bioRxiv Subject Collection: Neuroscience's Journal

THE BRAIN-MESH MODEL: A UNIFIED FRAMEWORK FORNEURAL SYNCHRONY, PLASTICITY, AND COHERENCE
The brain-mesh model introduces a novel three-layered architecture that integrates local and macroregional connectivity with an underlying, mesh-inspired network layer. This foundational mesh layer, based on metallic mesh structures, spans the entire brain and generates interference patterns, noise, and resonance effects that modulate both local and global neural dynamics. The fused model goes beyond traditional connectivity frameworks by providing a unified explanation for phenomena such as brain-wide phase gradients, stable low-frequency resonance frequencies, and long-range plasticity effects, which are often difficult to explain cohesively within existing models. In addition to accounting for classical neurobiological observations--such as phase synchrony, functional connectivity fluctuations, and local Hebbian plasticity--the fused model offers novel insights into less understood phenomena. Specifically, it predicts connectivity-independent phase gradients across non-synaptic regions, harmonic resonance peaks consistent across individuals, and diffuse plasticity driven by global interference patterns, all of which are challenging to explain under current frameworks. These unique predictions align with partial empirical observations, such as traveling wave dynamics, consistent low-frequency oscillations, and task-induced connectivity shifts, underscoring the model's relevance. Additionally, the brain-mesh model generates testable hypotheses that distinguish it from traditional approaches, providing a promising framework for future experimental validation and opening new avenues for understanding global brain function.

The cell-type underpinnings of regional brain entropy (BEN) in human brain
Brain entropy (BEN) indicates the irregularity, unpredictability and complexity of brain activity. Research using regional brain entropy (rBEN) based on fMRI has established its associations with structural and functional brain networks, as well as their coupling. These relationships are influenced by the sensorimotor-association (S-A) axis and cytoarchitectural organization. Recent studies have also revealed links between functional connectome gradients and cell-type, suggesting that rBEN may have a biological basis at the cellular level. However, this possibility remains unexplored at specifically cellular level. In this study, we analyzed mean rBEN maps derived from 176 participants using HCP 7T data and correlated these with publicly available cell-type datasets. Our findings rBEN exhibited a positive correlation with oligodendrocytes (Oligo) and a negative correlation with parvalbumin-positive interneurons (PVALB) under both resting-state and movie-watching conditions at the whole-brain level. Furthermore, we observed that the S-A axis modulates the relationship between rBEN and cell-type. Specifically, L5 extratelencephalic neurons (L5 ET) showed a positive correlation with rBEN in unimodal cortex but a negative correlation in multimodal cortex and interneurons somatostatin (SST) was correlated with rBEN only in multimodal cortex. These results provide further evidence that rBEN has a biological foundation at the cellular level, with spatial heterogeneity in its associations with different cell types. Moreover, rBEN appears to capture information beyond functional connectivity network.

Folate prevents the autism-related phenotype caused by developmental pyrethroid exposure in prairie voles
Neurodevelopmental disorders (NDDs) have dramatically increased in prevalence to an alarming one in six children, and yet both causes and preventions remain elusive. Recent human epidemiology and animal studies have implicated developmental exposure to pyrethroid pesticides, one of the most common classes of pesticides in the US, as an environmental risk factor for autism and NDDs. Our previous research has shown that low-dose chronic developmental pyrethroid exposure (DPE) changes folate metabolites in the adult mouse brain. We hypothesize that DPE acts directly on molecular targets in the folate metabolism pathway, and that high-dose maternal folate supplementation can prevent or reduce the biobehavioral effects of DPE. We exposed pregnant prairie vole dams to vehicle or deltamethrin (3 mg/kg every 3 days) with or without folate supplementation (5 mg/kg methylfolate every 3 days). The resulting DPE offspring showed broad deficits in five behavioral domains relevant to NDDs; increased plasma folate concentrations; and increased neural expression of SHMT1, a cellular folate cycle enzyme. Maternal folate supplementation prevented most of the behavioral phenotype (except for repetitive behaviors) and caused potentially compensatory changes in neural expression of FOLR1 and MTHFR, two other folate-related proteins. We conclude that DPE causes NDD-relevant behavioral deficits; DPE directly alters aspects of folate metabolism; and preventative interventions targeting folate metabolism are effective in reducing, but not eliminating, the behavioral effects of DPE.

Intranasal dantrolene nanoparticles inhibit inflammatory pyroptosis in 5XFAD mice brains
Background: This study investigates the effects of intranasal dantrolene nanoparticles on inflammation and programmed cell death by pyroptosis in 5XFAD Alzheimers Disease (AD) mice. Methods: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal dantrolene nanoparticles (5 mg/kg), daily, Monday to Friday, for 12 weeks continuously, starting at 9 months of age. Blood and brain were harvested at 13 months of age, one month after completion of 12 weeks intranasal dantrolene nanoparticle treatment. Blood biomarkers function of liver (Alanine transaminase, ALT), kidney (Creatinine), and thyroid (TSH: Thyroid-stimulating hormone) were measured using ELISA. The changes of whole brain tissue proteins on Ca2+ release channels on membrane of endoplasmic reticulum (type 2 ryanodine and type 1 InsP3 receptors, RyR-2 and InsP3R-1), lipid peroxidation byproduct malondialdehyde (MDA)-modified proteins, 4-HNE, pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, full length or N-terminal of Gasdermin D (GSDMD), cytotoxic (IL-1, IL-18, IL-6, TNF-) and cytoprotective (IL-10) cytokines, astrogliosis (GFAP), microgliosis (IBA-1) and synapse proteins (PSD-95, Synapsin-1) were determined using immunoblotting. Body weights were monitored regularly. Results: Intranasal dantrolene nanoparticles significantly inhibited the increase of RyR-2 and InsP3R-1 proteins, MDA-modified proteins, 4-NHE, pyroptosis regulatory proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD), cytotoxic cytokine (IL-1, IL-18, IL-6, TNF-), biomarkers for astrogliosis (GFAP) and microgliosis (IBA-1), and the decrease of cytoprotective cytokine (IL-10) and synaptic proteins (PSD-95, synpasin-1). Intranasal dantrolene nanoparticles for 12 weeks did not affect blood biomarkers for function of liver, kidney, and thyroid, not did it change body weight significantly. Conclusion: Intranasal dantrolene nanoparticles significantly inhibit the increase of RyR-2 and InsP3R-1 Ca2+ channel receptor proteins, ameliorate activation of the pyroptosis pathway and pathological inflammation, and the associated loss of synapse proteins. Intranasal dantrolene nanoparticles for three months did not affect liver, kidney and thyroid functions or cause other side effects.

Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish
Defects in DNA single-strand break repair are associated with neurodevelopmental and neurodegenerative disorders. One such disorder is that resulting from mutations in XRCC1, a scaffold protein that plays a central role in DNA single-strand base repair. XRCC1 is recruited at sites of single-strand breaks by PARP1, a protein that detects and is activated by such breaks and is negatively regulated by XRCC1 to prevent excessive PARP binding and activity. Loss of XRCC1 leads to the toxic accumulation and activity of PARP1 at single-strand breaks leading to base excision repair defects, a mechanism that may underlie pathological changes in patients carrying deleterious XRCC1 mutations. Here, we demonstrate that xrcc1 knockdown impairs development of the cerebellar plate in zebrafish. In contrast, parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae. These findings support the notion that PARP1 inhibition may be a viable therapeutic candidate in neurological disorders.

A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases
Background Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia. Methods We developed the hCSF1Bdes mouse line suitable as new transplantation model available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additional we crossed this model with two humanized App KI mice, the AppHu and the AppSAA . Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimers disease. Results Our results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore we confirmed the multipronged response of microglia in the context of Alzheimers disease. The hCSF1Bdes and the crosses with the Alzheimers disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community. Conclusion The hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.

Absolute quantification of cerebral metabolites using 2D 1H-MRSI with quantitative MRI-based water reference
Purpose: Metabolite concentrations are valuable biomarkers in brain tumors (BT). However, correction of water relaxation effects often requires time-consuming quantitative MRI (qMRI) sequences on top of a lengthy spectroscopic water reference acquisition. The goal of this work was to develop and validate a fast metabolite quantification method where a 2D spectroscopic water reference acquisition is obtained using a fast qMRI protocol and single-voxel STEAM sequence. Methods: A 2D sLASER sequence was acquired for MRSI. An 8-minute qMRI protocol was also acquired. A single-voxel unsuppressed water signal was acquired using a STEAM sequence. The H2O map, obtained from qMRI, was calibrated based on the STEAM-signal to obtain the spectroscopic water reference (proposed method). Five healthy volunteers and one BT patient were scanned at 3T. Concentrations obtained using the proposed and two reference methods, one where water relaxation effects were corrected using literature values (Reference method) and one where they were corrected using qMRI-derived values (Reference method with qMRI) were compared. Results: In healthy subjects, WM metabolite concentrations obtained using water relaxation using literature values (Reference method) significantly differed from those using individual-specific corrections (Reference method with qMRI and proposed method). Bland-Altman analyses revealed a very low bias and SD of the differences between the Reference method with qMRI and the proposed-method (Bias<0.5% and SD<10%). The BT regions showed a ~15% underestimation of metabolite concentrations using the Reference method. Conclusion: For metabolite quantification, accurate water referencing with individual-specific corrections for water relaxation times was obtained in 8 minutes using the proposed method.

Multimodal, multifaceted Imaging-based Human Brain White Matter Atlas
Comparable to an atlas for navigating the Earth, a brain atlas outlines the brain's neuroanatomical and functional landmarks. The tract-based brain's white matter atlas (WMA) captures only tract boundaries, neglecting functionally relevant information, including emerging evidence on reliable neurodynamic detection in WM. Thus, a suitable WMA for functional investigations is needed. We delineated WM areas from coarse to fine-grained parcellations using local anatomical architecture and global functional dynamics using multimodal 7-Tesla magnetic resonance imaging in the Human Connectome Project. The multimodal WMA (MWMA) exhibited high between-subject consistency (69.1%) and test-retest reliability (93.1%), which aligned with the spatial pattern of chemoarchitectural homogeneity derived from open molecular imaging sources. Compared to a tract-based atlas, the MWMA better described the white matter's cerebellum-association gradient axis, and precisely identified unique functional connectivity profiles of the corpus callosum. This improved MWMA will facilitate studies of WM functional organization, supporting cognition research and ultimately neuropathological vulnerability studies from a whole brain perspective.

The Virtual Brain links transcranial magnetic stimulation evoked potentials and inhibitory neurotransmitter changes in major depressive disorder
Background: Transcranial magnetic stimulation evoked potentials (TEPs) show promise as a biomarker in major depressive disorder (MDD), but the origin of the increased TEP amplitude in these patients remains unclear. Gamma aminobutyric acid (GABA) may be involved, as TEP peak amplitude is known to increase with GABAergic activity, but paradoxically MDD patients exhibit reduced GABA levels. We employed a computational modeling approach to investigate this contradiction. Methods: Whole-brain simulations in 'The Virtual Brain' (thevirtualbrain.org), employing the Jansen and Rit neural mass model, were optimized to simulate TEPs of healthy individuals (N=20, 14 females, 24.5+/-4.9 years). To mimic MDD, a GABAergic deficit was introduced to the simulations by altering one of two selected inhibitory parameters, the inhibitory synaptic time constant b or the number of inhibitory synapses C4. The TEP amplitude was quantified and compared for all simulations. Results: Both parameters, the inhibitory synaptic time constant (r=-0.6, p<0.001) and the number of inhibitory synapses (r=-0.79, p<0.001), showed a significant negative linear correlation to the TEP amplitude. Thus, under local parameter changes, we were able to alter the TEP amplitude towards pathological levels, i.e. creating an MDD-like increase of the global mean field amplitude in line with empirical results. Conclusions: Our model suggests specific GABAergic deficits as the cause of increased TEP amplitude in MDD patients, which may serve as therapeutic targets. This work highlights the potential of whole-brain simulations in the investigation of neuropsychiatric diseases.

Intuitive physical reasoning is not mediated by linguistic nor exclusively domain-general abstract representations
The ability to reason about the physical world is a critical tool in the human cognitive toolbox, but the nature of the representations that mediate physical reasoning remains debated. Here, we use fMRI to illuminate this question by investigating the relationship between the physical- reasoning system and two well-characterized systems: a) the domain-general Multiple Demand (MD) system, which supports abstract reasoning, including mathematical and logical reasoning, and b) the language system, which supports linguistic computations and has been hypothesized to mediate some forms of thought. We replicate prior findings of a network of frontal and parietal areas that are robustly engaged by physical reasoning and identify an additional physical-reasoning area in the left frontal cortex, which also houses components of the MD and language systems. Critically, direct comparisons with tasks that target the MD and the language systems reveal that the physical-reasoning system overlaps with the MD system, but is dissociable from it in fine-grained activation patterns, which replicates prior work. Moreover, the physical-reasoning system does not overlap with the language system. These results suggest that physical reasoning does not rely on linguistic representations, nor exclusively on the domain- general abstract reasoning that the MD system supports.

Fast Photostable Expansion Microscopy Using QDots andDeconvolution
Expansion microscopy (ExM) enables sub-diffraction imaging by physically expanding labeled tissue samples. This increases the tissue volume relative to the instrument point spread function (PSF), thereby improving the effective resolution by reported factors of 4 - 20X. However, this volume increase dilutes the fluorescence signal, reducing both signal-to noise ratio (SNR) and acquisition speed. This paper proposes and validates a method for mitigating these challenges. We overcame the limitations of ExM by developing a fast photo-stable protocol to enable scalable widefield three-dimensional imaging with ExM. We combined widefield imaging with quantum dots (QDots). Widefield imaging provides a significantly faster acquisition of a single field-of-view (FOV). However, the uncontrolled incoherent illumination induces photobleaching. We mitigated this challenge using QDots, which exhibit a long fluorescence lifetime and improved photostability. First, we developed a protocol for QDot labeling. Next, we utilized widefield imaging to obtain 3D image stacks and applied deconvolution, which is feasible due to reduced scattering in ExM samples. We show that tissue clearing, which is a side-effect of ExM, enables widefield deconvolution, dramatically reducing the acquisition time for three-dimensional images compared to laser scanning microscopy. The proposed QDot labeling protocol is compatible with ExM and provides enhanced photostability compared to traditional fluorescent dyes. Widefield imaging significantly improves SNR and acquisition speed compared to conventional confocal microscopy. Combining widefield imaging with QDot labeling and deconvolution has the potential to be applied to ExM for faster imaging of large three-dimensional samples with improved SNR.

Distinct decision processes for 3D and motion stimuli in both humans and monkeys revealed by computational modelling
Decision-making models distil principles of information processing that underlie a range of cognitive functions. For the cases of motion detection in random-dot kinematograms and decisions about the rotation of 3D structure-from-motion cylinders, contributing neural processes have been localized to specific circuits in extrastriate area V5/MT on the basis of both causal and correlative evidence, suggesting a common decision path. Here, we arranged for humans and rhesus monkeys to make perceptual choices about these two stimulus types, indicating their decision with either hand or eye movements. In both species, the parameter distributions of a hierarchical Drift Diffusion Model (DDM) revealed systematic differences for stimulus type but not the different modes of response. States in a hidden Markov model also indicated distinct decision strategies, again for the two stimulus types but not for response mode. Although physiological evidence points to area V5/MT as a vehicle for relevant perceptual signals for both stimulus types, computational modelling of the present results reveal distinct decision processes, therefore predicting that different neural processes underlie judgements about motion and 3D-depth, consistently for humans and monkeys.

Increased reluctant vesicles underlie synaptic depression by GPR55 in axon terminals of cerebellar Purkinje cells
Control of synaptic transmission efficacy by neuronal activity and neuromodulators is pivotal for brain function. Synaptic suppression by cannabinoids activating CB1 receptors has been extensively studied at the molecular and cellular levels to understand the neuronal basis for symptoms of cannabis intake. Here, we focused on another type of cannabinoid receptor GPR55, which shows sensitivity to cannabidiol, a chemical included in cannabis, aiming to highlight its actions on presynaptic function. Taking advantage of direct patch-clamp recordings from axon terminals of cerebellar Purkinje cells together with fluorescent imaging of vesicular exocytosis using synapto-pHluorin, we show that GPR55 suppresses synaptic transmission as CB1 receptor does, but through a distinct presynaptic modulation of release machinery. Activation of GPR55 reduced transmitter release by changing neither presynaptic action potential waveform nor Ca2+ influx, but by making a large population of Ca2+-responsive synaptic vesicles insensitive to Ca2+ influx through voltage-gated Ca2+ channels, leading to substantial reduction of the readily releasable pool of vesicles. Thus, the present study identifies a unique mechanism to suppress presynaptic transmitter release by atypical receptor for cannabinoid, which would enable subtype-specific modulation of neuronal computation by cannabinoid receptors.

Integration of hunger and hormonal state gates infant-directed aggression
Social behaviour is profoundly shaped by internal physiological states. While significant progress has been made in understanding how individual states such as hunger, stress, or arousal modulate behaviour, animals experience multiple states at any given time. The neural mechanisms that integrate such orthogonal states - and how this integration affects behaviour - remain poorly understood. Here we report how hunger and estrous state converge on neurons in the medial preoptic area (MPOA) to shape infant-directed behaviour. We find that hunger promotes pup-directed aggression in normally non aggressive virgin female mice. This behavioural switch occurs through inhibition of MPOA neurons, driven by the release of neuropeptide Y (NPY) from Agouti-related peptide-expressing neurons in the arcuate nucleus (ArcAgRP neurons). The propensity for hunger induced aggression is set by reproductive state, with MPOA neurons detecting changes in progesterone (P4) to estradiol (E2) ratio across the estrous cycle. Hunger and estrous state converge on HCN (hyperpolarization-activated cyclic nucleotide-gated) channels, which sets the baseline activity and excitability of MPOA neurons. Using micro endoscopic imaging, we confirm these findings in vivo, revealing that MPOA neurons encode a state for pup-directed aggression. This work thus provides a mechanistic understanding of how multiple physiological states are integrated to flexibly control social behaviour.

Embryonically generated interneurons (EGINs) exhibit a distinctive developmental program and lamination in the olfactory bulb
Interneurons (INs) in the mouse olfactory bulb (OB) develop during an extensive period of time that begins in the embryo and continues throughout the lifetime of an individual. The connectivity and location of these neurons is profoundly affected by the time of generation, making these developmental windows critical to understand the circuitry of the OB. Here, we focus on the OB embryonic generated interneurons (or EGINs), which have generally received less attention than those generated in the adult. Birthdates of EGINs were differentiated by embryonic injections of thymidine analogs and their final destinations and phenotypes analyzed by immunohistochemistry. We found that EGINs were retained in the adult and were distributed across all layers of the OB. However, a lateral-to-medial neurogenic gradient is seen only in the earliest generated EGINs. Within the granule cell layer (GCL), EGINs predominantly accumulated in the superficial region at almost all ages and remained there during adulthood. Immunostaining for calbindin, parvalbumin, tyrosine hydroxylase, and calretinin were largely negative suggesting that EGINs may represent subpopulations of OB INs that are not yet fully characterized. Using in utero electroporation to label EGIN progenitors, we demonstrated that they reach the primordial OB as early as E13 and begin to differentiate apical dendrites by E15. At E16, EGIN progenitors clustered into a chain of migrating neuroblasts denoting the embryonic rostral migratory stream (RMS). Collectively, our data highlight the importance of studying OB INs in isolated time windows to better understand the formation of circuits that define the olfactory responses.

H- and m-channel overexpression promotes seizure-like events by impairing the ability of inhibitory neurons to process correlated inputs
Channelopathies affecting h- and m-channels present a paradox in epilepsy research: while both over- and underexpression of these channels can be epileptogenic, channel overexpression does not appear to increase the excitatory-inhibitory (E-I) balance as caused by channel underexpression. We here derive a viable mechanism for ictogenesis driven by h- and m-channel overexpression from analysis of an in silico spiking neuronal microcircuit exhibiting spontaneous seizure-like events (SLEs). Such SLEs are dependent upon sufficiently strong gain in two adaptation terms phenomenologically modeling these channels' effects: voltage homeostasis (h-current) and spike-frequency adaptation (m-current). Excessive gain of these adaptation terms interferes with the circuit's processing of highly correlated input, promoting a sequence of network-level events that collectively provoke an SLE. Importantly, these changes do not cause increased excitability in isolated neurons, nor does this cascade require a change in the amplitude of external input to the circuit, suggesting an ictogenic pathway independent of classical changes to the E-I balance. The viability of this mechanism for SLE onset is strengthened by the host of experimentally-characterized features of seizure produced in this model reliant upon the presence of these adaptation terms, including the irregular initiation and termination of seizure-like events and time-varying peak frequency of oscillations during such events (i.e., chirps). Moreover, the cell-type dependent effects of changes in these adaptation terms, as delineated in our analyses, represent experimentally-testable predictions for future study of h- and m-channelopathies. These computational results provide vital new insights into the epileptogenic nature of h- and m-channel overexpression currently absent in the experimental literature.

Regionally specific picture naming benefits of focal tDCS are dependent on baseline performance in older adults
Word-finding difficulty is a common challenge in older age and is linked to various neuropathological conditions associated with ageing. Transcranial direct current stimulation (tDCS) has shown promise as a cognitive enhancement tool for both healthy aging and age-related cognitive disorders. However, its effectiveness in enhancing word-finding ability remains inconsistent, especially among healthy adults. This variability is likely due to factors such as task selection, stimulation parameters, and small sample sizes. Additionally, many studies have overlooked the role of baseline performance in evaluating tDCS efficacy. In this preregistered study, we examined 72 older and 72 younger adults using a double-blind, sham-controlled design, delivering anodal focal tDCS to either the left inferior frontal gyrus or the left temporoparietal junction. Baseline naming performance and fluid intelligence were measured before stimulation. Anodal stimulation of the left inferior frontal gyrus significantly increased response speed for object and action naming in older adults, but crucially only in older adults who performed poorly during the baseline naming session. Findings demonstrate regionally specific effects of focal tDCS in healthy older individuals in greater need for naming facilitation. Notably, performance on a broad measure of fluid intelligence was unrelated to stimulation response, suggesting task specificity of this effect.

Conspecific sociability is regulated by associative learning circuits
Sociability, an animal's ease and propensity to interact with members of its own species, is a prerequisite for many important social interactions including courtship, mating, brood rearing, and collective behavior. Despite its fundamental nature, the manner through which sociability arises -whether it is innate or acquired and its neural mechanisms- remains unknown. Here, we found that the fly, Drosophila melanogaster, produces a constellation of fearful reactions when it encounters another fly for the first time. However, these animals become sociable following several hours of exposure to conspecific (but not heterospecific) odors. Two large-scale neural silencing screens of 188 brain cell types revealed that both initial fearful reactions and learned sociability depend upon overlapping networks including circuits in the mushroom body, the principal center for associative learning and memory in the insect brain. Functional recordings of key mushroom body output neurons (MBONs) from this network over two hours of social interactions support a mechanistic model whereby fly odors modulate social valence by rebalancing MBON population activity, biasing action selection, and thereby driving sociable rather than fearful responses towards other flies. Thus, a center for learning and memory plays a fundamental role in establishing the basis for most social interactions.

Idiosyncratic navigation determines mouse CA1 representational structure in a multicompartment environment
Organisms from mice to humans rely on cognitive maps instantiated by the hippocampal formation to flexibly and efficiently navigate the world. Traditional theories of cognitive mapping posit that these representations encode geometric relationships among their contents, while recent alternative theories propose that they encode the predictive relationships among their contents that the navigator experiences. Here, we leverage longitudinal miniscope calcium imaging of CA1 in mice navigating a multicompartment environment to adjudicate between predictions of these theories. We find that different mice instantiate different representational structures across identical compartments. Within mouse, compartments with more similar navigational patterns on a particular spatiotemporal scale are represented more similarly, accounting for these individual differences. Finally, we demonstrate that manipulating navigational patterns on this scale induces a corresponding change in CA1 representational structure. Together, these results demonstrate that idiosyncratic navigation is a key determinant of hippocampal representational structure, consistent with predictive theories of cognitive mapping.

Cell-type specific responses to single-pulse electrical stimulation of the human brain
Neuromodulation techniques, such as deep brain stimulation, intraoperative brain mapping, and responsive neurostimulation, use electricity to alter brain activity. Despite daily clinical use in thousands of patients, it remains fundamentally unknown how human neurons respond to intracranial stimulation. We address this question at a basic level by characterizing neuronal cell-type specific firing rate responses to single pulses of electrical stimulation of the human brain. We carried out broadly distributed stimulation in 30 patients undergoing neuromonitoring for epilepsy while recording from isolated neurons on microwires implanted into the medial temporal and frontal lobes. Out of a total of 228 recorded units, 16.2% (N = 191) were classified as interneurons and 83.8% (N = 37) were classified as principal cells, using a threshold clustering method, based on intrinsic waveshape characteristics. To see how stimulation affected neuronal activation for each cell type, we calculated firing rate change between a pre-stimulation and post-stimulation window and observed that 174 units were significantly modulated with the vast majority (91%) showing firing rate suppression. We then characterized stimulation-evoked changes in firing rate to gain insight into cell type-specific responses. Additionally, in a subset of the units, we observed that firing rate responses were modulated by stimulation distance, where local stimulation (within approximately 40 mm) could evoke instantaneous firing, whereas distant stimulation reliably suppressed firing in the same units. Finally, we analyzed a subset of units within the seizure onset zone, which exhibited unique waveform features and responses to stimulation. This study bridges a gap in the neuromodulation field by examining the single-unit firing rate response to direct electrical stimulation of the human brain and analyzing cell-type specific firing rate responses. We show that low frequency, single-pulse stimulation broadly elicits firing rate suppression, but parameters, such as distance from the unit, can have diverse effects on firing rate responses. This work informs the neuronal basis of CCEP generation and therefore has implications for clinical mapping and informs novel "active probing" strategies for precision diagnosis and neuromodulation of seizure pathophysiology in surgical cases. Moreover, this research has general implications for understanding neuromodulation via direct brain stimulation.

Age-dependent effects of intranasal oxytocin administration were revealed by resting brain entropy (BEN)
Brain entropy (BEN) reflects the irregularity, disorderliness, and complexity of brain activity and has gained increased interest in recent years. The demonstrated sensitivity of BEN to caffeine and medicine suggests the existence of neurochemical effects of BEN. Oxytocin (OT), a neuropeptide associated with childbirth and lactation, affects both social behavior and brain activity. The purpose of this study was to examine whether OT affects BEN in young and old adults. A randomized, double-blind, placebo-controlled, two-factor (Age x OT) between-subjects design was used, and a total of seventy-five eligible healthy participants were included in the experiment. In the young adult group (YA), 23 participants received intranasal OT administration, while 18 received a placebo (PL) administration. In the older adult group (OA), 16 participants received intranasal OT administration, and 18 received PL administration. Using fMRI-based BEN mapping, we found the age-dependent effect of intranasal OT in the left temporal parietal junction (TPJ), where BEN increased in YA and BEN decreased in OA. A whole-brain functional connectivity (FC) analysis with the left TPJ as the seed and we found that FC between the left TPJ and right TPJ increased in both YA and OA. FC of left and right TPJ and plasma OT contribute to left TPJ BEN just found in YA with intranasal OT administration. These results indicate that BEN is sensitive to age-related effects of neurochemical signals and highlight plasma OT on the effects of intranasal OT in young adults.

Failed Double-Blind Replication of Offline 5Hz-rTUS-Induced Corticospinal Excitability
Introduction: Transcranial ultrasound stimulation (TUS) is a promising new form of non-invasive neuromodulation. As a nascent technique, replication of its effects on brain function is important. Of particular interest is offline 5Hz repetitive TUS (5Hz-rTUS), originally reported by Zeng and colleagues [1] to elicit lasting corticospinal excitability increases, with large effect sizes. Material and method: Here, we conducted a pre-registered (https://osf.io/p5n4q) replication of this protocol that benefitted from three additional features: double-blind application of TUS, neuronavigation for consistent TMS positioning, and acoustic simulations to assess M1 target exposure to TUS. Changes in resting motor thresholds (rMT), motor-evoked potential (MEP) amplitude, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in response to TUS (5Hz-rTUS vs. sham) were measured in the right first dorsal interosseous (FDI), abductor digiti minimi (ADM) and abductor pollicis brevis (APB) muscles, with unbiased selection of participants. Transducer location was determined by the TMS-hotspot for motor representations of the right FDI, as in the original work. Results: No significant effects of 5Hz-TUS (vs sham) were observed. Post-hoc simulations showed considerable variability of the acoustic focus, which was outside the anatomical M1-hand area in 67% of participants, in line with the known poor correspondence of TMS-hotspot location and M1-hand area. Conclusion: Our results indicate that the effect sizes of the neuromodulatory effects of 5Hz-rTUS on M1 may be more variable than previously appreciated. We suggest that double-blinding, neuronavigated TMS, individualised acoustic simulations for TUS targeting and pre-registration will aid reproducibility across studies.

Lateralised memory networks explain the use of higher-order visual features in navigating insects
Many insects use memories of their visual environment to adaptively drive spatial behaviours. In ants, visual memories are fundamental for navigation, whereby foragers follow long visually guided routes to foraging sites and return to the location of their nest. Whilst we understand the basic visual pathway to the memory centres (Optic Lobes to Mushroom Bodies) involved in the storage of visual information, it is still largely unknown what type of representation of visual scenes underpins view-based navigation in ants. Several experimental studies have shown ants using "higher-order" visual information - that is features extracted across the whole extent of a visual scene - which raises the question as to where these features are computed. One such experimental study showed that ants can use the proportion of a shape experienced left of their visual centre to learn and recapitulate a route, a feature referred to as "fractional position of mass" (FPM). In this work, we use a simple model constrained by the known neuroanatomy and information processing properties of the Mushroom Bodies to explore whether the use of the FPM could be a resulting factor of the bilateral organisation of the insect brain, all the whilst assuming a "retinotopic" view representation. We demonstrate that such bilaterally organised memory models can implicitly encode the FPM learned during training. We find that balancing the "quality" of the memory match across left and right hemispheres allows a trained model to retrieve the FPM defined direction, even when the model is tested with other shapes, as demonstrated by ants. The result is shown to be largely independent of model parameter values, therefore suggesting that some aspects of higher-order processing of a visual scene may be emergent from the structure of the neural circuits, rather than computed in discrete processing modules.

Enhanced Notch dependent gliogenesis and delayed physiological maturation underlie neurodevelopmental defects in Lowe syndrome
The activity of signaling pathways is required for coordinated cellular and physiological processes leading to normal development of brain structure and function. Mutations in OCRL, a phosphatidylinositol 4,5 bisphosphate [PIP2] 5-phosphatase leads to the neurodevelopmental disorder, Lowe Syndrome (LS). However, the mechanism by which mutations in OCRL leads to the brain phenotypes of LS is not understood. We find that on differentiation of LS patient derived iPSC, developing neural cultures show reduced excitability along with enhanced P levels of Glial Fibrillary Acidic Protein. Multiomic single-nucleus RNA and ATAC seq analysis of neural stem cells generated from LS patient iPSC revealed an enhanced number of cells with a gliogenic cell state. RNA seq analysis also revealed increased levels of DLK1, a non-canonical Notch ligand in LS patient NSC associated increased levels of cleaved Notch protein and elevation of its transcriptional target HES5, indicating upregulated Notch signaling. Treatment of iPSC derived brain organoids with an inhibitor of PIP5K, the lipid kinase that synthesizes PIP2, was able to restore neuronal excitability and rescue Notch signaling defects in LS patient derived organoid cultures. Overall, our results demonstrate a role for PIP2 dependent regulation of Notch signaling, cell fate specification and development of neuronal excitability regulated by OCRL activity.

Coupled aging of cyto- and myeloarchitectonic atlas-informed gray and white matter structural properties
A key aspect of brain aging that remains poorly understood is its high regional heterogeneity and heterochronicity. A better understanding of how the structural organization of the brain shapes aging trajectories is needed. Neuroimaging tissue types are often collected and analyzed as separate acquisitions, an approach that cannot provide a holistic view of age-related change of the related portions of the neurons (cell bodies and axons). Because neuroimaging can only assess indirect features at the gross macrostructural level, incorporating post-mortem histological information may aid in better understanding of structural aging gradients. Longitudinal design, coupling of gray and white matter (GM, WM) properties, and a biologically informed approach to organizing neural properties are needed. Thus, we tested aging of the regional coupling between GM (cortical thickness, surface area, volume) and WM (fractional anisotropy, mean, axial, and radial diffusivities) structural metrics using linear mixed effects modeling in 102 healthy adults aged 20-94 years old, scanned on two occasions over a four-year period. The association between age-related within-person change in GM morphometry and the diffusion properties of the directly neighboring portion of white matter were assessed, capturing both aspects of neuronal health in one model. Additionally, we parcellated the brain utilizing the histological-staining informed von Economo-Koskinas atlas to consider regional cyto- and myelo-architecture. Results demonstrate several gradients of coupled association in the age-related decline of neighboring white and gray matter. Most notably, gradients of coupling along the heteromodal association to sensory axis were found for several areas (e.g., anterior frontal and lateral temporal cortices, vs pre- and post-central gyrus, occipital, and limbic areas), in line with heterochronicity and retrogenesis theories of aging. Further effort to bridge across data and measurement scales will enhance understanding of the mechanisms of the aging brain.

Multisensory integration across reference frames with additive feed-forward networks
The integration of multiple sensory inputs is essential for human perception and action in uncertain environments. This process includes reference frame transformations as different sensory signals are encoded in different coordinate systems. Studies have shown multisensory integration in humans is consistent with Bayesian optimal inference. However, neural mechanisms underlying this process are still debated. Different population coding models have been proposed to implement probabilistic inference. This includes a recent suggestion that explicit divisive normalization accounts for empirical principles of multisensory integration. However, whether and how divisive operations are implemented in the brain is not well understood. Indeed, all existing models suffer from the curse of dimensionality and thus fail to scale to real-world problems. Here, we propose an alternative model for multisensory integration that approximates Bayesian inference: a multilayer-feedforward neural network of multisensory integration (MSI) across different reference frames trained on the analytical Bayesian solution. This model displays all empirical principles of multisensory integration and produces similar behavior to that reported in Ventral intraparietal (VIP) neurons in the brain. The model achieved this without a neatly organized and regular connectivity structure between contributing neurons, such as required by explicit divisive normalization. Overall, we show that simple feedforward networks of purely additive units can approximate optimal inference across different reference frames through parallel computing principles. This suggests that it is not necessary for the brain to use explicit divisive normalization to achieve multisensory integration.