bioRxiv Subject Collection: Neuroscience's Journal

Electroencephalographic Biomarkers of Relaxation: A Systematic Review and Meta-analysis
The human electroencephalogram (EEG) is composed of synchronous oscillations within characteristic frequency bands, including 8-13 Hz alpha oscillations that often appear during relaxation. Relaxation is critical for physical and mental health, but the extent to which various EEG components reflect relaxation remains uncertain. This systematic review and meta-analysis investigated associations between EEG components and concurrently measured reference indices of relaxation in healthy adults. A comprehensive database search and screening using preset criteria identified 38 studies involving 1,120 participants published between January 1940 and January 2022 for qualitative synthesis. These studies used various reference relaxation measures such as electrocardiographic indices related to parasympathetic nervous system activity and introspective indices obtained through questionnaires. Risks of bias were evaluated following the risk of bias assessment tool for nonrandomized studies. A meta-analysis of 23 studies using a random-effects model revealed positive correlations between relaxation index and the power of alpha oscillations at central channels (Fisher's z-transformed correlation coefficient and [95% confidence interval]: 0.23 [0.10-0.36]) and frontal channels (0.16 [0.02-0.31]). The correlation was significantly higher for the central channel compared with other channels. No significant correlations were detected between relaxation indices and other EEG frequencies or channels. The causal relationships between relaxation and alpha power at central and frontal channels warrant further study.

Bidirectional modulation of reward-guided decision making by dopamine
The neuromodulator dopamine is known to play a key role in reward-guided decision making, where choice options are often characterized by multiple attributes. Different decision strategies can be used to merge these choice attributes with personal preferences (e.g. risk preferences) and integrate them into a single subjective value. While the influence of dopamine on risk preferences has been investigated, it is unknown whether dopamine is also involved in arbitrating between decision strategies. We investigated this using a reward-guided decision-making task which was performed by 31 healthy participants under the influence of the dopamine D2/D3-receptor antagonist amisulpride, the dopamine precursor L-DOPA, or placebo in a double-blind within-subject design. Notably, we observed that the dopaminergic interventions shifted the (overall) weighting of option attributes without changing how option attributes are integrated into a subjective value (decision strategy). These effects were bidirectional: Amisulpride reduced the degree to which choices were influenced by both reward magnitude and reward probability, whereas the opposite was observed under L-DOPA, where we found an increased effect of reward magnitude and reward probability on choice. These effects occurred in the absence of changes in statistically optimal behavior. Together, our data provide evidence for a role of dopamine in controlling the influence of value parameters on choice irrespective of decision strategies.

Variations of autonomic arousal mediate the reportability of mind-blanking occurrences
Mind-blanking (MB) is the inability to report mental events during unconstraint thinking. Previous work shows that MB is linked to decreased levels of cortical arousal, indicating dominance of cerebral mechanisms when reporting mental states. What remains inconclusive is whether MB can also ensue from autonomic arousal manipulations, pointing to the implication of peripheral physiology to mental events. Using experience-sampling, neural, and physiological measurements in 26 participants, we first show that MB was reported more frequently in low arousal conditions, elicited by sleep deprivation. Also, there was partial evidence for a higher number of MB reports in high arousal conditions, elicited by intense physical exercise. Transition probabilities revealed that, after sleep deprivation, mind-wandering was more likely to be followed by MB and less likely to be followed by more mind-wandering reports. Using classification schemes, we show higher performance of a balanced random forest classifier trained on both neural and physiological markers in comparison to performance when solely neural or physiological were used. Collectively, we show that both cortical and autonomic arousal affect MB report occurrences. Our results establish that MB is supported by combined brain-body configurations, and, by linking mental and physiological states they pave the way for novel, embodied accounts of spontaneous thinking.

Tracking how attentional focusing in working memory benefits long-term memory
Human working memory serves as a key gateway to the formation of lasting memories in long-term memory. While it is well established how attentional focusing during working memory can prioritize internal representation for an imminent task, how such internal focusing affects subsequent long-term memory remains less understood. Here, we developed a two-stage visual working memory/long-term memory task in which we cued attention during working memory and tracked the dynamics of attentional deployment through a recently established gaze marker of internal focusing. Across two experiments, we found that attentional focusing in visual working memory reliably affects subsequent visual long-term memory, driven by a benefit to internally attended objects without a cost to unattended objects. Gaze biases associated with internal focusing revealed how this benefit was mediated by the speed - but not necessarily the degree - of attentional deployment, with faster attentional deployment predicting better subsequent memory. Together, these results highlight how attentional focusing in working memory benefits subsequent long-term memory, and uncover the dynamic processes that instill such lasting benefits - offering new insights into the catalyst function of attention in bridging working memory and long-term memory.

Mechanical cues of extracellular matrix determines tumor innervation
Peripheral tumors can establish local autonomic and sensory nerve networks, termed as tumor innervation (TIN), to support tumorigenesis and metastasis. While nerve dependence in cancers is well-established, the mechanisms governing TIN remain unclear. Here, we report that extracellular matrix (ECM) stiffness, a major mechanical abnormality in the tumor microenvironment (TME), is an essential contributor of TIN. In preclinical models, reducing lysyl oxidase-mediated ECM crosslinking lowers tissue stiffness and TIN in pancreatic cancer, while inflammation-induced matrix stiffening boosts the hyperinnervation of the pancreatic precursor lesions. Mechanistically, beta1-containing integrins sense the mechanical cues exerted by ECM stiffness, and the translational co-activator YAP1 acts as an essential nuclear relay to induce the expression of neurotropic genes, particularly brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). 3D imaging of the whole cleared pancreas reveals that blockade of mechanosensor integrin {beta}1 or pharmacological inhibition of the mechanotransducer YAP1 effectively reduces TIN. In clinical settings, tumor samples with a dense, crosslinked, and stiffened ECM exhibit significant TIN. In summary, these findings identify ECM stiffness as an important driver of TIN and suggest that targeting integrin beta1/YAP1-dependent mechanotransduction may counteract TIN.

Frequency-specific changes in prefrontal activity associated with maladaptive belief updating in volatile environments in euthymic bipolar disorder
Bipolar disorder (BD) involves altered reward processing and decision-making, with inconsistencies across studies. Here, we integrated hierarchical Bayesian modelling with magnetoencephalography (MEG) to characterise maladaptive belief updating in this condition. First, we determined if previously reported increased learning rates in BD stem from a heightened expectation of environmental changes. Additionally, we examined if this increased expectation speeds up belief updating in decision-making, associated with modulation of rhythmic neural activity within the prefrontal, orbitofrontal, and anterior cingulate cortex (PFC, OFC, ACC). Twenty-two 22 euthymic BD and 27 healthy control (HC) participants completed a reward-based motor decision-making task in a volatile setting. Hierarchical Bayesian modelling revealed BD participants anticipated greater environmental volatility, resulting in a more stochastic mapping from beliefs to actions and paralleled by lower win rates and a reduced tendency to repeat rewarded actions than HC. Despite this, BD individuals adjusted their expectations of action-outcome contingencies more slowly, but both groups invigorated their actions similarly. On a neural level, while healthy individuals exhibited an alpha-beta suppression and gamma increase during belief updating, BD participants showed dampened effects, extending across the PFC, OFC, and ACC regions. This was accompanied by an abnormally increased beta-band directed information flow in BD. Overall, the results suggest euthymic BD individuals anticipate environmental change without adequately learning from it, contributing to maladaptive belief updating. Alterations in frequency-domain amplitude and functional connectivity within the PFC, OFC, and ACC during belief updating underlie the computational effects and could serve as potential indicators for predicting relapse in future research.

IT IS NOT A SMALL WORLD FOR PSYCHIATRIC PATIENTS
Individuals suffering from Obsessive Compulsive Disorder (OCD) and Schizophrenia (SCZ) frequently exhibit symptoms of cognitive disassociations, which are linked to poor functional integration among brain regions. The loss of integration can be assessed using graph metrics computed from functional connectivity matrices (FCMs) derived from neuroimaging data. A healthy brain with an effective connectivity pattern exhibits small-world features with high clustering coefficients and shorter path lengths in contrast to random networks. We analyzed neuroimaging data from 60 subjects (13 healthy controls, 21 OCD and 26 SCZ) using functional near-infrared spectroscopy (fNIRS) during a color word matching Stroop Task and computed FCMs. Small-world features were evaluated using the Global Efficiency (GE), Clustering Coefficient (CC), Modularity (Q), and small-world parameter (sigma). The proposed pipeline in this study for fNIRS data processing demonstrates that patients with OCD and SCZ exhibit small-world features resembling random networks, as indicated by higher GE and lower CC values compared to healthy controls, implying a higher operational cost for these patients.

Ultrasound pulse repetition frequency preferentially activates different neuron populations independent of cell type
Transcranial ultrasound activates mechanosensitive cellular signaling and modulates neural dynamics. Given that intrinsic neuronal activity is limited to a couple hundred hertz and often exhibits frequency preference, we examined whether pulsing ultrasound at physiologic pulse repetition frequencies (PRFs) could selectively influence neuronal activity in the mammalian brain. We performed calcium imaging of individual motor cortex neurons, while delivering 0.35 MHz ultrasound at PRFs of 10, 40, and 140 Hz in awake mice. We found that most neurons were preferentially activated by only one of the three PRFs, highlighting unique cellular effects of physiologic PRFs. Further, ultrasound evoked responses were similar between excitatory neurons and parvalbumin positive interneurons regardless of PRFs, indicating that individual cell sensitivity dominates ultrasound-evoked effects, consistent with the heterogeneous mechanosensitive channel expression we found across single neurons in mice and humans. These results highlight the feasibility of tuning ultrasound neuromodulation effects through varying PRFs.

Expert Navigators Deploy Rational Hierarchical Priorization Over Predictive Maps For Large-Scale Real-World Planning
Efficient planning is a distinctive hallmark of human intelligence. Computational analyses of human behavior during planning provide evidence for hierarchically segmented representations of the state space of options. However, such evidence derives from simplistic tasks with small state-spaces that belie the complexity of real-world planning. Here, we examine the street-by-street route plans of London taxi drivers navigating across more than 26,000 streets in London (UK). Response times were faster for states with higher successor representations, providing evidence for predictive mapping. We also find an effect for the interaction between the successor representation of a state and local transition entropy, which indicates hierarchical chunking of transition sequences, and thus provides real-world support to existing theories of hierarchical state-space representations and planning. Finally, we explored how planning unfolded dynamically over different phases of the constructed journey and identify theoretic principles by which expert planners rationally prioritize specific states during the planning process. Overall, our findings provide real-world evidence for predictive maps and rational hierarchical prioritization in expert route planning.

KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3
Intellectual disability (ID) affects ~2% of the general population and is often genetic in origin. ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose de novo heterozygous mutations cause KAT6A Syndrome (or Arboleda-Tham Syndrome), with ID as a common clinical feature. However, the underlying molecular mechanisms remain elusive. Here, we show that haploinsufficiency of Kat6a impairs learning and memory in mice, and specific deletion of Kat6a in excitatory neurons recapitulates the hippocampus-dependent memory deficits. Unexpectedly, KAT6A deficiency results in impaired synaptic structure and plasticity in hippocampal CA3, but not in CA1 region. Combining single-nucleus RNA-sequencing and chromatin analysis, we identify a CA3-enriched gene Rspo2, encoding a Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Moreover, deletion of Rspo2 in excitatory neurons phenocopies the loss of Kat6a, resulting in defective Wnt/{beta}-catenin signaling and synaptic plasticity in CA3, and abnormal cognitive behaviors in mice. Importantly, restoring RSPO2 expression in CA3 pyramidal neurons rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A plays a critical role in regulating synaptic plasticity and memory formation through RSPO2-mediated Wnt signaling in hippocampal CA3, shedding new light on the fundamental mechanisms of ID and providing potential therapeutic targets for the treatment of KAT6A Syndrome and related neurodevelopmental diseases.

Essential Dynamics of CB1 Receptor-Agonist Complexes: Implications for Signalling Bias
The CB1 cannabinoid receptor is implicated in a broad range of physiological processes and disease states, however CB1-targeting drugs in clinical use remain based on tetrahydrocannabinol (THC). Ligands that exhibit functional selectivity for different intracellular signalling pathways are currently an area of rapid development, and hold significant potential as therapeutic agents. Improved understanding of the exact molecular mechanisms underpinning biased activation of intracellular effector proteins for CB1 is necessary to enable drug development of biased CB1 ligands into candidates for treatment of human disease. Using molecular dynamics, this study shows that CB1 conformations resulting from activation by the orthosteric ligands CP55940, {Delta}9-THC or 5F-MDMB-PICA exhibit differences in the dynamic organisation of key residues and receptor substructures involved in coupling to G proteins and {beta}-arrestins, that leads to selective activation of downstream signalling pathways. The identification of conformationally distinct CB1-agonist complexes that demonstrate different functional profiles provides an important step in unravelling the molecular determinants for biased signalling, and lays a platform for future rational design of novel therapeutic leads.

Challenges and Efficacy of Astrocyte-to-Neuron Reprogramming in Spinal Cord Injury: In Vitro Insights and In Vivo Outcomes
Traumatic spinal cord injury (SCI) leads to the disruption of neural pathways, causing loss of neural cells, with subsequent reactive gliosis and tissue scarring that limit endogenous repair. One potential therapeutic strategy to address this is to target reactive scar-forming astrocytes with direct cellular reprogramming to convert them into neurons, by overexpression of neurogenic transcription factors. Here we used lentiviral constructs to overexpress Ascl1 or a combination of microRNAs (miRs) miR124, miR9/9*and NeuroD1 transfected into cultured and in vivo astrocytes. In vitro experiments revealed cortically-derived astrocytes display a higher efficiency (70%) of reprogramming to neurons than spinal cord-derived astrocytes. In a rat cervical SCI model, the same strategy induced only limited reprogramming of astrocytes. Delivery of reprogramming factors did not significantly affect patterns of breathing under baseline and hypoxic conditions, but significant differences in average diaphragm amplitude were seen in the reprogrammed groups during eupneic breathing, hypoxic, and hypercapnic challenges. These results show that while cellular reprogramming can be readily achieved in carefully controlled in vitro conditions, achieving a similar degree of successful reprogramming in vivo is challenging and may require additional steps.

How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimers disease brain by a strain-relief mechanism
Reducing fibrous aggregates of protein tau is a possible strategy for halting progression of Alzheimer's dis-ease (AD). Previously we found that in vitro the D-peptide D-TLKIVWC disassembles tau fibrils from AD brains (AD-tau) into benign segments with no energy source present beyond ambient thermal agitation. This disassembly by a short peptide was unexpected, given that AD-tau is sufficiently stable to withstand disas-sembly in boiling SDS detergent. To consider D peptide-mediated disassembly as a potential therapeutic for AD, it is essential to understand the mechanism and energy source of the disassembly action. We find as-sembly of D-peptides into amyloid-like fibrils is essential for tau fibril disassembly. Cryo-EM and atomic force microscopy reveal that these D-peptide fibrils have a right-handed twist and embrace tau fibrils which have a left-handed twist. In binding to the AD-tau fibril, the oppositely twisted D-peptide fibril produces a strain, which is relieved by disassembly of both fibrils. This strain-relief mechanism appears to operate in other examples of amyloid fibril disassembly and provides a new direction for the development of first-in-class therapeutics for amyloid diseases.

Modulation of Temporoammonic-CA1 Synapses by Neuropeptide Y is Through Y1 Receptors
The reduction of neuropeptide Y (NPY), an abundant neuromodulator in the brain, has been implicated in multiple neuropsychiatric disorders, such as depression and post-traumatic stress disorder (PTSD). The CA1 region of hippocampus is an important area for anxiety and highly expresses NPY. Injection of NPY into the CA1 is anxiolytic and has been shown to alleviate behavioral symptoms in a model of traumatic stress. It is known that activation of NPY Y1 receptors has anxiolytic effects and that NPY's anxiolytic effects in CA1 are blocked by an NPY Y1 receptor antagonist. However, the location of Y1 receptors mediating NPY's anxiolytic effects in CA1 is not yet known. CA1 receives inputs from entorhinal cortex through the temporammonic pathway (TA), which has been shown to be important for fear learning and sensitive to stress. Our lab previously showed that NPY reduces TA-evoked synaptic responses, however, the subtype of NPY receptor mediating this effect is not yet known. In this study, we show that Y1 receptors mediate the effects of both exogenous (bath-applied) and endogenously- released NPY in the TA pathway. This is the first demonstration of a Y1 receptor-mediated effect on synaptic function in CA1. Interestingly, chronic cell-type specific overexpression of NPY impairs the sensitivity of the TA pathway to NPY and the Y1 receptor agonist. However, the effect of NPY in the Schaffer collateral (SC) pathway, which is mediate by NPY Y2 receptors, is unaffected by NPY overexpression. There are pathway-specific differences in NPY receptors that modulate NPY's effects in CA1 and respond differently to NPY overexpression. Our results demonstrating that NPY acts at Y1 receptors in the TA pathway are consistent with the idea that the TA pathway underlies the anxiolytic effects of NPY in CA1.

A role for δ subunit-containing GABA-A receptors on parvalbumin positive neurons in maintaining electrocortical signatures of sleep states
GABA-A receptors containing {delta} subunits have been shown to mediate tonic/slow inhibition in the CNS. These receptors are typically found extrasynaptically and are activated by relatively low levels of ambient GABA in the extracellular space. In the mouse neocortex, {delta} subunits are expressed on the surface of some pyramidal cells as well as on parvalbumin positive (PV+) interneurons. An important function of PV+ interneurons is the organization of coordinated network activity that can be measured by EEG; however, it remains unclear what role tonic/slow inhibitory control of PV+ neurons may play in shaping oscillatory activity. After confirming a loss of functional {delta} mediated tonic currents in PV cells in cortical slices from mice lacking Gabrd in PV+ neurons (PV {delta}cKO), we performed EEG recordings to survey network activity across wake and sleep states. PV {delta}cKO mice showed altered spectral content of EEG during NREM and REM sleep that was a result of increased oscillatory activity in NREM and the emergence of transient high amplitude bursts of theta frequency activity during REM. Viral reintroduction of Gabrd to PV+ interneurons in PV {delta}cKO mice rescued REM EEG phenotypes, supporting an important role for {delta} subunit mediated inhibition of PV+ interneurons for maintaining normal REM cortical oscillations.

Functional states of prelimbic and related circuits during the acquisition of a GO/noGO task in rats
GO/noGO tasks enable assessing decision-making processes and the ability to suppress a specific action according to the context. Here, rats had to discriminate between two visual stimuli (GO or noGO) shown on an iPad screen. The execution (for GO) or non-execution (for noGO) of the selected action (to touch or not the visual display) were reinforced with food. The main goal was to record and to analyze local field potentials (LFPs) collected from cortical and subcortical structures when the visual stimuli were shown on the touch screen and during the subsequent activities. Rats were implanted with recording electrodes in the prelimbic cortex, primary motor cortex, nucleus accumbens septi, basolateral amygdala, dorsolateral and dorsomedial striatum, hippocampal CA1, and mediodorsal thalamic nucleus. Spectral analyses of the collected data demonstrate that the prelimbic cortex was selectively involved in the cognitive and motivational processing of the learning task but not in the execution of reward-directed behaviors. In addition, the other recorded structures presented specific tendencies to be involved in these two types of brain activity in response to the presentation of GO or noGO stimuli. Spectral analyses, spectrograms, and coherence between the recorded brain areas indicate their specific involvement in GO vs. noGO tasks.

Teaching deep networks to see shape: Lessons from a simplified visual world.
Deep neural networks have been remarkably successful as models of the primate visual system. One crucial problem is that they fail to account for the strong shape-dependence of primate vision. Whereas humans base their judgements of category membership to a large extent on shape, deep networks rely much more strongly on other features such as color and texture. While this problem has been widely documented, the underlying reasons remain unclear. We design simple, artificial image datasets in which shape, color, and texture features can be used to predict the image class. By training networks to classify images with single features and feature combinations, we show that some network architectures are unable to learn to use shape features, whereas others are able to use shape in principle but are biased towards the other features. We show that the bias can be explained by the interactions between the weight updates for many images in mini-batch gradient descent. This suggests that different learning algorithms with sparser, more local weight changes are required to make networks more sensitive to shape and improve their capability to describe human vision.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses
The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic, and sensory and information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirement. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Functional-based parcellation of the mouse prefrontal cortex for network perturbation analysis
The prefrontal cortex (PFC) is a region of the brain involved in higher-order cognitive processes such as attention, emotional regulation, and social behavior, making it a hotspot for an ongoing clinical and fundamental research. Importantly, its functionality is intricately interconnected within a wide array of functional networks encompassing multiple other brain areas. However, the delineation of distinct subdivisions within the mouse PFC and their contributions to the broader brain network function remain topics of ongoing debate. In the current study, we used resting-state functional magnetic resonance imaging (rsfMRI) from a large cohort of wildtype animals to derive the functional-connectivity (FC) based parcellation of the mouse PFC with voxel resolution. Our findings indicate the presence of FC-based clusters that deviate from the established anatomical subdivisions within the cingulate and prelimbic areas, while they align in infralimbic and orbital cortices. To further underscore the association of these FC-based clusters with distinct functional networks, we performed network-specific perturbations using chemogenetics in the identified clusters in dorsal PFC and monitor the elicited effects with fMRI (chemo-fMRI). Our recordings revealed that FC perturbations were observed only within the functional networks linked to the targeted clusters and did not spread to neighbouring anatomical areas or functional clusters. We propose that FC-based parcellation is a valuable approach for tracking the impact of external activations and confirming the precise site of activation.

Distinct Motor Map Characteristics for Biceps and Triceps Muscles in Persons with Chronic Tetraplegia: Implications for Arm Function
Following spinal cord injury (SCI), intact neural resources undergo widespread reorganization within the brain. Animal models reveal motor cortical representations devoted to spared muscles above injury expand at the expense of territories occupied by weaker muscles. In this study, we investigated whether motor representations are similarly reorganized between a relatively spared biceps muscle and a weakened triceps muscle in persons with chronic tetraplegia following traumatic cervical SCI in association with upper limb motor function. Twenty-four adults with cervical SCI and 15 able-bodied participants underwent motor mapping using transcranial magnetic stimulation. We determined following map characteristics: area, amplitude (maximal motor evoked potential and volume), and center of gravity. Maximal voluntary contraction (MVC) and motor function (Capabilities of the Upper Extremity Test or CUE-T) were also assessed. Findings reveal that participants with SCI had hyper-excitable biceps maps than triceps, and hyper-excitable biceps maps also compared to biceps maps in able-bodied participants. Higher amplitude of biceps and triceps maps was associated with better motor function (higher CUE-T) and more distal injury (i.e., more spared segments) in persons with SCI. Amplitudes of biceps but not the triceps maps were associated with higher muscle MVCs. In conclusion, over-excitable biceps than triceps map in SCI may represent deafferentation plasticity. For the first time, we demonstrate how map reorganization of spared and weaker muscles in persons with chronic cervical SCI is associated with upper limb motor status. Use-dependent mechanisms may shift neural balance in favor of spared muscles, supporting potential use as response biomarkers in rehabilitation studies.

Converging inputs compete at the lateral parabrachial nuclei to dictate the affective-motivational responses to cold pain
The neural mechanisms of the affective-motivational symptoms of chronic pain are poorly understood. In chronic pain, our innate coping mechanisms fail to provide relief leading to heightened manifestation of these behaviors. In laboratory animals, such as mice and rats, licking the affected areas is a behavioral coping mechanism and it is sensitized in chronic pain. Hence, we have focused on delineating the brain circuits mediating licking in mice with chemotherapy-induced peripheral neuropathy (CIPN). Mice with CIPN develop intense cold hypersensitivity and lick their paws upon contact with cold stimuli. We studied how the lateral parabrachial nucleus (LPBN) neurons facilitate licking behavior when mice are exposed to noxious thermal stimuli. Taking advantage of transsynaptic viral, optogenetic, and chemogenetic strategies, we observed that the LPBN neurons become hypersensitive to cold in mice with CIPN and facilitate licks. Further, we found that the expression of licks depends on competing excitatory and inhibitory inputs from the spinal cord and lateral hypothalamus (LHA), respectively. We anatomically traced the post-synaptic targets of the spinal cord and LHA in the LPBN and found that they synapse onto overlapping populations. Activation of this LPBN population was sufficient to promote licking due to cold allodynia. In sum, our data indicate that the nociceptive inputs from the spinal cord and information on brain states from the hypothalamus impinge on overlapping LPBN populations to modulate their activity and, in turn, regulate the elevated affective-motivational responses in CIPN.

Non-canonical adrenergic neuromodulation of motoneuron intrinsic excitability through beta-receptors in wild-type and ALS mice
Altered neuronal excitability and synaptic inputs to motoneurons are part of the pathophysiology of Amyotrophic Lateral Sclerosis. The cAMP/PKA pathway regulates both of them but therapeutic interventions at this level are limited by the lack of knowledge about suitable pharmacological entry points. Here we used transcriptomics on microdissected and in situ motoneurons to reveal the modulation of PKA-coupled receptorome in SOD1(G93A) ALS mice, vs WT, demonstrating the dysregulation of multiple PKA-coupled GPCRs, in particular on vulnerable MNs, and the relative sparing of beta-adrenergic receptors. In vivo MN electrophysiology showed that beta2/beta3 agonists acutely increase excitability, in particular the input/output relationship, demonstrating a non-canonical adrenergic neuromodulation mediated by beta2/beta3 receptors both in WT and SOD1 mice. The excitability increase corresponds to the upregulation of immediate-early gene expression and dysregulation of ion channels transcriptome. However the beta2/beta3 neuromodulation is submitted to a strong homeostasis, since a ten days delivery of beta2/beta3 agonists results in an abolition of the excitability increase. The homeostatic response is largely caused by a substantial downregulation of PKA-coupled GPCRs in MNs from WT and SOD1 mice. Thus, beta-adrenergic receptors are physiologically involved in the regulation of MN excitability and transcriptomics, but, intriguingly, a strong homeostatic response is triggered upon chronic pharmacologic intervention.

Locus Coeruleus Contrast and Diffusivity: Effects of Age and Relations to Memory
Neurocognitive aging researchers are increasingly focused on the locus coeruleus, a neuromodulatory brainstem structure that degrades with age. With this rapid growth, the field will benefit from consensus regarding which magnetic resonance imaging (MRI) metrics of locus coeruleus structure are most sensitive to age and cognition. To address this need, the current study acquired magnetization transfer- and diffusion-weighted MRI images in younger and older adults who also completed a free recall memory task. Results revealed significantly larger differences between younger and older adults for maximum than average magnetization transfer-weighted contrast (MTC), axial than mean or radial single-tensor diffusivity (DTI), and free than restricted multi-compartment diffusion (NODDI) metrics in the locus coeruleus; with maximum MTC being the best predictor of age group. Age effects for the MTC and NODDI metrics interacted with sex such that larger age group differences were seen in males than females. Age group differences were also larger for DTI metrics in the rostral, and NODDI metrics in the caudal, locus coeruleus subdivision. Within older adults, however, there were no significant effects of age on any measure of locus coeruleus structure. Finally, independent of age and sex, higher restricted diffusion in the locus coeruleus was significantly related to better (lower) recall variability, but not mean recall. Whereas MTC has been widely used in the literature, our comparison between the average and maximum MTC metrics, and inclusion of DTI and NODDI metrics, make important and novel contributions to our understanding of the aging of locus coeruleus structure.

Temporal prediction captures retinal spiking responses across animal species
The retina's role in visual processing has been viewed as two extremes: an efficient compressor of incoming visual stimuli akin to a camera, or as a predictor of future stimuli. Addressing this dichotomy, we developed a biologically-detailed spiking retinal model trained on natural movies under metabolic-like constraints to either encode the present or to predict future scenes. Our findings reveal that when optimized for efficient prediction approximately 100 ms into the future, the model not only captures retina-like receptive fields and their mosaic-like organizations, but also exhibits complex retinal processes such as latency coding, motion anticipation, differential tuning, and stimulus-omission responses. Notably, the predictive model also more accurately predicts the way retinal ganglion cells respond across different animal species to natural images and movies. Our findings demonstrate that the retina is not merely a compressor of visual input, but rather is fundamentally organized to provide the brain with foresight into the visual world.

Integrating Optogenetic Stimulation of Olfactory Bulb Glomeruli with Foot Shock Fear Conditioning: A Robust Method for Investigating Olfactory-based Fear Conditioning
The integration of optogenetic techniques with traditional behavioral paradigms has provided novel insights into the neural mechanisms underlying olfactory-based fear conditioning. Olfactory cues are potent triggers for fear responses, and understanding the intricate neural dynamics involved in olfactory fear learning is crucial for unraveling the complexities of aversive memory formation. In this study, a robust method is presented that combines optogenetic stimulation of olfactory bulb glomeruli with foot shock fear conditioning to investigate olfactory-based fear learning in mice. By merging optogenetic manipulation with behavioral assays, a comprehensive framework for studying the mechanisms of olfactory fear conditioning is provided. This method offers new avenues for exploring the neural dynamics of adaptive responses to olfactory threats and may have implications for understanding fear-related disorders.

Associations between parenting and cognitive and language abilities at age 2 depend on prenatal exposure to disadvantage
Objective: To investigate whether parenting and/or neonatal brain volumes mediate the associations between prenatal social disadvantage (PSD) and cognitive/language abilities; and whether these mechanisms vary by level of disadvantage. Study Design: Pregnant women were recruited from obstetric clinics in St Louis, Missouri. PSD encompassed access to social (e.g., education) and material (e.g., income-to-needs, health insurance, area deprivation, and nutrition) resources during pregnancy. Neonates underwent brain magnetic resonance imaging. Mother-child dyads (N=202) returned at age 1 for parenting measures and at age 2 for cognition/language assessments (Bayley-III). Generalized additive and mediation models tested hypotheses. Results: Greater PSD was nonlinearly associated with poorer cognitive/language scores. The relation between parenting and cognition/language was moderated by PSD, such that supportive and non-supportive parenting behaviors only related to cognition/language in children with low PSD. Further, parenting mediations differed by level of PSD, such that both supportive and non-supportive parenting mediated PSD-cognition/language associations in children with low PSD, but not in children with high PSD. PSD-associated reductions in neonatal subcortical grey matter ({beta}=.19, q=.03), white matter ({beta}=.23, q=.02), and total brain volume ({beta}=.18, q=.03) were associated with lower cognition, but they did not mediate PSD-cognition associations. Conclusions: Parenting moderates and mediates associations between PSD and early cognitive and language development, but only in families with lower levels of social disadvantage. These findings, while correlational, suggest that there may be a critical threshold of disadvantage, below which mediating or moderating factors become less effective, highlighting the importance of reducing disadvantage as primary prevention.

Effects of early life adversity and adolescent basolateral amygdala inhibition on corticolimbic connectivity and anxiety behaviors
Early postnatal life is a dynamic period of brain development that involves a coordinated symphony of circuit maturation. As many regions within the brain continue to develop and mature postnatally, external stimuli impact this development and regulate the degree of connectivity to other brain areas. Since subcortical limbic regions undergo substantial synapse formation and pruning during early development while higher-order areas such as the prefrontal cortex (PFC) mature during adolescence, early postnatal life and adolescence are two sensitive periods when limbic and prefrontal regions form functional connections in response to external stimuli and neuronal activity. Thus, activity within limbic regions over the course of development can affect the strength and quantity of efferent connections to cortical areas. Prior work has shown hyper-innervation of glutamatergic basolateral amygdala (BLA) projections to the prefrontal cortex (PFC) in the adolescent time period following rearing in an adverse early life environment, but how these ELA-induced connectivity changes alter the startle circuitry required to execute a startle response and whether the BLA-PFC pathway is responsible for previously reported blunted startle response remains unknown. We directly tested whether BLA activity during a discrete adolescent period altered later anxiety behaviors, and if behavioral changes were driven by altered PFC innervation. To test these questions, we exposed rat pups to an ELA model of maternal separation on postnatal days (P) 2-21. Rats then underwent an injection of an inhibitory DREADD in the BLA in order to silence the excitatory projections during the adolescent time period of P33-39. Finally, rats were tested in an acoustic startle paradigm in late adolescence to assess the effects of reduced BLA-PFC connectivity on the ELA-induced blunted startle response. Density, intensity, and volume of axonal boutons in the BLA projecting PFC neurons were then assessed to elucidate how BLA inhibition during adolescence affects innervation later in life. These results explore how altered early life environments may affect the development of anxiety-related circuitry and anxiety responses later in life, and how rescue of this maladaptive response may be sex and developmentally specific.

Exploring dynamic brain oscillations in motor imagery and low-frequency sound
While both motor imagery (MI) and low-frequency sound listening have independently demonstrated the ability to modulate brain activity, there remains an unexplored frontier regarding the potential synergistic effects that may arise from their combined application. Any further modulation derived from this combination may be relevant for motor learning and/or rehabilitation. We conducted an experiment probing the electrophysiological activity of brain during these processes. By means of EEG, we recorded alpha and beta band power amplitude, which serve as markers of brain activity. Twenty volunteers were instructed to i) explicitly imagine finger flexion/extension movements in a kinaesthetic modality, ii) listen to low-frequency sounds, iii) imagine finger flexion while listening to low-frequency sounds, and iv) stay at rest. We observed a bimodal distribution, suggesting the presence of variability in brain activity across participants during both MI and low-frequency sound listening. One group of participants (12 individuals) displayed increased alpha power within contralateral sensorimotor and ipsilateral medial parieto-occipital regions during MI. Another group (8 individuals) exhibited a decrease in alpha and beta band power within sensorimotor areas. Interestingly, low-frequency sound listening elicited a similar pattern of brain activity within both groups. Surprisingly, the combination of MI and sound listening did not result in additional changes in alpha and beta power amplitudes compared to these processes in isolation, regardless of group. Altogether, these findings shed significant insight into the brain activity and its variability generated during MI and low-frequency sound listening. Nevertheless, it appears that the simultaneous engagement of MI and low-frequency sound listening could not further modulate alpha power amplitude, possibly due to concurrent cortical activations. This prompts us to inquire whether administering these interventions sequentially could uncover any additional modulation.

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function
Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically-evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered - swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.

MANIPULATING MITOCHONDRIAL REACTIVE OXYGEN SPECIES ALTERS SURVIVAL IN UNEXPECTED WAYS IN A DROSOPHILA MODEL OF NEURODEGENERATION
Reactive oxygen species (ROS) are associated with aging and neurodegeneration, but the significance of this association remains obscure. Here, using a Drosophila model of age-related neurodegeneration, we probe this relationship in the pathologically relevant tissue, the brain, by quantifying three specific mitochondrial ROS and manipulating these redox species pharmacologically. Our goal is to ask whether pathology-associated changes in redox state are detrimental for survival, whether they may be beneficial responses, or whether they are simply covariates of pathology that do not alter viability. We find, surprisingly, that increasing mitochondrial H2O2 correlates with improved survival. We also find evidence that drugs that alter the mitochondrial glutathione redox potential modulate survival primarily through the compensatory effects they induce rather than through their direct effects on the final mitochondrial glutathione redox potential per se. We also find that the response to treatment with a redox-altering drug varies dramatically depending on the age at which the drug is administered, the duration of the treatment, and the genotype of the individual receiving the drug. These data have important implications for the design and interpretation of studies investigating the effect of redox state on health and disease as well as on efforts to modify the redox state to achieve therapeutic goals.

Thalamic blood flow and EEG frequency band power during hyperventilation in idiopathic generalized epilepsy
Absence seizures in idiopathic generalised epilepsy (IGE) involve thalamo-cortical circuits. Hyperventilation (HV) is a standard technique to trigger epileptiform discharges and absence seizures in IGE. HV also increases electroencephalography (EEG) delta band power and decreases global cerebral blood flow (CBF). The relationships between HV, EEG band power, and regional CBF have not been investigated in the same patients at the same time. We compared the effects of hyperventilation between 13 individuals with IGE and 18 healthy controls on thalamic CBF assessed with pseudo-continuous Arterial Spin Labelling (pCASL) simultaneously to EEG frequency band power during three periods of hyperventilation interleaved with three periods of rest, normalised to each participant's pre-HV values. Pre-HV, there were no differences between patients and controls. During the three rest periods combined, patients had higher normalised respiratory rates but no difference in CBF or EEG band power compared with controls. During HV, CBF decreases were similar in controls and IGE patients in cortical gray matter (37.1 +/- 1.3% in controls, 37.9 +/- 2.0% in patients) and basal ganglia (35.6 +/- 2.0% in controls, 33.3 +/- 2.3% in patients). In the thalamus, CBF decreased by 35.5 +/- 1.9% in controls, but only by 27.1 +/- 2.5% in patients (p=0.011). Delta band power increased by 42% in patients, but only by 27% in patients (p<0.045). Both controls and patients thalamic CBF significantly decreased as a function of respiratory rate, but the relationship was weaker in patients (rho -0.38 [0.95 confidence interval lower limit -0.629; upper limit -0.059] vs -0.51 (-0.698; -0.255) in controls). Delta power correlated with thalamic CBF only in controls (rho -0.21 (-0.388; -0.017)) but not in patients (rho -0.1 (-0.345; 0.157)). EEG power and respiratory rate were not significantly correlated in either group.

Neurovascular unit adjustments following chronic distress explain motivational deficits in mice
Background. The neurovascular unit (NVU) represents the structural and functional relationship between the neural tissue and the blood. Neurovascular dysfunction has been highlighted in neuropsychiatric afflictions, but whether it is a cause or a consequence of the pathology remains to be elucidated. Thus, to elucidate the role of the NVU on the emergence of emotional-cognitive dysfunction, it is necessary to study how its individual components associate. This study therefore aims at investigating whether the development of depressive-related loss of motivation is grounded on NVU adjustments impacting the permeability of the blood-brain barrier (BBB) and in particular, of the structural scaffolding of microvessels. Methods. Adult male C57BL/6jRj mice chronically treated with corticosterone (CORT) and showing severe motivational deficits in an operant progressive ratio (PR) schedule of reinforcement task, presented altered neural activation assessed through FosB expression in key brain regions involved in motivational processing (anterior insular cortex, basolateral amygdala, bed nucleus of the stria terminalis and ventral tegmental area). We evaluated NVU modifications through immunofluorescence staining targeting specific markers of microglia (IBA-1), endothelial tight junctions (ZO-1) and astrocytes (GFAP). The effect of chronic CORT administration on mice BBB permeability was evaluated through in vivo perfusion of fluorescent 40 kDa Dextran. Results. Our results highlight that where sustained neuronal activation failed, NVU modifications predict behavioural deficits in CORT-treated animals. Notably, our analyses show that NVU modifications within the ventral tegmental area are essential to understand effort-based related behavioural performance in mice, and most particularly, that the key element of microvessels' tight junctions ZO-1 plays a pivotal role on motivation-related behavioural output. Conclusions. Our results confirm a direct role of neurovascular adaptations on emotional and cognitive behavioural performance in mice, and therefore place the NVU in a key position in the research of the biological substrate at the origin of neuropsychiatric disorders.

Thermotherapy has Sexually Dimorphic Responses in APP/PS1 Mice
A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30{degrees}C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30{degrees}C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-{beta} (A{beta})42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy with potential nonpharmacological management for some individuals with AD, and provides further evidence for the necessity of adopting personalized patient care.

Chilean brush tailed mouse (Octodon degus): a diurnal precocial rodent as a new model to study visual receptive field properties of superior colliculus neurons
Lab rodent species used to study the visual system and its development (hamsters, rats, and mice) are nocturnal, altricial, and possess simpler visual systems than carnivores and primates. To widen the spectra of studied species, here we introduce an alternative model, the Chilean degu (Octodon degus), a diurnal, precocial Caviomorph rodent with a cone enriched, well-structured retina, and well-developed central visual projections. To assess degu visual physiological properties, we characterized the visual responses and receptive field (RF) properties of isolated neurons in the superficial layers of the superior colliculus (sSC). To facilitate comparison with studies in other rodent species, we used four types of stimuli: (1) a moving white square, (2) sinusoidal gratings, (3) an expanding black circle (looming), and (4) a stationary black circle. We found that as in other mammalian species, RF size increases from superficial to deeper SC layers. Interestingly, compared to other lab rodents, degus have smaller RF sizes, likely indicating higher acuity. sSC neurons displayed spatial frequency tuning to grating stimuli from 0.08 to 0.24 cycles/degree. Additionally, neurons from sSC showed transient ON, OFF, or ON-OFF responses to stationary stimuli but increased their firing rates as a looming object increased in size. Our results suggests that degus have higher visual acuity, higher frequency tuning, and lower contrast sensitivity than commonly used nocturnal lab rodents, positioning degus as a well-suited model for studies of diurnal vision that are more relevant to humans.

Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model
Cellular senescence, characterized by expressing the cell cycle inhibitory protein p21/CDKN1A, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D+Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), and structural MRI, and longitudinally assessed brain physiology and regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D+Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D+Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p21/CDKN1A. D+Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D+Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.

Volume Electron Microscopy Analysis of Synapses in Associative and Primary Regions of the Human Cerebral Cortex
Functional and structural studies investigating macroscopic connectivity in the human cerebral cortex suggest that high-order associative regions exhibit greater connectivity compared to primary ones. However, the synaptic organization of these brain regions remains unexplored due to the difficulties involved in studying the human brain at the nanoscopic level. In the present work, we conducted volume electron microscopy to investigate the synaptic organization of the human brain obtained at autopsy. Specifically, we examined layer III of Brodmann areas 17, 3b, and 4, as representative areas of primary visual, somatosensorial, and motor cortex. Additionally, we conducted comparative analyses with our previous synaptic datasets of layer III from temporopolar and anterior cingulate associative cortical regions (Brodmann areas 24, 38, and 21). 9,690 synaptic junctions were 3D reconstructed, showing that certain synaptic characteristics appeared to be specific to particular cortical regions. The number of synapses per volume, the proportion of the postsynaptic targets, and the synaptic size may distinguish one region from another, regardless of whether they are associative or primary cortex. By contrast, other synaptic characteristics were common to all analyzed regions, such as the proportion of excitatory and inhibitory synapses, their shapes, their spatial distribution, and a higher proportion of synapses located on dendritic spines. These observations may be included within the general rules of synaptic organization of the human cerebral cortex. The present results on nanoscopic characteristics of synapses provide further insights into the structural design of the human cerebral cortex.

Multitasking practice eliminates modality-based interference by separating task representations in sensory brain regions
The debate on the neural basis of multitasking costs evolves around neural overlap between concurrently performed tasks. Recent evidence suggests that training-related reductions in representational overlap in fronto-parietal brain regions predict multitasking improvements. Cognitive theories assume that overlap of task representations may lead to unintended information exchange between tasks (i.e., crosstalk). Modality-based crosstalk was suggested as a source for multitasking costs in multisensory settings. Robust findings of increased costs for certain modality mappings may be explained by crosstalk between the stimulus modality in one task and sensory action consequences in the concurrently performed task. Whether modality-based crosstalk emerges from representational overlap in general fronto-parietal multitasking regions or modality-specific regions is not known yet. In this functional neuroimaging study, we investigate neural overlap in multitasking performance, focusing on modality compatibility by employing multivariate pattern analysis and modality-specific practice interventions in three groups (total N = 54). We observed significant differences between modality compatible and modality incompatible single-task representations, specifically in the auditory cortex but not in fronto-parietal regions. Notably, improved auditory decoding accuracy related to modality incompatible tasks was predictive of performance gains in the corresponding dual task along with complete elimination of modality-specific dual-task costs. This predictive relationship was evident only in the group practicing modality incompatible mappings, suggesting that specific practice on task sets with modality overlap influenced both neural representations and subsequent multitasking performance. This study contributes to the integration of cognitive theory and neuroscience and the role of task representations in dual-task interference.

Model-based frequency-and-phase correction of 1H MRS data with 2D linear-combination modeling.
Purpose: Retrospective frequency-and-phase correction (FPC) methods attempt to remove frequency-and-phase variations between transients to improve the quality of the averaged MR spectrum. However, traditional FPC methods like spectral registration struggle at low SNR. Here, we propose a method that directly integrates FPC into a two-dimensional linear-combination model (2D-LCM) of individual transients ("model-based FPC"). We investigated how model-based FPC performs compared to the traditional approach, i.e., spectral registration followed by 1D-LCM in estimating frequency-and-phase drifts and, consequentially, metabolite level estimates. Methods: We created synthetic in-vivo-like 64-transient short-TE sLASER datasets with 100 noise realizations at 5 SNR levels and added randomly sampled frequency and phase variations. We then used this synthetic dataset to compare the performance of 2D-LCM with the traditional approach (spectral registration, averaging, then 1D-LCM). Outcome measures were the frequency/phase/amplitude errors, the standard deviation of those ground-truth errors, and amplitude Cramer Rao Lower Bounds (CRLBs). We further tested the proposed method on publicly available in-vivo short-TE PRESS data. Results: 2D-LCM estimates (and accounts for) frequency-and-phase variations directly from uncorrected data with equivalent or better fidelity than the conventional approach. Furthermore, 2D-LCM metabolite amplitude estimates were at least as accurate, precise, and certain as the conventionally derived estimates. 2D-LCM estimation of frequency and phase correction and amplitudes performed substantially better at low-to-very-low SNR. Conclusion: Model-based FPC with 2D linear-combination modeling is feasible and has great potential to improve metabolite level estimation for conventional and dynamic MRS data, especially for low-SNR conditions, e.g., long TEs or strong diffusion weighting.

Retinotopic biases in contextual feedback signals to V1 for object and scene processing
Identifying the objects embedded in natural scenes relies on recurrent processing between lower and higher visual areas. How is cortical feedback information related to objects and scenes organised in lower visual areas? The spatial organisation of cortical feedback converging in early visual cortex during object and scene processing could be retinotopically specific as it is coded in V1, or object centred as coded in higher areas, or both. Here, we characterise object and scene-related feedback information to V1. Participants identified foreground objects or background scenes in images with occluded central and peripheral subsections, allowing us to isolate feedback activity to foveal and peripheral regions of V1. Using fMRI and multivoxel pattern classification, we found that feedback of object information is projected to foveal V1 cortex with increased detail during an object identification task. Background scene information is projected to both foveal and peripheral V1 but can be disrupted by a sufficiently demanding object discrimination task. We suggest that the feedback connections during scene perception project back to earlier visual areas an automatic sketch of occluded information to the predicted retinotopic location. In the case of a cognitive task however, feedback pathways project content to foveal retinotopic space, potentially for introspection, functioning as a cognitive active blackboard and not necessarily predicting the object's location. This feedback architecture could reflect the internal mapping in V1 of the brain's endogenous models of the visual environment that are used to predict perceptual inputs.

Sustained bias of spatial attention in a 3T MRI scanner
The static magnetic field of MRI scanners induces magneto-hydrodynamic stimulation of the vestibular organ (MVS) in the inner ear. This not only causes a horizontal vestibular nystagmus but also induces a horizontal bias in spatial attention. In this study, we aimed to determine the time course of MVS-induced biases in both VOR and spatial attention inside a 3T MRI-scanner as well as their respective aftereffects after participants left the scanner. Eye movements and overt spatial attention in a visual search task were assessed in healthy volunteers before, during and after a one-hour MVS period. All participants exhibited a VOR inside the scanner, which declined over time but never vanished completely. Importantly, there was also an MVS-induced horizontal bias in spatial attention and exploration, which persisted throughout the entire hour within the scanner. Upon exiting the scanner, we observed aftereffects in the opposite direction manifested in both the VOR and in spatial attention, lasting for about 6 minutes. Sustained MVS effects on spatial attention have important implications for the design and interpretation of fMRI-studies and for the development of therapeutic interventions counteracting spatial neglect.

The Interplay Between Multisensory Processing and Attention in Working Memory: Behavioral and Neural Indices of Audio-Visual Object Storage
Although real-life events are multisensory, how audio-visual objects are stored in working memory is an open question. At a perceptual level, evidence shows that both top-down and bottom-up attentional processes can play a role in multisensory interactions. To understand how attention and multisensory processes interact in working memory, we designed an audio-visual delayed match-to-sample task in which participants were presented with one or two audio-visual memory items, followed by an audio-visual probe. In three different blocks, participants were instructed to either (a) attend to the auditory features, (b) attend to the visual features, or (c) attend to both auditory and visual features. Participants were instructed to indicate whether the task-relevant features of the probe matched one of the task-relevant feature(s) or objects in working memory. Behavioral results showed interference from task-irrelevant features, suggesting bottom-up integration of audio-visual features and their automatic encoding into working memory, irrespective of their task relevance. Yet, ERP analyses revealed no evidence for active maintenance of these task-irrelevant features, while they clearly taxed greater attentional resources during recall. Notably, alpha oscillatory activity revealed that linking information between auditory and visual modalities required more attentional demands at retrieval. Overall, these results offer critical insights into how and at which processing stage multisensory interactions occur in working memory.

EEG biomarkers of GABA α5 positive allosteric modulators in rodents
Reduced cortical inhibition mediated by gamma-aminobutyric acid (GABA) is reported in depression, anxiety disorders, and aging. Novel positive allosteric modulator that specifically target 5-GABAA receptor subunit (5-PAM), ligand GL-II-73, shows anxiolytic, antidepressant, and pro-cognitive effects without the common side effects associated with non-specific modulation by benzodiazepines such as diazepam (DZP), thus suggesting novel therapeutic potential. However, it is unknown if 5-PAM has detectable signatures in clinically-relevant brain electroencephalography (EEG). We analyzed EEG in freely moving rats at baseline and following injections of 5-PAM and DZP. We showed that 5-PAM specifically decreased theta peak power whereas DZP shifted peak power from high to low theta, while increasing beta and gamma power. EEG decomposition showed that these effects were periodic and corresponded to changes in theta oscillation event duration. Our study thus shows that 5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable non-invasive monitoring of 5-PAM treatment efficacy.

Robust encoding of sub-sniff temporal information in the mouse olfactory bulb
The sensory world is highly dynamic, and the temporal structure of stimuli contains rich information about the environment. Odour plumes are shaped by complex airflow that imprint information about the nature and spatial organisation of the olfactory environment onto their temporal dynamics. Whilst insects and mammals alike can discern high-frequency information, how temporal properties of the olfactory environment are represented in the brain remains largely unknown. Here, we presented temporally rich and systematically varying odour stimuli whilst electrically recording from the output neurons of the mouse olfactory bulb, mitral and tufted cells (MTC). We found that temporal aspects of odour stimuli could readily be read out from MTC responses, with a temporal resolution of up to 20 ms. Remarkably, temporal representation was virtually identical across three different odours. To understand which temporal features are encoded, we developed a single-cell model accurately describing both single-cell and population responses. Temporal receptive fields of MTCs translated between different odours, indicating that MTC tuning to odour quality and dynamics are partially separable. Together, this suggests a stereotypical representation of odour dynamics across projection neurons and can serve as an entry point into dissecting mechanisms underlying how information about the environment is extracted from temporally fluctuating odour plumes.

Prevalent co-release of glutamate and GABA throughout the mouse brain
Several neuronal populations in the brain transmit both the excitatory and inhibitory neurotransmitters, glutamate, and GABA, to downstream neurons. However, it remains largely unknown whether these opposing neurotransmitters are co-released onto the same postsynaptic neuron simultaneously or are independently transmitted at different time and locations (called co-transmission). Here, using whole-cell patch-clamp recording on acute mouse brain slices, we observed biphasic miniature postsynaptic currents, i.e., minis with time-locked excitatory and inhibitory currents, in striatal spiny projection neurons (SPNs). This observation cannot be explained by accidental coincidence of monophasic miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively), arguing for the co-release of glutamate and GABA. Interestingly, these biphasic minis could either be an mEPSC leading an mIPSC or vice versa. Although dopaminergic axons release both glutamate and GABA in the striatum, deletion of dopamine neurons did not eliminate biphasic minis, indicating that the co-release originates from another neuronal type. Importantly, we found that both types of biphasic minis were detected in other neuronal subtypes in the striatum as well as in nine out of ten additionally tested brain regions. Our results suggest that co-release of glutamate and GABA is a prevalent mode of neurotransmission in the brain.

Heterogeneity of morphometric similarity networks in health and schizophrenia
Introduction: Morphometric similarity is a recently developed neuroimaging phenotype of inter-regional connectivity by quantifying the similarity of a region to other regions based on multiple MRI parameters assessed at each region. At the group-level, altered average morphometric similarity has been reported in psychotic disorders. At the individual level variability of morphometric similarity exists. We used normative modeling to address inter-individual heterogeneity of morphometric similarity in health and schizophrenia. Methods: Morphometric similarity for 68 cortical regions were obtained from baseline and follow-up T1-weighted scans of healthy individuals and patients with chronic schizophrenia. Using Bayesian Linear Regression and taking into account age, sex, image quality and scanner, normative models were trained and validated in healthy controls from multi-site data (n = 4310). Individual deviations from the norm (z-scores) were computed for each participant for each region at both timepoints. A z-score [greater double equals] than 1.96 was considered supra-normal and a z-score [less double equals] -1.96 infra-normal. As a longitudinal metric we calculated the change over time of the total number of infra- or supra-normal regions per participant. Regions were classified into seven predefined brain networks that have been derived from resting state functional MRI in order to assess morphometric similarity of functional networks. Results: The percentage of patients with infra- or supra-normal values for any region at baseline and follow-up was low (<6%) and not different from healthy controls. There were no longitudinal group differences in change over time of the total number of infra- or supra-normal regions per participant. At baseline, patients had decreased morphometric similarity of the default mode network and increased morphometric similarity of the somatomotor network when compared to healthy controls. Conclusions: In a case-control setting, a decrease of morphometric similarity within the default mode network may be a robust finding implicated in schizophrenia. Nevertheless, significant reductions were evident only in a minority of patients indicating that caution is warranted when extrapolating group-average results to the individual.

Beyond Accuracy: Refining Brain-Age Models for Enhanced Disease Detection
This study critically reevaluates the utility of brain-age models within the context of detecting neurological and psychiatric disorders, challenging the conventional emphasis on maximizing chronological age prediction accuracy. Our analysis of T1 MRI data from 46,381 UK Biobank participants reveals a paradox: simpler machine learning models, and notably those with excessive regularization, demonstrate superior sensitivity to disease-relevant changes compared to their more complex counterparts. This counterintuitive discovery suggests that models traditionally deemed less accurate in predicting chronological age might, in fact, offer a more meaningful biomarker for brain health by capturing variations pertinent to disease states. Our findings challenge the traditional understanding of brain-age prediction as normative modeling, emphasizing the inadvertent identification of non-normative pathological markers over precise age prediction.

Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration
Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, ribosomal proteins (RPs), mitochondrial-encoded RNAs, and long non-coding RNAs (lncRNAs). Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a subset of previously unreported TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analyzed KIF1C-knockout (KO) CNs, modeling hereditary spastic paraplegia (HSP), a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent in KIF1C-KO axons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact of KIF1C on the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment specific disease mechanisms.

Single nucleus RNA-sequencing reveals transcriptional synchrony across different relationships
Relationships are shaped by reciprocal interaction and feedback between individuals. As relationships mature, pairs share common goals, improve their ability to work together, and experience coordinated emotions. However, the neural underpinnings responsible for this unique, pair-specific experience remain largely unexplored. Here, we used single nucleus RNA-sequencing to examine the transcriptional landscape of the nucleus accumbens (NAc) in socially monogamous prairie voles in long-term peer or mating-based relationships. We identified cell type-specific transcriptional differences between relationship types, including proportional differences in subpopulations of medium spiny neurons and module-based gene expression differences in interneurons. We also identified five gene modules correlated with different facets of social preference behavior. Finally, we show that, regardless of relationship type, prairie vole pairs exhibit transcription-based synchrony at the level of individual cells. Together, our results are consistent with a model in which a subset of gene expression changes promote relationship type-appropriate behaviors, while other non-overlapping gene expression changes support the social behaviors that are common across affiliative relationships. In addition, the similarity of gene expression observed across partners suggests an important role for the pair-specific social environment in shaping the NAc transcriptional landscape. This represents an emergent cellular property of social bonds that provides a potential biological mechanism by which shared social experience reinforces and strengthens relationships.

Astrocytic metabolic control of orexinergic activity in the lateral hypothalamus regulates sleep and wake architecture
Neuronal activity undergoes significant changes during vigilance states, accompanied by an accommodation of energy demands. While the astrocyte-neuron lactate shuttle has shown that lactate is the primary energy substrate for sustaining neuronal activity in multiple brain regions, its role in regulating sleep/wake architecture is not fully understood. We manipulated the cell-specific expression of monocarboxylate transporters (MCTs), the major lactate transporters, to examine the involvement of astrocytic lactate supply in maintaining consolidated wakefulness. Our results demonstrate that reduced expression of MCT4 in astrocytes disrupts lactate supply to orexin neurons in the lateral hypothalamus (LH), impairing wakefulness stability. We also show that MCT2-mediated lactate uptake is necessary for maintaining tonic firing of orexinergic neurons and stabilizing wakefulness. Our findings provide both in vivo and in vitro evidence supporting the critical role of astrocyte-to-orexinergic neuron lactate shuttle in regulating proper sleep/wake stability, a crucial step for maintaining physiological functions and overall well-being.

Junctional Adhesion Molecule (JAM)-C recruitment of Pard3 and drebrin to cell contacts initiates neuron-glia recognition and layer-specific cell sorting in developing cerebella.
Sorting maturing neurons into distinct layers is critical for brain development, with disruptions leading to neurological disorders and pediatric cancers. Lamination coordinates where, when, and how cells interact, facilitating events that direct migrating neurons to their destined positions within emerging neural networks and control the wiring of connections in functional circuits. While the role of adhesion molecule expression and presentation in driving adhesive recognition during neuronal migration along glial fibers is recognized, the mechanisms by which the spatial arrangement of these molecules on the cell surface dictates adhesive specificity and translates contact-based external cues into intracellular responses like polarization and cytoskeletal organization remain largely unexplored. We used the cerebellar granule neuron (CGN) system to demonstrate that JAM-C receptor cis-binding on the same cell and trans-binding to neighboring cells controls the recruitment of the Pard3 polarity protein and drebrin microtubule-actin crosslinker at CGN to glial adhesion sites, complementing previous studies that showed Pard3 controls JAM-C exocytic surface presentation. Leveraging advanced imaging techniques, specific probes for cell recognition, and analytical methods to dissect adhesion dynamics, our findings reveal: 1) JAM-C cis or trans mutants result in reduced adhesion formation between CGNs and cerebellar glia, 2) these mutants exhibit delayed recruitment of Pard3 at the adhesion sites, and 3) CGNs with JAM-C mutations experience postponed sorting and entry into the cerebellar molecular layer (ML). By developing a conditional system to image adhesion components from two different cells simultaneously, we made it possible to investigate the dynamics of cell recognition on both sides of neuron-glial contacts and the subsequent recruitment of proteins required for CGN migration. This system and an approach that calculates local correlation based on convolution kernels at the cell adhesions site revealed that CGN to CGN JAM recognition preferentially recruits higher levels of Pard3 and drebrin than CGN to glia JAM recognition. The long latency time of CGNs in the inner external germinal layer (EGL) can be attributed to the combined strength of CGN-CGN contacts and the less efficient Pard3 recruitment by CGN-BG contacts, acting as gatekeepers to ML entry. As CGNs eventually transition to glia binding for radial migration, our research demonstrates that establishing permissive JAM-recognition sites on glia via cis and trans interactions of CGN JAM-C serves as a critical temporal checkpoint for sorting at the EGL to ML boundary. This mechanism integrates intrinsic and extrinsic cellular signals, facilitating heterotypic cell sorting into the ML and dictating the precise spatial organization within the cerebellar architecture.

An EEG Signature of MCH Neuron Activities Predicts Cocaine Seeking
Background: Identifying biomarkers that predict substance use disorder (SUD) propensity may better strategize anti-addiction treatment. The melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) critically mediates interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. Methods: Surface EEG signals and real-time Ca2+ activities of LH MCH neurons (Ca2+MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. Results: An EEG waveform derivative - a modified theta-to-delta ratio (EEG Ratio) - accurately tracks real-time Ca2+MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through REMS manipulations, wakefulness, circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG Ratio suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG Ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG Ratio also exhibited advantages over conventional REMS measures for the predictions. Conclusions: The identified EEG Ratio may serve as a non-invasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker predicting drug use propensity.

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of vascular cognitive impairment and dementia. A genetic arteriolosclerotic disease, the molecular mechanisms driving vascular brain degeneration and decline remain unclear. With the goal of driving discovery of disease-relevant biological perturbations in CADASIL, we used machine learning approaches to extract proteomic disease signatures from large-scale proteomics generated from plasma collected from three distinct cohorts in US and Colombia: CADASIL-Early (N = 53), CADASIL-Late (N = 45), and CADASIL-Colombia (N = 71). We extracted molecular signatures with high predictive value for early and late-stage CADASIL and performed robust cross- and external-validation. We examined the biological and clinical relevance of our findings through pathway enrichment analysis and testing of associations with clinical outcomes. Our study represents a model for unbiased discovery of molecular signatures and disease biomarkers, combining non-invasive plasma proteomics with clinical data. We report on novel disease-associated molecular signatures for CADASIL, derived from the accessible plasma proteome, with relevance to vascular cognitive impairment and dementia.

Formation and Retrieval of Cell Assemblies in a Biologically Realistic Spiking Neural Network Model of Area CA3 in the Mouse Hippocampus
The hippocampal formation is critical for episodic memory, with area Cornu Ammonis 3 (CA3) a necessary substrate for auto-associative pattern completion. Recent theoretical and experimental evidence suggests that the formation and retrieval of cell assemblies enable these functions. Yet, how cell assemblies are formed and retrieved in a full-scale spiking neural network (SNN) of CA3 that incorporates the observed diversity of neurons and connections within this circuit is not well understood. Here, we demonstrate that a data-driven SNN model quantitatively reflecting the neuron type-specific population sizes, intrinsic electrophysiology, connectivity statistics, synaptic signaling, and long-term plasticity of the mouse CA3 is capable of robust auto-association and pattern completion via cell assemblies. Our results show that a broad range of assembly sizes could successfully and systematically retrieve patterns from heavily incomplete or corrupted cues after a limited number of presentations. Furthermore, performance was robust with respect to partial overlap of assemblies through shared cells, substantially enhancing memory capacity. These novel findings provide computational evidence that the specific biological properties of the CA3 circuit produce an effective neural substrate for associative learning in the mammalian brain.

Measuring the time-dependent effects of dobutamine on the modulations of cardiac activity in rats
The measurement of the autonomic modulations of cardiac dynamics plays a crucial role in the understanding of cardiovascular health and disease. We aimed to estimate the time-resolved sympathetic and parasympathetic modulations of cardiac dynamics in a rat model. In this study, we present the adaptation of the method for rat cardiac analysis and compare it with standard measures of low-frequency (LF) and high-frequency (HF) components, which are commonly used for sympathetic and parasympathetic activity estimation, respectively. To evaluate the performance of our method, we study a dataset comprising spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). These rats were administered dobutamine to elicit autonomic dynamics. The results obtained from our method demonstrated accurate time-resolved depiction of sympathetic reactivity induced by dobutamine administration. These responses closely resembled the expected autonomic alterations observed during physical exercise conditions, albeit emulated pharmacologically. The comparisons with LF and HF measures further confirmed the effectiveness of our method in better capturing autonomic changes in rat cardiac dynamics. Our findings highlight the potential of our adapted method for time-resolved analysis in future clinical and translational studies involving rodents' models. The validation of our approach in animal models opens new avenues for investigating the relationship between ongoing changes in cardiac activity and parallel changes in brain dynamics. Such investigations are crucial for advancing our understanding of the intricate brain-heart connection, particularly in cases involving neurodegeneration, brain injuries, and cardiovascular conditions.

An adverse rearing environment alters maternal responsiveness to infant ultrasonic vocalizations
Rodent pups use a variety of ultrasonic vocalizations (USVs) to facilitate maternal care. Importantly, infant USV repertoires are dependent on both the age and early life experiences of the pups. We have shown that an adverse rearing environment modeled with the maternal separation (MS) paradigm alters caregiving behavior, but little is known about how pup USVs differentially elicit maternal attention. In the present study, maternal approach towards a vocalizing pup over a non-vocalizing pup was tested in a Y-maze apparatus at two developmental time points over the course of MS. At the postnatal day (P) 10, dams engaged in longer interaction times with the vocalizing pup compared to the non-vocalizing pup. This effect was modulated by rearing environment and the sex of the pup, with only MS dams spending more time with vocalizing male pups. As expected at P20, dams did not show a preference for either the vocalizing or non-vocalizing pups regardless of rearing environment, however, MS dams spent a greater amount of time in the center of the apparatus as compared to control dams, which can be interpreted as a measure of uncertainty and indecision. These effects are important considering the sex specific effects of MS exposure across all developmental stages. Our novel findings support the hypothesis that sex-specific pup-dam interactions may drive later life outcomes following adversity.