bioRxiv Subject Collection: Neuroscience's Journal

EGR3 Deletion Rescues Developmental and Epileptic Encephalopathy in Kcna1-null Mice
KCNA1 encodes the a-subunit of the voltage-gated potassium channel KV1.1. Mutations in the pore domain result in developmental and epileptic encephalopathy (DEE), where early life seizures and a culprit lesion synergistically disrupt neurodevelopmental trajectories, resulting in intellectual disability that often presents with disturbances in sleep, sociability and sensory processing. Abnormalities in the subcellular localization of Kv1.1, via mutations in/autoantibodies against LGI1 and CNTNAP2, also give rise to syndromes of epilepsy and neuropsychiatric impairment. Mice with deletions of Kcna1(-/-) display spontaneous seizures at 2-3 weeks of age and premature mortality. In this study, we applied instrumented home-cage monitoring to examine how aberrations in KCNA1 expression may result in pervasive alterations in spontaneous behavior. Compared to wildtype, Kcna1-/- mice displayed a robust multifaceted behavioral syndrome featuring marked nocturnal hyperactivity, insomnia, reduced sheltering, fragmented feeding/drinking rhythms, sensory over- responsivity and diminished wheel-running. In identical recordings, Kcna1+/- mice only displayed increased sheltering, Lgi1+/- mice displayed mild insomnia and Cntnap2-/- mice showed home-cage hypoactivity. Kcna1 loss in parvalbumin-positive interneurons (Pv-Cre) resulted in a subtle phenocopy, with mild insomnia accompanied by reduced sheltering behavior, while similar deletions in forebrain pyramidal neurons (Emx1-Cre) or dopaminergic neurons (DAT-Cre) were asymptomatic. Adult-onset conditional deletions of Kcna1 also produced only mild insomnia 6 weeks later. To survey the molecular landscape in Kcna1-/- mice, we conducted a mass spectrometry proteomic analysis of dissected hippocampal tissue (a predominant seizure onset zone and where astrogliosis is observed). This revealed significant upregulations in BDNF (brain-derived neurotrophic factor) and the immediate early transcription factor EGR3 (early growth response-3), which is necessary for the induction of BDNF following electroconvulsive seizures. Heterozygous or homozygous deletions of Egr3 in Kcna1-/- mice resulted in significant survival prolongation, a partial neurobehavioral rescue, and a significant improvement in the frequency of spontaneous seizures and spreading depolarization events. These clinical improvements were associated with an amelioration of BDNF induction, hippocampal astrogliosis and proteomic disturbances. Together, these data illustrate how an ion channel that governs excitability at millisecond scales also shapes the spatiotemporal structure of spontaneous behavior at meso- or macroscopic time scales. Our results provide a model and a set of precision endpoints to understand how ictal and interictal features of DEE may be ameliorated by inhibiting the long-term downstream transcriptional alterations imparted by early life seizures.

Melanopsin-mediated signals in natural and human-made environments
Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) play a critical role in regulating physiological and behavioral responses to light. However, little is known about how melanopsin and ipRGC signals are shaped by the statistical properties of real-world environments. Here, we analyzed statistics of melanopsin, ipRGC codification of extrinsic and intrinsic photoresponses, and luminance using hyperspectral images of natural and human-made scenes under daylight illumination. The statistics were obtained simulating receptive fields from current knowledge about ipRGCs anatomy and physiology. Our findings reveal that human-made environments exhibit significantly higher melanopsin, luminance, and ipRGC excitations compared to natural environments. In natural scenes, luminance contrasts were higher than melanopsin and ipRGC contrasts across most of the range. Melanopsin contrast was largely independent of excitation, and was significantly reduced for larger receptive fields. Differences between ipRGC codification models suggest an interaction between input weighting and environmental structure. These results indicate that modifications of natural regularities by human-made environments could affect ipRGC-driven physiology in everyday life.

Neural and behavioral consequences of bilateral maps in primary somatosensory cortex
Mice rely heavily on their sophisticated whisker somatosensory system to explore and navigate their surroundings. The primary whisker somatosensory cortex (wS1) receives sensory input through the lemniscal pathway, which exclusively carries signals from the contralateral side of the face due to a complete crossover of axonal projections from the brainstem to the thalamus. This contralateral whisker input organization is disrupted in mice with a conditional knockout of the Robo3 gene (Robo3cKO mice), leading to abnormal bilateral representations of the whiskers in wS1. We investigated the behavioral and neural consequences of these bilateral whisker representations in Robo3cKO mice. Performance on a discrimination task in which mice reported whether a left-side or a right-side whisker was deflected was on par with that of wild-type littermates. Unilateral optogenetic inhibition of wS1 showed that activity in the wS1 contralateral to a stimulated whisker was required for mice to report its side correctly, despite a representation of that whisker in the uninhibited hemisphere. Single-unit recordings in wS1 and the whisker primary motor cortex (wM1), a major downstream target of wS1, showed abnormal bilateral whisker responses in wS1 but largely normal responses in wM1, suggesting that the bilateral responses in wS1 were filtered out along the sensorimotor processing stream. Our results demonstrate that the brain can adapt to fundamental alterations in tactile input to construct accurate sensorimotor representations.

Connectivity Is All You Need: Inferring Neuronal Types with NTAC
Recent advances in electron microscopy and computer vision have enabled the mapping of complete wiring diagrams--called connectomes--of brain regions and even entire brains. The emergence of these increasingly large-scale connectomic datasets have intensified the need for efficient and accurate neuronal cell type identification. Traditional approaches rely on labor-intensive analyses of molecular, anatomical, and physiological features. As a step toward fully automated neuronal cell type classification, we present NTAC (Neuronal Type Assignment from Connectivity) -- a method for grouping neurons into cell types based solely on synaptic connectivity. Our approach is grounded in the hypothesis that synaptic connectivity is key to determining neuronal cell types (Seung 2012), and our results provide the strongest evidence to date supporting its validity. NTAC comes in two flavors: a semi-supervised variant that requires some of the neurons to be labeled, and an unsupervised variant that requires no labels at all. The first can be naturally formalized as a learning problem on graphs: given labels for a subset of neurons, use connectivity to label the rest. We present a simple and fast algorithm that achieves over 95% accuracy on the fly's visual system starting with just 2% of neurons labeled, within minutes on a standard PC. In contrast, morphology based parallel achieves lower accuracy even on smaller datasets and with significantly more labels. Formalizing the problem as a fully unsupervised learning task is more challenging. To address this, we introduce a novel computational problem, approximate equitable partitioning, and design an efficient heuristic for it, using the semi-supervised algorithm as a subroutine. Remarkably, the unsupervised method achieves ~70% accuracy on the fly's visual system, drastically outperforming its morphology based parallel and providing concrete evidence that synaptic connectivity alone can reveal cell types. Both variants of NTAC are evaluated on multiple state of the art connectomes including optic lobes, central brain and nerve cord of adult fruit flies.

Motor Neurons Decode Cholinergic Inputs via Spatially Distinct nAChR Subunits to Drive Locomotion in Drosophila larvae
Neural circuits consist of neurons that differ not only in their neurotransmitter identities but also in the types and subcellular localization of neurotransmitter receptors (NRs) they express. This receptor diversity enables distinct responses to the same neurotransmitter, highlighting the need to understand NR distribution and function to fully interpret circuit logic. Here, we focus on nicotinic acetylcholine receptors (nAChRs), the primary mediators of fast excitatory transmission in the Drosophila central nervous system (CNS). Functional nAChRs are pentamers assembled from a pool of 10 subunits (alpha1-alpha7 and beta1-beta3), yet their in vivo expression and function remain poorly defined. We used T2A-Gal4 lines and endogenous protein tagging to examine nAChR expression in larval motor neurons (MNs) and identified eight subunits expressed in these cells. MN-specific knockdown of individual subunits caused distinct locomotor defects, indicating their functional importance. Co-localization analysis revealed some subunit pairs are frequently co-expressed at the same synapses, while others localize to distinct subcellular domains. Supporting this, double knockdown of co-localized subunits did not worsen locomotor phenotypes compared to single knockdowns, whereas knockdown of non-co-localized subunit pairs produced additive defects. These results suggest that different nAChR subtypes are strategically positioned in discrete synaptic domains within single MNs, where they serve non-redundant roles. Our findings provide new insight into the spatial organization and functional diversity of nAChRs in motor circuits that drive locomotion.

Adaptive suppression of threat-history stimuli
The present study investigated whether adaptive suppression mechanisms can be applied to stimuli with a history of threat association. In the experiment, a threat-conditioning task was first used to associate one of two colors (green or cyan) with an electric shock, thereby establishing conditions of threat-history and no-threat-history. Subsequently, in a visual search task, 30 participants reported the orientation of the line inside the target diamond while occasionally being either undistracted or distracted by threat-history or no-threat-history distractors, which appeared across various spatial locations. The results showed that distractors appearing at high-probability locations were effectively suppressed, with suppression being stronger for threat-history distractors than for no-threat-history distractors. These findings indicate that threat history may facilitate visual search through an adaptive attentional suppression mechanism.

Changes in Ocular Fixation Characteristics Over Time during Reading
In this report, we evaluate eye-movements during reading. There is a huge literature on this topic, but our report is not focused on the typical questions raised in this literature and our task design is very atypical for an eye-movement/reading study. While most reading studies evaluate mental processes during reading, the only mental process we evaluate is fatigue. While most reading studies use stimuli presented in the middle of the screen, our poem sections are presented in 24 lines of text that span the top to the bottom of the display. While most multi-line reading studies use a very large interline spacing, our interline spacing is more typical of text reading in newspapers, magazines and books. We report on changes in the characteristics of fixations as a function of time-on-task (TOT). We determine the start and end of reading for each subject/session and divide this reading time into 10 equal length (number of samples) periods (referred to as epochs). We looked for changes in fixation characteristics across epochs. We emphasize our results for horizontal position because these changes were monotonic and interpretable. For horizontal position signals, we found that the mean intersample distances in fixations increases, the rate of changes of fixation position decreases and the total fixation width increases as a function of epoch. We interpret our results to mean that, as reading progresses, it becomes more difficult to hold the eye still. Early in reading, the total fixation width is lower, the mean intersample distance is lower and there are frequent adjustments (i.e., changes in direction) to keep the eye well focused on the target word. As time progresses, it becomes more and more difficult to hold the eye perfectly steady, so fixations become wider and mean intersample distance increases.

Increased basal ganglia volume in older adults with tinnitus
Tinnitus is the perception of sounds without external stimuli, affecting 10%-15% of the general population and up to 25% of individuals over 70 years of age. While traditionally viewed as an auditory phenomenon, growing evidence highlights the role of the central nervous system in its pathophysiology. One of the proposed mechanisms, the "gating hypothesis" of tinnitus, suggests an alteration in the modulation of sensory activity by the frontostriatal network. Although structural changes in frontal areas support this idea, gray matter differences in subcortical regions -such as the auditory pathway and basal ganglia- remain poorly understood. Here, we examined subcortical structures and auditory function in older adults with mild presbycusis from the ANDES cohort, including 51 tinnitus patients and 40 age-matched controls. We analyzed brain volume via structural magnetic resonance imaging and subcortical auditory functionality via auditory brainstem responses (ABRs). We found non-significant differences in age, hearing loss, cognitive performance, and ABR amplitudes between the groups. Notably, tinnitus patients presented a significant increase in the volume of basal ganglia structures (striatum and pallidum) but not in auditory areas. These findings reinforce the role of the basal ganglia in age-related tinnitus pathophysiology.

On the relationship between neuronal heterogeneity and entropy
Neuronal size has often been used to explain the "superiority" of the human brain. By deriving the Shannon entropy of different statistical distributions, we show that the entropy of different distributions is solely accounted for by the variance of the distribution. We use total dendritic length (TDL) of neurons from different species as an example to show that entropy computed from TDL distributions has nothing to do with the absolute size of neurons, but the increased variance seen in the larger neurons.

Test-retest reliability of multi-metabolite edited MRS at 3T using PRESS and sLASER
Purpose: Spectral editing is the most common MRS approach for noninvasive in vivo measurement of low-concentration, strongly overlapped metabolites in the brain, such as {gamma}-aminobutyric acid (GABA) and glutathione (GSH). Multi-metabolite editing methods, including HERMES and HERCULES, have recently been introduced, where multiple J-coupled metabolites can be edited in a single acquisition without increasing total scan time. Yet little is known regarding the reliability of these methods. This study assessed the test-retest reliability of HERMES and HERCULES, where volume localization was achieved using either PRESS or sLASER. Methods: Sixteen healthy adult volunteers were scanned twice in two separate sessions. Single-voxel edited MRS data were acquired in the medial parietal lobe using the following sequences: (1) HERMES-PRESS; (2) HERMES-sLASER; (3) HERCULES-PRESS; (4) HERCULES-sLASER. Spectra were processed and metabolites were quantified using the Osprey software. Data quality metrics and reliability statistics were estimated for all four acquisitions. Results: HERMES-sLASER demonstrated lower within-subjects coefficients of variation (CVws) for GSH, glutamine (Gln), and glutamate (Glu) + Gln (Glx), suggesting improved reliability compared to HERMES-PRESS. However, GABA + co-edited macromolecules (GABA+) and Glu showed higher CVws for HERMES-sLASER. HERCULES-sLASER produced better reliability than HERCULES-PRESS for GABA+, GSH, Glu, Gln, Glx, aspartate (Asp), and lactate (Lac). N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) showed higher CVws for HERCULES-sLASER. These findings suggest that sLASER may be more advantageous than PRESS for volume localization in simultaneous multi-metabolite editing. Conclusion: Using sLASER yielded better test-retest reliability for most metabolites than using PRESS for volume localization for HERMES and HERCULES.

Geometric Quantum Coherence Protection inFibonacci-Structured Microtubules: A Quantum Solution tothe Cognitive Paradox of Acute HIV-associatedNeuroinflammation
HIV-associated neurocognitive disorder (HAND) presents a fundamental paradox: patients maintain cognitive function during acute infection despite cytokine storms that meet sepsis criteria. Through computational modeling of quantum coherence in neural microtubules during HIV-induced neuroinflammation, we discovered that Fibonacci scaled microtubular architectures maintain quantum coherence up to 104-fold longer than regular structures through geometric optimization. This protection mechanism operates through resonant coupling at the golden ratio ({varphi} = 1.618), achieving 74.4% efficiency in preserving quantum information. Using five complementary computational models validated against recent experimental quantum data, we demonstrate: (1) power law decay (exponent = -1.015) in Fibonacci structures versus near-exponential collapse ( = -10.102) in regular grids; (2) quantum sanctuary formation at t = 0.6 time units creating coherence-preserving boundaries; (3) precise mathematical optimization at {varphi} = 1.618033988749895; (4) temperature resilience maintaining function during HIV-associated fever; (5) strong correlations with clinical neuroimaging (r = 0.74 - 0.82, p < 0.001). Monte Carlo analysis (n = 50) confirmed the probability 100% of sanctuary formation during acute inflammation above 38.5 C. These findings resolve the cognitive paradox of HAND by revealing how geometric structure enables preservation of quantum information despite extreme perturbation, suggesting novel therapeutic targets and establishing new principles for quantum biology and bioinspired quantum technologies.

A Numerical Alternative to MR Thermometry for Safety Validation of Multi-Channel RF Transmit Coils
Purpose: This study proposes an alternative approach to MR thermometry (MRT) for the safety validation of multi-channel RF transmit coils and demonstrates its use to enable human studies at 10.5T. Methods: To ensure patient safety, specific absorption rate (SAR) limits established under international guidelines must not be exceeded. Predicting SAR on state-of-the-art parallel transmit systems relies on electromagnetic simulations, which require extensive experimental validation. Despite a well-established validation workflow, SAR prediction errors are unavoidable and must be quantified as a safety margin. While MRT tests are commonly used for this purpose, their technical challenges necessitate an alternative. The proposed technique propagates the error between experimentally and numerically acquired B_1^+ distributions to the uncertainty in simulated peak local SAR using Monte-Carlo simulations without the need for MRT. This method was validated using a 16-channel transceiver coil for imaging the human torso (henceforth referred to as a "body" coil) at 10.5T with two excitation scenarios, as well as an 8-channel 10.5T head coil with four excitation scenarios. Results: The proposed numerical technique proved more conservative than existing MRT-based SAR error quantification methods across all tested scenarios. Its application to validate three state-of-the-art head coils (16Tx/32Rx, 16Tx/80Rx, and 16Tx/128Rx) led to regulatory approval for human head imaging and high-quality functional as well as diffusion MRI results at 10.5T. Conclusion: A numerical alternative to MRT requires only the experimental acquisition of B_1^+ maps for comparison with simulations, enabling the quantification of uncertainty in SAR prediction. This technique was applied to three 16-channel transmit arrays, each used in conjunction with high-channel-count receive arrays for in vivo imaging.

Multimodal Evidence for Hippocampal Engagement and Modulation by Functional Connectivity-Guided Parietal TMS
Hippocampal activity supports memory and many other brain functions. Transcranial magnetic stimulation (TMS) guided by hippocampal functional connectivity (FC) shows promise in improving memory, but direct neural evidence of its capacity to engage and modulate hippocampal activity is lacking. Here we combined TMS with intracranial electroencephalography (iEEG) in 8 neurosurgical patients and with functional magnetic resonance imaging (fMRI) in 79 neurologically healthy participants. We identified that (1) single-pulse TMS to individualized parietal cortex guided by hippocampal-FC preferentially evoked distinct temporal and spectral activity patterns in the hippocampus, (2) variability in TMS-evoked hippocampal responses related to individual differences in parietal-hippocampus FC strength, and (3) repetitive TMS to hippocampal-FC-guided parietal cortex selectively suppressed hippocampal theta oscillations. These findings provide multimodal causal neural evidence and important mechanistic insights supporting the development of personalized neuromodulation strategies aimed at improving hippocampus-dependent functions.

Toward Granular Brain Intrinsic Connectivity Networks and Insights into Schizophrenia
Spatial group independent component analysis (sgr-ICA) has become a crucial method to understand brain function in functional magnetic resonance imaging (fMRI) research, especially in resting-state fMRI (rsfMRI) studies. Early studies identified large-scale brain networks using sgr-ICA with lower order (e.g., 20 - 45 components); however, more recent studies have employed higher model orders (e.g., 200 components) to reveal more refined intrinsic connectivity networks (ICNs), offering a more detailed representation of functional brain architecture. This increased granularity has encouraged researchers to explore even higher model orders to better capture the brain's function. Although previous studies explored higher model orders, small datasets often limited them. In this study, we addressed this gap by assessing an sgr-ICA model with 500 components using a large rsfMRI dataset of over 100,000 subjects. This extensive data set allowed us to provide a robust estimation of fine-grained ICNs. We further assessed diagnostic effects and cognitive performance using whole-brain functional network connectivity (FNC) of 502 individuals with schizophrenia and 640 typical controls from these ICNs. We also compared the results with ICNs obtained using a lower-order, multi-spatial-scale template. Results demonstrate that our approach yields a large set of reliable and fine grained ICNs, enhancing characterization of schizophrenia related dysconnectivity patterns. Specifically, we observed a relatively large number of ICNs within the cerebellar and paralimbic area. We detected significant hypoconnectivity between the cerebellar and subcortical domains, including the basal ganglia and thalamic regions. We also found hyperconnectivity between the cerebellar domain and the visual, sensorimotor, and higher cognitive domains, as well as between the sensorimotor and subcortical domains. Our finding revealed that granular ICNs can detect significant FNC differences between cohorts which are missed in larger scale ICNs. This work highlights the capability of higher model order ICA to capture distinct, fine-grained ICNs, enriching our understanding of FNC and serving as a valuable addition to current multiscale ICN templates. The ICNs derived from this study may serve as valuable references for future research, with the potential to improve the clinical utility of rsfMRI and advance the study of psychiatric disorders.

Atypical weighting of sensory evidence and priors in causality perception along the autism-schizotypy continuum
The brain constructs a perceptual interpretation of the world by integrating sensory input with prior knowledge and expectations. Causality perception, a core example of this inferential process, enables observers to infer cause-effect relationships, such as whether a moving object causes another to move. Traditionally considered a low-level visual computation, causality perception is increasingly recognized as shaped by top-down dynamics, perceptual history, and individual predictive processing styles. Here, we examined how prior experience and cognitive-perceptual traits shape causal inference in 150 neurotypical individuals, using data-driven clustering to stratify participants along the autism-schizotypy (ASD-SSD) spectrum. Participants viewed dynamic collision events in which a moving circle contacted a stationary one, followed by variable temporal lags before the second objects motion, and judged whether the interaction appeared causal or non-causal. Causality judgments were influenced by both physical timing (sensory-driven) and serial dependence on previous perceptual decisions (prior-driven). Hierarchical drift diffusion modeling (HDDM) revealed that SSD-like individuals showed a strong prior bias toward causality, greater serial dependence, and lower decision thresholds, reflecting a prior-dominated perceptual style. Conversely, ASD-like individuals exhibited reduced influence of perceptual history and higher decision thresholds, reflecting a conservative, data-driven style. Crucially, prior bias, serial dependence, and decision-making dynamics were strongly interrelated, revealing a hierarchical structure to perceptual inference across neurocognitive profiles. These findings demonstrate that causality perception emerges from predictive processes operating at multiple timescales and shaped by individual differences in neurocognitive style and perceptual flexibility.

Significance StatementAccurate causality perception is a fundamental building block of cognition, supporting our ability to parse the sensory world, guide action, and construct coherent models of the environment. It provides a key example of perceptual inference, and thus how the brain integrates sensory input, prior expectations, and recent experience to shape subjective perception.

Here, we show that causality perception is not fixed, but varies systematically across individuals, mirroring broader variability in how different neurocognitive architectures balance sensory evidence and prior expectations along the autism-schizotypy (ASD-SSD) spectrum within the general population. By combining psychophysical data with hierarchical computational modeling, we reveal distinct perceptual inference styles along the autism-schizotypy continuum, ranging from sensory-driven to prior-driven processing.

These findings advance predictive processing accounts of individual variability and offer new insights into the mechanisms supporting flexible and adaptive perception in neurodiverse populations.

Cross-species comparative connectomics reveals the evolution of an olfactory circuit
Animal behavioural diversity ultimately stems from variation in neural circuitry, yet how central neural circuits evolve remains poorly understood. Studies of neural circuit evolution often focus on a few elements within a network. However, addressing fundamental questions in evolutionary neuroscience, such as whether some elements are more evolvable than others, requires a more global and unbiased approach. Here, we used synapse-level comparative connectomics to examine how an entire olfactory circuit evolves. We compared the full antennal lobe connectome of the larvae of two closely related Drosophila species, D. melanogaster and D. erecta, which differ in their ecological niches and odour-driven behaviours. We found that evolutionary change is unevenly distributed across the network. Some features, including neuron types, neuron numbers and interneuron-to-interneuron connectivity, are highly conserved. These conserved elements delineate a core circuit blueprint presumably required for fundamental olfactory processing. Superimposed on this scaffold, we find rewiring changes that mirror each species ecologies, including a systematic shift in the excitation-to-inhibition balance in the feedforward pathways. We further show that some neurons have changed more than others, and that even within individual neurons some synaptic elements remain conserved while others display major species-specific changes, suggesting evolutionary hot-spots within the circuit. Our findings reveal constrained and adaptable elements within olfactory networks, and establish a framework for identifying general principles in the evolution of neural circuits underlying behaviour.

A cortical code emerges in Layer5a of S1 through temporal integration of thalamic inputs
Tactile representations in the barrel field of the primary somatosensory cortex of rodents (wS1) receive inputs from two distinct thalamic nuclei, the ventro-posterior-medial nucleus (VPM) and the posterior medial complex (POm). Previous work has revealed a sweep-stick code in rat wS1 by using a novel whisker velocity-white noise stimulus. Sticks refer to high velocity single whisker bumps, while sweeps correspond to large multiwhisker displacements with extended temporal profiles. We hypothesized that barrel cortex neurons inherit stick responses from the VPM and sweep responses from the POm. Here we test this hypothesis by studying the coding strategy of both thalamic nuclei and wS1 in mice. We found a stratified wS1 representation of both sweep and stick functional classes, whereas VPM and POm contained mainly stick encoding neurons. Cortical layer 4 stick responses are a delayed version from VPM, while layer 5b sweep responses come from POm. Notably, layer 5a sweep responses result from a temporal integration of stick information from VPM and POm. Our results put forward a circuit scheme in which fast encoding stick events from VPM allow a fine-tuned texture processing in the cortex, modulated by sweep-responding cells that integrate multi-whisker information.

Hippocampal Commissural Circuitry Shows Asymmetric cAMP-Dependent Synaptic Plasticity
Hemispheric asymmetries in NMDAR-dependent synaptic plasticity have been described in hippocampal area CA1, but it remains unclear whether similar lateralized mechanisms exist for cyclic adenosine monophosphate (cAMP)-dependent plasticity. Here, we investigated whether cAMP-mediated potentiation of synaptic transmission in mouse CA1 exhibits hemisphere-specific properties. In recordings with electrical stimulation of CA1 inputs, a subset of recordings in the left, but not in the right hemisphere CA1, exhibited a pronounced cAMP-induced potentiation of field excitatory postsynaptic potentials (fEPSPs). To isolate input specific contributions, we expressed the optogenetic actuator ChrimsonR unilaterally in the CA3/CA2 region of wild-type mice. Light-evoked glutamate release from ipsilateral Schaffer collaterals showed no cAMP sensitivity in either hemisphere, while commissures originating from the right (COR) exhibited cAMP-mediated potentiation of transmission in a subset of experiments. Notably, this effect was absent at commissures originating from the left (COL). The selective presence of the effect prompted us to further investigate the underlying cell population using CA3-specific (G32-4 Cre) and CA2-specific (Amigo2-Cre) driver lines. Recordings from synapses of CA3 COR recapitulated the cAMP-induced potentiation of transmitter release observed in wild-type animals. However, the effect was again restricted to a subset of experiments and was absent in recordings with specific stimulation of CA2 COR. Our results demonstrate a variable cAMP-sensitivity of transmitter release at COR synapses in the left CA1. Altogether, we reveal a hemisphere-specific cAMP-mediated synaptic plasticity at CA3 COR onto CA1, underscoring hidden heterogeneity and lateralization in hippocampal circuit function.

Mapping functional, structural, and transcriptomic correlates of homotopic connectivity
Homotopic functional connectivity (HoFC)--the synchronous activity between homologous regions of the left and right cortical hemispheres--is a hallmark of inter-hemispheric brain architecture, yet its biological underpinnings remain incompletely understood. Here, we characterize spatial variation in resting-state HoFC and its relation to dominant natural axes of anatomical, functional, and transcriptomic organization across the human cerebral cortex. We show that the regional distribution of HoFC, from the lowest in association areas (especially limbic) to the highest in primary sensorimotor regions, is preserved in neuropsychiatric disorders in a separate neuroimaging cohort (including schizophrenia, bipolar I disorder, and attention-deficit hyperactivity disorder) despite disease-associated perturbations in magnitude. Regional variation in HoFC is not fully explained by properties of physical embedding or vascular innervation in the brain, suggesting involvement of alternative physiological processes. Furthermore, we find that regions with stronger HoFC are more functionally connected within and across hemispheres at rest, suggesting that homotopic functional coupling is positively associated with brain-wide functional synchrony. Our results collectively suggest that HoFC is inherently aligned with a fundamental natural axis of macroscopic cortical organization and shared global signal--advancing our understanding of the biological correlates of cortical homotopy and suggesting potential mechanisms to investigate in the future.

Cognition-centric brain activity across diverse imaging tasks constrains the representation of mental health in task-evoked brain function
Identifying individual differences in brain activity that reflect variation in domains of mental health - including those in the Research Domain Criteria (RDoC) framework - remains a core challenge in neuropsychiatry. Here, we cross-analyzed mental health and brain function profiles in hundreds of individuals using factor analysis of 87 neurocognitive/psychiatric assessments and tensor independent component analysis of functional magnetic resonance imaging (fMRI) data acquired during task and movie-watching paradigms with putative mental health relevance.Across 77 brain network variants evoked across five paradigms, univariate and multivariate network activity differences predominantly reflected and predicted cognition, weakly indexing other mental health domains despite their similar reliability and interindividual variability.Normative mental health variation was not reflected in comparatively homogeneous evoked brain activity, and clustering subjects by brain function versus mental health produced discordant subtypes. Brain activity evoked by common fMRI paradigms may contain insufficient non-cognitive information to differentiate mental health in the general population.

Multiple-level organizational logic of the locus coeruleus-norepinephrine system in structure and function
The locus coeruleus (LC) regulates various neural processes through a limited number of norepinephrine (NE)-releasing neurons with widespread axon projections. However, how the LC is organized to exert brain-wide regulatory functions remain elusive. Utilizing larval zebrafish as a whole-brain-scale model, we reveal that morphologically heterogenous but physiologically comparable LC-NE neurons assemble complementarily to implement region-specific regulation of brain-wide neural dynamics. Individual LC-NE neurons exhibit diverse axon projections with ipsilateral bias and region preference, but share comparable electrophysiological properties, sensory responses and neural function-related genes expression. Moreover, population LC-NE neurons display bilaterally symmetrical yet regionally different axon projections and fire synchronously, causing regionally patterned NE release. Along with the regional comparability of NE receptor expression, these enable the LC to tune brain-wide neural dynamics in an inverted-U manner with region difference. Thus, our study provides a comprehensive understanding of the organizational logic of the LC system.

Disentangling Prediction and Feedback in Social Brain Networks: A Predictive Processing Approach
While much research in social cognitive neuroscience has focused on which brain regions are engaged when processing social content, it remains unclear what these areas are doing in terms of underlying mechanisms. Here, we approached this question using predictive processing theory, which suggests that the brain instantiates a generative model of its sensory environment. Using a novel animated shapes fMRI task, we observed a functional double dissociation between brain regions that were engaged when forming a prediction for agentic movement - which involved the premotor cortex and the lateral parietal cortex, previously implicated in action observation and mirroring - from those associated with processing feedback for updating abstract priors to guide predictions - which involved the dorsomedial and ventrolateral prefrontal cortex, the temporoparietal area, and the lateral temporal cortex, previously associated with mentalizing/theory of mind. We observed parallel functional dissociations in the cerebellar areas affiliated with these networks. These findings suggest new insights into how brain regions associated with action observation/mirroring and mentalizing/theory of mind play complementary roles in supporting facets of a predictive processing architecture underlying social cognition.

Nucleus Basalis of Meynert as a DBS target
Several clinical attempts to use deep brain stimulation applied to nucleus basalis of Meynert to reduce cognitive decline in different types of dementia report inconclusive effects. At the same time, experiments in rodents have largely demonstrated cognitive improvement. The hypothesised basis for this difference was the application of different patterns of stimulation - tonic continuous over multiple sleep-wake cycles in human clinical trials vs intermittent bursts over shorter intervals in animal studies. However, since no systematic testing of the effects of different stimulation patterns applied in different states of vigilance was conducted, it remains unclear what specific attributes of cortical responses are associated with these patterns, and the effect of vigilance state on pattern response.

We hypothesised that communication between nucleus basalis and its cortical targets involves frequencies in both low and high ranges, making burst-type intermittent patterns potentially more effective. Therefore we studied preferred frequencies of neuronal synchronization within nucleus basalis as well as between nucleus basalis and its cortical targets in B6 mouse strain (N=9, age 4-6 month) by recording neuronal spiking and local field potentials (LFP) from 2 sites of the nucleus basalis and 4 cortical sites simultaneously across multiple sleep-wake cycles. Spike-field coherence (SFC) analysis revealed natural synchronization tendencies of nucleus basalis - all animals demonstrated significant SFC at delta-theta range and gamma coherence peaking between 57 and 88 Hz (SFC > 95% Jackknife confidence interval at frequency range > 2*bandwidth). SFC between cortical cells and local field potentials of nucleus basalis, which reflects cortical feedback, peaked at delta-theta frequencies.

Based on these results we constructed "nested" patterns of stimulation that included both delta-theta and individually assessed gamma peak for each animal (N=8). The effects of nested stimulation were compared to the ones of random and tonic (20Hz) stimulation patterns. These patterns of stimulation were applied across multiple sleep-wake cycles to freely behaving animals, and spectral power density in response to stimulation compared between patterns for different states of vigilance.

We report significant reduction of delta power during slow wave sleep and theta power in REM for all three patterns. Slow wave suppression was also present during wakefulness. This indicates all patterns may improve levels of alertness but highlights strong likelihood of sleep disturbances in response to stimulation during sleep. Thus, deep brain stimulation of nucleus basalis may be counterproductive during sleep.

The nested pattern of stimulation alone demonstrated preservation or even enhancement of gamma activity in the cortex while suppressing low frequencies. Broad-band suppression of cortical activity was shown in response to tonic stimulation, and to some extent to the random pattern as well, suggesting that tonic stimulation may be unsuitable for deep brain stimulation of the nucleus basalis of Meynert.

Functional connectivity in infants' visual cortex: Links to motion processing and autism
In a previously published study, we found atypical visual cortical laterality patterns during global motion perception in 5-month-old infants who showed high levels of autistic symptoms in toddlerhood. Here, using data from a separate experiment, we examined whether these results could reflect altered visual cortical functional connectivity in theta, alpha, and gamma rhythms. We assessed this in a sample of 5- month- old infants (n = 59; 39 elevated familial likelihood of autism) by means of electroencephalography (EEG) when they were watching videos showing social and non-social scenes. Gamma connectivity between midline and far-lateral visual cortex when viewing social scenes was linked to both later autism symptoms and global motion visual cortical laterality we reported in the previous study. This may indicate a shared integrative mechanism underlying social perception and global motion processing. Further, we found that higher midline-to-lateral theta connectivity in the visual cortex when perceiving non-social scenes in infancy was strongly associated with having more autistic symptoms at follow up, but uncorrelated with concurrent motion perception. Our study points to atypical functional connectivity in the visual cortex as a potential early marker of autistic symptoms and highlights a probable link between motion processing and social perception.

ATF4 activates a transcriptional program that chronically suppresses mTOR activity promoting neurodegeneration in Parkinson's disease models
The Integrated Stress Response (ISR) is a cell signaling pathway that enables cells to adapt to diverse cellular stresses. Conversely, during chronic/unmitigated cellular stress the ISR becomes maladaptive and has been implicated in a range of neurodegenerative conditions including Parkinsons Disease (PD). However, the mechanisms by which maladaptive ISR/ATF4 signaling contributes to neurodegeneration have not been elucidated. In this study we establish a critical mechanism by which chronic ISR activation becomes maladaptive and promotes neurodegeneration in neurotoxin and - synucleinopathy models of PD in vitro and in vivo.

Specifically, we demonstrate that chronic activation of ATF4, the central transcription factor of the ISR, promotes neurodegeneration by regulating the transcriptional induction of SESN2, DDIT4 and Trib3 that co-operate to suppress both mTORC1 and mTORC2 activity. Furthermore, we demonstrate that ATF4-mediated suppression of mTORC1/2 activity promotes dopaminergic neuronal death in PD models by facilitating the activation of the pro- apoptotic BCL-2 family protein PUMA. Taken together, we have discovered a novel maladaptive ISR/ATF4 signaling pathway leading to chronic suppression of mTORC1/2 activity resulting in PUMA-mediated neuronal death that may have therapeutic implications in a range of neurodegenerative conditions that exhibit chronic ISR activation.

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NDR kinase SAX-1 controls dendrite branch-specific elimination during neuronal remodeling in C. elegans
Neuronal remodeling is crucial for proper nervous system development and function, and can be initiated by developmental programs, activity-dependent mechanisms, or stress. Despite significant advances, the underlying mechanisms that govern this process remain poorly understood. Here, we adapted C. elegans IL2 sensory dendrites as a model system to study developmental and stress-mediated dendrite pruning. Upon entering a stress-induced developmental diapause, IL2 dendrites grow a complex dendritic arbor, which is later pruned when reproductive development resumes. We identified unexpected specificity in the pruning process, with distinct genetic requirements to direct branch-specific elimination of secondary, tertiary, and quaternary branches. The serine/threonine kinase SAX-1/NDR promotes elimination of secondary and tertiary, but not quaternary, dendrites. SAX-1 functions with its conserved interactors SAX-2/Furry and MOB-2 in the removal of both dendritic branches. The guanine-nucleotide exchange factor RABI-1/Rabin8 and the small GTPase RAB-11.2 mediate the elimination of secondary branches with SAX-1, but their effect on tertiary branches is minimal. Consistent with the known roles of RABI-1 and RAB-11.2 in regulating membrane dynamics, we find that SAX-1 promotes endocytosis during remodeling. Together, our findings reveal distinct mechanisms for branch-specific elimination under stress-induced and developmentally regulated neuronal remodeling.

Integration of Audiovisual Motion in Dorsolateral Prefrontal Cortical Neurons
The dorsolateral prefrontal cortex is well recognized for its role in cognitive functions and activating action plans. In contrast, the properties of prefrontal neurons with respect to multisensory processing are less well studied. To address this question, we recorded single units from areas 8a and 46 of two female rhesus macaques while they were presented with visual, auditory, and audiovisual motion stimuli. The majority of dorsolateral prefrontal neurons responded to these sensory stimuli, with similar percentages of auditory-only, visual-only and audiovisual neurons. Approximately one third of responsive neurons exhibited significant super- or sub-additive interactions in response to the pairing of auditory and visual stimuli, revealing significant nonlinearities in their response profiles. Decoding motion signals from the population activity robustly differentiated multisensory from unisensory trials and also unisensory auditory and visual trials from each other. These results demonstrate that dorsolateral prefrontal neurons integrate auditory and visual motion signals, extending multisensory computations beyond sensory cortices into prefrontal circuits that support higher-order cognition.

Heightened subcortical reactivity to uncertain-threat is associated with future internalizing symptoms, conditional on stress exposure
BackgroundAnxiety, depression, and related internalizing illnesses are a leading burden on global public health, and often emerge during times of stress. Yet the underlying neurobiology has remained enigmatic, hindering treatment development.

MethodsHere we used a combination of tools--including a well-established threat-anticipation fMRI paradigm and longitudinal assessments of internalizing symptoms and negative life events (NLEs)--to identify the neural systems associated with future internalizing illness in a risk-enriched sample of 224 emerging adults followed for 2.5 years. We performed parallel analyses in an overlapping sample of 209 participants who completed a popular threat-related faces paradigm.

ResultsHere we show that heightened reactivity to uncertain-threat anticipation in the bed nucleus of the stria terminalis and the periaqueductal gray is associated with a worsening longitudinal course of broadband internalizing symptoms among individuals with low levels of NLE exposure. These associations were specific to uncertain threat and generally remained significant when controlling for concurrent measures of threat-elicited distress or psychophysiological arousal, highlighting the added value of the neuroimaging measures. Symptom trajectories were unrelated to amygdala and frontocortical reactivity to anticipated threat. Contrary to past research, amygdala reactivity to threat-related faces was unrelated to future symptoms.

ConclusionsThese observations provide a novel neurobiological framework for conceptualizing transdiagnostic internalizing risk and lay the groundwork for mechanistic and therapeutics research. A racially diverse, risk-enriched sample and pre-registered, best-practices approach enhance confidence in the robustness and translational relevance of these results.

Dynamics of cortico-subthalamic neuronal patterns during dyskinesia in Parkinsons disease
People with Parkinsons disease suffer from levodopa-induced dyskinesia, adversely to chronic dopaminergic medication. These involuntary movements affect quality of life and are linked to lowered motor inhibition in the cortico-basal-ganglia motor network during hyperdopaminergic states. Several cortical and subcortical spectral biomarkers are associated with dyskinesia, but the oscillatory patterns associated with the behavioral complexity of involuntary movement and voluntary movement suppression that defines dyskinesia, is not studied so far. To elucidate these spatio-temporal dynamics and its behavioral relevance, we studied cortico-subthalamic oscillations in 21 Parkinsons patients during a dyskinesia-provoking experiment. We differentiated between non-dyskinetic and dyskinetic periods, and split data based on a kinematic movement registration, leading to respectively resting states and voluntary movement, and active movement suppression and dyskinetic movement. Elevated theta-activity and attenuated beta-activity was found in the subthalamic nucleus during voluntary movement suppression within dyskinetic periods, while cortico-subthalamic gamma-activity was only elevated during dyskinetic movement presence. Subthalamic spectral changes significantly predicted dyskinesia presence, and the amount of registered movement significantly affected the predictive value of dyskinesia predictions. We propose a dyskinetic macrostate to consist of distinct behavioral microstates of dyskinetic movements versus movement suppression, both associated with distinct oscillations in the cortico-subthalamic motor network.

Investigating the repeatability and behavioral relationships of acuity, contrast sensitivity, form, and motion perception measurements using a novel tablet-based vision test tool
Visual function tests are important in basic and clinical vision research but are typically limited to very few aspects of human vision, coarse diagnostic resolution, and require an administrator. Recently, the generalizable, response-adaptive, self-administered Angular Indication Measurement (AIM) and Foraging Interactive D-prime (FInD) methods were developed to assess vision across different visual functions. The AIM and FInD paradigms show a range of visual stimuli per display (4x4 stimuli) spanning {+/-}2{sigma} around an adaptively estimated perceptual threshold across multiple displays. Here, we investigated the repeatability and behavioral relationships of the AIM and FinD paradigms for near visual acuity, contrast sensitivity function (CSF), form, and motion coherence threshold measurements using a novel tablet-based vision test tool. 31 healthy participants were recruited and repeated two repetitions of each experiment in random order. Bland-Altman analyses were performed to calculate the Coefficient of Repeatability (precision) and Mean Bias (accuracy). Linear regressions and hierarchical cluster analysis were used to investigate the relationship between outcome parameters. Results show that AIM Form coherence and FInD Form horizontal coherence showed significant retest bias; all other tests were bias-free. Cluster analysis revealed overall clustering of CSF, form and motion outcomes. We further show significant correlations within CSF and between motion coherence outcomes but few significant correlations between form coherence outcomes. AIM and FInD near vision tests are generalizable across multiple visual functions and are precise and reliable. Most functions tested were bias-free. CSF, form, and motion outcomes clustered together, and CSF and motion outcomes correlated with one another. The combination of a generalizable, response-adaptive, and self-administered approach may be a suitable set of tests for basic science and clinical use cases.