bioRxiv Subject Collection: Neuroscience's Journal
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Monday, September 29th, 2025
| Time |
Event |
| 12:19a |
Flexible Working Memory in the Peripheral Nervous System
Working memory (WM) representations that are distributed across the brain can be flexibly recruited to best guide behavior. For instance, information may be represented relatively more strongly in visual cortex when a WM task requires fine visual detail, or more strongly in motor cortex when a specific response can be prepared. If WM is geared to prospectively guide actions, then we might also expect such task-oriented neural signals to propagate to the peripheral sensors and effectors that realize WM goals. Likewise, there is now evidence that oculomotor signals like saccade biases can track simple visuo-spatial WM features. However, it is unclear if such signatures are functionally meaningful, and how much information is contained in them. Here, we test the idea that WM content is adaptively distributed across the nervous system according to behavioral demands. Namely, we test whether visual WM stimulus features are expressed in patterns of both eye and hand movements during a WM delay, and whether the distribution of such peripheral motor activity shifts with the task context. In a delayed recall task, we manipulated how human participants reported their memory by having them either draw a line or adjust a wheel to match a remembered orientation. Via eye- and stylus-tracking, we found that remembered orientations were decodable from small inflections in both gaze and hand movements during the blank WM delay. Moreover, this decoding strength varied by response format: gaze patterns tracked memorized features relatively better in the wheel condition (vs. draw), while hand movements were better in the draw condition (vs. wheel). Individuals who showed greater wheel benefits in gaze-based decoding also showed greater draw benefits in hand-based decoding, suggesting a strategic processing shift to the more relevant system. Therefore, visually encoded WM contents may be adaptively allocated to the most task-relevant motor effectors, balancing WM representations across peripheral activity according to behavioral needs. | | 3:15p |
α2A-AR-Kv dysfunction drives LC hyperactivity and early sleep disturbance in amyloidogenic mice
Disrupted sleep-wake patterns are common in neurodegenerative disorders such as Alzheimer's disease (AD), can emerge early, and are proposed as potent risk factors for disease onset and progression. However, the underlying mechanisms remain poorly understood. Here, we report that 5xFAD transgenic mice exhibit hyperarousal and reduced brain-state transitions, particularly during the dark phase, as early as two months of age. The Locus Coeruleus (LC), a key regulator of arousal and brain-state transitions and a region highly vulnerable in AD, shows time-specific hyperactivity during this phase. This increased tonic LC activity is mediated by heightened neuronal excitability due to impaired Kv4 and Kv7 potassium channel conductance. Pharmacological activation of 2A adrenergic receptors restored Kv4 and Kv7 function and normalized LC activity. Furthermore, local administration of the 2A agonist guanfacine or the Kv7 positive allosteric modulator retigabine substantially rescued the sleep-wake disturbances in young 5xFAD mice. These findings identify dark-phase-selective LC hyperexcitability as a key driver of early-onset sleep disruption in AD mice and implicate 2A adrenergic receptors and Kv7 channels as promising targets for early intervention. | | 3:15p |
Early Aβ-induced changes in the enteric nervous system and gut: structure, function, and motility
Alzheimer's disease is increasingly recognized as affecting not only the central nervous system but also the autonomic nervous system, comprising the enteric nervous system, and thus the gut. Given the structural and functional similarities between the enteric and central nervous system, including susceptibility to A{beta}, this study investigated the early and acute effects of monomeric A{beta} on primary enteric neurons in vitro and on intestinal motility ex vivo. Acute A{beta} application caused marked neuronal hyperexcitability, with increased spike frequencies and calcium influx, and led to enhanced intestinal contractility without altering frequency or timing. Prolonged 72-hour exposure did not induce cell death or apoptosis but significantly reduced neurite outgrowth and decreased synaptic markers and beta II tubulin. These findings suggest that acute A{beta} primarily drives the excitability of enteric neurons and intestinal motility, while prolonged exposure subsequently leads to structural and synaptic changes. Overall, the study points to early dysfunction of the enteric nervous system in Alzheimer's disease and highlights the gut as a potential target for early interventions. | | 5:19p |
Distilling the neurophenomenological signatures of pure awareness during Transcendental Meditation
Pure awareness (PA) is described in contemplative traditions as a wakeful state largely devoid of cognitive content, often considered a case of minimal phenomenal experience (MPE). Transcendental Meditation (TM) provides an excellent empirical model for PA because it is standardized, effortless, and reliably induces reports of awareness with minimal content. We combined phenomenological and electrophysiological approaches to study PA in 33 experienced TM practitioners and matched controls (performing mental counting). Using Temporal Experience Tracing, TM practitioners reported greater intensity and variability of PA than controls, regardless of years of meditation practice, consistent with the notion of 'automatic self-transcendence'. Using electroencephalography (EEG) and multivariate classification analyses, our large-scale screening of theoretically motivated EEG markers revealed a double dissociation in neural signatures. When contrasting TM with controls, temporal entropy and aperiodic dynamics were the strongest discriminators, while functional connectivity based on phase coherence contributed the least. In contrast, when TM was compared with its own baseline, low-frequency functional connectivity dominated, while temporal entropy contributed minimally to classification. This dissociation suggests that PA is characterized by enhanced EEG signals' diversity and aperiodic neural dynamics compared to ordinary cognition but stabilized by slow-frequency oscillatory synchronization relative to rest. Finally, TM showed little evidence of carry-over effects from meditation into subsequent rest, in contrast to controls, where counting induced residual changes. Together, these results provide the most systematic electrophysiological characterization of PA to date and establish neurophenomenology as a robust framework for advancing the neuroscience of minimal phenomenal experience. | | 8:46p |
Deep Brain Ultrasound Augments Human Attention
Background: Deep brain ultrasound offers a novel means of modulating human cognition by noninvasively targeting subcortical structures that were previously accessible only through invasive procedures. While decades of research have mapped cortical circuits of attention, the causal roles of deep hubs such as the basal ganglia and thalamus remain poorly understood in the healthy human brain. Objectives/Hypothesis: To test whether low intensity transcranial ultrasound stimulation (TUS) of two nodes in the basal ganglia-thalamic network, the globus pallidus internus (GPi) and the pulvinar, causally alters visual attention. We hypothesized that TUS-induced modulations in attentional performance would be site specific, reflecting distinct circuit functions. Results: Across sessions, focal TUS accelerated reaction time in a visual search task, indicating augmented attention. Reaction time improvements were observed after stimulation relative to baseline. A dissociation emerged across sites: both GPi and pulvinar enhanced reaction times, but pulvinar yielded more robust benefits for target present trials at peripheral eccentricities, and improved search efficiency in the same trials. Conclusions: These findings provide causal evidence that human attentional control can be steered at deep subcortical sites. TUS offers a practical approach for dissecting circuit level contributions to cognition and a potential noninvasive avenue for enhancing attention and other cognitive or affective functions. | | 8:46p |
Astrocytic Activation Completely Corrects Memory Performancein an Alzheimer's Disease Model
Neural and glial dysfunction are thought to underlie memory impairments in Alzheimer's disease (AD). Conversely, astrocytes are known to play a central role in the healthy brain, and their activation has been shown to enhance memory. To test whether activation of astrocytes can correct memory deficits associated with AD, we expressed hM3Dq in CA1 astrocytes of 7 months old 5XFAD AD model mice, enabling astrocytic chemogenetic Gq pathway activation, following exposure to CNO. We report that astrocytic activation results in complete memory correction, and even memory improvement of AD model mice beyond that of untreated WT levels. We went further to discover the mechanisms underlying this memory improvement in AD mice: First, using 2-photon imaging and electrophysiology, we observed increased neuronal activity (displayed as elevated cFos expression and amplified awake Ca2+ events) as well as augmented in-vivo long term plasticity following astrocytic activation. Subsequently, we observed increased astrocytic endocytosis of A{beta} plaques. Finally, we report that the beneficial effects of astrocytic activation remained stable for an entire year, and persisted beyond the window of astrocytic Gq activation. Our findings that astrocytes correct memory impairments in an AD model could have important clinical implications towards treating this disease. | | 9:18p |
Multimodal Fusion Analysis of Florbetapir PET and Multiscale Functional Network Connectivity in Alzheimer's Disease
Accumulation of amyloid-beta plaques and disruption of intrinsic brain networks are two important characteristics of Alzheimer's disease (AD), yet the relationship between amyloid accumulation and network dysfunction remains unclear. In this study, we integrated [18F]Florbetapir PET and resting-state fMRI (rsfMRI) derived Functional Network Connectivity (FNC) from 552 temporally matched longitudinal PET-rsfMRI sessions across 395 participants spanning Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD stages. With a model order of 11, joint Independent Component Analysis (jICA) was applied to the fused PET-FNC data, identifying 11 stable components, of which 9 PET-derived components corresponded to previously characterized brain regions or networks. The multimodal analysis revealed disease progression markers, including (1) a pattern of reduced subject loadings across clinical stages (CN > MCI > AD) in white matter and cerebellar regions, reflecting structural degeneration; (2) increased amyloid accumulation in affected individuals in grey matter regions, particularly in frontal, sensori-motor, extended hippocampal, and default mode network (DMN) regions, accompanied by functional connectivity alterations that reflected both compensatory and disruptive network dynamics. We identified PET-derived components that captured distinct stages of disease progression, with the DMN component emerging as a late-stage biomarker and a white matter component showing early-stage changes with limited progression thereafter. Additionally, several components showed significant variation in loadings between APOE {varepsilon}4 carriers and non-carriers, linking the multimodal signatures to a well-established genetic risk factor for AD. | | 9:18p |
Metabolic organization of macaque visual cortex reflects retinotopic eccentricity and category selectivity
Neural activity requires energy metabolism, and the brain's metabolic architecture varies across regions. Yet, it remains unclear whether these variations are meaningfully related to the functional and perceptual demands of cortical processing. In high-level visual cortex, category-selective regions, such as those preferentially responding to faces and scenes, are consistently distributed along a topographic axis that varies in sensitivity to spatial scale, a feature dimension that imposes differing metabolic demands at the level of the retina. This axis reflects a broader organizing principle of the visual system: retinotopic eccentricity, the topographic mapping of visual space relative to gaze. Here, we tested whether cortical metabolic architecture reflects this principle by aligning in vivo fMRI maps of eccentricity and visual category selectivity with ex vivo cytochrome oxidase (CO) histology, a marker of oxidative metabolism, in macaque visual cortex. We found that face-selective region ML, which is biased toward central vision, exhibits higher CO intensity than the peripherally-biased scene-selective region LPP. More broadly, CO intensity covaries with eccentricity across the entire occipitotemporal cortex, though this gradient only partially accounts for the elevated CO in ML. These findings reveal a close correspondence between cortical energy consumption and retinotopic representation, suggesting that metabolic resources are shaped by the processing demands of visual perception. | | 9:18p |
Age-related Reorganization of Corticomuscular Connectivity During Locomotor Perturbations
Locomotor perturbations elicit cortical and muscular responses that help minimize motor errors through neural processes involving multiple brain regions. The anterior cingulate cortex monitors motor errors, the supplementary motor areas integrate sensory and executive control, and the posterior parietal cortices process sensorimotor predictions, while muscles show increased activation and co-contraction patterns. With aging, these neural control strategies shift; older adults demonstrate less flexible cortical and muscular responses, using compensatory overactivation and simpler muscle synergies to maintain performance comparable to young adults. We investigated corticomuscular connectivity patterns during perturbed recumbent stepping in seventeen young adults (age 25{+/-}4.9 years) and eleven older adults (age 68{+/-}3.6 years) using high-density EEG (128 electrodes) and EMG from six bilateral muscles. Brief mechanical perturbations (200ms of increased resistance) were applied at left or right leg extension-onset or mid-extension during continuous stepping at 60 steps per minute. We applied independent component analysis, source localization, and direct directed transfer function to quantify bidirectional information flow between cortical clusters and muscles in theta (3-8 Hz), alpha (8-13 Hz), and beta (13-35 Hz) bands. Young adults demonstrated concentrated electrocortical sources in anterior cingulate cortex, bilateral supplementary motor areas, and bilateral posterior parietal cortices, with strong theta-band synchronization following perturbations. In contrast, older adults showed fewer differentiated cortical sources, particularly lacking distinct anterior cingulate activity, and exhibited only minimal synchronization changes. Baseline corticomuscular connectivity was significantly stronger in older adults compared to young adults (p=0.012), suggesting fundamental differences in resting motor control states. During perturbations, young adults employed flexible, task-specific connectivity modulation involving error-processing networks, with the anterior cingulate showing selective bidirectional connectivity changes with specific muscles. Older adults relied on more diffuse (i.e., not focused to specific brain area) connectivity patterns dominated by motor and posterior parietal cortices, with strong connections to multiple upper and lower limb muscles simultaneously. These findings reveal an age-related strategic reorganization from dynamic, error-driven neural control to a more constrained, stability-focused approach that may reflect compensation for sensorimotor changes. The distinct connectivity signatures establish perturbed recumbent stepping as a valuable tool for assessing corticomuscular communication and provide normative benchmarks for developing targeted rehabilitation interventions to restore efficient motor control in aging and neurological populations. |
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