Monday, April 7th, 2025

Time	Event
3:32a	Nonlinear integration of sensory and motor inputs by a single neuron in C. elegans. Context is important for sensory integration. Rather than simply considering sensory information independently, the brain integrates this information to inform behavior, however identifying this property at the single-neuron level is not trivial. In Caenorhabditis elegans, the paired interneurons AIBL and AIBR (AIB) have a compartmentalized organization of presynapses along its singular process. Sensory and sensory interneurons primarily synapse along the proximal process, while motor and motor interneurons synapse along the distal process. Since this neuron has graded potentials, the simplest model for AIB integration is simply a convolution of its presynaptic inputs. Through a series of experiments to manipulate sensory and motor input onto AIB, we find that while AIB activity is primarily a convolution of motor inputs, its sensory responses are not integrated independently. Instead, the gain in sensory input is a function of the temporal dynamics of motor input. Sensory information is reinforced when it matches the expected behavioral response. We find this property is also observed in other whole-brain datasets. Context-dependent behavioral responses to sensory input is well-documented. Here, we show this property can be localized to single neurons in the worm nervous system. This integration property likely plays an important role in context-dependent decision-making, as well as the highly variable dynamics of the worm nervous system. (Comment on this)
3:32a	Incubation of oxycodone craving is associated with CP-AMPAR upregulation in D1 and D2 receptor-expressing medium spiny neurons in nucleus accumbens core and shell A major problem in treating opioid use disorder is persistence of craving after protracted abstinence. This has been modeled in rodents using the incubation of craving model, in which cue-induced drug seeking increases over the first weeks of abstinence from drug self-administration and then remains high for an extended period. Incubation has been reported for several opioids, including oxycodone, but little is known about underlying synaptic plasticity. In contrast, it is well established that incubation of cocaine and methamphetamine craving depends on strengthening of glutamate synapses in the nucleus accumbens (NAc) through incorporation of calcium-permeable AMPARs (CP-AMPARs). CP-AMPARs have higher conductance than the calcium-impermeable AMPARs that mediate NAc excitatory transmission in drug-naive animals, as well as other distinct properties. Here we examined AMPAR transmission in medium spiny neurons (MSN) of NAc core and shell subregions in rats during forced abstinence from extended-access oxycodone self-administration. In early abstinence (prior to incubation), CP-AMPAR levels were low. After 17-33 days of abstinence (when incubation is stably plateaued), CP-AMPAR levels were significantly elevated in both subregions. These results explain the prior demonstration that infusion of a selective CP-AMPAR antagonist into NAc core or shell subregions prevents expression of oxycodone incubation. Then, using transgenic rats, we found CP-AMPAR upregulation on both D1 and D2 receptor-expressing MSN, which contrasts with selective upregulation on D1 MSN after cocaine and methamphetamine incubation. Overall, our results demonstrate a common role for CP-AMPAR upregulation in psychostimulant and oxycodone incubation, albeit with differences in MSN subtype-specificity. (Comment on this)
3:32a	Dual Hypocretin Receptor Antagonism Reduces Oxycodone Seeking During Abstinence A major barrier in the treatment of opioid use disorder is persistent drug craving during abstinence. While opioid-based medications have been used to treat opioid use disorder for decades, there is an urgent need for novel, non-opioid-based pharmacotherapies. The hypocretin/orexin (hypocretin) system is a promising target for treating opioid use disorder due to its influence on motivation for drugs of abuse through actions on dopamine transmission. We recently showed that intermittent access (IntA) to oxycodone promoted sustained oxycodone seeking and alterations in dopamine transmission during abstinence. In the current studies, we investigated to what extent suvorexant, an FDA-approved dual hypocretin receptor antagonist, reduces oxycodone seeking and restores dopamine function during abstinence. Results indicated that IntA to oxycodone produced sustained cue-induced oxycodone seeking after a 14-day abstinence period, which was associated with reduced dopamine uptake in the nucleus accumbens core as we have previously shown. Treatment with suvorexant 24 h prior to a cue-induced seeking test significantly reduced oxycodone seeking and normalized aberrant dopamine uptake. These findings suggest that targeting hypocretin receptors may be a promising strategy for reducing opioid craving and associated neuroadaptations, thus lowering the risk of relapse. (Comment on this)
3:32a	A transgene harboring the human Glucose Transporter1 (GLUT1) gene locus ameliorates disease in GLUT1 deficiency syndrome model mice. Proper brain function relies on an adequate supply of energy - mainly glucose - to power neuronal activity. Delivery of this nutrient to the neuropil is mediated by the Glucose Transporter1 (GLUT1) protein. Perturbing glucose supply to the brain is profoundly damaging and exemplified by the neurodevelopmental disorder, GLUT1 deficiency syndrome (GLUT1DS). Resulting from haploinsufficiency of the SLC2A1 (GLUT1) gene, GLUT1DS is characterized by intractable infantile-onset seizures and a disabling movement disorder. Ketogenic diets, which supply the brain with an alternate energy source, ketone bodies, are currently the preferred therapeutic option for Glut1DS patients but do not address the underlying cause, low brain glucose, of the disease. One intuitively appealing therapeutic strategy that does, involves restoring GLUT1 levels to the patient brain. Here, we demonstrate that transgenic expression of the human GLUT1 genomic locus in a mouse model of GLUT1DS raises brain GLUT1 levels and reduces disease burden. Augmenting GLUT1 levels in mutants correspondingly raised cerebrospinal fluid (CSF) glucose levels, improved motor performance and reduced the frequency of seizures characteristically observed in GLUT1DS. Interestingly, the increased GLUT1 in mutants harboring the human GLUT1 locus was at least partly the result of an increase in murine Slc2a1 (Glut1) activity, most likely the effect of a long non-coding RNA (lncRNA) embedded in the human transgene. Collectively, our work has not only shown that repleting human GLUT1 mitigates GLUT1DS but also has yielded transgenic mice that constitute a useful tool to test and optimize clinically promising agents designed to stimulate this gene for therapeutic purposes. (Comment on this)
3:32a	Novel in situ seeding immunodetection assay uncovers neuronal-driven alpha-synuclein seeding in Parkinson's disease Aggregates of alpha-synuclein (-syn) and tau propagate through template-induced misfolding in the brains of Parkinson's (PD) and Alzheimer's disease (AD) patients. Prion-like seeding is crucial in disease initiation and progression and represents a major target for drug-modifying therapies. The detection of aggregated -syn and tau seeding activity with seeding amplification assays (SAAs) have remarkable diagnostic and research potential. However, current SAAs rely on bulk tissue homogenates or fluids, losing critical spatial and cellular resolution. Here, we report our novel in situ seeding immunodetection (isSID) assay that enables the visualization of -syn and tau seeding activities with unprecedented morphological detail in intact biological samples. Using the isSID assay, we confirm seeding activity in the pathological aggregates of PD and AD, among others, while uncovering neuron-driven -syn seeding events that precede the onset of clinical symptoms in PD. Our findings provide new fundamental insights into the pathogenesis underlying neurodegeneration and establish an invaluable tool for studying protein aggregation dynamics, with potential applications in biomarker discovery, diagnostics and drug testing. (Comment on this)
6:21a	Statistical Characterization of Cortical-Thalamic Dynamics Evoked by Cortical Stimulation in Mice Objective: Statistical models are powerful tools for describing biological phenomena such as neuronal spiking activity. Although these models have been widely used to study spontaneous and stimulated neuronal activity, they have not yet been applied to analyze responses to electrical cortical stimulation. In this study, we present an innovative approach to characterize neuronal responses to electrical stimulation in the mouse cortex, providing detailed insights into cortical-thalamic dynamics. Approach: Our method applies Mixture Models to analyze the Peri-Stimulus Time His togram of each neuron, predicting the probability of spiking at specific latencies following the onset of electrical stimuli. By applying this approach, we investigated neuronal re sponses to cortical stimulation recorded from the motor cortex, somatosensory cortex, and sensorimotor-related thalamic nuclei in the mouse brain. Main results: The characterization approach achieved high goodness of fit, and the model features were leveraged by applying machine learning methods for stimulus intensity decoding and classification of brain regions to which a neuron belongs given its response to the stimulus. The Random Forest model demonstrated the highest F1 scores, achieving 92.86% for stimulus intensity decoding and 84.35% for brain zone classification. Significance: This study presents a novel statistical framework for characterizing neu ronal responses to electrical cortical stimulation, providing quantitative insights into cortical thalamic dynamics. Our approach achieves high accuracy in stimulus decoding and brain region classification, providing valuable contributions for neuroscience research and neuro technology applications (Comment on this)
7:32a	Memory responses in visual cortex track recall success after single-trial encoding Classic models of episodic memory propose that retrieval relies on the reactivation of previous perceptual representations in sensory cortex, a phenomenon known as cortical reinstatement. Supporting this idea, visual memory retrieval has been shown to evoke activity patterns in visual areas similar to those during encoding. However, recent work suggests that memory responses systematically diverge from perceptual ones, challenging this idea. Critically, these studies have focused on highly trained memories, leaving open whether similar effects arise in more naturalistic, single-shot memory scenarios, which are hallmarks of episodic memory. Here, we used fMRI and population receptive field (pRF) modeling to test whether spatially tuned memory responses emerge in early visual cortex after a single encoding event. We scanned 19 participants with fMRI while testing them on their recognition and spatial recall of peripheral objects seen only once. We observed spatially tuned responses in early visual cortex during both recognition and recall, even though spatial location was never explicitly probed during recognition. These responses were better tuned for successfully remembered items, indicating a relationship between neural tuning and behavioral memory performance. Moreover, spatial tuning at encoding predicted subsequent memory: responses for subsequently remembered objects were stronger near the object location and suppressed elsewhere, relative to forgotten items. Taken together, our findings show that a single experience is sufficient to enable spatially tuned reactivation in early visual cortex when remembering an item. Further, our results indicate an important role, during both encoding and retrieval, for early visual cortex representations in successful episodic memory. (Comment on this)
10:16a	Spatiotemporal differences of GABAergic polarization and shunting during dendritic integration In the adult brain, GABA exerts either depolarizing or hyperpolarizing effects on neuronal membranes, depending on neuron type, subcellular location, and neuronal activity. Depolarizing GABA typically inhibits neurons through shunting, which is characterized by increased membrane conductance upon GABAA receptor activation; however, it can also excite neurons by recruiting voltage-dependent conductances. The net influence of these opposing actions of depolarizing GABA on glutamatergic synaptic inputs remains incompletely understood. Here, we examined the spatiotemporal characteristics of membrane polarization and shunting mediated by GABAA receptors and assessed their functional impact on the integration of GABAergic and glutamatergic inputs along dendrites. Using whole-cell current-clamp recordings in CA1 pyramidal neurons and dentate gyrus granule cells (GCs) from rat hippocampal slices, we mimicked GABAergic and glutamatergic inputs with local GABA puffs and glutamate spot-uncaging, respectively. A mathematical model further quantified the relative effects of local shunting and polarization. Depolarizing GABAergic postsynaptic responses (GPSRs) exhibited biphasic actions, exerting inhibitory effects at the synapse through shunting, and excitatory effects distally, where depolarization predominated. The excitatory component also persisted longer than the shunting inhibition. In contrast, hyperpolarizing GPSRs remained consistently inhibitory across both spatial and temporal dimensions. These findings highlight the complex spatiotemporal interplay between shunting and membrane polarization mediated by GABAergic inputs, providing new insights into dendritic computation and neuronal network dynamics. (Comment on this)
10:16a	Longitudinal multimodal neuroimaging after traumatic brain injury Traumatic brain injury is a major cause of long term cognitive impairment, yet the mechanisms underlying recovery remain poorly understood. Neuroimaging methods such as diffusion MRI, functional MRI, and positron emission tomography (PET) provide insight into micro and macro scale changes post TBI, but the relationships between regional cellular and functional alterations remain unclear. In this study, we conducted a longitudinal, multimodal neuroimaging analysis quantifying TBI-related pathologies in four biomarkers, namely flumazenil PET derived binding potential, dMRI derived structural connectivity, and resting state fMRI derived functional connectivity and fractional amplitude of low frequency fluctuations in individuals with mild to severe brain injury at the subacute (4 to 6 months post injury) and chronic (1 year post injury) stages. Brain injury related regional pathologies, and their changes over time, were correlated across the four biomarkers. Our results reveal complex, dynamic changes over time. We found that flumazenil PET binding potential was significantly reduced in frontal and thalamic regions in brain injured subjects, consistent with neuronal loss, with partial recovery over time. Functional hyperconnectivity was observed in brain injured subjects initially but declined while remaining elevated compared to non-injured controls, whereas cortical structural hypoconnectivity persisted. Importantly, we observed that brain injury related alterations across MRI modalities became more strongly correlated with flumazenil PET at the chronic stage. Regions with chronic reductions in flumazenil PET binding also showed weaker structural node strength and lower amplitude of low frequency fluctuations, a relationship that was not found at the subacute stage. This observation could suggest a progressive convergence of structural and functional disruptions with neuronal loss over time. Additionally, regions with declining structural node strength also exhibited decreases in functional node strength, while these same regions showed increased amplitude of low frequency fluctuations over time. This pattern suggests that heightened intrinsic regional activity may serve as a compensatory mechanism in regions increasingly disconnected due to progressive axonal degradation. Altogether, these findings advance our understanding of how multimodal neuroimaging captures the evolving interplay between neuronal integrity, structural connectivity, and functional dynamics after brain injury. Clarifying these interrelationships could inform prognostic models and enhance knowledge of degenerative, compensatory, and recovery mechanisms in traumatic brain injury. (Comment on this)
12:17p	Multi-modal brain properties are associated with interindividual differences in fear acquisition and extinction Interindividual differences in fear acquisition and extinction have been related to variation in specific brain correlates. However, variability in experimental setups complicates the integration of findings. Here, we present a combined fear acquisition (n = 101) and extinction (n = 88) experiment in which both phenomena were related to brain correlates obtained via functional magnetic resonance imaging in healthy, young participants. Correlates included regional brain volume, cortical surface area and thickness, neurite density and orientation dispersion, structural and functional connectivity. Fear responses were quantified as changes in skin conductance. Data from 376 brain areas and 70,500 network connections were used as independent variables in regularized regression models. Regression models of fear acquisition could be obtained for all modalities but regional brain volume. There were 284 predictors of which 77 appeared in exactly two models and 19 in exactly three. The latter primarily included brain areas from the somatosensory, insular, cingulate, and frontal cortices. Fear extinction yielded regression models based on neurite density, structural connectivity, and functional connectivity with 112 predictors in total. Two predictors, located in the dorsolateral prefrontal cortex, replicated across exactly two regression models (neurite density and structural connectivity). This study is the first to investigate the neural correlates of both fear acquisition and extinction in an explorative, multi-modal fMRI approach. Results show that numerous brain regions contribute to fear conditioning, some of them via more than one correlate. These findings call for further research to examine the potential interplay between brain correlates shaping fear conditioning. (Comment on this)
12:17p	Distorting anatomy to test MEG models and metrics Current flow that gives rise to non-invasive Magnetoencephalographic (MEG) data derives predominantly from pyramidal neurons oriented orthogonal to the cortical surface. The estimate of current flow based on extra-cranial magnetic fields is a well-known ill-posed problem; however, this current distribution must depend on anatomy. In other words, a veridical estimate of current flow should discriminate between true and distorted versions of the brain. Here, we make use of advances in diffeomorphic brain shape modelling to construct a set of parametrically deformable cortical surfaces. We use a latent space of 100 components to construct cortical surfaces that are representative of the population. We show how these geometric distortions can be used to quantify the performance of MEG source reconstruction algorithms and metrics of fit. (Comment on this)
12:17p	Neural and Behavioral Changes in Older Adults from Auditory-Cognitive Training Speech perception in noisy environments is a common challenge among older adults, even for those with clinically normal hearing. Cognitive decline may be one of the contributing factors, and, as such, auditory-cognitive training may enhance speech perception in these conditions. This study aims to determine if auditory-cognitive training can improve speech-in-noise listening in normal-hearing, older adults using neural and behavioral measures, supplemented with comparisons across younger and older adults. Neural responses were obtained using magnetoencephalography (MEG) while participants listened to long, narrative passages (60 s) under four noise conditions. Neural measures employed reverse correlation using encoding and decoding models, via the temporal response function (TRF) framework, to predict neural responses and reconstruct stimulus features, respectively, with the boosting algorithm to enforce sparsity. Behavioral measures, such as working memory (reading span; RSPAN), speech perception in noise (SPIN), and nonlinguistic auditory stream segregation (stochastic figure- ground; SFG) showed improvement post-training, along with neural and subjective ratings for listening effort. Additionally, auditory-cognitive training may enhance the neural contrast between the selectively attended and unattended stimulus reconstructions, and pre-training SFG performance may predict the extent of this neuroplasticity change. These results provide promising, additional insight into the effects of auditory-cognitive training, both perceptually and neurally. (Comment on this)
2:17p	Distinct cerebrospinal fluid DNA methylation signatures linked to Alzheimer's disease Alzheimer's disease (AD) accounts for more than 60% of the dementia cases and currently there is no curative treatment for it. With the emergence of potentially disease modifying treatments, early diagnosis is key to identify patient groups that would benefit from such treatments, aiming to prevent severe cognitive decline. We previously identified a set of DNA methylation signatures that allow for accurate diagnosis of AD in cortical neurons and brain tissue, even before clinical manifestation of the disease [1]. Here we investigate 11 of these signature regions via targeted next-generation sequencing in cell-free DNA (cfDNA) isolated from cerebrospinal fluid (CSF) of AD patients homozygous for APOE4 (n=4) and sporadic AD (n=5) cases compared to age-matched control samples (n=5). Our analyses demonstrated that 6/11 of the tested DNA methylation signatures that had initially been identified in cortical neurons and brain tissue were also validated in cfDNA. The remainder of the tested regions either showed opposite trends (3/11) or did not result in any differences (2/11) between control and AD cases. Thus, this presents a direct approach allowing to test for these DNA methylation signatures in CSF-derived cfDNA, and bypasses the need to generate induced pluripotent stem cell-derived cortical neurons from patients. (Comment on this)
3:30p	Altered Neural Processing in Middle Frontal Gyrus and Cerebellum During Temporal Recalibration of Action-Outcome Predictions in Schizophrenia Spectrum Disorders A key function of the perceptual system is to predict the (multi)sensory outcomes of actions and recalibrate these predictions in response to changing conditions. In schizophrenia spectrum disorders (SSD), impairments in this ability have been linked to difficulties in self-other distinction. This study investigated the neural correlates of the recalibration of action-outcome predictions to delays, the transfer of this process across sensory modality, and whether patients with SSD exhibit alterations in the underlying neural processes. Patients and healthy controls (HC) underwent fMRI while exposed to delays between active or passive button presses and auditory outcomes. A delay detection task assessed recalibration effects on auditory perception (unimodal trials) and its transfer to visual perception (cross-modal trials). In unimodal trials, HC exhibited reduced activation in left middle frontal gyrus (MFG) after recalibration, particularly for active movements, whereas this effect was reversed in SSD. In cross-modal trials, recalibration was linked to increased activation in bilateral cerebellum in HC, especially for active movements, a pattern significantly reduced in SSD. These findings suggest that unimodal temporal recalibration of action-outcome predictions in HC is reflected in reduced prediction error-related MFG activity, which is significantly reduced in SSD revealing potentially disrupted recalibration processes. Additionally, cerebellar engagement appears crucial for cross-modal transfer of recalibrated action-outcome timings, a process that may be impaired in SSD, leading to severe perceptual disturbances like hallucinations. (Comment on this)
3:30p	Fast-spiking neurons in monkey orbitofrontal cortex underlie economic value computation Inhibitory interneurons are fundamental constituents of cortical circuits that process information to shape economic behaviors. However, the role of inhibitory interneurons in this process remains elusive at the core cortical reward-region, orbitofrontal cortex (OFC). Here, we show that presumed parvalbumin-containing GABAergic interneurons (fast-spiking neurons, FSNs) cooperate with presumed regular-spiking pyramidal neurons (RSNs) during economic-values computation. While monkeys perceived a visual lottery for probability and magnitude of rewards, identified FSNs occupied a small subset of OFC neurons (12%) with high-frequency firing-rates and wide dynamic-ranges, both are key intrinsic cellular characteristics to regulate cortical computation. We found that FSNs showed higher sensitivity to the probability and magnitude of rewards than RSNs. Unambiguously, both neural populations signaled expected values (i.e., probability times magnitude), but FSNs processed these reward's information strongly governed by the dynamic range. Thus, cooperative information processing between FSNs and RSNs provides a common cortical framework for computing economic values. (Comment on this)

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