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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 -
Neurobiology of Disease Mar 2024Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often...
Gait ataxia is one of the most common and impactful consequences of cerebellar dysfunction. Purkinje cells, the sole output neurons of the cerebellar cortex, are often involved in the underlying pathology, but their specific functions during locomotor control in health and disease remain obfuscated. We aimed to describe the effect of gradual adult-onset Purkinje cell degeneration on gaiting patterns in mice, and to determine whether two different mechanisms that both lead to Purkinje cell degeneration cause different patterns in the development of gait ataxia. Using the ErasmusLadder together with a newly developed limb detection algorithm and machine learning-based classification, we subjected mice to a challenging locomotor task with detailed analysis of single limb parameters, intralimb coordination and whole-body movement. We tested two Purkinje cell-specific mouse models, one involving stochastic cell death due to impaired DNA repair mechanisms (Pcp2-Ercc1), the other carrying the mutation that causes spinocerebellar ataxia type 1 (Pcp2-ATXN1[82Q]). Both mouse models showed progressive gaiting deficits, but the sequence with which gaiting parameters deteriorated was different between mouse lines. Our longitudinal approach revealed that gradual loss of Purkinje cell function can lead to a complex pattern of loss of function over time, and that this pattern depends on the specifics of the pathological mechanisms involved. We hypothesize that this variability will also be present in disease progression in patients, and that our findings will facilitate the study of therapeutic interventions in mice, as subtle changes in locomotor abilities can be quantified by our methods.
Topics: Humans; Mice; Animals; Purkinje Cells; Gait Ataxia; Mice, Transgenic; Spinocerebellar Ataxias; Neurons; Cerebellum; Disease Models, Animal
PubMed: 38286390
DOI: 10.1016/j.nbd.2024.106422 -
PLoS Pathogens Aug 2023Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1...
Astroviruses (AstVs) can cause of severe infection of the central nervous system (CNS) in immunocompromised individuals. Here, we identified a human AstV of the VA1 genotype, HAstV-NIH, as the cause of fatal encephalitis in an immunocompromised adult. We investigated the cells targeted by AstV, neurophysiological changes, and host responses by analyzing gene expression, protein expression, and cellular morphology in brain tissue from three cases of AstV neurologic disease (AstV-ND). We demonstrate that neurons are the principal cells targeted by AstV in the brain and that the cerebellum and brainstem have the highest burden of infection. Detection of VA1 AstV in interconnected brain structures such as thalamus, deep cerebellar nuclei, Purkinje cells, and pontine nuclei indicates that AstV may spread between connected neurons transsynaptically. We found transcriptional dysregulation of neural functions and disruption of both excitatory and inhibitory synaptic innervation of infected neurons. Importantly, transcriptional dysregulation of neural functions occurred in fatal cases, but not in a patient that survived AstV-ND. We show that the innate, but not adaptive immune response was transcriptionally driving host defense in the brain of immunocompromised patients with AstV-ND. Both transcriptome and molecular pathology studies showed that most of the cellular changes were associated with CNS-intrinsic cells involved in phagocytosis and injury repair (microglia, perivascular/parenchymal border macrophages, and astrocytes), but not CNS-extrinsic cells (T and B cells), suggesting an imbalance of innate and adaptive immune responses to AstV infection in the brain as a result of the underlying immunodeficiencies. These results show that VA1 AstV infection of the brain in immunocompromised humans is associated with imbalanced host defense responses, disruption of neuronal somatodendritic compartments and synapses and increased phagocytic cellular activity. Improved understanding of the response to viral infections of the human CNS may provide clues for how to manipulate these processes to improve outcomes.
Topics: Adult; Humans; Brain; Central Nervous System; Astroviridae Infections; Neurons; Immunity
PubMed: 37595007
DOI: 10.1371/journal.ppat.1011544 -
Molecular Neurobiology Feb 2024Although uncoupling protein 4 (UCP4) is the most abundant protein reported in the brain, the biological function of UCP4 in cerebellum and pathological outcome of UCP4...
Although uncoupling protein 4 (UCP4) is the most abundant protein reported in the brain, the biological function of UCP4 in cerebellum and pathological outcome of UCP4 deficiency in cerebellum remain obscure. To evaluate the role of Ucp4 in the cerebellar Purkinje cells (PCs), we generated the conditional knockdown of Ucp4 in PCs (Pcp2;Ucp4 mice) by breeding Ucp4 mice with Pcp2 mice. Series results by Western blot, immunofluorescent staining, and triple RNAscope in situ hybridization confirmed the specific ablation of Ucp4 in PCs in Pcp2;Ucp4 mice, but did not affect the expression of Ucp2, the analog of Ucp4. Combined behavioral tests showed that Pcp2;Ucp4 mice displayed a characteristic bradykinesia in the spontaneous movements. The electromyogram recordings detection excluded the possibility of hypotonia in Pcp2;Ucp4 mice. And the electrical patch clamp recordings showed the altered properties of PCs in Pcp2;Ucp4 mice. Moreover, transmission electron microscope (TEM) results showed the increased mitochondrial circularity in PCs; ROS probe imaging showed the increased ROS generation in molecular layer; and finally, microplate reader assay showed the significant changes of mitochondrial functions, including ROS, ATP, and MMP in the isolated cerebellum tissue. The results suggested that the specific knockdown of mitochondrial protein Ucp4 could damage PCs possibly by attacking their mitochondrial function. The present study is the first to report a close relationship between UCP4 deletion with PCs impairment, and suggests the importance of UCP4 in the substantial support of mitochondrial function homeostasis in bradykinesia. UCP4 might be a therapeutic target for the cerebellar-related movement disorder.
Topics: Animals; Mice; Brain; Cerebellum; Hypokinesia; Purkinje Cells; Reactive Oxygen Species
PubMed: 37688710
DOI: 10.1007/s12035-023-03607-1 -
Biophysical Journal Dec 2023Discovered just over 25 years ago in cerebellar Purkinje neurons, resurgent Na current was originally described operationally as a component of voltage-gated Na current... (Review)
Review
Discovered just over 25 years ago in cerebellar Purkinje neurons, resurgent Na current was originally described operationally as a component of voltage-gated Na current that flows upon repolarization from relatively depolarized potentials and speeds recovery from inactivation, increasing excitability. Its presence in many excitable cells and absence from others has raised questions regarding its biophysical and molecular mechanisms. Early studies proposed that Na channels capable of generating resurgent current are subject to a rapid open-channel block by an endogenous blocking protein, which binds upon depolarization and unblocks upon repolarization. Since the time that this mechanism was suggested, many physiological and structural studies of both Na and K channels have revealed aspects of gating and conformational states that provide insights into resurgent current. These include descriptions of domain movements for activation and inactivation, solution of cryo-EM structures with pore-blocking compounds, and identification of native blocking domains, proteins, and modulatory subunits. Such results not only allow the open-channel block hypothesis to be refined but also link it more clearly to research that preceded it. This review considers possible mechanisms for resurgent Na current in the context of earlier and later studies of ion channels and suggests a framework for future research.
PubMed: 38130058
DOI: 10.1016/j.bpj.2023.12.016 -
BioRxiv : the Preprint Server For... Dec 2023Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study collected patients from twelve unrelated families with variants...
Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study collected patients from twelve unrelated families with variants in the gene , a neutral sphingomyelinase which metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These patients have severe developmental brain malformations including microcephaly and cerebellar hypoplasia. However, the mechanism of was not known and we pursued a new mouse model. We hypothesized that the role of in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells exhibit neural progenitor cell death and have shortened primary cilia which is rescued by adding exogenous ceramide. production of ceramide is crucial for human brain development.
PubMed: 38168190
DOI: 10.1101/2023.12.15.571873 -
Frontiers in Physiology 2023In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive...
In addition to gap junction conduction, recent reports implicate possible ephaptic coupling contributions to action potential (AP) propagation between successive adjacent cardiomyocytes. Here, AP generation in an active cell, withdraws Na from, creating a negative potential within, ephaptic spaces between the participating membranes, the initially quiescent neighbouring cardiomyocyte. However, sustainable ephaptic transmission requires subsequent complete of the ephaptic charge difference. We explore physical contributions of passive electrodiffusive ion exchange with the remaining extracellular space to this recovery for the first time. Computational, finite element, analysis examined limiting, temporal and spatial, ephaptic [Na], [Cl], and the consequent Gaussian charge differences and membrane potential recovery patterns following a Δ∼130 mV AP upstroke at physiological (37°C) temperatures. This incorporated Nernst-Planck formalisms into equations for the time-dependent spatial concentration gradient profiles. Mammalian atrial, ventricular and purkinje cardiomyocyte ephaptic junctions were modelled by closely apposed circularly symmetric membranes, specific capacitance 1 μF cm, experimentally reported radii 8,000, 12,000 and 40,000 nm respectively and ephaptic axial distance = 20 nm. This enclosed an ephaptic space containing principal ions initially at normal extracellular [Na] = 153.1 mM and [Cl] = 145.8 mM, respective diffusion coefficients = 1.3 10 and = 2 10 nms. Stable, concordant computational solutions were confirmed exploring ≤1,600 nm mesh sizes and Δ≤0.08 ms stepsize intervals. The corresponding membrane voltage profile changes across the initially quiescent membrane were obtainable from computed, graphically represented and -dependent ionic concentration differences adapting Gauss's flux theorem. Further simulations explored biological variations in ephaptic dimensions, membrane anatomy, and diffusion restrictions within the ephaptic space. Atrial, ventricular and Purkinje cardiomyocytes gave 40, 180 and 2000 ms 99.9% recovery times, with 720 or 360 ms high limits from doubling ventricular radius or halving diffusion coefficient. Varying , and and markedly affected recovery time-courses with logarithmic and double-logarithmic relationships, Varying exerted minimal effects. We thereby characterise the properties of, and through comparing atrial, ventricular and purkinje recovery times with interspecies background cardiac cycle duration data, (blue whale ∼2000, human∼90, Etruscan shrew, ∼40 ms) can determine physical limits to, electrodiffusive contributions to ephaptic recovery.
PubMed: 38235384
DOI: 10.3389/fphys.2023.1280151 -
Communications Biology Oct 2023Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which...
Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV). We have developed a mouse model of mitochondrial dysfunction specifically in PV cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and POLG variants showing PV interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction.
Topics: Mice; Animals; Humans; Parvalbumins; Neurons; Interneurons; Mitochondrial Diseases; Mitochondria
PubMed: 37872380
DOI: 10.1038/s42003-023-05238-7 -
Nature Communications Nov 2023Local feedforward and recurrent connectivity are rife in the frontal areas of the cerebral cortex, which gives rise to rich heterogeneous dynamics observed in such...
Local feedforward and recurrent connectivity are rife in the frontal areas of the cerebral cortex, which gives rise to rich heterogeneous dynamics observed in such areas. Recently, similar local connectivity motifs have been discovered among Purkinje and molecular layer interneurons of the cerebellar cortex, however, task-related activity in these neurons has often been associated with relatively simple facilitation and suppression dynamics. Here, we show that the rodent cerebellar cortex supports heterogeneity in task-related neuronal activity at a scale similar to the cerebral cortex. We provide a computational model that inculcates recent anatomical insights into local microcircuit motifs to show the putative basis for such heterogeneity. We also use cell-type specific chronic viral lesions to establish the involvement of cerebellar lobules in associative learning behaviors. Functional heterogeneity in neuronal profiles may not merely be the remit of the associative cerebral cortex, similar principles may be at play in subcortical areas, even those with seemingly crystalline and homogenous cytoarchitectures like the cerebellum.
Topics: Cerebellar Cortex; Cerebellum; Neurons; Interneurons; Cerebral Cortex; Purkinje Cells
PubMed: 37989740
DOI: 10.1038/s41467-023-43139-9 -
BioRxiv : the Preprint Server For... Jun 2024Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological...
Transcranial direct-current stimulation (tDCS) of the cerebellum is a promising non-invasive neuromodulatory technique being proposed for the treatment of neurological and neuropsychiatric disorders. However, there is a lack of knowledge about how externally applied currents affect neuronal spiking activity in cerebellar circuits . We investigated how Cb-tDCS affects the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex to understand the underlying mechanisms behind the polarity-dependent modulation of neuronal activity induced by tDCS. Mice (n = 9) were prepared for the chronic recording of LFPs to assess the actual electric field gradient imposed by Cb-tDCS in our experimental design. Single-neuron extracellular recording of PCs in awake (n = 24) and anesthetized (n = 27) mice was combined with juxtacellular recordings and subsequent staining of PC with neurobiotin under anesthesia (n = 8) to correlate their neuronal orientation with their response to Cb-tDCS. Finally, a high-density Neuropixels recording system was used to demonstrate the relevance of neuronal orientation during the application of Cb-tDCS in awake mice (n = 6). In this study, we observe that Cb-tDCS induces a heterogeneous polarity-dependent modulation of the firing rate of Purkinje cells (PC) and non-PC in the mouse cerebellar cortex. We demonstrate that the apparently heterogeneous effects of tDCS on PC activity can be explained by taking into account the somatodendritic orientation relative to the electric field. Our findings highlight the need to consider neuronal orientation and morphology to improve tDCS computational models, enhance stimulation protocol reliability, and optimize effects in both basic and clinical applications.
PubMed: 36824866
DOI: 10.1101/2023.02.18.529047