bioRxiv Subject Collection: Neuroscience's Journal
 
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Tuesday, January 7th, 2025

    Time Event
    12:31a
    In vivo imaging of inferior olive neurons reveals roles of co-activation and cerebellar feedback in olivocerebellar signaling
    Complex spikes (CSs), generated by inferior olive (IO) neurons, are foundational to most theories of cerebellar function and motor learning. Despite their importance, recordings from IO neurons in living animals have been limited to single-electrode methods, providing no insights into multineuron dynamics within intact circuits. Here, we used a novel ventral surgical approach that allows calcium imaging-based monitoring of multicellular activity in the IO of anesthetized mice. This method provides direct optical access to the ventral medulla, enabling simultaneous recording of spontaneous and sensory-evoked activity within localized clusters of IO neurons, specifically in the principal (PO) and dorsal accessory olives (DAO). Our findings reveal that spontaneous activity rates and event magnitudes differ between the PO and DAO, consistent with observations from cerebellar cortex recordings in zebrin-positive (Z+) and zebrin-negative (Z-) zones, respectively. We further demonstrate that spontaneous event amplitudes are influenced by co-activation among neighboring neurons, so that events occurring in clusters are larger than single ones. Event co-activation is more pronounced in the PO than in the DAO, potentially explaining the differences in complex spike sizes observed in Z+ and Z- zones. Sensory-evoked events induced by periocular airpuff stimulation were larger than spontaneous ones, as expected. However, this difference diminishes when accounting for the higher levels of co-activation during sensory stimulation. By comparing spontaneous and sensory-evoked events categorized as clustered or single, we find no intrinsic differences in amplitudes, emphasizing the role of co-activation in shaping event magnitude. Next, we optogenetically activated cerebellar nucleo-olivary (N-O) axons, a pathway central to theories of CS generation. To our surprise, while this robustly suppressed spontaneous IO activity, sensory-evoked events showed no reduction in either their probability or waveform. Our findings challenge the traditional view of the N-O pathway as purely inhibitory or desynchronizing, revealing instead a selective suppression of background activity while preserving sensory-driven responses. Together with the role of local co-activation in shaping IO event magnitudes, this work offers new insight into the timing and variation in complex spike sizes and their functional significance for behavior.
    12:31a
    Tastes and retronasal odours evoke a shared flavour-specific neural code in the human insula
    During food consumption, tastes combine with retronasal odours to form flavour, which leads to a link so robust that retronasal odours can elicit taste sensations without concurrent taste stimulation. However, the cortical integration of these parallel sensory signals remains unclear. Here, we combine a flavour-binding paradigm and functional neuroimaging to test whether retronasal odorants evoke encoding patterns in the insula similar to those of their paired tastants. Healthy participants attended a familiarisation session with congruent sweet and savoury flavours followed by two fMRI sessions where they separately received the constituent tastants and odorants. Multivariate pattern analysis revealed classification of retronasal odours within the insula, exhibiting overlapping representations with their associated tastes, particularly in the ventral anterior insula. Additionally, we observed temporal instability in insular taste representations, paralleling findings in rodent gustatory cortex. These findings underscore the robust integration of gustatory and retronasal olfactory processing that underpin the flavour percept.
    12:31a
    Looking for the optimal pathway to stimulate hippocampus in human participants using transcranial ultrasound stimulation (TUS): a simulation study
    At present, very limited methods can directly modulate the neural activities in deep brain structures in human participants. Low-intensity transcranial ultrasound stimulation (TUS), as an emerging and advanced modality of non-invasive brain stimulation (NIBS), has great potential for focally stimulating the subcortical structures that are related to sleep, emotion and the functions of motor of cognition. Due to the focality, the integration of various methods, including magnetic resonance imaging and possible pathways, is important to perform TUS intervention for precise targeting and dosing. Based on structural MRI scans, we constructed a simulation model of low-intensity TUS, with a particular focus on the optimal pathways of targeting hippocampus in human participants. Finally, we outlooked the future perspectives of TUS in clinical applications in neurological and psychiatric fields.
    6:16a
    Optimal sparsity in autoencoder memory models of the hippocampus
    Storing complex correlated memories is significantly more efficient when memories are recoded to obtain compressed representations. Previous work has shown that compression can be implemented in a simple neural circuit, which can be described as a sparse autoencoder. The activity of the encoding units in these models recapitulates the activity of hippocampal neurons recorded in multiple experiments. However, these investigations have assumed that the level of sparsity is fixed and that inputs have the same statistics and, hence, that they are uniformly compressible. In contrast, biological agents encounter environments with vastly different memory demands and compressibility. Here, we investigate whether the compressibility of inputs determines optimal sparsity in sparse autoencoders. We find 1) that as the compressibility of inputs increases, the optimal coding level decreases, 2) that the desired coding level diverges from the observed coding level as a function of both memory demand and input compressibility, and 3) that optimal memory capacity is achieved when sparsity is weakly enforced. In addition, we characterize how sparsity and the strength of sparsity enforcement jointly control optimal performance. These results provide predictions for how sparsity in the hippocampus should change in response to environmental statistics and theoretical grounds for why sparsity is dynamically tuned in the brain.
    6:16a
    Psilocybin induces sex- and context-specific recruitment of the stress axis
    Psychedelics have reemerged as potential treatments for mental health disorders, yet their impact on stress-related brain regions remains poorly understood. Here, we provide the first real-time, in vivo evidence of psilocybin-induced neuronal activation, specifically in hypothalamic corticotropin-releasing hormone neurons. Notably, psilocybin elicited more pronounced responses in female mice and produced context-related alterations in threat assessment. Our findings provide valuable insight into the impact of psychedelics on a key stress center in the brain.
    6:16a
    Regulation of eye movements and pupil size in natural scenes
    The visual diet of humans is complex in space, time, spectrum, and consequently the activation of the retinal photoreceptors. While analyses of natural scenes have yielded valuable insights, the naturalistic natural stimulus on the retina is not very well understood. In the present study, we performed eye tracking in naturalistic indoor and outdoor real-world scenes. We recorded pupil size, several saccade and fixation metrics, as well as subjective scene perception ratings derived from subjective questionnaires. For the first five seconds of eye tracking, the descriptive data analysis revealed significantly increased average saccade frequency (p =.0025), amplitude (p =.0049), peak velocity (p =.0072), as well as pupil size (p = 1.307e-09) in the indoor environments. After this initial phase, these differences vanished, except for pupil size. Using an exploratory analysis on the whole 4-minute measurement, we found that saccade and fixation metrics, along with scene ratings, showed significantly different correlations between indoor and outdoor conditions. Despite the inherent constraints of such a naturalistic study (reduced ability to exert control over the precise task and the environmental conditions), we contend that the dataset holds substantial value for the field of eye movement research, as it has effectively minimized confounding factors that have been prevalent in previous eye tracking studies.
    6:16a
    Topography of scene memory and perception activity in posterior cortex - a publicly available resource
    Adaptive behavior in complex environments requires integrating visual perception with memory of our spatial environment. Recent work has implicated three brain areas in posterior cerebral cortex - the place memory areas (PMAs) that are anterior to the three visual scene perception areas (SPAs) - in this function. However, PMAs' relationship to the broader cortical hierarchy remains unclear due to limited group-level characterization. Here, we examined the PMA and SPA locations across three fMRI datasets (44 participants, 29 female). SPAs were identified using a standard visual localizer where participants viewed scenes versus faces. PMAs were identified by contrasting activity when participants recalled personally familiar places versus familiar faces (Datasets 1-2) or places versus multiple categories (familiar faces, bodies, and objects, and famous faces; Dataset 3). Across datasets, the PMAs were located anterior to the SPAs on the ventral and lateral cortical surfaces. The anterior displacement between PMAs and SPAs was highly reproducible. Compared to public atlases, the PMAs fell at the boundary between externally-oriented networks (dorsal attention) and internally-oriented networks (default mode). Additionally, while SPAs overlapped with retinotopic maps, the PMAs were consistently located anterior to mapped visual cortex. These results establish the anatomical position of the PMAs at inflection points along the cortical hierarchy between unimodal sensory and transmodal, apical regions, which informs broader theories of how the brain integrates perception and memory for scenes. We have released probabilistic parcels of these regions to facilitate future research into their roles in spatial cognition.
    6:46a
    Gut epithelium modifies enteric behaviors during nutritional adversity via distinct peptidergic signaling axes
    Interorgan signaling events are emerging as key regulators of behavioral plasticity. The foregut and hindgut circuits of the C. elegans enteric nervous system (ENS) control feeding and defecation behavior, respectively. Here we show that epithelial cells in the midgut integrate feeding state information to control these behavioral outputs by releasing distinct neuropeptidergic signals. In favorable conditions, insulin and non-insulin peptides released from midgut epithelia activate foregut and hindgut enteric neurons, respectively, to sustain normal feeding and defecation behavior. During food scarcity, altered insulin signaling from sensory neurons activates the transcription factor DAF-16/FoxO in midgut epithelia, which blocks both peptidergic signaling axes to the ENS by transcriptionally shutting down the intestinal neuropeptide secretion machinery. Our findings demonstrate that midgut epithelial cells act as integrators to relay internal state information to distinct parts of the enteric nervous system to control animal behavior.
    6:46a
    Accumbal acetylcholine signals associative salience
    Learning in dynamic environments requires animals to not only associate cues with outcomes but also to determine cue salience, which modulates how quickly related associations are updated. While dopamine (DA) in the nucleus accumbens core (NAcc) has been implicated in learning associations, the mechanisms of salience are less understood. Here, we tested the hypothesis that acetylcholine (ACh) in the NAcc encodes cue salience. We conducted four odor discrimination experiments in rats while simultaneously measuring accumbal ACh and DA. We found that ACh developed characteristic dips to cues over learning before DA signals differentiated cues by value, with these dips persisting through value decreases and developing faster during meta-learning. The dips reflected the cue salience across learning stages and tasks, as predicted by a hybrid attentional associative learning model that integrated principles from the Mackintosh and Pearce-Hall models, suggesting that accumbal ACh signals encode salience and potentially gate the learning process.
    6:46a
    Maturation of striatal dopamine supports the development of habitual behavior through adolescence
    Developmental trajectories during the transition from adolescence to adulthood contribute to the establishment of stable, adult forms of operation. Understanding the neural mechanisms underlying this transition is crucial for identifying variability in normal development and the onset of psychiatric disorders, which typically emerge during this time. Habitual behaviors can serve as a model for understanding brain mechanisms underlying the stabilization of adult behavior, while also conferring risk for psychopathologies. Dopaminergic (DA) processes in the basal ganglia are thought to facilitate the formation of habits; however, developmental trajectories of habits and the brain systems supporting them have not been characterized in vivo in developing humans. The current study examined trajectories of habitual behavior from adolescence to adulthood and sought to understand how the maturing striatal DA system may act as a potential mechanism in the process of habit formation. We used data from two longitudinal studies (combined n = 217, 10 - 32 years of age, 1-3 visits each, 320 total sessions) to characterize normative developmental trajectories of basal ganglia tissue iron concentration (a proxy for DA-related neurophysiology) and goal-direct and habitual control behaviors in a two-stage decision-making task. Tissue iron concentrations across the basal ganglia and habitual responding during the two-stage sequential decision-making task both increased with age (all p < 0.001). Importantly, habitual responding was associated with tissue iron concentrations in the putamen (F = 4.34, p = 0.014), such that increases in habitual responding were supported by increases in putamen tissue iron concentration during childhood through late adolescence. Exploratory analyses of further subdivisions of anatomical regions found that this association was specific to the posterior putamen. These results provide novel evidence in humans that habitual behavior continues to mature into adulthood and may be supported by increased specialization of reward systems.
    6:46a
    Targeted stimulation of motor cortex neural ensembles drives learned movements
    During the execution of learned motor skills, the neural population in the layer 2/3 (L2/3) of the primary motor cortex (M1) expresses a reproducible spatiotemporal activity pattern. It is debated whether M1 actively participates in generating the activity pattern or it only passively reflects patterned inputs. Furthermore, it is unclear whether this learned activity pattern causally drives the learned movement. We addressed these issues using in vivo two-photon calcium imaging combined with holographic optogenetic stimulation of specific ensembles of M1 L2/3 neurons in mice engaged in a skilled lever-press task. We briefly and synchronously stimulated ~20 neurons whose activity onset in voluntary trials precedes movement onsets. This stimulation, despite lacking temporal patterns, induced movements that resembled the learned movement, while producing spatiotemporal activity patterns in other M1 neurons not directly stimulated that resembled the activity during the voluntary learned movement. Trial-by-trial variability of optogenetically triggered population activity in the non-target neurons correlated with the variability in the induced movements. These trial-by-trial variabilities were predicted by the initial state of M1 population activity immediately preceding the optogenetic stimulation. Stimulation of the neurons whose activity followed voluntary movement onsets failed to induce the learned movement. Thus, the learned activity pattern in M1 L2/3 can be generated when the M1 network is prepared at the optimal initial state and receives precise triggering inputs, supporting the active role of M1 in learned activity generation. The resulting activity pattern then causally drives the learned movement.
    6:46a
    The superior colliculus gates dopamine responses to conditioned stimuli in visual classical conditioning
    In classical Pavlovian conditioning, it is well-established that midbrain dopamine neurons respond to conditioned stimuli (CS) that predict a reward. However, how the dopamine neurons associate a neutral CS to a reward remains unknown. Here, we show that the superior colliculus (SC) develops neuronal responses to a visual CS during conditioning, which in turn drive the responses of dopamine neurons. Visual responses in the SC were only potentiated when a behaviorally meaningful time interval separated the visual stimulus and reward. Potentiation also required the convergence of visual, dopamine and serotonin inputs to the SC. Importantly, blocking potentiation of the visual response was sufficient to suppress the dopamine responses following a CS. These results reveal a mechanism for how the brain forms associations between unconditioned stimuli and behaviorally meaningful visual information during classical conditioning.
    8:49a
    Attention in Irritable Bowel Syndrome: A Systematic Review of Affected Domains and Brain-Gut Axis Interactions
    Background: Irritable Bowel Syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits, significantly impacting patients' quality of life. Recent research suggests that attention may be affected in individuals with IBS, potentially influencing symptom perception and emotional distress. Objective: This systematic review aims to investigate the relationship between attention and IBS, focusing on the affected domains of attention and the interactions within the brain-gut axis. Methods: A comprehensive literature search was conducted across multiple databases, including MEDLINE/PubMed, PsychINFO, and Scopus, from January 1990 to December 2024. Studies were included if they assessed attention in adult IBS patients and employed valid measurement tools. A total of 24 studies were selected for analysis, encompassing various methodologies, including neuroimaging and behavioral assessments. Results: The findings indicate that IBS patients exhibit significant attentional biases, particularly towards gastrointestinal-related stimuli, reflecting heightened sensitivity and hypervigilance. Specific domains of attention, including selective attention, sustained attention, and pre-attentional processing, were identified as being affected. The review highlights the role of psychological factors, such as anxiety and depression, in modulating attention in IBS. Neuroimaging studies revealed altered brain activation patterns in regions associated with attention and emotional processing, suggesting a complex interplay between cognitive function and the brain-gut axis. Conclusion: This systematic review underscores the multifaceted nature of attention in IBS, revealing specific attentional deficits and biases that may contribute to symptom exacerbation and emotional distress. The findings emphasize the need for further research to explore the underlying mechanisms and potential therapeutic interventions aimed at addressing attention in IBS patients.
    9:25a
    Does white matter structure relate to hemispheric language lateralisation? A systematic review
    The relationship between functional language lateralisation and diffusion MRI-based white matter metrics remains a subject of considerable interest and complexity. This systematic review aims to synthesise existing diffusion MRI studies examining white matter correlates of functional language dominance. Twenty-five studies were identified through searches of Web of Science, Scopus, and Ovid MEDLINE (search period: inception to 16th March 2023) involving adults with epilepsy, tumours, or healthy controls. The results suggest that while the arcuate fasciculus, particularly its fractional anisotropy (FA), is commonly associated with language lateralisation in clinical populations, the findings in healthy individuals are more variable, often influenced by factors such as handedness. Other white matter tracts, including the corpus callosum and uncinate fasciculus, showed less consistent associations with language dominance across studies. Interestingly, temporal lobe regions, especially those involved in semantic processing, exhibited stronger correlations with diffusion measures compared to areas associated with phonological tasks. Methodological inconsistencies, such as variability in sample selection, task design, and analytical techniques, were identified as significant challenges in comparing findings across studies. Future research should aim for larger, more diverse sample sizes, whole-brain approaches, and a wider range of fMRI tasks to better elucidate the role of white matter in language lateralisation. If regions of interest (ROI)-based studies are utilised, a more standardised approach to tract segmentation should be adopted to ensure consistency and improve comparability across studies.
    1:30p
    Mirror effect of genomic deletions and duplications on cognitive ability across the human cerebral cortex
    Regulation of gene expression shapes the interaction between brain networks which in turn supports psychological processes such as cognitive ability. How changes in the level of gene expression across the cerebral cortex influence cognitive ability remains unknown. Here, we tackle this by leveraging genomic deletions and duplications - copy number variants (CNVs) that fully encompass one or more genes expressed in the human cortex - which lead to large effects on gene expression levels. We assigned genes to 180 regions of the human cerebral cortex based on their preferential expression across the cortex computed using data from the Allen Human Brain Atlas. We aggregated CNVs in cortical regions, and ran a burden association analysis to compute the mean effect size of genes on general cognitive ability for each of the 180 regions. When affected by CNVs, most of the regional gene-sets were associated with lower cognitive ability. The spatial patterns of effect sizes across the cortex were correlated negatively between deletions and duplications. The largest effect sizes for deletions and duplications were observed for gene-sets with high expression in sensorimotor and association regions, respectively. These two opposing patterns of effect sizes were not influenced by intolerance to loss of function, demonstrating orthogonality to dosage-sensitivity scores. The same mirror patterns were also observed after stratifying genes based on cell types and developmental epoch markers. These results suggest that the effect size of gene dosage on cognitive ability follows a cortical gradient. The same brain region and corresponding gene set may show different effects on cognition depending on whether variants increase or decrease transcription. The latter has major implications for the association of brain networks with phenotypes.
    1:30p
    Navigating uncertainty: reward location variability induces reorganization of hippocampal spatial representations
    Navigating uncertainty is crucial for survival, with the location and availability of reward varying in different and unsignalled ways. Hippocampal place cell populations over-represent salient locations in an animal's environment, including those associated with rewards; however, how the spatial uncertainties impact the cognitive map is unclear. We report a virtual spatial navigation task designed to test the impact of different levels and types of uncertainty about reward on place cell populations. When the reward location changed on a trial-by-trial basis, inducing expected uncertainty, a greater proportion of place cells followed along, and the reward and the track end became anchors of a warped spatial metric. When the reward location then unexpectedly moved, the fraction of reward place cells that followed was greater when starting from a state of expected, compared to low, uncertainty. Overall, we show that different forms of potentially interacting uncertainty generate remapping in parallel, task-relevant, reference frames.
    3:30p
    Diurnal Modulation of Locus Coeruleus Noradrenergic Neurons in Anesthetized Adult Male Rats
    The locus coeruleus (LC) is the primary source of noradrenaline (NA) in brain and its activity is essential for learning, memory, stress, arousal, and mood. LC-NA neuron activity varies over the sleep-wake cycle, with higher activity during wakefulness, correlating with increased CSF NA levels. Whether spontaneous and burst firing of LC-NA neurons during active and inactive periods is controlled by mechanisms independent of wakefulness and natural sleep, is currently unknown. Here, using multichannel in vivo electrophysiology under anesthesia, we assessed LC-NA neuron firing in adult male Fisher 344 rats at two different times of day- ZT4- the inactive period (light phase) and ZT16-the active period (dark phase)- independent of contributions from behavioral arousal and natural sleep. In the dark phase, LC-NA neurons exhibit increased average firing rate during baseline compared to the light phase. Using a relatively weak foot shock paradigm, we observed distinct populations of LC-NA neurons with some increasing, and others decreasing, their firing rate compared to baseline. Additionally, while spike frequency during spontaneous and evoked bursts is consistent across the dark-light phase, units recorded during the dark phase have more frequent bursts with a longer duration than those during the light phase. Our findings show that independent of wake state, LC-NA neurons exhibit intrinsic diurnal activity, and that the variability of response to foot shock stimulation demonstrates a physiological heterogeneity of LC-NA neurons that is just beginning to be appreciated.
    3:30p
    Endocannabinoids facilitate transitory reward engagement through retrograde gain control
    Neuromodulatory signaling is poised to serve as a neural mechanism for gain control, acting as a crucial tuning factor to influence neuronal activity by dynamically shaping excitatory and inhibitory fast neurotransmission. The endocannabinoid (eCB) signaling system, the most widely expressed neuromodulatory system in the mammalian brain, is known to filter excitatory and inhibitory inputs through retrograde, pre-synaptic action. However, whether eCBs exert retrograde gain control to ultimately facilitate reward-seeking behaviors in freely moving mammals is not established. Using a suite of in vivo physiological, imaging, genetic, and machine learning-based approaches, we report a fundamental role for eCBs in controlling behavioral engagement in reward-seeking behavior through a defined thalamo-striatal circuit.
    3:30p
    Transcriptional responses to prolonged oxidative stress require cholinergic activation of G-protein-coupled receptor signaling
    Organisms have evolved protective strategies that are geared toward limiting cellular damage and enhancing organismal survival in the face of environmental stresses, but how these protective mechanisms are coordinated remains unclear. Here, we define a requirement for neural activity in mobilizing the antioxidant defenses of the nematode Caenorhabditis elegans both during prolonged oxidative stress and prior to its onset. We show that acetylcholine-deficient mutants are particularly vulnerable to prolonged oxidative stress. We find that prolonged oxidative stress mobilizes a broad transcriptional response which is strongly dependent on both cholinergic signaling and activation of the muscarinic G-protein acetylcholine coupled receptor (mAChR) GAR-3. Gene enrichment analysis revealed a lack of upregulation of proteasomal proteolysis machinery in both cholinergic-deficient and gar-3 mAChR mutants, suggesting that muscarinic activation is critical for stress-responsive upregulation of protein degradation pathways. Further, we find that GAR-3 overexpression in cholinergic motor neurons prolongs survival during prolonged oxidative stress. Our studies demonstrate neuronal modulation of antioxidant defenses through cholinergic activation of G protein-coupled receptor signaling pathways, defining new potential links between cholinergic signaling, oxidative damage, and neurodegenerative disease.
    3:30p
    Conditional Denoising Diffusion Probabilistic Models with Attention for Subject-Specific Brain Network Synthesis
    The development of diffusion models, such as Glide, DALLE 2, Imagen, and Stable Diffusion, marks a significant advancement in generative AI for image synthesis. In this paper, we introduce a novel framework for synthesizing intrinsic connectivity networks (ICNs) by utilizing the nonlinear capabilities of denoising diffusion probabilistic models (DDPMs). This approach builds upon and extends traditional linear methods, such as independent component analysis (ICA), which are commonly used in neuroimaging studies. A central contribution of our work is the integration of attention mechanisms into conditional DDPMs, enabling the generation of subject-specific 3D ICNs. Conditioning the resting-state fMRI (rs-fMRI) data on the corresponding ICNs enables the extraction of individualized brain connectivity patterns, effectively capturing within-subject and between-subject variability. Unlike prior models limited to 2D visualization, this framework generates 3D representations, providing a more comprehensive depiction of ICNs. The model's performance is validated on an external dataset to prevent overfitting and for overall generalizability. Furthermore, comparative evaluations also demonstrate that the proposed DDPM-based approach outperforms state-of-the-art generative models in producing more detailed and accurate ICNs, as validated through qualitative assessments.
    3:30p
    WormID-Benchmark: Extracting Whole-Brain Neural Dynamics of C. elegans At the Neuron Resolution
    The nematode C. elegans is a well-studied model organism for characterizing the structure, connectivity, and function of a complete nervous system. Recent technical breakthroughs in 3D light microscopy and fluorescent protein tagging of individual neurons have brought us closer to capturing the neural dynamics of the worm at whole-brain resolution. Nevertheless, capturing a complete map of neural dynamics using these high-resolution recordings requires solving three specific challenges: i) detection of individual neurons in fluorescence videos, ii) identification of these neurons according to their anatomically defined classes, and iii) tracking of neural positions over time. Successfully addressing these challenges with high sensitivity, specificity, and throughput can enable us to analyze a large population sample, providing unprecedented insights into the structure and function of an entire brain at single-neuron resolution, a feat previously unaccomplished in any organism. To facilitate this scientific goal, we have curated publicly available annotated datasets from 118 worms across five distinct laboratories and established systematic benchmarks, decomposing the overarching objective into three well-defined tasks: i) neural detection, ii) identification, and iii) spatiotemporal tracking. Our preliminary analysis has revealed considerable room for improvement in existing state-of-the-art computational methods. Consequently, we envision that our WormID-Benchmark can catalyze efforts by a broad audience specializing in computer vision to develop robust and accurate methods that significantly enhance the throughput of generating annotated whole-brain neural dynamics datasets. We make our benchmark results reproducible; our code is publicly available at https://github.com/focolab/WormND.
    3:30p
    Dorsal hippocampus mediates light-tone sensory preconditioning task in mice
    Daily choices are often influenced by environmental cues that are not directly linked to reinforcers. This process is known as higher-order conditioning and can be measured using sensory preconditioning tasks in rodents. This behavioral paradigm requires the repeated and simultaneous presentation of two low-salience stimuli, such as a light and a tone, followed by a devaluation phase where one stimulus is paired with an unconditioned stimulus, such as a mild footshock. The outcome is a conditioned response (i.e. freezing response) to both the conditioned stimulus (direct learning) and the non-conditioned stimulus (mediated learning). In our study, we set up a successful light-tone sensory preconditioning task in male and female mice. Sex differences were seen on the number of conditioning sessions required to acquire mediated learning and in the behavioral responses observed in certain control experimental groups. We used in vivo calcium imaging to characterize the activity of hippocampal neurons in the dorsal and ventral subregions of the hippocampus when associations between low-salience stimuli and reinforcers occur. Finally, we combined our sensory preconditioning task with chemogenetic approaches to assess the role of these two hippocampal subregions in mediated learning. Our results indicate that dorsal, but not ventral, CaMKII-positive cells mediate the encoding of low-salience stimuli during the preconditioning phase. Overall, we implemented a novel light-tone sensory preconditioning protocol in mice that allowed us to detect sex differences and to further elucidate the role of particular hippocampal subregions and cell types in regulating these complex cognitive processes.
    3:30p
    NMDA-dependent coplasticity in VIP interneuron-driven inhibitory circuits
    Inhibitory plasticity is emerging as a key regulator of excitation/inhibition (E/I) balance, a fundamental determinant of brain network dynamics. While significant progress has been made in understanding inhibitory plasticity at synapses targeting excitatory principal neurons (I - E), the mechanisms and functional implications of plasticity at interneuron-interneuron (I - I) synapses remain largely unexplored. Herein, we investigated the properties and plasticity of inhibitory inputs from vasoactive intestinal peptide (VIP) interneurons onto stratum oriens interneurons (soINs) in the hippocampal CA1 region. Using optogenetics, patch-clamp electrophysiology, and morphological reconstructions, we characterized the kinetics, short-term plasticity, and NMDA receptor-dependent long-term plasticity at VIP[->]soIN synapses in two distinct soIN subtypes: fast-spiking (FS) and oriens-lacunosum moleculare (OLM)/bistratified interneurons. Optogenetically evoked VIP - soIN IPSCs showed faster rise times and slower decay kinetics in FS interneurons compared to OLM/bistratified cells, although both subtypes exhibited similar short-term plasticity profiles. Brief NMDA receptor activation (1 min) induced long-term depression (iLTD) at VIP - OLM/bistratified synapses, but not at VIP - FS synapses, underscoring subtype-specific plasticity. However, prolonged NMDA exposure (2 min) elicited iLTD in both interneuron subtypes. Interestingly, excitatory inputs to soINs demonstrated NMDA-induced long-term potentiation (E - I LTP) after brief NMDA exposure, but not after prolonged application. Notably, coplasticity analysis in individual soINs revealed asymmetric co-expression of I - I LTD and E - I LTP in OLM/bistratified interneurons. In contrast, FS interneurons exhibited a duration-dependent transition between asymmetric and symmetric coplasticity. These findings reveal a target-cell-specific landscape of inhibitory I - I plasticity and its co-expression with excitatory plasticity, highlighting VIP interneurons as key modulators of E/I balance within local hippocampal circuits.
    3:30p
    Noncanonical Short-Latency Auditory Pathway Directly Activates Deep Cortical Layers
    Auditory processing in the cerebral cortex is considered to begin with thalamocortical inputs to layer 4 (L4) of the primary auditory cortex (A1). In this canonical model, A1 L4 inputs initiate a hierarchical cascade, with higher-order cortices receiving pre-processed information for the slower integration of complex sounds. Here, we identify alternative ascending pathways in mice that bypass A1 and directly reach multiple layers of the secondary auditory cortex (A2), indicating parallel activation of these areas alongside sequential information processing. We found that L6 of both A1 and A2 receive short-latency (<10 ms) sound inputs, comparable in speed to the canonical A1 L4 input but transmitted through higher-order thalamic nuclei. Additionally, A2 L4 is innervated by a caudal subdivision within the traditionally defined primary thalamus, which we now identify as belonging to the non-primary system. Notably, both thalamic regions receive projections from distinct subdivisions of the higher-order inferior colliculus, which in turn are directly innervated by cochlear nucleus neurons. These findings reveal alternative ascending pathways reaching A2 at L4 and L6 via secondary subcortical structures. Thus, higher-order auditory cortex processes both slow, pre-processed information and rapid, direct sensory inputs, enabling parallel and distributed processing of fast sensory information across cortical areas.
    3:30p
    Mapping Early Brain Maturation: Anatomical Substrates of Cortical Connectivity Shifts in Neonates
    Understanding the early development of brain connectivities is essential for unraveling the mechanisms of brain maturation. In this study, we utilized diffusion MRI data from 242 term neonates to chart the developmental trajectory of cortical connectivities in infants. We quantified interareal connectivity variations and identified three distinct global connectopies (GCs) along the rostrocaudal, dorsoventral, and mediolateral axes through gradient mapping techniques. A pivotal age-dependent shift between the dorsoventral and mediolateral GCs occurred at 40 postmenstrual weeks, which was diminished by virtual thalamic fiber lesions, underscoring the critical role of thalamic projections. Longitudinal analysis disclosed delayed structural connectivity pattern development in preterm infants who failed to exhibit the anticipated shift. This research clarifies the topographic principles that shape infant brain organization and emphasizes the influence of thalamic connectivity on early brain development. Our findings elucidate the anatomical underpinnings of early brain development, providing critical insights into the formation of cortical hierarchies and highlighting the influence of thalamic connectivity on developmental trajectories, essential for understanding typical brain growth and the pathogenesis of neurodevelopmental disorders.
    3:30p
    Early amyloid spine response and impaired synaptic transmission of pyramidal neurons in human biopsies with Alzheimer's Disease-related pathology
    Studies of neuronal functions during the pathological progression of Alzheimers disease (AD) in humans are limited due to the lack of live human brain tissue from patients with AD. To address this gap, we have established an exceptional approach to study the electrophysiological properties and cell morphologies of human neurons in acute slices obtained from cortical biopsies of patients with idiopathic normal pressure hydrocephalus (iNPH). Histological examination of Broadman area 8-9 cortical biopsies from these patients have revealed that approximately 40% of the patients show signs of early AD-related pathology in the form of low to moderate, often fleecy beta-amyloid (A{beta}) deposits and additional, occasional tau in 10% of the cases. Thus, the iNPH brain biopsies, obtained during the shunt surgery to treat the patients, offer a unique window to investigate how existing AD-related pathology alters the operational properties of human cortical neurons. Here we carried out integrative analysis of human neuronal electrophysiology at single neuron and network level followed by subsequent cellular morphological reconstructions to register the primary pathological changes in neuronal functions in correlation with existing AD-related pathology. The presence of A{beta} plaques induced a decrease in basal excitatory synaptic activity in pyramidal neurons residing on supragranular layers of the cortex. These neurons received less of L1-induced inhibition and appeared hyperexcitable in response to application to NMDA in multielectrode array (MEA) recordings. Interestingly, the global spine density of supraganular pyramidal neurons was increased in biopsies with AD-related pathology. The increase in spine density was coincidental with a partial recovery of excitatory transmission (frequency but not amplitude), of L1-induced inhibition in supragranular layers pyramidal neurons and of NMDA induced supragranular firing (but not of bursting hyperexcitability) indicating a potential differential effect of tau in the presence of A{beta} on the progression of neuronal functions. Despite the partial renormalization of deficits seen in cases with A{beta} pathology only, pyramidal neurons in cases with both A{beta} and tau exhibited more consistent deficits in the intrinsic neuronal properties with increase in sodium and potassium currents and a strong propensity to bursting under NMDA stimulation. We conclude that complex mechanisms operate in response to accumulation of A{beta} and tau including re-structuring of the apparatus of synaptic transmission and consolidation of a hyperexcitable supragranular cortical network phenotype. The observed changes in spine density and synaptic activity are reminiscent of parallels seen in homeostatic plasticity and synaptic scaling and may depend on strong interactions with the local microenvironment (astrocytes and microglia). This is the first study to report the impact of AD-related pathology on single-neuron operational properties and morphology in humans.
    4:46p
    Intrastriatal delivery of a zinc finger protein targeting the mutant HTT gene obviates lipid phenotypes in zQ175DN HD mice
    Abstract: Reducing the burden of mutant Huntingtin (mHTT) protein in brain cells is a strategy for treating Huntington's disease (HD). However, it is still unclear what pathological changes can be reproducibly reversed by mHTT lowering. We previously found that lipid changes that occur with HD progression could be prevented by attenuating HTT transcription of the mutant allele in a genetic mouse model (LacQ140) with inducible whole body lowering. Here, we tested whether intrastriatal injection of a therapeutic capable of repressing the mutant HTT allele with expanded CAG can provide similar protection against lipid changes in HD mice with a deletion of neo cassette (zQ175DN). Methods: Wild-type or zQ175DN mice were injected with AAV9 bearing a cDNA for a zinc finger protein (ZFP) which preferentially targets mutant HTT (ZFP-HTT) to repress transcription (Zeitler et al., 2019). Proteins were analyzed using western blot, capillary electrophoresis, and nitrocellulose filtration methods. Lipid analyses were conducted by liquid chromatography and mass spectrometry (LC-MS). Somatic expansion index was assessed using capillary gel electrophoresis of PCR products. Conclusions: Lowering mHTT levels by 43% for 4 months prevented numerous changes in lipids of caudate-putamen in zQ175DN mice. Our data support the idea that mHTT lowering can provide meaningful benefits and support brain health. Furthermore, our data demonstrate that analyzing lipid signatures is a valuable method for evaluating potential therapies in a preclinical model of HD. Key words: AAV9, striatum, Huntington's disease, transcription, metabolomics, gene therapy
    4:46p
    Attentional cueing effects are reversed during locomotion
    Everyday human cognition and behaviour evolved in dynamic and ever-changing environments, but static paradigms still dominate experimental research despite concerns about generalisability of the results. In the case of attention, traditional stationary studies show that pre-orienting attention with spatial cues leads to faster, more accurate responses. However, how movement and environmental features shape such attentional processes in everyday behaviour remains unknown. Here we show that active movement through curved corridors reverses the typical spatial attention effect, with faster response times and higher accuracy for stimuli incongruent to implicit spatial cues provided by the movement direction, contradicting previous findings from static settings. We found that early (N1) and late (P3) attention-related electrophysiological responses were modulated by environmental features and motor demands. The posterior N1-component, reflecting visuo-spatial attention, showed decreasing amplitudes as turning angles and motor-control demands increased for congruent stimuli appearing on the side of the turning direction. Similarly, the P3-complex varied with motor and visual processing demands for congruent stimuli, showing decreased amplitudes as motor-control demands increased. We propose that congruent stimuli, displayed against a dynamically changing visual context, increase pulvino-cortical processing load and slowing early visual processing that affect behavioural responses. Incongruent stimuli, however, are displayed against a predictable context allowing faster target processing. These findings challenge attentional mechanisms' assumed consistency across static and dynamic settings, revealing instead their dependence on behavioural and environmental context. We advocate for naturalistic paradigms, arguing that moving beyond static experiments could reshape core views on cognition and behaviour.
    4:46p
    Dynamic Transcriptomic Remodeling in Human Neural Progenitor Cells Reveals Mechanisms for Vision Preservation in Retinitis Pigmentosa Model
    Human neural progenitor cells (hNPCs) have shown promise in slowing down retinal degeneration in animal models and are currently being tested in clinical trials for treating retinitis pigmentosa (RP). However, the status of grafted hNPCs and their interaction with host retinal cells over time is largely unknown. Here, we investigated single-cell transcriptomic changes in grafted hNPCs and host retinal cells following injection into a rodent model for RP. Grafted hNPCs and host retinal cells undergo dynamic transcriptomic changes in the degenerative retinal environment. Grafted hNPCs protect vision through multiple mechanisms, including trophic factor support, modulation of metabolic activity, reduction of apoptosis, oxidative stress, and inflammation, alongside extracellular matrix remodeling. CellChat analysis revealed a progressive decline in intercellular signaling and communication strength between hNPCs and host retinal cells over time. This study indicates that enhancing trophic factor supports and improving host retinal environment are key targets to enable long-term vision preservation.
    10:33p
    Identification of low copy synaptic glycine receptors in the mouse brain using single molecule localisation microscopy
    Glycine receptors (GlyRs) are heteropentameric chloride channels that mediate fast inhibitory neurotransmission in the brainstem and spinal cord, where they regulate motor and sensory processes. GlyRs are clustered at the post-synaptic membrane by a strong interaction of the beta subunit with the scaffold protein gephyrin. Even though GlyRbeta mRNA is highly expressed throughout the brain, the existence of synaptic GlyRs remains controversial as there is little conclusive evidence using conventional fluorescence microscopy and electrophysiological recordings. Here we exploit the high sensitivity and spatial resolution of single molecule localisation microscopy (SMLM) to investigate the presence of GlyRs at inhibitory synapses in the brain, focusing on several areas in the telencephalon, including hippocampus and striatum. Making use of a knock-in mouse model expressing endogenous mEos4b-tagged GlyRbeta we identified low-copy GlyR complexes at inhibitory synapses in different hippocampal regions. Dual-colour SMLM further revealed that the sparse GlyRs are integrated within the post-synaptic gephyrin domain, pointing to a possible role in maintaining the structural integrity of inhibitory synapses. In contrast, we found functionally relevant numbers of synaptic GlyRs at inhibitory synapses in the ventral striatum. Our results further highlight the strength of SMLM to detect few and sparsely distributed synaptic molecules in complex samples and to analyse their organisation with high spatial precision.
    10:33p
    Stress, Epigenetic Remodeling and FKBP51: Pathways to Chronic Pain Vulnerability
    Stress is thought to contribute to the persistence of pain and comorbid anxiety, yet the underlying mechanisms remain unclear. In our pre-clinical model, sub-chronic stress exacerbated subsequently induced inflammatory pain and accelerated the development of comorbid anxiety. DNA methylation analysis of spinal cord tissue after stress exposure revealed hypomethylation in the Fkbp5 promoter site for the canonical FKBP51 transcript and other stress-related genes. However, most epigenetic changes in key regulatory regions did not correlate with changes in gene expression assessed by RNA sequencing, suggesting that stress exposure had remodeled the epigenome without altering gene activity and primed genes for hyper-responsiveness to future challenges. FKBP51 inhibition during stress exposure reduced the exacerbation of inflammatory pain by stress and reversed several stress-induced DNA methylation changes in promoter regions of genes associated with stress and nociception, including Rtn4, Cdk5 and Nrxn1, but not Fkbp5. These results indicate that sub-chronic stress leads to the hypomethylation of Fkbp5 and increased susceptibility to chronic pain driven by FKBP51, but reversing Fkbp5 hypomethylation is not necessary to prevent chronic pain vulnerability, which is likely driven by complex epigenetic regulation of multiple stress-regulated genes.
    10:33p
    Using magnetoencephalography to track the propagation of 40 Hz invisible spectral flicker
    Brain stimulation with novel 40 Hz invisible spectral flicker (ISF) has been proposed as a therapy for Alzheimer's disease, with leading hypotheses suggesting local promotion of glymphatic clearance of amyloid as the mechanism of action. Neural signals in the gamma range and their spatial propagation over the brain can be tracked using magnetoencephalography (MEG) with high temporal and good spatial detail. However, stimulation with 40 Hz ISF requires specialised hardware which causes electromagnetic interference (EMI) with MEG equipment. MEG measures the tiny magnetic fields of the brain, which are easily distorted by external magnetic fields. Using MEG to track the propagation of 40 Hz ISF requires multiple modifications to the experimental setup. These include, at least 1) an experimental design that promotes modulation of the neural signal, but not the artifact, 2) removal of all electronics not strictly necessary for light production from the stimulators, and 3) signal processing for 40 Hz EMI artifact suppression. Here, we present an MEG study on the cortical propagation of 40 Hz ISF. In two experiments, we investigate the modulation that visual and non-visual cognitive tasks have on the power and propagation of cortical activity induced by 40 Hz ISF. With the chosen experimental setup and design, the 40 Hz EMI artifact could not be entirely disentangled from the neural signal of interest, thus rendering inference on the spatial propagation of the 40 Hz signal impossible. Further improvements need to be implemented in a follow-up experimental design. We present potential solutions to allow for future investigation of 40 Hz ISF with MEG.
    10:33p
    Loss of Elp3 impairs the maturation tempo of brain ependymal cells
    Conditional deletion of Elp3 in the mouse forebrain leads to microcephaly at birth. In this study, we demonstrate that these mice also develop postnatal hydrocephalus, associated with an enlargement of the brain ventricles. In wild-type mice, ependymal motile cilia are properly aligned to facilitate the circulation of cerebrospinal fluid (CSF) within the ventricles. Our findings reveal that Elp3 loss induces endoplasmic reticulum (ER) stress and upregulation of ATF4 expression in ependymal cell progenitors, which compromises Notch signaling and accelerates their maturation. This is accompanied by a disruption in the establishment of rotational and translational polarities of the motile cilia of maturing ependymal cells, resulting in disorganized cilia bundles. Collectively, these molecular abnormalities lead to the premature and abnormal development of ependymal cells, culminating in cilia beating dysfunction, impaired CSF clearance, and the development of hydrocephalus.
    10:33p
    Neural encoding of biomechanically (im)possible human movements in occipitotemporal cortex
    Understanding how the human brain processes body movements is essential for clarifying the mechanisms underlying social cognition and interaction. This study investigates the encoding of biomechanically possible and impossible body movements in occipitotemporal cortex using ultra-high field 7Tesla fMRI. By predicting the response of single voxels to impossible/possible movements using a computational modelling approach, our findings demonstrate that a combination of postural, biomechanical, and categorical features significantly predicts neural responses in the ventral visual cortex, particularly within the extrastriate body area (EBA), underscoring the brain's sensitivity to biomechanical plausibility. Lastly, these findings highlight the functional heterogeneity of EBA, with specific regions (middle/superior occipital gyri) focusing on detailed biomechanical features and anterior regions (lateral occipital sulcus and inferior temporal gyrus) integrating more abstract, categorical information.
    10:33p
    Intuitive sensorimotor decisions under risk take Newtonian physics into account
    The success of our interactions with objects in natural tasks depends on generating motor actions, which are subject to sensorimotor variability, the objects' physical properties, which are governed by the laws of kinematics, and the costs and benefits associated with the actions' outcomes. Therefore, such interactions jointly involve sensorimotor control, intuitive physics, and decision-making under risk. Here, we devised a mixed reality experiment, which allows investigating human behavior involving the interaction of all three of these cognitive faculties. Participants slid pucks to target areas associated with monetary rewards and losses within an immersive, naturalistic virtual environment. In this task, signal-dependent variability inherent in motor control interacts non-linearly with the physical relationships governing objects' motion under friction. By systematically testing generative models of behavior incorporating different assumptions about how participants may generate the slides, we find decisive evidence that participants' decision under risk readily took their individual motor variability and Newtonian physics into account to gain monetary rewards without relying on trial by trial learning.
    10:33p
    Human sleep spindles track experimentally excited brain circuits
    Spindles are hallmark oscillations during non-rapid-eye-movement (NREM) sleep. Together with slow oscillations (SOs), they are thought to play a mechanistic role in the consolidation of learned information. The quantity and spatial distribution of spindles has been linked to brain activity during learning before sleep and to memory performance after sleep. If spindles are drawn to cortical areas excited through pre-sleep learning tasks, this begs the question whether the spatial distribution of spindles is flexible, and whether their regional expression can also be manipulated with experimental brain stimulation. We used excitatory transcranial direct current stimulation (tDCS) to stimulate the left and right motor cortex in a repeated-measures experimental design. After stimulation, we recorded high-density electroencephalography (EEG) during sleep to test how local stimulation modulated the regional expression of sleep spindles. Indeed, we show that excitatory tDCS of local cortical sites before sleep biases the expression of spindles to the excited locations during subsequent sleep. No effects of localised tDCS excitation were seen for SOs. These results demonstrate that the spatial topography of sleep spindles is neither hard-wired nor random, with spindles being flexibly directed to exogenously excited cortical circuits.

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