-
Annals of Clinical and Translational... Jun 2024To define tauopathy-associated changes in the human gray and white matter proteome.
OBJECTIVE
To define tauopathy-associated changes in the human gray and white matter proteome.
METHOD
We applied tandem mass tagged labeling and mass spectrometry, consensus, and ratio weighted gene correlation network analysis (WGCNA) to gray and white matter sampled from postmortem human dorsolateral prefrontal cortex. The sampled tissues included control as well as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal degeneration with tau pathology, and chronic traumatic encephalopathy.
RESULTS
Only eight proteins were unique to gray matter while six were unique to white matter. Comparison of the gray and white matter proteome revealed an enrichment of microglial proteins in the white matter. Consensus WGCNA sorted over 6700 protein isoforms into 46 consensus modules across the gray and white matter proteomic networks. Consensus network modules demonstrated unique and shared disease-associated microglial and endothelial protein changes. Ratio WGCNA sorted over 6500 protein ratios (white:gray) into 33 modules. Modules associated with mitochondrial proteins and processes demonstrated higher white:gray ratios in diseased tissues relative to control, driven by mitochondrial protein downregulation in gray and upregulation in white.
INTERPRETATION
The dataset is a valuable resource for understanding proteomic changes in human tauopathy gray and white matter. The identification of unique and shared disease-associated changes across gray and white matter emphasizes the utility of examining both tissue types. Future studies of microglial, endothelial, and mitochondrial changes in white matter may provide novel insights into tauopathy-associated changes in human brain.
PubMed: 38924699
DOI: 10.1002/acn3.52134 -
Brain and Behavior Jun 2024To assess changes in neurovascular coupling (NVC) by evaluating the relationship between cerebral perfusion and brain connectivity in patients with end-stage renal...
PURPOSE
To assess changes in neurovascular coupling (NVC) by evaluating the relationship between cerebral perfusion and brain connectivity in patients with end-stage renal disease (ESRD) undergoing hemodialysis versus in healthy control participants. And by exploring brain regions with abnormal NVC associated with cognitive deficits in patients, we aim to provide new insights into potential preventive and therapeutic interventions.
MATERIALS AND METHODS
A total of 45 patients and 40 matched healthy controls were prospectively enrolled in our study. Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. Arterial spin labeling (ASL) was used to calculate cerebral blood flow (CBF), and graph theory-based analysis of results from resting-state functional magnetic resonance imaging (rs-fMRI) was used to calculate brain network topological parameters (node betweenness centrality [BC], node efficiency [Ne], and node degree centrality [DC]). Three NVC biomarkers (CBF-BC, CBF-Ne, and CBF-DC coefficients) at the whole brain level and 3 NVC biomarkers (CBF/BC, CBF/Ne, and CBF/DC ratios) at the local brain region level were used to assess NVC. Mann-Whitney U tests were used to compare the intergroup differences in NVC parameters. Spearman's correlation analysis was used to evaluate the relationship among NVC dysfunctional pattern, cognitive impairment, and clinical characteristics multiple comparisons were corrected using a voxel-wise false-discovery rate (FDR) method (p < .05).
RESULTS
Patients showed significantly reduced global coupling coefficients for CBF-Ne (p = .023) and CBF-BC (p = .035) compared to healthy controls. Coupling ratios at the local brain region level were significantly higher in patients in 33 brain regions (all p values < .05). Coupling ratio changes alone or accompanied by changes in CBF, node properties, or both CBF and node properties were identified. In patients, negative correlations were seen between coupling ratios and MoCA scores in many brain regions, including the left dorsolateral superior frontal gyrus, the bilateral median cingulate and paracingulate gyri, and the right superior parietal gyrus. The correlations remained even after adjusting for hemoglobin and hematocrit levels.
CONCLUSION
Disrupted NVC may be one mechanism underlying cognitive impairment in dialysis patients.
Topics: Humans; Male; Female; Middle Aged; Magnetic Resonance Imaging; Neurovascular Coupling; Kidney Failure, Chronic; Cognitive Dysfunction; Brain; Adult; Cerebrovascular Circulation; Renal Dialysis; Neuroimaging; Aged; Prospective Studies; Mental Status and Dementia Tests; Nerve Net
PubMed: 38923330
DOI: 10.1002/brb3.3598 -
Progress in Neuro-psychopharmacology &... Jun 2024The impulsive choice is characterized by the preference for a small immediate reward over a bigger delayed one. The mechanisms underlying impulsive choices are linked to...
BACKGROUND
The impulsive choice is characterized by the preference for a small immediate reward over a bigger delayed one. The mechanisms underlying impulsive choices are linked to the activity in the Nucleus Accumbens (NAc), the orbitofrontal cortex (OFC), and the dorsolateral striatum (DLS). While the study of functional connectivity between brain areas has been key to understanding a variety of cognitive processes, it remains unclear whether functional connectivity differentiates impulsive-control decisions.
METHODS
To study the functional connectivity both between and within NAc, OFC, and DLS during a delay discounting task, we concurrently recorded local field potential in NAc, OFC, and DLS in rats. We then quantified the degree of phase-amplitude coupling (PAC), coherence, and Granger Causality between oscillatory activities in animals exhibiting either a high (HI) or low (LI) tendency for impulsive choices.
RESULTS
Our results showed a differential pattern of PAC during decision-making in OFC and NAc, but not in DLS. While theta-gamma PAC in OFC was associated with self-control decisions, a higher delta-gamma PAC in both OFC and NAc biased decisions toward impulsive choices in both HI and LI groups. Furthermore, during the reward event, Granger Causality analysis indicated a stronger NAc➔OFC gamma contribution in the HI group, while the LI group showed a higher OFC➔NAc gamma contribution.
CONCLUSIONS
The overactivity in NAc during reward in the HI group suggests that exacerbated contribution of NAcCore can lead to an overvaluation of reward that biases the behavior toward the impulsive choice.
PubMed: 38917880
DOI: 10.1016/j.pnpbp.2024.111064 -
Neuron Jun 2024Inhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway, but little is known...
Inhibitory interneurons in the dorsolateral geniculate nucleus (dLGN) are situated at the first central synapse of the image-forming visual pathway, but little is known about their function. Given their anatomy, they are expected to be multiplexors, integrating many different retinal channels along their dendrites. Here, using targeted single-cell-initiated rabies tracing, we found that mouse dLGN interneurons exhibit a degree of retinal input specialization similar to thalamocortical neurons. Some are anatomically highly specialized, for example, toward motion-selective information. Two-photon calcium imaging performed in vivo revealed that interneurons are also functionally specialized. In mice lacking retinal horizontal direction selectivity, horizontal direction selectivity is reduced in interneurons, suggesting a causal link between input and functional specialization. Functional specialization is not only present at interneuron somata but also extends into their dendrites. Altogether, inhibitory interneurons globally display distinct visual features which reflect their retinal input specialization and are ideally suited to perform feature-selective inhibition.
PubMed: 38917805
DOI: 10.1016/j.neuron.2024.06.001 -
Epilepsy & Behavior : E&B Jun 2024Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES...
BACKGROUND AND OBJECTIVES
Psychogenic nonepileptic (functional) seizures (FS) clinically resemble epileptic seizures (ES) with both often preceded by traumatic brain injury (TBI). FS and ES emergence and occurrence after TBI may be linked to aberrant neurobehavioral stress responses. We hypothesized that neural activity signatures in response to a psychosocial stress task would differ between TBI + FS and TBI + ES after controlling for TBI status (TBI-only).
METHODS
In the current multicenter study, participants were recruited prospectively from Rhode Island Hospital, Providence Rhode Island Veterans Administration Medical Center, and the University of Alabama at Birmingham Medical Center. Previous diagnoses of TBI, ES, and FS were verified based on data collected from participants, medical chart and record review, and, where indicated, results of EEG and/or video-EEG confirmatory diagnosis. TBI + ES (N = 21) and TBI + FS (N = 21) were matched for age and sex and combined into an initial group (TBI + SZ; N = 42). A TBI-only group (N = 42) was age and sex matched to the TBI with seizures (TBI + SZ) group. All participants completed an fMRI control math task (CMT) and stress math task (SMT) based on the Montreal Imaging Stress Task (MIST).
RESULTS
The TBI + SZ group (n = 24 female) did not differ in mood or anxiety severity compared to TBI-only group (n = 24 female). However, TBI + FS group (n = 11 female) reported greater severity of these symptoms compared to TBI + ES (n = 13 female). The linear mixed effects analysis identified neural responses that differed between TBI-only and TBI + SZ during math performance within the left premotor cortex and during auditory feedback within bilateral prefrontal cortex and hippocampus/amygdala regions. Additionally, neural responses differed between TBI + ES and TBI + FS during math performance within the right dorsolateral prefrontal cortex and bilateral amygdala during auditory feedback within the supplementary motor area. All tests comparing neural stress responses to psychiatric symptom severity failed to reach significance.
DISCUSSION
Controlling for TBI and seizure status, these findings implicate specific nodes within frontal, limbic, and sensorimotor networks that may maintain functional neurological symptoms and possibly distinguish FS from ES. This study provides class II evidence of differences in neural responses to psychosocial stress between ES and FS after TBI.
PubMed: 38917672
DOI: 10.1016/j.yebeh.2024.109877 -
BioRxiv : the Preprint Server For... Jun 2024Motor skill learning induces long-lasting synaptic plasticity at not only the inputs, such as dendritic spines , but also at the outputs to the striatum of motor...
Motor skill learning induces long-lasting synaptic plasticity at not only the inputs, such as dendritic spines , but also at the outputs to the striatum of motor cortical neurons . However, very little is known about the activity and structural plasticity of corticostriatal axons during learning in the adult brain. Here, we used longitudinal in vivo two-photon imaging to monitor the activity and structure of thousands of corticostriatal axonal boutons in the dorsolateral striatum in awake mice. We found that learning a new motor skill induces dynamic regulation of axonal boutons. The activities of motor corticostriatal axonal boutons exhibited selectivity for rewarded movements (RM) and un-rewarded movements (UM). Strikingly, boutons on the same axonal branches showed diverse responses during behavior. Motor learning significantly increased the fraction of RM boutons and reduced the heterogeneity of bouton activities. Moreover, motor learning-induced profound structural dynamism in boutons. By combining structural and functional imaging, we identified that newly formed axonal boutons are more likely to exhibit selectivity for RM and are stabilized during motor learning, while UM boutons are selectively eliminated. Our results highlight a novel form of plasticity at corticostriatal axons induced by motor learning, indicating that motor corticostriatal axonal boutons undergo dynamic reorganization that facilitates the acquisition and execution of motor skills.
PubMed: 38915677
DOI: 10.1101/2024.06.10.598366 -
BioRxiv : the Preprint Server For... Jun 2024In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have...
UNLABELLED
In schizophrenia, layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC) are thought to receive fewer excitatory synaptic inputs and to have lower expression levels of activity-dependent genes and of genes involved in mitochondrial energy production. In concert, these findings from previous studies suggest that DLPFC L3PNs are hypoactive in schizophrenia, disrupting the patterns of activity that are crucial for working memory, which is impaired in the illness. However, whether lower PN activity produces alterations in inhibitory and/or excitatory synaptic strength has not been tested in the primate DLPFC. Here, we decreased PN excitability in rhesus monkey DLPFC using adeno-associated viral vectors (AAVs) to produce Cre recombinase-mediated overexpression of Kir2.1 channels, a genetic silencing tool that efficiently decreases neuronal excitability. In acute slices prepared from DLPFC 7-12 weeks post-AAV microinjections, Kir2.1-overexpressing PNs had a significantly reduced excitability largely attributable to highly specific effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1-overexpressing DLPFC PNs had reduced strength of excitatory synapses whereas inhibitory synaptic inputs were not affected. The decrease in excitatory synaptic strength was not associated with changes in dendritic spine number, suggesting that excitatory synapse quantity was unaltered in Kir2.1-overexpressing DLPFC PNs. These findings suggest that, in schizophrenia, the excitatory synapses on hypoactive L3PNs are weaker and thus might represent a substrate for novel therapeutic interventions.
SIGNIFICANCE STATEMENT
In schizophrenia, dorsolateral prefrontal cortex (DLPFC) pyramidal neurons (PNs) have both transcriptional and structural alterations that suggest they are hypoactive. PN hypoactivity is thought to produce synaptic alterations in schizophrenia, however the effects of lower neuronal activity on synaptic function in primate DLPFC have not been examined. Here, we used, for the first time in primate neocortex, adeno-associated viral vectors (AAVs) to reduce PN excitability with Kir2.1 channel overexpression and tested if this manipulation altered the strength of synaptic inputs onto the Kir2.1-overexpressing PNs. Recordings in DLPFC slices showed that Kir2.1 overexpression depressed excitatory (but not inhibitory), synaptic currents, suggesting that, in schizophrenia, the hypoactivity of PNs might be exacerbated by reduced strength of the excitatory synapses they receive.
PubMed: 38915638
DOI: 10.1101/2024.06.12.598658 -
Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.BioRxiv : the Preprint Server For... Jun 2024Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's...
Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.
PubMed: 38915595
DOI: 10.1101/2024.06.13.598842 -
Pediatric Research Jun 2024Stuttering affects approximately 5% of children; however, its neurological basis remains unclear. Identifying imaging biomarkers could aid in early detection....
BACKGROUND
Stuttering affects approximately 5% of children; however, its neurological basis remains unclear. Identifying imaging biomarkers could aid in early detection. Accordingly, we investigated resting-state cerebral blood flow (CBF) in children with developmental stuttering.
METHODS
Pulsed arterial spin labelling magnetic resonance imaging was utilised to quantify CBF in 35 children with developmental stuttering and 27 healthy controls. We compared normalised CBF between the two groups and evaluated the correlation between abnormal CBF and clinical indicators.
RESULTS
Compared with healthy controls, the stuttering group exhibited decreased normalised CBF in the cerebellum lobule VI bilaterally, right cuneus, and left superior occipital gyrus and increased CBF in the right medial superior frontal gyrus, left rectus, and left dorsolateral superior frontal gyrus. Additionally, normalised CBF in the left cerebellum lobule VI and left superior occipital gyrus was positively correlated with stuttering severity.
CONCLUSIONS
Children who stutter display decreased normalised CBF primarily in the cerebellum and occipital gyrus, with increased normalised CBF in the frontal gyrus. Additionally, the abnormal CBF in the left cerebellum lobule VI and left superior occipital gyrus was associated with more severe symptoms, suggesting that decreased CBF in these areas may serve as a novel neuroimaging clue for stuttering.
IMPACT
Stuttering occurs in 5% of children and often extends into adulthood, which may negatively affect quality of life. Early detection and treatment are essential. We used pulsed arterial spin labelling magnetic resonance imaging to visualise the resting-state cerebral blood flow (CBF) in children who stutter and healthy children. Normalised CBF was decreased in stutterers in the cerebellum and occipital gyrus and increased in the frontal gyrus. Stuttering severity was linked to abnormal normalised CBF in the left cerebellum lobule VI and left superior occipital gyrus, suggesting that CBF may serve as a novel neuroimaging clue for stuttering.
PubMed: 38914760
DOI: 10.1038/s41390-024-03359-1 -
The Clinical Neuropsychologist Jun 2024Multiple sclerosis (MS) may include not only severe neurological signs and symptoms, but also cognitive and psychiatric disturbances. When psychiatric symptoms precede...
Multiple sclerosis (MS) may include not only severe neurological signs and symptoms, but also cognitive and psychiatric disturbances. When psychiatric symptoms precede or are comorbid with MS, it poses a clinical challenge, because it may lead to a mistaken diagnosis of MS as a psychiatric disorder, delaying proper treatment. We describe the neuropsychological profile of a female patient with MS whose diagnosis was delayed due to neuropsychiatric symptoms. : A comprehensive analysis of the medical history and the results of a teleneuropsychological assessment of a 36-year-old Mexican woman with a diagnosis of relapsing--remitting MS (RRMS) was performed. : The patient indicates a long history of psychotic, anxious, and depressive features years before the first neurological symptom that led to MS going unnoticed for several years. Language, attentional, perceptual, motor, and learning skills were found to be preserved. Short-term memory and spatial orientation problems were identified, with decreased processing speed and executive dysfunction, including working memory and planning deficits. : The patient has a non-typical presentation of neuropsychological alterations with cognitive and behavioral symptoms that resemble dorsolateral frontal lobe syndrome. This case study highlights the importance of considering MS in differential diagnosis of patients with psychiatric symptoms, even in the absence of obvious neurological signs.
PubMed: 38914594
DOI: 10.1080/13854046.2024.2370963