bioRxiv Subject Collection: Neuroscience's Journal

Neural Heterogeneity Enhances Reliable Neural information Processing: Local Sensitivity and Globally Input-slaved Transient Dynamics
Cortical neuronal activity exhibits variability over time and across repeated stimulation trials, yet consistently represents stimulus features. However, the dynamical mechanism underlying this reliable representation and computation remains elusive. This study uncovers a mechanism that achieves reliable neural processing, leveraging a biologically plausible network model with spatial extension and neuronal timescale diversity. Our findings demonstrate that timescale diversity disrupts intrinsic coherent spatiotemporal patterns, enhancing local sensitivity and aligning neural network activity closely with inputs. This underscores the significant role of timescale diversity in shaping consistent stimulus representation, leading to local sensitivity and globally input-slaved transient dynamics, essential for reliable neural processing. This mechanism offers a potentially general framework for understanding the role of neural heterogeneity in reliable computation. Our work informs the design of new reservoir computing models endowed with liquid wave reservoirs for neuromorphic computing.

Electrical and G-protein Regulation of CaV2.2 (N-type) Channels
How G-proteins inhibit N-type, voltage-gated, calcium-selective channels (CaV2.2) during presynaptic inhibition is a decades-old question. G-proteins G{beta}{gamma} bind to intracellular CaV2.2 regions, but the inhibition is voltage-dependent. Using the hybrid electrophysiological and optical approach voltage-clamp fluorometry, we show that G{beta}{gamma} acts by selectively inhibiting a subset of the four different CaV2.2 voltage-sensor domains (VSDs I-IV). During regular "willing" gating, VSDs I and IV activation resemble pore opening, VSD III activation is hyperpolarized, and VSD II appears unresponsive to depolarization. In the presence of G{beta}{gamma}, CaV2.2 gating is "reluctant": pore opening and VSD-I activation are strongly and proportionally inhibited, VSD IV is modestly inhibited while VSD III is not. We propose that G{beta}{gamma} inhibition of VSD-I and -IV underlies reluctant CaV2.2 gating and subsequent presynaptic inhibition.

The distribution and evolutionary dynamics of dopaminergic neurons in molluscs
Dopamine is one of the most versatile neurotransmitters in invertebrates. Its distribution and plethora of functions are likely coupled to feeding ecology, especially in Euthyneura (the largest clade of mollusks), which presents the broadest spectrum of environmental adaptations. Still, the analyses of dopamine-mediated signaling were dominated by studies of grazers. Here, we characterize the distribution of dopaminergic neurons in representatives of two distinct ecological groups: the sea angel - obligate predatory pelagic mollusk Clione limacina (Pteropoda, Gymnosomata) and its prey - the sea devil Limacina helicina (Pteropoda, Thecosomata) as well as the plankton eater Melibe leonina (Nudipleura, Nudibranchia). By using tyrosine hydroxylase-immunoreactivity (TH-ir) as a reporter, we showed that the dopaminergic system is moderately conservative among euthyneurans. Across all studied species, small numbers of dopaminergic neurons in the central ganglia contrast to significant diversification of TH-ir neurons in the peripheral nervous system, primarily representing sensory-like cells, which predominantly concentrated in the chemotactic areas and projecting afferent axons to the central nervous system. Combined with -tubulin immunoreactivity, this study illuminates the unprecedented complexity of peripheral neural systems in gastropod mollusks, with lineage-specific diversification of sensory and modulatory functions.

Coding odor modality in piriform cortex efficiently with low-dimensional subspaces: a Shared Covariance Decoding approach
A fundamental question in neuroscience is how sensory signals are decoded from noisy cortical activity. We address this question in the olfactory system, decoding the route by which odorants arrive into the nasal cavity: through the nostrils during inhalation or sniffing (orthonasal), or through the back of the throat during exhalation (retronasal). We recently showed with modeling and novel experiments on anesthetized rats that orthonasal versus retronasal modality information is encoded in the olfactory bulb (OB, a pre-cortical region). However, key questions remain: is modality information transmitted from OB to anterior piriform cortex (aPC)? How can this information be extracted from a much noisier cortical population with overall less firing? With simultaneous spike recordings of populations of neurons in OB and aPC, we show that an unsupervised and biologically plausible algorithm we call Shared Covariance Decoding (SCD) can indeed linearly encode modality in low dimensional subspaces. Specifically, our SCD algorithm improves encoding of ortho/retro in aPC compared to Fisher's linear discriminant analysis (LDA). Consistent with our theoretical analysis, when noise correlations between OB and aPC are low and OB well-encodes modality, modality in aPC tends to be encoded optimally with SCD. We observe that with several algorithms (LDA, SCD, optimal) that the decoding accuracy distributions are invariant when GABA_A (ant-)agonists (bicuculline and muscimol) are applied to OB. Overall, we show modality information can be encoded efficiently in piriform cortex.

EEG Electrodes and Where to Find Them: Automated Localization From 3D Scans
Objective: The accurate localization of electroencephalography (EEG) electrode positions is crucial for accurate source localization. Recent advancements have proposed alternatives to labor-intensive, manual methods for spatial localization of the electrodes, employing technologies such as 3D scanning and laser scanning. These novel approaches often integrate Magnetic Resonance Imaging (MRI) as part of the pipeline in localizing the electrodes. The limited global availability of MRI data restricts its use as a standard modality in several clinical scenarios. This limitation restricts the use of these advanced methods. Approach: In this paper, we present a novel, versatile approach that utilizes 3D scans to localize EEG electrode positions with high accuracy. Importantly, while our method can be integrated with MRI data if available, it is specifically designed to be highly effective even in the absence of MRI, thus expanding the potential for advanced EEG analysis in various resource-limited settings. Our solution implements a two-tiered approach involving landmark/fiducials localization and electrode localization, creating an end-to-end framework. Main results: The efficacy and robustness of our approach have been validated on an extensive dataset containing over 400 3D scans from 278 subjects. The framework identifies pre-auricular points and achieves correct electrode positioning accuracy in the range of 85.7% to 91.0%. Additionally, our framework includes a validation tool that permits manual adjustments and visual validation if required. Significance: This study represents, to the best of the authors' knowledge, the first validation of such a method on a substantial dataset, thus ensuring the robustness and generalizability of our innovative approach. Our findings focus on developing a solution that facilitates source localization, contributing to the critical discussion on balancing cost effectiveness with methodological accuracy to promote wider adoption in both research and clinical settings.

Activity-dependent synthesis of Emerin gates neuronal plasticity by regulating proteostasis
Neurons dynamically regulate their proteome in response to sensory input, a key process underlying experience-dependent plasticity. We characterized the visual experience-dependent nascent proteome within a brief, defined time window after stimulation using an optimized metabolic labeling approach. Visual experience induced cell type-specific and age-dependent alterations in the nascent proteome, including proteostasis-related processes. We identified Emerin as the top activity-induced candidate plasticity protein and demonstrated that its rapid activity-induced synthesis is transcription-independent. In contrast to its nuclear localization and function in myocytes, activity-induced neuronal Emerin is abundant in the endoplasmic reticulum and broadly inhibits protein synthesis, including translation regulators and synaptic proteins. Downregulating Emerin shifted the dendritic spine population from predominantly mushroom morphology to filopodia and decreased network connectivity. In mice, decreased Emerin reduced visual response magnitude and impaired visual information processing. Our findings support an experience-dependent feed-forward role for Emerin in temporally gating neuronal plasticity by negatively regulating translation.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-Treated Adult Zebrafish as a Model for Parkinsons Disease
Dopamine (DA) is a neuroprotective catecholamine and neurotransmitter that works to regulate cognitive functions (Channer et al., 2023). Patients affected by Parkinsons Disease (PD) experience a loss of dopaminergic neurons, lower levels of DA, and downregulated neural DA production. This leads to cognitive and physical decline that is the hallmark of PD. Currently, no cure exists for this prevalent neurodegenerative disease. Danio rerio, or zebrafish, have become an increasingly popular disease model used in PD pharmaceutical development. This model still requires extensive development to better characterize which PD features are adequately represented. Furthermore, the great majority of PD zebrafish models have been performed by treating embryos, which may not be relevant towards age-related human PD development. As an improvement, mature D. rerio (18 months) were treated with the neurotoxic prodrug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through intraperitoneal injection to induce Parkinsonianism. Behavioral analysis confirmed the disparity in movement between saline-injected control and the MPTP experimental group, in which swim distance and speed were significantly lowered seven days after MPTP injection. Simultaneously, cognitive decline was apparent in MPTP zebrafish compared to control, demonstrated by decreased alternation in a y-maze. RT-qPCR confirmed trends consistent with downregulation in Parkinsonian genetic markers, specifically DA transporter (DAT), MAO-B, PINK1. In summary, mature zebrafish injected with MPTP present with similar movement and cognitive decline as compared to human disease. Despite its benefits, this model does not appear to recapitulate full pathophysiology of the disease with the full profile of expected gene downregulation. Because of this, it is important that researchers looking for pharmacological interventions for PD only use this zebrafish model when targeting the human-relevant PD symptoms and causes that are represented.

A level adjusted cochlear frequency-to-place map for estimating tonotopic frequency mismatch with a cochlear implant
Objectives: To provide a level-adjusted correction to the current standard relating anatomical cochlear place to characteristic frequency in humans, and to re-evaluate anatomical frequency mismatch in cochlear implant (CI) recipients considering this correction. It is hypothesized that a level-adjusted place-frequency function may represent a more accurate tonotopic benchmark for CIs in comparison to the current standard. Design: The present analytical study compiled data from fifteen previous animal studies that reported iso-intensity responses from cochlear structures at different stimulation levels. Extracted outcome measures were characteristic frequencies and centroid-based best frequencies at 70 dB SPL input from 47 specimens spanning a broad range of cochlear locations. A simple relationship was used to transform these measures to human estimates of characteristic and best frequencies, and non-linear regression was applied to these estimates to determine how the standard human place-frequency function should be adjusted to reflect best frequency rather than characteristic frequency. The proposed level-adjusted correction was then compared to average place-frequency positions of commonly used CI devices when programmed with clinical settings. Results: The present study showed that the best frequency at 70 dB SPL (BF70) tends to shift away from characteristic frequency (CF). The amount of shift was statistically significant (signed-rank test z = 5.143, p < 0.001), but the amount and direction of shift depended on cochlear location. At cochlear locations up to 600 degrees from the base, BF70 shifted downwards in frequency relative to CF by about 4 semitones on average. Beyond 600 degrees from the base, BF70 shifted upwards in frequency relative to CF by about 6 semitones on average. In terms of spread (90% prediction interval), the amount of shift between CF and BF70 varied from relatively no shift to nearly an octave of shift. With the new level-adjusted frequency-place function, the amount of anatomical frequency mismatch for devices programmed with standard of care settings is less extreme than originally thought, and may be nonexistent for all but the most apical electrodes. Conclusions: The present study validates the current standard for relating cochlear place to characteristic frequency, and introduces a level-adjusted correction for how best frequency shifts away from characteristic frequency at moderately loud stimulation levels. This correction may represent a more accurate tonotopic reference for CIs. To the extent that it does, its implementation may potentially enhance perceptual accommodation and speech understanding in CI users, thereby improving CI outcomes and contributing to advancements in the programming and clinical management of CIs.

Dopamine-induced Relaxation of Connectivity Diversifies Burst Patterns in Cultured Hippocampal Networks
The intricate interplay of neurotransmitters orchestrates a symphony of neural activity in the hippocampus, with dopamine emerging as a key conductor in this complex ensemble. Despite numerous studies uncovering the cellular mechanisms of dopamine, its influence on hippocampal neural networks remains elusive. Combining in vitro electrophysiological recordings of rat embryonic hippocampal neurons, pharmacological interventions, and computational analyses of spike trains, we found that dopamine induces a relaxation in network connectivity, characterised by a reduction in spike coherence. This relaxation expands the repertoire of burst dynamics within these hippocampal networks, a phenomenon notably absent under the administration of dopamine antagonists. Our study provides a thorough understanding of the roles of dopamine signalling in shaping functional networks of hippocampal neurons.

A widespread electrical brain network encodes anxiety in health and depressive states
In rodents, anxiety is charactered by heightened vigilance during low-threat and uncertain situations. Though activity in the frontal cortex and limbic system are fundamental to supporting this internal state, the underlying network architecture that integrates activity across brain regions to encode anxiety across animals and paradigms remains unclear. Here, we utilize parallel electrical recordings in freely behaving mice, translational paradigms known to induce anxiety, and machine learning to discover a multi-region network that encodes the anxious brain-state. The network is composed of circuits widely implicated in anxiety behavior, it generalizes across many behavioral contexts that induce anxiety, and it fails to encode multiple behavioral contexts that do not. Strikingly, the activity of this network is also principally altered in two mouse models of depression. Thus, we establish a network-level process whereby the brain encodes anxiety in health and disease.

Large-Scale Motor Dynamics Associated with Reaching are Altered in Essential Tremor
Introduction: Essential Tremor (ET) is a common neurological disorder identified by involuntary rhythmic movements stemming from pathological synchronization within a network that overlaps significantly with the normal motor circuit. The efficacy of therapeutic brain stimulation for ET is impeded by a limited understanding of how tremor-related synchronization affects brain circuits and disrupts normal sensorimotor processing. This paper details the changes in brain-wide synchronization associated with ET and connects these to the oscillatory dynamics during voluntary movements. Methods: We used high-density electroencephalography (EEG, 11 controls, 12 patients), and for the first time in ET patients, optically pumped magnetoencephalography (OPM, 5 controls, 4 patients) to record brain activity during upper limb reaching. We localized and analysed brain sources that synchronize with pathological tremors, studying motor oscillations in these regions. Using a novel dimensionality reduction approach, we identified a set of simple, latent circuits with specific frequency characteristics and analysed their relationship to kinematics and tremor. Results: Despite slight reductions in velocity, ET patients demonstrated reaching movements with kinematics comparable to controls. Notably, key motor areas - including the supplementary motor area, lateral prefrontal cortex, posterior parietal cortex, and motor cerebellum - were synchronized to tremor frequencies. Motor oscillations were significantly changed in patients with ET relative to controls, including a 15% increase in movement responsive desynchronization in the low beta (14-21 Hz) band which inversely correlated with tremor severity. Oscillations in the beta and theta bands were key predictors of patients' overall tremor levels. Latent state analysis in EEG and OPM data located these changes to fronto-parietal and premotor/prefrontal circuits. High tremor trials were associated with diminished post-movement beta rebound in frontoparietal and premotor circuits and an increase in sensorimotor gamma activity (30-60 Hz). Latent dynamics were predictive of changes in patients' movement velocity and hold stability, suggesting that increased movement related beta desynchronization may reflect a compensatory mechanism in the brain. Conclusions: This study demonstrates that ET leads to significant changes in the oscillatory dynamics within individual motor regions and broader networks. Specifically, we suggest that increased desynchronization of networks in ET enables successful execution of movement, by freeing neural resources otherwise entrained by pathological synchronization at tremor frequencies. Our findings, reproducible across both EEG and OPM recordings, underline how motor-related brain signals can predict subject level tremor severity and offer a new set of candidate biomarkers crucial for developing advanced closed-loop stimulation therapies for ET.

Fast and reliable quantitative measures of white matter development with magnetic resonance fingerprinting
Developmental cognitive neuroscience aims to shed light on evolving relationships between brain structure and cognitive development. To this end, quantitative methods that reliably measure individual differences in brain tissue properties are fundamental. Standard qualitative MRI sequences are influenced by scan parameters and hardware-related biases, and also lack physical units, making the analysis of individual differences problematic. In contrast, quantitative MRI can measure physical properties of the tissue but with the cost of long scan durations and sensitivity to motion. This poses a critical limitation for studying young children. Here, we examine the reliability and validity of an efficient quantitative multiparameter mapping method - Magnetic Resonance Fingerprinting (MRF) - in children scanned longitudinally. We focus on T1 values in white matter, since quantitative T1 values are known to primarily reflect myelin content, a key factor in brain development. Forty-nine children (age range 8-13y) completed two scanning sessions 2-4 months apart. In each session, two 2-minute 3D-MRF scans at 1mm isotropic resolution were collected to evaluate the effect of scan duration on image quality and scan-rescan reliability. A separate calibration scan was used to measure B0 inhomogeneity and correct for bias. We examined the impact of scan time and B0 inhomogeneity correction on scan-rescan reliability of values in white matter, by comparing single 2-min and combined two 2-min scans, with and without B0-correction. Whole-brain voxel-based reliability analysis showed that combining two 2-min MRF scans improved reliability (Pearson's r=0.87) compared with a single 2-min scan (r=0.84), while B0-correction had no effect on reliability in white matter (r=0.86 and 0.83 4-min vs 2-min). Using diffusion tractography, we delineated MRF-derived T1 profiles along major white matter fiber tracts and found similar or higher reliability for T1 from MRF compared to diffusion parameters (based on a 10-minute dMRI scan). Lastly, we found that T1 values in multiple white matter tracts were significantly correlated with age. In sum, MRF-derived T1 values were highly reliable in a longitudinal sample of children and replicated known age effects. Reliability in white matter was improved by longer scan duration but was not affected by B0-correction, making it a quick and straightforward scan to collect. We propose that MRF provides a promising avenue for acquiring quantitative brain metrics in children and patient populations where scan time and motion are of particular concern.

Laminar CBV and BOLD response-characteristics over time and space in the human primary somatosensory cortex at 7T
Uncovering the cortical representation of the body has been at the core of human brain mapping for decades, with special attention given to the digits. In the last decade, advances in functional magnetic resonance imaging (fMRI) technologies have opened the possibility of non-invasively unraveling the 3rd dimension of digit representations in humans along cortical layers. In laminar fMRI it is common to combine the use of the highly sensitive blood oxygen level dependent (BOLD) contrast with cerebral blood volume sensitive measurements, like vascular space occupancy (VASO), that are more specific to the underlying neuronal populations. However, the spatial and temporal VASO response characteristics across cortical depth to passive stimulation of the digits are still unknown. Therefore, we characterized haemodynamic responses to vibrotactile stimulation of individual digit-tips across cortical depth at 0.75 mm in-plane spatial resolution using BOLD and VASO fMRI at 7T. We could identify digit-specific regions of interest (ROIs) in putative Brodmann area 3b, following the known anatomical organization. In the ROIs, the BOLD response increased towards the cortical surface due to the draining vein effect, while the VASO response was more shifted towards middle cortical layers, likely reflecting bottom-up input from the thalamus, as expected. Interestingly, we also found slightly negative BOLD and VASO responses for non-preferred digits in the ROIs, potentially indicating neuronal surround inhibition. Finally, we explored the temporal signal dynamics for BOLD and VASO as a function of distance from activation peaks resulting from stimulation of contralateral digits. With this analysis, we showed a triphasic response consisting of an initial peak and a subsequent negative deflection during stimulation, followed by a positive post-stimulus response in BOLD and to some extent in VASO. While similar responses were reported with invasive methods in animal models, here we demonstrate a potential neuronal excitation-inhibition mechanism in a center-surround architecture across layers in the human somatosensory cortex. Given that, unlike in animals, human experiments do not rely on anesthesia and can readily implement extensive behavioral testing, obtaining this effect in humans is an important step towards further uncovering the functional significance of the different aspects of the triphasic response.

Dopamine transmission at D1 and D2 receptors in the nucleus accumbens contributes to the expression of incubation of cocaine craving
Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or incubates during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.

Transcranial focused ultrasound activates feedforward and feedback cortico-thalamo-cortical pathways by selectively activating excitatory neurons
Transcranial focused ultrasound stimulation (tFUS) has been proven capable of altering focal neuronal activities and neural circuits non-invasively in both animals and humans. The abilities of tFUS for cell-type selection within the targeted area like somatosensory cortex have been shown to be parameter related. However, how neuronal subpopulations across neural pathways are affected, for example how tFUS affected neuronal connections between brain areas remains unclear. In this study, multi-site intracranial recordings were used to quantify the neuronal responses to tFUS stimulation at somatosensory cortex (S1), motor cortex (M1) and posterior medial thalamic nucleus (POm) of cortico-thalamo-cortical (CTC) pathway. We found that when targeting at S1 or POm, only regular spiking units (RSUs, putative excitatory neurons) responded to specific tFUS parameters (duty cycle: 6%-60% and pulse repetition frequency: 1500 and 3000 Hz ) during sonication. RSUs from the directly connected area (POm or S1) showed a synchronized response, which changed the directional correlation between RSUs from POm and S1. The tFUS induced excitation of RSUs activated the feedforward and feedback loops between cortex and thalamus, eliciting delayed neuronal responses of RSUs and delayed activities of fast spiking units (FSUs) by affecting local network. Our findings indicated that tFUS can modulate the CTC pathway through both feedforward and feedback loops, which could influence larger cortical areas including motor cortex.

Motor adaptation is reduced by symbolic compared to sensory feedback
Motor adaptation, the process of reducing motor errors through feedback and practice, is an essential feature of human competence, allowing us to move accurately in dynamic and novel environments. Adaptation typically results from sensory feedback, with most learning driven by visual and proprioceptive feedback that arises with the movement. In humans, motor adaptation can also be driven by symbolic feedback. In the present study, we examine how implicit and explicit components of motor adaptation are modulated by symbolic feedback. We conducted three reaching experiments involving over 400 human participants to compare sensory and symbolic feedback using a task in which both types of learning processes could be operative (Experiment 1) or tasks in which learning was expected to be limited to only an explicit process (Experiments 2 and 3). Adaptation with symbolic feedback was dominated by explicit strategy use, with minimal evidence of implicit recalibration. Even when matched in terms of information content, adaptation to rotational and mirror reversal perturbations was slower in response to symbolic feedback compared to sensory feedback. Our results suggest that the abstract and indirect nature of symbolic feedback disrupts strategic reasoning and/or refinement, deepening our understanding of how feedback type influences the mechanisms of sensorimotor learning.

Spatiotemporal patterns in cortical development: Age, puberty, and individual variability from 9 to 13 years of age
Humans and nonhuman primate studies suggest that timing and tempo of cortical development varies neuroanatomically along a sensorimotor-to-association (S-A) axis. Prior human studies have reported a principal S-A axis across various modalities, but largely rely on cross-sectional samples with wide age-ranges. Here, we investigate developmental changes and individual variability in cortical organization along the S-A axis between the ages of 9-13 years using a large, longitudinal sample (N = 2487-3747, 46-50% female) from the Adolescent Brain Cognitive Development Study (ABCD Study). This work assesses multiple aspects of neurodevelopment indexed by changes in cortical thickness, resting-state functional fluctuations, and cortical microarchitecture. First, we evaluated S-A organization in age-related changes and, then, computed individual-level S-A alignment in brain changes and assessing differences therein due to age, sex, and puberty. Varying degrees of linear and quadratic age-related brain changes were identified along the S-A axis. Yet, these patterns of cortical development were overshadowed by considerable individual variability in S-A alignment. Even within individuals, there was little correspondence between S-A patterning across the different aspects of neurodevelopment investigated (i.e., cortical morphology, microarchitecture, function). Some of the individual variation in developmental patterning of cortical morphology and microarchitecture was explained by age, sex, and pubertal development. Altogether, this work contextualizes prior findings that regional age differences do progress along an S-A axis at a group level, while highlighting broad variation in developmental change between individuals and between aspects of cortical development, in part due to sex and puberty.

Longitudinal trajectories of brain development from infancy to school age and their relationship to literacy development
Reading is one of the most complex skills that we utilize daily, and it involves the early development and interaction of various lower-level subskills, including phonological processing and oral language. These subskills recruit brain structures, which begin to develop long before the skill manifests and exhibit rapid development during infancy. However, how longitudinal trajectories of early brain development in these structures supports long-term acquisition of literacy subskills and subsequent reading is unclear. Children underwent structural and diffusion MRI scanning at multiple timepoints between infancy and second grade and were tested for literacy subskills in preschool and decoding and word reading in early elementary school. We developed and implemented a reproducible pipeline to generate longitudinal trajectories of early brain development to examine associations between these trajectories and literacy (sub)skills. Furthermore, we examined whether familial risk of reading difficulty and home literacy environment, two common literacy-related covariates, influenced those trajectories. Results showed that individual differences in curve features (e.g., intercepts and slopes) for longitudinal trajectories of volumetric, surface-based, and white matter organization measures in left-hemispheric reading-related regions and tracts were linked directly to phonological processing and indirectly to second-grade decoding and word reading skills via phonological processing. Altogether, these findings suggest that the brain bases of phonological processing, previously identified as the strongest behavioral predictor of reading and decoding skills, may already begin to develop early in infancy but undergo further refinement between birth and preschool. The present study underscores the importance of considering academic skill acquisition from the very beginning of life.

The frontal cortex adjusts striatal integrator dynamics for flexible motor timing
Flexible control of motor timing is crucial for behavior. Before movement begins, the frontal cortex and striatum exhibit ramping spiking activity, with variable ramp slopes anticipating movement onsets. This activity may function as an adjustable 'timer,' triggering actions at the desired timing. However, because the frontal cortex and striatum share similar ramping dynamics and are both necessary for timing behaviors, distinguishing their individual roles in this timer function remains challenging. To address this, we conducted perturbation experiments combined with multi-regional electrophysiology in mice performing a lick-timing task. Following transient silencing of the frontal cortex, cortical and striatal activity swiftly returned to pre-silencing levels and resumed ramping, leading to a shift in lick timing close to the silencing duration. Conversely, briefly inhibiting the striatum caused a gradual decrease in ramping activity in both regions, with ramping resuming from post-inhibition levels, shifting lick timing beyond the inhibition duration. Thus, inhibiting the frontal cortex and striatum effectively paused and rewound the timer, respectively. Additionally, the frontal cortex, but not the striatum, encodes trial-history information guiding lick timing. These findings suggest specialized functional allocations within the forebrain: the striatum temporally integrates input from the frontal cortex to generate ramping activity that regulates motor timing.

Human Accelerated Regions regulate gene networks implicated in apical-to-basal neural progenitor fate transitions
The evolution of the human cerebral cortex involved modifications in the composition and proliferative potential of the neural stem cell (NSC) niche during brain development. Human Accelerated Regions (HARs) exhibit a significant excess of human-specific sequence changes and have been implicated in human brain evolution. Multiple studies support that HARs include neurodevelopmental enhancers with novel activities in humans, but their biological functions in NSCs have not been empirically assessed at scale. Here we conducted a direct-capture Perturb-seq screen repressing 180 neurodevelopmentally active HARs in human iPSC-derived NSCs with single-cell transcriptional readout. After profiling >188,000 NSCs, we identified a set of HAR perturbations with convergent transcriptional effects on gene networks involved in NSC apicobasal polarity, a cellular process whose precise regulation is critical to the developmental emergence of basal radial glia (bRG), a progenitor population that is expanded in humans. Across multiple HAR perturbations, we found convergent dysregulation of specific apicobasal polarity and adherens junction regulators, including PARD3, ABI2, SETD2, and PCM1. We found that the repression of one candidate from the screen, HAR181, as well as its target gene CADM1, disrupted apical PARD3 localization and NSC rosette formation. Our findings reveal interconnected roles for HARs in NSC biology and cortical development and link specific HARs to processes implicated in human cortical expansion.

Stimulus selection drives value-modulated somatosensory processing in superior colliculus
A fundamental trait of intelligent behavior is the ability to respond selectively to stimuli with higher value. Where along the somatosensory hierarchy does information transition from a map of stimulus location to a map of stimulus value? To address this question, we recorded single-unit activity from populations of neurons in somatosensory cortex (S1) and midbrain superior colliculus (SC) in mice conditioned to respond to a positive-valued whisker stimulus and withhold responses using an adjacent, negative-valued whisker stimulus. The stimulus preference of the S1 population was equally weighted towards either whisker, in line with a somatotopic map. Surprisingly, we discovered a large population of SC neurons that were disproportionately biased towards the positive stimulus. This disproportionate bias was controlled by spike facilitation for the positive stimulus and spike suppression for the negative stimulus in single neurons. Removing the opportunity for mice to select the positive stimulus reduced stimulus bias in SC but not S1, suggesting that sensory processing in SC neurons was partially controlled by movement preparation. Similarly, the spontaneous firing rates of SC but not S1 neurons accurately predicted reaction times, suggesting that SC neurons play a persistent role in perceptual decision-making. Taken together, these data indicate that the somatotopic map in S1 is transformed into a value-based map in SC that encodes stimulus priority.

Behavioral state regulates the dynamics of memory consolidation
Long-term memories are consolidated over time, progressively becoming more stable and resistant to interference. Memory consolidation occurs offline and often involves transfer of memories from one brain site to another. For many motor memories, consolidation is thought to involve early learning in cerebellar cortex that is subsequently transferred to the cerebellar nuclei. Here we report that in mice, engaging in locomotor activity during training in a classical conditioning task shifts the critical time window for memory consolidation, from just after training sessions, to between trials, within sessions. This temporal shift requires natural patterns of cerebellar granule cell activity during intertrial intervals and is accompanied by earlier involvement of the downstream cerebellar nucleus. These results reveal that the critical time window for cerebellar memory consolidation can be surprisingly brief, on a timescale from seconds to minutes, and that it is dynamically regulated by behavioral state.

A Markovian neural barcode representing mesoscale cortical spatiotemporal dynamics.
Mesoscale cortical dynamics consist of stereotyped patterns of recurring activity motifs, however the constraints and rules governing how these motifs assemble over time is not known. Here we propose a Continuous Time Markov Chain model that probabilistically describes the temporal sequence of activity motifs using Markov Elements derived using semi-binary non-negative matrix factorization. Although derived from a discovery sample, these can be applied to new recordings from new mice. Unwrapping the associated transition probability matrix creates a 'Markovian neural barcode' describing the probability of Markov element transitions as a compact and interpretable representation of neocortical dynamics. We show broad utility across a range of common mesoscale cortical imaging applications, ranging from time-locked events to pathological models. Moreover, it allows the discovery of new and emergent Markov Elements that unmask the flexibility of constraints governing cortical dynamics. The Markovian neural barcode provides a novel and powerful tool to characterize cortical function.