bioRxiv Subject Collection: Neuroscience's Journal

Traveling waves enhance hippocampal-parahippocampal couplings in humanepisodic and working memory
Multiple brain regions in the human medial temporal lobe (MTL) are coordinated in memory processing. Traveling waves is a potential mechanism to coordinate information transfer through organizing the timing or spatiotemporal patterns of wave propagation. Based on direct human intracranial EEG recordings, we detected bidirectional hippocampal and parahippocampal traveling waves (4-10 Hz) along the posterior-anterior axis during a verbal memory task. Hippocampal traveling waves enhanced hippocampal- parahippocampal and intra-hippocampal couplings in both amplitude and phase as well as hippocampal theta phase-gamma amplitude coupling, suggesting a facilitatory role of TWs. Granger causality analysis showed asymmetric information flow, with greater predictability in the parahippocampal-to-hippocampal direction and dominant peak at the beta band (20-30 Hz). Hippocampal power and bidirectional hippocampal-parahippocampal information flow at the gamma band (35-50 Hz) showed reductions during successful memory encoding trials. These results support functional significance of frequency-specific parahippocampal-hippocampal and intra-hippocampal communications during memory encoding and retrieval.

Exploring the relationship between GBA1 host genotype and gut microbiome in the GBA1L444P/WT mouse model: Implications for Parkinson disease pathogenesis
Background: Heterozygous variants in GBA1 are the commonest genetic risk factor for Parkinson disease (PD) but penetrance is incomplete. GBA1 dysfunction can cause gastrointestinal disturbances and microbiome changes in preclinical models. Mounting evidence suggests that the microbiota-gut-brain axis is potentially implicated in PD pathogenesis. Whether the gut microbiome composition is influenced by host GBA1 genetics in heterozygosis has never been explored. Objectives: To evaluate whether heterozygosity for the GBA1 pathogenic L444P variant can cause perturbations in gut microbiome composition. Methods: Faecal samples collected from GBA1L444P/WT and GBA1WT/WT mice at 3 and 6 months of age were analysed through shotgun metagenomic sequencing. Results: No differences in - and {beta}-diversity were detected between genotyped groups, at either time points. Overall, we found a little variation of the gut microbiome composition and functional potential between GBA1L444P/WT and GBA1WT/WT mice over time. Conclusion: Host GBA1 genotype does not impact gut microbiome structure and composition in the presented GBA1L444P/WT mouse model. Studies investigating the effect of a second hit on gut physiology and microbiome composition could explain the partial penetrance of GBA1 variants in PD.

Structures of the human adult muscle-type nicotinic receptor in resting and desensitised states
Muscle-type nicotinic acetylcholine receptor (AChR) is the key signalling molecule in neuromuscular junctions. Here we present the structures of full-length human adult receptors in complex with Fab35 in -bungarotoxin (BuTx)-bound resting states, and in acetylcholine (ACh)-bound desensitised states. In addition to identifying the conformational changes during recovery from desensitisation, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in congenital myasthenic syndrome (CMS) patients, revealing they cause either slow- or fast-channel CMS characterised by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both AChR state transition and the pathogenic mechanisms of disease variants.

Stimulation of the Medial SNr Promotes Sustained Motor Recovery and Counteracts Parkinsonian Pathophysiology in Dopamine Depleted Mice
Dopamine loss alters the activity of neural circuits in the basal ganglia, contributing to motor symptoms of Parkinsons disease and catalepsy. Treatments that reduce basal ganglia pathophysiology alleviate motor symptoms but require maintenance. Cell-type specific interventions can reduce pathophysiology and provide sustained therapeutic benefits, but a lack of understanding of pathways involved limits translation. Here, we establish patterns of neuromodulation and electrophysiological biomarkers at the level of basal ganglia output that predict the duration of therapeutic effects. Focal activation of neurons in the ventromedial substantia nigra reticulata (SNr) engaged a gradual recovery of movement that persisted for hours after treatment, accompanied by a persistent reduction in parkinsonian pathophysiology. Global SNr inhibition, as prescribed by the classic rate model, provided only transient effects on movement and did not reverse network pathophysiology. These findings represent important steps towards developing therapeutic strategies that aim to repair, rather than simply mask, circuit dysfunction in disease.

Experimental Design Optimization for Brain Microstructure Imaging via Automatic Differentiation
Accurate characterization of brain microstructure using diffusion MRI (dMRI) relies on optimal, information-rich scanning protocols. Presently, without such protocols, extensive datasets are necessary to image intricate brain microarchitecture by fitting complex biophysical models to data. This impedes full realization of dMRI's potential, particularly in time-constrained clinical scans. To tackle this, we introduce a novel framework based on the Cramer-Rao lower bound to optimize dMRI protocols for any multi-compartment biophysical models, to accurately capture features like axonal diameter index and multiple fiber orientations in a voxel. Unlike previous methods, limited in model complexity or parameter scope, our framework handles all model parameters, including water diffusivities, enhancing estimation fidelity. Leveraging automatic differentiation and parallel computing via TensorFlow, this approach systematically explores the entire parameter space for comprehensive protocol optimization. By optimizing dMRI protocols, this work stands to significantly enhance biophysical modeling accuracy, deepening our understanding of brain microstructure in health and disease.

4-Phenylbutyric acid modulates Connexin 43 expression restricting murine-β-coronavirus infectivity and virus-induced demyelination
Gap junction intercellular communication, particularly involving Connexin 43 and Connexin 47, plays a critical role in maintaining CNS homeostasis and has been implicated in Multiple Sclerosis (MS) pathology. Thus, warranting further studies in experimental animal models to understand how modulation of Cx43 expression can influence MS pathology. Intracranial infection with murine {beta}-coronavirus Mouse Hepatitis Virus (MHV-A59) in mice results in acute pathology characterized by high viral titers, glial activation in the brain and chronic neuroinflammatory demyelination, effectively mimicking key pathological hallmarks of MS and serving as a robust model to investigate its viral etiology. MHV-A59 infection leads to a pronounced downregulation of Cx43 during the acute phase, emphasizing its critical role in virus-induced CNS pathology. In this study, we investigated the potential of in vivo 4-phenylbutyric acid (4-PBA) administration in modulating Cx43 expression in this MHV-induced model and its consequence on chronic virus-induced demyelination. Our results reveal that 4-PBA treatment reduced acute MHV-A59 infectivity and viral spread in the brain while modulating the glial cell response, mounting host immunity. Treatment with 4-PBA effectively preserved the expression of both Cx43 and Cx47 in infected CNS cells, counteracting their infection-induced downregulation. Furthermore, MHV-A59 infection downregulated the expression of ER-resident thioredoxin family protein (ERp29), a well-known molecular chaperone of Cx43, which was rescued by 4-PBA treatment. We further validated if such downregulation of ERp29 is also evident in MS demyelinating plaques. In human MS patient-derived brain tissue, reduced Cx43 and ERp29 staining was observed in demyelinating plaques. Our studies revealed that 4-PBA treatment not only limits viral replication and spread throughout the brain but also protects the mice against severe chronic neuroinflammatory demyelination. These findings suggest that targeting Cx43 with 4-PBA holds significant therapeutic potential for addressing virus-induced neuroinflammatory demyelination and MS by preserving gap junction intercellular communication.

The Role of the Dorsolateral Prefrontal Cortex in Ego Dissolution and Emotional Arousal During the Psychedelic State
Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression. This study investigated the role of the DLPFC in the psycho-emotional effects of LSD with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) data of healthy human participants during the acute LSD experience. In the fMRI data, we measured the correlation between changes in resting-state functional connectivity (RSFC) of the DLPFC and post-scan subjective ratings of positive mood, emotional arousal, and ego dissolution. We found significant, positive correlations between ego dissolution and functional connectivity between the left & right DLPFC, thalamus, and a higher-order visual area, the fusiform face area (FFA). Additionally, emotional arousal was significantly associated with increased connectivity between the right DLPFC, intraparietal sulcus (IPS), and the salience network (SN). A confirmational reverse analysis, in which the outputs of the original RSFC analysis were used as input seeds, substantiated the role of the right DLPFC and the aforementioned regions in both ego dissolution and emotional arousal. Subsequently, we measured the effects of LSD on directed functional connectivity in MEG data that was source-localized to the input and output regions of both the original and reverse analyses. The Granger causality (GC) analysis revealed that LSD increased information flow between two nodes of the ego dissolution network, the thalamus and the DLPFC, in the theta band, substantiating the hypothesis that disruptions in thalamic gating underlie the experience of ego dissolution. Overall, this multimodal study elucidates a role for the DLPFC in LSD-induced states of consciousness and sheds more light on the brain basis of ego dissolution.

Computational Primitives for Cost-Benefit Decision-Making
Summary Cost-benefit decision-making is a critical process performed by all organisms, including humans. Various factors, including risk, uncertainty, age, sex, and neuropsychiatric disorders, can alter decision-making. To explore cost-benefit decision-making in humans, we developed a comprehensive task and analysis framework that presents participants with a series of approach-avoid trade-offs across a variety of contexts. With this system, we found that cost-benefit decisions in humans are made using a set of computational strategies that may be used for integrating costs and rewards, which we term decision-making primitives. We further show that these decision-making primitives are used by rodents performing a similar decision-making task. We find that utilization of these primitives in both rodents and humans shifts based on factors like hunger and sex, and that individuals use primitives differently. We additionally demonstrate that using a naturally-inspired neural network architecture generates output that overlaps with human and rodent performance over a non-constrained neural network. This novel conceptual framework, by isolating discrete decision-making primitive, has potential to help us identify how different brain regions give rise to decision-making behavior, as well as to facilitate better diagnosis of neuropsychiatric disorders and development of naturally-inspired artificial intelligence systems of decision-making.

Cortically-mediated muscle responses to balance perturbations increase with perturbation magnitude in older adults with and without Parkinson's disease
We lack a clear understanding of how cortical contributions to balance are altered in aging and Parkinson's disease (PD), which limits development of rehabilitation strategies. Processes like balance control are typically mediated through brainstem circuits, with higher-order circuits becoming engaged as needed. Using reactive balance recovery, we investigated how hierarchical neural mechanisms shape balance-correcting muscle activity across task difficulty in older adults (OAs) with and without PD. We hypothesize that feedback loops involving brainstem and cortical circuits contribute to balance control, and cortical engagement increases with challenge, aging, and PD. We decomposed perturbation-evoked agonist and antagonist muscle activity into hierarchical components based on latency using neuromechanical models consisting of two feedback loops with different delays to reflect different neural conduction and processing times. Agonist muscle activity was decomposed into two components that both increased with balance challenge in both groups. The first component occurred ~120ms and the second occurred ~210ms, consistent with the latencies of brainstem and transcortical circuits, respectively. Exploratory comparisons to young adults revealed larger transcortical components in OA and PD groups at lower balance challenge levels, consistent with increased cortical involvement with aging. Antagonist muscle activity included destabilizing and stabilizing components, with the destabilizing component correlating to balance ability in OAs but not in PD. These findings demonstrate that neuromechanical models can identify changes in the hierarchical control of balance without direct brain measurements. Identifying cortical contributions during balance control may complement clinical measures of balance ability to inform balance rehabilitation and assistive devices.

Episodic slow breathing in mice markedly reduces fear responses
We sought to delineate neural mechanisms underlying the effects of controlled breathing in humans, such as in meditation or breathwork, which can reduce depression, anxiety, stress, and pain. Thus, we developed a murine model, where breathing frequency in awake mice can be substantially slowed. When done for 30 min/day for 4 weeks, these mice had significant reductions in stress-related changes in behavior compared to control mice. We conclude that slow breathing effects on emotional state are present in mice, and which cannot be attributed directly to top-down influences such as volitional or emotional control or placebo effects. Our study paves the way for investigations of the neural mechanisms underlying body-brain interactions related to the effects of controlled breathing as well as a platform for optimization of its therapeutic use for amelioration of ordinary and pathological stress and anxiety in humans.

The Impact of Memory and Stress on Choice Consistency
Choice consistency is a fundamental aspect of rational decision-making, reflecting the stability and reliability of an individual's preferences. However, real-world decision-making often deviates from this ideal, as individuals frequently make irrational or inconsistent choices in value-based decision-making. This study combined computational modeling, neuroimaging, and behavioral assessments to elucidate the mechanisms by which stress and memory affect choice consistency. Remembered items exhibited higher choice consistency compared to forgotten items. Computational modeling further indicated that the drift rate was higher, and the decision threshold lower, for remembered food items compared to forgotten ones. Stress was found to impair both choice consistency and memory retrieval, with stress-induced declines in memory accuracy positively correlating with reductions in choice reaction times. Activation of the dorsolateral prefrontal cortex (DLPFC) during the pre-choice anticipation period was positively associated with choice consistency. Similarly, activation of the orbitofrontal cortex (OFC) during the memory retrieval of food stimuli correlated with improved memory accuracy. These findings suggest that stress may impair choice consistency by disrupting memory retrieval processes. Overall, our study provides novel insights into the role of stress and memory in decision-making, offering a more nuanced understanding of the neural and cognitive processes that govern choice behavior.

Soleus H-Reflex Up-Conditioning during Sciatic Nerve Regeneration in Rats Improves Recovery of Locomotion
Operant conditioning of the spinal stretch reflex or its electrical analog, the H-reflex, induces plasticity in the brain and spinal cord that increases (up-conditioning) or decreases (down-conditioning) the reflex elicited by primary afferent input to the spinal motoneuron. In rats in which the sciatic nerve is transected and repaired, soleus (SOL) H-reflex up-conditioning during regeneration strengthens primary afferent reinnervation of SOL motoneurons and improves recovery of the SOL H-reflex. This suggests that H-reflex up-conditioning could improve functional recovery after nerve injury and repair. To explore this possibility, we examined the impact of SOL H-reflex up- or down-conditioning during sciatic regeneration on recovery of locomotor symmetry. Sprague-Dawley rats were implanted with EMG electrodes in right SOL and a stimulating cuff on right posterior tibial nerve. After control data collection, right sciatic nerve was transected and repaired. Control EMG and H-reflex data collection continued for 20 more days. The rat was then exposed for 100 days to either: continued control data collection; SOL H-reflex up-conditioning; or SOL H-reflex down-conditioning. Locomotor EMG, H-reflex, and kinematics were assessed before nerve transection and 120 days after transection. H-reflex up-conditioning improved H-reflex recovery and also restored right/left step symmetry. H-reflex down-conditioning did not worsen H-reflex recovery or right/left step asymmetry. These results suggest that H-reflex up-conditioning might enhance functional recovery after nerve injury in humans. They also confirm previous results indicating that compensatory plasticity prevents inappropriate H-reflex conditioning (i.e., down-conditioning) from further impairing function.

Oxytocin enhances acquisition in a social trust task in mice, whereas both oxytocin and its antagonist block trust violation learning
The complex effects of the neurohormone oxytocin (OT) on socio-cognitive phenomena have recently been proposed to be complementary with safety learning, where a stimulus acquires safety-predicting properties when it predicts non-occurrence of an aversive event. OT may enhance saliency of safety stimuli and promote positive social behavior, such as trust, by reducing anxiety and stress. Complementary, OT may reduce the ability to modulate previously learned behaviors based on new, contradicting information. This occurs through its attenuation of prediction error (PE)--the discrepancy between expectations and actual outcomes. In the current study, we stimulated or inhibited (with antagonist cligosiban, CL) the OT system and subjected male and female mice to our social transmission of food preference (STFP) protocol to assess social safety learning. STFP is based on the observation that food neophobia of rodents is attenuated when a conspecific signals the safety of the food. We used safe food preference as putative murine homologue of human trust acquisition, and modeled trust violation (PE) using lithium chloride (LiCl)-induced food aversion after social interaction. In males, results revealed that OT enhanced trust acquisition, whereas both OT and its antagonist CL similarly blocked trust violation learning. None of the manipulations affected female behavior. Our findings highlight the complexities of OT's role in social behavior, emphasizing caution in therapeutic manipulations of this system.

Dissecting origins of wiring specificity in dense cortical connectomes
Wiring specificity in the cortex is observed across scales from the subcellular to the network level. It describes the deviations of connectivity patterns from those expected in randomly connected networks. Understanding the origins of wiring specificity in neural networks remains difficult as a variety of generative mechanisms could have contributed to the observed connectome. To take a step forward, we propose a generative modeling framework that operates directly on dense connectome data as provided by saturated reconstructions of neural tissue. The computational framework allows testing different assumptions of synaptic specificity while accounting for anatomical constraints posed by neuron morphology, which is a known confounding source of wiring specificity. We evaluated the framework on dense reconstructions of the mouse visual and the human temporal cortex. Our template model incorporates assumptions of synaptic specificity based on cell type, single-cell identity, and subcellular compartment. Combinations of these assumptions were sufficient to model various connectivity patterns that are indicative of wiring specificity. Moreover, the identified synaptic specificity parameters showed interesting similarities between both datasets, motivating further analysis of wiring specificity across species.

Test-retest reliability of auditory MMN measured with OPM-MEG
In this paper, we report results from an investigation of auditory mismatch responses as measured by magnetoencephalography (MEG) based on optically pumped magnetometers (OPM). Specifically, as part of a quality control study, we examined the reliability and validity of auditory mismatch negativity (MMN) recordings, obtained with a newly installed OPM-MEG system. Based on OPM-MEG data from 30 healthy volunteers, measured twice with an established auditory MMN paradigm with frequency deviants, we examined the following questions: First, we focused on construct validity and examined whether OPM-MEG measurements of MMN responses (in terms of event-related fields, ERFs) were qualitatively comparable to previous MMN findings from studies using EEG or MEG based on superconducting quantum interference devices (SQUIDs). In particular, we examined whether significant MMN responses measured by OPM-MEG occurred in a comparable time window and showed a similar topography as in previous EEG/MEG studies of MMN. Second, we quantified test-retest reliability of MMN amplitude and latency over two separate measurement sessions. The results of our analyses show that MMN responses recorded with OPM-MEG are in good agreement with previously reported MMN results in terms of timing and topography. Furthermore, the comparison of group-level MMN topographies and timeseries shows excellent consistency across the two measurement sessions. Our quantitative test-retest reliability analyses at the sensor level indicate good reliability for MMN amplitude, but poor reliability for MMN latency. Overall, our findings suggest that OPM-MEG (i) produces comparable results as EEG and SQUID-based MEG for auditory MMN and (ii) shows good test-retest reliability for amplitude measures at the sensor level. Notably, these results were achieved in an "out of the box" state of the OPM-MEG system, shortly after installation and without further optimisation. The reason for the insufficient reliability for MMN latency we observed is currently under investigation and represents an important target for future improvements.

Assembly of a functional neuronal circuit in embryos of an ancestral metazoan is influenced by environmental signals including the microbiome
Understanding how neural populations evolve to give rise to behavior is a major goal in neuroscience. However, the complexity of the nervous system in most invertebrates and vertebrates complicates the deciphering of underlying fundamental processes. Here, we explore the self-assembly of neural circuits in Hydra, an organism with a simple nervous system but no centralized information processing, to improve the understanding of nervous system evolution. The N4 neuronal circuit in embryos develops through activity-driven self-assembly, where neurons in distinct regions increase connectivity and synchronization. Gap junctions and vesicle-mediated communication between neuronal and non-neuronal cells drive rapid assembly, with the embryo's prospective oral region exhibiting the highest neuronal density. An artificial electrical circuit-based model demonstrates dynamic increases in synchronization over time, along with predictions for selective dynamic adaptions of connections. Environmental factors, like temperature and an absent microbiome, modify neural architecture, suggesting the existence of a certain plasticity in neural development. We propose that these fundamental features originated in the last common bilaterian ancestor, supporting the hypothesis that the basic architecture of the nervous system is universal.

A simple neural circuit model explains diverse types of integration kernels in perceptual decision-making
The ability to accumulate evidence over time for deliberate decision is essential for both humans and animals. Decades of decision-making research have documented various types of integration kernels that characterize how evidence is temporally weighted. While numerous normative models have been proposed to explain these kernels, there remains a gap in circuit models that account for the complexity and heterogeneity of single neuron activities. In this study, we sought to address this gap by using low-rank neural network modeling in the context of a perceptual decision-making task. Firstly, we demonstrated that even a simple rank-one neural network model yields diverse types of integration kernels observed in human data--including primacy, recency, and non-monotonic kernels--with a performance comparable to state-of-the-art normative models such as the drift diffusion model and the divisive normalization model. Moreover, going beyond the previous normative models, this model enabled us to gain insights at two levels. At the collective level, we derived a novel explicit mechanistic expression that explains how these kernels emerge from a neural circuit. At the single neuron level, this model exhibited heterogenous single neuron response kernels, resembling the diversity observed in neurophysiological recordings. In sum, we present a simple rank-one neural circuit that reproduces diverse types of integration kernels at the collective level while simultaneously capturing complexity of single neuron responses observed experimentally.

Non-ionotropic signaling through the NMDA receptor GluN2B carboxy terminal domain drives morphological plasticity of dendritic spines and reverses fragile X phenotypes in mouse hippocampus
It is well known that activation of NMDA receptors (NMDAR) can trigger long-term synaptic depression (LTD) and that a morphological correlate of this functional plasticity is spine retraction and elimination. Recent studies have led to the surprising conclusion that NMDA-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis, highlighting an unappreciated contribution of mRNA translation to non-ionotropic NMDAR signaling. Here we used NMDA-induced spine shrinkage in slices of mouse hippocampus as a readout to investigate this novel modality of synaptic transmission. By using subtype selective pharmacological and genetic tools, we find that structural plasticity is dependent on the ligand binding domain (LBD) of GluN2B-containing NMDARs and that metabotropic signaling occurs via the GluN2B carboxy terminal domain (CTD). Disruption of signaling by replacing the GluN2B CTD with the GluN2A CTD leads to an increase in spine density, dysregulated basal protein synthesis, exaggerated mGluR-LTD, and epileptiform activity reminiscent of phenotypes observed in the Fmr1 knockout (KO) model of fragile X syndrome. By crossing the Fmr1 KO mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism.

Early-life adversity mediates a thalamo-amgydalar circuit dysfunction underlying chronic pain and anxiety
Childhood adversity increases the risk of developing a vicious cycle of chronic pain and comorbid anxious avoidance, yet the underlying biological mechanisms remain unclear. Here, we investigated the role of a brain circuit from the paraventricular thalamus (PVT) to the central amygdala (CeA) in mediating hyperalgesia and comorbid anxiety following early life stress. Using a vulnerability-stress model, we exposed both male and female mice to early social isolation (vulnerability) followed by nerve injury (stress) and showed increased hyperalgesia and anxious avoidance behavior in nerve-injured female mice following early adversity. Chemogenetic, electrophysiological, and optophysiological analyses revealed a causal contribution of a hyperexcitable PVT-CeA circuit dysfunction to chronic hyperalgesia and anxiety in nerve-injured female mice after early life stress. Our findings reveal a neural mechanism linking childhood adversity to chronic pain and anxiety, and suggest that reprogramming this pathway may reverse the impact of childhood adversity.

Eye movements organize excitability state, information coding and network connectivity in the human hippocampus
Natural vision is an active sensing process that entails frequent eye movements to sample the environment. Nonetheless vision is often studied using passive viewing with eye position held constant. Using closed-loop eye-tracking, with saccade-contingent stimulation and simultaneous intracranial recordings in surgical epilepsy patients, we tested the critical role of eye movement signals during natural visual processing in the hippocampus and hippocampal-amygdala circuit. Prior work shows that saccades elicit phase reset of ongoing neural excitability fluctuations across a broad array of cortical and subcortical areas. Here we show that saccade-related reset systematically modulates neuronal ensemble responses to visual input, enables phase-coding of information across the saccade-fixation cycle and modulates network connectivity between hippocampus and amygdala. The saccade-fixation cycle thus emerges as a fundamental sampling unit, organizing a range of neural operations including input representation, network connectivity and information coding.

Approach-Avoidance Bias in Virtual and Real-World Simulations: Insights from a Systematic Review of Experimental Setups
Background: Approach and avoidance bias (AAB) describes automatic behavioral tendencies to react toward environmental stimuli regarding their emotional valence. Traditional setups have provided evidence but often lack ecological validity. The study of the AAB in naturalistic contexts has recently increased, revealing significant methodological challenges. This systematic review evaluates the use of virtual reality (VR) and real-world setups to study the AAB, summarizing methodological innovations and challenges. Methods: We systematically reviewed peer-reviewed articles employing VR and real-world setups to investigate the AAB. We analyzed experimental designs, stimuli, response metrics, and technical aspects to assess their alignment with research objectives and identify limitations. Results: This review included 21 studies revealing diverse methodologies, stimulus types, and novel behavioral responses, highlighting significant variability in design strategies and methodological coherence. Several studies used traditional reaction time measures yet varied in their application of VR technology and participant interaction paradigms. Some studies showed discrepancies between simulated and natural bodily actions, while others showcased more integrated approaches that preserved their integrity. Only a minority of studies included control conditions or acquired (neuro)physiological data. Conclusions: VR offers a potential ecological setup for studying the AAB, enabling dynamic and immersive interactions. Our results underscore the importance of establishing a coherent framework for investigating the AAB tendencies using VR. Addressing the foundational challenges of developing baseline principles that guide VR-based designs to study the AAB within naturalistic contexts is essential for advancing the AAB research and application. This will ultimately contribute to more reliable and reproducible experimental paradigms and develop effective interventions that help individuals recognize and change their biases, fostering more balanced behaviors.

Effects of Electric Field Direction on TMS-based Motor Cortex Mapping
Background: Transcranial magnetic stimulation (TMS) modulates brain activity by inducing electric fields (E-fields) that can elicit action potentials in cortical neurons. Neuronal responses to TMS depend not only on the magnitude of the induced E-field but also on various physiological factors. In this study, we incorporated a novel average response model that efficiently estimates the firing threshold of neurons based on their orientation relative to the applied E-field, thereby advancing TMS mapping for motor function. Methods: We conducted a regression-based TMS mapping experiment with fourteen subjects to localize cortical origins of motor evoked potential (MEP) on the first dorsal interosseous (FDI) muscle. Firing thresholds were estimated for excitatory neurons in cortical layers 2/3 and 5 via an average response model. Regression was performed between MEPs and three E-field quantities: the magnitude (magnitude model), the normal component (cosine model), and the effective E-field, which scales the E-field magnitude based on the firing thresholds specific to the neuronal orientation (neuron model). To validate, we applied TMS to ten subjects with optimized coil placements based on these three models to determine which model could yield the highest MEPs. Results: The magnitude and neuron models performed similarly, while the cosine model showed lower explained variance in regression results, required more TMS trials for stable mapping, and yielded the lowest MEP in the validation. Conclusion: This study is the first to advance TMS modeling by incorporating neuron-specific factors at the individual level. Results show that on the motor cortex, the magnitude model is, as expected, a good approximation of cortical TMS effects as it shows similar results as the neuron model. In contrast, the classic cosine model exhibited lower performance and required more TMS trials for stable results, and is not recommended for future studies.

SENSITIVITY OF MEDIAL/LATERAL BALANCE CONTROL TO VISUAL DISTURBANCES WHILE WALKING IN YOUNG AND OLDER ADULTS
Humans integrate multiple sources of sensory information to estimate body orientation in space. Balance control experiments while standing provide evidence that the contributions of these sensory channels change under different conditions in a process called sensory reweighting. This study aims to address whether there is evidence for sensory reweighting while walking and explores age-related differences in medial/lateral balance control under visually perturbing walking conditions. Thirty young adults (18-35 years) and thirty older adults (55-79 years) walked on a self-paced treadmill within a virtual environment that delivered frontal plane multi-sine visual disturbances at three amplitudes (6{degrees}, 10{degrees}, and 15{degrees}). Frequency response functions were used to quantify visual sensitivity to balance disturbances, while spatiotemporal gait parameters (e.g., step width, step-width variability) were measured to assess balance control. Visual sensitivity decreased in both populations with increasing stimulus amplitude, analogous to the sensory reweighting hypothesis in balance control while standing. Despite the decrease in visual sensitivity, the compensatory upweighting of other sensory systems was not observed through measurements of remnant sway. Older adults exhibited higher visual sensitivity at all amplitudes compared to young adults, indicating a more sensitive response to visual disturbances to balance control. Both groups showed increases in step width and step width variability with higher visual amplitudes, with older adults demonstrating more pronounced effects. Weak correlations existed between changes in visual sensitivity and changes in step width and step width variability suggesting a limited interaction between sensory reweighting and gait stability.

Evidence for reduced choroid plexus volume in the aged brain
Background: The choroid plexus plays an important role in brain homeostasis, including the active secretion of cerebrospinal fluid. Its function and structure have been reported to be affected by normal ageing. However, existing measures of choroid plexus volume may be complicated by partial volume (in-vivo MRI) and tissue fixation artefacts (histology). In this study, we investigate possible changes in choroid plexus volume within the lateral ventricles of a mouse model of ageing utilising two structural MRI protocols explicitly designed for time-efficient, high-resolution in-vivo imaging of the choroid plexus. Methods: Two MRI sequences were utilised to examine in-vivo choroid plexus volume in the lateral ventricles of young (~6 months) and aged (~24 months) mouse brains: 1) an ultra-long echo-time T2 weighted fast-spin-echo and 2) a multi-TE T2* mapping protocol. A test-retest study was performed on a subset of the data to examine the reproducibility of choroid plexus volume estimation. A two-way ANOVA test was performed to determine possible differences in choroid plexus volume in young and aged mouse groups across the two distinct MRI protocols. Results: Reproducibility tests showed a low test-retest variability of the manual segmentation pipeline for both MRI protocols. A statistically significant reduction of in vivo choroid plexus volume was found in the aged mouse brain. This finding is concordant with previous histology studies that have observed a reduction in epithelial cell height with ageing across a wide range of species. Conclusions: Here, we present an in vivo investigation of changes to lateral ventricle choroid plexus volume in the mouse brain utilising a manual segmentation approach based on two bespoke MRI protocols designed for time-efficient high resolution imaging of the choroid plexus. We provide evidence for a reduction in choroid plexus volume in the aged brain. This research provides insight for studies utilising MRI measurements of choroid plexus volume as a biomarker of age-related neurologic conditions as it indicates that the ageing process itself does not result in hypertrophy of the choroid plexus.

Risk optimization during ongoing movement: Insights from movement and gaze behavior in throwing
Handling motor noise is fundamental to successful sensorimotor behavior, especially in high-risk situations. Research using finger-pointing tasks shows that humans account for motor noise and costs of potential outcomes in movement planning. However, does this mechanism generalize to more complex movement tasks? Here, we investigate sensorimotor behavior under risk in throwing across three experiments with 20 participants each. Their task was to throw balls at a target circle, partially overlapped by a penalty circle. This task challenged participants to find strategies that trade off potential penalties and rewards. In the experiments, penalty magnitude and the distance between the circles were manipulated. We measured the location of their final gaze fixation before movement - as an indicator of their planned aiming point - and the ball's impact location. Without penalty, the final gaze fixation and the ball's impact location were both centered on the target. In the penalty condition, the location of the participants' final gaze fixations and the ball's impact shifted away from the penalty circle, with larger shifts for higher penalties and smaller distances. Interestingly, the shifts in the ball's impact locations were not only larger ("more conservative") but also closer to the statistically optimal (expected gain-maximizing) location compared to the fixated aim points. Movement trajectory analyses show that, in penalty conditions, the shifts away from the penalty zone increased until the final phases of the movement. These results suggest that risk evaluation is not completed in a pre-movement planning phase but is further optimized during movement execution.

Chronic High Intensity Interval Training (HIIT) exercise in adolescent rat's result in cocaine place aversion and ΔFosB induction
High-Intensity Interval Training (HIIT) is a form of exercise that has been greatly popularized over the past few years for its many health benefits. Similar to other forms of exercise, HIIT may be beneficial in the prevention of substance use behaviors; however, the extent to which HIIT can impact the reinforcing effects of drugs of abuse during adolescence has not been fully evaluated. Here, we assess the effects of HIIT during adolescence on subsequent cocaine conditioned place preference (CPP) in male Lewis rats. The HIIT exercise exposed rats ran on a treadmill for 30 minutes daily (ten three-minute cycles) for six weeks with progressive speed-increased up to 0.8 mph (21.5m/min), while the sedentary rats remained in their home cage. Following the six weeks of exercise, rats were tested for cocaine (25 mg/kg) CPP. Following completion of the behavior test {Delta}FosB levels were measured in the brain. Results showed that the HIIT rats showed significantly attenuated place preference (-19%) in their time spent in the cocaine-paired chamber compared to the sedentary environment rats. In addition, HIIT rats had significantly higher (65%) striatum {Delta}FosB levels compared to the sedentary rats. Our findings show that HIIT exercise during adolescence could be protective against cocaine abuse which may be mediated by an increase in {Delta}FosB. This finding has important clinical implications with respect to exercise mediated protection against substance misuse and abuse. Future studies will examine this effect in females as well as the potential underlying mechanisms.

A multiscale electro-metabolic model of a rat neocortical circuit reveals the impact of ageing on central cortical layers
The high energetic demands of the brain arise primarily from neuronal activity. Neurons consume substantial energy to transmit information as electrical signals and maintain their resting membrane potential. These energetic requirements are met by the neuro-glial-vascular (NGV) ensemble, which generates energy in a coupled metabolic process. In ageing, metabolic function becomes impaired, producing less energy and, consequently, the system is unable to sustain the neuronal energetic needs. We propose a multiscale model of electro-metabolic coupling in a reconstructed rat neocortex. This combines an electro-morphologically reconstructed electrophysiological model with a detailed NGV metabolic model. Our results demonstrate that the large-scale model effectively captures electro-metabolic processes at the circuit level, highlighting the importance of heterogeneity within the circuit, where energetic demands vary according to neuronal characteristics. Finally, in metabolic ageing, our model indicates that the middle cortical layers are particularly vulnerable to energy impairment.

Adaptation shapes the representational geometry in mouse V1 to efficiently encode the environment
Sensory adaptation dynamically changes neural responses as a function of previous stimuli, profoundly impacting perception. The response changes induced by adaptation have been characterized in detail in individual neurons and at the population level after averaging across trials. However, it is not clear how adaptation modifies the aspects of the representations that relate more directly to the ability to perceive stimuli, such as their geometry and the noise structure in individual trials. To address this question, we recorded from a population of neurons in the mouse visual cortex and presented one stimulus (an oriented grating) more frequently than the others. We then analyzed these data in terms of representational geometry and studied the ability of a linear decoder to discriminate between similar visual stimuli based on the single-trial population responses. Surprisingly, the discriminability of stimuli near the adaptor increased, even though the responses of individual neurons to these stimuli decreased. Similar changes were observed in artificial neural networks trained to reconstruct the visual stimulus under metabolic constraints. We conclude that the paradoxical effects of adaptation are consistent with the efficient coding framework, allowing the brain to improve the representation of frequent stimuli while limiting the associated metabolic cost.

Corticospinal excitability is facilitated during coordinative action observation and motor imagery of adapted single-leg sit-to-stand movements in young healthy adults
Combined action observation and motor imagery (AOMI) facilitates corticospinal excitability (CSE). This study used single-pulse transcranial magnetic stimulation (TMS) to explore changes in CSE for coordinative AOMI of a single-leg sit-to-stand (SL-STS) movement. Twenty-one healthy adults completed two testing sessions, where they engaged with baseline (BL), action observation (AO), and motor imagery (MI) control conditions, and three experimental conditions where they observed a slow-paced SL-STS while simultaneously imagining a slow- (AOMIHICO), medium- (AOMIMOCO), or fast-paced (AOMILOCO) SL-STS, with imagery guided through audio sonification. A TMS pulse was delivered to the right leg representation of the left primary motor cortex at three stimulation timepoints aligned with peak EMG activity of the knee extensor muscle group for the slow-, medium-, and fast-paced SL-STS during each condition. Motor evoked potential (MEP) amplitudes were recorded from the KE muscle group as a marker of CSE for all stimulation timepoints and conditions. A main effect for experimental condition was reported for all three stimulation timepoints. MEP amplitudes were significantly greater for AOMIHICO at T1 and T3, and AOMIMOCO and AOMILOCO at all stimulation timepoints, when compared with control conditions. The findings provide empirical support for the propositions of the Dual-Action Simulation Hypothesis and Visual Guidance Hypothesis accounts for coordinative AOMI. This study builds on existing neurophysiological support for the use of coordinative AOMI as an alternative method for movement (re)learning. Longitudinal research incorporating neurophysiological and behavioral measures is warranted to explore the efficacy of coordinative AOMI for this purpose.