bioRxiv Subject Collection: Neuroscience's Journal

Microsaccade direction reveals the variation in auditory selective attention processes
Selective spatial attention plays a critical role in perception in the daily environment where multiple sensory stimuli exist. Even covertly directing attention to a specific location facilitates the brain's information processing of stimuli at the attended location. Previous behavioral and neurophysiological studies have shown that microsaccades, tiny involuntary saccadic eye movements, reflect such a process in terms of visual space and can be a marker of spatial attention. However, it is unclear whether auditory spatial attention processes that are supposed to interact with visual attention processes influence microsaccades and vice versa. Here, we examine the relationship between microsaccade direction and auditory spatial attention during dichotic oddball sound detection tasks. The results showed that the microsaccade direction was generally biased contralateral to the ear to which the oddball sound was presented or that to which sustained auditory attention was directed. The post-oddball modulation of microsaccade direction was associated with the behavioral performance of the detection task. The results suggest that the inhibition of stimulus-directed microsaccade occurs to reduce erroneous orientation of ocular responses during selective detection tasks. We also found that the correlation between microsaccade direction and neural response to the tone originated from the auditory brainstem (frequency-following response: FFR). Overall, the present study suggests that microsaccades can be a marker of auditory spatial attention and that the auditory neural activity fluctuates over time with the states of attention and the oculomotor system, also involving the auditory subcortical processes.

A sticky Poisson Hidden Markov Model for spike data
Fitting a hidden Markov Model (HMM) to neural data is a powerful method to segment a spatiotemporal stream of neural activity into sequences of discrete hidden states. Application of HMM has allowed to uncover hidden states and signatures of neural dynamics that seem relevant for sensory and cognitive processes. This has been accomplished especially in datasets comprising ensembles of simultaneously recorded cortical spike trains. However, the HMM analysis of spike data is involved and requires a careful handling of model selection. Two main issues are: (i) the cross-validated likelihood function typically increases with the number of hidden states; (ii) decoding the data with an HMM can lead to very rapid state switching due to fast oscillations in state probabilities. The first problem is related to the phenomenon of over-segmentation and leads to overfitting. The second problem is at odds with the empirical fact that hidden states in cortex tend to last from hundred of milliseconds to seconds. Here, we show that we can alleviate both problems by regularizing a Poisson-HMM during training so as to enforce large self-transition probabilities. We call this algorithm the "sticky Poisson-HMM" (sPHMM). When used together with the Bayesian Information Criterion for model selection, the sPHMM successfully eliminates rapid state switching, outperforming an alternative strategy based on an HMM with a large prior on the self-transition probabilities. The sPHMM also captures the ground truth in surrogate datasets built to resemble the statistical properties of the experimental data.

Astrocyte Regulation of Synaptic Plasticity Balances Robustness and Flexibility of Cell Assemblies
Cell assemblies are believed to represent the substrate of memory. Although long-term plasticity likely enables the formation of cell assemblies, how other factors, such as astrocytes and short-term plasticity (STP), affect their properties is poorly understood. To close this gap, we investigated cell assembly dynamics in a recurrent network model mimicking the hippocampal area CA3. As shown in experiment, recurrent connections in our model obey a symmetric spike-timing-dependent plasticity (STDP), in which weight change may or may not depend on the releasable amount of neurotransmitter. The former case involves an interplay between STDP and STP. In addition, we implicitly modeled the effect of astrocyte NMDA receptors by manipulating the breadth of the distribution of neurotransmitter release probability in STP. Both STP-dependent and STP-independent STDP enabled spontaneous cell assembly formation. Under the former, however, cell assemblies tend to be smaller and more responsive to external stimulation, improving the network's memory capacity and enabling flexible network restructuring. Furthermore, astrocyte regulation of the STP-dependent STDP facilitates stimulus-driven reorganization of neural networks without destroying existing assembly structure, thus balancing cell assemblies' flexibility and robustness. Our findings elucidate the computational advantages of interaction between STP and STDP and highlight astrocytes' possible regulatory role in memory formation.

Deletion of endocannabinoid synthesizing enzyme DAGLα from cerebellar Purkinje cells decreases social preference and elevates anxiety
The endocannabinoid (eCB) signaling system is robustly expressed in the cerebellum starting from the embryonic developmental stages to adulthood. There it plays a key role in regulating cerebellar synaptic plasticity and excitability, suggesting that impaired eCB signaling will lead to deficits in cerebellar adjustments of ongoing behaviors and cerebellar learning. Indeed, human mutations in DAGL are associated with neurodevelopmental disorders. In this study, we show that selective deletion of the eCB synthesizing enzyme diacylglycerol lipase alpha (Dagl) from mouse cerebellar Purkinje cells (PCs) alters motor and social behaviors, disrupts short-term synaptic plasticity in both excitatory and inhibitory synapses, and reduces Purkinje cell activity during social exploration. Our results provide the first evidence for cerebellar-specific eCB regulation of social behaviors and implicate eCB regulation of synaptic plasticity and PC activity as the neural substrates contributing to these deficits.

Reduced gene dosage of the psychiatric risk gene Cacna1c is associated with impairments in hypothalamic-pituitary-adrenal axis activity in rats
Common and rare variation in CACNA1C gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression, however the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage of Cacna1c have increased basal corticosterone levels in the periphery and reduced Nr3c1 gene expression in the hippocampus and hypothalamus. These results are consistent with an effect of Cacna1c dosage on hypothalamus-pituitary-adrenal (HPA) axis function. We also show that the reduction of Nr3c1 in the hippocampus may be caused by epigenetic modification of exon 17 of Nr3c1, including the reduced interaction with the histone modifying markers H3K4me3 and H3K27ac. Heterozygous Cacna1c rats additionally show increased anxiety behaviours. These results support an association of Cacna1c heterozygosity with the altered activity of the HPA axis and function in the resting state and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress.

All-Diamond Boron-Doped Microelectrodes for Neurochemical Sensing with Fast-Scan Cyclic Voltammetry
Neurochemical sensing with implantable devices has gained remarkable attention over the last few decades. A promising area of this research is the progress of novel electrodes as electrochemical tools for neurotransmitter detection in the brain. The boron-doped diamond (BDD) electrode is one such candidate that previously has been reported for its excellent electrochemical properties, including a wide working potential, superior chemical inertness and mechanical stability, good biocompatibility, and resistance to fouling. Meanwhile, limited research has been conducted on the BDD as a microelectrode for neurochemical detection. Our team has developed a freestanding, all-diamond microelectrode consisting of a boron-doped polycrystalline diamond core, encapsulated in an insulating polycrystalline diamond shell, with a cleaved planar tip for electrochemical sensing. This all-diamond electrode is advantageous due to its - (1) batch fabrication using wafer technology that eliminates traditional hand fabrication errors and inconsistencies, (2) absence of metal-based wires, or foundations, to improve biocompatibility and flexibility, and (3) sp3 carbon surface with resistance to biofouling, i.e. adsorption of proteins or unwanted molecules at the electrode surface in a biological environment that impedes overall electrode performance. Here, we provide findings on further in vitro testing and development of the freestanding boron-doped diamond microelectrode (BDDME) for neurotransmitter detection using fast-scan cyclic voltammetry (FSCV). In this report, we elaborate on - 1) an updated fabrication scheme and workflow to generate all diamond BDDMEs, 2) slow scan cyclic voltammetry measurements of reference and target analytes to understand basic electrochemical behavior of the electrode, and 3) FSCV characterization of common neurotransmitters, and overall favorability of serotonin (5-HT) detection. The BDDME showed a 2-fold increased FSCV response for 5-HT in comparison to dopamine (DA), with a limit of detection of 0.16 M for 5-HT and 0.26 M for DA. These results are intended to expand on the development of the next-generation BDDME and guide future in vivo experiments, adding to the growing body of literature on implantable devices for neurochemical sensing.

Neuropeptide oxytocin facilitates its own brain-to-periphery uptake by regulating blood flow dynamics and permeability
The hypothalamo-neurohypophyseal system is an important neuroendocrine brain-to-blood conduit through which the neurohormones oxytocin and arginine-vasopressin are released from the brain into the general circulation to affect peripheral physiological functions such as salt balance, metabolism and reproduction. However, whether an active mechanism executes fast and efficient neurohormone release to the periphery remains unsolved. We show that a hyperosmotic physiological challenge elicits a local increase in neurohypophyseal blood flow velocities and a change in capillary diameter, which is dictated by the geometry of the hypophyseal vascular microcircuit. Genetic ablation of oxytocin neurons and inhibition of oxytocin receptor signaling attenuated capillary blood flow and diameter. Optogenetic stimulation of oxytocin neurons resulted in an oxytocin receptor-dependent increase in blood flow velocities. Lastly, both osmotic challenge and oxytocin neuronal activation elicited a local rise in neurohypophyseal capillary permeability in an oxytocin signaling-dependent manner. Our study demonstrates that physiologically elicited changes in neurohypophyseal blood flow and permeability are regulated by oxytocin. We propose that oxytocin-dependent neuro-vascular coupling facilitates its efficient uptake into the blood circulation, suggesting a self-perpetuating mechanism of peripheral hormone transfer.

Conclusions about Neural Network to Brain Alignment are Profoundly Impacted by the Similarity Measure
Deep neural networks are popular models of brain activity, and many studies ask which neural networks provide the best fit. To make such comparisons, the papers use similarity measures such as Linear Predictivity or Representational Similarity Analysis (RSA). It is often assumed that these measures yield comparable results, making their choice inconsequential, but is it? Here we ask if and how the choice of measure affects conclusions. We find that the choice of measure influences layer-area correspondence as well as the ranking of models. We explore how these choices impact prior conclusions about which neural networks are most "brain-like". Our results suggest that widely held conclusions regarding the relative alignment of different neural network models with brain activity have fragile foundations.

Stability of cross-sensory input to primary somatosensory cortex across experience
Merging information from across sensory modalities is key to forming robust, disambiguated percepts of the world, yet how the brain achieves this feat remains unclear. Recent observations of cross-modal influences in primary sensory cortical areas have suggested that multisensory integration may occur in the earliest stages of cortical processing, but the role of these responses is still poorly understood. We address these questions by testing several hypotheses about the possible functions served by auditory influences on the barrel field of mouse primary somatosensory cortex (S1) using in vivo 2-photon calcium imaging. We observed sound-evoked spiking activity in a small fraction of cells overall, and moreover that this sparse activity was insufficient to encode auditory stimulus identity; few cells responded preferentially to one sound or another, and a linear classifier trained to decode auditory stimuli from population activity performed barely above chance. Moreover S1 did not encode information about specific audio-tactile feature conjunctions that we tested. Our ability to decode auditory audio-tactile stimuli from neural activity remained unchanged after both passive experience and reinforcement. Collectively, these results suggest that while a primary sensory cortex is highly plastic with regard to its own modality, the influence of other modalities are remarkably stable and play a largely stimulus-non-specific role.

The effect of performance contingent reward prospects flexibly adapts to more versus less specific task goals
In some situations, e.g., when we expect to gain a reward in case of good performance, goal-driven top-down attention is particularly strong. Little is known about the task specificity of such increases of top-down attention due to environmental factors. To understand to what extent performance-contingent reward prospects can result in specific and unspecific changes in cognitive processing, we here investigate reward effects under different levels of task specification. Thirty-two participants performed a visual or an auditory discrimination task cued by two consecutive visual stimuli: First, a reward cue indicated if good performance was rewarded. Second, a task cue announced either which of the two tasks would follow (precise cue) or that both tasks would follow equally likely (imprecise cue). Reward and task cue preciseness both significantly improved performance. Moreover, the response time difference between precisely and imprecisely cued trials was significantly stronger in rewarded than in unrewarded trials. These effects were reflected in ERP slow wave amplitudes: Reward and preciseness both significantly enhanced the contingent negative variation (CNV) prior to the task stimulus. In an early CNV time interval, both factors also showed an interaction. A negative slow wave prior to the task cue was also significantly enhanced for rewarded trials. This effect correlated with the reward difference in response times. These results indicate that reward prospects trigger task-specific changes in preparatory top-down attention which can flexibly adapt over time and across different task requirements. This highlights that a reward-induced increase of cognitive control can occur on different specificity levels.

Targeted Time-Varying Functional Connectivity
To elucidate the neurobiological basis of cognition, which is dynamic and evolving, various methods have emerged to characterise time-varying functional connectivity (FC) and track the temporal evolution of functional networks. However, given a selection of regions, many of these methods are based on modelling all possible pairwise connections, diluting a potential focus of interest on individual connections. This is the case with the hidden Markov model (HMM), which relies on region-by-region covariance matrices across all pairs of selected regions, assuming that fluctuations in FC occur across all investigated connections; that is, that all connections are locked to the same temporal pattern. To address this limitation, we introduce Targeted Time-Varying FC (T-TVFC), a variant of the HMM that explicitly models the temporal dynamics between two sets of regions in a targeted fashion, rather than across the entire connectivity matrix. In this study, we apply T-TVFC to both simulated and real-world data. Specifically, we investigate thalamocortical connectivity, hypothesizing distinct temporal signatures compared to corticocortical networks. Given the thalamus's role as a critical hub, thalamocortical dynamics might contain unique information about cognitive processing that could be overlooked in a coarser representation. We tested these hypotheses on high-field functional magnetic resonance data from 60 participants engaged in a reasoning task with varying complexity levels. Our findings demonstrate that the temporal dynamics captured by T-TVFC contain task-related information not detected by more traditional decompositions.

Impaired neurogenesis and synaptogenesis in iPSC-derived Parkinson's patient cortical neurons with D620N VPS35 mutation
Presynaptic dysfunction is an important early process in the pathophysiology of Parkinson's disease (PD) that drives disease progression. To gain insight into the intrinsic synapse impairment in PD, we performed comprehensive electrophysiological and morphological analysis of iPSC-derived cortical neurons derived from PD patients with the VPS35-D620N mutation. Our findings reveal significant impairment in neurogenesis and synaptogenesis within individual patient neurons, culminating to synaptic dysfunction even in the absence of neuronal interactions. The neurons exhibited significantly reduced synaptic responsiveness, fewer synapse and decreased dendritic length and complexity. Thus, the VPS35-D620N mutation in human cortical neurons independently can cause pathophysiology via synaptic dysfunction. Our study highlights the urgent need to develop disease-modifying therapies aimed at preserving synaptic function in PD.

Effects of serotonergic psychedelics on synaptogenesis and immediate early genes expression - comparison with ketamine, fluoxetine and lithium
Background: Recent evidence suggests that psychedelics are able to induce rapid and long-lasting antidepressant effects. The generally acknowledged explanation for these traits is the phenomenon of neuroplasticity, although exact underlying molecular mechanisms remain unclear. Aims: This study investigates selected neuroplastic effects of psilocin, lysergic acid diethylamide (LSD) and N,N-dimethyltryptamine (DMT) in direct comparison with ketamine, fluoxetine and lithium after acute (1 h) and/or prolonged (24 h) treatment in vitro. Methods: Rat primary cortical cultures were treated with 10 uM psilocin, 1 uM lysergic acid diethylamide (LSD), 90 uM N, N-dimethyltryptamine (DMT), 1 uM ketamine, 10 uM fluoxetine and 5 mM lithium. Analysis of synaptic puncta was performed; puncta of presynaptic marker synapsin I/II, postsynaptic density protein 95 (PSD-95), and their co-localization (established synapse) were assessed 24 h after drug treatment. Next, expressions of immediate early genes (IEGs) encoding activity-regulated cytoskeleton-associated protein (Arc), early growth response 1 (Egr1), and neuronal PAS (Per-ArntSim) domain protein 4 (Npas4) were analysed 1 and 24 h after drug treatments. Results: Psilocin increased synaptic puncta count and induced Arc expression. The effect to promote synaptogenesis was comparable to ketamine and lithium; ketamine additionally increased PSD-95 puncta count. LSD and DMT didn't induce any significant effect. Interestingly, fluoxetine had no effect on synaptic puncta count, but upregulated Egr1 and Npas4. Conclusions: Psilocin demonstrated a significant neuroplastic effect comparable to that of ketamine and lithium, adding another piece of evidence to its profile as a promising therapeutic agent.

Selective injury of thalamocortical tract in neonatal rats impairs forelimb use: modelvalidation and behavioral effects
Unilateral brain injury in neonates results in largely contralateral hand function in children. Most research investigating neurorehabilitation targets for movement recovery has focused on the effects of brain injury on descending motor systems, especially the corticospinal tract. However, a recent human study demonstrated that sensory tract injury may have larger effects on dexterity than motor tract injury. To validate that the sensory tract injury impairs dexterity, we modeled the most common site of sensory tract injury in neonates by targeting the thalamocortical tract. In the postnatal day 7 rats, we used three types of lesions to the thalamocortical tract: periventricular blood injection, photothrombotic lesion, and electrolytic lesion. To test the sensitivity and specificity of these techniques, viral tracers were injected into the primary sensory or motor cortex immediately after injury. Electrolytic lesions were the most specific and reproducible for inducing a lesion compared to the other two methods. Electrolytic lesions disrupted 63% of the thalamocortical tract, while sparing the adjacent corticospinal tract in the internal capsule. To measure the impact on dexterity, the cylinder exploration and pasta handling tests were used to test the changes of forelimb use at 8 weeks after injury when the rats reached maturity. Lesions to the thalamocortical tract were associated with a significant decrease in the use of the contralateral forelimb in the cylinder task, and the degree of impairment positively correlated with the degree of injury. Overall, specific sensory system lesions of the thalamocortical tract impair forelimb use, suggesting a key role for skilled movement.

Outer hair cells stir cochlear fluids
Recent observations regarding the non-selective action of outer hair cells contradict frequency-selective cochlear amplification. We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering a neurotoxin, kainic acid, to the round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid-structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently indicate that broadband outer-hair-cell action is for cochlear fluid circulation.

Wink or blush? Pupil-linked brain arousal signals both change and uncertainty during assessment of changing environmental regularities
One main cornerstone of adaptive behavior is belief updating, whereby new and unexpected observations lead to the updating of learned associations between events, behaviors and outcomes. This process necessitates the detection of changed environmental contingencies which in turn leads to uncertainty about the environmental regularities. Change and uncertainty are thus inherently linked, and both constructs have been linked to pupil size changes, which might reflect activity in neural networks underlying belief updating. Thus, in our study, we aimed to disentangle the effects of change and uncertainty on pupil-linked brain arousal. We used a probabilistic reversal learning task, where participants had to act according to changing preferences of a fictional character, and used specific cues to independently manipulate the level of change and uncertainty (e.g. the fictional character winked for signalizing change, or his face was blushed to indicate uncertainty). We found that when the cues triggered the same amount of uncertainty, larger levels of change in beliefs led to a transient increase in pupil size during cue processing. In contrast, when the cues signalized a similar amount of change, then increased belief uncertainty was associated with a sustained increase in pupil size, extending in time beyond cue processing. Thus, change and uncertainty exerted independent influence on pupil-linked brain arousal, suggesting the activity of different neural networks, and highlighting the need to disentangle the effects of these overlapping but distinct theoretical constructs.

Neuropathology in an α-synuclein preformed fibril mouse model occurs independent of the Parkinson's disease-linked lysosomal ATP13A2 protein
Loss-of-function mutations in the ATP13A2 (PARK9) gene are implicated in early-onset autosomal recessive Parkinson's disease (PD) and other neurodegenerative disorders. ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase that is highly expressed in brain and specifically within the substantia nigra. Recent studies have revealed its normal role as a lysosomal polyamine transporter, although its contribution to PD-related pathology remains unclear. Cellular studies report that ATP13A2 can regulate -synuclein (-syn) secretion via exosomes. However, the relationship between ATP13A2 and -syn in animal models remains inconclusive. ATP13A2 knockout (KO) mice exhibit lysosomal abnormalities and reactive astrogliosis but do not develop PD-related neuropathology. Studies manipulating -syn levels in mice lacking ATP13A2 indicate minimal effects on pathology. The delivery of -syn preformed fibrils (PFFs) into the mouse striatum is a well-defined model to study the development and spread of -syn pathology. In this study, we unilaterally injected wild-type (WT) and homozygous ATP13A2 KO mice with mouse -syn PFFs in the striatum and evaluated mice for neuropathology after 6 months. The distribution, extent and spread of -syn aggregation in multiple regions of the mouse brain was largely independent of ATP13A2 expression. The loss of nigrostriatal pathway dopaminergic neurons and their nerve terminals induced by PFFs were equivalent in WT and ATP13A2 KO mice. Reactive astrogliosis was induced equivalently by -syn PFFs in WT and KO mice but was significantly higher in ATP13A2 KO mice due to pre-existing gliosis. We did not identify asymmetric motor disturbances, microglial activation, or axonal damage induced by -syn PFFs in WT or KO mice after 6 months. Although -syn PFFs induce an increase in lysosomal number in the substantia nigra in general, TH-positive dopaminergic neurons did not exhibit either increased lysosomal area or intensity, regardless of ATP13A2 genotype. Our study evaluating the spread of -syn pathology reveals no exacerbation of -syn pathology, neuronal loss, astrogliosis or motor deficits in ATP13A2 KO mice, suggesting that selective lysosomal abnormalities resulting from ATP13A2 loss do not play a major role in -syn clearance or propagation in vivo.

A principled approach to community detection in interareal cortical networks
Structural connectivity between cortical areas, as revealed by tract-tracing is in the form of highly dense, weighted, directed, and spatially embedded complex networks. Extracting the community structure of these networks and aligning them with brain function is challenging, as most methods use local density measures, best suited for sparse graphs. Here we introduce a principled approach, based on distinguishability of connectivity profiles using the Hellinger distance, which is relatable to function. Applying it to tract-tracing data in the macaque, we show that the cortex at the interareal level is organized into a hierarchy of link-communities alongside with a node-community hierarchy. We find that the 1/2-Renyi divergence of connection profiles, a non-linear transform of the Hellinger metric, follows a Weibull-like distribution and scales linearly with the interareal distances, a quantitative expression between functional organization and cortical geometry. We discuss the relationship with the extensively studied SLN-based hierarchy.

PTEN deletion in the adult dentate gyrus induces Epilepsy
Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential. PTEN deletion was accomplished by injecting AAV-Cre either bilaterally or unilaterally into the dentate gyrus of double transgenic PTEN-floxed, ROSA-reporter mice. Hippocampal recording electrodes were implanted for continuous digital EEG with concurrent video recordings in the home cage. Electrographic seizures and epileptiform spikes were assessed manually by two investigators, and corelated with concurrent videos. Spontaneous electrographic and behavioral seizures appeared after focal PTEN deletion in adult dentate granule cells, commencing around 2 months post-AAV-Cre injection. Seizures occurred in the majority of mice with unilateral or bilateral PTEN deletion and led to death in several cases. PTEN-deletion provoked epilepsy was not associated with apparent hippocampal neuron death; supra-granular mossy fiber sprouting was observed in a few mice. In summary, focal, unilateral deletion of PTEN in the adult dentate gyrus suffices to provoke time-dependent emergence of a hyperexcitable circuit generating hippocampus-origin, generalizing spontaneous seizures, providing a novel model for studies of adult-onset epileptogenesis.

Disrupted stimulus encoding shapes tactile perception in autism.
Atypical sensory experience is an almost universal feature of autism. Amongst sensory modalities, tactile perception is particularly impacted, with alterations including difficulties detecting and discriminating low-level stimuli. However, we have not yet defined the neural underpinnings of low-level tactile perception and how they change in autism. Here we recapitulate the multifaceted tactile features of autistic individuals in the Fmr1-/y mouse model of autism and show tactile hyposensitivity and unreliable responses in a subgroup of Fmr1-/y mice. We reveal that weak stimulus encoding in the primary somatosensory cortex of Fmr1-/y-hyposensitive mice renders perception vulnerable to the ongoing network state and thus unreliable. Increasing the number and reliability of stimulus-recruited neurons by targeting the large conductance calcium-activated potassium (BKCa) channels improves tactile perception. Our work shows an evolutionarily conserved role for the primary somatosensory cortex in low-level tactile perception and encompasses a highly translational approach for probing perceptual changes in neurodevelopmental conditions.

Fidelity of focal sound source reproduction by higher (9th) order ambisonics and perceptual effects of reproduction errors
Higher-order ambisonic rendering is an increasingly common acoustic field reproduction technique that enables presentation of virtual sounds at nearly any location in 3D space, relatively unconstrained by the veridical locations of loudspeakers. We evaluated whether 3D sound reproduction through a 9th order ambisonic system was sufficiently accurate to probe the limits of human spatial perception. In Experiment 1, we estimated minimum audible angles for human listeners at a variety of reference points on the horizontal plane. Our estimated values are similar to absolute thresholds obtained using single-channel free-field presentation for locations within {+/-}51{degrees} on the horizontal plane, including values approaching 1{degrees} on the midline, regardless of speaker density. This demonstrates the adequacy of the AudioDome for studies of human auditory spatial perception, at least for displacement in the horizontal plane. In Experiment 2 we estimated monaural and binaural localization cues by presenting linear chirp sweeps (0-22050 Hz) at the horizontal reference points tested in Experiment 1 and recorded ear canal signals through a head and torso simulator. Although localization cues for low-frequency components were well preserved, they were distorted for components above 4000 Hz. In Experiment 3 we provide evidence that these high-frequency distortions are processed as cues to elevation.

The neural correlates of social rejection in the cyberball paradigm: An arterial spin labelling study
The cyberball paradigm has been used in numerous neuroimaging studies to elicit activation in neural substrates of social exclusion. Using arterial spin labelling, an approach allowing quantitative estimates of blood perfusion, we replicate findings of meta-analyses of this paradigm in the inferior frontal gyrus and ventral cingular cortex, but show that these areas were also active in a watch condition (in which participants were not excluded), although less so. These findings relativize a simple interpretation of these areas as the neural substrates of social exclusion, as in previous studies. In a broader experimental context, similar activations have been reported by neuroimaging studies when semantic disambiguation and evaluation of action goals are required, an interpretation that may apply also to the cyberball effects.

Spatial Transcriptomic Analysis Reveals HDAC Inhibition Modulates Microglial Dynamics to Protect Against Ischemic Stroke in Mice
Ischemic stroke significantly contributes to global morbidity and disability through a cascade of neurological responses. Microglia, the immune modulators within the brain, exhibit dual roles in exacerbating and ameliorating ischemic injury through neuroinflammatory and neuroprotective roles, respectively. Despite emerging insights into microglias role in neuronal support, the potential of epigenetic intervention to modulate microglial activity remains largely unexplored. We have previously shown that sodium butyrate, a histone deacetylase inhibitor (HDACi) epigenetically regulates inflammatory response of microglia after ischemic stroke and this study was aimed to characterize the transcriptomic profiles of microglia and their spatial distribution in the stroke brain followed by HDACi administration. We hypothesized that the administration of HDACi epigenetically modulates microglial activation and a region-specific microglial phenotype in the stroke brain, shifting their phenotype from neurotoxic to neuroprotective and facilitating neuronal repair and recovery in the ischemic penumbra. Utilizing a rodent model of middle cerebral artery occlusion (MCAo), spatial transcriptomics and 3D morphometric reconstruction techniques were employed to investigate microglial responses in critical penumbral regions, such as the hippocampus, thalamus, cortex and striatum following HDACi administration. We found that HDACi significantly altered the microglial transcriptomic landscape involving biological pathways of neuroinflammation, neuroprotection and phagocytosis as well as morphological phenotype, promoting a shift towards reparative, neurotrophic profiles within the ischemic penumbra. These changes were also associated with enhanced neuronal survival and reduced neuroinflammation in specific regions in the ischemic brain. By elucidating the mechanisms through which HDAC inhibition influences microglial function, our findings propose therapeutic avenues for neuroprotection and rehabilitation in ischemic stroke, and possibly other neurodegenerative conditions that involve microglia-mediated neuroinflammation.

Myo-inositol and total NAA in the hippocampus are linked to CSF tau pathology in cognitively normal older adults
INTRODUCTION: Understanding relationships between in vivo neurometabolic changes and Alzheimer's disease (AD) pathology in the hippocampus, a region vulnerable to early changes in AD, will support early diagnosis. METHODS: Two studies using 1H-MRS examined concentrations of myo-inositol (MI), total creatine (tCr) and total NAA (tNAA) in the hippocampus. The first study compared hippocampal metabolite concentrations in healthy young and older adults and the second study assessed relationships between hippocampal metabolites and cerebrospinal fluid (CSF) measurements of A{beta}42, phosphotau 181 (pTau181), and total tau (t-Tau) while adjusting for demographic covariates and spectral characteristics (linewidth, signal-to-noise ratio) in a separate group of older adults ranging from cognitively normal (CN) to AD-dementia. RESULTS: Hippocampal MI, but not tCr or tNAA, was increased in cognitively normal older versus young adults. Within the second older adult group, MI and tNAA, but not tCr, were linked to increases in CSF pTau181 and t-Tau, but not A{beta}42. DISCUSSION: Tau deposition in cognitively normal individuals is associated with biochemical changes related to glial reactivity and neural integrity in the hippocampus.

Magnetoencephalography dimensionality reduction informed by dynamic brain states
Complex spontaneous brain dynamics mirror the large number of interactions taking place among regions, supporting higher functions. Such complexity is manifested in the inter-regional dependencies among signals derived from different brain areas, as observed utilising neuroimaging techniques, like magnetoencephalography. The dynamics of this data produce numerous subsets of active regions at any moment as they evolve. Notably, converging evidence shows that these states can be understood in terms of transient coordinated events that spread across the brain over multiple spatial and temporal scales. Those can be used as a proxy of the "effectiveness" of the dynamics, as they become stereotyped or disorganised in neurological diseases. However, given the high dimensional nature of the data, representing them has been challenging thus far. Dimensionality reduction techniques are typically deployed to describe complex interdependencies and improve their interpretability. However, many dimensionality reduction techniques lose information about the sequence of configurations that took place. Here, we leverage a newly described algorithm, PHATE (Potential of Heat-diffusion for Affinity-based Transition Embedding), specifically designed to preserve the dynamics of the system in the low-dimensional embedding space. We analysed source-reconstructed resting-state magnetoencephalography from 18 healthy subjects to represent the dynamics of the configuration in low-dimensional space. After reduction with PHATE, unsupervised clustering via K-means is applied to identify distinct clusters. The topography of the states is described, and the dynamics are represented as a transition matrix. All the results have been checked against null models, providing a parsimonious account of the large-scale, fast, aperiodic dynamics during resting-state.

Ion channels that mediate calcium-dependent control of spike patterns are spatially organized across the soma in relation to a cytoskeletal assembly
Sodium and potassium channels that regulate axonal spike propagation are highly organized at nodes of Ranvier by a spectrin-actin membrane periodic skeleton. STORM-TIRF microscopy was used to define the spatial organization over the soma of a complex of Cav1.3 calcium, RyR2, and IK potassium channels (CaRyK complex) that generate a slow AHP in hippocampal neurons. Nearest neighbor distance and non-negative matrix factorization analyses identified two spatial patterns as linear rows of 3-8 immuno-labeled clusters with 155 nm periodicity that extended to branchpoints, or as isolated clusters with 600-800 nm separation. The rows and isolated clusters for each of the CaRyK complex proteins closely overlapped with the patterns for spectrin {beta}II and the actin linking proteins actinin I and II. Together the data reveal a close correspondence between the placement of CaRyK complex proteins and that of a net-like organization of spectrin {beta}II across the soma. The regularity in the pattern of expression of these proteins at ER-PM junctions suggest their role as functional nodes of calcium- and calcium-gated potassium channels to control the pattern of spike output at the soma.

Enhancement of response learning in male rats with intrastriatal infusions of a BDNF -TrkB agonist, 7,8-dihydroxyflavone
Enhancement of learning and memory by cognitive and physical exercise may be mediated by brain-derived neurotrophic factor (BDNF) acting at tropomyosin receptor kinase B (TrkB). Upregulation of BDNF and systemic administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), enhance learning of several hippocampus-sensitive tasks in rodents. Although BDNF and 7,8-DHF enhance functions of other brain areas too, these effects have mainly targeted non-cognitive functions. One goal of the present study was to determine whether 7,8-DHF would act beyond the hippocampus to enhance cognitive functions sensitive to manipulations of the striatum. Here, we examined the effects of intrastriatal infusions of 7,8-DHF on learning a striatum-sensitive response maze and on phosphorylation of TrkB receptors in 3-month-old male Sprague Dawley rats. Most prior studies of BDNF and 7,8-DHF effects on learning and memory have administered the drugs for days to months before assessing effects on cognition. A second goal of the present study was to determine whether a single drug treatment near the time of training would effectively enhance learning. Moreover, 7,8-DHF is often tested for its ability to reverse impairments in learning and memory rather than to enhance these functions in the absence of impairments. Thus, a third goal of this experiment was to evaluate the efficacy of 7,8-DHF in enhancing learning in unimpaired rats. In untrained rats, intrastriatal infusions of 7,8-DHF resulted in phosphorylation of TrkB receptors, suggesting that 7,8-DHF acted as a TrkB agonist and BDNF mimic. The findings that a single, intra-striatal infusion of 7,8-DHF 20 min before training enhanced response learning in rats suggest that, in addition to its trophic effects, BDNF modulates learning and memory through receptor mediated cell signaling events.

Aperiodic neural activity distinguishes between phasic and tonic REM sleep
Introduction: Traditionally categorized as a uniform sleep phase, rapid eye movement (REM) sleep exhibits substantial heterogeneity with its phasic and tonic constituents showing marked differences regarding neuronal network activity, environmental alertness and information processing. Here, we investigate how tonic and phasic states differ with respect to aperiodic neural activity, a marker of arousal levels, sleep stages, depth of sleep and sleep intensity. We also attempt to challenge the binary categorisation of REM sleep states by introducing graduality into their definition. Specifically, we quantify the intensity of phasic oculomotor events and investigate their temporal relationships with aperiodic activity. Method: We analyzed 57 polysomnographic recordings from three open-access datasets of healthy young volunteers aged 21.7 {+/-} 1.4 years. REM sleep heterogeneity was assessed using either binary phasic-tonic categorization or quantification of eye movement (EM) amplitudes detected by electrooculography with the YASA algorithm. Slopes of the aperiodic power component measured by electroencephalography in the low (2 - 30Hz) and high (30 - 48Hz) frequency bands were calculated using the Irregularly Resampled Auto-Spectral Analysis. For statistical analyses, we used ANOVA, Spearman correlations and cross-correlations. Results: The binary approach revealed that the phasic state is characterized by steeper low-band aperiodic slopes compared to the tonic state with the strongest effect observed over the frontal area. The phasic state also showed flatter high-band slopes with the strongest effect over central and parietal areas. The gradual approach confirmed this result further showing that higher EM amplitudes are linked to steeper low-band and flatter high-band aperiodic slopes. The temporal analysis within REM episodes revealed that aperiodic activity preceding or following EM events did not cross-correlate with EM amplitudes. Conclusion: This study demonstrates that aperiodic slopes can serve as a reliable objective marker able to differentiate between phasic and tonic constituents of REM sleep and reflect the intensity of phasic oculomotor events for instantaneous measurements. However, EM events could not be predicted by preceding aperiodic activity and vice versa, at least not with scalp electroencephalography.

Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner
Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from loss-of-function mutations in the neurofibromin gene and subsequent reduction in the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increases spontaneous grooming in a nonlinear spatial and temporal pattern, differentially increasing grooming of certain body parts, including the abdomen, head, and wings. This increase in grooming was internal state-dependent, and could be overridden by hunger in food-deprived foraging animals, demonstrating that the Nf1 effect on grooming is plastic and internal state-dependent. Stimulus-evoked grooming patterns were altered as well, with nf1 mutants exhibiting reductions in wing grooming when coated with dust, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. Thus, loss of Nf1 alters motor function without affecting overall motor coordination, in contrast to other genetic disorders that impair coordination. Overall, these results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting motor coordination.