic and connectivity data, we show that realistic cortical connectivity can generate a significantly higher level of macroscopic traveling waves than local and uniform connectivity. By quantifying the traveling waves in the 3-D domain, we discovered that the level of macroscopic traveling waves depends not only on the network connectivity but also non-monotonically depends on the coupling strength between neurons in the network. We also found that slow oscillations (0.5 - 4 Hz) are more likely to form large-scale, macroscopic traveling waves than other faster oscillations in the network with realistic connectivity. Together, our work shows how flexible macroscopic traveling waves can emerge in the mouse cortex and offers a computational framework to further study traveling waves in the mouse brain at the single-cell level. |
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