bioRxiv Subject Collection: Neuroscience's Journal

Mu-opioid receptor activation potentiates excitatory transmission at the habenulo-peduncular synapse
The continuing opioid epidemic poses a huge burden on public health. Identifying the neurocircuitry involved and how opioids modulate their signaling is essential for developing new therapeutic strategies. The medial habenula (MHb) is a small epithalamic structure that projects predominantly to the interpeduncular nucleus (IPN) and represents a mu-opioid receptor (MOR) hotspot. This habenulo-peduncular (HP) circuit can regulate nicotine and opioid withdrawal; however, little is known about the physiological impact of MOR on its function. Using MOR-reporter mice, we observed that MORs are expressed in a subset of MHb and IPN cells. Patch-clamp recordings revealed that MOR activation inhibited action potential firing in MOR+ MHb neurons and induced an inhibitory outward current in IPN neurons, consistent with canonical inhibitory effects of MOR. We next used optogenetics to stimulate MOR+ MHb axons to investigate the effects of MOR activation on excitatory transmission at the HP synapse. In contrast to its inhibitory effects elsewhere, MOR activation significantly potentiated evoked glutamatergic transmission to IPN. The facilitatory effects of MOR activation on glutamate co-release was also observed from cholinergic-defined HP synapses. The potentiation of excitatory transmission mediated by MOR activation persisted in the presence of blockers of GABA receptors or voltage-gated sodium channels, suggesting a monosynaptic mechanism. Finally, disruption of MOR in the MHb abolished the faciliatory action of DAMGO, indicating that this non-canonical effect of MOR activation on excitatory neurotransmission at the HP synapse is dependent on pre-synaptic MOR expression. Our study demonstrates canonical inhibitory effects of MOR activation in somatodendritic compartments, but non-canonical faciliatory effects on evoked glutamate transmission at the HP synapse, establishing a new mode by which MOR can modulate neuronal function.

Cervical transcutaneous vagus nerve stimulation enhances speech recognition in noise: A crossover, placebo-controlled study
Understanding speech in noisy environments is a widespread challenge, even for people with clinically normal hearing and users of hearing aids and cochlear implants. While these devices improve speech audibility, they do not optimize the brain's ability to isolate relevant speech from background noise. Tonic vagus nerve stimulation (VNS) has been shown to rapidly improve sensory processing in the brain and enhance auditory perception in humans. Here, we investigated whether tonic cervical transcutaneous VNS (ctVNS) can enhance speech-in-noise recognition. Two cohorts of older human adults (60-84 years) completed audiological speech-in-noise assessments, QuickSIN (n=16) or AzBio (n=14), while receiving tonic ctVNS or placebo stimulation to the neck-shoulder junction in a counterbalanced, crossover fashion. Participants repeated sentences spoken amid various levels of background babble. Relative to placebo stimulation, tonic ctVNS improved the signal-to-noise ratio for reliable speech perception (SNR-50) by an average of 0.72 dB in QuickSIN (p=0.033) and 0.38 dB in AzBio (p=0.045), and enhanced word recognition accuracy by 4% (QuickSIN: p=0.0066, AzBio: p=0.000025). Notably, ctVNS benefits exceeded minimum clinically important differences in 39% of participants on average. Improvements by tonic ctVNS were most pronounced in individuals with speech-in-noise deficits (p=0.0089), peaked at noise levels typical of real-world environments (p=0.029), and did not depend on hearing loss severity (p=0.97) or age (p=0.88). Our findings demonstrate that tonic ctVNS delivers immediate, clinically meaningful improvements in speech-in-noise recognition, highlighting its potential to complement traditional assistive hearing technologies and inform novel therapies for sensory processing disorders.

Voxel-wise or Region-wise Nuisance Regression for Functional Connectivity Analyses: Does it matter?
Removal of nuisance signals (such as motion) from the BOLD time series is an important aspect of preprocessing to obtain meaningful resting-state functional connectivity (rs-FC). The nuisance signals are commonly removed using denoising procedures at the finest resolution, i.e. the voxel time series. Typically the voxel-wise time series are then aggregated into predefined regions or parcels to obtain a rs-FC matrix as the correlation between pairs of regional time series. Computational efficiency can be improved by denoising the aggregated regional time series instead of the voxel time series. However, a comprehensive comparison of the effects of denoising on these two resolutions is missing. In this study, we systematically investigate the effects of denoising at different time series resolutions (voxel- and region-level) in 370 unrelated subjects from the HCP-YA dataset. Alongside the time series resolution, we considered additional factors such as aggregation method (Mean and first eigenvariate [EV]) and parcellation granularity (100, 400, and 1,000 regions). To assess the effect of those choices on the utility of the resulting whole-brain rs-FC, we evaluated the individual specificity (fingerprinting) and the capacity to predict age and three cognitive scores. Our findings show generally equal or better performance for region-level denoising with notable differences depending on the aggregation method. Using mean aggregation yielded equal individual specificity and prediction performance for voxel- and region-level denoising. When EV was employed for aggregation, the individual specificity of voxel-level denoising was reduced compared to region-level denoising. Increasing parcellation granularity generally improved individual specificity. For the prediction of age and cognitive test scores, only fluid intelligence indicated worse performance for voxel-level denoising in the case of aggregating with the EV. Based on these results, we recommend the adoption of region-level denoising for brain-behavior investigations when using mean aggregation. This approach offers equal individual specificity and prediction capacity with reduced computational resources for the analysis of rs-FC patterns.

Axon initial segment plasticity caused by auditory deprivation degrades time difference sensitivity in a model of neural responses to cochlear implants
Synaptic and neural properties can change during periods of auditory deprivation. These changes may disrupt the computations that neurons perform. In the brainstem of chickens, auditory deprivation can lead to changes in the size and biophysics of the axon initial segment (AIS) of neurons in the sound source localization circuit. This is the phenomenon of axon initial segment (AIS) plasticity. Individuals who use cochlear implants (CIs) experience periods of hearing loss, and so we ask whether AIS plasticity in neurons of the medial superior olive (MSO), a key stage of sound location processing, would impact time difference sensitivity in the scenario of hearing with cochlear implants. The biophysical changes that we implement in our model of AIS plasticity include enlargement of the AIS and replacement of low-threshold Potassium conductance with the more slowly-activated M-type Potassium conductance. AIS plasticity has been observed to have a homeostatic effect with respect to excitability. In our model, AIS plasticity has the additional effect of converting MSO neurons from phasic firing type to tonic firing type. Phasic firing is known to have greater temporal sensitivity to coincident inputs. Consistent with this, we find AIS plasticity degrades time difference sensitivity in the auditory deprived MSO neuron model across a range of stimulus parameters. Our study illustrates a possible mechanism of cellular plasticity in a non-peripheral stage of neural processing that could impose barriers to sound source localization by bilateral cochlear implant users.

Mapping Global Causal Responses to Noninvasive Modulation of Genetically and Spatially Targeted Neural Populations with Sonogenetic-fPET
Despite significant progress in brain circuit mapping over recent decades, a major challenge remains: no method currently allows for the noninvasive modulation of genetically and spatially defined neural populations while simultaneously monitoring their global effects throughout the brain and body. Here, we present sonogenetic-fPET, a technique that integrates sonogenetics with [18F]-2-fluoro-2-deoxy-D-glucose functional positron emission tomography (FDG-fPET) to overcome this challenge. Sonogenetics enables noninvasive, spatially targeted modulation of neurons genetically engineered to express the ultrasound-sensitive ion channel TRPV1, while FDG-fPET captures glucose metabolic changes triggered by this stimulation across the brain and body. We demonstrate the effectiveness of this technique by targeting neurons in the dorsal striatum, showcasing its capability to map global network responses to specific neuronal activation. Incorporating an acoustic hologram for sonogenetics further enables flexible modulation of different brain regions within a single mouse while concurrently mapping the resulting network activity. In summary, sonogenetic-fPET offers a tool for dissecting the global responses of the brain and body to the noninvasive modulation of genetically and spatially defined neuronal populations.

Intentionally vs. Spontaneously Prolonged Gaze: A MEG Study of Active Gaze-Based Interaction
Eye fixations are increasingly used to control computers through gaze-sensitive interfaces, yet the brain mechanisms underlying this non-visual use of gaze remain poorly understood. In this study, we recorded 306-channel magnetoencephalography (MEG) signals while participants played a video game controlled by their eye movements. Each move required selecting an object by fixating on it for at least 500 ms. Gaze dwells were classified as intentional if followed by a confirmation gaze on a special location and as spontaneous otherwise. In contrast to previous EEG studies on gaze-based interaction, we identified both oscillatory and sustained phase-locked MEG activity differentiating intentional and spontaneous gaze dwells, emerging near dwell onset and persisting until its termination. Thus, despite the apparent ease of controlling eye movements for gaze-based interaction, this process engages distinct neural signatures detectable with MEG, which are only partially similar to those observed in tasks requiring explicit inhibition of prepotent oculomotor responses. These findings highlight that contrasting spontaneous and intentional gaze dwells collected during free-behavior gaze-based interaction can serve as a novel methodology for studying mechanisms of voluntary control. Unlike traditional tasks in voluntary eye movement research, this approach avoids unnatural efforts from participants, offering a more naturalistic context for investigation.

Investigating the effect of mechanical adaptation on mid-air ultrasound vibrotactile stimuli
Gesture control systems based on mid-air haptics are increasingly used in infotainment systems in cars, where they can provide rich haptic feedback to improve human-computer interactions. Laboratory studies show that mid-air haptic feedback reduces drivers' distractions and improve safety. However, it is unclear how the perception of mid-air ultrasound stimuli is affected by prolonged exposure to vibrational noise, e.g., from the steering wheel of a moving vehicle. Studies on vibrotactile adaptation show that perception of mechanical vibration is impaired by prior exposure to stimuli of the same frequency. Here, we investigated the effect of mechanical adaptation on the perception of mid-air ultrasound stimuli. We measured participants' detection threshold for ultrasound stimuli of different frequencies both before and after exposure to 30 s mechanical vibrations. Across two experiments, we systematically manipulated the frequency and amplitude of the adapting stimulus. We found that exposure to low-frequency mechanical vibrations significantly impaired the detection of low-frequency ultrasound stimuli. In contrast, exposure to high-frequency mechanical vibrations equally impaired perception of both low- and high-frequency ultrasound stimuli. This effect was mediated by the amplitude of the adapting stimulus, with stronger mechanical vibrations producing a larger increase in participants' detection threshold. Overall, these findings show that perception of mid-air ultrasound stimuli is affected by specific sources of mechanical noise. Crucially, frequency-specificity in the low-frequency band also points toward possible mitigating solutions that could help minimising unwanted desensitization of mechanoreceptor channels during mid-air haptic interactions.

Juvenile fluoxetine treatment affects the maturation of the medial prefrontal cortex and behavior of adolescent female rats
Background Serotonin is strongly involved in the regulation of brain development. An early-life imbalance in brain serotonin levels may influence the proper formation of neuronal circuits and synaptic plasticity. One of the factors that can affect serotonin concentrations is exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, the first-line pharmacological treatment for depression and anxiety in the pediatric population. Women are more prone to depression and anxiety from a young age. The safety of early-life FLX treatment is still questionable. We hypothesized that juvenile FLX treatment influences the brain maturation and behavior of adolescent females. Methods On postnatal days (PNDs) 20-28, juvenile female rats were injected once daily with FLX. Five days later, anxiety- and fear-related behaviors and the response to amphetamine were assessed. On PND 40, the numbers of neurons and glial cells in the medial prefrontal cortex (mPFC) and hippocampus were estimated via stereological methods. Additionally, the mRNA expression of cell survival/apoptosis and synaptic plasticity markers was evaluated via RT qPCR. Results Juvenile FLX attenuated anxiety-like behaviors, impaired fear memory and blunted the locomotor response to amphetamine in adolescent females. Simultaneously, FLX increased the regional volume and the numbers of neurons and astrocytes in specific subregions of the mPFC but not in the hippocampus. Additionally, FLX-treated females presented increased expression of genes regulating cell survival and reduced mRNA levels of AMPA glutamate receptors in the mPFC. Conclusions Juvenile FLX affects the maturation of the mPFC; therefore, this psychotropic drug should be used with caution in young people.

Random Tree Model of Meaningful Memory
Traditional studies of memory for meaningful narratives focus on specific stories and their semantic structures but do not address common quantitative features of recall across different narratives. We introduce a statistical ensemble of random trees to represent narratives as hierarchies of key points, where each node is a compressed representation of its descendant leaves, which are the original narrative segments. Recall is modeled as constrained by working memory capacity from this hierarchical structure. Our analytical solution aligns with observations from large-scale narrative recall experiments. Specifically, our model explains that (1) average recall length increases sublinearly with narrative length, and (2) individuals summarize increasingly longer narrative segments in each recall sentence. Additionally, the theory predicts that for sufficiently long narratives, a universal, scale-invariant limit emerges, where the fraction of a narrative summarized by a single recall sentence follows a distribution independent of narrative length.

Modulating Prestimulus Alpha and Beta Power with tRNS Establishes Their Causal Role in Visual Perception
Variability in visual perception in response to consistent stimuli is a fundamental phenomenon linked to fluctuations in prestimulus low-frequency neural oscillations--particularly in the alpha (8-13 Hz) and beta (13-30 Hz) bands--typically measured by their power in electroencephalography (EEG) signals. However, the causal role of these prestimulus alpha and beta power fluctuations in visual perception remains unestablished. In this study, we investigated whether prestimulus alpha and beta power causally affect visual perception using transcranial random noise stimulation (tRNS). In a sham-controlled, single-blind, within-subject design, 29 participants performed a visual detection task while receiving occipital tRNS. Online functional near-infrared spectroscopy (fNIRS) was used to measure cortical excitability during stimulation, and offline EEG signals were collected after stimulation. Mental fatigue was incorporated as a state-dependent factor influencing tRNS effects. Our findings demonstrate that, primarily under low fatigue states, tRNS increased cortical excitability during stimulation (indicated by increased fNIRS oxyhemoglobin amplitude), decreased subsequent prestimulus EEG alpha and beta power, and consequently reduced the visual contrast threshold (VCT), indicating enhanced visual perception. Sensitivity analysis revealed that alpha oscillations contributed more significantly to visual perception than beta oscillations under low fatigue. Additionally, the state-dependent effects of tRNS may result from different sensitivities of VCT to neural oscillations across fatigue states. These results provide causal evidence linking prestimulus alpha and beta power to visual perception and underscore the importance of considering brain states in neuromodulation research. Our study advances the understanding of the neural mechanisms underlying visual perception and suggests potential therapeutic applications targeting neural oscillations.

A core set of neural states underlying memory reactivation of naturalistic events in the posterior medial cortex
In sensory and mid-level regions of the brain, stimulus information is often topographically organized; functional responses are arranged in maps according to features such as retinal coordinates, auditory pitch, and object animacy or size. However, such organization is typically measured during stimulus input, e.g., when subjects are viewing gratings or images. Much less is known about the possible spatial organization of function during episodic recall of real-world events, which seems to drive higher-order cortical regions in the default mode network, particularly in posterior midline areas. Prior studies have shown that when multiple people remember a common experience, event-specific activity patterns in the posterior medial cortex are similar across individuals. This indicates that spatially organized functional responses underlying episodic recall do exist. In this paper we leverage fMRI data collected during recall of naturalistic movies to identify a core set of neural states in the posterior medial cortex. These states are stimulus-locked, reactivated during recall, and have a shared spatial organization across brains. We show that a surprisingly small number of these states (16 states across hemispheres) is sufficient to achieve the same levels of reactivation in the posterior medial cortex as when using the standard methods of the field. Furthermore, these states are significantly related to actions and social-affective features of events in the movies. Together, these findings elucidate the properties of a spatially organized code within the posterior default mode network which appears during natural recollection of memories.

T-type calcium channels participate in intrinsic and synaptic activity of PKCγ neurons of the dorsal horn of the spinal cord during chronic pain
The disinhibition of the excitatory PKCgamma interneurons plays a central role during mechanical allodynia in the dorsal horn of the spinal cord, routing harmless information to nociceptive pathways. The T-type calcium channel Cav3.2, necessary for mechanical and cold allodynia, is found in most PKCgamma neurons of the spinal cord. In this study, the role of Cav3.2 in PKCgamma neurons was studied after its pharmacological inhibition and its conditional deletion (KO) in Cav3.2GFP-Flox KI x PKCgamma-CreERT2 x Ai14 mice in normal conditions and in the spared-nerve-injury (SNI) model of neuropathic pain. Conditional deletion of Cav3.2 increased the hindpaw basal mechanical sensitivity before surgery, and decreased mechanical pain 7 days, but not 28 days, after surgery. At the cellular level, Cav3.2 participated in the low-threshold currents of PKCgamma neurons and the T-type calcium current of PKCgamma neurons was decreased in KO mice as compared to wild-type (WT). This loss did not convert into proportional alterations in subthreshold properties including rebound potentials, suggesting the involvement of other T-type channels. Action potential kinetics and firing properties seemed similar in WT and KO mice too, but rebound potentials were diminished in the SNI model in WT but not in KO mice. In addition, the modulations of firing properties induced by T-type channel pharmacological blocker Z944 observed in WT mice were absent in KO mice and after SNI. Furthermore, the pairing of action potentials was modified after SNI in WT mice, and not in KO mice. At the synaptic level, excitatory currents were lowered 7- and 28-days after surgery, while inhibitory currents were lowered only at 28 days. These changes were not found in Cav3.2-ablated neurons. Miniature currents analysis indicated that Cav3.2 was involved in both excitatory and inhibitory synaptic transmissions at the level of PKCgamma neurons. Surprisingly, Z944 did not mimic the effects of Cav3.2 ablation in PKCgamma neurons, suggesting distinct and eventually opposite roles of other T-type calcium channels. Altogether, our results show that Cav3.2 is not mandatory for firing of PKCgamma neurons of the dorsal horn of the spinal cord, but that it participates to the SNI-induced changes in their intrinsic and synaptic activity, including changes in their excitatory and inhibitory controls.

Cortical state change by auditory deviants: a mismatch response generation mechanism in unconsciousness
Mismatch negativity is an auditory-evoked biomarker for an array of neuropsychological disorders that occurs irrespective of consciousness, yet the generation mechanisms are still debated. Cortical slow oscillations occur during sleep or anesthesia and consist of reliable changes between Up and Down phases, characterised by high and low neural activity, respectively. Here we measure electrocorticography responses in the urethane-anesthetised rat and we demonstrate that during an auditory oddball paradigm, deviants trigger cortical Up phase initiations. Triggering of Up phases creates a mismatch response across the cortex, and when deviants fail to trigger Up phases, no mismatch response is present. We therefore propose triggering of cortical Up phases as a mechanism for mismatch negativity generation in unconscious states.

A Model of Place Field Reorganization During Reward Maximization
When rodents learn to navigate in a novel environment, a high density of place fields emerges at reward locations, fields elongate against the trajectory, and individual fields change spatial selectivity while demonstrating stable behavior. Why place fields demonstrate these characteristic phenomena during learning remains elusive. We develop a normative framework using a reward maximization objective, whereby the temporal difference (TD) error drives place field reorganization to improve policy learning. Place fields are modeled using Gaussian radial basis functions to represent states in an environment, and directly synapse to an actor-critic for policy learning. Each field's amplitude, center, and width, as well as downstream weights, are updated online at each time step to maximize cumulative reward. We demonstrate that this framework unifies three disparate phenomena observed in navigation experiments. Furthermore, we show that these place field phenomena improve policy convergence when learning to navigate to a single target and relearning multiple new targets. To conclude, we develop a normative model that recapitulates several aspects of hippocampal place field learning dynamics and unifies mechanisms to offer testable predictions for future experiments.

Punishing temporal judgement boosts sense of agency and modulates its underlying neural correlates
Feeling in control of one's actions is fundamental to the formation of action-outcome relationships. Reinforcement and its valence also change the action-outcome relationship, either through behavior promotion or diminishment. In this study we evaluated how reward and punishment reinforcement modulate sense of agency, as measured by intentional binding. Moreover, using electroencephalography (EEG) we evaluated how reward and punishment reinforcement changes outcome event related potentials associated with the accuracy of participants' judgement of the time interval between a key press and audio tone. We found that punishment reinforcement increased intentional binding between the action and outcome more than reward and control feedback. This was also reflected in the outcome event related potentials, where punishment elicited greater P300s and Late Positive Potentials compared to reward and control. We also found increased N100s and diminished P300s and Late Positive Potentials when the participants did not actively participate in evoking the tone. Taken together, our findings showcase that punishment reinforcement boosts sense of agency and modulates associated neural activity more than reward and no reinforcement, as a function of increasing attention and arousal. These findings illuminate the greater effect punishment reinforcement has on behavior and brain activity by its modification of sense of agency, which is important for the development of treatments in psychiatric and neurological diseases.

Prefrontal cortex dopamine responds to the total valence of stimuli
The prefrontal cortex (PFC) dopamine system plays an essential role in cognitive flexibility, working memory and psychiatric disease, but determining the conditions under which dopamine in the PFC is released remains an open problem. Both rewarding and aversive stimuli have been found to trigger release, but studies have disagreed on whether the valence of a stimulus or other variables like novelty and salience are the most important. Here we report on recordings of dopamine-dependent fluorescence using a high-sensitivity dopamine indicator. We deliver an array of rewarding, aversive and mixed valence stimuli, as well as stimuli without any obvious valence. We observe that stimuli without valence, as well as the omission of expected stimuli, do not lead to large changes in fluorescence, even when these stimuli and omissions are both novel and engaging. In contrast, both rewarding and aversive stimuli lead to increases in fluorescence, with the most rewarding and most aversive stimuli leading to the largest increases. We test the effect of adding an aversive component to a rewarding stimulus and find that the increases in fluorescence are consistent with a summation of the rewarding and aversive components. We propose that dopamine release in the PFC responds to the total valence of a stimulus, in contrast with the traditional view of basal ganglia dopamine release that depends on the net valence.

Restoring Oscillatory Dynamics in Alzheimer's Disease: A Laminar Whole-Brain Model of Serotonergic Psychedelic Effects
Classical serotonergic psychedelics show promise in addressing neurodegenerative disorders such as Alzheimer's disease by modulating pathological brain dynamics. However, the precise neurobiological mechanisms underlying their effects remain elusive. This study introduces a personalized whole-brain model built upon a laminar neural mass framework to elucidate these effects. Using multimodal neuroimaging data from thirty subjects diagnosed with Alzheimer's disease, we simulate the impact of serotonin 2A receptor activation, characteristic of psychedelics, on cortical dynamics. By modulating the excitability of layer 5 pyramidal neurons, our models reproduce hallmark changes in EEG power spectra observed under psychedelics, including alpha power suppression and gamma power enhancement. These spectral shifts are shown to correlate strongly with the regional distribution of serotonin 2A receptors. Furthermore, simulated EEG reveals increased complexity and entropy, suggesting restored network function. These findings underscore the potential of serotonergic psychedelics to reestablish healthy oscillatory dynamics in the prodromal and early phases of Alzheimer's disease and offer mechanistic insights into their potential therapeutic effects in neurodegenerative disorders.

Synergistic Neural Circuits for Novelty and Goal-Directed Behavior
The ability to adapt in a dynamic world relies on detecting, learning, and responding to environmental changes. The detection of novelty serves as a critical indicator of such changes, prompting mechanisms to detect and respond to goal-relevant information. However, neural regions that support novelty detection and learning (hippocampus), salience detection (dopaminergic midbrain [VTA]), and executive function (prefrontal cortex [PFC]) have yet to be described as a sequential process that unfolds over time. Using functional magnetic resonance imaging (fMRI) we explored interactions between the hippocampus, VTA, and PFC in humans performing a novelty-imbued target-detection task. Hippocampal novelty activation predicted subsequent goal-directed VTA activity, enhancing readiness to detect goal-relevant information. Concurrently, goal-directed PFC activation modulated VTA target activation, refining focus on behaviorally significant cues. These circuits function both synergistically and independently, promoting subsequent hippocampal activity. This work provides new insights into how distributed circuits coordinate to optimize adaptive behavior.

Higher-Order Interactions in Neuronal Function: From Genes to Ionic Currents in Biophysical Models
Neuronal firing patterns are the consequence of precise varia- tions in neuronal membrane potential, which are themselves shaped by multiple ionic currents. In this study, we use bio- physical models, statistical methods, and information theory to explore the interaction between these ionic currents and neuron electrophysiological phenotype. We created numerous electrical models with diverse firing patterns using Monte Carlo Markov Chain methods. By analyzing these models, we identified intricate relationships between model parameters and electrical features. Our findings show that neuronal features are often influenced by multiple ionic currents sharing synergistic relationships. We also applied our methods to single-cell RNAseq data, discovering gene expression modules specific to certain interneuron types. This research sheds light on the complex links between biophysical parameters and neuronal phenotypes.

Variability of axon initial segment geometry and its impact on hippocampal pyramidal cell function
Action potentials, the primary information units of the nervous system, are usually generated at the axon initial segment (AIS). Changes in the length and position of the AIS are associated with alterations in neuronal excitability but there is only limited information about the baseline structural variability of the AIS. This work provides a comprehensive atlas of the diversity of proximal cell geometries across all anatomical axes of the murine hippocampus, encompassing dorsal-ventral, superficial-deep, and proximal-distal regions. We analyzed the morphology of 3,936 hippocampal pyramidal neurons in 12 animals of both sexes, focusing on AIS length, position, and their association with proximal cellular features such as the soma and dendritic geometries. Notably, neurons with axon-carrying dendrites were significantly more common in ventral compared to dorsal hippocampal areas, suggesting a functional adaptation to regional demands. Validation of this finding in human samples confirms the translational relevance of our murine model. We employed NEURON simulations to assess the functional implications of this variability. Here, variation in proximal geometry only minimally contributed to neuronal homeostasis, but instead increased heterogeneity of response patterns across neurons.

Atypical scene-selectivity in the retrosplenial complex in individuals with autism spectrum disorder
A small behavioral literature on individuals with autism spectrum disorder (ASD) has shown that they can be impaired when navigating using map-based strategies (i.e., memory-guided navigation), but not during visually guided navigation. Meanwhile, there is neuroimaging evidence in typically developing (TD) individuals demonstrating that the retrosplenial complex (RSC) is part of a memory-guided navigation system, while the occipital place area (OPA) is part of a visually-guided navigation system. A key identifying feature of the RSC and OPA is that they respond significantly more to pictures of places compared to faces or objects - i.e., they demonstrate scene-selectivity. Therefore, we predicted that scene-selectivity would be weaker in the RSC of individuals with ASD compared to a TD control group, while the OPA would not show such a difference between the groups. We used functional MRI to scan groups of ASD individuals and matched TD individuals while they viewed pictures of places and faces and performed a one-back task. As predicted, scene-selectivity was significantly lower in the RSC, but not OPA, in the ASD group compared to the TD group. These results suggest that impaired memory-guided navigation in individuals with ASD may, in part, be due to atypical functioning in the RSC.

Longitudinal assessment of the conversion of mild cognitive impairment into Alzheimer's dementia: Observations and mechanisms from neuropsychological testing and electrophysiology
INTRODUCTION: Elucidating and better understanding functional biomarkers of Alzheimer's disease (AD) is crucial. By analysing a detailed longitudinal dataset, this study aimed to create a model-based toolset to characterise and understand the conversion of mild cognitive impairment (MCI) to AD. METHODS: EEG, MRI, and neuropsychological data were collected from participants in San Marino: AD (n = 10), MCI (n = 20), and controls (n = 11). Across two additional years, MCI participants were classified as converters or non-converters. RESULTS: We identified the Stroop Color and Word Test as the largest differentiator for MCI conversion (ROC AUC = 0.795). This was underpinned by disconnectivity in working memory and attention networks. Unsupervised clustering of EEG spectra also differentiated MCI conversion (ROC AUC = 0.710) and was underpinned by reduced excitatory and enhanced inhibitory synaptic efficacy in (prodromal) AD. Combining electrophysiological and neuropsychological assessments increased the accuracy of the differentiation (ROC AUC = 0.880) in comparison to each measure considered individually. CONCLUSION: Combining electrophysiological and neuropsychological assessment with mathematical models can inform the development of non-invasive, low-cost tools for the early diagnosis of AD.

Functional Brain Connectivity and Musical Training: Insights from EEG Phase Synchronization During Music Perception
Musical training profoundly impacts brain organization, fostering functional and structural adaptations that enhance auditory, motor, and cognitive processes. This study investigates functional connectivity differences between professional musicians and non-musicians during tasks involving music perception and different graphic notations. Using EEG phase-locking value (PLV) analysis, we examined synchronization across alpha, beta, and gamma frequency bands. Results revealed that musicians exhibited enhanced functional connectivity between brain regions, reflecting their ability to integrate auditory, visual, and cognitive information efficiently. In the alpha band, strong connectivity between the occipital and temporal regions was observed during all tasks, with additional synchronization between the parietal and temporal regions in tasks lacking pitch information. In the beta band, significant frontal-temporal connectivity was detected, indicating cognitive processing, while temporal-occipital synchronization emerged in specific tasks. In the gamma band, musicians demonstrated robust frontal-temporal and frontal-frontal synchronization, reflecting emotional and structural processing of music. Non-musicians showed reduced task-specific connectivity, relying on generalized strategies. These findings underscore the role of musical training in enhancing multimodal brain integration and cognitive flexibility, contributing to advanced music perception and processing.

Patient-derived Induced Pluripotent Stem Cells as a Model to Study Frontotemporal Dementia Pathologies
The neurodegenerative disorder Frontotemporal Dementia (FTD) can be caused by a repeat expansion (GGGGCC; G4C2) in C9orf72. The function of wild-type C9orf72 and the mechanism by which the C9orf72-G4C2 mutation causes FTD, however, remain unresolved. Diverse disease models including human brain samples and differentiated neurons from patient-derived induced pluripotent stem cells (iPSCs) identified some hallmarks associated with FTD, but these models have limitations, including biopsies capturing only a static snapshot of dynamic processes and differentiated neurons being labor-intensive, costly, and post-mitotic. We find that patient-derived iPSCs, without being differentiated into neurons, exhibit established FTD hallmarks, including increased lysosome pH, decreased lysosomal cathepsin activity, cytosolic TDP-43 proteinopathy, and increased nuclear TFEB. Moreover, lowering lysosome pH in FTD iPSCs mitigates TDP-43 proteinopathy, suggesting a key role for lysosome dysfunction. RNA-seq reveals dysregulated transcripts in FTD iPSCs affecting calcium signaling, cell death, synaptic function, and neuronal development. We confirm differences in protein expression for some dysregulated genes not previously linked to FTD, including CNTFR (neuronal survival), Annexin A2 (anti-apoptotic), NANOG (neuronal development), and moesin (cytoskeletal dynamics). Our findings underscore the potential of FTD iPSCs as a model for studying FTD cellular pathology and for drug screening to identify therapeutics.

Multi-Stable Bimodal Perceptual Coding within the Ventral Premotor Cortex
Neurons of the primate ventral premotor cortex (VPC) respond to tactile or acoustic stimuli. But how VPC neurons process and integrate information from these two sensory modalities during perception remains unknown. To investigate this, we recorded the activity of VPC neurons in two trained monkeys performing a bimodal detection task (BDT). In the BDT, subjects reported the presence or absence of a tactile or an acoustic stimulus. Initial single-cell analyses revealed a diverse range of responses during the BDT: purely tactile, purely acoustic, bimodal and others that exhibited sustained activity during the decision maintenance delay, between the stimulus offset and motor report. To further explore the VPC's role in the BDT, we applied dimensionality reduction techniques to uncover the low-dimensional latent dynamics of the neuronal population and conducted parallel analyses on a recurrent neural network (RNN) model trained on the same task. Neural trajectories associated with tactile responses diverged strongly from those related to acoustic responses. Conversely, during the stimulus-absent trials the neural dynamics remained at rest. During the delay, the trajectories demonstrated a pronounced rotational dynamic toward a subspace orthogonal to the sensory response space, supporting memory maintenance in stable equilibria. This suggests that the network dynamics can sustain distinct stable states corresponding to the three potential task outcomes. Using low-dimensional modeling, we propose a universal dynamical mechanism underlying the transition from sensory to mnemonic processing, consistent with our experimental and computational observations. These findings show that the VPC contains neurons capable of bimodal coding and that its population can integrate competing sensory information and maintain decisions throughout the delay period, regardless of the sensory modality.

Differential effects of aging, Alzheimer's pathology, and APOE4 on longitudinal functional connectivity and episodic memory in older adults
Both aging and Alzheimer's disease (AD) affect episodic memory networks. How this relates to region-specific early differences in functional connectivity (FC), however, remains unclear. We assessed resting-state FC strength in the medial temporal lobe (MTL) - posteromedial cortex (PMC) - prefrontal network and cognition over two years in cognitively normal older adults from the PREVENT-AD cohort. FC strength within PMC and between posterior hippocampus and inferomedial precuneus decreased in normal aging (amyloid- and tau-negative adults). Lower FC strength within PMC was associated with poorer longitudinal episodic memory performance. Increasing FC between anterior hippocampus and superior precuneus was related to higher baseline AD pathology. Higher FC strength was differentially associated with memory trajectories depending on APOE4 genotype. Findings suggest differential effects of aging and AD pathology on longitudinal FC. MTL-PMC hypoconnectivity was related to aging and cognitive decline. Furthermore, MTL-PMC hyperconnectivity was related to early AD pathology and cognitive decline in APOE4 carriers.

Dopaminergic responses to identity prediction errors depend differently on the orbitofrontal cortex and hippocampus
Adaptive behavior depends on the ability to predict specific events, particularly those related to rewards. Armed with such associative information, we can infer the current value of predicted rewards based on changing circumstances and desires. To support this ability, neural systems must represent both the value and identity of predicted rewards, and these representations must be updated when they change. Here we tested whether prediction error signaling of dopamine neurons depends on two areas known to represent the specifics of rewarding events, the HC and OFC. We monitored the spiking activity of dopamine neurons in rat VTA during changes in the number or flavor of expected rewards designed to induce errors in the prediction of reward value or reward identity, respectively. In control animals, dopamine neurons registered both error types, transiently increasing firing to additional drops of reward or changes in reward flavor. These canonical firing signatures of value and identity prediction errors were significantly disrupted in rats with ipsilateral neurotoxic lesions of either HC or OFC. Specifically, HC lesions caused a failure to register either type of prediction error, whereas OFC lesions caused persistent signaling of identity prediction errors and much more subtle effects on signaling of value errors. These results demonstrate that HC and OFC contribute distinct types of information to the computation of prediction errors signaled by dopaminergic neurons.