-
Advances in Experimental Medicine and... 2024Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent... (Review)
Review
Temporal information processing in the range of a few hundred milliseconds to seconds involves the cerebellum and basal ganglia. In this chapter, we present recent studies on nonhuman primates. In the studies presented in the first half of the chapter, monkeys were trained to make eye movements when a certain amount of time had elapsed since the onset of the visual cue (time production task). The animals had to report time lapses ranging from several hundred milliseconds to a few seconds based on the color of the fixation point. In this task, the saccade latency varied with the time length to be measured and showed stochastic variability from one trial to the other. Trial-to-trial variability under the same conditions correlated well with pupil diameter and the preparatory activity in the deep cerebellar nuclei and the motor thalamus. Inactivation of these brain regions delayed saccades when asked to report subsecond intervals. These results suggest that the internal state, which changes with each trial, may cause fluctuations in cerebellar neuronal activity, thereby producing variations in self-timing. When measuring different time intervals, the preparatory activity in the cerebellum always begins approximately 500 ms before movements, regardless of the length of the time interval being measured. However, the preparatory activity in the striatum persists throughout the mandatory delay period, which can be up to 2 s, with different rate of increasing activity. Furthermore, in the striatum, the visual response and low-frequency oscillatory activity immediately before time measurement were altered by the length of the intended time interval. These results indicate that the state of the network, including the striatum, changes with the intended timing, which lead to different time courses of preparatory activity. Thus, the basal ganglia appear to be responsible for measuring time in the range of several hundred milliseconds to seconds, whereas the cerebellum is responsible for regulating self-timing variability in the subsecond range. The second half of this chapter presents studies related to periodic timing. During eye movements synchronized with alternating targets at regular intervals, different neurons in the cerebellar nuclei exhibit activity related to movement timing, predicted stimulus timing, and the temporal error of synchronization. Among these, the activity associated with target appearance is particularly enhanced during synchronized movements and may represent an internal model of the temporal structure of stimulus sequence. We also considered neural mechanism underlying the perception of periodic timing in the absence of movement. During perception of rhythm, we predict the timing of the next stimulus and focus our attention on that moment. In the missing oddball paradigm, the subjects had to detect the omission of a regularly repeated stimulus. When employed in humans, the results show that the fastest temporal limit for predicting each stimulus timing is about 0.25 s (4 Hz). In monkeys performing this task, neurons in the cerebellar nuclei, striatum, and motor thalamus exhibit periodic activity, with different time courses depending on the brain region. Since electrical stimulation or inactivation of recording sites changes the reaction time to stimulus omission, these neuronal activities must be involved in periodic temporal processing. Future research is needed to elucidate the mechanism of rhythm perception, which appears to be processed by both cortico-cerebellar and cortico-basal ganglia pathways.
Topics: Animals; Cerebellum; Basal Ganglia; Time Perception; Saccades; Time Factors; Humans
PubMed: 38918348
DOI: 10.1007/978-3-031-60183-5_6 -
PloS One 2024Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation of inspiratory neurons in the...
Orexin receptor 2 agonist activates diaphragm and genioglossus muscle through stimulating inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons in rodents.
Orexin-mediated stimulation of orexin receptors 1/2 (OX[1/2]R) may stimulate the diaphragm and genioglossus muscle via activation of inspiratory neurons in the pre-Bötzinger complex, which are critical for the generation of inspiratory rhythm, and phrenic and hypoglossal motoneurons. Herein, we assessed the effects of OX2R-selective agonists TAK-925 (danavorexton) and OX-201 on respiratory function. In in vitro electrophysiologic analyses using rat medullary slices, danavorexton and OX-201 showed tendency and significant effect, respectively, in increasing the frequency of inspiratory synaptic currents of inspiratory neurons in the pre-Bötzinger complex. In rat medullary slices, both danavorexton and OX-201 significantly increased the frequency of inspiratory synaptic currents of hypoglossal motoneurons. Danavorexton and OX-201 also showed significant effect and tendency, respectively, in increasing the frequency of burst activity recorded from the cervical (C3-C5) ventral root, which contains axons of phrenic motoneurons, in in vitro electrophysiologic analyses from rat isolated brainstem-spinal cord preparations. Electromyogram recordings revealed that intravenous administration of OX-201 increased burst frequency of the diaphragm and burst amplitude of the genioglossus muscle in isoflurane- and urethane-anesthetized rats, respectively. In whole-body plethysmography analyses, oral administration of OX-201 increased respiratory activity in free-moving mice. Overall, these results suggest that OX2R-selective agonists enhance respiratory function via activation of the diaphragm and genioglossus muscle through stimulation of inspiratory neurons in the pre-Bötzinger complex, and phrenic and hypoglossal motoneurons. OX2R-selective agonists could be promising drugs for various conditions with respiratory dysfunction.
Topics: Animals; Diaphragm; Motor Neurons; Orexin Receptors; Rats; Phrenic Nerve; Mice; Male; Hypoglossal Nerve; Rats, Sprague-Dawley; Inhalation; Medulla Oblongata; Isoquinolines; Pyridines
PubMed: 38917189
DOI: 10.1371/journal.pone.0306099 -
Cell Jun 2024Somatic and sympathetic tones fluctuate together seamlessly across daily behaviors. In this issue of Cell, Zhang et al. describe populations of spinal projecting...
Somatic and sympathetic tones fluctuate together seamlessly across daily behaviors. In this issue of Cell, Zhang et al. describe populations of spinal projecting neurons in the rostral ventromedial medulla (rVMM) that harmonize somatic motor function and sympathetic activation. The coordinated regulation plays a vital role in supporting behaviors associated with various arousal states.
Topics: Animals; Medulla Oblongata; Brain Stem; Autonomic Nervous System; Neurons; Humans; Sympathetic Nervous System; Arousal
PubMed: 38906100
DOI: 10.1016/j.cell.2024.05.019 -
Medicine Jun 2024This study aimed to characterize the risk factors, etiology, clinical manifestations, anatomical characteristics, stroke mechanisms, imaging features, and prognosis of... (Observational Study)
Observational Study
This study aimed to characterize the risk factors, etiology, clinical manifestations, anatomical characteristics, stroke mechanisms, imaging features, and prognosis of bilateral medial medullary infarction (BMMI). A retrospective analysis was conducted on 11 patients with BMMI who met the inclusion criteria at the Affiliated Hospital of Xuzhou Medical University from January 2013 to January 2023. The patients' imaging and clinical features were analyzed and summarized. Eleven patients (7 male, 4 female), aged 46 to 62 years, met the inclusion criteria. Common clinical presentations included dysarthria (90.9%), dysphagia (90.9%), quadriplegia (81.8%), and so on. Within 72 hours of onset, 8 cases presented with quadriplegia, 2 cases with hemiplegia, and 1 case without limb paralysis. The main risk factor for BMMI was hypertension, followed by diabetes. "Heart appearance" infarcts occurred in 4 cases (36.4%), while "Y appearance" infarcts occurred in 7 cases (63.6%). Among the patients, 3 had unilateral vertebral artery stenosis or occlusion, 5 had bilateral vertebral artery stenosis or occlusion, 2 had normal vertebral basilar artery, and 1 did not undergo cerebrovascular examination. All patients received standardized treatment for cerebral infarction. The prognosis was poor, with 81.8% of patients having an unfavorable outcome, including 1 death, 9 cases of disability, and only 1 patient achieving self-care ability after recovery. BMMI is more prevalent in males aged 45 to 60 years. The main risk factors are hypertension and diabetes. Atherosclerosis is the primary etiological subtype. The main clinical manifestations are dyskinesia, dizziness, quadriplegia, and dysarthria. The prognosis of BMMI is poor. The specific imaging features of "heart appearance" or "Y appearance" infarcts aid in the diagnosis of BMMI.
Topics: Humans; Male; Female; Middle Aged; Retrospective Studies; Medulla Oblongata; Brain Stem Infarctions; Risk Factors; Prognosis; Quadriplegia; Hypertension
PubMed: 38905383
DOI: 10.1097/MD.0000000000038336 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2024The locus coeruleus-norepinephrine system plays a key role in supporting brain health along the lifespan, notably through its modulatory effects on neuroinflammation....
The locus coeruleus-norepinephrine system plays a key role in supporting brain health along the lifespan, notably through its modulatory effects on neuroinflammation. Using ultra-high field diffusion magnetic resonance imaging, we examined whether microstructural properties (neurite density index and orientation dispersion index) in the locus coeruleus were related to those in cortical and subcortical regions, and whether this was modulated by plasma glial fibrillary acidic protein levels, as a proxy of astrocyte reactivity. In our cohort of 60 healthy individuals (30 to 85 yr, 50% female), higher glial fibrillary acidic protein correlated with lower neurite density index in frontal cortical regions, the hippocampus, and the amygdala. Furthermore, under higher levels of glial fibrillary acidic protein (above ~ 150 pg/mL for cortical and ~ 145 pg/mL for subcortical regions), lower locus coeruleus orientation dispersion index was associated with lower orientation dispersion index in frontotemporal cortical regions and in subcortical regions. Interestingly, individuals with higher locus coeruleus orientation dispersion index exhibited higher orientation dispersion index in these (sub)cortical regions, despite having higher glial fibrillary acidic protein levels. Together, these results suggest that the interaction between locus coeruleus-norepinephrine cells and astrocytes can signal a detrimental or neuroprotective pathway for brain integrity and support the importance of maintaining locus coeruleus neuronal health in aging and in the prevention of age-related neurodegenerative diseases.
Topics: Humans; Female; Male; Locus Coeruleus; Astrocytes; Aged; Middle Aged; Adult; Aged, 80 and over; Glial Fibrillary Acidic Protein; Magnetic Resonance Imaging; Cerebral Cortex; Brain; Diffusion Magnetic Resonance Imaging; Neurites
PubMed: 38904081
DOI: 10.1093/cercor/bhae261 -
Neurology Jul 2024Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar...
BACKGROUND AND OBJECTIVES
Amyotrophic lateral sclerosis (ALS) is predominantly associated with motor cortex, corticospinal tract (CST), brainstem, and spinal cord degeneration, and cerebellar involvement is much less well characterized. However, some of the cardinal clinical features of ALS, such as dysarthria, dysphagia, gait impairment, falls, and impaired dexterity, are believed to be exacerbated by coexisting cerebellar pathology. Cerebellar pathology may also contribute to cognitive, behavioral, and pseudobulbar manifestations. Our objective was to systematically assess both intracerebellar pathology and cerebrocerebellar connectivity alterations in a genetically stratified cohort of ALS.
METHODS
A prospective, multimodal neuroimaging study was conducted to evaluate the longitudinal evolution of intracerebellar pathology and cerebrocerebellar connectivity, using structural and functional measures.
RESULTS
A total of 113 healthy controls and 212 genetically stratified individuals with ALS were included: (1) hexanucleotide carriers ("C9POS"), (2) sporadic patients who tested negative for ALS-associated genetic variants, and (3) intermediate-length CAG trinucleotide carriers in ("ATXN2"). Flocculonodular lobule ( = 0.014, 95% CI -5.06e-5 to -3.98e-6) and crura ( = 0.031, 95% CI -1.63e-3 to -5.55e-5) volume reductions were detected at baseline in sporadic patients. Cerebellofrontal and cerebelloparietal structural connectivity impairment was observed in both C9POS and sporadic patients at baseline, and both projections deteriorated further over time in sporadic patients ( = 0.003, (249) = 3.04 and = 0.05, (249) = 1.93). Functional cerebelloparietal uncoupling was evident in sporadic patients at baseline ( = 0.004, 95% CI -0.19 to -0.03). ATXN2 patients exhibited decreased cerebello-occipital functional connectivity at baseline ( = 0.004, 95% CI -0.63 to -0.06), progressive cerebellotemporal functional disconnection ( = 0.025, (199) = -2.26), and progressive flocculonodular lobule degeneration ( = 0.017, (249) = -2.24). C9POS patients showed progressive ventral dentate atrophy ( = 0.007, (249) = -2.75). The CSTs ( < 0.001, 95% CI 4.89e-5 to 1.14e-4) and transcallosal interhemispheric fibers ( < 0.001, 95% CI 5.21e-5 to 1.31e-4) were affected at baseline in C9POS and exhibited rapid degeneration over the 4 time points. The rate of decline in CST and corpus callosum integrity was faster than the rate of cerebrocerebellar disconnection ( = 0.001, (190) = 6.93).
DISCUSSION
ALS is associated with accruing intracerebellar disease burden as well as progressive corticocerebellar uncoupling. Contrary to previous suggestions, we have not detected evidence of compensatory structural or functional changes in response to supratentorial degeneration. The contribution of cerebellar disease burden to dysarthria, dysphagia, gait impairment, pseudobulbar affect, and cognitive deficits should be carefully considered in clinical assessments, monitoring, and multidisciplinary interventions.
Topics: Humans; Amyotrophic Lateral Sclerosis; Male; Female; Middle Aged; Cerebellum; Aged; C9orf72 Protein; Prospective Studies; Ataxin-2; Magnetic Resonance Imaging; Disease Progression; Cerebral Cortex; Adult; Longitudinal Studies
PubMed: 38900989
DOI: 10.1212/WNL.0000000000209623 -
PloS One 2024Neurons of the lateral superior olive (LSO) in the auditory brainstem play a fundamental role in binaural sound localization. Previous theoretical studies developed...
Neurons of the lateral superior olive (LSO) in the auditory brainstem play a fundamental role in binaural sound localization. Previous theoretical studies developed various types of neuronal models to study the physiological functions of the LSO. These models were usually tuned to a small set of physiological data with specific aims in mind. Therefore, it is unclear whether and how they can be related to each other, how widely applicable they are, and which model is suitable for what purposes. In this study, we address these questions for six different single-compartment integrate-and-fire (IF) type LSO models. The models are divided into two groups depending on their subthreshold responses: passive (linear) models with only the leak conductance and active (nonlinear) models with an additional low-voltage-activated potassium conductance that is prevalent among the auditory system. Each of these two groups is further subdivided into three subtypes according to the spike generation mechanism: one with simple threshold-crossing detection and voltage reset, one with threshold-crossing detection plus a current to mimic spike shapes, and one with a depolarizing exponential current for spiking. In our simulations, all six models were driven by identical synaptic inputs and calibrated with common criteria for binaural tuning. The resulting spike rates of the passive models were higher for intensive inputs and lower for temporally structured inputs than those of the active models, confirming the active function of the potassium current. Within each passive or active group, the simulated responses resembled each other, regardless of the spike generation types. These results, in combination with the analysis of computational costs, indicate that an active IF model is more suitable than a passive model for accurately reproducing temporal coding of LSO. The simulation of realistic spike shapes with an extended spiking mechanism added relatively small computational costs.
Topics: Models, Neurological; Superior Olivary Complex; Action Potentials; Neurons; Humans; Computer Simulation; Olivary Nucleus; Animals; Sound Localization
PubMed: 38900820
DOI: 10.1371/journal.pone.0304832 -
Science Advances Jun 2024Mutations in the transcription factors encoded by or correlate with congenital central hypoventilation disorders. These conditions are typically characterized by...
Mutations in the transcription factors encoded by or correlate with congenital central hypoventilation disorders. These conditions are typically characterized by pronounced hypoventilation, central apnea, and diminished chemoreflexes, particularly to abnormally high levels of arterial PCO. The dysfunctional neurons causing these respiratory disorders are largely unknown. Here, we show that distinct, and previously undescribed, sets of medullary neurons coexpressing both transcription factors (dB2 neurons) account for specific respiratory functions and phenotypes seen in congenital hypoventilation. By combining intersectional chemogenetics, intersectional labeling, lineage tracing, and conditional mutagenesis, we uncovered subgroups of dB2 neurons with key functions in (i) respiratory tidal volumes, (ii) the hypercarbic reflex, (iii) neonatal respiratory stability, and (iv) neonatal survival. These data provide functional evidence for the critical role of distinct medullary dB2 neurons in neonatal respiratory physiology. In summary, our work identifies distinct subgroups of dB2 neurons regulating breathing homeostasis, dysfunction of which causes respiratory phenotypes associated with congenital hypoventilation.
Topics: Hypoventilation; Animals; Neurons; Homeodomain Proteins; Mice; Transcription Factors; Medulla Oblongata; Sleep Apnea, Central; Phenotype; Humans
PubMed: 38896627
DOI: 10.1126/sciadv.adj0720 -
International Journal of Molecular... May 2024A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in...
Differential Roles of Key Brain Regions: Ventral Tegmental Area, Locus Coeruleus, Dorsal Raphe, Nucleus Accumbens, Caudate Nucleus, and Prefrontal Cortex in Regulating Response to Methylphenidate: Insights from Neuronal and Behavioral Studies in Freely Behaving Rats.
A total of 3102 neurons were recorded before and following acute and chronic methylphenidate (MPD) administration. Acute MPD exposure elicits mainly increases in neuronal and behavioral activity in dose-response characteristics. The response to chronic MPD exposure, as compared to acute 0.6, 2.5, or 10.0 mg/kg MPD administration, elicits electrophysiological and behavioral sensitization in some animals and electrophysiological and behavioral tolerance in others when the neuronal recording evaluations were performed based on the animals' behavioral responses, or amount of locomotor activity, to chronic MPD exposure. The majority of neurons recorded from those expressing behavioral sensitization responded to chronic MPD with further increases in firing rate as compared to the initial MPD responses. The majority of neurons recorded from animals expressing behavioral tolerance responded to chronic MPD with decreases in their firing rate as compared to the initial MPD exposures. Each of the six brain areas studied-the ventral tegmental area, locus coeruleus, dorsal raphe, nucleus accumbens, prefrontal cortex, and caudate nucleus (VTA, LC, DR, NAc, PFC, and CN)-responds significantly ( < 0.001) differently to MPD, suggesting that each one of the above brain areas exhibits different roles in the response to MPD. Moreover, this study demonstrates that it is essential to evaluate neuronal activity responses to psychostimulants based on the animals' behavioral responses to acute and chronic effects of the drug from several brain areas simultaneously to obtain accurate information on each area's role in response to the drug.
Topics: Animals; Methylphenidate; Prefrontal Cortex; Rats; Neurons; Caudate Nucleus; Male; Ventral Tegmental Area; Nucleus Accumbens; Behavior, Animal; Locus Coeruleus; Rats, Sprague-Dawley; Dorsal Raphe Nucleus; Central Nervous System Stimulants
PubMed: 38892125
DOI: 10.3390/ijms25115938 -
International Journal of Molecular... May 2024The central nervous system of Pacific salmon retains signs of embryonic structure throughout life and a large number of neuroepithelial neural stem cells (NSCs) in the...
The central nervous system of Pacific salmon retains signs of embryonic structure throughout life and a large number of neuroepithelial neural stem cells (NSCs) in the proliferative areas of the brain, in particular. However, the adult nervous system and neurogenesis studies on rainbow trout, , are limited. Here, we studied the localization of glutamine synthetase (GS), vimentin (Vim), and nestin (Nes), as well as the neurons formed in the postembryonic period, labeled with doublecortin (DC), under conditions of homeostatic growth in adult cerebellum and brainstem of using immunohistochemical methods and Western Immunoblotting. We observed that the distribution of vimentin (Vim), nestin (Nes), and glutamine synthetase (GS), which are found in the aNSPCs of both embryonic types (neuroepithelial cells) and in the adult type (radial glia) in the cerebellum and the brainstem of trout, has certain features. Populations of the adult neural stem/progenitor cells (aNSPCs) expressing GS, Vim, and Nes have different morphologies, localizations, and patterns of cluster formation in the trout cerebellum and brainstem, which indicates the morphological and, obviously, functional heterogeneity of these cells. Immunolabeling of PCNA revealed areas in the cerebellum and brainstem of rainbow trout containing proliferating cells which coincide with areas expressing Vim, Nes, and GS. Double immunolabeling revealed the PCNA/GS PCNA/Vim coexpression patterns in the neuroepithelial-type cells in the PVZ of the brainstem. PCNA/GS coexpression in the RG was detected in the submarginal zone of the brainstem. The results of immunohistochemical study of the DC distribution in the cerebellum and brainstem of trout have showed a high level of expression of this marker in various cell populations. This may indicate: (i) high production of the adult-born neurons in the cerebellum and brainstem of adult trout, (ii) high plasticity of neurons in the cerebellum and brainstem of trout. We assume that the source of new cells in the trout brain, along with PVZ and SMZ, containing proliferating cells, may be local neurogenic niches containing the PCNA-positive and silent (PCNA-negative), but expressing NSC markers, cells. The identification of cells expressing DC, Vim, and Nes in the IX-X cranial nerve nuclei of trout was carried out.
Topics: Animals; Oncorhynchus mykiss; Cerebellum; Neurogenesis; Neuronal Plasticity; Neural Stem Cells; Brain Stem; Vimentin; Neurons; Proliferating Cell Nuclear Antigen; Glutamate-Ammonia Ligase
PubMed: 38891784
DOI: 10.3390/ijms25115595