bioRxiv Subject Collection: Neuroscience's Journal

The effect of semantic content on the perception of audiovisual movieclips
Abstract Our brain is skilled with the ability to perceive and process multimodal stimuli. This process known as crossmodal perceptual integration, has been in the research spotlight for a long time, providing evidence for the integration of information coming from different modalities. Prior research mostly utilized pictures and focused on the semantic content of a single sound or word. The present study aims to investigate crossmodal perceptual integration in realistic conditions using short movieclips (1500ms) and auditory meaningful three-word sentences to evaluate target detection in terms of accuracy and response times. Two experimental tasks were developed using PsychoPy, where participants had to indicate whether a target (noun for Experiment 1, verb for Experiment 2) was present or absent. In trials without a target, target-related information was always present, either through one of the two senses (vision or audition; incongruent condition) or through both senses (congruent condition). We observed superior performance when the target was absent generally (Mexp1 =93.9%, SDexp1 =0.04, Mexp2 =84.2%, SDexp2 =0.182) compared to when it was present (Mexp1 =82.3%, SDexp1 =0.143, Mexp2 =73.7%, SDexp2 =0.184). Moreover, superior performance was noted in incongruent target-related movieclips, which significantly decreased during congruent target-related movieclips. In Experiment 1, we observed that in the audio condition when the target-related word was a noun, participant performance was superior compared to when it was a verb (M=99.4% vs. M=86.7%; tincVerb vs. incNoun =-8.428, p=.001). In Experiment 2, the judgment scores were similarly high in incongruent movieclips and significantly lower in congruent ones regardless of whether the target-related information presented was a verb or noun. The present results provide evidence regarding the role of complexity of semantics, and especially the diverse role verbs and nouns could play in crossmodal perceptual integration in more realistic situations. Our findings can enrich the content of learning techniques, as well as the design of AI models, by taking advantage of the supporting role of semantic audiovisual information, while taking into consideration the potential confusion that the complexity of semantic information can induce to perception experience.

Evaluating the effect of denoising submillimeter auditory fMRI data with NORDIC
Functional magnetic resonance imaging (fMRI) has emerged as an essential tool for exploring human brain function. Submillimeter fMRI, in particular, has emerged as a tool to study mesoscopic computations. The inherently low signal to noise ratio (SNR) at submillimeter resolutions warrants the use of denoising approaches tailored at reducing thermal noise; the dominant contributing noise component in high resolution fMRI. NORDIC PCA is one of such approaches, and has been benchmarked against other approaches in several applications. Here, we investigate the effects that two versions of NORDIC denoising have on auditory submillimeter data. As investigating auditory functional responses poses unique challenges, we anticipated that the benefit of this technique would be especially pronounced. Our results show that NORDIC denoising improves the detection sensitivity and the reliability of estimates in submillimeter auditory fMRI data. These effects can be explained by the reduction of the noise-induced signal variability. However, we also observed a reduction in the average response amplitude (percent signal), which may suggest that a small amount of signal was also removed. We conclude that, while evaluating the effects of the signal reduction induced by NORDIC may be necessary for each application, using NORDIC in high resolution auditory fMRI studies may be advantageous because of the large reduction in variability of the estimated responses.

Dual effects of ARX poly-alanine mutations in human cortical and interneuron development
Mutations in ARX, an X-linked gene, are implicated in a wide spectrum of neurological disorders including patients who have intellectual disability and epilepsy. Mouse models have shown that Arx is critical for cortical development and interneuron migration, however they do not recapitulate the full phenotype observed in patients. Moreover, the epilepsy in many patients with poly-alanine tract expansion (PAE) mutations in ARX show pharmacoresistance, emphasizing the need to develop new treatments. Here, we used human neural organoid models to study the consequences of PAE mutations, one of the most prevalent mutations in ARX. We found that PAE mutations result in an early increase in radial glia cells and intermediate progenitor cells, and premature differentiation leading to a loss of cortical neurons at later timepoints. Moreover, ARX expression is upregulated in CO derived from patient at 30 DIV which alters the expression of CDKN1C, SFRP1, DLK1 and FABP7, among others. We also found a cell autonomously enhanced interneuron migration, which can be rescued by CXCR4 inhibition. Furthermore, ARXPAE assembloids had hyper-activity and synchrony evident from the early stages. These data provide novel insights to the pathogenesis of these and likely related human neurological disorders and identifies a critical window for therapeutic interventions.

TRESK background potassium channel in MrgprA3+ pruriceptors regulates acute and chronic itch.
TRESK (K2P18.1) is a background K+ channel expressed in sensory neurons, where it modulates the resting membrane potential, action potential firing and neuronal excitability. A subset of these sensory neurons, which express specific TRPs and Mas-related G protein-coupled receptors (Mrgprs), are activated by pruritogens and mediate itch sensations. Because TRESK is involved in somatosensation and pain transduction, we evaluated the contribution of this channel to pruritic sensitivity and its potential as a target for the treatment of chronic itch pathologies. By combining RNA in situ hybridization, calcium imaging, electrophysiological and behavioral approaches, we found that TRESK is involved in the modulation of non-histaminergic itch. TRESK is coexpressed with MrgprD+ and MrgprA3+ in sensory neurons and MrgprA3+ neurons from TRESK-/- animals display an enhanced firing compared to WT counterparts. Interestingly, acute itch to intradermal injection of chloroquine is significantly enhanced in the absence of TRESK but not the response to histamine, BAM8-22 or LTC4. TRESK deletion also enhanced chronic itch in mice models of Allergic Contact Dermatitis and Dry Skin. In the mouse model imiquimod-induced psoriasiform dermatitis, the absence of TRESK produced a significantly enhanced scratching behavior, which developed earlier and was more robust. Finally, enhancing TRESK function with the channel activator cloxyquin diminished both acute and chronic itch in WT mice but not in KO animals. In summary, our data indicates that TRESK is involved in regulating the excitability of a subset of sensory neurons that mediate histaminergic-independent itch. Enhancing the channel function with specific activators constitutes a novel anti-pruritic therapeutic method that can be combined with other compounds for the treatment of non-histaminergic itch, for which appropriate treatments are lacking.

A microglia clonal inflammatory disorder in Alzheimer's Disease
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimer's Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.

The voltage-gated potassium channel Shal (Kv4) contributes to active hearing in Drosophila
The full complement of ion channels which influence insect auditory mechanotransduction, and the mechanisms by which their influence is exerted, remain unclear. Shal (Kv4), a Shaker family member encoding voltage-gated potassium channels in Drosophila melanogaster, has been shown to localize to dendrites in some neuron types, suggesting a potential role for Shal in Drosophila hearing, including mechanotransduction. A GFP-protein trap was used to visualize the localization of the Shal channel in Johnston's organ neurons responsible for hearing in the antenna. Shal protein was localized to the cell body and the proximal dendrite region of sensory neurons, suggesting its involvement not only in general auditory function, but specifically in mechanotransduction. Electrophysiological recordings conducted to assess neural responses to auditory stimuli in mutant Shal flies revealed significant decreases in auditory responses. Laser Doppler Vibrometer recordings indicated abnormal antennal free fluctuation frequencies in mutant lines, indicating an effect on active antennal tuning, and thus active transduction mechanisms. This suggests that Shal participates in coordinating energy-dependent antennal movements in Drosophila that are essential for tuning the antenna to courtship song frequencies.

m6A-dependent circular RNA formation mediatestau-induced neurotoxicity
Circular RNAs (circRNAs), covalently closed RNA molecules that form due to back-splicing of RNA transcripts, have recently been implicated in Alzheimer disease and related tauopathies. circRNAs are regulated by N6-methyladenosine (m6A) RNA methylation, can serve as sponges for proteins and RNAs, and can be translated into protein via a cap-independent mechanism. Mechanisms underlying circRNA dysregulation in tauopathies and causal relationships between circRNA and neurodegeneration are currently unknown. In the current study, we aimed to determine whether pathogenic forms of tau drive circRNA dysregulation and whether such dysregulation causally mediates neurodegeneration. We identify circRNAs that are differentially expressed in the brain of a Drosophila model of tauopathy and in induced pluripotent stem cell (iPSC)-derived neurons carrying a tau mutation associated with autosomal dominant tauopathy. We leverage Drosophila to discover that depletion of circular forms of muscleblind (circMbl), a circRNA that is particularly abundant in brains of tau transgenic Drosophila, significantly suppresses tau neurotoxicity, suggesting that tau-induced circMbl elevation is neurotoxic. We detect a general elevation of m6A RNA methylation and circRNA methylation in tau transgenic Drosophila and find that tau-induced m6A methylation is a mechanistic driver of circMbl formation. Interestingly, we find that circRNA and m6A RNA accumulate within nuclear envelope invaginations of tau transgenic Drosophila and in iPSC-derived cerebral organoid models of tauopathy. Taken together, our studies add critical new insight into the mechanisms underlying circRNA dysregulation in tauopathy and identify m6A-modified circRNA as a causal factor contributing to neurodegeneration. These findings add to a growing literature implicating pathogenic forms of tau as drivers of altered RNA metabolism.

Ultrahigh Resolution Mass Spectrometry Imaging Maps Brain Lipidome Alterations Associated with Mild Traumatic Brain Injury
Background: Traumatic brain injury (TBI) is a global public health problem, with 50-60 million incidents per year, most of which are considered mild (mTBI). Despite its massive impact, the pathology of TBI is not fully understood, and there is a paucity of information on brain lipid dysregulation following mTBI. To gain more insight on mTBI pathology, a non-targeted spatial metabolomics workflow utilizing ultrahigh resolution mass spectrometry imaging was developed to measure brain region-specific lipid alterations in rats. Results: Multivariate models were created for regions of interest including the hippocampus, cortex, corpus callosum, white matter and gray matter to identify lipids that discriminated between control and injured brains. The hippocampus model differentiated control and injured brains with an area under the curve of 0.994, using only four lipid markers. Lipid classes that were consistently selected for discrimination included polyunsaturated fatty acid -containing phosphatidylcholines (PC), lysophosphatidylcholines (LPC), LPC-plasmalogens (LPC-P), PC potassium adducts and ceramide phosphoinositols (PI-Cer). Many of the polyunsaturated fatty acid-containing PC, LPC-P, and PI-Cer selected have never been previously reported as altered in TBI. Significance: The lipid alterations observed indicate that neuroinflammation, oxidative stress and disrupted sodium-potassium pumps are important pathologies that can explain cognitive deficits associated with mTBI. Therapeutics which target and attenuate these pathologies may be beneficial to limit persistent damage following a mild brain injury.

Grasp context-dependent uncertainty alters the relative contribution of anticipatory and feedback-based mechanisms in object manipulation
Predictive control within dexterous object manipulation while allowing for the choice of contact points has been shown to employ a predominantly feedback-based force modulation. Anticipation is thought to be facilitated through the internal representation of the object dynamics being integrated and updated on a trial-to-trial basis with the feedback of contact locations on the object. This is as opposed to the classically studied memory representation-based fingertip force control for grasping with pre-selected contact locations. We designed a study to examine this grasp context-dependent asymmetry in sensorimotor integration by introducing binary uncertainty about the grasp type before movement initiation within the framework of motor planning. An inverted T-shaped instrumented object was presented to 24 participants as the manipulandum, and they were asked to reach, grasp, and lift it while minimising the roll. We dissociated the planning and the execution phases by pseudo-randomly manipulating the availability of visual contact cues on the object after movement onset. Our results suggest that uncertainty about the grasp type during movement preparation anterogradely modulated the differential weighting of feedback and feedforward mechanisms in anticipatory coordination.

The Increasing Authorship trend in Neuroscience: A scientometric analysis across 11 countries
Previous studies have demonstrated an increasing trend of the number of authors across various fields over the years. This trend has been attributed to the necessity for larger collaborations and, at times, to ethical issues regarding authorship attribution. Our study focuses on the evolution of authorship trends in the field of Neuroscience. We conducted our analysis based on a dataset containing 576,647 neuroscience publications produced from 2000 to 2022, focusing on the publications within the Group of ten (G10) countries. Using a matrix-based methodology, we extracted and analyzed the average number of authors per country. Our findings reveal a consistent rise in authorship across all G10 countries over the past two decades. Italy emerged with the highest average number of authors, while the Netherlands stood out for experiencing the most significant increase, particularly in the last decade. The countries with the lowest number of authors per publication were the USA, UK, and Canada.

Electrically silent KvS subunits associate with native Kv2 channels in brain and impact diverse properties of channel function
Voltage-gated K+ channels of the Kv2 family are highly expressed in brain and play dual roles in regulating neuronal excitability and in organizing endoplasmic reticulum - plasma membrane (ER-PM) junctions. Studies in heterologous cells suggest that the two pore forming alpha subunits Kv2.1 and Kv2.2 assemble with electrically silent KvS subunits to form heterotetrameric channels with distinct biophysical properties. Here, using mass spectrometry-based proteomics, we identified five KvS subunits as components of native Kv2.1 channels immunopurified from mouse brain, the most abundant being Kv5.1. We found that Kv5.1 co-immunoprecipitates with Kv2.1 and to a lesser extent with Kv2.2 from brain lysates, and that Kv5.1 protein levels are decreased by 70% in Kv2.1 knockout mice and 95% in Kv2.1/2.2 double knockout mice. Multiplex immunofluorescent labelling of rodent brain sections revealed that in neocortex Kv5.1 immunolabeling is apparent in a large percentage of Kv2.1 and Kv2.2-positive layer 2/3 neurons, and in a smaller percentage of layer 5 and 6 neurons. At the subcellular level, Kv5.1 is co-clustered with Kv2.1 and Kv2.2 at ER-PM junctions in cortical neurons, although clustering of Kv5.1-containing channels is reduced relative to homomeric Kv2 channels. We also found that in heterologous cells coexpression with Kv5.1 reduces the clustering and alters the pharmacological properties of Kv2.1 channels. Together, these findings demonstrate that the Kv5.1 electrically silent subunit is a component of a substantial fraction of native brain Kv2 channels, and that its incorporation into heteromeric channels can impact diverse aspects of Kv2 channel function.

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
The strongest risk factors for Alzheimer's disease (AD) include the {epsilon}4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

High-speed two-photon microscopy with adaptive line-excitation
We present a two-photon fluorescence microscope designed for high-speed imaging of neural activity in cellular resolution. Our microscope uses a new adaptive sampling scheme with line illumination. Instead of building images pixel by pixel via scanning a diffraction-limited spot across the sample, our scheme only illuminates the regions of interest (i.e., neuronal cell bodies), and samples a large area of them in a single measurement. Such a scheme significantly increases the imaging speed and reduces the overall laser power on the brain tissue. Using this approach, we performed high-speed imaging of the neural activity of mouse cortex in vivo. Our method provides a new sampling strategy in laser-scanning two-photon microscopy, and will be powerful for high-throughput imaging of neural activity.

Acquiring musculoskeletal skills with curriculum-based reinforcement learning
Efficient, physiologically-detailed musculoskeletal simulators and powerful learning algorithms provide new computational tools to tackle the grand challenge of understanding biological motor control. Our winning solution for the first NeurIPS MyoChallenge leverages an approach mirroring human learning and showcases reinforcement and curriculum learning as mechanisms to find motor control policies in complex object manipulation tasks. Analyzing the policy against data from human subjects reveals insights into efficient control of complex biological systems. Overall, our work highlights the new possibilities emerging at the interface of musculoskeletal physics engines, reinforcement learning and neuroscience.

Neuroinflammation underlies the development of social stress induced cognitive deficit in sickle cell disease.
Cognitive deficit is a debilitating complication of SCD with multifactorial pathobiology. Here we show that neuroinflammation and dysregulation in lipidomics and transcriptomics profiles are major underlying mechanisms of social stress-induced cognitive deficit in SCD. Townes sickle cell (SS) mice and controls (AA) were exposed to social stress using the repeat social defeat (RSD) paradigm concurrently with or without treatment with minocycline. Mice were tested for cognitive deficit using novel object recognition (NOR) and fear conditioning (FC) tests. SS mice exposed to RSD without treatment had worse performance on cognitive tests compared to SS mice exposed to RSD with treatment or to AA controls, irrespective of their RSD or treatment disposition. Additionally, compared to SS mice exposed to RSD with treatment, SS mice exposed to RSD without treatment had significantly more cellular evidence of neuroinflammation coupled with a significant shift in the differentiation of neural progenitor cells towards astrogliogenesis. Additionally, brain tissue from SS mice exposed to RSD was significantly enriched for genes associated with blood-brain barrier dysfunction, neuron excitotoxicity, inflammation, and significant dysregulation in sphingolipids important to neuronal cell processes. We demonstrate in this study that neuroinflammation and lipid dysregulation are potential underlying mechanisms of social stress-related cognitive deficit in SS mice.

A C-terminal motif containing a PKC phosphorylation site regulates γ-Protocadherin-mediated dendrite arborization in the cerebral cortex in vivo
The Pcdhg gene cluster encodes 22 {gamma}-Protocadherin ({gamma}-Pcdh) cell adhesion molecules that critically regulate multiple aspects of neural development, including neuronal survival, dendritic and axonal arborization, and synapse formation and maturation. Each {gamma}-Pcdh isoform has unique protein domains--a homophilically interacting extracellular domain and a juxtamembrane cytoplasmic domain--as well as a C-terminal cytoplasmic domain shared by all isoforms. The extent to which isoform-specific vs. shared domains regulate distinct {gamma}-Pcdh functions remains incompletely understood. Our previous in vitro studies identified PKC phosphorylation of a serine residue within a shared C-terminal motif as a mechanism through which {gamma}-Pcdh promotion of dendrite arborization via MARCKS is abrogated. Here, we used CRISPR/Cas9 genome editing to generate two new mouse lines expressing only non-phosphorylatable {gamma}-Pcdhs, due either to a serine-to-alanine mutation (PcdhgS/A) or to a 15-amino acid C-terminal deletion resulting from insertion of an early stop codon (PcdhgCTD). Both lines are viable and fertile, and the density and maturation of dendritic spines remains unchanged in both PcdhgS/A and PcdhgCTD cortex. Dendrite arborization of cortical pyramidal neurons, however, is significantly increased in both lines, as are levels of active MARCKS. Intriguingly, despite having significantly reduced levels of {gamma}-Pcdh proteins, the PcdhgCTD mutation yields the strongest phenotype, with even heterozygous mutants exhibiting increased arborization. The present study confirms that phosphorylation of a shared C-terminal motif is a key {gamma}-Pcdh negative regulation point, and contributes to a converging understanding of {gamma}-Pcdh family function in which distinct roles are played by both individual isoforms and discrete protein domains.

Joint signatures of morphological and microstructural inter-individual variation in the Alzheimer's spectrum
Alzheimer's disease (AD) is primarily characterized by the accumulation of amyloid and tau pathologies. However, alterations in the detailed organization and composition of neural tissue also contribute to the disease's early stages. Here, we sought to explore whether hippocampal and cortical microstructural changes, such as myelin alterations and inflammation-mediated increases in iron, could serve as indices of AD-related pathophysiology. In this study, we included 158 participants across the AD spectrum: from individuals without cognitive impairment, at high risk for AD, in the prodromal phase with mild cognitive impairment, and suffering from clinical dementia. We measured atrophy using structural magnetic resonance imaging (MRI) and estimated myelin and iron content using quantitative MRI (qMRI) metrics derived from T1 and T2* relaxation, times respectively. We integrated these contrasts to estimate a joint multivariate signature of tissue alterations across the cortex and hippocampus using non-negative matrix factorization. The relevance of these signatures to AD-spectrum measures of medical history, lifestyle, and cognition were further explored using partial least squares correlation. Our results reveal lower disease-related cortical thickness over large areas of the cortex while T2* provided specific variation across the brain (lower in dorsomedial and superior temporal areas, superior frontal cortex, and premotor cortex, and higher in the occipital lobe). Additionally, we observed longer T1 and T2* times in the hippocampus associated with specific lifestyle risk factors like past smoking, high blood pressure, high cholesterol levels, and higher anxiety. These patterns were significantly related to older age, associated with AD progression, being female, and being an APOE-{epsilon}4 carrier. Taken together, our results suggest that qMRI metrics could serve as a valuable non-invasive tool for exploring the role of myelin and inflammation in AD-related pathophysiology and could be sensitive to modifiable risk factors related to lifestyle and medical history. Future studies may use these signatures to investigate their relationship in investigations related to lifestyle interventions or novel therapeutics.

Functional benefit of CRISPR/Cas9-induced allele deletion for RYR1 dominant mutation
More than 700 pathogenic or probably pathogenic variations have been identified in the RYR1 gene causing various myopathies collectively known as "RYR1-related myopathies". Currently, there is no treatment for these myopathies, and gene therapy stands out as one of the most promising approaches. In the context of a dominant form of Central Core Disease due to a RYR1 mutation , we aimed at showing the functional benefit of inactivating specifically the mutated RYR1 allele by guiding CRISPR/Cas9 cleavages onto frequent single nucleotide polymorphisms (SNPs) segregating on the same chromosome. Whole-genome sequencing was used to pinpoint SNPs localized on the mutant RYR1 allele and identified specific CRISPR/Cas9 guide-RNAs. Lentiviruses encoding these guide-RNAs and the SpCas9 nuclease were used to transduce immortalized patient muscle cells, inducing the specific deletion of the mutant RYR1 allele. The efficiency of the deletion was assessed at both DNA and RNA levels and at the functional level after monitoring calcium release induced by the stimulation of the RyR1-channel. This study provides in-cellulo proof of concept regarding the benefits of mutant RYR1 allele deletion, in the case of a dominant RYR1 mutation, from both a molecular and functional perspective.

Synaptic vesicle release regulates pre-myelinating oligodendrocyte-axon interactions in a neuron subtype-specific manner
Oligodendrocyte-lineage cells are central nervous system (CNS) glia that perform multiple functions including the selective myelination of some but not all axons. During myelination, synaptic vesicle release from axons promotes sheath stabilization and growth on a subset of neuron subtypes. In comparison, it is unknown if pre-myelinating oligodendrocyte process extensions selectively interact with specific neural circuits or axon subtypes, and whether the formation and stabilization of these neuron-glia interactions involves synaptic vesicle release. In this study, we used fluorescent reporters in the larval zebrafish model to track pre-myelinating oligodendrocyte process extensions interacting with spinal axons utilizing in vivo imaging. Monitoring motile oligodendrocyte processes and their interactions with individually labeled axons revealed that synaptic vesicle release regulates the behavior of subsets of process extensions. Specifically, blocking synaptic vesicle release decreased the longevity of oligodendrocyte process extensions interacting with reticulospinal axons. Furthermore, blocking synaptic vesicle release increased the frequency that new interactions formed and retracted. In contrast, tracking the movements of all process extensions of singly-labeled oligodendrocytes revealed that synaptic vesicle release does not regulate overall process motility or exploratory behavior. Blocking synaptic vesicle release influenced the density of oligodendrocyte process extensions interacting with reticulospinal and serotonergic axons, but not commissural interneuron or dopaminergic axons. Taken together, these data indicate that alterations to synaptic vesicle release cause changes to oligodendrocyte-axon interactions that are neuron subtype specific.

Probing the Link Between Vision and Language in Material Perception
The ability to visually discriminate and recognize materials (e.g., candy or crystal) is crucial in planning actions (e.g., determining edibility) in the environment. Meanwhile, language is a powerful channel for communicating the characteristics of materials. However, the connection between these two modalities in material perception has remained elusive. Here, we created a diverse set of perceptually convincing material appearances with deep generative networks that model the statistical structure of real-world photos. Besides generating familiar materials (e.g., soaps, rocks, and squishy toys), we also synthesized unfamiliar novel materials with cross-category morphing (e.g., transforming a soap into a rock). With stimuli sampled from this expansive space, we compared the representations of materials from two cognitive tasks: visual material similarity judgments and verbal descriptions. Our analysis unveiled a moderate but significant correlation between vision and language within individuals. In contrast, the image-based representation derived from the latent code of the generative model only weakly correlated with human visual judgments. Furthermore, we showed that joining image- and semantic-level representations could improve the prediction of human perception. Material perception may actively involve a high-level understanding of materials and objects to resolve the ambiguity of visual information, and it cannot be merely explained by low-to-mid-level image features. Together, our findings highlight the necessity of leveraging semantic description and visual feature extraction to unveil the critical dimensions of material perception and further improve computer vision models targeting material-related tasks.

Branch-specific clustered parallel fiber input controls dendritic computation in Purkinje cells
Most central neurons have intricately branched dendritic trees that integrate massive numbers of synaptic inputs. Intrinsic active mechanisms in dendrites can be heterogenous and be modulated in a branch-specific way. However, it remains poorly understood how heterogenous intrinsic properties contribute to processing of synaptic input. We propose the first computational model of the cerebellar Purkinje cell with dendritic heterogeneity, in which each branch is an individual unit and is characterized by its own set of ion channel conductance densities. When simultaneously activating a cluster of parallel fiber synapses, we measure the peak amplitude of a response (PAR) and observe how changes in P-type calcium channel conductance density shift PAR from a linear one to a bimodal one including dendritic calcium spikes and vice-versa. These changes relate to the morphology of each branch. We show how dendritic calcium spikes propagate and how Kv4 channels block spreading depolarization to nearby branches.

Optogenetic silencing hippocampal inputs to the retrosplenial cortex causes a prolonged disruption of working memory
Working memory is a fundamental cognitive ability, allowing us to keep information in memory for the time needed to perform a given task. A complex neural circuit fulfills these functions, among which is the retrosplenial cortex (RSC). Functionally and anatomically connected to primary sensory cortices, namely visual areas, and to higher cognitive areas such as the cingulate, midcingulate, and subicular cortex, the RSC bears intimate anatomical and functional connections with the hippocampus, and has been implicated in integrating and translating spatial-temporal contextual information between ego- and allocentric reference frames, to compute predictions about goals in goal-directed behaviors. The relative contribution of the hippocampus and retrosplenial cortex in working memory-guided behaviors remains unclear due to the lack of studies reversibly interfering with synapses connecting the two regions during such behaviors. We here used eArch3.0, a hyperpolarizing proton pump, to silence hippocampal axon terminals in RSC while animals perform a standard delayed non-match to place task. We found that such manipulation impairs memory retrieval, significantly decreasing performance and hastening decision-making. Furthermore, we found that such impairment outlasts light-activation of the opsin, its effects being noticed up to 3 subsequent trials.

Epitranscriptomic Reader YTHDF2 Regulates SEK1(MAP2K4)-JNK-cJUN Inflammatory Signaling in Astrocytes during Neurotoxic Stress
As the most abundant glial cells in the CNS, astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress have remained elusive. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stresser, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, neurotoxic stress induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechnistically, YTHDF2 RIP-sequencing identified MAP2K4 (MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed Mn-exposed astrocytes mediates proinflammatory response by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves a key upstream molecular switch controlling SEK1(MAP2K4)-JNK-cJUN proinflammatory signaling in astrocytes.

Generation of human iPSC-derived phrenic-like motor neurons to model respiratory motor neuron degeneration in ALS
The fatal motor neuron (MN) disease Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive MN degeneration. Phrenic MNs (phMNs) controlling the activity of the diaphragm are prone to degeneration in ALS, leading to death by respiratory failure. Understanding of the mechanisms of phMN degeneration in ALS is limited, mainly because human experimental models to study phMNs are lacking. Here we describe a method enabling the derivation of phrenic-like MNs from human iPSCs (hiPSC-phMNs) within 30 days. This protocol uses an optimized combination of small molecules followed by cell-sorting based on a cell-surface protein enriched in hiPSC-phMNs, and is highly reproducible using several hiPSC lines. We show further that hiPSC-phMNs harbouring ALS-associated amplification of the C9orf72 gene progressively lose their activity and undergo increased death compared to isogenic controls. These studies establish a previously unavailable protocol to generate human phMNs, offering a disease-relevant system to study mechanisms of respiratory MN dysfunction.

Regional specialization manifests in the reliability of neural population codes
The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions, whereas the OFC is necessary for waiting for and learning from the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.

Efficient Inference on a Network of Spiking Neurons using Deep Learning
The process of making inference on networks of spiking neurons is crucial to decipher the underlying mechanisms of neural computation. Mean-field theory simplifies the interactions between neurons to produce macroscopic network behavior, facilitating the study of information processing and computation within the brain. In this study, we perform inference on a mean-field model of spiking neurons to gain insight into likely parameter values, uniqueness and degeneracies, and also to explore how well the statistical relationship between parameters is maintained by traversing across scales. We benchmark against state-of-the-art optimization and Bayesian estimation algorithms to identify their strengths and weaknesses in our analysis. We show that when confronted with dynamical noise or in the case of missing data in the presence of bistability, generating probability distributions using deep neural density estimators outperforms other algorithms, such as adaptive Monte Carlo sampling. However, this class of deep generative models may result in an overestimation of uncertainty and correlation between parameters. Nevertheless, this issue can be improved by incorporating time-delay embedding. Moreover, we show that training deep Neural ODEs on spiking neurons enables the inference of system dynamics from microscopic states. In summary, this work demonstrates the enhanced accuracy and efficiency of inference on networks of spiking neurons when deep learning is harnessed to solve inverse problems in neural computation.

High-dimensional cortical signals reveal rich bimodal and working memory-like representations among S1 neuron populations
Complexity is important for flexibility of natural behavior and for the remarkably efficient learning of the brain. Here we assessed the signal complexity among neuron populations in somatosensory cortex (S1). To maximize our chances of capturing population level signal complexity, we used highly repeatable resolvable visual, tactile and visuo-tactile inputs and neuronal unit activity recorded at high temporal resolution. We found the state space of the spontaneous activity to be extremely high-dimensional in S1 populations. Their processing of tactile inputs was profoundly modulated by visual inputs and even fine nuances of visual input patterns were separated. Moreover, the dynamic activity states of the S1 neuron population signaled the preceding specific input long after the stimulation had terminated, i.e. resident information that could be a substrate for a working memory. Hence, the recorded high dimensional representations carried rich multimodal and internal working memory-like signals supporting high complexity in cortical circuitry operation.

Characterisation of laminar and vascular spatiotemporal dynamics of CBV and BOLD signals using VASO and ME-GRE at 7T in humans
Interpretation of cortical laminar functional magnetic resonance imaging (fMRI) activity requires detailed knowledge of the spatiotemporal haemodynamic response across vascular compartments due to the well-known vascular biases (e.g. the draining veins). Further complications arise from the spatiotemporal hemodynamic response that differs depending on the duration of stimulation. This information is crucial for future studies using depth-dependent cerebral blood volume (CBV) measurements, which promise higher specificity for the cortical microvasculature than the blood oxygenation level dependent (BOLD) contrast. To date, direct information about CBV dynamics with respect to stimulus duration, cortical depth and vasculature is missing in humans. Therefore, we characterized the cortical depth-dependent CBV-haemodynamic responses across a wide set of stimulus durations with 0.9 mm isotropic spatial and 0.785 seconds effective temporal resolution in humans using slice-selective slab-inversion vascular space occupancy (SS-SI VASO). Additionally, we investigated signal contributions from macrovascular compartments using fine-scale vascular information from multi-echo gradient-echo (ME-GRE) data at 0.35 mm isotropic resolution. In total, this resulted in >7.5h of scanning per participant (n=5). We have three major findings: (I) While we could demonstrate that 1 second stimulation is viable, more than 12 seconds stimulation provides the optimal CBV responses most sensitive to microvasculature, but durations beyond 24 seconds of stimulation may be wasteful for certain applications. (II) We observe that CBV responses show dilation patterns across the cortex. (III) While we found increasingly strong BOLD signal responses in vessel-dominated voxels with longer stimulation durations, we found increasingly strong CBV signal responses in vessel-dominated voxels only until 4 second stimulation durations. After 4 seconds, only the non-vessel dominated voxel signal kept increasing. This might explain why CBV responses are more specific to the underlying neuronal activity for long stimulus durations.

Exposure to epoxiconazole induces hyperlocomotion in adult zebrafish
Global agricultural production is sustained by an elevated use of pesticides. Their application in crops results in environmental contamination, which is demonstrated by widespread detections of these chemicals in aquatic ecosystems. This presence poses a risk to non-target organisms and ecological balance since the effects of potential exposure are misunderstood. Epoxiconazole (EPX) is a widely employed triazole fungicide, which has been frequently reported as a contaminant in superficial waters. However, the behavioral effects of EPX exposure in non-target organisms such as fish remain unexplored. We aimed to investigate the effects of EPX exposure on behavioral and biochemical outcomes, using zebrafish as a model organism. For this purpose, a static system was set with concentrations (24, 144, 240 g/L) based on the fungicide environmental detection. The novel tank test (NTT) was performed after 96 h of exposure. The social preference test (SPT) was executed after 120 h, as well as the biochemical assays. In the NTT, the animals increased distance traveled, crossings, entries in the top area, and mean speed, indicating hyperlocomotion. No significant effects were observed in the SPT and the biochemical analyses. We suggest that the increased locomotion is related to the stimulant properties of EPX. Our results contribute to an in-depth understanding of this fungicide effects in zebrafish, which is essential for environmental contamination monitoring and management.

Neurocan regulates axon initial segment organization and neuronal activity in cultured cortical neurons
The neural extracellular matrix (ECM) accumulates in the form of perineuronal nets (PNNs), particularly around fast-spiking GABAergic interneurons in the cortex and hippocampus, but also in association with the axon initial segments (AIS) and nodes of Ranvier. Increasing evidence highlights the role of Neurocan (Ncan), a brain-specific component of ECM, in the pathophysiology of neuropsychiatric disorders like bipolar disorder and schizophrenia. Ncan localizes at PNNs, nodes of Ranvier and the AIS, highlighting its potential role in regulation of axonal excitability. Here, we used knockdown and knockout approaches in mouse primary cortical neurons in combination with immunocytochemistry, western blotting and electrophysiological techniques to characterize the role of Ncan in the organization of PNNs and AIS and in the regulation of neuronal activity. We found that reduced Ncan levels led to remodeling of PNNs around neurons via upregulated Aggrecan mRNA and protein levels, increased expression of activity-dependent c-Fos and FosB genes and elevated spontaneous synaptic activity. The latter correlated with increased levels of Ankyrin-G in the AIS particularly in excitatory neurons, and with the elevated expression of Nav1.6 channels. Our results suggest that Ncan regulate expression of key proteins in PNNs and AISs and provide new insights into its role in the fine-tuning of neuronal functions.

Cortical representational geometry of diverse tasks reveals subject-specific and subject-invariant cognitive structures
The variability in brain function forms the basis for our uniqueness. Prior studies indicate smaller individual differences and larger inter-subject correlation (ISC) in sensorimotor areas than in the association cortex. These studies, deriving information from brain activity, leave individual differences in cognitive structures based on task similarity relations unexplored. This study quantitatively evaluates these differences by integrating ISC, representational similarity analysis, and vertex-wise encoding models using functional magnetic resonance imaging across 25 cognitive tasks. ISC based on cognitive structures enables subject identification with 100% accuracy using at least 14 tasks. ISC is larger in the fronto-parietal association and higher-order visual cortices, suggesting subject-invariant cognitive structures in these regions. Principal component analysis reveals different cognitive structure configurations within these regions. This study provides new evidence of individual variability and similarity in abstract cognitive structures.

Leptin Activated Hypothalamic BNC2 Neurons Acutely Suppress Food Intake
Leptin is an adipose tissue hormone that maintains homeostatic control of adipose tissue mass by regulating the activity of specific neural populations controlling appetite and metabolism. Leptin regulates food intake by inhibiting orexigenic agouti-related protein (AGRP) neurons and activating anorexigenic pro-opiomelanocortin (POMC) neurons. However, while AGRP neurons regulate food intake on a rapid time scale, acute activation of POMC neurons has only a minimal effect. This has raised the possibility that there is a heretofore unidentified leptin-regulated neural population that suppresses appetite on a rapid time scale. Here, we report the discovery of a novel population of leptin-target neurons expressing basonuclin 2 (Bnc2) that acutely suppress appetite by directly inhibiting AGRP neurons. Opposite to the effect of AGRP activation, BNC2 neuronal activation elicited a place preference indicative of positive valence in hungry but not fed mice. The activity of BNC2 neurons is finely tuned by leptin, sensory food cues, and nutritional status. Finally, deleting leptin receptors in BNC2 neurons caused marked hyperphagia and obesity, similar to that observed in a leptin receptor knockout in AGRP neurons. These data indicate that BNC2-expressing neurons are a key component of the neural circuit that maintains energy balance, thus filling an important gap in our understanding of the regulation of food intake and leptin action.

Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries
Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific signs and vulnerabilities. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following repetitive mild traumatic brain injuries (rmTBIs). In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and Neurite Orientation Dispersion and Density Imaging (NODDI). Utilizing the CHIMERA model, we conducted rmTBIs or sham (control) procedures on young (2.5-3 months old) and aged (22-month-old) male and female mice to model high-risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposing effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean, radial, axial diffusivity, fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Inflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in aged animals. These findings provide a comprehensive understanding of the intricate interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBIs.

Inhibitory control of gait initiation in humans: an electroencephalography study
Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go-NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time (RT), without any difference for the other parameters of gait initiation. Proactive inhibition, i.e. Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative - Go-uncertain versus Go-certain and NoGo versus Go-uncertain - stimuli. These findings demonstrate that the uncertainty context induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows protracted influence of inhibitory control in gait initiation.

Hippocampal reactive neural stem cells are able to phagocytose and have an immunological molecular signature
Hippocampal neural stem cells (NSCs) are the drivers of neurogenesis in the dentate gyrus (DG) of most mammals including humans. During neuronal hyperactivity NSCs become reactive NSCs (react-NSCs), characterized by their activation, morphological changes, and symmetric division, abandoning their neurogenic programme and transforming into reactive astrocytes. Here, using different pathological models that induce react-NSCs in the DG, we looked for novel features of react-NSCs both histologically and by total RNA sequencing. We report that in two pathological models were react-NSCs emerge (mesial temporal lobe epilepsy (MTLE) and traumatic brain injury (TBI)) react-NSCs are capable of phagocytosis of dead cells, a typical immunological function carried out mainly by microglia in the brain. Importantly, MTLE-induced react-NSCs show phagocytic function in tissue and a predominantly immunological molecular signature, with a broad upregulation of phagocytosis-related gene expression. Our results describe a new function of react-NSCs as phagocytic and immunologically active cells in the hippocampal neurogenic niche.

Amplifying post-stimulation oscillatory dynamics by engaging synaptic plasticity with periodic stimulation: a modelling study
Periodic brain stimulation (PBS) techniques, either intracranial or non-invasive, electrical or magnetic, represent promising neuromodulatory tools for the treatment of neurological and neuropsychiatric disorders. Through the modulation of endogenous oscillations, PBS may engage synaptic plasticity, hopefully leading to persistent lasting effects. However, stabilizing such effects represents an important challenge: the interaction between induced electromagnetic fields and neural circuits may yield highly variable responses due to heterogeneous neuronal and synaptic biophysical properties, limiting PBS clinical potential. In this study, we explored the conditions on which PBS leads to amplified post-stimulation oscillatory power, persisting once stimulation has been turned off. We specifically examined the effects of heterogeneity in neuron time scales on post-stimulation dynamics in a population of balanced leaky-integrated and fire (LIF) neurons that exhibit synchronous-irregular spiking activity. Our analysis reveals that such heterogeneity enables PBS to engage synaptic plasticity, amplifying post-stimulation power. Our results show that such post-stimulation aftereffects result from selective frequency- and cell-type-specific synaptic modifications. We evaluated the relative importance of stimulation-induced plasticity amongst and between excitatory and inhibitory populations. Our results indicate that heterogeneity in neurons' time scales and synaptic plasticity are both essential for stimulation to support post-stimulation aftereffects, notably to amplify the power of endogenous rhythms.

Functional brain adaptations during speech processing in 4-month-old bilingual infants
Language learning is influenced by both neural development and environmental experiences. This work investigates the influence of early bilingual experience on the neural mechanisms underlying speech processing in 4-month-old infants. We study how an early environmental factor such as bilingualism interacts with neural development by comparing monolingual and bilingual infants' brain responses to speech. We used functional near-infrared spectroscopy (fNIRS) to measure 4-month-old Spanish-Basque bilingual and Spanish monolingual infants' brain responses while they listened to forward (FW) and backward (BW) speech stimuli in Spanish. We reveal distinct neural signatures associated with bilingual adaptations, including increased engagement of bilateral inferior frontal and temporal regions during speech processing in bilingual infants, as opposed to left hemispheric specialization observed in monolingual infants. This study provides compelling evidence of bilingualism-induced brain adaptations during speech processing in infants as young as four months. These findings emphasize the role of early language experience in shaping neural plasticity during infancy suggesting that bilingual exposure at this young age profoundly influences the neural mechanisms underlying speech processing.

The Temporal Dynamics of Aperiodic Neural Activity Track Changes in Sleep Architecture
The aperiodic (1/f-like) component of electrophysiological data - whereby power systematically decreases with increasing frequency, as quantified by the aperiodic exponent - has been shown to differentiate sleep stages. Earlier work, however, has typically focused on measuring the aperiodic exponent across a narrow frequency range. In this work, we sought to further investigate aperiodic activity during sleep by extending these analyses across broader frequency ranges and considering alternate model definitions. This included measuring knees in the aperiodic component, which reflect bends in the power spectrum, indicating a change in the exponent. We also sought to evaluate the temporal dynamics of aperiodic activity during sleep. To do so, we analyzed data from two sources: intracranial EEG (iEEG) from 106 epilepsy patients and high-density EEG from 17 healthy individuals, and measured aperiodic activity, explicitly comparing different frequency ranges and model forms. In doing so, we find that fitting broadband aperiodic models and incorporating a knee feature effectively captures sleep-stage-dependent differences in aperiodic activity as well as temporal dynamics that relate to sleep stage transitions and responses to external stimuli. In particular, the knee parameter shows stage-specific variation, suggesting an interpretation of varying timescales across sleep stages. These results demonstrate that examining broader frequency ranges with the more complex aperiodic models reveals novel insights and interpretations for understanding aperiodic neural activity during sleep.

Detection of cell assemblies in high-density extracellular electrophysiological recordings
Cell assemblies, i.e., concurrently active groups of neurons, likely underlie neural processing for higher brain functions. Recent technological progress has enabled large-scale recording of neuronal activity, permitting the exploration and analysis of cell assembly dynamics. This article aims to provide both conceptual insights and practical knowledge pertaining to principal methodologies used for detecting cell assemblies in the last fifteen years. The goal is to assist readers in selecting and comparing various protocols to optimize their data processing and analysis pipeline. Each algorithm is explained with its fundamental principles, their application in neuroscience for cell assembly detection, and illustrated with published studies. Finally, we implemented these methods on a simulated recording with known ground truth and compared their performances. Recognizing the similarities, advantages, and drawbacks of diverse methodologies may pave the way for developing new procedures for cell assembly identification to facilitate future endeavors in the understanding of brain activity.

Adult-Onset Deletion of ATP13A2 in Mice Induces Progressive Nigrostriatal Pathway Dopaminergic Degeneration and Lysosomal Abnormalities
Although most cases of Parkinson's disease (PD) are sporadic, mutations in over 20 genes are known to cause heritable forms of PD. A surprising number of familial PD-linked genes and PD risk genes are involved in intracellular trafficking and protein degradation. Recessive loss-of-function mutations in ATP13A2, a lysosomal transmembrane P5B-type ATPase and polyamine exporter, can cause early-onset familial PD. Familial ATP13A2 mutations are also linked to related neurodegenerative diseases, including Kufor-Rakeb syndrome (KRS), hereditary spastic paraplegias (HSPs), neuronal ceroid lipofuscinosis, and amyotrophic lateral sclerosis (ALS). Given the severe effects of ATP13A2 mutations in humans, it is surprising that ATP13A2 knockout (KO) mice fail to exhibit neurodegeneration even at advanced ages. This discrepancy between human subjects and rodents makes it challenging to study the neuropathological effects of ATP13A2 loss in vivo. Germline deletion of ATP13A2 in rodents may trigger the upregulation of compensatory pathways during embryonic development that mask the full neurotoxic effects of ATP13A2 loss in the brain. To explore this idea, we selectively deleted ATP13A2 in the adult mouse brain by the unilateral delivery of an AAV-Cre vector into the substantia nigra of young adult mice carrying conditional loxP-flanked ATP13A2 KO alleles. We observe a progressive loss of striatal dopaminergic nerve terminals at 3 and 10 months after AAV-Cre delivery. Cre-injected mice also exhibit robust dopaminergic neuronal degeneration in the substantia nigra at 10 months. Adult-onset ATP13A2 KO also recreates many of the phenotypes observed in aged germline ATP13A2 KO mice, including lysosomal abnormalities, p62-positive inclusions, and neuroinflammation. Our study demonstrates that the adult-onset homozygous deletion of ATP13A2 in the nigrostriatal pathway produces robust and progressive dopaminergic neurodegeneration that serves as a useful in vivo model of ATP13A2-related neurodegenerative diseases.

Prolactin-mediates a lactation-induced suppression of arcuate kisspeptin neuronal activity necessary for lactational infertility in mice
The specific role that prolactin plays in lactational infertility, as distinct from other suckling or metabolic cues, remains unresolved. Here, deletion of the prolactin receptor (Prlr) from forebrain neurons or arcuate kisspeptin neurons resulted infailure to maintain normal lactation-induced suppression of estrous cycles. Kisspeptin immunoreactivity and pulsatile LH secretion were increased in these mice, even in the presence of ongoing suckling stimulation and lactation. GCaMP6 fibre photometry of arcuate kisspeptin neurons revealed that the normal episodic activity of these neurons is rapidly suppressed in pregnancy and this was maintained throughout early lactation. Deletion of Prlr from arcuate kisspeptin neurons resulted in early reactivation of episodic activity of kisspeptin neurons prior to a premature return of reproductive cycles in early lactation. These observations show dynamic variation in arcuate kisspeptin neuronal activity associated with the hormonal changes of pregnancy and lactation, and provide direct evidence that prolactin action on arcuate kisspeptin neurons is necessary for suppressing fertility during lactation.

Spyglass: a data analysis framework for reproducible and shareable neuroscience research
Sharing data and reproducing scientific results are essential for progress in neuroscience, but the community lacks the tools to do this easily for large datasets and results obtained from intricate, multi-step analysis procedures. To address this issue, we created Spyglass, an open-source software framework designed to promote the shareability and reproducibility of data analysis in neuroscience. Spyglass integrates standardized formats with reliable open-source tools, offering a comprehensive solution for managing neurophysiological and behavioral data. It provides well-defined and reproducible pipelines for analyzing electrophysiology data, including core functions like spike sorting. In addition, Spyglass simplifies collaboration by enabling the sharing of final and intermediate results across custom, complex, multi-step pipelines as well as web-based visualizations. Here we demonstrate these features and showcase the potential of Spyglass to enable findable, accessible, interoperable, and reusable (FAIR) data management and analysis by applying advanced state space decoding algorithms to publicly available data from multiple laboratories.

Breaking free from the clocks tyranny restores memory to brain damaged flies
The relationship between sleep and memory is an active topic of investigation. In this context, we demonstrate that enhancing sleep restores memory to flies with ablated Mushroom Bodies (MB), a key memory center; this is consistent across several memory assays. Mapping the underlying circuitry reveals circadian modulation of a subset of Dopaminergic neurons (DANs) that modulate aversive learning. Using imaging, we show that MB-ablation disrupts, and sleep restores the time of day these neurons are most responsive. Knocking down the receptor for the clock output signal, Pigment-dispersing factor (Pdfr), in this subset of DANs restores memory to MB-ablated flies. Crucially, MB-ablation does not result in memory impairments in the absence of a functioning clock. Our results reveal neuromodulation's key role in cognitive restoration, where sleep aids memory in damaged brains, but a functioning clock unexpectedly hinders this process.

Superagers resist typical age-related white matter structural changes
Superagers are elderly individuals with the memory ability of people 30 years younger and provide evidence that age-related cognitive decline is not inevitable. In a sample of 64 superagers (mean age 81.9; 59% women) and 55 typical older adults (mean age 82.4; 64% women) from the Vallecas Project, we studied, cross-sectionally and longitudinally over 5 years with yearly follow-ups, the global cerebral white matter status as well as region-specific white matter microstructure assessment derived from diffusivity measures. Superagers and typical older adults showed no difference in global white matter health (total white matter volume, Fazekas score, and lesions volume) cross-sectionally or longitudinally. However, analyses of diffusion parameters revealed better white matter microstructure in superagers than in typical older adults. Cross-sectional differences showed higher fractional anisotropy (FA) in superagers mostly in frontal fibres and lower mean diffusivity (MD) in most white matter tracts, expressed as an anteroposterior gradient with greater group differences in anterior tracts. FA decrease over time is slower in superagers than in typical older adults in all white matter tracts assessed, which is mirrored by MD increases over time being slower in superagers than in typical older adults in all white matter tracts except for the corticospinal tract, the uncinate fasciculus and the forceps minor. The better preservation of white matter microstructure in superagers relative to typical older adults supports resistance to age-related brain structural changes as a mechanism underpinning the remarkable memory capacity of superagers, while their regional ageing pattern is in line with the last-in-first-out hypothesis.

Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females
This study aimed to investigate the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hind paws and dorsal root ganglia (DRG). Bulk RNA seq was used to investigate the gene expression changes in the paw and DRG collected at 1, 16, and 31 days post PTX. At these time points, differentially expressed DEGs were predominantly related to reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes were accompanied by regulation of DEGs related to cytoskeleton, extracellular matrix organization and cellular energy production. This gene plasticity during persistent painful neuropathy progression likely represents biological processes linked to tissue regeneration and degeneration. Unlike regeneration/degeneration, gene plasticity related to immune processes was minimal at 1 to 31 days post PTX. It was also noted that despite similarities in biological processes and pain chronicity in males and females, specific DEGs showed dramatic sex-dependency. The main conclusions of this study are that gene expression plasticity in paws and DRG during PTX neuropathy progression relates to tissue regeneration and degeneration, minimally affects the immune system processes, and is heavily sex-dependent at the individual gene level.