bioRxiv Subject Collection: Neuroscience's Journal
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Friday, February 28th, 2025
| Time |
Event |
| 3:17a |
Physical Network Constraints Define the Lognormal Architecture of the Brain's Connectome
The brain has long been conceptualized as a network of neurons connected by synapses. However, attempts to describe the connectome using established network science models have yielded conflicting outcomes, leaving the architecture of neural networks unresolved. Here, by performing a comparative analysis of eight experimentally mapped connectomes, we find that their degree distributions cannot be captured by the well-established random or scale-free models. Instead, the node degrees and strengths are well approximated by lognormal distributions, although these lack a mechanistic explanation in the context of the brain. By acknowledging the physical network nature of the brain, we show that neuron size is governed by a multiplicative process, which allows us to analytically derive the lognormal nature of the neuron length distribution. Our framework not only predicts the degree and strength distributions across each of the eight connectomes, but also yields a series of novel and empirically falsifiable relationships between different neuron characteristics. The resulting multiplicative network represents a novel architecture for network science, whose distinctive quantitative features bridge critical gaps between neural structure and function, with implications for brain dynamics, robustness, and synchronization. | | 3:17a |
INFLUENCE OF LIFESTYLE ON BRAIN SENSITIVITY TO CIRCULATING INSULIN-LIKE GROWTH FACTOR 1
Life style conditions such as social relationships and diet impinge on mood homeostasis, a mechanism that becomes dysregulated in high-incidence mental illnesses such as depression or Alzheimer dementia (AD). Since insulin-like growth factor 1 (IGF-1) modulates mood and its blood levels are altered both in AD and in affective disorders, we investigated whether its activity was altered in the brain of mice submitted to isolation or fed with a high-fat diet (HFD). As in humans, both life style conditions increased anxiety and depression-like behavior. Significantly, both life style conditions abrogated neuronal responses to systemic IGF-1. Thus, enhanced neuronal activity in response to intraperitoneal IGF-1, as determined by Ca++ fiber-photometry in the prefrontal cortex, was lost in isolated or HFD-fed mice. However, only the latter had elevated serum IGF-1 levels. These findings suggest that loss of brain IGF-1 input may contribute to mood disturbances observed in lonely and obese subjects. Furthermore, they provide additional insight into the heightened risk of depression and Alzheimer's disease associated with these conditions. Importantly, since the reduction of IGF-1 activity in the brain is not consistently mirrored by its serum levels, serum measurements do not reliably reflect brain IGF-1 activity. | | 3:17a |
Decoding the neural basis of sensory phenotypes in Autism
Background: Differences in sensory processing are a defining characteristic of autism, affecting up to 87% of autistic individuals. These differences cause widespread perceptual changes that can negatively impact cognition, development, and daily functioning. Recent research identified five sensory processing phenotypes with varied behavioural presentations; however, their neural basis remains unclear. This study aims to ground these sensory phenotypes in unique patterns of functional connectivity. Methods: We analyzed data from 146 autistic participants in the Province of Ontario Neurodevelopmental Network. We classified participants into sensory phenotypes using k-means clustering of scores from the Short Sensory Profile. We then computed a connectivity matrix from 200 cortical and 32 subcortical regions and calculated graph-theoretic measures (betweenness centrality, strength, local efficiency, clustering coefficient) to assess information exchange between these regions. We then trained machine learning models to use these measures to classify between all pairs of sensory phenotypes. Results: We replicated that our sample of autistic participants was best categorized into five sensory phenotypes. The machine learning models distinguished 7/10 phenotype pairs using graph-theoretic measures (p < 0.005). Information exchange within and between the somatomotor network, orbitofrontal cortex, posterior parietal cortex, prefrontal cortex and subcortical areas were highly predictive of sensory phenotype. Conclusions: This study shows that distinct sensory phenotypes in autism correspond with unique patterns of functional connectivity. Cortical, subcortical, and network-level connectivity all play a role in shaping distinct sensory processing styles in autism. These findings lay the groundwork for understanding these phenotypes and highlight opportunities to develop interventions in cases of maladaptive sensory processing | | 3:17a |
Distinct distributed brain networks dissociate self-generated mental states
Human cognition relies on two modes: a perceptually-coupled mode where mental states are driven by sensory input and a perceptually-decoupled mode featuring self-generated mental content. Past work suggests that imagined states are supported by the reinstatement of activity in sensory cortex, but transmodal systems within the canonical default network are also implicated in mind-wandering, recollection, and imagining the future. We identified brain systems supporting self-generated states using precision fMRI. Participants imagined different scenarios in the scanner, then rated their mental states on several properties using multi-dimensional experience sampling. We found that thinking involving scenes evoked activity within or near the default network, while imagining speech evoked activity within or near the language network. Imagining-related regions overlapped with activity evoked by viewing scenes or listening to speech, respectively; however, this overlap was predominantly within transmodal association networks, rather than adjacent unimodal sensory networks. The results suggest that different association networks support imagined states that are high in visual or auditory vividness. | | 3:17a |
Unraveling the distinct motion bias of TrkA-NGF complex in NGFR100W-driven HSAN V disease
Nerve growth factor (NGF), which binds to tropomyosin-related kinase A (TrkA) receptor, plays essential roles in neuronal survival and function and is also a potent mediator of pain sensation. Mutations in NGF, particularly NGFR100W, cause hereditary sensory autonomic neuropathy V (HSAN V), which is characterized by insensitivity to pain but without impairment of neurotrophin function. Even though several studies reported the mechanism of growing HSAN V disease, the dynamic mechanisms that dictate its functional specificity remain unclear. In this study, we performed a microsecond scale molecular dynamics (MD) simulation to elucidate the changes in the structural dynamics of NGF by NGFR100W at an atomic level to dissect the distinct motion bias for specific TrkA functions. We found that the NGFR100W reduced NGF dimerization while its binding to the TrkA remained unchanged. NGFR100W enhanced the magnitude of bond formation in the different regions from TrkA, which induced different correlated and dynamic motions associated with impaired nociceptive signaling. The dynamics scenario from this study, shedding light on the deleterious role of NGFR100W, provides new structural insights into the function-oriented dynamics motion of the TrkA-NGF complex, offering potential avenues for designing new therapeutics. | | 3:17a |
Microelectrode array scaled for recording human hippocampal slices
Temporal lobe epilepsy (TLE) is a prevalent neurological disorder characterized by recurrent seizures originating from the cortex, amygdala and especially hippocampus. While two-thirds of TLE patients achieve seizure control through medication, approximately one-third remain refractory to pharmacological interventions. For these individuals, surgical resection offers a potential curative option, with approximately 70% achieving seizure freedom. However, the pathogenesis of TLE remains incompletely understood, necessitating further investigation. Therefore, resected brain tissue obtained during the surgery provides a valuable resource for ex vivo study of pathological neuronal activity. Currently, microelectrode array (MEA) technology is widely used for electrophysiological studies. However, commercially available MEAs are limited in their ability to record from large tissue samples, such as an entire hippocampal section. To address this limitation, we have developed a custom MEA and sample chamber compatible with commercially available headstages. This system enables recording of extracellular action potentials (EAPs) and local field potentials (LFPs) across human hippocampal tissue, providing a valuable tool for investigating the neurophysiological mechanisms underlying TLE. | | 3:45a |
Focus-Tunable Two-Photon Fiberscope Enabling in vivo Imaging at Selected Depths
Miniaturized two-photon imaging devices enable real-time in vivo and in situ imaging at subcellular resolution, highly valuable for clinical applications and basic research (such as neuroscience). However, achieving high-quality volumetric imaging at varying depths remains challenging. In this study, we demonstrated a 2P fiberscope capable of three-dimensional imaging over a cylindrical volume of a 350 m diameter and a 400 m depth. Depth scanning was achieved by incorporating a miniature electrowetting-based varioptic lens (VL) into a two-dimensional scanning 2P fiberscope, whose focus was tuned by modulating the VL drive voltage. The performance of the fiberscope was first characterized using phantoms and then demonstrated by ex vivo imaging of fluorescently stained convallaria and GFP mouse brain sections, as well as in vivo dynamic GCaMP-based calcium imaging of cortical neurons in an awake mouse. | | 3:45a |
Growth hormone is required for hippocampal engram cell maturation
Memory is thought to be stored in a sparse population of neurons or synapses 1. These neurons or synapses collectively termed the engram are necessary and sufficient for memory recall 2,3. Learning induces synaptic strengthening in engram cells at both pre- and postsynaptic sites 4,5. However, the critical time window and the molecule related to the induction of such synaptic changes are unknown. Here we show that the initial translation plays a key role in engram maturation by facilitating pre- and postsynaptic strengthening and that growth hormone (GH) is required to induce this process in the Dentate Gyrus. Using anisomycin, a protein synthesis inhibitor, we found that blocking the initial and the subsequent second wave of translation arrests the maturation of engram cells. Revisiting our hippocampal translatome during memory formation 6 proposed GH as a mediator of engram maturation. Overexpression of the dominant negative (G118R) GH blocked the maturation of the hippocampal engram cell 7. Facilitating activity-dependent GH uptake by injecting recombinant human GH (rhGH) into the animal rescued the arrestment caused by anisomycin. Together, our findings propose GH as a key mediator of hippocampal engram cell maturation. | | 3:45a |
Mapping Hand Function with Simultaneous Brain-Spinal Cord Functional MRI
INTRODUCTION: Hand motor control depends on intricate brain-spinal cord interactions that regulate muscle activity. Hand function can be disrupted by injury to the brain, spinal cord, and peripheral nerves leading to weakness and impaired coordination. Functional MRI (fMRI) can map motor-related neural activity and potentially characterize the mechanisms underlying hand weakness and diminished coordination. Although brain motor control has been extensively studied, spinal cord mechanisms remain less explored. Here we use simultaneous brain-spinal cord fMRI to map neural activity related to hand strength and dexterity across the central nervous system using force matching and finger tapping tasks. This study pioneers the use of simultaneous brain-spinal cord fMRI to comprehensively map hand function, offering novel insights into coordinated motor processing across the central nervous system. METHODS: We performed simultaneous brain-spinal cord fMRI in 28 right-handed healthy volunteers (age: 40.0 {+/-} 13.8 years, 14 females, 14 males) using a 3T GE SIGNA Premier scanner equipped with a 21-channel head-neck coil. Participants performed a force-matching task at 10%, 20%, and 30% of maximum voluntary contraction using a hand dynamometer. For the finger tapping task, participants completed button-presses at 1 Hz with a 5-button response pad for three task levels: single-digit response with the second digit only (low), single-digit response with all digits in a sequential order (medium), single-digit response with all digits in a random order (high). Visual cues and feedback were provided during the tasks. Brain and spinal cord images were processed separately using FSL and the Spinal Cord Toolbox, with motion correction, physiological noise filtering, and spatial normalization to standard templates. Subject level activity maps were generated and entered into group level analyses to explore both activations and deactivations. For the brain, we used a mixed effect design with a voxelwise threshold of Z score > 3.10 and cluster threshold of p < 0.05. For the spinal cord, we used a fixed effect design with a voxelwise threshold of Z score > 1.64 and cluster threshold of p < 0.05. Region of interest (ROI) analyses were conducted to examine localized changes in activation across task levels RESULTS: Both tasks elicited activation in motor and sensory regions of the brain and spinal cord, with graded responses in the left primary motor (M1), left primary sensory (S1) cortex, and right spinal cord gray matter across task levels. Deactivation of the right M1 and S1 was also present for both tasks. Deactivation of the left spinal cord gray matter was present in the high task level of the force matching task. The ROI analysis findings complemented the group level activity maps. DISCUSSION: Our study provides a detailed map of brain-spinal cord interactions in hand function, revealing graded neural activation and inhibition patterns across motor and sensory regions. Interhemispheric inhibition, reflected in right M1 deactivation, likely restricts extraneous motor output during unilateral tasks. For force matching, the deactivation of the left ventral and dorsal horns of the spinal cord, provides the first evidence that the inhibition of motor areas during a unilateral motor task extends to the spinal cord. Whether this inhibition results from direct descending modulation from the brain or interneuronal inhibition in the cord remains to be interrogated. These findings expand our understanding of central motor control mechanisms and could inform rehabilitation strategies for individuals with motor impairments. CONCLUSIONS: Our simultaneous brain-spinal cord fMRI approach provides novel insights into the neural coordination of hand function, enhancing our understanding of motor control and its modulation. This approach may offer a foundation for studying motor dysfunction in conditions such as stroke, spinal cord injury, and neurodegenerative diseases. | | 3:45a |
Copper supplementation mitigates Parkinson-like wild-type SOD1 pathology and nigrostriatal degeneration in a novel mouse model
Wild-type superoxide dismutase 1 (disSOD1) protein misfolding and deposition is implicated in the death of substantia nigra (SN) dopamine neurons in Parkinson disease. Regionally reduced copper availability, and subsequent reduced copper binding to SOD1, is a key factor driving the development of this pathology, suggesting brain copper supplementation may constitute an effective means of preventing its formation. We evaluated the potential of the blood-brain-barrier-permeable copper delivery drug, CuATSM, to attenuate the misfolding and deposition of wild-type disSOD1, and associated neuron death, in a novel mouse model that expresses this pathology. Using proteomic and elemental mass spectrometry, together with biochemical and histological workflows, we demonstrated copper supplementation corrects altered post-translational modifications on soluble SOD1 and improves the enzymatic activity of the protein in the brains of these animals. These changes were associated with a significant reduction in disSOD1 pathology and preservation of dopamine neurons in the SN, which were highly correlated with tissue copper levels. These data position wild-type disSOD1 pathology as a novel drug target for Parkinson disease and suggest that brain copper supplementation may constitute an effective means of slowing SN dopamine neuron death in this disorder. | | 9:16a |
Extracellular matrix proteolysis maintains synapse plasticity during brain development
Maintaining a dynamic neuronal synapse pool is critical to brain development. The extracellular matrix (ECM) regulates synaptic plasticity via mechanisms that are still being defined and are studied predominantly in adulthood. Using live imaging of excitatory synapses in zebrafish hindbrain we observed a bimodal distribution of short-lived (dynamic) and longer-lived (stable) synapses. Disruption of ECM via digestion or brevican deletion destabilized dynamic but not stable synapses and led to decreased synapse density. Conversely, loss of matrix metalloproteinase 14 (MMP14) led to accumulation of brevican and increased the stable synapse pool, resulting in increased synapse density. Microglial MMP14 was essential to these effects in both fish and human iPSC-derived cultures. Both MMP14 and brevican were required for experience-dependent synapse plasticity in a motor learning assay. These data, complemented by mathematical modeling, define an essential role of ECM remodeling in maintaining a dynamic subset of synapses during brain development. | | 9:16a |
Predictive Coding Explains Asymmetric Connectivity in the Brain: A Neural Network Study
Seminal frameworks of predictive coding propose a hierarchy of generative modules, each attempting to infer the neural representation of the module one level below; the predictions are carried by top-down feedback projections, while the predictive error is propagated by reciprocal forward pathways. Such symmetric feedback connections support visual processing of noisy stimuli in computational models. However, neurophysiological studies have yielded evidence of asymmetric cortical feedback connections. We investigated the contribution of neural feedback during sensorimotor processes, in particular visual processing during grasp planning, by utilizing convolutional neural network models that had been augmented with predictive feedback and were trained to compute grasp positions for real-world objects. After establishing an ameliorative effect of symmetric feedback on grasp detection performance when evaluated on noisy stimuli, we characterized the performance effects of asymmetric feedback, similar to that observed in the cortex. Specifically, we tested model variants extended with short-, medium- and long-range feedback connections (i) originating at the same source layer or (ii) terminating at the same target layer. We found that the performance-enhancing effect of predictive coding under adverse conditions was optimal for medium-range asymmetric feedback. Moreover, this effect was most prominent when medium-range feedback originated at a level of representational abstraction that was proximal to the input layer, in contrast to more distal layers. To conclude, our simulations show that introducing biologically realistic asymmetric predictive feedback improves model robustness to noisy visual stimuli in a neural network model optimized for grasp detection. | | 9:46a |
Functional connectivity in the social perception pathway at birth is linked with attention to faces at 4 months
Background. Processing faces and speech is supported by the right-lateralized social visual perception pathway (social pathway) involving medial temporal/visual 5 area (MT/V5) and superior temporal sulcus (STS). Little is known about development of the social pathway and its links with later social outcomes. We examined intrinsic functional connectivity (iFC) in the right social pathway in neurotypical neonates, compared it with iFC in the left social and bilateral dorsal attention pathways, and interrogated prospective links between iFC and social attention in neurodiverse neonates. Methods. iFC in the social and dorsal pathways was measured in 517 full-term neonates from the developing Human Connectome Project (dHCP) and 73 full-term Yale neonates [Mage=41.5 weeks (SD=1.9)]. Social attention was assessed in 36 Yale neonates at Mage=4.2 months (SD=0.4) months. Results. In the dHCP sample, the iFC indices were positive in all the pathways (all p-values < 0.001) and did not vary by sex [all p>0.275], but the iFC in the right-lateralized social pathway was higher than in the remaining pathways [all p<0.001] and was positively associated with age at scan [r(517)=0.251, p<0.011]. In the prospective neurodiverse Yale sample, the iFC in the right social pathway was positively associated with social attention at 4 months [p=0.007], and greater social attention at 4 months predicted better social functioning in the second year [p=0.010]. Conclusions. The early development of intrinsic functional connectivity in the right social perception pathway represents an area of interest for identifying neural mechanisms underlying emergence of atypical social attention associated with autism. | | 9:46a |
Linking Motor Working Memory to Explicit and Implicit Motor Learning
While explicit and implicit motor learning have been widely studied, the extent to which working memory for recent movements -- motor working memory (MWM) -- contributes to these processes remains unclear. Previous research suggests that visuospatial working memory may facilitate explicit motor learning but is either uninvolved in or detrimental to implicit learning. Here, we ask if and how these findings extend to non-visual MWM. Based on recent work pointing to separate effector-independent and effector-specific MWM codes, we hypothesized that: (1) explicit motor learning processes would correlate with effector-independent MWM, and (2) implicit motor learning processes would correlate with effector-specific MWM. To test these hypotheses, human participants completed both a MWM task and a visuomotor adaptation task. Our results revealed significant correlations between the quality of effector-independent MWM and the degree of explicit motor learning, extending previous findings on visuospatial working memory. Additionally, we present evidence supporting our second hypothesis, that effector-specific MWM correlates with implicit motor learning. | | 3:31p |
Müller glial Kir4.1 channel Dysfunction in APOE4-KI model of Alzheimer's disease
Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein E4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Muller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K+ channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Muller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. Mitoquinol (MitoQ) was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential ({Delta}{Psi}m) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD. |
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