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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 -
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 -
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 -
BMC Veterinary Research Jun 2024Neurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is...
BACKGROUND
Neurological inherited disorders are rare in domestic animals. Cerebellar cortical degeneration remains amongst the most common of these disorders. The condition is defined as the premature loss of fully differentiated cerebellar components due to genetic or metabolic defects. It has been studied in dogs and cats, and various genetic defects and diagnostic tests (including magnetic resonance imaging (MRI)) have been refined in these species. Cases in cats remain rare and mostly individual, and few diagnostic criteria, other than post-mortem exam, have been evaluated in reports with multiple cases. Here, we report three feline cases of cerebellar cortical degeneration with detailed clinical, diagnostic imaging and post-mortem findings.
CASE PRESENTATION
The three cases were directly (siblings, case #1 and #2) or indirectly related (same farm, case #3) and showed early-onset of the disease, with clinical signs including cerebellar ataxia and tremors. Brain MRI was highly suggestive of cerebellar cortical degeneration on all three cases. The relative cerebrospinal fluid (CSF) space, relative cerebellum size, brainstem: cerebellum area ratio, and cerebellum: total brain area ratio, were measured and compared to a control group of cats and reference cut-offs for dogs in the literature. For the relative cerebellum size and cerebellum: total brain area ratio, all affected cases had a lower value than the control group. For the relative CSF space and brainstem: cerebellum area ratio, the more affected cases (#2 and #3) had higher values than the control group, while the least affected case (#3) had values within the ranges of the control group, but a progression was visible over time. Post-mortem examination confirmed the diagnosis of cerebellar cortical degeneration, with marked to complete loss of Purkinje cells and associated granular layer depletion and proliferation of Bergmann glia. One case also had Wallerian-like degeneration in the spinal cord, suggestive of spinocerebellar degeneration.
CONCLUSION
Our report further supports a potential genetic component for the disease in cats. For the MRI examination, the relative cerebellum size and cerebellum: total brain area ratio seem promising, but further studies are needed to establish specific feline cut-offs. Post-mortem evaluation of the cerebellum remains the gold standard for the final diagnosis.
Topics: Animals; Cats; Cat Diseases; Male; Magnetic Resonance Imaging; Female; Cerebellar Cortex; Cerebellum
PubMed: 38890680
DOI: 10.1186/s12917-024-04127-3 -
Frontiers in Endocrinology 2024Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However,...
Food intake behavior is under the tight control of the central nervous system. Most studies to date focus on the contribution of neurons to this behavior. However, although previously overlooked, astrocytes have recently been implicated to play a key role in feeding control. Most of the recent literature has focused on astrocytic contribution in the hypothalamus or the dorsal vagal complex. The contribution of astrocytes located in the lateral parabrachial nucleus (lPBN) to feeding behavior control remains poorly understood. Thus, here, we first investigated whether activation of lPBN astrocytes affects feeding behavior in male and female rats using chemogenetic activation. Astrocytic activation in the lPBN led to profound anorexia in both sexes, under both feeding schedule and after a fasting challenge. Astrocytes have a key contribution to glutamate homeostasis and can themselves release glutamate. Moreover, lPBN glutamate signaling is a key contributor to potent anorexia, which can be induced by lPBN activation. Thus, here, we determined whether glutamate signaling is necessary for lPBN astrocyte activation-induced anorexia, and found that pharmacological N-methyl D-aspartate (NMDA) receptor blockade attenuated the food intake reduction resulting from lPBN astrocyte activation. Since astrocytes have been shown to contribute to feeding control by modulating the feeding effect of peripheral feeding signals, we further investigated whether lPBN astrocyte activation is capable of modulating the anorexic effect of the gut/brain hormone, glucagon like peptide -1, as well as the orexigenic effect of the stomach hormone - ghrelin, and found that the feeding effect of both signals is modulated by lPBN astrocytic activation. Lastly, we found that lPBN astrocyte activation-induced anorexia is affected by a diet-induced obesity challenge, in a sex-divergent manner. Collectively, current findings uncover a novel role for lPBN astrocytes in feeding behavior control.
Topics: Animals; Astrocytes; Male; Female; Rats; Eating; Parabrachial Nucleus; Anorexia; Feeding Behavior; Rats, Sprague-Dawley; Glutamic Acid; Receptors, N-Methyl-D-Aspartate
PubMed: 38887265
DOI: 10.3389/fendo.2024.1389589 -
CNS Neuroscience & Therapeutics Jun 2024In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In absence of drug therapy options, standard treatment for spinocerebellar ataxia consists of symptomatic physiotherapy and speech therapy. New therapeutic options are urgently needed. Transcranial magnetic stimulation is a promising therapeutic option, but applicability is limited by lengthy duration of stimulation protocols.
METHODS
In this randomized sham controlled clinical trial, patients were assigned to verum (n = 15) or sham (n = 18) cerebellar transcranial magnetic stimulation. To yield best possible treatment effects, both intervention groups received intensified physiotherapy for the duration of the study.
RESULTS
Ataxia severity was reduced by 1.6 points on the Scale for assessment and Rating of Ataxia among patients in the verum group (p < 0.001). Clinical improvement was significantly larger in the verum group, compared to the sham group (p < 0.01). The treatment effect was mainly carried by improved appendicular coordination. Patients in the verum group also significantly improved in the 8 Meter Walk Test (p < 0.05) and PATA rate (p < 0.01).
CONCLUSIONS
Cerebellar rTMS ameliorates ataxia severity in patient with spinocerebellar ataxia. Condensing treatment duration to only 5 days without reduction of treatment effects facilitates applicability and therefore broadens availability to larger patient populations.
Topics: Humans; Spinocerebellar Ataxias; Male; Female; Transcranial Magnetic Stimulation; Middle Aged; Adult; Cerebellum; Physical Therapy Modalities; Treatment Outcome; Combined Modality Therapy; Aged; Severity of Illness Index
PubMed: 38887169
DOI: 10.1111/cns.14797 -
Alzheimer's Research & Therapy Jun 2024Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a...
BACKGROUND
Autopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer's disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine's neuroprotective effects, potentially compromising the neuronal integrity of LC's cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.
METHODS
A total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.
RESULTS
Across the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.
CONCLUSIONS
Our findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.
Topics: Humans; Locus Coeruleus; Female; Alzheimer Disease; Male; Aged; Magnetic Resonance Imaging; tau Proteins; Aged, 80 and over; Cohort Studies; Amyloid beta-Peptides; Positron-Emission Tomography; Cerebral Cortex; Carbolines; Thiazoles; Aniline Compounds; Brain Cortical Thickness
PubMed: 38886798
DOI: 10.1186/s13195-024-01500-0