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Alzheimer's Research & Therapy May 2024Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and...
BACKGROUND
Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aβ)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology.
METHODS
142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aβ)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates.
RESULTS
At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity.
CONCLUSIONS
Our findings demonstrate that the LC can provide resilience against Aβ-related attention decline. However, when Aβ accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aβ-related cognitive decline.
Topics: Humans; Female; Male; Alzheimer Disease; Aged; Locus Coeruleus; Magnetic Resonance Imaging; Parietal Lobe; Aged, 80 and over; Attention; Frontal Lobe; Positron-Emission Tomography; Cross-Sectional Studies; Neural Pathways; Cognitive Dysfunction; Neuropsychological Tests
PubMed: 38822365
DOI: 10.1186/s13195-024-01485-w -
Nature Communications May 2024Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic...
Non-synaptic (intrinsic) plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic long-term potentiation or plays a permissive role in determining the impact of synaptic weight increase. We use tactile stimulation and electrical activation of parallel fibers to probe intrinsic and synaptic contributions to receptive field plasticity in awake mice during two-photon calcium imaging of cerebellar Purkinje cells. Repetitive activation of both stimuli induced response potentiation that is impaired in mice with selective deficits in either synaptic or intrinsic plasticity. Spatial analysis of calcium signals demonstrated that intrinsic, but not synaptic plasticity, enhances the spread of dendritic parallel fiber response potentiation. Simultaneous dendrite and axon initial segment recordings confirm these dendritic events affect axonal output. Our findings support the hypothesis that intrinsic plasticity provides an amplification mechanism that exerts a permissive control over the impact of long-term potentiation on neuronal responsiveness.
Topics: Animals; Purkinje Cells; Mice; Neuronal Plasticity; Cerebellum; Long-Term Potentiation; Dendrites; Synapses; Calcium; Male; Axons; Mice, Inbred C57BL; Electric Stimulation; Female
PubMed: 38821918
DOI: 10.1038/s41467-024-48373-3 -
Nature Communications May 2024Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may...
Deep Brain Stimulation can improve tremor, bradykinesia, rigidity, and axial symptoms in patients with Parkinson's disease. Potentially, improving each symptom may require stimulation of different white matter tracts. Here, we study a large cohort of patients (N = 237 from five centers) to identify tracts associated with improvements in each of the four symptom domains. Tremor improvements were associated with stimulation of tracts connected to primary motor cortex and cerebellum. In contrast, axial symptoms are associated with stimulation of tracts connected to the supplementary motor cortex and brainstem. Bradykinesia and rigidity improvements are associated with the stimulation of tracts connected to the supplementary motor and premotor cortices, respectively. We introduce an algorithm that uses these symptom-response tracts to suggest optimal stimulation parameters for DBS based on individual patient's symptom profiles. Application of the algorithm illustrates that our symptom-tract library may bear potential in personalizing stimulation treatment based on the symptoms that are most burdensome in an individual patient.
Topics: Humans; Deep Brain Stimulation; Parkinson Disease; Male; Female; Middle Aged; Aged; Tremor; Motor Cortex; Algorithms; Hypokinesia; White Matter; Muscle Rigidity; Cerebellum; Cohort Studies; Treatment Outcome
PubMed: 38821913
DOI: 10.1038/s41467-024-48731-1 -
ELife May 2024Neurexins play diverse functions as presynaptic organizers in various glutamatergic and GABAergic synapses. However, it remains unknown whether and how neurexins are...
Neurexins play diverse functions as presynaptic organizers in various glutamatergic and GABAergic synapses. However, it remains unknown whether and how neurexins are involved in shaping functional properties of the glycinergic synapses, which mediate prominent inhibition in the brainstem and spinal cord. To address these issues, we examined the role of neurexins in a model glycinergic synapse between the principal neuron in the medial nucleus of the trapezoid body (MNTB) and the principal neuron in the lateral superior olive (LSO) in the auditory brainstem. Combining RNAscope with stereotactic injection of AAV-Cre in the MNTB of neurexin1/2/3 conditional triple knockout mice, we showed that MNTB neurons highly express all isoforms of neurexins although their expression levels vary remarkably. Selective ablation of all neurexins in MNTB neurons not only reduced the amplitude but also altered the kinetics of the glycinergic synaptic transmission at LSO neurons. The synaptic dysfunctions primarily resulted from an impaired Ca sensitivity of release and a loosened coupling between voltage-gated Ca channels and synaptic vesicles. Together, our current findings demonstrate that neurexins are essential in controlling the strength and temporal precision of the glycinergic synapse, which therefore corroborates the role of neurexins as key presynaptic organizers in all major types of fast chemical synapses.
Topics: Animals; Mice, Knockout; Glycine; Mice; Trapezoid Body; Synaptic Transmission; Neural Cell Adhesion Molecules; Superior Olivary Complex; Brain Stem; Synapses; Neurons; Cell Adhesion Molecules, Neuronal; Nerve Tissue Proteins; Neurexins; Calcium-Binding Proteins
PubMed: 38814174
DOI: 10.7554/eLife.94315 -
Turkish Journal of Medical Sciences 2024This study aims to determine the possible embryotoxic effects of propofol on the cerebellum and spinal cord using fertile chicken eggs.
BACKGROUND/AIM
This study aims to determine the possible embryotoxic effects of propofol on the cerebellum and spinal cord using fertile chicken eggs.
MATERIALS AND METHODS
A total of 430 fertile eggs were divided into 5 groups: control, saline, 2.5 mg.kg, 12.5 mg.kg, and 37.5 mg.kg propofol. Injections were made immediately before incubation via the air chamber. On the 15th, 18th, and 21st day of incubation, 6 embryos from each group were evaluated. Serial paraffin sections taken from the cerebellum and spinal cord were stained with hematoxylin-eosin, Kluver-Barrera, toluidine blue, and periodic acid-Schiff's reaction. The outer granular layer and total cortex thickness were measured, and the linear density of the Purkinje cells was determined. The ratios of the substantia grisea surface area to the total surface area of the spinal cord were calculated. The transverse and longitudinal diameters of the canalis centralis were also assessed.
RESULTS
No structural malformation was observed in any embryos examined macroscopically. No significant difference was observed between the groups in terms of development and histologic organization of the cerebellum and spinal cord. However, on the 15th, 18th, and 21st day, the outer granular layer (p < 0.001 for all days) and the total cortex thickness (p < 0.01, p < 0.001, and p < 0.001, respectively) decreased significantly in different propofol dose groups in varying degrees in the cerebellum. Similarly, in the spinal cord, there were significant changes in the ratios of the substantia grisea surface area to the total surface area (p < 0.01 and p < 0.001, respectively).
CONCLUSION
It was concluded that the in-ovo-administered propofol given immediately before incubation has adverse effects on the developing cerebellum and spinal cord. Therefore, it is important for anesthesiologists always to remain vigilant when treating female patients of childbearing age.
Topics: Animals; Propofol; Cerebellum; Spinal Cord; Chick Embryo; Anesthetics, Intravenous
PubMed: 38812654
DOI: 10.55730/1300-0144.5760 -
PLoS Computational Biology May 2024The dorsal (DRN) and median (MRN) raphe are important nuclei involved in similar functions, including mood and sleep, but playing distinct roles. These nuclei have a...
The dorsal (DRN) and median (MRN) raphe are important nuclei involved in similar functions, including mood and sleep, but playing distinct roles. These nuclei have a different composition of neuronal types and set of neuronal connections, which among other factors, determine their neuronal dynamics. Most works characterize the neuronal dynamics using classic measures, such as using the average spiking frequency (FR), the coefficient of variation (CV), and action potential duration (APD). In the current study, to refine the characterization of neuronal firing profiles, we examined the neurons within the raphe nuclei. Through the utilization of nonlinear measures, our objective was to discern the redundancy and complementarity of these measures, particularly in comparison with classic methods. To do this, we analyzed the neuronal basal firing profile in both nuclei of urethane-anesthetized rats using the Shannon entropy (Bins Entropy) of the inter-spike intervals, permutation entropy of ordinal patterns (OP Entropy), and Permutation Lempel-Ziv Complexity (PLZC). Firstly, we found that classic (i.e., FR, CV, and APD) and nonlinear measures fail to distinguish between the dynamics of DRN and MRN neurons, except for the OP Entropy. We also found strong relationships between measures, including the CV with FR, CV with Bins entropy, and FR with PLZC, which imply redundant information. However, APD and OP Entropy have either a weak or no relationship with the rest of the measures tested, suggesting that they provide complementary information to the characterization of the neuronal firing profiles. Secondly, we studied how these measures are affected by the oscillatory properties of the firing patterns, including rhythmicity, bursting patterns, and clock-like behavior. We found that all measures are sensitive to rhythmicity, except for the OP Entropy. Overall, our work highlights OP Entropy as a powerful and useful quantity for the characterization of neuronal discharge patterns.
Topics: Animals; Rats; Action Potentials; Neurons; Nonlinear Dynamics; Models, Neurological; Raphe Nuclei; Male; Computational Biology; Rats, Sprague-Dawley
PubMed: 38805554
DOI: 10.1371/journal.pcbi.1012111 -
Frontiers in Immunology 2024Cerebellar ataxia is an uncommon and atypical manifestation of anti--methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric...
Cerebellar ataxia is an uncommon and atypical manifestation of anti--methyl-D-aspartate receptor (NMDAR) encephalitis, often accompanied by seizures, psychiatric symptoms, and cognitive deficits. Previous cases of isolated brainstem-cerebellar symptoms in patients with anti-NMDAR encephalitis have not been documented. This report presents a case of anti-NMDAR encephalitis in which the patient exhibited cerebellar ataxia, nystagmus, diplopia, positive bilateral pathological signs, and hemiparesthesia with no other accompanying symptoms or signs. The presence of positive CSF anti-NMDAR antibodies further supports the diagnosis. Other autoantibodies were excluded through the use of cell-based assays. Immunotherapy was subsequently administered, leading to a gradual recovery of the patient.
Topics: Humans; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Brain Stem; Autoantibodies; Female; Cerebellar Ataxia; Cerebellum; Receptors, N-Methyl-D-Aspartate; Adult; Immunotherapy; Male; Magnetic Resonance Imaging
PubMed: 38799430
DOI: 10.3389/fimmu.2024.1388667 -
Human Brain Mapping Jun 2024Twin studies have found gross cerebellar volume to be highly heritable. However, whether fine-grained regional volumes within the cerebellum are similarly heritable is...
Twin studies have found gross cerebellar volume to be highly heritable. However, whether fine-grained regional volumes within the cerebellum are similarly heritable is still being determined. Anatomical MRI scans from two independent datasets (QTIM: Queensland Twin IMaging, N = 798, mean age 22.1 years; QTAB: Queensland Twin Adolescent Brain, N = 396, mean age 11.3 years) were combined with an optimised and automated cerebellum parcellation algorithm to segment and measure 28 cerebellar regions. We show that the heritability of regional volumetric measures varies widely across the cerebellum ( 47%-91%). Additionally, the good to excellent test-retest reliability for a subsample of QTIM participants suggests that non-genetic variance in cerebellar volumes is due primarily to unique environmental influences rather than measurement error. We also show a consistent pattern of strong associations between the volumes of homologous left and right hemisphere regions. Associations were predominantly driven by genetic effects shared between lobules, with only sparse contributions from environmental effects. These findings are consistent with similar studies of the cerebrum and provide a first approximation of the upper bound of heritability detectable by genome-wide association studies.
Topics: Humans; Cerebellum; Male; Adolescent; Female; Magnetic Resonance Imaging; Young Adult; Child; Adult; Organ Size; Twins, Monozygotic
PubMed: 38798116
DOI: 10.1002/hbm.26717 -
Hearing Research Aug 2024Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential...
Although rats and mice are among the preferred animal models for investigating many characteristics of auditory function, they are rarely used to study an essential aspect of binaural hearing: the ability of animals to localize the sources of low-frequency sounds by detecting the interaural time difference (ITD), that is the difference in the time at which the sound arrives at each ear. In mammals, ITDs are mostly encoded in the medial superior olive (MSO), one of the main nuclei of the superior olivary complex (SOC). Because of their small heads and high frequency hearing range, rats and mice are often considered unable to use ITDs for sound localization. Moreover, their MSO is frequently viewed as too small or insignificant compared to that of mammals that use ITDs to localize sounds, including cats and gerbils. However, recent research has demonstrated remarkable similarities between most morphological and physiological features of mouse MSO neurons and those of MSO neurons of mammals that use ITDs. In this context, we have analyzed the structure and neural afferent and efferent connections of the rat MSO, which had never been studied by injecting neuroanatomical tracers into the nucleus. The rat MSO spans the SOC longitudinally. It is relatively small caudally, but grows rostrally into a well-developed column of stacked bipolar neurons. By placing small, precise injections of the bidirectional tracer biotinylated dextran amine (BDA) into the MSO, we show that this nucleus is innervated mainly by the most ventral and rostral spherical bushy cells of the anteroventral cochlear nucleus of both sides, and by the most ventrolateral principal neurons of the ipsilateral medial nucleus of the trapezoid body. The same experiments reveal that the MSO densely innervates the most dorsolateral region of the central nucleus of the inferior colliculus, the central region of the dorsal nucleus of the lateral lemniscus, and the most lateral region of the intermediate nucleus of the lateral lemniscus of its own side. Therefore, the MSO is selectively innervated by, and sends projections to, neurons that process low-frequency sounds. The structural and hodological features of the rat MSO are notably similar to those of the MSO of cats and gerbils. While these similarities raise the question of what functions other than ITD coding the MSO performs, they also suggest that the rat MSO is an appropriate model for future MSO-centered research.
Topics: Animals; Superior Olivary Complex; Auditory Pathways; Sound Localization; Axons; Rats; Male; Dextrans; Biotin; Acoustic Stimulation; Efferent Pathways; Olivary Nucleus; Female; Neuroanatomical Tract-Tracing Techniques; Rats, Wistar
PubMed: 38797037
DOI: 10.1016/j.heares.2024.109036 -
Nature Communications May 2024About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related...
About half of the neurons in the parabrachial nucleus (PB) that are activated by CO are located in the external lateral (el) subnucleus, express calcitonin gene-related peptide (CGRP), and cause forebrain arousal. We report here, in male mice, that most of the remaining CO-responsive neurons in the adjacent central lateral (PBcl) and Kölliker-Fuse (KF) PB subnuclei express the transcription factor FoxP2 and many of these neurons project to respiratory sites in the medulla. PBcl neurons show increased intracellular calcium during wakefulness and REM sleep and in response to elevated CO during NREM sleep. Photo-activation of the PBcl neurons increases respiration, whereas either photo-inhibition of PBcl or genetic deletion of PB/KF neurons reduces the respiratory response to CO stimulation without preventing awakening. Thus, augmenting the PBcl/KF response to CO in patients with sleep apnea in combination with inhibition of the PBel neurons may avoid hypoventilation and minimize EEG arousals.
Topics: Animals; Hypercapnia; Neurons; Male; Parabrachial Nucleus; Forkhead Transcription Factors; Mice; Carbon Dioxide; Wakefulness; Respiration; Mice, Inbred C57BL; Calcitonin Gene-Related Peptide; Sleep, REM; Repressor Proteins
PubMed: 38796568
DOI: 10.1038/s41467-024-48773-5