bioRxiv Subject Collection: Neuroscience's Journal

Cytoplasmic TDP-43 leads to early functional impairments without neurodegeneration in a Serotonergic Neuron-Specific C. elegans Model
TDP-43 proteinopathies, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are marked by the pathological cytoplasmic accumulation of TAR DNA-binding protein 43 (TDP-43), leading to progressive neuronal dysfunction and degeneration. To investigate the early functional consequences of TDP-43 mislocalization, we generated Caenorhabditis elegans models expressing either wild-type human TDP-43 or a variant with a mutated nuclear localization signal ({Delta}NLS), specifically in serotonergic neurons. These neurons were chosen because i) serotonin deficits are a feature of ALS/FTD and ii) in C. elegans, they regulate well-characterized behaviors, providing a straightforward readout of neuronal function. We found that expression of either TDP-43 variant impaired serotonin-dependent behaviors, including pharyngeal pumping, egg-laying, and locomotion slowing upon food encounter, with the cytoplasmic {Delta}NLS form causing more severe deficits. Serotonergic neurons remained i) morphologically intact, indicating that neuronal dysfunction precedes overt neurodegeneration; and ii) partially responsive to the selective serotonin reuptake inhibitor fluoxetine, suggesting that neurotransmitter release is still partially functional. Altogether, our findings demonstrate that cytoplasmic TDP-43 disrupts neuronal signaling and behavior early in disease progression. This C. elegans model provides a genetically tractable system to dissect early mechanisms of TDP-43-mediated dysfunction and to identify therapeutic strategies targeting predegenerative stages of ALS/FTD.

Extracellular vesicles released from endothelial cells of the blood-brain barrier mediate brain Iron accumulation during LPS-induced brain Inflammation
Introduction: Brain inflammation leads to an increase in the amount of iron in brain tissue; however, studies do not address the source of the iron that could lead to the accumulation. Most of the brain iron uptake is mediated through the blood-brain barrier (BBB), but studies have not examined whether inflammation increases or decreases iron flux across the BBB. Our recent in vitro study discovered a novel alternate mechanism that iron transport across the BBB is mediated via the extracellular vesicles (EVs). Herein, we investigated the impact of brain inflammation on iron release and iron transport via EVs from the brain microvasculature (BMV). Methods: For this study, we developed an in vivo brain inflammation model. We induced brain inflammation in three-month-old C57BL/6 by intracerebroventricular injection of lipopolysaccharide (LPS,12 microgram/mice). For in vitro, we used human blood-brain barrier endothelial cells derived from human-induced pluripotent stem cells (hiPSCs). We separated the BMV from brain parenchyma by using density gradient centrifugation. To inhibit the EVs synthesis, we injected intraperitoneally for 21 days GW4869 (60 microgram/mice), an inhibitor of neutral sphingomyelinase 2, a key regulatory enzyme necessary for EV formation. The brain EVs were isolated by ultracentrifugation. We measured the BMV and parenchyma iron concentration by Inductively coupled plasma mass spectrometry (ICP-MS). Furthermore, we performed immunoblotting to measure the protein expression in BMV and EVs. Results: The LPS injection activated microglia and astrocytes as well as increased the brain proinflammatory cytokines compared to the control mice. Furthermore, brain inflammation increased the iron levels in the brain parenchyma but decreased the iron levels in BMV. Brain inflammation was associated with the degradation of ferroportin (FPN1), an iron exporter, in the BMV. CD63, an EVs membrane protein, was increased in the BMV and associated with increased FTH1-iron release via EVs from BMVs to the brain. Moreover, brain inflammation induced iron deficiency in BMV as evidenced by an increase in the transferrin receptor and decreased FTH1, suggestive of increased iron uptake. Pharmacological reduction of EVs by GW4869 reduced iron accumulation in the inflamed brain parenchyma compared to control mice. Conclusion: This is the first study to demonstrate that EV inhibition decreases iron in the brain. Degradation of FPN1 in the BMV during inflammation did not limit iron accumulation but there was an increase in FTH1-iron-enriched EVs indicating these are responsible for brain iron accumulation during inflammation. Thus, in summary, we have discovered a novel mechanism that involves BMV-released EVs enriched with iron that is the mechanism for brain iron accumulation during inflammation.

Multivariate Associations Between Neurophysiological Activity and Sensory Motor Cortical Morphometry in Parkinson's Disease
Parkinson's disease (PD) involves progressive neurodegeneration and distinctive structural and functional alterations in cortico-basal ganglia circuits. This study proposes bridging the gap between structural and functional biomarkers to uncover fundamental mechanisms underlying PD pathophysiology and support more comprehensive diagnostic and therapeutic approaches. We examined 50 PD patients using high-resolution MRI to quantify cortical thickness, surface area, and volume in sensorimotor regions, alongside intraoperative neurophysiological recordings of spectral power, burst parameters, and coherence. Pairwise correlation and Sparse Partial Least Squares analyses revealed significant low-dimensional latent relationships, particularly linking cortical atrophy in Brodmann areas BA1-BA6 with alpha and low-beta burst abnormalities. These associations remained robust after controlling for age, disease duration, and symptom severity, and were absent in a control cohort with essential tremor. These findings highlight value of multimodal approaches for uncovering structure-function interactions in PD, and the potential of integrated biomarkers for improving diagnosis, and treatment strategies.

An anterior-posterior gradient in hippocampal subfield volumes linking sleep health to cognition in young adults
Sleep plays a critical role in maintaining hippocampal integrity and supporting cognitive function. However, it remains unclear how variations in sleep are associated with the structurally heterogeneous subfields of the hippocampus and how this association relates to cognition in healthy young adults. This study aimed to elucidate the multivariate relationships among sleep duration, quality, and timing, the specific hippocampal subfield volumes, and cognitive functions in a large sample of healthy young adults. We applied multiset canonical correlation analysis to data from 942 young adults (ages 22-37) from the Human Connectome Project. We examined relationships among self-reported sleep parameters (via the Pittsburgh Sleep Quality Index), high-resolution hippocampal subfield volumes, and a broad set of cognitive performance measures. We identified a single significant mode of covariation, wherein better sleep health-characterized by a moderate sleep duration (reflecting a nonlinear, inverted U-shaped relationship), higher sleep quality (e.g., fewer awakenings, less discomfort), and optimal sleep timing-was robustly associated with larger hippocampal volumes, particularly in the anterior subfields. This sleep-hippocampus pattern was also associated with enhanced cognitive performance. Our findings reveal a specific link among sleep, an anterior-dominant pattern of hippocampal structure, and cognition in healthy young adulthood. The anterior hippocampus may serve as a key neural hub through which the cognitive benefits of healthy sleep are manifested early in life.

Blood and Neuronal Extracellular Vesicle Mitochondrial Disruptions in Schizophrenia
The high energy demand of the human brain obligates robust mitochondrial energy metabolism, while mitochondrial dysfunctions have been linked to neuropsychiatric disorders including schizophrenia spectrum disorders (SSD). However, in vivo assessments that can directly inform brain mitochondrial functioning and its etiopathophysiological path to SSD remain difficult to obtain. We hypothesized that system and brain mitochondrial dysfunctions in SSD may be indexed by elevated cell-free mitochondrial DNA (cf-mtDNA) levels in the blood and in neuronal extracellular vesicles (nEVs). We also explored if these mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS). We examined blood cf-mtDNA in 58 SSD patients and 33 healthy controls, followed by assessing nEV mtDNA and metabolite levels using MRS in a subgroup of patients and controls. We found that people with SSD had significantly elevated cf-mtDNA levels in both the blood (p=0.0002) and neuronal EVs (p=0.003) compared to controls. These mtDNA abnormalities can be linked back to brain lactate+ levels such that higher blood and nEV mtDNA levels were significantly associated with higher lactate+ levels measured at the anterior cingulate cortex (r=0.53, 0.53; p=0.008, 0.03, respectively) in SSD patients. Furthermore, higher developmental stress and trauma were significantly associated with higher cf-mtDNA levels in both the blood and neuronal EVs in SSD patients (r=0.29, 0.49; p=0.01, 0.03, respectively). In conclusion, if replicated and fully developed, blood and neuronal EV-based cell free mtDNA may provide a clinically accessible biomarker to more directly evaluate the mitochondrial hypothesis and the abnormal bioenergetics pathways in schizophrenia.

A molecular and spinal circuit basis for the functional segregation of itch and pain
Recent advances reveal an extensive cellular diversity within the dorsal horn. How this complexity processes distinct sensations, like itch and pain, remains a fundamental question. We discovered hidden within a population of neurons expressing the gastrin-releasing peptide receptor (Grpr+), thought to be itch-specific, are highly homologous yet functionally distinct subtypes distinguished by expression of Tachykinin-1 (Tac1). While the Tac1- subtype mediates itch, the Tac1+ subtype mediates mechanical allodynia across diverse pain states. Inhibitory populations and differential sensitivities to GRP serve as key modulators of the Grpr+ neuron subtypes, shaping modality specific output. Leveraging computationally designed genomic enhancers to silence the Tac1- population reverses itch while silencing the Tac1+ subtype reverses mechanical allodynia broadly. The work demonstrates the nuance of differential sensory modality coding within the dorsal horn and the power of genomic enhancer-based strategies for modality-specific targeting.

The superficial white matter in language processing: Broca's area connections are bilaterally associated with individual performance in children and adults
While deeper white matter connections, such as the arcuate fasciculus and frontal aslant tract, are well known for their role in language and show leftward asymmetries in adults, the contribution of the short-range cortico-cortical superficial white matter (SWM) connections remains less understood. In this preregistered study, we examined white matter connections of Broca's area and its right hemisphere homolog in early adolescents and young adults using two large, publicly available datasets: the Adolescent Brain Cognitive Development Study and the Human Connectome Project Young Adult Study, totaling over 10,000 participants. We anatomically curated the O'Donnell Research Group (ORG) tractography atlas to identify SWM fiber clusters intersecting Broca's area (pars opercularis and pars triangularis), confirmed through expert visual inspection. We investigated the microstructure, structural connectivity, and lateralization of Broca's area SWM and its relationship with language performance (Picture Vocabulary and Oral Reading Recognition assessments), in comparison to the deeper white matter connections of the frontal aslant tract and arcuate fasciculus. The arcuate fasciculus demonstrated the strongest and most consistent leftward lateralization of both microstructure (fractional anisotropy, FA) and structural connectivity (number of streamlines, NoS), with structure-function associations that were bilateral in adolescents and left-dominant in adults. Interestingly, despite weaker lateralization than the arcuate fasciculus, both the SWM and the frontal aslant tract demonstrated comparable associations with language performance. The frontal aslant tract showed greater leftward lateralization (FA and NoS) with age and was bilaterally associated with language performance, particularly in adolescents. Compared to these deeper tracts, Broca's area SWM demonstrated left-lateralized FA and right-lateralized NoS in both adolescents and adults, with stronger FA lateralization in adults. Bilateral SWM FA and NoS were significantly associated with language performance in both hemispheres and age groups. Overall, these results suggest that Broca's area SWM may support language in a more bilaterally distributed manner and highlight the importance of considering SWM connections in studies of language development and neurosurgical planning.

The astroglial protein S100β regulates axon initial segment plasticity
One key regulator of neuronal excitability is the axon initial segment (AIS), a highly specialized axonal region, enriched in ion channels, where action potentials are initiated. The AIS can undergo significant morphological changes to fine-tune neuronal excitability in response to external perturbations. Long considered solely a homeostatic mechanism operating over long timescales (hours to days) to adjust excitability, we show here that this phenomenon can also occur rapidly, within minutes, following a brief period of high activity in layer 5 pyramidal neurons of the visual cortex. Because astrocytes have been known to regulate neuronal excitability, we explored the effects of gliotransmitters on this process and identified the calcium-binding protein S100{beta} from astrocytes to be required for the rapid reorganization of the AIS.

Ubiquitous predictive processing in the spectral domain of sensory cortex
The appearance at the anatomical level of a canonical laminar microcircuit suggests that each six-layer column of granular cortex may mediate a canonical computation. Hypotheses for such computations include predictive coding, predictive routing, efficient coding, and others. However, single-neuron recordings capture only the individual elements of the hypothesized laminar microcircuit, while local field potentials (LFPs) from a laminar probe offer insight into the broader population activity. Through the Allen Institute's OpenScope Brain Observatory, data in mice performing a visual oddball task during multi-area laminar recording was used to test predictive processing hypotheses in the spectral domain. Histological labeling of the cortical laminae enabled a fine-grained examination of their roles in the task, and frequency bands capturing both feedforward and feedback effects were analyzed. Gamma-band local-field potential (LFP) oscillations conveyed feedforward prediction errors in lower sensory areas of cortex; alpha/beta-band oscillations weakened in unpredictable conditions compared to predictable ones; and theta-band oscillations additionally signalled slower, longer-scale temporal prediction errors. In combination with the previous findings, predictive routing explains these experiments where neither ubiquitous predictive coding nor feedforward adaptation can.

Neuromodulatory systems partially account for the topography of cortical networks of learning under uncertainty
Human learning in a dynamic and stochastic environment relies on computational variables such as confidence and surprise. If the learning process is shaped by neuromodulation, then the spatial distribution of receptors and transporters across the brain could put constraints on the spatial distribution of learning-related neural activity. Here, using fMRI data from four probabilistic learning studies and a Bayesian ideal observer model, we reveal a strong spatial invariance across tasks for the functional correlates of confidence, and to a lesser extent, surprise. Using 20 PET receptor/transporter density maps, we then show that this invariance could be partly explained by the chemoarchitecture of the cortex. We identified multiple receptors and transporters whose distribution aligned with the spatial distribution of neural activity in the cortex. While many of these receptors/transporters are in line with previous proposals of neuromodulation of learning, the results also revealed novel associations that can be targeted in experimental studies.

Efficient uniform sampling explains non-uniform memory of narrative stories
Humans do not remember all experiences uniformly. We remember certain moments better than others, and central gist better than detail. Current theories focus exclusively on surprise to explain why some moments are better remembered, and do not explain gist memory. We propose that humans uniformly sample incoming information in time, which explains both non-uniform memory and gist. Rather than surprise, this model predicts that the mutual information between a given moment and the rest of the experience drives memory. To test this model, participants listened to narrative stories and recalled them immediately afterward. Using large language models to quantify the information structure of narrative stories and participants' recall, we found that our parsimonious uniform sampling model explained memory better than earlier theories. These findings suggest an alternative, simpler account of human memory that does not rely on costly feedback mechanisms for prioritizing encoding of specific information.

Altered striatal dopamine regulation in ADGRL3 knockout mice
Dopaminergic signaling is essential for regulating movement, learning, and reward. Disruptions in this system are linked to neuropsychiatric disorders such as ADHD. ADGRL3, an adhesion G protein-coupled receptor highly expressed in the brain, is genetically associated with increased ADHD risk. ADGRL3 knockout in animals alters expression of dopaminergic markers and induces dopamine-related behavioral changes. However, its precise role in modulating dopamine signaling remains unclear. We investigated how ADGRL3 knockout affects striatal dopamine release in mice using ex vivo fast-scan cyclic voltammetry and in vivo fiber photometry with a dopamine sensor. Ex vivo measurements showed increased electrically-evoked dopamine release across the striatum. Conversely, in vivo recordings revealed reduced task-induced dopamine signals in the nucleus accumbens during an operant fixed interval task. This reduction was not due to impaired dopamine availability, as amphetamine-evoked release was unchanged. These findings suggest ADGRL3 modulates dopamine release in complex ways via different pre- and postsynaptic mechanisms.

Aeon: an open-source platform to study the neural basis of ethological behaviours over naturalistic timescales
Ethological behaviours are a powerful tool for neuroscience since they leverage the robust neural computations shaped by the species' evolution to study the neural basis of high-level cognitive functions. However, such behaviours are often transitory and dependent on factors that vary over space, time and number of individuals, making them difficult to capture with standard laboratory tasks. Here we present Aeon, an open-source platform designed for continuous, long-term study of self-guided behaviours in multiple mice and simultaneous recording of brain activity within large customizable habitats. By integrating specialized modules for navigation, nesting and sleeping, escaping, foraging, and social interaction, Aeon enables the expression of key ethological behaviours while achieving experimental control and multi-dimensional quantifications from sub-milliseconds to month-long durations. Its software architecture ensures robust data acquisition via many synchronized data streams and seamless analysis pipelines that delivers a new standardised and unified data format. Using tasks such as digging-to-threshold and social foraging, Aeon reveals how mice adapt strategies in a changing environment and in response to conspecifics. This approach therefore bridges ecological relevance with rigorous experimental control to advance our understanding of how neural circuit activity give rises to a range of highly conserved and adaptive behaviours.

Estrogen Receptor Beta Localized on Ventral Tegmental Area Dopamine Neurons Regulates Nicotine Self-Administration Acquisition in Ovary-Intact Female Rats
Women exhibit greater nicotine use vulnerability than men. High estradiol (E2) exacerbates nicotine use outcomes in women, effects which have been modeled in preclinical nicotine self-administration (SA) studies. Nicotine SA is maintained by dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NA). E2 exerts its effects by binding to estrogen receptors (ER), including ER, ER{beta}, and G-protein coupled ER-1 (GPER-1)s. E2 action at ERs specifically has been shown to potentiate DA neuronal excitability within the VTA. Further, we have shown that ovariectomy decreases both nicotine use during SA and VTA ER{beta} protein. Despite clear evidence of mechanistic relationships between E2, ERs, DA, and nicotine, no studies to date have functionally evaluated the specific role of ER{beta} located on VTA DA cells in driving nicotine consumption during SA in females. There are currently no tools that allow for evaluations of relationships between nicotine neurobiology and ERs with cell-type specificity, as ER{beta} is also localized on other (non-DA) cell types within the VTA. As such, the goals of the present studies were (1) to build and validate a novel adeno-associated viral construct that produces long-term knockdown of ER{beta} specifically on VTA DA neurons, and (2) to determine if VTA DA ER{beta} viral knockdown reduces nicotine SA in ovary-intact female rats. Here we show that ER{beta} regulates VTA DA neuron excitability, and that ER{beta} knockdown in VTA DA neurons reduces DA neuron firing frequency. We also show that VTA ER{beta} knockdown in DA neurons reduces nicotine SA acquisition in ovary-intact female rats. Together, our results demonstrate a critical role of ER{beta} in driving nicotine use in females, underscoring the need for future studies to evaluate neurobehavioral mechanisms of smoking through the lens of sex differences.

Regional BOLD variability reflects microstructural maturation and neuronal ensheathment in the preterm infant cortex
BOLD variability reflects meaningful brain activity, yet its structural and biological correlates during early development remain unknown. We aimed to investigate how BOLD variability evolves in very preterm (VPT) infants, its relationship with cortical microstructure and gene expression, and how it differs from full-term (FT) newborns at term-equivalent age (TEA). Using resting-state fMRI and multi-shell diffusion imaging, acquired in 54 VPT (longitudinally at 33-weeks GA and at TEA) and 24 FT newborns, we evaluated regional differences in cortical BOLD variability and microstructural maturation, and compared to patterns of gene expression in the fetal cortex, using the BrainSpan dataset. BOLD variability increased in primary sensory-sensorimotor and proto-DMN regions, accompanied by decreased cortical diffusivity. Gene expression analysis revealed concurrent upregulation of genes mediating gliogenesis and neuronal ensheathment. Compared to FT newborns, VPT at TEA showed decreased BOLD variability and increased cortical diffusivity. BOLD variability reflects cortical microstructure, mediated by upregulation of gliogenesis and neuronal ensheathment. Interruption of these processes by preterm birth identifies putative mechanisms of preterm brain injury.

Imagined Speech Reconstruction with 3D Neural Metabolism and Large Language Model Integration
Cognitive linguistics posits that language underpins human thought, and this principle has influenced the study and development of large language models (LLMs). In particular, several studies have investigated the metabolic costs of sentence formation using neuroimaging techniques such as positron emission tomography, functional magnetic resonance imaging, electroencephalography (EEG), and imagined speech reconstruction (ISR). In this study, EEG data corresponding to imagined English-language speech phonemes were used for ISR, in combination with an LLM trained on an abridged autobiography. The LLM-generated text responses guided the synthesis of EEG data from relevant phonemes, which were then used to estimate corresponding metabolic activity, and the changes in simulated neurometabolic and electrical parameters were visually represented. Notably, introducing pseudorandom variance significantly (p < 0.001) enhanced the models ability to reflect biological variability. Future directions include expanding the ISR system with lightweight or locally run LLMs, incorporating training data from larger and more diverse populations, and utilizing truly random variability sources. Further optimization for broader hardware compatibility and implementation--such as neural phantoms, emotional context integration, or human-computer interaction platforms--offer promising pathways for advancement. Overall, this work establishes a foundation for the next generation of biologically inspired, modular, and adaptable ISR systems for both research and practical applications.

The effects of adolescent stress on adult social behavior and basolateral amygdala GABAergic neurons with perineuronal nets depend on prenatal stress history
Developmental stress is a well-established risk factor for mental health disorders, yet the neural mechanisms underlying these outcomes remain incompletely understood. Inhibitory brain networks, particularly within the amygdala, are disrupted by stress and implicated in stress-related psychopathologies. Using a rodent model, the current study investigated the isolated and combined effects of prenatal and adolescent stress on adult social interactions and GABAergic neurons surrounded by perineuronal nets (PNNs) in the basolateral amygdala (BLA). Male and female rats were exposed to chronic variable stressors (CVS) prenatally (PS), during adolescence (AS), or during both prenatal and adolescent periods (PS+AS). In adulthood, all animals were tested for social behavior with same-sex weight-matched partners, and brains were collected for identification of BLA inhibitory neurons (GAD67 staining) and PNNs (Wisteria Floribunda Agglutinin staining). For social behavior, AS alone robustly increased social investigation in adulthood relative to non-stressed (NS) controls and animals exposed to combined PS+AS. PS+AS subjects did not significantly differ from NS controls, suggesting that prenatal stress exposure prevented adolescent stress-induced increases in adult social investigation. An analogous data pattern was observed in the BLA. AS alone decreased the number GAD67+ neurons surrounded by PNNs (co-labeled) relative to NS controls and subjects exposed to combined PS+AS. When the percentage of total GAD67+ neurons co-labeled with PNNs was assessed, both PS alone and AS alone reduced the proportion of GAD67+ neurons surrounded by PNNs, whereas combined PS+AS had no effect. Overall, these data suggest that prenatal stress exposure prevents adolescent stress-induced disruptions to perineuronal nets surrounding inhibitory neurons in the BLA, potentially conferring resilience to adolescent stress-induced changes in inhibitory function and social behavior.

KiF1a-regulated neuronal infrastructures in sensory and prefrontal cortices essential for fear memory and anxiety
Stress in social activities induces fears. Cellular infrastructures and molecular profiles underlying fear memory to psychological stress remain elusive for designing therapeutic strategies. With making mice psychological trauma by watching fear scenes in a resident/intruder paradigm, we have studied the features of neuronal infrastructures in visual, auditory and medial prefrontal cortices correlated to this learned fear by the approaches of behavioral task, neural tracing, electrophysiology and molecular biology. This psychological trauma causes observational mice fear memory specific to resident mouse. This learned fear is associated with the formation of synapse interconnections among visual, auditory and medial prefrontal cortices and the strengthening of synapse interconnections among intramodal neurons. These cortical neurons receive new synapse innervations from their interconnected neurons alongside innate synapse innervations and become to encode the stress signals including battle image and battle sound inputted from these synapses. The KiF1a knockdown in the medial prefrontal cortex precludes the onsets of the neuronal infrastructures and the learned fear. KiF1a-mediated intracellular transportation in the medial prefrontal cortex is essential for the recruitment of associative memory neurons that encode fear scenes and anxiety.

Jagged-mediated lateral induction patterns Notch3 signaling within adult neural stem cell populations
In the adult brain, Notch3 signaling promotes neural stem cell (NSC) quiescence and stemness. It remains unknown how Notch3 signaling levels are controlled and relate to these NSC decisions. Here we directly measure the nuclear translocation of the Notch3 intracellular fragment (N3ICD) and quantify Notch3 signaling in NSCs of the zebrafish adult telencephalon in situ. We report that Notch3 signaling levels match NSC quiescence and stemness levels. In physical space, Notch3 signaling is patterned and high signaling levels surround N3ICDlow cells, which also express the deltaA (dla) ligand. Another ligand, jagged1b (jag1b), expressed in all NSCs, positively interacts with Notch3 and sustains expression of the stemness factor Sox2. Finally, lowering jag1b preserves the structured distribution of Notch3 signaling levels in space but attenuates their variance. We propose that Notch3 signaling integrates Dla-mediated lateral inhibition and Jag1b-mediated lateral induction to control quiescence and stemness and their spatiotemporal dynamics in adult NSCs.

Spatiotemporal Dynamics of fMRI Signal Changes Induced by High Concentration Normobaric Oxygen Inhalation
While it is well known that oxygen supports the brain's metabolic demands, it remains unclear how increased oxygen concentration influences intrinsic neural activity over time and across brain regions. Using resting-state functional magnetic resonance imaging (fMRI), we examined the dynamic responses to high-concentration normobaric oxygen across distinct phases of exposure and withdrawal. We revealed three patterns in the BOLD signals: increased activation during inhalation, an undershoot following immediate oxygen withdrawal, and reactivation even without continued oxygen. These responses were most pronounced in the default mode network (DMN), but also exhibited spatiotemporally heterogeneous patterns across the brain, a map we term Brain Oxygen Sensitivity Topography (BOST). Functional connectivity analyses further revealed increased between-network connectivity during inhalation and enhanced within-network connectivity in the DMN during the aftereffect. This spatiotemporal heterogeneity and transient network reorganization suggests that distinct physiological processes are engaged at each phase, enabling us to predict how different oxygen protocols will enhance specific cognitive functions.

Global brain circuitry control of behavior emerging from self-governing vector field dynamics in subnetworks
Behavior ultimately depends on the spatiotemporal patterns of the neuron population activity across the brain. Here we address the issue of how the evolving patterns of population activity can be governed by the intrinsically available mechanisms within the brain. We show how the control of the evolving activity can be represented by a high-dimensional vector field, which is an emergent effect of the integrative effects afforded by the membrane capacitance of the neurons and the weights of the synaptic connections between them. For each subnetwork of the brain, its intrinsic connectivity defines the structure of a lower-dimensional vector field with a local attractor point, towards which the subnetwork activity is constantly drawn. We show that other subnetworks, defined by having a degree of independence from but an impact on the first subnetwork, will constantly move the location of the local attractor point, causing the activity in the first subnetwork to constantly "chase its own tail". We show how this principle can explain how minor differences in the corticospinal control signal can produce a variety of movement patterns through the spinal interneuron circuitry. At the global level, we show how the cortical neuron population can be thought of as many concatenated subnetworks that produce diverse dynamic evolutions across the cortical neuron population globally. This operational principle can produce a dynamic population activity reminiscent of that observed across the brain in vivo and explain the foundational mechanisms underlying autonomous cortical control of its own activity evolution.

Distributed control circuits across a brain-and-cord connectome
Just as genomes revolutionized molecular genetics, connectomes (maps of neurons and synapses) are transforming neuroscience. To date, the only species with complete connectomes are worms1-3 and sea squirts4 (103-104 synapses). By contrast, the fruit fly is more complex (108 synaptic connections), with a brain that supports learning and spatial memory5,6 and an intricate ventral nerve cord analogous to the vertebrate spinal cord7-11. Here we report the first adult fly connectome that unites the brain and ventral nerve cord, and we leverage this resource to investigate principles of neural control. We show that effector cells (motor neurons, endocrine cells and efferent neurons targeting the viscera) are primarily influenced by local sensory cells in the same body part, forming local feedback loops. These local loops are linked by long-range circuits involving ascending and descending neurons organized into behavior-centric modules. Single ascending and descending neurons are often positioned to influence the voluntary movement of multiple body parts, together with endocrine cells or visceral organs that support those movements. Brain regions involved in learning and navigation supervise these circuits. These results reveal an architecture that is distributed, parallelized and embodied (tightly connected to effectors), reminiscent of distributed control architectures in engineered systems12,13.

Phasor diagrams clock oscillatory hemodynamic switching between overt speech production and micro resting states
This study investigates the intricate interplay between the task-positive network and the default mode network (DMN) during transitions between overt language tasks and brief resting periods. While previous research suggests that these networks are not invariably anticorrelated, the precise timing of transitions has remained elusive. We employed rapid phase-encoded fMRI to decode brain dynamics with ultimate precision, capturing these transitions in real time. By utilizing phasor diagrams to represent the oscillatory activities, we examined the amplitudes and phases of hemodynamic fluctuations within the language network and DMN. Our findings align with existing empirical and theoretical perspectives on DMN functions and cognitive task performance, affirming the validity of our approach. We identified heterogeneous micro resting states interwoven with periods of overt speech production. Notably, various core regions of the DMN exhibited task-dependent amplitude and phase modulations, with activation strength and delay rising in line with increasing task complexity, ranging from comprehension to immediate and delayed speech production. This study sheds light on the dynamic engagement of the DMN during overt speech production, providing precise timing data of transitions between the DMN and language network. It demonstrates that rapid phase-encoded fMRI and phasor diagrams are powerful tools for measuring the switching between active tasks and micro resting states with subsecond accuracy, while also elucidating task load-dependent changes in the DMN. By accurately measuring the timing of these transitions, we gain insights into cognitive flexibility, attention, and the efficiency of information processing.

Galvanic vestibular stimulation alters the sense of upright
Given the vestibular system's important role in the perception of upright, we investigated the possible effects of galvanic vestibular stimulation (GVS) on the perception of one's own upright body orientation in relation to gravity, the so-called Subjective Postural Vertical (SPV). Two groups of healthy participants with an average age of 25.4 years and 64.5 years respectively, each consisting of 28 healthy participants, sat (blindfolded) on a tilting chair. The subjects' feeling of being upright was tested under three different conditions of GVS: right-sided anodal stimulation, left-sided anodal stimulation, and sham stimulation. Our findings revealed that right-sided anodal GVS significantly altered the SPV in both age groups, whereas left-sided anodal GVS did not. The observed effect of GVS on perceived upright body posture was numerically small (up to 0.87 degree on average) and not due to a loss of sensitivity to the perception of body verticality. The unexpected asymmetry of the behavioral effects of GVS could be related to the known right hemispheric asymmetry of cortical activation in vestibular projection areas, which would need to be further clarified in future studies.

A water-based platform test of paired or group social dominance and neural activity in male and female mice
Social hierarchy is an evolutionarily-conserved phenomenon determined by social dominance behavior that has profound influence on health and relevance in neuropsychiatric disorders. Despite this, the neural mechanisms underlying social dominance remain unclear and current behavioral tests are limited. Here, we describe a novel platform test of social dominance where mice compete for space on a small, elevated platform surrounded by cold water and rank is calculated by total time spent on platform. To validate this assay, we conducted tube test followed by platform test in cages of male and female mice. We observed stable rank in both sexes using the platform test and saw notable differences in overall cage hierarchy between tube and platform. Motivated behavior as measured by attempts to get on the platform was reduced over time. Cooperative behavior as measured by shared time on platform was observed across all ranks but predominantly demonstrated by subordinate mice. Corticosterone levels were significantly higher in females but showed no rank-specific differences. Neuronal activity in the prefrontal cortex was not rank-dependent, however activity in the habenula scaled with rank in both sexes and was significantly correlated with dominance in males. We also investigated group social dynamics using the platform test and identified stable hierarchies with more exaggerated dominance compared to paired platform testing. These results introduce the platform test as a novel method for assessing social dominance behavior in male and female mice, which can be used to further our understanding of the neurobiology underlying social hierarchy.

Sex-specific vulnerability to behavioural and morphological alterations in a mouse model of Parkinson's disease overexpressing mutant A53T alpha-synuclein
Parkinson's disease (PD) is characterised by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and accumulation of misfolded -synuclein (-syn). Neuroinflammation also contributes to disease onset and progression. Notably, PD exhibits sexual dimorphism in clinical presentation and treatment response. This study investigated sex-specific behavioural and morphological changes in a mouse model overexpressing A53T -syn. Male and female C57BL/6J mice received bilateral intranigral injections of adeno-associated viral vectors encoding mutant A53T -syn or empty vectors. Motor function was assessed at 60 and 120 days post-surgery using open field, wire hang, pole, and balance beam tests. Brains were collected for immunohistochemical analyses of -syn pathology, nigrostriatal integrity (tyrosine hydroxylase, TH), axonal degeneration, and neuroinflammation. -Syn overexpression induced early, subtle motor deficits primarily in males, despite preserved SNc neuronal density. Automated analysis of balance beam walking behaviour (DeepLabCut, SimBA) revealed increased immobility and reduced walking time in -syn males. At 120 days only, striatal TH levels were significantly reduced, driven by reductions in -syn males. Although undetected at 60 days, an axonal degeneration index (combining striatal TH optical density and axonal swellings) revealed more advanced degeneration in -syn males, suggesting faster disease progression. At both time points, -syn mice showed increased striatal astrogliosis without sex differences, indicating -syn-associated neuroinflammation. These findings support a PD model of early axonal degeneration and reactive astrogliosis preceding neuronal loss. The sex-specific behavioural and neuropathological patterns underscore the importance of incorporating sex as a biological variable in preclinical models and developing tailored therapeutic strategies.

Development of a Targeted Choroidal Injury Model for the Study of Retinal Degenerations and Therapeutic Cell Replacement
Purpose: Choroidal loss is an important pathophysiological step in many retinal diseases, but few reliable translational models of choroidal injury exist. Here, we report a new targeted choroidal injury model using bioconjugated saporins and compare it models of systemic sodium iodate administration. Methods: Wild-type Sprague-Dawley rats were given suprachoroidal injections of anti-CD38 or anti-CD105 antibodies conjugated to saporin immunotoxin (10 ul at 0.05 ug/uL) to induce selective choroidal endothelial cell injury. These animals were compared to wild-type rats given sodium iodate (75 mg/kg) via tail vein injections, with a dose escalation study (25, 50, and 75 mg/kg) in immunocompromised (Sprague-Dawley Rag2/Il2g double-knockout) rats. Animals were examined at 1-, 2-, and 3-weeks post-treatment, and the degree of choroidal injury compared using fundus photography, optical coherence tomography, and immunohistochemistry. Results: Suprachoroidal administration of anti-CD38 or anti-CD105 saporins resulted in severe choroidal vascular injury localized to the injection site, without damage to adjacent choroidal vasculature, progressive injury over time, or development of choroidal neovascularization. By contrast, sodium iodate treated animals had rapid, diffuse choroidal loss which progressed throughout the study time points, with fatal systemic side effects at the highest (75 mg/kg) dose. Conclusions: Suprachoroidal injection of anti-CD38 and anti-CD105 saporins results in targeted, localized, non-progressive choroidal injury in rats. These models offer alternatives to systemic sodium iodate administration, which causes diffuse, progressive choroidal injury. Translational Relevance: Immunotoxin-based models of targeted choroidal injury may be useful for understanding pathways of retinal degeneration and facilitating development of therapies for diseases involving choroidal cell loss.

Next Generation AAV-F Capsid gene therapy rescues disease pathology in a model of Pyruvate Dehydrogenase Complex Deficiency
Pyruvate dehydrogenase complex deficiency (PDHD) is a severe mitochondrial disorder most frequently caused by pathogenic variants in PDHA1, leading to neurodevelopmental delay and early mortality, necessitating brain-targeted interventions. Using a brain-specific Pdha1 knockout mouse model, we compared intracerebroventricular delivery of AAV9 capsid and a recently described synthetic neurotropic AAV-F capsid, both expressing human PDHA1 coding sequence driven by a constitutive CAG promoter. Newborn mice received, titre matched AAV9 or AAV-F or AAV9 at ten-fold higher dose. Low-dose AAV-F and high-dose AAV9 significantly improved survival, and restored PDH enzyme activity, metabolite profiles, and brain histopathology to near wild-type levels. However, treated mice showed reduced locomotion by P100 and impaired motor function. Importantly, AAV-F achieved broad CNS transduction with minimal liver expression, outperforming AAV9 at lower dose. There results support the therapeutic potential of AAV-based gene therapy for PDHD and highlighting AAV-F as a promising capsid for efficient, CNS specific delivery.

Automatic pairing of complex stimuli in younger and older adults: An event-related potential study
Contextual information can influence object perception, even when it is irrelevant to the task. When two unrelated stimuli frequently occur in close temporal succession, they may become associated. This process might be stronger in older adults due to age-related decline in inhibitory control, leading to deeper processing of irrelevant context. Automatic associations and their violations can be studied using visual mismatch negativity (vMMN), an event-related potential component reflecting the detection of violations of regularity in unattended stimuli. In our study, younger (n=18, M=21.2 {+/-} 2.1 yrs) and older (n=17, M=69.8 {+/-} 2.8 yrs) adults viewed pairs of images presented in succession: a scene (forest or street) followed by an emotional face (happy or angry). One scene-emotional face combination occurred frequently, the other rarely, forming a contextual oddball sequence. All individual stimuli appeared equally often. Participants performed an unrelated colour-change detection task, ensuring that the scene-emotional face pairs were unattended. We expected a vMMN to the emotional face in rare pairings, especially in older adults if they formed stronger associations. A control oddball condition with only emotional faces verified automatic emotion discrimination. In the control condition, vMMN emerged for both deviant emotions (in various ranges within the 94-276 ms post-stimulus time window). However, no vMMN was observed in the scene-emotional face condition. Instead, younger adults showed an early posterior positivity (90-161 ms) to rare pairings, while older adults exhibited a later negativity (356-384 ms). These results suggest that task-irrelevant, thematically unrelated visual events can become associated through temporal proximity. However, violations of these associations evoke neural responses distinct from vMMN and vary across age groups.

Elevated brain α-synuclein, phosphorylated-tau, and oxidative stress in mice that survived influenza A pneumonitis
Influenza virus infection increases the incidence of parkinsonism in humans. We have previously shown that allelic variants at the Parkinson's disease (PD)-linked Lrrk2 locus modulate host responses in vivo. Here, we asked whether Lrrk2 kinase activity alters disease outcomes in adult mice that survived a nasally acquired infection. We inoculated mice with the mouse adapted A/Fort Monmouth/1/1947 influenza A virus, serotype H1N1 (LD50, 2x10^3 plaque forming units), leading to pneumonitis. We found that neither the hyperkinase-active Lrrk2 p.G2019S knock-in mutant nor the kinase-dead Lrrk2 p.D1994S mutant altered the course of an acute H1N1 lung infection. We then probed for long-term effects of H1N1 pneumonitis on brain health by monitoring surviving mice for six weeks post-inoculation. Intriguingly, at this time point, when mice had recovered and showed no detectable viral proteins in the brain, levels of H2O2 and protein nitrotyrosination were significantly elevated in H1N1 survivors vs. mock-treated littermates. In addition, total -synuclein concentrations were increased in an infection-dependent manner but independent of the Lrrk2 genotype. Intriguingly, at the same timepoint, the ratio of phosphorylated-to-total tau (but not total tau itself) was significantly increased in the brains of H1N1-virus exposed Lrrk2 p.G2019S mice compared to wild-type animals. Our collective results demonstrate that a preceding pneumotropic influenza A virus infection can lead to a rise in several neurodegeneration-linked markers in the brains of surviving mice. The increased ratio of phosphorylated-to-total tau in Lrrk2 p.G2019S animals adds to the growing evidence of interactions between specific microbial pathogens and allelic variants at the Lrrk2 locus. The described outcomes in animals that survived an influenza A virus infection may be of relevance to the incidence of neurodegenerative diseases in ageing humans.

Decision signals in the absence of spiking activity in primate visual cortex
Fluctuations in single-neuron activity in sensory cortex often correlate with perceptual decisions. This kind of correlation has been hypothesized to reflect a causal influence of sensory signals on decisions, a feedback influence of decisions on sensory signals, and various other factors as well. To disentangle these different possibilities, we have examined local field potentials (LFPs) recorded from the middle temporal (MT) area of non-human primates performing a motion discrimination task. Compared to single-neuron spiking, LFPs have the advantage of being decomposable into different frequencies that are associated with different anatomical sources of input. More importantly, they persist when spiking activity is inactivated, which precludes a causal influence of the corresponding neural activity on behavior. We found that high frequency (70-150 Hz) LFP power was correlated with perceptual decisions and that this correlation disappeared when spikes were inactivated, consistent with a causal role for this frequency band in decision making. These signals overlapped in time with decision signals in lower gamma-band power (30-50 Hz), which persisted after spiking inactivation, suggesting a non-causal, feedback input. Interestingly, lower-frequency LFP signals (5-30 Hz) reflected both impending perceptual decisions and the outcome of previous trials. Our results therefore reveal that neural activity multiplexes different sources of information about perceptual decisions and that these types of information can be estimated reliably from different LFP frequencies.

EEG frequency-tagging captures the neural integration of bilateral periodic thermonociceptive stimulation
Sustained periodic stimuli are known to elicit a periodic neural response (i.e. steady-state evoked potential) in the EEG frequency spectrum. These responses can easily be traced at their frequency of stimulation and corresponding harmonics using a "frequency-tagging" approach. To date, sustained periodic thermonociceptive stimuli have only been used on one extremity (e.g. right volar forearm) at a time. Extending this paradigm to a bilateral application would enable its use to study the sensory integration of concomitant nociceptive stimuli and cognitive modulations during e.g. spatial attention tasks. This study demonstrates that bilaterally applied slow sustained periodic sinusoidal thermonociceptive stimuli using two different frequencies of stimulation (i.e. f1, f2, one on each forearm) can indeed be differentiated at the neural level by eliciting two distinct periodic responses at the respective frequency of stimulation and their harmonics. Additionally, we showed that there seems to be an interaction between the neural populations involved in the response to these stimuli, marked by neural activity at intermodulation frequencies (n* f1 {+/-} m* f2). So far, this non-linear integration of sensory information has already been observed following visual and auditory stimuli, but never following thermonociceptive stimuli.

Alteration of Water Exchange Rates Following Focused Ultrasound-Mediated BBB Opening in the Dorsal Striatum of Non-Human Primates: A Diffusion-Prepared pCASL Study
This study applied diffusion-prepared pseudo-continuous arterial spin labeling (DP-pCASL) to quantify cerebral blood flow (CBF), arterial transit time (ATT), and blood-brain barrier (BBB) water exchange rate (Kw) before and after focused ultrasound (FUS)-mediated blood-brain barrier opening (BBBO) in the dorsal striatum of four non-human primates. Six baseline and seven BBBO sessions were performed. DP-pCASL was acquired approximately 45 minutes after FUS sonication combined with intravenous microbubbles, and contrast-enhanced T1-weighted imaging was subsequently used to confirm the BBBO region. Whole-brain analyses revealed no significant changes in CBF or ATT following BBBO (permutation p > 0.05). Region-of-interest analysis within the sonicated caudate demonstrated a significant localized decrease in Kw, with median (IQR) values of 45.0 (40.6 - 55.6) min-1 at the BBBO site versus 61.6 (58.3 - 70.4) min-1 in the contralateral control region (p < 0.05), confirming spatially specific suppression of transendothelial water flux. In contrast, whole-brain Kw increased significantly following BBBO, with median (IQR) values of 49.8 (46.3 - 55.9) min-1 in non-BBBO sessions versus 59.4 (56.6 - 66.3) min-1 in BBBO sessions (p < 0.01), indicating a diffuse enhancement of water exchange across the brain. These findings establish DP-pCASL-derived Kw as a sensitive, non-contrast biomarker for both local and global BBB permeability changes induced by focused ultrasound, supporting its potential for longitudinal monitoring in preclinical and clinical neurotherapeutic applications.

Intrinsic Resistance of the Hippocampal CA2 Subfield to Neuroinflammation After Status Epilepticus
Objective: To determine the spatiotemporal patterns of pro-inflammatory (IL-1beta) and anti-inflammatory (IL-10) cytokines in hippocampal subfields, focusing on the CA2 region, using a pilocarpine-induced status epilepticus (SE) model. Methods: Status epilepticus was induced in adult male Wistar rats with pilocarpine. Animals were divided into control, 1-day post-SE and 7-day post-SE groups (n = 5, 3 and 3). Hippocampi were processed for immunohistochemistry using antibodies against IL-1beta, IL-10, NeuN (mature neurons), and PCP4 (CA2 marker). Microglial activation states (M1/M2) were inferred from cytokine profiles: sustained IL-1beta expression indicated a pro-inflammatory milieu (M1), whereas declining IL-1beta in the presence of IL-10 suggested an anti-inflammatory or reparative state (M2). Results: The CA2 region exhibited IL-1beta immunoreactivity at 1 day post-SE, which decreased by day 7, while CA3 maintained elevated IL-1beta levels. Anti-IL-10 immunostaining was prominent across hippocampal subregions in the control group and 1-day SE group but was absent by day 7 in all regions. NeuN staining revealed limited neuronal death in CA2 at 1 day post-SE, with substantial loss across CA1, CA3, and CA4 by day 7. Significance: The CA2 subfield appears relatively protected from sustained inflammation and neuronal loss, likely owing to unique microglial responses and structural features such as perineuronal nets. These findings highlight microglial polarization as a potential determinant of subfield vulnerability in temporal lobe epilepsy and support further investigation of glial-targeted therapies.

Diurnal Modulation of Persistent Inward Current Contribution to Spinal Motor Neuron Behaviour
Despite the critical role of persistent inward currents (PICs) in modulating motor neuron output, and thus neuromuscular performance, it remains unknown whether their contribution to motor neuron discharge behaviour varies throughout the day. This study aimed to determine whether PIC-related effects on motor neuron activity during submaximal dorsiflexion tasks differ between the early morning and late afternoon. Eighteen healthy adults (4 females; 27.4 {+/-} 5.6 years) performed triangular isometric contractions at two time-points: early morning (7:00 - 8:30 a.m.) and late afternoon (5:00 - 7:30 p.m.). Two conditions were tested: (1) a relative condition, where the target force corresponded to 40% of the maximal voluntary force (MVF) measured during that session, and (2) an absolute condition, where the target force was 40% of the MVF recorded during the first session. High-density surface electromyography signals were recorded from the tibialis anterior and decomposed into motor unit spike trains. The prolongation effect of PICs, estimated via {Delta}F, was significantly greater in the late afternoon in both the relative and absolute force conditions. The amplification effect of PICs, estimated by the acceleration phase of the discharge trajectory, was also higher in the late afternoon, but only in the relative force condition. No time-of-day differences were found for brace height, while attenuation was reduced in the late afternoon in the relative force condition. Collectively, these findings provide evidence for a diurnal modulation of the influence of PICs on motor neuron discharge behaviour, likely mediated by reduced inhibitory input in the late afternoon rather than by changes in neuromodulatory drive.

Human hippocampal ripples prioritise model-based learning
Humans often learn optimally, inferring the value of options they have never directly experienced by leveraging internal models of the world, a process known as model-based learning. Yet how the brain decides which unexperienced options to update first remains unclear. Here we recorded intracranial EEG from 34 epilepsy patients performing a reinforcement-learning task that required using task structure to infer the value of unvisited (non-local) paths. After each reward, brief hippocampal "ripple" events signalled which indirect experience was most valuable, thereby encoding that path's priority. Longer ripples carried the strongest priority signals, allowing the brain to update high value, unvisited options first and thereby optimise learning. Ripple events also coincided with selective cortical reactivation of these high-priority paths, consistent with prioritised replay. Crucially, when hippocampal ripples were precisely synchronised with activity in the lateral frontopolar cortex (LFPC), individuals showed greater model-based learning: stronger ripple-LFPC coupling predicted more effective use of task structure and more accurate learning of non-local values. Our findings establish hippocampal ripple-centred prefrontal coordination as a fundamental mechanism that prioritises valuable experiences for model-based learning, explaining how the human brain learns so efficiently.

Fast photostimulus optimization for holographic control of neural ensemble activity in vivo
Determining the intricate structure and function of neural circuits requires the ability to precisely manipulate circuit activity. Two-photon holographic optogenetics has emerged as a powerful tool for achieving this via flexible excitation of user-defined neural ensembles. However, the precision of two-photon optogenetics has been constrained by off-target stimulation, an effect where proximal non-target neurons can be unintentionally activated due to imperfect spatial confinement of light onto target neurons. Here, we introduce a real-time computational approach to mitigating off-target stimulation by first empirically sampling each neuron's sensitivity to stimulation at proximal locations, and then optimizing stimulation sites using a fast, interpretable model based on adaptive non-negative basis function regression (NBFR). NBFR is highly scalable, completing model fitting for hundreds of neurons in just a few seconds and then optimizing stimulation sites in several hundred milliseconds per stimulus -- fast enough for most closed-loop behavioral experiments. We characterize the performance of our approach in both simulations and in vivo experiments in mouse hippocampus, showing its efficacy under realistic experimental conditions. Our results thus establish NBFR-based photostimulus optimization as an important addition to an emerging computational toolkit for scalable precision optogenetics.

Sleep pressure is differentially regulated by molecularly distinct subtypes of Lhx6-positive and Lhx6-negative neurons of the zona incerta.
Sleep pressure, the accumulating drive towards sleep during wakefulness, is shaped by Lhx6-positive GABAergic neurons in the zona incerta (ZI). Here, we show that these neurons are broadly activated both by spontaneous and experimentally-elevated sleep pressure, and remain active for hours into recovery sleep. Activation is stronger in anterior ZI and varies across molecularly defined subgroups: Nkx2-2-positive neurons respond vigorously, whereas Calb2-positive neurons respond weakly. We also identify Lhx6-negative/Slc32a1-positive GABAergic ZI neurons with distinct sleep pressure responses. Selective genetic ablation of Nkx2-2 in Lhx6-positive neurons reduces the number of Lhx6-positive neurons, alters their distribution, blunts sleep pressure-induced activation of both Lhx6-positive and negative cells, and increases sleep duration. These findings show that developmentally specified, molecularly heterogeneous Lhx6-positive ZI neurons form a key hub for regulating sleep homeostasis, and offer new insight into the circuitry that controls sleep pressure.

MR-AIV reveals in-vivo brain-wide fluid flow with physics-informed AI
The circulation of cerebrospinal and interstitial fluid plays a vital role in clearing metabolic waste from the brain, and its disruption has been linked to neurological disorders. However, directly measuring brain-wide fluid transport, especially in the deep brain, has remained elusive. Here, we introduce magnetic resonance artificial intelligence velocimetry (MR-AIV), a framework featuring a specialized physics-informed architecture and optimization method that reconstructs three-dimensional fluid velocity fields from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MR-AIV unveils brain-wide velocity maps while providing estimates of tissue permeability and pressure fields, quantities inaccessible to other methods. Applied to the brain, MR-AIV reveals a functional landscape of interstitial and perivascular flow, quantitatively distinguishing slow diffusion-driven transport (~0.1 um/s) from rapid advective flow ~3 um/s). This approach enables new investigations into brain clearance mechanisms and fluid dynamics in health and disease, with broad potential applications to other porous media systems, from geophysics to tissue mechanics.

Cat brains age like humans: Translating Time shows pet cats live to be natural models for human aging
Translating biological time across species is a powerful tool to identify new models of human aging and disease. Currently, it is not clear whether any animal reaches an age comparable to a human in their 80s. Most species seem to age differently compared with humans. Some preliminary observations suggest that cats may share common patterns of aging with humans. Cats could serve as a promising model for human aging. Here, we find corresponding ages between cats, humans and other species to test whether cats can live to the equivalent of a human in their 80s. We analyzed 3,754 observations across species from sudden and gradual changes in anatomy, physiology, and behavior. Some of these data are from clinical records, whereas others are from brain scans using high-resolution MRI (7T and 3T). We studied pet cats, research colony cats, and wildcats living in zoos to encapsulate species variation in the speed of development and aging. We found that cat and human brains atrophy with age, and that their age-related patterns in brain aging are sufficiently similar that we could use them to generate cross-species age alignments. We also found that human postnatal development is stretched compared with cats and mice. Interestingly, some pet cats that visit clinics are much older than those in colonies. Therefore, cats, and especially pet cats, are natural model systems of human aging. Our findings call for increased integration across veterinary and human medicine to understand aging.

Spatially distributed and regionally unbound cellular resolution brain-wide processing loops in mice
Until recently, it has been possible to examine activity in the brain globally through regional averaging or locally at cellular resolution. These studies characterized regions as functionally homogeneous entities (e.g. V1 for extracting low-level visual features) or single neurons in a region as heterogeneously tuned (e.g. mixed selectivity). Here, we leverage the unprecedentedly dense IBL electrophysiological recordings in mouse brains during a sensorimotor decision-making task and computationally combine these to generate a global event-aligned high temporal precision cellular-resolution functional map. We find that individual neurons specialize in simple functions, and ordering neurons by functional similarity reveals at cellular and millisecond resolution the temporal arc of computations unfurling over the phases of a trial and across the brain, providing a way to interpret neural variance beyond sensory and motor responses. Functionally similar cells are highly dispersed across regions, and each region contains cells of nearly all response types. Functional tuning is barely predictable by cytoarchitectural boundaries or spatial coordinates, or vice versa. The primary regional distinction is between cortical and subcortical processing, with subcortical neurons carrying most of the internal computations of expert animals, from integration to decision making and movement initiation. At most, the brain exhibits regional structure in a distributional sense: the flatness of an area's distribution of different functional cell types is lowest in cortical regions, but there is no clear correlation between distributional specialization and anatomical measures of cortical hierarchy. Finally, the high temporal resolution of electrophysiological recordings and the inclusion of subcortical areas reveal the existence of a novel set of robust collective and distributed processing networks in the brain, which rapidly emerge and dissolve across phases of a trial. These results point toward the idea of spatially wide-ranging dynamical processing - winding through most brain regions and involving a subset of neurons in each - to carry out basic functions, and contrast with the idea that brain areas are functionally specialized units.

Revisiting object contextual cueing: A replication study on implicit learning
Object contextual cueing is an implicit learning paradigm in which the repeated co-occurrence of certain objects facilitates target detection, even when their spatial arrangement varies. In two experiments - where participants performed a visual search task in which the target was accompanied by either consistently repeated or randomly varying distractors - we attempted to replicate Chun and Jiang's (1999) study. In Experiment 1 (N = 25, M = 20.8 years), although participants became faster and more accurate over time, no significant difference emerged between repeated and new configurations. Thus, using the same experimental design, we were unable to replicate the object contextual cueing effect. In Experiment 2, we tested whether search strategy influences the effect by instructing one group to adopt an active search strategy and another to use a passive one (N = 20 per group, M = 21.8 and 21.7 years, respectively; active: actively search for the target, passive: let the unique item pop out). However, the manipulation had no effect: the contextual cueing effect did not emerge in either group. Importantly, within each group we observed substantial individual differences - some participants showed a facilitation effect, others no effect, and some even showed a reverse pattern. These findings suggest that object contextual cueing may not be a robust or universal phenomenon and may instead depend on individual cognitive styles or learning tendencies.

Myelin Decompaction in Mice Given Anesthetics during Magnetic Resonance Imaging
The objective of this secondary analysis of a prior investigation was to determine if prolonged exposure to the anesthetics isoflurane and dexmedetomidine during MRI was associated with a higher proportion of axons with myelin decompaction. 16 mice underwent an MRI protocol in which they had prolonged exposure to isoflurane and dexmedetomidine, while 10 mice did not undergo this protocol. All mice were sacrificed and electron microscope images were taken of various brain regions including the right prefrontal cortex (anterior cingulate and prelimbic area), the nucleus accumbens, the amygdala, and the ventral hippocampus. Proportion of decompacted axons was calculated for each mouse, and an inter-rater reliability score of 80% was achieved. Welch's t-tests were used to test the hypothesis that mice undergoing MRI with prolonged anesthesia had greater levels of myelin decompaction than mice that did not experience prolonged anesthesia. Mice with prolonged anesthetic exposure during MRI had significantly higher proportions of decompacted axons than mice that did not experience prolonged anesthesia (p-value of 0.00003642). Prolonged exposure to anesthetics, particularly isoflurane, may be associated with myelin decompaction. These findings, if replicated, have potential to impact future anesthesia use in clinical work and scientific research.

The protocol for mesoscopic wide-field optical imaging in mice: from zero to hero
This article provides protocols that make possible to master mesoscopic wide-field optical brain imaging from scratch. The protocols describe surgery for wide-field cranial window creation in mice, and wide-field imaging process and setup. The protocols for components of imaging system selection and assembly, creation of a headplate for fixation, and mice training are also provided. The last part briefly describes methods for data processing. The above procedure can be used to visualize dorsal cortex via wide-field optical imaging as well as laser-speckle contrast imaging methods. The distinguishing features of our protocol are: a wide cranial window (up to 60% of the entire cortex), scull thinning (without craniotomy), ultraviolet-curable transparent coating (gel polish), measurements in awake behaving mice. During the surgery the helicopter-like headplate with its lower surface congruent to scull surface is mounted on mouse head. This headplate is lightweight and enable to fix head securely during movement to avoid frames alignment during data processing. Cranial window remains sufficiently transparent for at least 3 months. Wide-field optical imaging method enables to record brain haemodynamics and energy metabolism (FAD concentration dynamics) in wild-type mice. Use of transgenic animals expressing genetically-encoded sensors enable measurements of ions concentration (e.g. Ca2+-dynamics) and other compounds (e.g. glutamate). The article describes measurements by wide-field optical imaging of oxy-, deoxy-, and total haemoglobin concentrations changes in combination with various intracellular parameters: {Delta}[FAD] or {Delta}[Ca2+] or {Delta}pH with {Delta}[Cl-].

Distinct cortical encoding of acoustic and electrical cochlear stimulation
Cochlear implants are neuroprosthetic devices that restore hearing and speech comprehension to profoundly deaf humans, and represent an exemplar application of biomedical engineering and research to clinical conditions. However, the utility of these devices in many subjects is limited, largely due to lack of information about how neural circuits respond to implant stimulation. Recently we showed that deafened rats can use cochlear implants to recognize sounds, and that this training refined the responses of single neurons in the primary auditory cortex. Here we asked how local populations of cortical neurons represent acute implant stimuli, using electrode arrays we developed for cortical surface recordings for micro-electrocorticography ({micro}ECoG), a form of intracranial electroencephalography (iEEG). We found that there was a limited tonotopic organization across recording sites, relative to a clearer tonotopic spatial representation in normal-hearing rats. Single-trial iEEG responses to acoustic inputs were more reliable than responses to cochlear implant stimulation, although stimulus identity could be successfully decoded in both cases. However, the spatio-temporal response profiles to acoustic vs cochlear implant stimulation were substantially different. Decoders trained on acoustic responses showed essentially zero information transfer when tested on electrical stimulation responses in the same animals after deafening and cochlear implant stimulation. Thus while acute cochlear implant stimulation might activate the auditory cortex in a cochleotopic manner, the dynamics of network activity are quite distinct, suggesting that pitch percepts from acoustic and electrical stimulation are fundamentally different.

iSTTC: a robust method for accurate estimation of intrinsic neural timescales from single-unit recordings
Intrinsic neural timescales (ITs) are an emerging measure of how neural circuits integrate information over time. ITs are dynamically regulated by behavioral context and cognitive demands, making them suitable for mapping high-level cognitive phenomena onto the underlying neural computations. In particular, IT measurements derived from single-unit activity (SUA) offer fine-grained resolution, critical for mechanistically linking individual neuron dynamics to cognition. However, current methods for estimating ITs from SUA suffer significant biases and instabilities, particularly when applied to sparse, noisy, or epoched neural spike data. Here, we introduce the intrinsic Spike Time Tiling Coefficient (iSTTC), a novel metric specifically developed to address these limitations. Leveraging synthetic and experimental single-unit recordings, we systematically assessed the performance of iSTTC relative to traditional approaches. Our findings demonstrate that iSTTC provides more accurate estimates of neural timescales across a wide range of conditions, reducing estimation error especially under challenging yet biologically relevant conditions. Crucially, iSTTC can be applied to both continuous and epoched data, overcoming a critical limitation of existing methods. Furthermore, iSTTC substantially relaxes inclusion criteria, increasing the fraction of neurons suitable for analysis and thereby improving the representativeness and robustness of IT measurements. The methodological advances introduced by iSTTC represent a substantial step forward in accurately capturing neural circuit dynamics, ultimately enhancing our ability to link neural mechanisms to cognitive phenomena.

Long-term Dietary Fat Intervention Affects Retinal Health in APOE Mice
The APOE genotype influences metabolic and neurodegenerative outcomes, with APOE4 carriers at higher risk for Alzheimers disease (AD) and metabolic dysfunction. This study examines how long-term dietary interventions affect systemic metabolism, retinal structure/ function in APOE3-knock-in (KI, neutral for AD) and APOE4-KI mice. Humanized APOE3 and APOE4-KI mice received either a control diet (CD) or a Western diet (WD) for 2, 6, or 12 months. Body weight, glucose metabolism, lipid profiles, retinal structure, function, vasculature, visual performance, and inflammatory markers were analyzed. WD induced early glucose intolerance in APOE4 mice (2 months). APOE3 mice showed impairment only after prolonged exposure (6-12 months). Notably, WD-fed APOE3 mice exhibited more pronounced hyperlipidemia than APOE4 mice. APOE4 CD mice displayed early retinal thinning (6 months), while APOE4 WD mice initially exhibited retinal swelling, followed by degeneration (12 months). WD exacerbated retinal vascular dysfunction in APOE4 mice, with increased tortuosity and reduced vascular area. Elevated Il1b expression in WD-fed APOE4 mice confirmed inflammation-associated retinal dysfunction. APOE4 mice showed heightened vulnerability to diet, with WD worsening metabolic, retinal, and vascular impairments. While CD improved glucose metabolism, it did not prevent retinal dysfunction. These findings underscore genotype-specific dietary strategies to mitigate APOE4-associated risks.

A tale of three types of internal object representations in the human brain
Both object knowledge retrieval and sensory imagery generation engage perceptual regions in the brain and exhibit representational overlap with perception. However, whether they rely on common or distinct representational mechanisms remains unclear. In this study, we conducted an fMRI visual working memory experiment in individuals with (visualizers) and without (aphantasics) visual imagery, combined with support vector machine decoding to identify regions that contained shared neural representations across the presence and absence of visual input. Critically, we applied representational similarity analysis using a multimodal deep neural network (DNN) model comprising text and image encoders to dissociate language-structured and visual-structured knowledge representations. Comparisons between visualizers and aphantasics allowed us to test the relevance of voluntary imagery experience to these representations. We found that while ventral occipitotemporal regions contained shared representations across visual presence and absence, anatomically distinct regions supported different representational structures with differential associations to imagery experience: 1) the left ventral lateral occipitotemporal cortex (LOTC) encoded visual-structured knowledge representations and was linked to imagery experience; 2) the bilateral fusiform gyrus, left dorsal LOTC, and right ventral LOTC encoded language-structured knowledge representations, irrelevant to imagery experience; 3) the left superior parietal lobule encoded priorless knowledge-absent visual maintenance representation, also irrelevant to imagery experience. Together, these findings suggest that shared neural representations between the presence and absence of sensory input arise from multiple, functionally and computationally distinct mechanisms, which vary in their reliance on prior knowledge and imagery experience.

Simultaneous 2- and 3-photon multiplane imaging across cortical layers in freely moving mice
Head-mounted multiphoton microscopes enable imaging of activity from neuronal populations spread throughout the cortical layers in freely moving mice, but so far have been restricted to recording from one cortical layer at a time. Here, combining 2- and 3-photon based excitation delivered through multiple fibers, we built a head-mounted multiplane microscope enabling near simultaneous imaging (8ns between planes) of neuronal activity from five vertically separated planes, spread across multiple cortical layers. Both excitation pathways had remote focusing mechanisms for fine axial adjustments enabling activity recordings from the same neuronal populations over weeks in freely behaving mice. The lightweight microscope utilized an onboard, 2-channel detection system designed to enable activity recordings from neuronal populations spread across visual-cortex layers in both lit and dark conditions as well as imaging activity across posterior parietal cortex layers during complex gap-crossing behaviors. We show that during gap-crossing tasks, layer 5 and 2/3 neuronal subpopulations in posterior parietal cortex have differential pattern sequences during free decision making.

Entorhinal cortex signals dimensions of past experience that can be generalised in a novel environment
No two situations are identical. They can be similar in some aspects but different in others. This poses a key challenge when attempting to generalise our experience from one situation to another. How do we distinguish the aspects that transfer across situations from those that do not? One hypothesis is that the medial temporal lobe (MTL) meets this challenge by forming factorised representations that allow for increased neural similarity between events that share generalisable features. We tested this hypothesis in a functional magnetic resonance imaging study. Forty people were trained to report behavioural sequences based on an underlying graph structure. People then made decisions in a new environment where some, but not all graph transitions from the previous structure could be generalised. Behavioural results showed that participants distinguished the generalisable transition information. Accuracy was significantly higher in blocks in which sequence transitions were shared across environments, than those in which transitions differed. This boost in accuracy was especially pronounced during early exposure to the novel environment. Throughout this early phase, neural patterns in the entorhinal cortex (EC) showed a corresponding differentiation of the generalisable aspects. Neural patterns representing starting locations in familiar and novel environments were significantly more similar in the EC on trials where sequences could be generalised from prior experience, compared to trials with new sequential transitions. This signalling was associated with improved performance when prior sequence knowledge could be reused. Our results suggest that during early exposure to novel environments, the EC may signal dimensions of past experience that can be generalised.

On the role of L-type Ca2+ and BK channels in a biophysical model of cartwheel interneurons
Cartwheel interneurons (CWCs) in the auditory system exhibit a range of activity patterns relevant to auditory function and pathologies. Although experiments have shown how these patterns can vary across individual neurons and can change under pharmacological manipulations, the field has lacked a computational framework in which to explore the contributions of particular currents to these observations and to generate new predictions about the effects of manipulations on CWCs. In this work, we address this deficiency by presenting a conductance-based CWC computational model. This model captures the diversity of CWC activity patterns observed experimentally and suggests parameter changes that may underlie differences across cells. Bifurcation analysis of this model provides an explanation of how distinct dynamic mechanisms contribute to these differences, while direct simulations suggest how cells with different baseline dynamics will respond to variations in certain experimentally-accessible potassium and calcium channel conductances. In addition to the full model that we introduce, we present a reduced model that preserves CWC dynamic regimes. We classify the reduced model variables in terms of distinct dynamic timescales and show that the key transitions in dynamic patterns can be explained based on equilibria of the averaged dynamics of the slowest model variables, in a regime where the faster model variables exhibit oscillations. Overall, this study predicts how changes in parameters will influence CWC behavior, suggests how bifurcations contribute to changes in CWC dynamics, and provides a theoretical foundation that supports our simulation findings.

Postsynaptic induction and presynaptic expression of long-term potentiation at excitatory synapses on layer 2/3 VIP interneurons in the somatosensory cortex
Aims: The complex function of the neocortex depends on neuronal circuits composed of highly interconnected excitatory (glutamatergic) neurons and diverse types of inhibitory (GABAergic) interneurons. Synaptic transmission between specific connection motifs undergoes plastic changes during learning process, however, exact mechanisms underlying synaptic plasticity are still under intense investigation. Long-term potentiation (LTP) of synaptic transmission is a widely used cellular model of synaptic plasticity occurring during learning. Here, we focused on studying LTP at excitatory synapses on layer (L) 2/3 vasoactive intestine polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory (barrel) cortex. Methods: Acute brain slices were prepared from transgenic mice with fluorescently labeled VIP-INs. LTP was induced by a pairing protocol of postsynaptic depolarization with extracellular stimulation. Results: The pairing protocol evoked LTP in L2/3 VIP-INs in control condition, however, pharmacological blocking GABAaR inhibition enhanced LTP. Looking for mechanisms of LTP induction, we found that LTP at excitatory connections to VIP-INs is dependent on metabotropic glutamate receptor type 1 (mGluR-1) and L-type voltage-gated calcium channels (L-type VGCC) but not on NMDARs nor mGluR-5. Next, we showed that mGluR-1 acts through G-coupled signaling, Src-family pathway, independently of transient receptor potential channels (TRPC). Analyses of paired-pulse ratio (PPR) and coefficient of variation (CV) indicated a presynaptic locus of LTP expression. Presynaptic expression of LTP in VIP-INs relies on retrograde signaling through endocannabinoids (eCBs) but not on brain-derived neurotrophic factor (BDNF). Conclusions: We dissected mechanisms of LTP induction and expression at excitatory inputs to L2/3 VIP-INs in the mouse barrel cortex. LTP at excitatory synapses on VIP-INs might serve as a positive feedback for enhanced VIP-IN-mediated inhibition of SST-INs, leading to disinhibition of excitatory neurons from SST-IN inhibition during learning process.

Robust and replicable effects of ageing on resting state brain electrophysiology measured with MEG.
Non-invasive recordings using brain electrophysiology provide credible insights into decline in neuronal functioning with age. New approaches are required to translate these results into compelling clinical metrics and meet the global challenge of preserving brain health in ageing. Changes in neuronal dynamics with ageing are observable in the power spectra of EEG and MEG recordings. Highly promising candidates for electrophysiological markers have been identified, but progress is hindered by substantial methodological variability across studies. This makes it challenging to establish a clear consensus on the frequency, location, and direction of any single reported effect within the larger body of research. We estimate a full-frequency whole-head profile of the ageing effect on eyes-closed resting-state MEG using the GLM-Spectrum. This data representation is easily sharable, facilitates meta-analyses and provides a framework for estimating statistical power of age effects for future study planning. We use this to show that the effect of age replicates across open-access MEG datasets and is robust to modelling of common covariates. Distinct components within the full frequency profile have different effect sizes, indicating that sample-size planning for ageing effects must consider the specific features of interest. The frequency profile of ageing is strongly robust to a range of common covariates and partially robust to modelling of grey matter volume. We establish that what seems a well-powered study may become underpowered when analyses target an age effect that is linearly separable from an age-relevant covariate such as grey matter volume. These results provide a pathway towards formal comparison and assessment of candidate markers for brain health in ageing.

Integrating multiple sensory modalities during dyadic interactions drives self-other differentiation at the behavioral and electrocortical level
Interpersonal motor interactions represent a key setting for processing signals from multiple sensory channels simultaneously, possibly modulating cross-modal multisensory integration, that is a crucial perceptual mechanism where different sensory sources of information are combined into one single percept. Here we explored whether integrating sensorimotor signals while interacting with a partner can lead to shared sensorimotor representations, and possibly to a recalibration of individual's multisensory perception. In detail, we investigated whether engaging individuals in dyadic activities that utilized either single (e.g., visual or tactile/proprioceptive) or combined (e.g., visuo-tactile/proprioceptive) sensory modalities would impact the behavioral and electrocortical markers associated with interpersonal cross-modal integration. We show that interactions requiring the integration of multiple sensory modalities lead to higher interpersonal differentiation resulting in reduced interpersonal cross-modal integration in a subsequent spatial detection task and alter its distributed neural representations. Specifically, the neural patterns elicited by interpersonal visuo-tactile stimuli vary based on the sensory nature of the previous interpersonal interaction, with the one involving multiple sensory modalities resulting in improved performance of a neural classifier. These findings suggest new avenues for sensorimotor approaches in social neuroscience, emphasizing the malleability of self-other representations based on the nature of interpersonal interactions.

Selective Observation Under Limited Resources Biases Social Inference Through Hysteresis
Despite limited access to others' actions and outcomes, humans excel at inferring hidden intentions. Given only partial access, how do they decide what to observe, and how does selective observation shape inference? Here, we examined how choosing what to observe can bias the inference about others' intentions. Participants played a game where they pursued a fleeing target while a computerized opponent acted competitively or cooperatively. Participants overestimated the opponent's competitiveness after the opponent acted more competitively than expected, whereas no such bias occurred when the opponent was more cooperative than expected. This asymmetry depended on the sequence of events, resembling hysteresis, a form of path dependence observed in physical systems. We found that these biases became stronger when participants chose to observe the opponent instead of their own avatar, and this choice came at the cost of losing precise control over their avatar. Our findings highlight the trade-off in selecting what to observe, as the resulting inference biases propagate differently depending on the interaction history.

Higher attention is associated with stronger sensorimotor connectivity during a target pursuit task
Attention is critical in processes related to motor learning and recovery. While neuroimaging studies have highlighted its relevance to frontal-parietal networks, it is unclear how attention affects movement-related activity from the sensorimotor regions of the brain during a motor task. In this study, participants pursued a moving target with a computer mouse, and the level of attention was manipulated via two conditions in which the target moved in either a predictable or unpredictable fashion. We compared event-related desynchronization (ERD) between rest and movement as well as coherence during movement between the predictable and unpredictable trials. We found that alpha- and beta-band ERDs in the contralateral central areas did not change significantly between the two conditions. However, unpredictable trials had larger alpha-band suppression in the frontal and parietal areas, larger beta-band suppression in the ipsilateral parietal area, and larger alpha-band functional connectivity across the central areas. Our study highlights that performing limb movements with higher levels of attention was associated with stronger cortical communication in the sensorimotor areas, rather than strengthening neural activity in these areas. However, higher levels of attention were associated with stronger activation in the frontal and parietal areas which reflects engagement in attention-related networks. This increased activation of attentional networks and stronger sensorimotor communication may facilitate the formation of neural connections that occur in motor skill training and recovery.

Network dynamics for sensory prioritization: Functional connectivity related to individual sensory weighting of vision versus proprioception during upper limb control
Precise control of the hand requires the dynamic integration of visual and proprioceptive (body position sense) sensory cues with internal models, task goals, and motor plans. Individual differences in how visual and proprioceptive cues are weighted have been related to neural substrates, such as posterior parietal regions, yet the underlying neural dynamics are unclear. This study investigated the relationship between visuo-proprioceptive perception during a bimanual pointing task and the whole-brain network dynamics using resting-state functional magnetic resonance imaging (rsfMRI) with both atlas-based and individually-localized ROI seeds. Our results confirm the existence of individual sensory biases, and find they have systematic influences on functional connectivity. Activity between sensorimotor regions and default mode network (DMN) nodes was related to sensory weighting (e.g. individual degree of reliance on vision versus proprioception) and may reflect updating of internal models. The ventral premotor cortex (PMv) emerged as an important node with functional connections suggesting its role for integrating motor plans, internal models, and sensory percepts. Connections from multisensory integration regions like the middle temporal gyrus (MTG) and the superior parietal lobule (SPL), and motor coordination regions in the cerebellum, were related to increased reliance on visual versus proprioceptive information. These findings suggest that individual sensory biases during sensorimotor behavior may be characterized by specific and specialized patterns of neural activity. This research establishes a foundational exploration of the neural systems underlying sensorimotor processing, supporting theories suggesting that learning in either the sensory or motor system may also cause plasticity in the other.

Behavioural and physiological evidence for the development of cardiac-exteroceptive integration during the first year of life
Continuous integration of environmental exteroceptive and internal interoceptive signals is fundamental for perception and adaptive behaviours, yet its developmental trajectory remains poorly understood. Here, we introduced a modified 'iBEATs' paradigm, based on prior work, to investigate cardiac-exteroceptive integration in 3- to 8-month-old infants. Using behavioural measures of looking time and physiological measures of pupillometry, we found that the ability to detect cardiac-exteroceptive synchrony emerges during the first year of life. Critically, this was evident only when stimuli coincided with systole, the baroreceptor-active phase of the cardiac cycle, supporting central multimodal integration interpretable within a predictive coding framework. Furthermore, individual differences in behavioural sensitivity were accounted for by the degree of autonomic maturation. These findings provide the first evidence for the developmental emergence and mechanisms of cardiac-exteroceptive integration, and establish the modified iBEATs paradigm as a promising tool for assessing interoceptive development in early life.

Improved Sleep Spindle Detection Using the BOSC Method: A Comparison with Traditional Approaches
Sleep spindles are brief bursts of 6 - 20 Hz local field potential (LFP/EEG) activity that occur during non-rapid eye movement sleep. Traditional spindle detection methods rely on manually set amplitude and duration thresholds, but this approach can be vulnerable to false detections and could miss low-amplitude spindles due to the inflexible nature of the thresholding technique. The Better OSCillation (BOSC) detection method offers a more robust alternative by applying frequency-specific power thresholds calibrated to the signal itself and requiring a minimum number of oscillation cycles. In this study, we compared traditional and BOSC methods for spindle detection in a variety of ways. First, we created two synthetic datasets: one with synthetic spindles modelled on previous data and one with single wave pulses that had a period consistent with the spindle frequency band. These datasets were used to demonstrate each method's performance when given events that should be detected (synthetic spindles) and those that should not (single wave pulses). Second, we analyzed cortical local field potentials from recordings of rats during natural sleep using both methods to determine their relative effectiveness given biological LFP data. BOSC consistently outperformed the traditional approach in all situations, identifying more valid spindles while minimizing false (or likely false) detections. These findings validate BOSC as a superior method of spindle detection due to its better calibration to the actual signal.

Artificially induced torpor during pregnancy impairs fetal growth in mice
Fetal development in endothermic mammals relies on a tightly regulated maternal body temperature. In animal models, deviations from normothermia during gestation cause fetal developmental abnormalities. However, the direct and physiological manipulation of the maternal core temperature has been technologically challenging, as traditional methods involve the imposition of external thermal stress. Recent advances in the identification of thermoregulatory neurons in the mouse preoptic area have allowed precise control of maternal body temperature without altering environmental conditions. Here we show that the activation of excitatory neurons in the medial preoptic area (MPO) induces a torpor-like hypothermic state in pregnant mice. When induced during early gestation, this state resulted in pregnancy loss, likely due to implantation failure. Hypothermia in mid- and late-gestation reduced fetal liver and kidney size and caused severe growth retardation. Similar outcomes were observed following pyroglutamylated RFamide peptide (Qrfp)-expressing neuron activation in the MPO, whereas inhibitory neuron activation had minimal effect. Furthermore, activating MPO excitatory neurons projecting to the dorsomedial hypothalamic nucleus reproduced both the torpor-like state and fetal growth retardation. These results underscore the importance of a stable maternal body temperature in fetal development and establish a new model for studying the effects of altered maternal temperature on embryogenesis.

Age-Related Alterations in the Expression of Mesencephalic Astrocyte-derived Neurotrophic Factor in the Brain and Their Impact on Neurobehavioral Functions
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. MANF plays an important role in mitigating neurodegenerative processes. Aging, the primary risk factor for neurodegenerative diseases (NDDs), is associated with significant alterations in ER function. The ER, central to protein synthesis, folding, degradation and secretion (proteostasis), experiences considerable stress in NDDs, which activates the unfolded protein response (UPR). We hypothesized that MANF and UPR is crucial for maintaining proteostasis during aging, but their efficacy declines with age, therefore increasing vulnerability to NDDs. We measured MANF levels in the brain and plasma of 1-, 4-, 11-, and 22-month-old male and female mice. A progressive decline of MANF levels was observed, with the lowest levels detected in 22 months. Reduced MANF expression was found in aged mice across several brain areas, including the cerebral cortex, olfactory bulb, thalamus, hypothalamus, hippocampus, and cerebellum. There was a sex difference in MANF levels in aged mice. Aging also altered the expression of UPR and MANF interacting proteins. Using cerebellar Purkinje cell (PC)-specific MANF deficient mice, we showed that MANF deficiency impaired motor coordination in female, but not male mice. MANF deficiency weakened spatial learning and memory in both male and female mice. Male MANF deficient mice displayed increased sociability, whereas female mice exhibit social withdrawal. Taken together, MANF expression in the brain declined with age and MANF deficiency impacted neurobehaviors in the aging animal in a sex-specific manner.

Dynamic Graphs Analysis of EEG
In this study, we investigate the use of temporal dynamics in brain connectivity for the classification of electroencephalography (EEG) signals using dynamic Graph Neural Networks (GNNs). Our methods are applied to several large-scale EEG datasets focused on abnormality and epilepsy detection. The implemented models demonstrate competitive performance on unseen test subjects across all three datasets, outperforming previous graph-based baselines in terms of accuracy and F1 score. We explore multiple architectures designed to capture temporal variations in graph-structured data, demonstrating their effectiveness in modeling dynamic brain activity. In addition to classification, we employ graph-theoretical metrics to analyze temporal changes in brain networks, such as network efficiency and node degree, across time windows of EEG recordings. The goal is to characterize differences between pathological and healthy groups at both the node and network levels. We particularly examine epilepsy and healthy subject groups to highlight differences in local network efficiency and node degrees, with statistical significance confirmed via F-tests.

Seeing more than schemas: the vmPFC represents imagery- rich mental scenarios
Mental imagery varies dramatically across individuals, from vivid scene construction to the complete absence of visual experience, as seen in aphantasia. While the ventromedial prefrontal cortex (vmPFC) is traditionally associated with abstract, schematic representations, emerging theories suggest it may also contribute to constructing vivid, visual mental content. To test this, we developed a novel 7T fMRI experiment varying imagery demands across conditions: Prior to scanning, participants memorized richly detailed scenarios, more constrained, stationary objects, and finally semantic definitions for each of three abstract German words (e.g., hope). During fMRI and eye-tracking, the same word was presented across trials, but participants vividly re-engaged with one of three distinct representations (i.e., scenarios, objects, and definitions), allowing for comparison across richly different cognitive modes triggered by identical visual input. Univariate analyses confirmed previous findings; highlighting the roles of the vmPFC, hippocampus, parahippocampal cortex, and visual- perceptual cortex in imagery-rich scenario construction. We further performed multivoxel pattern analysis (MVPA) to examine distributed neural representations, which can reveal the informational content of mental imagery beyond activation magnitude. Critically, the vmPFC was the only brain region where MVPA classifier accuracy was higher for scenario construction than for object and abstract conditions, directly supporting our hypothesis that the vmPFC encodes imagery-rich details rather than solely abstract, schematic information. Eye movement variability also distinguished between conditions. These findings advance our understanding of vmPFC function, emphasising its role in representing vivid mental content.

Loss of miR-9-2 Causes Cerebral Hemorrhage and Hydrocephalus by Widespread Disruption of Cell-Type-Specific Neurodevelopmental Gene Networks.
MIR-9-2 is a broadly and highly expressed microRNA in the developing brain and is frequently deleted in 5q14.3 Microdeletion Syndrome, a rare but severe neurodevelopmental disorder. Despite this, little attention has been paid to the unique contributions of MIR-9-2 to neurodevelopment and disease. We find that deletion of this microRNA leads to embryonic cerebral hemorrhages and severe hydrocephalus, while disrupting gene networks across a wide range of cell types in the developing brain, thus revealing underappreciated and non-redundant molecular, cellular, and system-wide functions for MIR-9-2 in neurodevelopment.

The effects of chronic social stress on cognitive flexibility in adult female macaques
Chronic social subordination stress in macaques, particularly when it begins early in life, is associated with negative health and cognitive aging outcomes. Utilizing a longitudinal, translational monkey model of early life stress, we report the cognitive performance of adult female Rhesus macaques (Macaca mulatta) that had received social subordination stress associated with Low Social Status (LSS) since birth. Social subordination stress is the means by which macaque social groups establish their hierarchical organization. Higher ranked monkeys maintain their rank by aggression towards lower ranked animals, that in order to avoid harassment, engage in submissive behaviors. This chronic social stress in lower ranked monkeys produces physiological stress responses that over time can accelerate biological and cognitive aging. For this study, we compared 25 adult female Rhesus monkeys, 14 of which were of Low Birth Rank and had received higher levels of social subordination stress since infancy resulting in higher chronic stress. The remaining 11 were of High Birth Rank, and had committed, rather than received, social aggression/harassment on lower ranked subjects. These two groups have been followed longitudinally from birth to adolescence to assess long-term behavioral, physiological, and neural consequences of social stress. Now as they reached adulthood (ages 7-8 years), we assessed their cognitive abilities, focusing on executive function/cognitive flexibility, as a first assessment to map the trajectory of cognitive decline with aging. We trained subjects on the Intra-/Extra-dimensional shift task (ID/ED), which is a Wisconsin Card Sort analog using visual stimuli. This task is relevant for age-related cognitive decline, particularly in executive function, and cognitive flexibility. Cognitive results indicated only mild differences between High and Low ranking subjects on the simple discrimination, and the reversal learning stages of the task. We did find an interaction between High Birth Rank and performance across the three dimensional-shift stages, but no main effect of Rank. Thus, at this first age, we detected no performance differences indicating accelerated cognitive decline. We discuss other factors impacting performance, such as social housing and temperament measures and comparisons with neuroimaging data on these subjects.

Human neurons undergo protracted functional maturation into adulthood
Human cognitive development is uniquely prolonged, reflecting the extended postnatal maturation of the cerebral cortex where cell-type differentiation, synaptogenesis, myelination and transcriptional regulation all follow protracted developmental timelines. However, when human cortical neurons reach functional electrophysiological maturity and how their developmental trajectory compares to other species remains unknown. Here we show through patch-clamp recordings of human temporal cortex from infancy to adulthood that supragranular pyramidal neurons exhibit pronounced neoteny of their functional properties, with physiological maturation continuing well into adulthood. Comparing human and mouse developmental trajectories reveals human neurons are on a much slower developmental timeline, maturing physiologically hundreds of times slower than mouse and 2-6 times slower than would be predicted from anatomical brain growth differences between species. This reflects a fundamentally different allometric relationship between physiological and anatomical maturation; while mouse neuronal physiology closely tracks brain growth, human physiological development follows its own extended timeline. This slow maturation results in different stages of cognitive development being supported by functionally distinct neuronal populations, with the progression from infancy to middle age characterized by specific electrophysiological profiles. Notably, a neuronal subtype thought to be human-specific, with electrophysiological traits that enhance computational capacity, appears only in late adolescence or early adulthood. This extreme protraction of neurophysiological development provides a cellular basis for prolonged human cognitive maturation, demonstrating that neuronal physiological neoteny represents a fundamental evolutionary adaptation in human brain development.

Hunchback functions in the post-mitotic larval MDN to restrict axon outgrowth, synapse formation, and backward locomotion
During neurodevelopment, a single progenitor cell can generate many different neuron types. As these neurons mature, they form unique morphologies, integrate into neural circuits, and contribute to behavior. However, the integration of these developmental events is understudied. Here, we show that the same transcription factor is important for both the generation of neuronal diversity and maintaining mature neuronal identity, providing novel insights on how the generation of neuronal identity and morphology are coordinated. We utilized a previously characterized larval locomotor circuit in Drosophila, where activation of the Moonwalker Descending Neuron (MDN) triggers backward locomotion via its presynaptic connection with the premotor neuron A18b. MDN expresses the temporal transcription factor Hunchback (Hb), which has a well-characterized role in neural progenitors. Loss of Hb in the post-mitotic MDN increases axon/dendrite branching, leading to additional functional synapses on A18b and increasing backward locomotion. We conclude that the endogenous function of Hb is to restrain axon/dendrite outgrowth, including limiting MDN-A18b synapses, thereby dampening backward locomotion. Our work provides insights on how a transcription factor can have different functions throughout life - i.e. Hb generates neuronal diversity in the progenitor and regulates neuronal connectivity in the mature neuron to generate an appropriately tuned behavior.

Amyloidogenic proteolysis of APP regulates glutamatergic presynaptic function
Disease causing mutations of Alzheimer[s] disease (AD) point to dysregulations of APP proteolysis. During asymptomatic and early stages of AD, brain recordings revealed hyperexcitation reverting into over-inhibition as dementia progresses. Here, we show that endogenous APP and its proteolytic product APP-CTF{beta}, the precursors of A{beta}, accumulate preferentially at excitatory synapses. Using pharmacological treatments to modulate physiological concentrations of APP-CTF{beta} and A{beta}, we identify APP-CTF{beta} as a key regulator of glutamatergic synaptic transmission. Accumulation of APP-CTF{beta} increases the probability of synaptic vesicles. Strickingly, monomeric A{beta} counteracts this APP-CTF{beta}-driven hyperexcitability. This suggests that therapeutic strategies clearing monomeric A{beta}, could be detrimental during the early hyperexcitability phase of AD.

Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates
Background: Stress response obligates increased mitochondrial activities to meet stress induced high energy requirement. This stress mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress mitochondrial response paradigm to study the process in humans. Method: We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress induced cf mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high resolution brain imaging based cortical thickness focusing on the mPFC. Results: We found that salivary cf mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct mtDNA response variance (p=0.003). Conclusion: This stress challenge-salivary cf mtDNA assay paradigm may offer a new, noninvasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

Human tau compromises neuronal structural integrity in C. elegans promoted by age, stress and phosphorylation
Tauopathies are a group of progressive neurodegenerative diseases amongst which Alzheimer's disease is the most prevalent. They typically have a late age of onset and lead to cognitive decline. Tau is a highly soluble, intrinsically disordered microtubule binding protein that aggregates in these diseases. The mechanisms by which age-associated changes alter tau functionality and compromise neuronal structural integrity remain poorly understood. Here, we show with the use of single-copy gene insertion Caenorhabditis elegans models that human tau preferentially localises to neuronal processes in the nematode, consistent with its function of binding to microtubules. The expression of tau in the nervous system leads to age-associated changes in neuronal structural integrity. The observed "buckling" phenotype was exacerbated by exposure of the animals to different stressors which are known to enhance tau phosphorylation. Expressing phosphomimic tau or co-expressing human kinases both severely worsened the buckling phenotype. Kinase expression additionally induced tau inclusions in a small proportion of animals. These results point to an interplay between ageing, stress and phosphorylation leading to structural changes in neuronal processes prior to widespread tau aggregation.

Concerted actions of distinct serotonin neurons orchestrate female pup care behavior
In many mammalian species, female behavior towards infant conspecifics changes across reproductive stages. Sexually naive females interact minimally or aggressively with infants, whereas the same animals exhibit extensive care behavior, even towards unrelated infants, after parturition1-6. Here, we discovered that two distinct sets of serotonin neurons collectively mediate this dramatic transition in maternal behavior--serotonin neurons projecting to the medial preoptic area (mPOA) promote pup care in mothers, whereas those projecting to the bed nucleus of the stria terminalis (BNST) suppress pup interaction in virgin female mice. Disrupting serotonin synthesis in either of these subpopulations or stimulating either subpopulation is sufficient to toggle pup-directed behavior between that displayed by virgin females and that of lactating mothers. In virgin female mice, the first pup interaction triggers an increase in serotonin release in BNST but a decrease in mPOA. In mothers, serotonin activity becomes greatly elevated in mPOA during pup interactions. Acute interruption of serotonin signaling locally in either mPOA or BNST disrupts the stage-dependent switch in pup care. Together, these results highlight how functionally distinct serotonin subpopulations orchestrate social behaviors appropriate for a given reproductive state, and suggest a circuit logic for how a neuromodulator coordinates adaptive behavioral changes across life stages.

Distinct inhibitory connectivity motifs trigger distinct forms of anticipation in the retinal network
Motion is an important feature of visual scenes and retinal neuronal circuits selectively signal different motion features. It has been shown that the retina can extrapolate the position of a moving object, thereby compensating sensory transmission delays and enabling signal processing in real-time. Amacrine cells, the inhibitory interneurons of the retina, play essential roles in such computations although their precise function remain unclear. Here, we computationally explore the effect of two different inhibitory connectivity motifs on the retinas response to moving objects: feed-forward and recurrent feed-back inhibition. We show that both can account for motion anticipation with two different mechanisms. Feed-forward inhibition truncates motion responses and shifts peak responses forward via subtractive inhibition, whereas recurrent feedback coupling evokes, via divisive inhibition, excitatory and inhibitory waves with different phases that add up and shift the response peak. A key difference between the two mechanisms is how the peak response scales with the speed of a moving object. Motion prediction with feed-forward circuits monotonically decreases with increasing speeds, while recurrent feedback coupling induces tuning curves that exhibit a preferred speed for which motion prediction is maximal.

Serotonin modulates neural dynamics in a subspace orthogonal to the choice space
Serotonin (5-HT) is a central neuromodulator which is implicated in, amongst other functions, cognitive flexibility. 5-HT is released from the dorsal raphe nucleus (DRN) throughout nearly the entire forebrain. Little is known, however, about how serotonin affects downstream populations of neurons and how this modulation might support its cognitive functions. Here, we optogenetically stimulated serotonergic neurons in the DRN while recording large parts of the brain with Neuropixels during quiet wakefulness and performance of a perceptual decision-making task. During quiet wakefulness, 5-HT stimulation induced a rapid switch in internal state, as indicated by dilation of the pupil, suppression of hippocampal sharp wave ripples, and increased exploratory behaviors, such as whisking. To elucidate the brain-wide effect of serotonin release we performed acute Neuropixel recordings in seven target locations, a total of 7,478 neurons were recorded across 17 mice. We found that 5-HT stimulation significantly modulated neural activity in all the recorded brain regions, both during quiet wakefulness and task performance. During task performance, however, we observed no change in behavior when stimulating 5-HT. We found that the 5-HT modulation of high-dimensional neural dynamics is confined to a subspace which is orthogonal relative to the choice axis. These observations describe a possible mechanism for the induction of state-dependent stimulus representations, suggesting a neural basis for neuromodulatory effects on brain-wide circuits to flexible decision-making.

How individual differences shape ERP responses to visual statistical learning
Statistical learning (SL) enables the extraction of regularities from sensory input, yet the neural dynamics supporting this process--particularly in the visual modality--remain incompletely understood. Sixty-seven adults were familiarized with a continuous stream of shape sequences containing statistical structure that defined shape triplets. We recorded EEG to familiar sequences (presented in isolation) and unfamiliar foils. Both early (N100) and late (N400) event related potential (ERP) components were significantly more negative for unfamiliar than familiar sequences, reflecting robust neural sensitivity to learned structure. Notably, these familiarity effects were evident in both high- and low-performing participants and were not predicted by overall behavioral sensitivity, suggesting that neural indices of learning can emerge independently of explicit recognition. Follow-up analyses incorporating trial-level accuracy revealed a striking crossover interaction: for sensitive participants, ERP familiarity effects were stronger on correct trials, whereas for insensitive participants, effects were larger on incorrect trials. These findings highlight a dissociation between neural and behavioral measures of statistical learning and underscore the value of ERPs in capturing latent learning processes that may elude conscious awareness.

Fast voxel and structural MRI realignment to mitigate inter-acquisition motion for spectroscopy
Magnetic resonance spectroscopy (MRS) non-invasively measures the biochemical composition within a predefined brain region, enabling quantification of neurochemicals with biological and clinical relevance, such as N-acetylaspartate, creatine, choline, glutamate, and gamma-aminobutyric acid. However, accurate MRS quantification is compromised by subject motion displacing the prescribed location, a common problem during long scans or with motion-prone populations such as children and patients. Furthermore, displacement into bone tissue contaminates MRS data with noisy artifacts, often rendering them unusable. While promising solutions exist to address motion-related issues, many rely on specialized infrastructure and expertise available only at a limited number of research centers. We propose a fast and straightforward method that acquires a head scout (18 s) MRI sequence following potential motion, automatically repositions the prescribed voxel with the scanner's built-in AutoAlign function, and realigns the T1-weighted image to the updated position for anatomical segmentation. Using voxels prescribed in the prefrontal cortex, thalamus, and left superior temporal gyrus, we demonstrated that this realignment method successfully restored displaced voxels to their intended locations, eliminating bone contamination while improving voxel targeting through greater overlap with intended regions and more consistent voxel placement across subjects. This solution offers a quick and practical way for correcting subject motion between scans by combining available tools that are readily accessible even to new users, while more sophisticated motion correction technologies continue to develop towards broader adoption.

Differential Bioenergetic Profile of Human Glioblastoma following Transplantation of Myocyte-derived Mitochondria
Glioblastoma (GBM) exhibits profound plasticity, enabling adaptation to fluctuating microenvironmental stressors such as hypoxia and nutrient deprivation. However, this metabolic rewiring also creates subtype-specific vulnerabilities that may be exploited therapeutically. Here, we investigate whether mitochondrial transplantation using non-neoplastic, human myocyte-derived mitochondria alters the metabolic architecture of GBM cells and modulates their response to ionizing radiation. Using a cell-penetrating peptide-mediated delivery system, we successfully introduced mitochondria into two mesenchymal-subtype GBM cell lines, U3035 and U3046. Transplanted cells exhibited enhanced mitochondrial polarization and respiratory function, particularly in the metabolically flexible U3035 line. Bioenergetic profiling revealed significant increases in basal respiration, spare respiratory capacity, and glycolytic reserve in U3035 cells post-transplantation, whereas U3046 cells showed minimal bioenergetic augmentation. Transcriptomic analyses using oxidative phosphorylation (OXPHOS) and glycolysis gene sets confirmed these functional findings. At baseline, U3035 cells expressed high levels of both glycolytic and OXPHOS genes, while U3046 cells were metabolically suppressed. Following radiation, U3035 cells downregulated key OXPHOS and glycolysis genes, suggesting metabolic collapse. In contrast, U3046 cells transcriptionally upregulated both pathways, indicating compensatory adaptation. These results identify and establish mitochondrial transplantation as a metabolic priming strategy that sensitizes adaptable GBM subtypes like U3035 to therapeutic stress by inducing bioenergetic overextension. Conversely, rigid subtypes like U3046 may require inhibition of post-radiation metabolic compensation for effective targeting. Our findings support a novel stratified approach to GBM treatment which integrates metabolic subtype profiling with bioenergetic modulation.

CCB79 is a primate-specific cilium initiation factor essential to maintain neural progenitor diversity in developing brain tissue.
Identifying the genes that regulate the accurate diversity of neural progenitor cells (NPCs) helps understand the mechanisms of human neocortex expansion. In primate brains, an additional intermediate progenitor layer, the outer subventricular zone (oSVZ) facilitates the expansion of the neocortex. Here, we identify an uncharacterized gene, KIAA0408, and show that its expression is enriched in intermediate progenitors. Removing KIAA0408 in human-induced pluripotent stem cell (iPSC)-derived brain organoids results in an impaired cortical organization characterized by abnormal cell fate and patterning defects, including the depletion of intermediate and ventral progenitors. Molecularly, KIAA0408 is a 79-kilodalton centriolar distal appendage protein (DAP) that controls cilium biogenesis (hereafter CCB79). CCB79 forms a complex with other DAP components and specifically localizes in the DAP at the onset of ciliogenesis, and its absence blocks ciliogenesis. Mechanistically, progenitors in 3D brain tissues are unable to form cilia, which induces aberrant hedgehog signaling and causes premature differentiation. Finally, human CCB79, rather than the mouse ortholog, rescues cilia defects, suggesting that CCB79 has undergone rapid evolution from rodents to primates to fine-tune ciliogenesis for proper brain development.

Cortical α-synuclein pathology induces cell autonomous neuronal hypoactivity and compensatory circuit changes in a model of early Lewy Body Dementia
Cognitive impairment is a common non-motor symptom of Parkinson's disease (PD) and a defining feature of Dementia with Lewy Bodies (DLB). Although many cognitive domains can be affected, impairments in visuospatial/perceptual function are relatively specific for PD and DLB compared to other dementias. Across populations, cognitive impairments correlate with the presence of -synuclein (-syn) pathology in limbic and neocortical brain regions. However, the specific role that -syn pathology plays in driving cortical circuit dysfunction and cognitive impairment remains controversial. We hypothesized that inducing -syn pathology in visual cortex in mice would impair neuronal activity and encoding of visual information, leading to visuoperceptual impairments. To test this hypothesis, we injected -syn pre-formed fibrils (PFF) into primary visual cortex (V1) to seed endogenous -syn pathology. Using longitudinal in vivo two-photon (2P) calcium imaging over 6 months, we recorded visually evoked activity of pyramidal cells in layer 2/3 (L2/3) and quantified -syn pathology using C05-05, a fluorescent ligand that binds aggregated -syn. Injection of PFFs led to the formation of sparse Lewy-like pathology in V1 and other anatomically connected regions. Measuring population activity, we found a greater percentage of neurons in PFF-injected mice were responsive to visual stimuli with lower direction selectivity compared to controls at 4-5 months post-injection (MPI). Within PFF-injected mice, neurons with large somatic Lewy-like inclusions had significantly lower visually evoked activity compared to neighboring neurons without inclusions. Conversely, the activity of neurons without somatic inclusions showed increased activity, positively correlated with the nearby burden of -syn pathology. Measuring visuoperceptual function using a head-fixed coherent motion discrimination task, we found no impairments in visuoperceptual ability in PFF-injected mice up to 6 MPI. Our results demonstrate, for the first time in vivo, that -syn pathology leads to cell autonomous reductions in neuronal activity and reciprocal changes in local population activity that may be compensatory, helping to preserve visuoperceptual function. Reflecting the early stages of neocortical -syn pathology, our model provides a framework for future studies incorporating risk factors for dementia in PD to better understand the heterogeneity of cognitive symptoms and -syn pathology across patients.