bioRxiv Subject Collection: Neuroscience's Journal
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Tuesday, March 4th, 2025
| Time |
Event |
| 12:30a |
Expression of Fibroblast Growth Factor Receptor 3 (FGFR3) in the Human Peripheral Nervous System: Implications for the Putative Pathogenic Role of FGFR3 Autoantibodies in Neuropathy
Introduction: Autoantibodies to the Fibroblast Growth Factor Receptor 3 (FGFR3-AAbs) have been associated with idiopathic sensory-predominant neuropathy. The pathogenicity of FGFR3-AAbs in this disorder is unknown. Pathogenic mechanisms of autoantibodies in other dysimmune neuropathies commonly involve their direct binding to antigens on either neurons or glia. The expression of FGFR3 in the human peripheral nervous system is unknown. Therefore, as an initial step toward clarifying the pathogenicity of FGFR3-AAbs, we characterized the expression of FGFR3 in nerve (hNerve), dorsal root ganglia (hDRG) and spinal cord (hSC) in human. Methods: FGFR3 mRNA was assayed via in situ hybridization (ISH) on post-mortem sections of hNerve, hDRG and hSC, and by re-analysis of RNA-sequencing data from hDRG. FGFR3 protein was assayed in these tissues using capillary electrophoretic immunoassays (CEIA) with several validated anti-FGFR3 antibodies. Results: FGFR3 mRNA was not detected in hNerve or hDRG but was abundant in hSC by ISH. FGFR3 protein was absent from hNerve and hDRG by CEIA but was moderately expressed in hSC. Discussion: A direct pathogenic mechanism of FGFR3-AAbs in sensory neuropathy would require the expression of FGFR3 in either neurons or non-neuronal cells in nerve or DRG. Using multiple methods, we did not detect FGFR3 expression at the mRNA or protein levels in these tissues. Given the absence of FGFR3 from hNerve and hDRG, it is improbable that FGFR3-AAbs cause direct damage to the neural components involved in neuropathy and thus are unlikely to be pathogenic, although indirect mechanisms via non-neural cells cannot be excluded. | | 12:30a |
Increased Callosal Thickness in Early Trained Opera Singers
Extensive research has shown how the corpus callosum adapts to early sensorimotor training in instrumental musicians, yet less is known about these effects in professional singers. This study used high-resolution MRI to investigate variations in callosal thickness in relation to vocal training in 55 participants, including 27 professionally trained opera singers and 28 non-singers. Results indicated trend-level differences with thicker callosal regions in singers, particularly at the anterior-posterior midbody border and the isthmus, though these did not survive corrections for multiple comparisons. However, a significant negative correlation between age at first singing lesson and callosal thickness was found in the anterior third (rostrum, genu, rostral body), the anterior-posterior midbody border, and the isthmus, suggesting that early vocal training facilitates lasting neuroplastic adaptations in these regions. Additionally, a positive trend between years of professional singing and greater thickness in the midbody was observed but did not remain significant after correction for multiple comparisons. Greater callosal thickness likely enhances interhemispheric connectivity to meet the demands of operatic performance, highlighting the adaptability of the corpus callosum to early, sustained sensorimotor training. By extending evidence from instrumental musicians to singers, these results underscore developmental timing as a key factor in how sensorimotor training shapes brain structure. | | 5:04a |
Parental origin of transgene determines recombination efficiency in GFAP-creERT2 mice
The Cre-loxP system is a powerful tool for spatial and temporal genetic manipulations. However, the system is prone to several limitations and caveats with respect to variable expression and recombination in unintended cell types. Using one of the most widely used astrocyte Cre lines, hGFAP-creERT2 (GFAP-cre/ERT2)505Fmv/J), we found that parental origin of the hGFAP-creERT2 transgene is a determinant of recombination efficiency. Recombination was robust in animals with paternally inherited hGFAP-creERT2. However, animals with maternally inherited Cre exhibited little to no recombination. This result was recapitulated using female hGFAP-creERT2 mice procured directly from Jackson Laboratory. We did not observe transgenerational suppression of Cre recombination in maternally inherited hGFAP-CreERT2. These data highlight the need for careful planning and documentation of breeding schemes when working with Cre mice. | | 12:21p |
Differential glutamatergic and GABAergic responses drive divergent prefrontal cortex neural outcomes to low and high frequency stimulation
Background: Repetitive brain stimulation is hypothesized to bidirectionally modulate excitability, with low-frequency trains decreasing and high-frequency (>5 Hz) trains increasing activity. Most insights on the neuroplastic effects of repetitive stimulation protocols stem from non-invasive human studies (TMS/EEG) or data from rodent slice physiology. Here, we developed a rodent experimental preparation enabling simultaneous imaging of cellular activity during stimulation in vivo to understand the mechanisms by which brain stimulation modulates the excitability of the prefrontal cortex. Methods: Repetitive trains of intracortical stimulation were applied to the medial prefrontal cortex using current parameters mapped to human rTMS electric-field estimates. Calcium imaging of glutamatergic (CamKII) and GABAergic (mDLX) neurons was performed before, during, and after stimulation in awake rodents (n=9 females). Protocols included low-frequency (1 Hz, 1000 pulses) and high-frequency (10 Hz, 3000 pulses), with sham stimulation as a control. Results: Glutamatergic neurons were differentially modulated by stimulation frequency, with 10 Hz increasing and 1 Hz decreasing activity. Post-stimulation, 1 Hz suppressed both glutamatergic and GABAergic activity, whereas 10 Hz selectively suppressed GABAergic neurons. Conclusions: These findings provide direct evidence that clinical brain stimulation protocols induce long-term modulation of cortical excitability, with low-frequency stimulation broadly suppressing activity and high-frequency stimulation preferentially inhibiting GABAergic neurons after stimulation. | | 12:21p |
Neural representation of action symbols in primate frontal cortex
At the core of intelligence is proficiency in solving new problems, including those that differ dramatically from problems seen before. Problem-solving, in turn, depends on goal-directed generation of novel thoughts and behaviors, which has been proposed to rely on internal representations of discrete units, or symbols, and processes that can recombine them into a large set of possible composite representations. Although this view has been influential in formulating cognitive-level explanations of behavior, definitive evidence for a neuronal substrate of symbols has remained elusive. Here, we identify a neural population encoding action symbols--internal, recombinable representations of discrete units of motor behavior--localized to a specific area of frontal cortex. In macaque monkeys performing a drawing-like task designed to assess recombination of learned action symbols into novel sequences, we found behavioral evidence for three critical features that indicate actions have an underlying symbolic representation: (i) invariance over low-level motor parameters; (ii) categorical structure, reflecting discrete classes of action; and (iii) recombination into novel sequences. In simultaneous neural recordings across motor, premotor, and prefrontal cortex, we found that planning-related population activity in ventral premotor cortex encodes actions in a manner that, like behavior, reflects motor invariance, categorical structure, and recombination, three properties indicating a symbolic representation. Activity in no other recorded area exhibited this combination of properties. These findings reveal a neural representation of action symbols localized to PMv, and therefore identify a putative neural substrate for symbolic cognitive operations. | | 12:21p |
Novel function of Contactin associated protein 1 (Caspr 1)/ Paranodin in embryonic cortical neurons: hypoxia modulated neurite development.
Hypoxia, a condition of inadequate oxygen supply, is a common phenomenon affecting neurons and brain tissue, leading to significant implications for neuronal health and function. The prevalence of hypoxia in the brain is associated with various neurological conditions, making it a critical area of study. Neuritogenesis, the process of neurite outgrowth, is an essential aspect of neuronal development and connectivity and is particularly sensitive to hypoxic stress. Investigating how hypoxia affects neurite outgrowth is vital for understanding neuronal response and adaptation under low oxygen conditions. This study explores how hypoxic stress affects neurite regulation mediated by Contactin Associated Protein-1 (Caspr1) in primary mouse embryonic cortical neurons. Hypoxia, induced by culturing neurons in a 2% oxygen environment, significantly reduced neurite length and induced notable changes in growth cone morphology. Concurrently, we observed an upregulation in the expression of Caspr1 and its transcriptional regulator C/EBP, suggesting a compensatory role for Caspr1 in neurite extension under low oxygen conditions. Shorter hypoxia exposure periods revealed a dynamic biphasic response in Caspr1 levels, with an initial decrease followed by a substantial increase, correlating with corresponding changes in neurite length. This pattern emphasizes the critical involvement of Caspr1 in adapting neurite growth to fluctuating hypoxia duration. Furthermore, comparative analyses using wild-type and Caspr1 knockout Neuro2a cells demonstrated that the absence of Caspr1 mitigates hypoxia-induced neurite shortening, indicating a potential protective role against hypoxic stress. Additionally, hypoxia profoundly impacted mitochondrial morphology and function. Under hypoxic conditions, mitochondria transitioned to a more spherical shape. Mitochondrial respiration analysis revealed significant reductions in oxygen consumption rates (OCR), highlighting compromised mitochondrial function during hypoxia. These findings underscore the multifaceted role of Caspr1 in neurite regulation and mitochondrial adaptation to hypoxic stress. The study provides insights into the molecular mechanisms underpinning hypoxia-induced changes in neuronal morphology and function. Understanding these processes opens avenues for therapeutic strategies targeting Caspr1 in treating neurological disorders characterized by hypoxic stress. Future research will benefit from extending these investigations to more complex models, such as brain organoids, to further elucidate the metabolic and structural changes under hypoxia and their implications for neurodegenerative diseases. | | 12:21p |
Oxytocin and Dopamine Receptor Expression: Cellular Level Implications for Pair Bonding
Oxytocin (Oxtr) and dopamine (Drd1, Drd2) receptors provide a canonical example for how differences in neuromodulatory receptors drive individual and species-level behavioral variation. These systems exhibit striking and functionally-relevant differences in nucleus accumbens (NAc) expression across monogamous prairie voles (Microtus ochrogaster) and promiscuous meadow voles (Microtus pennsylvanicus). However, their cellular organization remains largely unknown. Using multiplex in situ hybridization, we mapped Oxtr, Drd1, and Drd2 expression in sexually naive and mate-paired prairie and meadow voles. Prairie voles have more Oxtr+ cells than meadow voles, but Oxtr distribution across dopamine-receptor cell class was similar, indicating a general upregulation rather than cell class bias. Oxtr was enriched in cells that express both dopamine receptors (Drd1+/Drd2+) in prairie voles, suggesting these cells may be particularly sensitive to oxytocin. We found no species or pairing-induced differences in Drd1+ or Drd2+ cell counts, suggesting prior reports of expression differences may reflect upregulation in cells already expressing these receptors. Finally, we used single-nucleus sequencing to provide the first comprehensive map of Oxtr and Drd1-5 across molecularly-defined NAc cell types in the prairie vole. These results provide a critical framework for understanding how nonapeptide and catecholamine systems may recruit distinct NAc cell types to shape social behavior. | | 12:21p |
Laminar Architecture of a Decision Circuit in Orbitofrontal Cortex
During economic choice, different neurons in orbitofrontal cortex (OFC) encode individual offer values, the binary choice outcome, and the chosen value. Previous work suggests that these cell groups form a decision circuit, but the anatomical organization of this circuit is poorly understood. Using calcium imaging, we recorded from layer 2/3 (L2/3) and layer 5 (L5) of mice choosing between juice flavors. Decision variables were differentially represented across layers: juice-specific offer values and their spatial configuration were predominant in L2/3, while spatial offer values, chosen side, and chosen value were predominant in L5. Within each layer, functional cell groups were organized in clusters. The temporal dynamics of neural signals in the two layers indicated a combination of feed-forward and feed-back processes, and pointed to L5 as the locus for winner-take-all value comparison. These results reveal that economic decisions rely on a complex architecture distributed across layers of OFC. | | 2:18p |
Distinct Connectivity Signatures of Emotions Enhance Precision of Network Biomarkers in Mood Disorders
Mood disorders, including Major Depressive (MDD) and Bipolar (BD) Disorder, are highly prevalent and debilitating conditions that contribute significantly to the global disease burden. These disorders are characterized by persistent emotional dysregulations, such as pervasive sadness and anhedonia, resulting in substantial functional impairments. Although neuroimaging studies have identified differences in brain activity and connectivity between individuals with MDD (MDDs) or BD (BDs) and healthy controls (HCs), reliable and reproducible neurofunctional markers for clinical diagnosis and treatment remain elusive. This study seeks to address this gap by introducing a novel approach that utilizes Divergent Emotional Functional Networks (DEFN), derived from functional magnetic resonance imaging (fMRI) during dynamic emotional processing in naturalistic contexts. Using a combination of naturalistic induction of sustained emotional experience with dynamic functional connectivity (dFC) and machine learning techniques, we decoded emotion-specific patterns of happiness and sadness in healthy individuals. Based on the dynamic functional connectivity signatures, we identify the DEFN and applied it to large clinical mood disorder datasets, including MDD (n=63) and BD patients (n=61). The model with DEFN demonstrated significant improvements in classification accuracy compared to conventional baseline models, achieving up to 10.75% and 9.92% performance increases in MDD and BD datasets, respectively. Additionally, DEFN were found to be highly reproducible across age, gender and models from emotion dataset, supporting the robustness of this model in distinguishing mood disorders from healthy controls. In conclusion, the DEFN approach presents a promising, reproducible, and clinically relevant neural marker for diagnosing and understanding emotional dysfunction in mood disorders, offering potential for more effective and timely interventions. | | 5:47p |
Multimodal optical imaging and modulation through Smart Dura in non-human primates
A multimodal neural interface integrating electrical and optical functionalities is a promising tool for recording and manipulating neuronal activity, providing multiscale information with enhanced spatiotemporal resolution. However, most technologies for multimodal implementation are limited in their applications to small animal models and lack the ability to translate to larger brains, such as non-human primates (NHPs). Recently, we have developed a large-scale neural interface for NHPs, Smart Dura, which enables electrophysiological recordings and high optical accessibility. In this paper, we demonstrate the multimodal applications of Smart Dura in NHPs by combining with multiphoton imaging, optical coherence tomography angiography (OCTA), and intrinsic signal optical imaging (ISOI), as well as optical manipulations such as photothrombotic lesioning and optogenetics. Through the transparent Smart Dura, we could obtain fluorescence images down to 200 m and 550 m depth using two-photon and three-photon microscopy, respectively. Integrated with simultaneous electrophysiology using the Smart Dura, we could also assess vascular and neural dynamics with OCTA and ISOI, induce ischemic stroke, and apply optogenetic neuromodulation over a wide coverage area of 20 mm diameter. This multimodal interface enables comprehensive investigations of brain dynamics in NHPs, advancing translational neurotechnology for human applications. | | 5:47p |
Decoding neuronal wiring by joint inference of cell identity and synaptic connectivity
Animal behaviors are executed by motor neurons (MNs), which receive information from complex pre-motor neuron (preMN) circuits and output commands to muscles. How motor circuits are established during development remains an important unsolved problem in neuroscience. Here we focus on the development of the motor circuits that control the movements of the adult legs in Drosophila melanogaster. After generating single-cell RNA sequencing (scRNAseq) datasets for leg MNs at multiple time points, we describe the time course of gene expression for multiple gene families. This analysis reveals that transcription factors (TFs) and cell adhesion molecules (CAMs) appear to drive the molecular diversity between individual MNs. In parallel, we introduce ConnectionMiner, a novel computational tool that integrates scRNAseq data with electron microscopy-derived connectomes. ConnectionMiner probabilistically refines ambiguous cell type annotations by leveraging neural wiring patterns, and, in turn, it identifies combinatorial gene expression signatures that correlate with synaptic connectivity strength. Applied to the Drosophila leg motor system, ConnectionMiner yields a comprehensive transcriptional annotation of both MNs and preMNs and uncovers candidate effector gene combinations that likely orchestrate the assembly of neural circuits from preMNs to MNs and ultimately to muscles. | | 5:47p |
Molecular and cellular signatures differentiate Parkinson's disease from Parkinson's disease with dementia
Parkinsons disease (PD) affects millions of people worldwide, and up to 40% of these patients develop dementia, profoundly affecting their quality of life. Whether Parkinsons disease dementia (PDD) simply represents a late stage of PD or constitutes a distinct neurodegenerative process remains unresolved. To clarify this, we generated the largest single nuclear transcriptomic atlas of PD and PDD to date--almost one million nuclei derived from the anterior cingulate cortex and inferior parietal lobule of 64 post-mortem donors. By integrating these data with long-read RNA-seq, we found that the cellular compositions, biological pathways, and molecular profiles diverge substantially between PD and PDD, with minimal overlap in differentially expressed genes and pathways. While PD was characterised by widespread upregulation of gene expression programs and robust regional signatures, PDD showed extensive pathway downregulation, loss of cortical regional identity, and significant shifts in transcript usage, including alterations in APP isoforms that may influence pathological amyloid beta accumulation. These findings reveal that PD and PDD represent fundamentally distinct disease states, offering important insights for understanding their underlying mechanisms and will guide the development of targeted therapies and more effective clinical trials. | | 5:47p |
Oxygen/glucose-deprivation causes long-term impairment of synaptic CaMKII movement
Learning and memory are thought to require hippocampal long-term potentiation (LTP), a form of synaptic plasticity that is persistently impaired after cerebral ischemia and that requires movement of the Ca2+/calmodulin-dependent protein kinase II (CaMKII) to excitatory synapses. We show here that oxygen/glucose-deprivation (OGD) in cultures hippocampal neurons causes a long-lasting impairment of CaMKII movement. Notably, CaMKII inhibition at 30 min after onset of OGD prevented the impairment in CaMKII movement. Thus, CaMKII mediates both, LTP mechanisms and their ischemia-induced impairment. These findings provide a mechanism by which ischemic conditions can impair LTP and explain how CaMKII inhibition after cerebral ischemia can prevent these LTP impairments. |
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