bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, January 23rd, 2025
| Time |
Event |
| 12:30a |
Mef2c Controls Postnatal Callosal Axon Targeting by Regulating Sensitivity to Ephrin Repulsion
Cortical connectivity is contingent on ordered emergence of neuron subtypes followed by the formation of subtype-specific axon projections. Intracortical circuits, including long-range callosal projections, are crucial for information processing, but mechanisms of intracortical axon targeting are still unclear. We find that the transcription factor Myocyte enhancer factor 2-c (Mef2c) directs the development of somatosensory cortical (S1) layer 4 and 5 pyramidal neurons during embryogenesis. During early postnatal development, Mef2c expression shifts to layer 2/3 callosal projection neurons (L2/3 CPNs), and we find a novel function for Mef2c in targeting homotopic contralateral cortical regions by S1-L2/3 CPNs. We demonstrate, using functional manipulation of EphA-EphrinA signaling in Mef2c-mutant CPNs, that Mef2c downregulates EphA6 to desensitize S1-L2/3 CPN axons to EphrinA5-repulsion at their contralateral targets. Our work uncovers dual roles for Mef2c in cortical development: regulation of laminar subtype specification during embryogenesis, and axon targeting in postnatal callosal neurons.
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/634300v1_ufig1.gif" ALT="Figure 1">
View larger version (51K):
org.highwire.dtl.DTLVardef@2d97f9org.highwire.dtl.DTLVardef@154741eorg.highwire.dtl.DTLVardef@19377e5org.highwire.dtl.DTLVardef@a49396_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIMef2c is required for the development of L4 and L5 neurons in the embryonic neocortex
C_LIO_LIPostnatally, Mef2c is enriched in L2/3 neurons and is required for axon targeting
C_LIO_LIL2/3-specific Mef2c deletion leads to EphA6 upregulation
C_LIO_LIMef2c deletion in L2/3 neurons sensitizes them to EfnA5 repulsion in the contralateral cortex
C_LI | | 12:30a |
Sensorimotor adaptation reveals systematic biases in 3D perception.
The existence of biases in visual perception and their impact on visually guided actions has long been a fundamental yet unresolved question. Evidence revealing perceptual or visuomotor biases has typically been disregarded because such biases in spatial judgments can often be attributed to experimental measurement confounds. To resolve this controversy, we leveraged the visuomotor systems adaptation mechanism -- triggered only by a discrepancy between visual estimates and sensory feedback -- to directly indicate whether systematic errors in perceptual and visuomotor spatial judgments exist. To resolve this controversy, we leveraged the adaptive mechanisms of the visuomotor system to directly reveal whether systematic biases or errors in perceptual and visuomotor spatial judgments exist. In a within-subject study (N=24), participants grasped a virtual 3D object with varying numbers of depth cues (single vs. multiple) while receiving haptic feedback. The resulting visuomotor adaptations and aftereffects demonstrated that the planned grip size, determined by the visually perceived depth of the object, was consistently overestimated. This overestimation intensified when multiple cues were present, despite no actual change in physical depth. These findings conclusively confirm the presence of inherent biases in visual estimates for both perception and action, and highlight the potential use of visuomotor adaptation as a novel tool for understanding perceptual biases. | | 12:30a |
Large Animal Epilepsy Model Platform: Kainic Acid Porcine Model of Mesial Temporal Lobe Epilepsy
Objective: Translational animal models are essential for advancing neuromodulation therapies for drug-resistant epilepsy. Large animal epilepsy models that accommodate implantable neuromodulation devices designed for humans are needed to advance electrical brain stimulation and sensing applicaitons. We establish a kainic acid (KA) porcine model of mesial temporal lobe epilepsy (mTLE) for pre-clinical research and development of novel stimulating therapies. Methods: We developed a platform integrating MRI-guided stereotactic electrode and chemotoxin delivery with intraoperative and long-term electrophysiology monitoring. Six domestic pigs underwent MRI-guided stereotactic implantation of bilateral hippocampal (HPC) and anterior nucleus of the thalamus (ANT) electrodes, followed by KA infusion into the right HPC. Local field potential (LFP) monitoring was conducted intraoperatively with a bedside workstation and chronically with an implantable neural sensing and recording (INSR) device designed for human use. Cresyl violet staining, commonly used to visualize neurons, was used to assess the neuropathophysiological effect of the KA infusion. Results: KA infusion led to the emergence of interictal epileptiform discharges (IEDs), acute status epilepticus (SE), and spontaneous seizure activity. Acute IEDs and electrographic SE was observed in all cases, with two pigs euthanized due to uncontrolled seizures. Of the surviving four pigs, spontaneous IEDs were detected in all, and spontaneous seizures within 2 weeks were observed in three. Seizures in freely behaving animals varied from subclinical events to focal and generalized tonic-clonic seizures. Single pulse evoked response potentials (SPEP) measured in two pigs demonstrated functional connectivity between ANT and HPC circuits. Neuronal disorganization and loss, both major components of mTLE neuropathology were observed. Significance: The KA-induced porcine mTLE model supports the feasibility of testing human neuromodulation devices and provides a translational platform for studying therapeutic electrical sensing and stimulation. In particular, the model should be useful for advancing automated seizure diaries, closed-loop and adaptive therapies targeting Papez circuit nodes. | | 1:46a |
Demonstrating the need for long inter-stimulus intervals when studying the post-movement beta rebound following a simple button press
Voluntary movements reliably elicit event-related synchronization of oscillatory neuronal rhythms in the beta (15-30 Hz) range immediately following movement offset, as measured by magneto/electroencephalography (M/EEG). This response has been termed the post-movement beta rebound (PMBR). While early work on the PMBR advocated for long inter-stimulus intervals (ISIs) - arguing that the PMBR might persist for several seconds - these concerns have since fallen by the wayside, with many recent studies employing very short (< 5 s) ISIs. In this work we interrogated sensor-level MEG time courses in 635 individuals who participated in a cued button-pressing paradigm as part of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) project. We focussed on a subset of trials in which button presses were separated by at least 15 seconds and, using curve modelling and Bayesian inference, estimated the point at which beta power returned to baseline levels. We show that beta power takes around 4-5 seconds to return to baseline levels following movement. These results have important implications for experimental design. The PMBR is ubiquitously defined relative to a preceding baseline period; we argue that short ISIs preclude true baseline estimation and, in turn, accurate estimation of PMBR magnitude. We recommend that future studies targeting the PMBR use ISIs of at least 7-5 seconds for beta power to return to baseline, plus a 1-2 second period for proper baseline estimation. Further work is needed to clarify PMBR duration in the context of different sensorimotor paradigms and clinical populations. | | 9:47a |
Tool-use brain representations are independent of the acting body part and motor experience
The sensorimotor system is broadly organized somatotopically. However, an action-type organization has also been found: a division based on action-type independent of acting body parts has been shown for reaching and grasping actions. Does this generalization extend to non-ethological actions? Here, we examined fMRI responses for tool-use actions that participants performed with their hands or feet. We additionally tested individuals born without hands to control for hand motor imagery when performing foot actions. We show that the primary sensorimotor cortices have hand and foot selectivity, consistent with a somatotopic organization. In contrast, higher-level motor areas within the tool-use network, such as the premotor cortex, supplementary motor area, and superior parietal cortices, showed a shared preference for tool-use independent of the executing body part and sensorimotor experience. Multivariate decoding of action-type in these areas generalized between controls' hand and foot and was successful in individuals born without hands. Finally, the temporal dynamics pattern in primary and association areas carried effector-specific and action-type information, respectively. Altogether, we show that the tool-use network in motor association areas represents higher-order action information beyond concrete motor parameters associated with specific effectors, and regardless of hand motor experience. This suggests that an action-type, effector-independent organization extends beyond ethological actions, supporting a hierarchical organization in the action domain. Further, it shows that functional organization in congenital handlessness is based on the hierarchical organization of the intact cortex. | | 12:31p |
Regionally specific resting-state beta neural power predicts brain injury and symptom recovery in adolescents with concussion: a longitudinal study
Mild traumatic brain injury (mTBI) is common in adolescents. Magnetoencephalography (MEG) studies (primarily reporting on adult males) have demonstrated abnormal resting-state (RS) brain activity in mTBI. The present study sought to identify RS abnormalities in male and female adolescents with mTBI (no previous mTBI and no previous DSM-5 diagnosis) identified from an outpatient specialty care concussion program setting as a basis for evaluating potential clinical utility. Visit 1 MEG RS data were obtained from 46 adolescents with mTBI (mean age: 15.4 years, 25 females) within 4 months of a mTBI (mTBI acute to sub-acute period) as well as from 34 typically developing (TD) controls (mean age: 14.8 years; 17 females) identified from the local community. Visit 2 RS data (follow-up ~4.3 months after Visit 1; mTBI sub-chronic period) were obtained from 36 mTBI (19 females) and 29 TD (14 females) of those participants. Source-space RS neural activity was examined from 4 to 56 Hz. Visit 1 t-tests showed that group differences were largest in the beta range (16-30 Hz; mTBI < TD), with Visit 2 whole-brain linear mixed model (LMM) analyses examining beta-band group differences as a function of Visit. A main effect of Group indicated Visit 1 and 2 beta-band group differences in midline superior frontal gyrus, right temporal pole, and right central sulcus (all mTBI < TD). The group effects were large (Cohen's d values 0.75 to 1.31). Of clinical significance in the mTBI group, a decrease in mTBI symptoms from Visit 1 to 2 was associated with an increase in beta power in 4 other brain regions. Present findings suggest that RS beta power has potential as a measure and perhaps as a mechanism of clinical recovery in adolescents with mTBI. | | 1:51p |
Standardised TruAI automated quantification of intracellular neuromelanin granules in human brain tissue sections
Aims: To standardise and automate the quantitation of human-unique neuromelanin granules in catecholamine neurons in post-mortem tissue sections from healthy individuals at different ages to understand any changes in these granules with age. Methods: 5-6m thick fixed and paraffin-embedded transverse midbrain tissue sections were supplied from 47 cases from three brain banks following ethics approvals. Sections were prepared and automated digital images acquired. Standardisation and automation of the quantification of neuromelanin granules was performed using the TruAI feature of the Olympus VS200 desktop platform. Comparisons between stained and unstained sections as well as correlations with age were performed. Results: The automated platform reliably identified both stained and unstained intracellular and extracellular neuromelanin granules, showing high reproducibility in measurements across laboratories using different tissue processing methods. Extracellular neuromelanin granules were significantly smaller than intracellular neuromelanin granules. Sections processed for hematoxylin and eosin staining impacted on size and colour of both neuromelanin and the neurons containing neuromelanin. Hematoxylin made neuromelanin bluer and the increased tissue processing made the intracellular area occupied by neuromelanin smaller in younger people. There was an increase in neuromelanin optical density and colour change (more brown) with age. Conclusions: The TruAI automated platform reliably quantifies individual neuromelanin granules in catecholamine neurons. Extracellular neuromelanin is considerably smaller in size than intracellular neuromelanin, and intracellular neuromelanin changes its properties with age. The darkening and colour change of intracellular neuromelanin suggests an increase in eumelanin over time in healthy individuals. These changes can be reliably identified using the automated platform. | | 6:47p |
A synaptic-astrocytic proteomic signature associated with synaptopathy in Alzheimer's Disease
Synapse loss is the greatest correlate of cognitive impairment in Alzheimer's Disease (AD) and offers a therapeutic avenue alongside disease-modifying therapies. However, the events preceding synapse loss in the human condition have not been well characterised. In this study, we describe a pseudotemporal profile of alterations in the synaptic proteome prior to excitatory synapse loss in human post-mortem brain AD tissue using synapse proteomics and synaptome mapping techniques. In a region with early-stage disease pathology, the most predominant changes were pre-synaptic and featured changes in metabolism and exocytosis. In a mid-stage disease state, alongside initial synapse loss, there was a dominance of inhibitory synaptic changes. In a region with late-stage disease pathology and profound synapse loss, post-synaptic changes were most prevalent with a range of canonical synaptic transmission pathways reduced and differential excitatory synapse subtype pathology. Synapse loss was associated with changes in astrocytic proteins which were enriched for those at peri-synaptic astrocytic processes, including an upregulation of complement activation and endocytosis; a signature that differed from the astrocyte cytosolic proteome. Taken together, this provides evidence of a cascade of events leading to synapse loss with multiple points for therapeutic intervention to alleviate cognitive decline in AD. Data are available via ProteomeXchange with identifier PXD056052. | | 7:17p |
Development of a floxed Gabbr2 gene allows for widespread conditional disruption of GABBR2 and recapitulates the phenotype of germline Gabbr2 knockout mice
GABBR1 and GABBR2 are widely expressed in the brain and genetic inhibition of their function leads to widespread neurologic dysfunction and premature death in mice. Given that GABBR1 and GABBR2 heterodimerize to form a functional receptor, global knockout of GABBR1 or GABBR2 results in a similar phenotype, characterized by spontaneous epileptiform activity, hyperlocomotor activity, hyperalgesia, impaired memory and premature death. It is now known that both GABBR1 and GABBR2 are expressed in a variety of tissues outside the nervous system and that GABA-B receptors can heterodimerize with other class C GPCRs, including the extracellular calcium-sensing receptor (CaSR). Studies in vitro have demonstrated that interactions with GABBR1 and GABBR2 can alter CaSR signaling in human embryonic kidney cells and breast cancer cells. The neurologic consequences of global loss of function of GABBR1 or GABBR2 has made it difficult to study the effects of loss of GABBR function in other organs. While a conditional knockout for GABBR1 is available, the GABBR2 gene had not been "floxed". We have used CRISPR to insert loxP sites into the GABBR2 locus in mice. These mice are normal at baseline but when bred with mice expressing Cre-recombinase under the control of the ubiquitously expressed Actin gene promoter, they recapitulate the phenotype of global GABBR2 knockout mice. Phenotypic changes through the brain, including the cortex, hippocampus and cerebellum. Evidence of abnormal neuronal function, increase cell death, and changes in neuronal architecture are seen throughout the brain of CRISPR knockout mice. These mice should be useful tools to study cell type-specific loss of GABBR2 function in the brain and other organs. | | 7:17p |
Shallow-angle intracranial cannula for repeated infusion and in vivo imaging with multiphoton microscopy
Multiphoton microscopy serves as an essential tool for high-resolution imaging of the living mouse brain. To facilitate optical access to the brain during imaging, the cranial window surgery is commonly used. However, this procedure restricts physical access above the imaging area and hinders the direct delivery of imaging agents and drugs. To overcome this limitation, we have developed a cannula delivery system that enables the implantation of a low-profile cannula nearly parallel to the brain surface at angles as shallow as 8 degrees, while maintaining compatibility with multiphoton microscopy. To validate this approach, we perform direct infusion and imaging of various fluorescent cell markers in the brain. Additionally, we successfully demonstrate tracking of degenerating neurons over time in Alzheimer's disease mice using Fluoro-Jade C. Furthermore, we show longitudinal imaging of brain tissue partial pressure of oxygen using a phosphorescent oxygen sensor. Our developed technique should enable a wide range of new longitudinal imaging studies in the mouse brain. | | 7:17p |
A phenomenological interpretation of multiple bursting patterns in Lateral Habenula neurons
We present lateral habenula (LHb) neural data that display a variety of bursting patterns, with two dominant types and a third one that appears as a mix of the other two. We analyse these patterns using elementary statistical tools and characterise them from the perspective of average frequency during the burst and burst duration, which yields two main categories. We then propose an idealised multiple-timescale dynamical model that captures the two main types of bursting patterns observed in the data, namely square-wave and parabolic bursting, as well as the intermediate mixed-type (also termed triangular) bursting. We identify a special point in parameter space, termed saddle-node homoclinic, which acts as an organising center to distinguish between the two main bursting patterns. Finally, we relate the bursting categories inherent to the model and those identified through statistical analysis, discussing their possible convergence and limitations. | | 7:17p |
Motor cortical beta power reflects adaptation to task constraints
The amplitude of beta oscillations over motor cortical regions (beta power; 13-30 Hz) is used as a marker of motor function for various applications, including bradykinesia assessment in Parkinson's disease and brain-computer interface control. However, the impact of beta power changes on movement execution remains unclear, as beta power has been alternately associated with motor vigor and motor adaptation. The present study aimed to address this issue through two experiments (EXP1 and EXP2, 60 participants in total). In each experiment, participants were trained to down- and up-regulate beta power recorded over motor regions with electroencephalography, through real-time feedback, before executing a motor task (force task in EXP1, speed task in EXP2) in order to probe the effects of beta power changes on motor function. In EXP1, downregulation of beta power was associated with increased force exertion, but it did not significantly affect movement time nor reaction time. In EXP2, downregulation of beta power was associated with faster movements when instructed to move quickly and, conversely, slower movements when instructed to move slowly. Thus, the impact of online changes in beta power on motor execution specifically relied on task constraints, with a negative linear relationship linking beta power and motor adaptation. These findings demonstrate that beta power better predicts motor adaptation than strength of motor output, thereby highlighting the importance of considering environmental constraints for beta power-based applications. | | 7:17p |
The Effects of Acute Trazodone Administration on Sleep in Mice
Study Objectives: Trazodone is an antidepressant with robust hypnotic effects, frequently prescribed off-label to treat insomnia. Trazodone has gained recent attention in the context of neurodegenerative diseases because sleep has been proposed as a novel target for disease-modifying therapeutics. Preclinical research in rodents examining the effects of trazodone on sleep is limited, so here we aimed to develop a translationally-focused protocol to study the sleep-promoting effects of trazodone in mice. Methods: We investigated the effects of voluntary oral trazodone administration at doses of 0 mg/kg, 10 mg/kg, 40 mg/kg, and 60 mg/kg on sleep in C57BL/6J mice (n = 15; females = 6; age 10-13 months). Mice were dosed with trazodone for 6 consecutive nights, while being recorded with intracranially implanted 2-channel electroencephalogram (EEG) and electromyography (EMG). EEG/EMG recordings were analyzed for time spent in each vigilance state and power spectra. Results: A single dose of trazodone, administered prior to the onset of the 12-h rest phase, dose-dependently increased non-rapid eye movement (NREM) sleep and delta power during NREM sleep, at the expense of rapid eye movement (REM) sleep. These effects on sleep persisted after six consecutive days of dosing, albeit to a lesser extent. Conclusion: We have validated a novel voluntary oral administration protocol for trazodone use in mice and have shown that trazodone effectively promotes NREM in mice. Our novel protocol will be useful for future research investigating the effects of trazodone on sleep in mouse models of disease. |
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