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ELife Mar 2024Determining the sites and directions of plasticity underlying changes in neural activity and behavior is critical for understanding mechanisms of learning. Identifying...
Determining the sites and directions of plasticity underlying changes in neural activity and behavior is critical for understanding mechanisms of learning. Identifying such plasticity from neural recording data can be challenging due to feedback pathways that impede reasoning about cause and effect. We studied interactions between feedback, neural activity, and plasticity in the context of a closed-loop motor learning task for which there is disagreement about the loci and directions of plasticity: vestibulo-ocular reflex learning. We constructed a set of circuit models that differed in the strength of their recurrent feedback, from no feedback to very strong feedback. Despite these differences, each model successfully fit a large set of neural and behavioral data. However, the patterns of plasticity predicted by the models fundamentally differed, with the direction of plasticity at a key site changing from depression to potentiation as feedback strength increased. Guided by our analysis, we suggest how such models can be experimentally disambiguated. Our results address a long-standing debate regarding cerebellum-dependent motor learning, suggesting a reconciliation in which learning-related changes in the strength of synaptic inputs to Purkinje cells are compatible with seemingly oppositely directed changes in Purkinje cell spiking activity. More broadly, these results demonstrate how changes in neural activity over learning can appear to contradict the sign of the underlying plasticity when either internal feedback or feedback through the environment is present.
Topics: Cerebellum; Purkinje Cells; Learning; Reflex, Vestibulo-Ocular; Feedback; Neuronal Plasticity
PubMed: 38451856
DOI: 10.7554/eLife.84770 -
Narra J Aug 2023Preterm infants, born before the 37-week gestation period, have limited storage for nutrients at birth and are vulnerable to poor feeding, severe nutritional deficits... (Review)
Review
Preterm infants, born before the 37-week gestation period, have limited storage for nutrients at birth and are vulnerable to poor feeding, severe nutritional deficits and growth retardation. The immature gastrointestinal system leads preterm infants to experience a delay in initiating enteral nutrition. Inappropriate feeding can cause acute and long-term morbidity, prolonged hospitalization and increased treatment cost. Generally, preterm infants that are born after 32 weeks of gestation without severe comorbidities do not have dysphagia and should start oral feeding soon after birth. Preterm infants should have well-developed sucking-swallowing-breathing coordination by 32-34 weeks of gestational age. However, some infants take days or weeks to master the skill. The oral feeding development involves forkhead box protein 2 (FOXP2)-expressing neurons that are found in the deep layers of the cortex, basal ganglia, parts of the thalamus and Purkinje cells of the cerebellum. In mammals, these areas belong to the brain network circuits working for motor coordination in learning and acquiring sensorimotor skills. This review aimed to describe the role of FOXP2 in oral-motor skills in preterm infants, including oral feeding, sucking-swallowing-breathing coordination and language development. The oral-motor skills development could be an early predictor for language delay in premature infants, representing a vulnerable group susceptible to such delays.
PubMed: 38450264
DOI: 10.52225/narra.v3i2.237 -
Biochemistry and Biophysics Reports Jul 2024Lgl1 protein plays a critical role in neurodevelopment, including hippocampus, olfactory bulb, and Purkinje cell. However, the specific mechanism of LGL1 function in the...
Lgl1 protein plays a critical role in neurodevelopment, including hippocampus, olfactory bulb, and Purkinje cell. However, the specific mechanism of LGL1 function in the midbrain remains elusive. In this study, we generated Lgl1 conditional knockout mice using Pax2-Cre, which is expressed in the midbrain, and examined the functions of Lgl1 in the midbrain. Histological analysis exhibited abnormal midbrain development characterized by enlarged ventricular aqueduct and thinning tectum cortex. Lgl1 deletion caused excessive proliferation and heightened apoptosis of neural progenitor cells in the tectum of LP cko mice. BrdU labeling studies demonstrated abnormal neuronal migration. Immunofluorescence analysis of Nestin demonstrated an irregular and clustered distribution of glial cell fibers, with the adhesion junction marker N-cadherin employed for immunofluorescent labeling, unveiling abnormal epithelial connections within the tectum of LP cko mice. The current findings suggest that the deletion of Lgl1 leads to the disruption of the expression pattern of N-cadherin, resulting in abnormal development of the midbrain.
PubMed: 38444736
DOI: 10.1016/j.bbrep.2024.101671 -
Sheng Li Xue Bao : [Acta Physiologica... Feb 2024Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurodegenerative diseases that have been currently identified with numerous subtypes exhibiting genetic... (Review)
Review
Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurodegenerative diseases that have been currently identified with numerous subtypes exhibiting genetic heterogeneity and clinical variability. Purkinje neuronal degeneration and cerebellar atrophy are common pathological features among most SCA subtypes. The physiological functions of Purkinje cells are regulated by multiple factors, and their dysfunction in signal transduction may lead to abnormal cerebellar motor control. This review summarizes the abnormalities in voltage-gated ionic channels, intracellular calcium signaling, and glutamate signaling transduction of Purkinje cells in SCAs, aiming to provide a theoretical basis for further understanding the common pathogenesis of SCAs and developing specific treatments.
Topics: Humans; Purkinje Cells; Spinocerebellar Ataxias; Calcium Signaling
PubMed: 38444133
DOI: No ID Found -
ACS Omega Feb 2024Vitamin C was examined to ameliorate the neurotoxicity of thimerosal (THIM) in an animal model (Wistar albino rats). In our work, oxidative and antioxidative biomarkers...
Vitamin C was examined to ameliorate the neurotoxicity of thimerosal (THIM) in an animal model (Wistar albino rats). In our work, oxidative and antioxidative biomarkers such as SOD, LPO, and GSH were investigated at various doses of THIM with or without concurrent vitamin C administration. Furthermore, the adverse effects of THIM on hepatic tissue and cerebral cortex morphology were examined in the absence or presence of associated vitamin C administration. Also, we studied the effect of vitamin C on the metallothionein isoforms (MT-1, MT-2, and MT-3) and using the RT-PCR assay. The results showed that the antioxidant biomarker was reduced as the THIM dose was raised and vice versa. THIM-associated vitamin C reduced the adverse effects of the THIM dose. The computation studies demonstrated that vitamin C has a lower Δ of -4.9 kcal/mol compared to -4.1 kcal/mol for THIM to bind to the MT-2 protein, which demonstrated that vitamin C has a greater ability to bind with MT-2 than THIM. This is due to multiple hydrogen bonds that exist between vitamin C and MT-2 residues Lys31, Gln23, Cys24, and Cys29, and the sodium ion represents key stabilizing interactions. Hydrogen bonds involve electrostatic interactions between hydrogen atom donors (, hydroxyl groups) and acceptors (, carbonyl oxygens). The distances between heavy atoms are typically 2.5-3.5 Å. H-bonds provide directed, high-affinity interactions to anchor the ligand to the binding site. The five H-bonds formed by vitamin C allow it to form a stable complex with MT, while THIM can form two H-bonds with Gln23 and Cys24. This provides less stabilization in the binding pocket, contributing to the lower affinity compared to vitamin C. The histopathological morphologies in hepatic tissue displayed an expansion in the portal tract and the hepatocytes surrounding the portal tract, including apoptosis, binucleation, and karyomegaly. The histopathological morphologies in the brain tissue revealed a significant decrease in the number of Purkinje cells due to THIM toxicity. Interestingly, THIM toxicity was associated with hemorrhage and astrogliosis. Both intracellular and vasogenic edema appeared as the concentrations of THIM rose. Finally, vitamin C ameliorated the adverse effect on the cerebral cortex in Wistar albino rats.
PubMed: 38434836
DOI: 10.1021/acsomega.3c07239 -
Frontiers in Cellular Neuroscience 2024Protein kinase C γ (PKCγ), a neuronal isoform present exclusively in the central nervous system, is most abundantly expressed in cerebellar Purkinje cells (PCs)....
Protein kinase C γ (PKCγ), a neuronal isoform present exclusively in the central nervous system, is most abundantly expressed in cerebellar Purkinje cells (PCs). Targeted deletion of PKCγ causes a climbing fiber synapse elimination in developing PCs and motor deficit. However, physiological roles of PKCγ in adult mouse PCs are little understood. In this study, we aimed to unravel the roles of PKCγ in mature mouse PCs by deleting PKCγ from adult mouse PCs of PKCγ mice via cerebellar injection of adeno-associated virus (AAV) vectors expressing Cre recombinase under the control of the PC-specific L7-6 promoter. Whole cell patch-clamp recording of PCs showed higher intrinsic excitability in PCs virally lacking PKCγ [PKCγ-conditional knockout (PKCγ-cKO) PCs] than in wild-type (WT) mouse PCs in the zebrin-negative module, but not in the zebrin-positive module. AAV-mediated PKCγ re-expression in PKCγ-deficient mouse PCs in the zebrin-negative module restored the enhanced intrinsic excitability to a level comparable to that of wild-type mouse PCs. In parallel with higher intrinsic excitability, we found larger hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents in PKCγ-cKO PCs located in the zebrin-negative module, compared with those in WT mouse PCs in the same region. However, pharmacological inhibition of the HCN currents did not restore the enhanced intrinsic excitability in PKCγ-cKO PCs in the zebrin-negative module. These results suggested that PKCγ suppresses the intrinsic excitability in zebrin-negative PCs, which is likely independent of the HCN current inhibition.
PubMed: 38433862
DOI: 10.3389/fncel.2024.1349878 -
Cell Discovery Feb 2024Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial...
Human cerebellum encompasses numerous neurons, exhibiting a distinct developmental paradigm from cerebrum. Here we conducted scRNA-seq, scATAC-seq and spatial transcriptomic analyses of fetal samples from gestational week (GW) 13 to 18 to explore the emergence of cellular diversity and developmental programs in the developing human cerebellum. We identified transitory granule cell progenitors that are conserved across species. Special patterns in both granule cells and Purkinje cells were dissected multidimensionally. Species-specific gene expression patterns of cerebellar lobes were characterized and we found that PARM1 exhibited inconsistent distribution in human and mouse granule cells. A novel cluster of potential neuroepithelium at the rhombic lip was identified. We also resolved various subtypes of Purkinje cells and unipolar brush cells and revealed gene regulatory networks controlling their diversification. Therefore, our study offers a valuable multi-omics landscape of human fetal cerebellum and advances our understanding of development and spatial organization of human cerebellum.
PubMed: 38409116
DOI: 10.1038/s41421-024-00656-1 -
BioRxiv : the Preprint Server For... Feb 2024Prairie voles () and Syrian, or golden, hamsters () are closely related to mice () and rats (, for example) and are commonly used in studies of social behavior including...
Prairie voles () and Syrian, or golden, hamsters () are closely related to mice () and rats (, for example) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. The CA2 region of the hippocampus is known to play a key role in social memory and aggression in mice and responds to social stimuli in rats, likely owing to its high expression of oxytocin and vasopressin 1b receptors. However, CA2 has yet to be identified and characterized in hamsters or voles. In this study, we sought to determine whether CA2 could be identified molecularly in vole and hamster. To do this, we used immunofluorescence with primary antibodies raised against known molecular markers of CA2 in mice and rats to stain hippocampal sections from voles and hamsters in parallel with those from mice. Here, we report that, like in mouse and rat, staining for many CA2 proteins in vole and hamster hippocampus reveals a population of neurons that express regulator of G protein signaling 14 (RGS14), Purkinje cell protein 4 (PCP4) and striatal-enriched protein tyrosine phosphatase (STEP), which together delineate the borders with CA3 and CA1. These cells were located at the distal end of the mossy fiber projections, marked by the presence of Zinc Transporter 3 (ZnT-3) and calbindin in all three species. In addition to staining the mossy fibers, calbindin also labeled a layer of CA1 pyramidal cells in mouse and hamster but not in vole. However, Wolframin ER transmembrane glycoprotein (WFS1) immunofluorescence, which marks all CA1 neurons, was present in all three species and abutted the distal end of CA2, marked by RGS14 immunofluorescence. Staining for two stress hormone receptors-the glucocorticoid (GR) and mineralocorticoid (MR) receptors-was also similar in all three species, with GR staining found primarily in CA1 and MR staining enriched in CA2. Interestingly, although perineuronal nets (PNNs) are known to surround CA2 cells in mouse and rat, we found that staining for PNNs differed across species in that both CA2 and CA3 showed staining in voles and primarily CA3 in hamsters with only some neurons in proximal CA2 showing staining. These results demonstrate that, like in mouse, CA2 in voles and hamsters can be molecularly distinguished from neighboring CA1 and CA3 areas, but PNN staining is less useful for identifying CA2 in the latter two species. These findings reveal commonalities across species in molecular profile of CA2, which will facilitate future studies of CA2 in these species. Yet to be determined is how differences in PNNs might relate to differences in social behavior across species.
PubMed: 38405991
DOI: 10.1101/2024.02.12.579957 -
BioRxiv : the Preprint Server For... Feb 2024Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje...
Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic duplication with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties, and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional knockout (KO and cKO, respectively) mouse lines. KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in cKO animals. By Golgi staining, KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrates a significant increase in Bergmann glia volume in the molecular layer of KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.
PubMed: 38405978
DOI: 10.1101/2024.02.18.580354 -
BioRxiv : the Preprint Server For... Feb 2024We identified a novel variant, E171Q, in a neonate with very frequent ectopy and reduced ejection fraction which normalized after arrhythmia suppression by flecainide....
BACKGROUND
We identified a novel variant, E171Q, in a neonate with very frequent ectopy and reduced ejection fraction which normalized after arrhythmia suppression by flecainide. This clinical picture is consistent with multifocal ectopic Purkinje-related premature contractions (MEPPC). Most previous reports of MEPPC have implicated variants such as R222Q that neutralize positive charges in the S4 voltage sensor helix of the channel protein Na1.5 and generate a gating pore current.
METHODS AND RESULTS
E171 is a highly conserved negatively-charged residue located in the S2 transmembrane helix of Na1.5 domain I. E171 is a key component of the Gating Charge Transfer Center, a region thought to be critical for normal movement of the S4 voltage sensor helix. We used heterologous expression, CRISPR-edited induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and molecular dynamics simulations to demonstrate that E171Q generates a gating pore current, which was suppressed by a low concentration of flecainide (IC50 = 0.71±0.07 µM). R222Q shifts voltage dependence of activation and inactivation in a negative direction but we observed positive shifts with E171Q. E171Q iPSC-CMs demonstrated abnormal spontaneous activity and prolonged action potentials. Molecular dynamics simulations revealed that both R222Q and E171Q proteins generate a water-filled permeation pathway that underlies generation of the gating pore current.
CONCLUSION
Previously identified MEPPC-associated variants that create gating pore currents are located in positively-charged residues in the S4 voltage sensor and generate negative shifts in the voltage dependence of activation and inactivation. We demonstrate that neutralizing a negatively charged S2 helix residue in the Gating Charge Transfer Center generates positive shifts but also create a gating pore pathway. These findings implicate the gating pore pathway as the primary functional and structural determinant of MEPPC and widen the spectrum of variants that are associated with gating pore-related disease in voltage-gated ion channels.
PubMed: 38405820
DOI: 10.1101/2024.02.13.580021