bioRxiv Subject Collection: Neuroscience's Journal

Parallel Labeled-Line Organization of Sympathetic Outflow for Selective Organ Regulation in Mice
The sympathetic nervous system is vital in maintaining homeostasis and responding to environmental changes. This regulation is coordinated by the spinal sympathetic preganglionic neurons (SPNs), which influence various organs both through neuronal pathways via postganglionic neurons and through endocrine processes by innervating the adrenal gland. Despite decades of research supporting the concept of selective control within this system, the neural circuit organization responsible for the specificity of sympathetic outflow remains poorly understood. Notably, classical anatomical studies in rats have not revealed a definitive molecular code governing SPNs, nor have they confirmed the existence of SPNs strictly corresponding to specific output targets. To reconcile this discrepancy, we aim to integrate recent transcriptome data of SPNs in mice with viral-genetic toolkits to map axonal projections and manipulate the functions of SPNs governing the gastrointestinal tract and adrenal gland. Here, we have identified two subtypes of SPNs in the lower thoracic spinal cord, defined at the molecular level, exhibiting non-overlapping patterns of innervation. Chemogenetic manipulations on these distinct SPN subtypes revealed selective impacts on the digestive functions in the gastrointestinal tracts or glucose metabolism mediated by the adrenal gland, respectively. This molecularly delineated parallel labeled-line organization in sympathetic outflows presents a potential avenue for selectively manipulating organ functions.

Enhanced behavioural and neural sensitivity to punishments in chronic pain and fatigue
Chronic pain and fatigue in musculoskeletal disease contribute significantly to disability, and recent studies suggest an association with reduced motivation and excessive fear avoidance. In this behavioural neuroimaging study in chronic inflammatory arthritis participants and healthy controls, we aimed to identify the specific behavioral and neural changes associated pain and fatigue during reward and loss decision-making. Computational modeling of behaviour identified a parametric signature, characterized most notably by increased punishment sensitivity. This signature is distinct from patterns previously reported in psychiatric conditions and it aligns with predictions of mechanistic models of chronic pain such as the fear avoidance model. Neural activity associated with the punishment prediction error was enhanced in the right posterior insular cortex, putamen, pallidum, and dorsolateral prefrontal cortex. Functional network connectivity analysis showed that insula centrality correlated with subjective reports of fatigue and pain. Overall, the findings show that pain and fatigue in chronic pain relate to objective behavioural changes, and can be mapped to a specific pattern of activity in brain circuits of motivation and decision-making.

Dynamics of Saccade Trajectory Modulation by Distractors: Neural Activity Patterns in the Frontal Eye Field
The sudden appearance of a visual distractor shortly before saccade initiation can capture spatial attention and modulate the saccade trajectory in spite of the ongoing execution of the initial plan to shift gaze straight to the saccade target. To elucidate the neural correlates underlying these curved saccades, we recorded from single neurons in the frontal eye field (FEF) of two rhesus monkeys shifting gaze to a target while an isoeccentric distractor appeared either left or right of the target at various delays after target presentation. We found that the population level of pre-saccadic activity encoded the direction of the saccade trajectory. Stronger activity occurred when saccades curved toward the distractor, and weaker when saccades curved away. This relationship held whether the distractor was ipsilateral or contralateral to the recorded neurons. Meanwhile, visually responsive neurons showed asymmetrical patterns of excitatory responses that varied with the location of the distractor and the duration of distractor processing relating to attentional capture and distractor inhibition. During earlier distractor processing, neurons encoded curvature towards the distractor. During later distractor processing, neurons encoded curvature away from the distractor. This was observed when saccades curved away from distractors contralateral to the recording site and when saccades curved towards distractors ipsilateral to the recording site. These findings indicate that saccadic motor planning involves dynamic push-pull hemispheric interactions producing attraction or repulsion for potential but unselected saccade targets.

Changes in Electroencephalography signals in a juvenile female Fragile X Syndrome mouse model
BackgroundFragile X syndrome (FXS) is the leading monogenic cause of Autism. Seizures, hyperactivity, and anxiety are common symptoms of FXS. No broadly effective support option currently exists for FXS, and drug development has suffered many failures in clinical trials based on promising preclinical findings. Thus, effective translational biomarkers of treatment outcomes are needed. Recently electroencephalography (EEG) has been proposed as a translational biomarker in FXS. Being X-linked, FXS is more prevalent in males than females, and there exist significant phenotype differences between males and females with FXS. Recent studies involving male FXS participants and rodent models have identified an increase in absolute gamma EEG power, while alpha power is found to be either decreased or unchanged. However, there is not enough research on female FXS patients or models. In addition, studying EEG activity in young FXS patients or rodent models is crucial for better understanding of the disorders effects on brain development.

Therefore, we aim to compare EEG signal between wild-type (WT) and fmr1 knockout (KO) female mice at the juvenile stage.

MethodsFrontal-parietal differential EEG was recorded using a stand-alone Open-Source Electrophysiology Recording system for Rodents (OSERR). EEG activity was recorded in three different conditions: a) in the subjects home cage and in the arenas for b) light and dark test and C) open field test. Absolute and relative EEG power as well as phase-amplitude coupling were computed for each condition.

ResultsIn our study, we found absolute alpha, beta, and gamma EEG power is increased in female fmr1 KO mice compared to WT controls at the juvenile age. Alongside, relative theta power is decreased in the fmr1 KO females. Furthermore, phase-amplitude coupling is increased in the fmr1 KO females.

Discussion and ConclusionComparing to the reported changes in EEG signal in male FXS patients and models, our results indicated the presence of sex-based differences in EEG phenotypes at the juvenile stage. Collectively, these findings suggest that sex is an importance factor to consider in utilizing EEG as a translational biomarker in FXS.

Corticospinal and corticoreticulospinal projections benefit motor behaviors in chronic stroke
After corticospinal tract (CST) stroke, several motor deficits in the upper extremity (UE) emerge, including diminished muscle strength, motor control, and muscle individuation. Both the ipsilesional CST and contralesional corticoreticulospinal tract (CReST) innervate the paretic UE and may have different innervation patterns for the proximal and distal UE segments. These patterns may underpin distinct pathway relationships to separable motor behaviors. In this cross-sectional study of 15 chronic stroke patients and 28 healthy subjects, we examined two key questions: (1) whether segmental motor behaviors differentially relate to ipsilesional CST and contralesional CReST projection strengths, and (2) whether motor behaviors segmentally differ in the paretic UE. We measured strength, motor control, and muscle individuation in a proximal (biceps, BIC) and distal muscle (first dorsal interosseous, FDI) of the paretic UE. We measured the projection strengths of the ipsilesional CST and contralesional CReST to these muscles using transcranial magnetic stimulation (TMS). Stroke subjects had abnormal motor control and muscle individuation despite strength comparable to healthy subjects. In stroke subjects, stronger ipsilesional CST projections were linked to superior motor control in both UE segments, whereas stronger contralesional CReST projections were linked to superior muscle strength and individuation in both UE segments. Notably, both pathways also shared associations with behaviors in the proximal segment. Motor control deficits were segmentally comparable, but muscle individuation was worse for distal motor performance. These results suggest that each pathway has specialized contributions to chronic motor behaviors but also work together, with varying levels of success in supporting chronic deficits.

Key points summaryO_LIIndividuals with chronic stroke typically have deficits in strength, motor control, and muscle individuation in their paretic upper extremity (UE). It remains unclear how these altered behaviors relate to descending motor pathways and whether they differ by proximal and distal UE segment.
C_LIO_LIIn this study, we used transcranial magnetic stimulation (TMS) to examine projection strengths of the ipsilesional corticospinal tract (CST) and contralesional corticoreticulospinal tract (CReST) with respect to quantitated motor behaviors in chronic stroke.
C_LIO_LIWe found that stronger ipsilesional CST projections were associated with better motor control in both UE segments, whereas stronger contralesional CReST projections were associated with better strength and individuation in both UE segments. In addition, projections of both pathways shared associations with motor behaviors in the proximal UE segment.
C_LIO_LIWe also found that deficits in strength and motor control were comparable across UE segments, but muscle individuation was worse with controlled movement in the distal UE segment.
C_LIO_LIThese results suggest that the CST and CReST have specialized contributions to chronic motor behaviors and also work together, although with different degrees of efficacy.
C_LI

Comparative specialization of intrinsic cardiac neurons in humans, mice, and pigs
Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exists. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs, and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry, and ultrastructure of these cells across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections, and had high synaptic efficacy constituting an obligatory synapse. At Pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold excitatory postsynaptic potentials like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles (SCVs) were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant VIP observed in human but not pig or mouse ganglia, and little SP or CGRP in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 93% of human cells were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs, and humans identifies similarities and differences in the evolution of ICNs.

STARDUST: a pipeline for the unbiased analysis of astrocyte regional calcium dynamics
Calcium imaging has become an increasingly popular way to probe the activity of astrocytes. However, the governing principles of astrocyte calcium dynamics are still elusive and their relationship to cellular events ill-defined. Useful assumptions and shortcuts commonly applied to neuronal recordings therefore do not hold true for astrocytes. The imaging of astrocyte calcium activity per se can be relatively straightforward, subsequent analysis methods that adequately capture the richness and complexity of calcium dynamics remain scant. Here, we introduce STARDUST, a pipeline and python-based data processing for the Spatio-Temporal Analysis of Regional Dynamics & Unbiased Sorting of Transients from astrocyte calcium recordings. STARDUST builds upon AQuA to identify patches of active signals, from which it builds a data-driven map of regions of activity (ROAs) that can be combined with cell-segmentation and/or correlated to cellular morphology. For each ROA, STARDUST extracts fluorescence time-series, and performs signal identification and features extraction. STARDUST is agnostic to cell morphology (or cells altogether) and putative calcium propagation across ROAs. Instead, it focuses on decomposing calcium dynamics in a regionalized fashion by treating ROAs as independent units, for instance allowing investigations by signal feature-based ROA rank. STARDUST also identifies ROAs as "stable" (active throughout), "ON" (turned on during drug application) and "OFF" (turned off during drug application) in pharmacology experiments, permitting studies of astrocyte calcium "micro-domains" based on their functional responses. With a systematic set of instructions and troubleshooting tips, and minimal computational/coding background required, STARDUST is a user-friendly addition to the growing toolbox for the exploration of astrocyte calcium dynamics.

Examining Cognitive Performance in Mice using the Open-Source Operant Feeding Device FED3
Cognitive impairments are prevalent in various neurological disorders, including chronic pain conditions, and pose significant therapeutic challenges. Preclinical rodent models serve as valuable tools for investigating the underlying mechanisms of and treatments for cognitive dysfunction. However, factors such as stress, age, sex, and disease duration present challenges to reliably capturing cognitive deficits in rodents. Here, we present a comprehensive and high-throughput protocol utilizing the open-source operant Feeding Experimentation Device 3 (FED3) for assessing cognitive performance in mice. We developed a data pipeline to streamline data compilation and analysis, and established operating conditions for a six-test cognitive battery which can be completed in as few as 20 days. We validated our testing procedures using bilateral orbitofrontal cortical lesions to capture deficits in executive function, and demonstrated the feasibility of assessing cognitive function in aged mice of both sexes to identify genotypic and sex-specific effects. Overall, our findings demonstrate that the FED3 is a versatile tool for evaluating cognitive function in mice, offering a low-cost, high-throughput approach for preclinical studies of neurological disorders. We anticipate that this protocol will facilitate broader implementation of cognitive testing in rodent models and contribute to the understanding and treatment of cognitive dysfunction in neurological diseases.

Intracranial neural representation of phenomenal and access consciousness in the human brain
After more than 30 years of extensive investigation, impressive progress has been made in identifying the neural correlates of consciousness (NCC). However, the functional role of spatiotemporally distinct consciousness-related neural activity in conscious perception is debated. Based on empirical EEG findings, e.g., of the enhanced early negative wave and late positive wave under conscious conditions, an influential framework proposed that consciousness-related neural activities could be dissociated into two distinct processes: phenomenal and access consciousness. This framework has been supported mainly by comparison of neural activity between report and no-report paradigms; however, though hotly debated, its authenticity has not been examined in a single paradigm with more informative intracranial recordings. In the present study, we employed a novel visual awareness task and recorded the local field potential (LFP) of epilepsy patients with electrodes implanted in cortical and subcortical regions. Overall, we found that the latency of visual awareness-related activity exhibited a bimodal distribution, and the recording sites with short and long latencies were largely separated in location, except in the lateral prefrontal cortex (lPFC). The mixture of short and long latencies in the lPFC indicates that it plays a critical role in linking phenomenal and access consciousness. However, the division between the two is not as simple as the central sulcus, as proposed previously. Moreover, in 4 patients with electrodes implanted in the bilateral prefrontal cortex, early awareness-related activity was confined to the contralateral side, while late awareness-related activity appeared on both sides. Finally, Granger causality analysis showed that awareness-related information flowed from the early sites to the late sites. These results provide the first LFP evidence of neural correlates of phenomenal and access consciousness, which sheds light on the spatiotemporal dynamics of NCC in the human brain.

Identification and characterization of a synaptic active zone assembly protein
At presynaptic active zones (AZs), scaffold proteins play a crucial role in coordinating synaptic vesicle (SV) release and forming intricate nanoarchitectures essential for synaptic function. Despite their suspected importance, factors governing the assembly of nanoscale AZ scaffolds have remained elusive. Here, we identify "Blobby" as a novel regulator of AZ nanopatterning, localized within the AZ scaffold. Genetic loss of the extended Blobby protein led to aberrant accumulation of AZ scaffold proteins ("blobs") and disrupted the nanoscale architecture of the AZ scaffold, resulting in a significant reduction in the packing density of voltage-gated Ca2+ channels at AZs, as observed through intravital single-molecule imaging. This disruption correlated with decreased evoked synaptic currents and SV release probability. Our findings suggest that Blobby plays a crucial role in switching the AZ scaffold into a state which allows to fine-tune the dynamic nanopatterning of Ca2+ channels to maintain proper release.

Microstructural asymmetry in the human cortex
While macroscale brain asymmetry and its relevance for human cognitive function have been consistently shown, the underlying neurobiological signatures remain an open question. Here, we probe layer-specific microstructural asymmetry of the human cortex using intensity profiles from post-mortem cytoarchitecture. An anterior-posterior cortical pattern of left-right asymmetry was found, varying across cortical layers. A similar anterior-posterior pattern was observed using in vivo microstructural imaging, with in vivo asymmetry showing the strongest similarity with layer III. Microstructural asymmetry varied as a function of age and sex and was found to be heritable. Moreover, asymmetry in microstructure corresponded to asymmetry of intrinsic function, in particular in sensory areas. Last, probing the behavioral relevance, we found differential association of language and markers of mental health with asymmetry, illustrating a functional divergence between inferior-superior and anterior-posterior microstructural axes anchored in microstructural development. Our study highlights the layer-based patterning of microstructural asymmetry of the human cortex and its functional relevance.

A postnatal molecular switch drives the activity-dependent maturation of parvalbumin interneurons
Cortical neurons are specified during embryonic development but often only acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the function of the cerebral cortex. We found that the maturation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1). Developmental loss of PGC-1 prevents PV+ interneurons from acquiring unique structural, electrophysiological, synaptic, and metabolic features and disrupts their diversification into distinct subtypes. PGC-1 exerts its function as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERR{gamma} and Mef2c. Our results uncover a molecular switch that translates neural activity into a specific transcriptional program promoting the maturation of PV+ interneurons at the appropriate developmental stage.

A collicular map for touch-guided tongue control
Accurate goal-directed behavior requires the sense of touch to be integrated with information about body position and ongoing motion1,2,3. Behaviors like chewing, swallowing and speech critically depend on precise tactile events on a rapidly moving tongue4,5, but neural circuits for dynamic touch-guided tongue control are unknown. Using high speed videography, we examined 3D lingual kinematics as mice drank from a water spout that unexpectedly changed position during licking, requiring re-aiming in response to subtle contact events on the left, center or right surface of the tongue. Mice integrated information about both precise touch events and tongue position to re-aim ensuing licks. Surprisingly, touch-guided re-aiming was unaffected by photoinactivation of tongue sensory, premotor and motor cortices, but was impaired by photoinactivation of the lateral superior colliculus (latSC). Electrophysiological recordings identified latSC neurons with mechanosensory receptive fields for precise touch events that were anchored in tongue-centered, head- centered or conjunctive reference frames. Notably, latSC neurons also encoded tongue position before contact, information important for tongue-to-head based coordinate transformations underlying accurate touch-guided aiming. Viral tracing revealed tongue sensory inputs to the latSC from the lingual trigeminal nucleus, and optical microstimulation revealed a topographic map for aiming licks. These findings demonstrate for the first time that touch-guided tongue control relies on a collicular mechanosensorimotor map, analogous to collicular visuomotor maps associated with visually-guided orienting across many species.

Lateral Orbitofrontal Cortex Encodes Presence of Risk and Subjective Risk Preference During Decision-Making
Adaptive decision-making requires consideration of objective risks and rewards associated with each option, as well as subjective preference for risky/safe alternatives. Inaccurate risk/reward estimations can engender excessive risk-taking, a central trait in many psychiatric disorders. The lateral orbitofrontal cortex (lOFC) has been linked to many disorders associated with excessively risky behavior and is ideally situated to mediate risky decision-making. Here, we used single-unit electrophysiology to measure neuronal activity from lOFC of freely moving rats performing in a punishment-based risky decision-making task. Subjects chose between a small, safe reward and a large reward associated with either 0% or 50% risk of concurrent punishment. lOFC activity repeatedly encoded current risk in the environment throughout the decision-making sequence, signaling risk before, during, and after a choice. In addition, lOFC encoded reward magnitude, although this information was only evident during action selection. A Random Forest classifier successfully used neural data accurately to predict the risk of punishment in any given trial, and the ability to predict choice via lOFC activity differentiated between and risk-preferring and risk-averse rats. Finally, risk preferring subjects demonstrated reduced lOFC encoding of risk and increased encoding of reward magnitude. These findings suggest lOFC may serve as a central decision-making hub in which external, environmental information converges with internal, subjective information to guide decision-making in the face of punishment risk.

Meningeal-derived retinoic acid regulates neurogenesis via suppression of Notch and Sox2
The meninges act as a regulator of brain development by secreting ligands that act on neural cells to regulate neurogenesis and neuronal migration. Meningeal-derived retinoic acid (RA) promotes neocortical neural progenitor cell cycle exit; however, the underlying molecular mechanism is unknown. Here, we used spatial transcriptomics and profiling of retinoic-acid receptor- (RAR) DNA binding in Foxc1-mutant embryos that lack meninges-derived ligands to identify the neurogenic transcriptional mechanisms of RA signaling in telencephalic neural progenitors. We determined that meningeal-derived RA controls neurogenesis by suppressing progenitor self-renewal pathways Notch signaling and the transcription factor Sox2. We show that RAR binds in the Sox2ot promoter, a long non-coding RNA that regulates Sox2 expression, and RA promotes Sox2ot expression in neocortical progenitors. Our findings elucidate a previously unknown mechanism of how meningeal RA coordinates neocortical development and insight into how defects in meningeal development may cause neurodevelopmental disorders.

Mirror-assisted light-sheet microscopy: a simple upgrade to enable bi-directional sample excitation
Significance - Light-sheet microscopy is a powerful imaging technique that achieves optical sectioning via selective illumination of individual sample planes. However, when the sample contains opaque or scattering tissue, the incident light-sheet may not be able to uniformly excite the entire sample. For example, in the context of larval zebrafish whole-brain imaging, occlusion by the eyes prevents access to a significant portion of the brain during common implementations using unidirectional illumination. Aim - We introduce mirror-assisted light-sheet microscopy (mLSM), a simple inexpensive method that can be implemented on existing digitally scanned light-sheet setups by adding a single optical element - a mirrored micro-prism. The prism is placed near the sample to generate a second excitation path for accessing previously obstructed regions. Approach - Scanning the laser beam onto the mirror generates a second, reflected illumination path that circumvents the occlusion. Online tuning of the scanning and laser power waveforms enables near uniform sample excitation with dual illumination. Results - mLSM produces cellular-resolution images of zebrafish brain regions inaccessible to unidirectional illumination. Imaging quality in regions illuminated by the direct or reflected sheet is adjustable by translating the excitation objective. The prism does not interfere with visually guided behaviour. Conclusions - mLSM presents an easy to implement, cost-effective way to upgrade an existing light-sheet system to obtain more imaging data from a biological sample.

Microglia aging in the hippocampus advances through intermediate states that drive inflammatory activation and cognitive decline
During aging, microglia - the resident macrophages of the brain - exhibit dystrophic phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia dystrophy have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFbeta1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an inflammatory state. Furthermore, we utilized single-cell RNA-Seq in conjunction with an in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse model, to demonstrate that microglia advancement through intermediate aging states drives inflammatory activation and associated hippocampal-dependent cognitive decline.

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia
Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was not related to the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau vs bvFTD-TDP (p=0.039). In a structural model for long-range laminar connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio of mesocortex-to-isocortex SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

A functional screen uncovers circular RNAs regulating excitatory synaptogenesis in hippocampal neurons
Circular RNAs (circRNAs) are an expanding class of largely unexplored RNAs which are prominently enriched in the mammalian brain. Here, we systematically interrogated their role in excitatory synaptogenesis of rat hippocampal neurons using RNA interference. Thereby, we identified seven circRNAs as negative regulators of excitatory synapse formation, many of which contain high-affinity microRNA binding sites. Knockdown of one of these candidates, circRERE, surprisingly promoted the formation of electrophysiologically silent synapses. Mechanistically, circRERE knockdown resulted in a preferential upregulation of synaptic mRNAs containing binding sites for miR-128-3p because of a reduced protective interaction between miR-128-3p and circRERE. Accordingly, overexpression of circRERE rescued exaggerated synapse formation upon circRERE knockdown in a miR-128-3p binding site-specific manner. Overall, our results uncover circRERE-mediated stabilization of miR-128-3p as a novel mechanism to restrict the formation of silent excitatory synaptic co-clusters and more generally implicate circRNA-dependent microRNA regulation in the control of synapse development and function.

Neural and behavioral similarity-driven tuning curves for manipulable objects
In our daily activities, we encounter numerous objects that we successfully distinguish and recognize within a fraction of a second. This holds for coarse distinctions (e.g., cat vs. hammer) but also for more challenging within-category distinctions that require fine-grain analysis (e.g., cat vs. dog). The efficiency of this recognition depends on how the brain organizes object-related information. While several attempts have focused on unravelling large-scale organization principles, research on within-category organization of knowledge is rather limited. Here, we explored the fine-grain organization of object knowledge and investigated whether manipulable objects are organized and represented in terms of their similarity. To accomplish this, different groups of individuals participated in a behavioral and fMRI release from adaptation experiment. Adaptation was induced by presenting different exemplars of a particular object, and release from adaptation was elicited by the presentation of a deviant object. The relationship between adaptation and deviant objects was manipulated into four levels of similarity, measured by feature overlap between these objects. Our findings revealed that increasing object similarity provoked progressively slower reaction times and progressively weaker fMRI release from adaptation. Specifically, we identified similarity-driven tuning curves for the release from adaptation in the medial fusiform, collateral sulcus, parahippocampal gyri, lingual gyri, lateral occipital complex, and occipito-parietal cortex. These results suggest that the processing and representation of objects in the brain and our ability to perform fine discriminations between objects reflect real-world object similarity in a relatively parametric manner.

The persistence of memory: prior memory responses modulate behavior and brain state engagement
Memory brain states may influence how we experience an event. Memory encoding and retrieval constitute neurally dissociable brain states that individuals can selectively engage based on top-down goals. To the extent that memory states linger in time - as suggested by prior behavioral work - memory states may influence not only the current experience, but also subsequent stimuli and judgments. Thus lingering memory states may have broad influences on cognition, yet this account has not been directly tested utilizing neural measures of memory states. Here we address this gap by testing the hypothesis that memory brain states are modulated by memory judgments, and that these brain states persist for several hundred milliseconds. We recorded scalp electroencephalography (EEG) while participants completed a recognition memory task. We used an independently validated multivariate mnemonic state classifier to assess memory state engagement. We replicate prior behavioral findings; however, our neural findings run counter to the predictions made on the basis of the behavioral data. Surprisingly, we find that prior responses modulate current memory state engagement on the basis of response congruency. That is, we find strong engagement of the retrieval state on incongruent trials - when a target is preceded by a correct rejection of a lure and when a lure is preceded by successful recognition of a target. These findings indicate that cortical brain states are influenced by prior judgments and suggest that a non-mnemonic, internal attention state may be recruited to in the face of changing demands in a dynamic environment.