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ELife Nov 2023Astrocyte-derived L-lactate was shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic G signaling in the anterior...
Astrocyte-derived L-lactate was shown to confer beneficial effects on synaptic plasticity and cognitive functions. However, how astrocytic G signaling in the anterior cingulate cortex (ACC) modulates L-lactate levels and schema memory is not clear. Here, using chemogenetic approach and well-established behavioral paradigm, we demonstrate that astrocytic G pathway activation in the ACC causes significant impairments in flavor-place paired associates (PAs) learning, schema formation, and PA memory retrieval in rats. It also impairs new PA learning even if a prior associative schema exists. These impairments are mediated by decreased L-lactate in the ACC due to astrocytic G activation. Concurrent exogenous L-lactate administration bilaterally into the ACC rescues these impairments. Furthermore, we show that the impaired schema memory formation is associated with a decreased neuronal mitochondrial biogenesis caused by decreased L-lactate level in the ACC upon astrocytic G activation. Our study also reveals that L-lactate-mediated mitochondrial biogenesis is dependent on monocarboxylate transporter 2 (MCT2) and NMDA receptor activity - discovering a previously unrecognized signaling role of L-lactate. These findings expand our understanding of the role of astrocytes and L-lactate in the brain functions.
Topics: Rats; Animals; Gyrus Cinguli; Astrocytes; Organelle Biogenesis; Memory; Lactic Acid; Memory Disorders
PubMed: 37960975
DOI: 10.7554/eLife.85751 -
Molecular Psychiatry Dec 2023A body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. Linking measures of brain connectivity to the gut...
A body of pre-clinical evidence shows how the gut microbiota influence brain functioning, including brain connectivity. Linking measures of brain connectivity to the gut microbiota can provide important mechanistic insights into the bi-directional gut-brain communication. In this systematic review, we therefore synthesized the available literature assessing this association, evaluating the degree of consistency in microbiota-connectivity associations. Following the PRISMA guidelines, a PubMed search was conducted, including studies published up to September 1, 2022. We identified 16 studies that met the inclusion criteria. Several bacterial genera, including Prevotella, Bacteroides, Ruminococcus, Blautia, and Collinsella were most frequently reported in association with brain connectivity. Additionally, connectivity of the salience (specifically the insula and anterior cingulate cortex), default mode, and frontoparietal networks were most frequently associated with the gut microbiota, both in terms of microbial diversity and composition. There was no discernible pattern in the association between microbiota and brain connectivity. Altogether, based on our synthesis, there is evidence for an association between the gut microbiota and brain connectivity. However, many findings were poorly replicated across studies, and the specificity of the association is yet unclear. The current studies show substantial inter-study heterogeneity in methodology and reporting, limiting the robustness and reproducibility of the findings and emphasizing the need to harmonize methodological approaches. To enhance comparability and replicability, future research should focus on further standardizing processing pipelines and employing data-driven multivariate analysis strategies.
Topics: Humans; Gastrointestinal Microbiome; Brain; Brain-Gut Axis; Connectome; Nerve Net
PubMed: 37479779
DOI: 10.1038/s41380-023-02146-4 -
Brain : a Journal of Neurology Aug 2023Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While...
Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.
Topics: Humans; Focal Cortical Dysplasia; Reproducibility of Results; Malformations of Cortical Development; Brain; Magnetic Resonance Imaging
PubMed: 36852571
DOI: 10.1093/brain/awad060 -
Scientific Reports Jul 2023Examination of healthy and diseased human brain is essential to translational neuroscience. Protein-protein interactions play a pivotal role in physiological and...
Examination of healthy and diseased human brain is essential to translational neuroscience. Protein-protein interactions play a pivotal role in physiological and pathological processes, but their detection is difficult, especially in aged and fixed human brain tissue. We used the in-situ proximity ligation assay (PLA) to broaden the range of molecular interactions assessable in-situ in the human neuropathology. We adapted fluorescent in-situ PLA to detect ubiquitin-modified proteins in human brains with Alzheimer's disease (AD), including approaches for the management of autofluorescence and quantification using a high-content image analysis system. We confirmed that phosphorylated microtubule-associated protein tau (Serine202, Threonine205) aggregates were modified by ubiquitin and that phospho-tau-ubiquitin complexes were increased in hippocampal and frontal cortex regions in AD compared to non-AD brains. Overall, we refined PLA for use in human neuropathology, which has revealed a profound change in the distribution of ubiquitin in AD brain and its association with characteristic tau pathologies.
Topics: Humans; Aged; Alzheimer Disease; tau Proteins; Cerebral Cortex; Ubiquitin; Brain; Ubiquitinated Proteins
PubMed: 37488165
DOI: 10.1038/s41598-023-38000-4 -
Glia Aug 2023Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia...
Cerebral blood flow (CBF) is important for the maintenance of brain function and its dysregulation has been implicated in Alzheimer's disease (AD). Microglia associations with capillaries suggest they may play a role in the regulation of CBF or the blood-brain-barrier (BBB). We explored the relationship between microglia and pericytes, a vessel-resident cell type that has a major role in the control of CBF and maintenance of the BBB, discovering a spatially distinct subset of microglia that closely associate with pericytes. We termed these pericyte-associated microglia (PEM). PEM are present throughout the brain and spinal cord in NG2DsRed × CX CR1 mice, and in the human frontal cortex. Using in vivo two-photon microscopy, we found microglia residing adjacent to pericytes at all levels of the capillary tree and found they can maintain their position for at least 28 days. PEM can associate with pericytes lacking astroglial endfeet coverage and capillary vessel width is increased beneath pericytes with or without an associated PEM, but capillary width decreases if a pericyte loses a PEM. Deletion of the microglia fractalkine receptor (CX CR1) did not disrupt the association between pericytes and PEM. Finally, we found the proportion of microglia that are PEM declines in the superior frontal gyrus in AD. In summary, we identify microglia that specifically associate with pericytes and find these are reduced in number in AD, which may be a novel mechanism contributing to vascular dysfunction in neurodegenerative diseases.
Topics: Mice; Humans; Animals; Pericytes; Mice, Transgenic; Microglia; Brain; Blood-Brain Barrier; Alzheimer Disease
PubMed: 36994950
DOI: 10.1002/glia.24371 -
Journal of Alzheimer's Disease : JAD 2024Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer's disease. Diabetic retinopathy (DR) has...
BACKGROUND
Accumulating evidence has demonstrated that hyperglycemia is a possible risk factor for mild cognitive impairment or Alzheimer's disease. Diabetic retinopathy (DR) has been identified as a risk factor for dementia in patients with diabetes.
OBJECTIVE
This study aimed to investigate the causal relationships between DR and brain structure, cognitive function, and dementia.
METHODS
We performed bidirectional two-sample Mendelian randomization for DR, brain structure, cognitive function, and dementia using the inverse-variance weighted method.
RESULTS
Inverse-variance weighted analysis showed the association of DR with vascular dementia (OR = 1.68, 95% CI: 1.01-2.82), and dementia was significantly associated with the increased risk of non-proliferative DR (NPDR) (OR = 1.76, 95% CI: 1.04-2.98). Furthermore, better cognitive performance was significantly associated with a reduced risk of NPDR (OR = 0.85, 95% CI: 0.74-0.98). No association was observed between DR and brain structure.
CONCLUSIONS
These findings suggest that the association of DR with vascular dementia. The reciprocal effect of cognitive performance and dementia on NPDR risk highlights the potential benefits of dementia prevention for reducing the burden of DR.
Topics: Humans; Diabetic Retinopathy; Dementia, Vascular; Mendelian Randomization Analysis; Brain; Cognition; Genome-Wide Association Study; Diabetes Mellitus
PubMed: 38217603
DOI: 10.3233/JAD-231022 -
European Journal of Internal Medicine Feb 2024Hypertension has been recognized as a significant risk factor for cerebrovascular diseases and cognitive decline. However, the specific impact of hypertension,...
BACKGROUND
Hypertension has been recognized as a significant risk factor for cerebrovascular diseases and cognitive decline. However, the specific impact of hypertension, systolic/diastolic blood pressure, pulse pressure (PP) and mean arterial pressure (MAP) on brain cortical structure remains unclear. Mendelian randomization (MR) provides a robust approach to investigate the causal relationship between blood pressure components and brain cortical changes.
METHODS
In this MR study, data from large-scale genome-wide association studies for blood pressure components and neuroimaging were utilized to conduct our analyses. We leveraged genetic variants associated specifically with hypertension (122,620 cases and 332,683 controls), systolic (469,767 individuals), diastolic (490,469 individuals) blood pressure, PP (810,865 individuals) and MAP (over 1 million individuals) to evaluate their effects on brain cortex surficial area (51,665 individuals) and cortex thickness (51,665 individuals).
RESULTS
Our findings revealed a significant correlation between systolic blood pressure and abnormal reduction in brain cortex surficial area (β=-1330.69, 95% confident interval [CI]: -2655.35 to -6.02, p = 0.0489); however, no significant relationship was found between systolic blood pressure and brain cortex thickness (β=-0.0078, 95% CI: -0.0178 to 0.0022, p = 0.1287). Additionally, no significant associations were observed between hypertension (β=-200.05, p = 0.6884; β=-0.0051, p = 0.1179, respectively), diastolic blood pressure (β=-460.63, p = 0.5160; β=0.0047, p = 0.2448, respectively), PP (β=1041.84, p = 0.3725; β=-0.0112, p = 0.2212, respectively), MAP (β=-18.84, p = 0.8841; β=0.0002, p = 0.7654, respectively) and both brain cortex surficial area and brain cortex thickness.
CONCLUSION
Our MR study provides evidence supporting the hypothesis that systolic blood pressure, rather than diastolic blood pressure, PP or MAP, is associated with abnormal changes in brain cortical structure.
Topics: Humans; Blood Pressure; Genome-Wide Association Study; Mendelian Randomization Analysis; Hypertension; Brain
PubMed: 37852841
DOI: 10.1016/j.ejim.2023.10.018 -
Neurology Jul 2023Pathologic progression across the cortex is a key feature of Parkinson disease (PD). Cortical gyrification is a morphologic feature of human cerebral cortex that is...
BACKGROUND AND OBJECTIVES
Pathologic progression across the cortex is a key feature of Parkinson disease (PD). Cortical gyrification is a morphologic feature of human cerebral cortex that is tightly linked to the integrity of underlying axonal connectivity. Monitoring cortical gyrification reductions may provide a sensitive marker of progression through structural connectivity, preceding the progressive stages of PD pathology. We aimed to examine the progressive cortical gyrification reductions and their associations with overlying cortical thickness, white matter (WM) integrity, striatum dopamine availability, serum neurofilament light (NfL) chain, and CSF α-synuclein levels in PD.
METHODS
This study included a longitudinal dataset with baseline (T0), 1-year (T1), and 4-year (T4) follow-ups and 2 cross-sectional datasets. Local gyrification index (LGI) was computed from T1-weighted MRI data to measure cortical gyrification. Fractional anisotropy (FA) was computed from diffusion-weighted MRI data to measure WM integrity. Striatal binding ratio (SBR) was measured from Ioflupane SPECT scans. Serum NfL and CSF α-synuclein levels were also measured.
RESULTS
The longitudinal dataset included 113 patients with de novo PD and 55 healthy controls (HCs). The cross-sectional datasets included 116 patients with relatively more advanced PD and 85 HCs. Compared with HCs, patients with de novo PD showed accelerated LGI and FA reductions over 1-year period and a further decline at 4-year follow-up. Across the 3 time points, the LGI paralleled and correlated with FA ( = 0.002 at T0, = 0.0214 at T1, and = 0.0037 at T4) and SBR ( = 0.0095 at T0, = 0.0035 at T1, and = 0.0096 at T4) but not with overlying cortical thickness in patients with PD. Both LGI and FA correlated with serum NfL level (LGI: < 0.0001 at T0, = 0.0043 at T1; FA: < 0.0001 at T0, = 0.0001 at T1) but not with CSF α-synuclein level in patients with PD. In the 2 cross-sectional datasets, we revealed similar patterns of LGI and FA reductions and associations between LGI and FA in patients with more advanced PD.
DISCUSSION
We demonstrated progressive reductions in cortical gyrification that were robustly associated with WM microstructure, striatum dopamine availability, and serum NfL level in PD. Our findings may contribute biomarkers for PD progression and potential pathways for early interventions of PD.
Topics: Humans; alpha-Synuclein; Magnetic Resonance Imaging; Parkinson Disease; Cross-Sectional Studies; Dopamine; Cerebral Cortex; Biomarkers
PubMed: 37268433
DOI: 10.1212/WNL.0000000000207410 -
Nature Communications Oct 2023Associative learning is crucial for adapting to environmental changes. Interactions among neuronal populations involving the dorso-medial prefrontal cortex (dmPFC) are...
Associative learning is crucial for adapting to environmental changes. Interactions among neuronal populations involving the dorso-medial prefrontal cortex (dmPFC) are proposed to regulate associative learning, but how these neuronal populations store and process information about the association remains unclear. Here we developed a pipeline for longitudinal two-photon imaging and computational dissection of neural population activities in male mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC network topology. Using regularized regression methods and graphical modeling, we found that fear conditioning drove dmPFC reorganization to generate a neuronal ensemble encoding conditioned responses (CR) characterized by enhanced internal coactivity, functional connectivity, and association with conditioned stimuli (CS). Importantly, neurons strongly responding to unconditioned stimuli during conditioning subsequently became hubs of this novel associative network for the CS-to-CR transformation. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on the activity-dependent formation of the hub network within the dmPFC.
Topics: Male; Mice; Animals; Conditioning, Classical; Learning; Prefrontal Cortex; Fear; Neurons; Association Learning
PubMed: 37803014
DOI: 10.1038/s41467-023-41547-5 -
Biological Psychology Nov 2023Childhood maltreatment is considered as a robust predictor of depression. However, the underlying psychological and neurological mechanisms linking childhood...
BACKGROUND
Childhood maltreatment is considered as a robust predictor of depression. However, the underlying psychological and neurological mechanisms linking childhood maltreatment and depression remain poorly understood. Sufficient evidence demonstrates emotion dysregulation in individuals who have experienced childhood maltreatment, but it is unknown whether these changes represent vulnerability for depression. Here we speculated that decreased cognitive reappraisal and its corresponding neural basis might explain the relationship between childhood maltreatment and follow-up depression.
METHODS
First, we investigated whether cognitive reappraisal can explain the relationship between childhood maltreatment and depression, with a cross-sectional (n = 657) behavioral sample. Then we recruit 38 maltreated participants and 27 controls to complete the cognitive reappraisal functional magnetic resonance imaging (fMRI) task. The between-group difference in brain activation and functional connectivity (FC) were tested using independent t-tests. Finally, we investigated the relationship between childhood maltreatment, task-based brain activity and depression.
RESULTS
The behavior results suggested that cognitive reappraisal mediates the association between childhood maltreatment and depression. In addition, the maltreated group exhibited lower activation of orbitofrontal cortex (OFC) and higher FC of between the dorsolateral prefrontal cortex (DLPFC), posterior cingulate cortex (PCC), OFC, and amygdala during cognitive reappraisal, compared with healthy controls. Furthermore, the FC of DLPFC-amygdala mediates the association between childhood maltreatment and depression.
CONCLUSION
In summary, childhood maltreatment is associated with inefficient cognitive reappraisal ability, manifesting as aberrant modulation of cortical areas on amygdala. These cognitive and neural deficits might explain the relationship between childhood maltreatment and risk of depression in later life.
Topics: Humans; Child; Depression; Cross-Sectional Studies; Amygdala; Prefrontal Cortex; Brain Mapping; Magnetic Resonance Imaging; Cognition; Child Abuse; Emotions
PubMed: 37924935
DOI: 10.1016/j.biopsycho.2023.108716