bioRxiv Subject Collection: Neuroscience's Journal
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Friday, February 16th, 2024
| Time |
Event |
| 12:31a |
Local variation in brain temperature explains gender-specificity of working memory performance
Exploring gender differences in cognitive abilities offers vital insights into human brain functioning. Our study utilized advanced techniques like magnetic resonance thermometry, standard working memory n-back tasks, and functional MRI to investigate if gender-based variations in brain temperature correlate with distinct neuronal responses and working memory capabilities. Interestingly, our findings revealed no gender disparity in working memory performance. However, we observed a significant decrease in average brain temperature in males during working memory tasks, a phenomenon not seen in females. Although changes in female brain temperature were not statistically significant, we found an inverse relationship between the absolute temperature change (ATC) and cognitive performance, alongside a correlation with blood oxygen level dependent (BOLD) neuronal responses. This suggests that in females, ATC is a crucial determinant for the link between cognitive performance and BOLD responses, a linkage not evident in males. Our results also suggest that females compensate for their brains heightened temperature sensitivity by activating additional neuronal networks to support working memory. This study not only underscores the complexity of gender differences in cognitive processing but also opens new avenues for understanding how temperature fluctuations influence brain functionality.
SignificanceSex/gender differences in cognition are of high scientific and social interest. Yet, those differences (if any) remain elusive. Here we used magnetic resonance thermometry and functional MRI to examine, whether gender differences in working memory performance (WMP) are determined by subtle, yet detectable between-sex differences in local brain temperature fluctuations mediated by blood oxygen level-dependent (BOLD) neuronal responses. We found that WMP did not differ between genders. Yet, a females WMP was more sensitive to brain temperature variation compared to males. Furthermore, the negative impact of temperature on female cognitive functions was compensated by higher BOLD activity in other task-specific brain areas. This compensation may account for equivocal results of studies on the between-sex differences in cognitive performance. | | 8:33a |
Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells
Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally segregated subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GC) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and supra-threshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations wouldn't yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for, while assessing GCs and their robustness under physiological and pathological conditions. | | 8:33a |
Brain-handedness associations depend on how and when handedness is measured
Hand preference is ubiquitous, intuitive, and often simplified to right- or left-handed. Accordingly, differences between right- and left-handed individuals in the brain have been established. Nevertheless, considering handedness as a binarized construct fails to capture the variability of brain-handedness associations across different domains or activities. Further, many cultures, environments, and generations impose right-handed norms, and handedness preferences can change over the lifespan. As a result, brain-handedness associations may depend on how and when handedness is measured. We used two large datasets, the Human Connectome Project-Development (HCP-D; n=465; age=5-21 years) and Human Connectome Project-Aging (HCP-A; n=368; age=36-100 years), to explore handedness preferences and brain-handedness associations. Nine items from the Edinburgh Handedness Inventory were associated with resting-state functional connectomes. We show that brain-handedness associations differed across the two cohorts. Moreover, these differences depended on the way handedness was measured. Given that brain-handedness associations differ across handedness measures and datasets, we caution against a one-size-fits-all approach to neuroimaging studies of this complex trait. | | 9:45a |
Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction
Pharmacological approaches to induce N-methyl-D-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in mice that underwent a 7-day subchronic phencyclidine (PCP 10mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus (HPC) to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds. | | 9:45a |
Aberrant axon initial segment is an indicator for task-independent neural activity in autism model mice
Autism spectrum disorder (ASD) is a developmental disorder characterized by impairments in several communicative behaviors. Identification of biomarkers for ASD based on task-independent neural activity has been elusive. The axonal initial segment (AIS), located at the proximal part of the axon, is crucial for initiating action potentials (APs) and adaptable through activity-dependent AIS plasticity. In our study, we discovered decrease in AIS length in layer V pyramidal neurons (PyNs) of the prelimbic cortex (PrL) and increase in layer II/III PyNs in the somatosensory cortex of duplicated human 15q11-13 region (15q dup) ASD model mice. Electrophysiological studies using whole-cell patch-clamp recordings in the PrL revealed diminished ability to generate APs. We discovered lack of AIS plasticity in 15q dup mice under conditions of elevated potassium chloride. Retrograde tracing demonstrated that AIS shortening depends on the projection targets. These results indicate that activity-dependent aberrant AIS structures can serve as indicators of altered task-independent neural activity in ASD mouse models. | | 9:45a |
Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system
Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. In order to identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2auw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain, however do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.
Summary StatementJoubert Syndrome gene dysfunction in zebrafish leads to abnormal brain cilia, altered transcription of neuron-associated genes and abnormal swimming behaviour despite normal brain morphology. | | 9:45a |
Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity
Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early life adversity, with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of early life adversity, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21, in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. This finding suggests a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, these studies highlight a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of early-life adversity. | | 11:45a |
Oxytocin signaling regulates maternally-directed behavior during early life
Oxytocin is essential in shaping social behavior across the lifespan. While the role of oxytocin signaling in parental care has been widely investigated, little is known about its function in social behavior during early life. This is partly due to the lack of precise technologies for studying the developing brain. Here, we studied the role of oxytocin in pup social behavior under acute separation from and reunion with the mother. We show that the activity of oxytocin neurons was increased by acute maternal separation and returned to baseline after reunion. Behaviorally, maternally-separated pups emitted more ultrasonic vocalizations upon reunion, which were further modulated by nipple attachment behavior. These effects were attenuated by blocking the oxytocin receptor during maternal separation. To investigate the role of oxytocin neurons with higher precision, we established a method for transcranial optogenetic silencing of neuronal activity in untethered and freely behaving pups. Using this approach, we found that silencing of oxytocin neurons during maternal separation disrupted vocal behavior during separation and reunion in a sex-specific manner. Our findings reveal an important role of oxytocin in context-dependent vocal communication in pups, offering new insights into the mechanisms of social behavior during early life. | | 7:45p |
UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.
MAPK8IP3 (unc-16/JIP3) is a neurodevelopmental-disorder associated gene that can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3. | | 7:45p |
Importin-β specific nuclear transport defects recapitulate phenotypic and transcriptional alterations seen in neurodegeneration
Defects in Nucleocytoplasmic transport have been implicated as an important neurodegenerative pathway in ALS/FTD. Here, we show that a NemfR86S mutation results in the disruption of NCT both in vitro and in vivo. These disruptions are specific to Importin-{beta} nuclear import, and result in the nuclear loss and cytoplasmic gain of NEMF, Importin-{beta}, and TDP-43. We show that a transient nuclear import block is capable of inducing the mis-localization of TDP-43 and is associated with altered transcriptional expression of ALS, FTD, and AD/ARD genes. Taken together, these findings show that disrupted Importin-{beta} nuclear import, whether through genetic forms such as Nemf mutations, or through pharmacological inhibition, is the primary driver of TDP-43 pathology, disease-related transcriptional alterations, and neurodegeneration. | | 7:45p |
Spatiotemporal Changes in Netrin/Dscam1 Signaling Dictate Axonal Projection Direction in Drosophila Small Ventral Lateral Clock Neurons
Axon projection is a spatial and temporal-specific process in which the growth cone receives environmental signals guiding axons to their final destination. However, the mechanisms underlying changes in axonal projection direction without well-defined landmarks remain elusive. Here, we present evidence showcasing the dynamic nature of axonal projections in Drosophilas small ventral lateral clock neurons (s-LNvs). Our findings reveal that these axons undergo an initial vertical projection in the early larval stage, followed by a subsequent transition to a horizontal projection in the early-to-mid third instar larvae. The vertical projection of s-LNv axons correlates with mushroom body calyx expansion, while the s-LNv-expressed Down syndrome cell adhesion molecule (Dscam1) interacts with Netrins to regulate the horizontal projection. During a specific temporal window, locally newborn dorsal clock neurons (DNs) secrete Netrins, facilitating the transition of axonal projection direction in s-LNvs. Our study establishes a compelling in vivo model to probe the mechanisms of axonal projection direction switching in the absence of clear landmarks. These findings underscore the significance of dynamic local microenvironments in the synergetic regulation of axonal projection direction transitions. | | 8:16p |
Adeno-Associated Viral Tools to Trace Neural Development and Connectivity Across Amphibians
The development, evolution, and function of the vertebrate central nervous system (CNS) can be best studied using diverse model organisms. Amphibians, with their unique phylogenetic position at the transition between aquatic and terrestrial lifestyles, are valuable for understanding the origin and evolution of the tetrapod brain and spinal cord. Their metamorphic developmental transitions and unique regenerative abilities also facilitate the discovery of mechanisms for neural circuit remodeling and replacement. The genetic toolkit for amphibians, however, remains limited, with only a few species having sequenced genomes and a small number of transgenic lines available. In mammals, recombinant adeno-associated viral vectors (AAVs) have become a powerful alternative to genome modification for visualizing and perturbing the nervous system. AAVs are DNA viruses that enable neuronal transduction in both developing and adult animals with low toxicity and spatial, temporal, and cell-type specificity. However, AAVs have never been shown to transduce amphibian cells efficiently. To bridge this gap, we established a simple, scalable, and robust strategy to screen AAV serotypes in three distantly-related amphibian species: the frogs Xenopus laevis and Pelophylax bedriagae, and the salamander Pleurodeles waltl, in both developing larval tadpoles and post-metamorphic animals. For each species, we successfully identified at least two AAV serotypes capable of infecting the CNS; however, no pan-amphibian serotype was identified, indicating rapid evolution of AAV tropism. In addition, we developed an AAV-based strategy that targets isochronic cohorts of developing neurons - a critical tool for parsing neural circuit assembly. Finally, to enable visualization and manipulation of neural circuits, we identified AAV variants for retrograde tracing of neuronal projections in adult animals. Our findings expand the toolkit for amphibians to include AAVs, establish a generalizable workflow for AAV screening in non-canonical research organisms, generate testable hypotheses for the evolution of AAV tropism, and lay the foundation for modern cross-species comparisons of vertebrate CNS development, function, and evolution. | | 8:48p |
Effects of ketamine and propofol on muscarinic plateau potentials in rat neocortical pyramidal cells
Propofol and ketamine are widely used general anaesthetics, but have different effects on consciousness: propofol gives a deeply unconscious state, with little or no dream reports, whereas vivid dreams are often reported after ketamine anaesthesia.
Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, while propofol is a {gamma}-aminobutyric-acid (GABAA) agonist, but these mechanisms do not fully explain how these drugs alter consciousness.
Most previous in vitro studies of cellular mechanisms of anaesthetics have used brain slices or neurons in a nearly "comatose" state, because no "arousing" neuromodulators were added. Here we tested mechanisms of anaesthetics in slices after adding the cholinergic agonist muscarine to partly mimic an "awake-like" state.
Using whole-cell patch-clamp recordings from layer 2/3 pyramidal cells (L2/3PCs) in rat medial prefrontal cortex (mPFC) slices, we saw that muscarine induced long-lasting depolarizing plateau potentials (PPs) and spiking following brief depolarizing current injections. According to leading theories of consciousness and working memory, L2/3PCs and PPs are particularly important for these cognitive functions. After 2 hours of pre-incubation with ketamine or propofol, the muscarine-induced PPs were altered in different ways: 3 {micro}M propofol reduced the PPs and (significantly) spiking, whereas 20 {micro}M ketamine seemed to enhance PPs and spiking (non-significantly). Brief wash-in of these drug concentrations failed to induce such effects, probably due to insufficient equilibration by diffusion in the slices. In contrast, pre-incubation with 100 {micro}M ketamine suppressed the PPs and spiking.
The different effects on PPs may be related to contrasting clinical effects: ketamine causing atypical anaesthesia with vivid, "psychedelic" dreaming while propofol causes less dreaming. However, high ketamine or propofol concentrations both suppressed PPs, suggesting possible connections between PPs, desynchronized activity, and consciousness. More experiments are needed to test these tentative conclusions. | | 8:48p |
The flow of reward information through neuronal ensembles in the accumbens
The flow of reward information through neuronal ensembles in the nucleus accumbens shell (NAcSh) and its influence on decision-making remains poorly understood. We investigated these questions by training rats in a self-guided probabilistic choice task while recording single-unit activity in the NAcSh. We found that rats dynamically adapted their choices based on an internal representation of reward likelihood. NAcSh neurons encoded multiple task variables, including choices, outcomes (reward/no reward), and licking behavior. These neurons also exhibited sequential activity patterns resembling waves that peaked and dissipated with outcome delivery, potentially reflecting a global brain wave passing through the NAcSh. Further analysis revealed distinct neuronal ensembles processing specific aspects of reward-guided behavior, organized into four functionally specialized meta-ensembles. A Markov random fields graphical model revealed that NAcSh neurons form a small-world network with a heavy-tailed distribution, where most neurons have few functional connections and rare hubs are highly connected. This network architecture allows for efficient and robust information transmission. Neuronal ensembles exhibited dynamic interactions that reorganize depending on reward outcomes. Reinforcement learning within the session led to neuronal ensemble merging and increased network synchronization during reward delivery compared to omission. These findings offer a novel perspective of the flow of pleasure throughout neuronal ensembles in the NAcSh that dynamically changes its composition, with neurons dropping in and out, as the rat learns to obtain (energy) rewards in a changing environment and supports the idea that NAcSh ensembles encode the outcome of actions to guide decision making.
Graphical Abstract
O_FIG O_LINKSMALLFIG WIDTH=112 HEIGHT=200 SRC="FIGDIR/small/580379v1_ufig1.gif" ALT="Figure 1">
View larger version (24K):
org.highwire.dtl.DTLVardef@1e3c81borg.highwire.dtl.DTLVardef@16675feorg.highwire.dtl.DTLVardef@1ccb0dborg.highwire.dtl.DTLVardef@16f3a63_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINeuronal ensembles in the NAcSh act as dynamic modules to process different aspects of reward-guided behavior
C_LIO_LINAcSh ensembles dynamically change composition and interactions throughout reinforcement learning
C_LIO_LIThe NAcSh forms a highly connected network with neuronal hubs that facilitate an efficient reward information flow
C_LIO_LIReward triggers stronger interactions between ensembles and unifies network activity, while omission leads to less synchronization
C_LIO_LIThe NAcSh uses neuronal ensembles to process reward information and self-guide decision-making dynamically
C_LI | | 11:33p |
Near-optimal information relay by the neuronal population of layer 4 barrel cortex
Cortical function reflects the coordinated activities of populations of neurons, which, in turn, depend on the speed with which each neuron can respond to input, as revealed by dynamic gain analysis. In Layer 4 of the rodent barrel cortex, a finite population of interconnected, small, excitatory neurons rapidly and briefly relays input from the specific thalamus to the rest of the cortical column. Theory predicts that the determinants of a populations dynamic gain - cell number, cell size and the correlation time of the background noise - control the speed with which the population can respond to input. Here, we demonstrate how these parameters are optimized such that a single thalamocortical input spike is reliably reflected in the output population response of layer 4. We show that the synaptic receptor dynamics that dominate the background noise in layer 4 are slower than in other layers. We further show that the speed with which the spike-generation machinery can respond depends on the activity of KV7 channels, suggesting that the relay function of layer 4 is under muscarinic control.
One-Sentence SummaryIn layer 4 of the somatosensory cortex, the neuronal population is able to perform its precise temporal function because it is tuned by a set of disparate parameters. |
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