RESUMEN
Elevated hippocampal perfusion has been observed in people at clinical high risk for psychosis (CHR-P). Preclinical evidence suggests that hippocampal hyperactivity is central to the pathophysiology of psychosis, and that peripubertal treatment with diazepam can prevent the development of psychosis-relevant phenotypes. The present experimental medicine study examined whether diazepam can normalize hippocampal perfusion in CHR-P individuals. Using a randomized, double-blind, placebo-controlled, crossover design, 24 CHR-P individuals were assessed with magnetic resonance imaging (MRI) on two occasions, once following a single oral dose of diazepam (5 mg) and once following placebo. Regional cerebral blood flow (rCBF) was measured using 3D pseudo-continuous arterial spin labeling and sampled in native space using participant-specific hippocampus and subfield masks (CA1, subiculum, CA4/dentate gyrus). Twenty-two healthy controls (HC) were scanned using the same MRI acquisition sequence, but without administration of diazepam or placebo. Mixed-design ANCOVAs and linear mixed-effects models were used to examine the effects of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on rCBF in the hippocampus as a whole and by subfield. Under the placebo condition, CHR-P individuals (mean [±SD] age: 24.1 [±4.8] years, 15 F) showed significantly elevated rCBF compared to HC (mean [±SD] age: 26.5 [±5.1] years, 11 F) in the hippocampus (F(1,41) = 24.7, pFDR < 0.001) and across its subfields (all pFDR < 0.001). Following diazepam, rCBF in the hippocampus (and subfields, all pFDR < 0.001) was significantly reduced (t(69) = -5.1, pFDR < 0.001) and normalized to HC levels (F(1,41) = 0.4, pFDR = 0.204). In conclusion, diazepam normalized hippocampal hyperperfusion in CHR-P individuals, consistent with evidence implicating medial temporal GABAergic dysfunction in increased vulnerability for psychosis.
Asunto(s)
Circulación Cerebrovascular , Estudios Cruzados , Diazepam , Hipocampo , Imagen por Resonancia Magnética , Trastornos Psicóticos , Humanos , Diazepam/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/diagnóstico por imagen , Hipocampo/irrigación sanguínea , Masculino , Método Doble Ciego , Femenino , Circulación Cerebrovascular/efectos de los fármacos , Circulación Cerebrovascular/fisiología , Adulto Joven , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/fisiopatología , Adulto , AdolescenteRESUMEN
The vasculature is a key component of adult brain neural stem cell (NSC) niches. In the adult mammalian hippocampus, NSCs reside in close contact with a dense capillary network. How this niche is maintained is unclear. We recently found that adult hippocampal NSCs express VEGF, a soluble factor with chemoattractive properties for vascular endothelia. Here, we show that global and NSC-specific VEGF loss led to dissociation of NSCs and their intermediate progenitor daughter cells from local vasculature. Surprisingly, though, we found no changes in local vascular density. Instead, we found that NSC-derived VEGF supports maintenance of gene expression programs in NSCs and their progeny related to cell migration and adhesion. In vitro assays revealed that blockade of VEGF receptor 2 impaired NSC motility and adhesion. Our findings suggest that NSCs maintain their own proximity to vasculature via self-stimulated VEGF signaling that supports their motility towards and/or adhesion to local blood vessels.
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Células-Madre Neurales , Factor A de Crecimiento Endotelial Vascular , Animales , Hipocampo/irrigación sanguínea , Hipocampo/metabolismo , Células-Madre Neurales/metabolismo , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The human brain vasculature is of great medical importance: its dysfunction causes disability and death1, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders2,3. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment. We identify brain-region- and species-enriched genes and pathways. We reveal molecular principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In Alzheimer's disease, we observe selective vulnerability of ECM-maintaining pericytes and gene expression patterns that implicate dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 genes that have been linked to Alzheimer's disease risk by genome-wide association studies (GWASs) are expressed in the human brain vasculature, and we confirm this by immunostaining. Vascular GWAS genes map to endothelial protein transport, adaptive immune and ECM pathways. Many are microglia-specific in mice, suggesting a partial evolutionary transfer of Alzheimer's disease risk. Our work uncovers the molecular basis of the human brain vasculature, which will inform our understanding of overall brain health, disease and therapy.
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Enfermedad de Alzheimer , Encéfalo , Susceptibilidad a Enfermedades , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Animales , Encéfalo/irrigación sanguínea , Encéfalo/citología , Encéfalo/metabolismo , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Estudio de Asociación del Genoma Completo , Hipocampo/irrigación sanguínea , Hipocampo/citología , Hipocampo/metabolismo , Humanos , Ratones , Microglía/metabolismo , Pericitos/metabolismo , TranscriptomaRESUMEN
The hippocampus is a small but complex grey matter structure that plays an important role in spatial and episodic memory and can be affected by a wide range of pathologies including vascular abnormalities. In this work, we introduce the use of Ferumoxytol, an ultra-small superparamagnetic iron oxide (USPIO) agent, to induce susceptibility in the arteries (as well as increase the susceptibility in the veins) to map the hippocampal micro-vasculature and to evaluate the quantitative change in tissue fractional vascular density (FVD), in each of its subfields. A total of 39 healthy subjects (aged 35.4 ± 14.2 years, from 18 to 81 years old) were scanned with a high-resolution (0.22×0.44×1 mm3) dual-echo SWI sequence acquired at four time points during a gradual increase in Ferumoxytol dose (final dose = 4 mg/kg). The volumes of each subfield were obtained automatically from the pre-contrast T1-weighted data. The dynamically acquired SWI data were co-registered and adaptively combined to reduce the blooming artifacts from large vessels, preserving the contrast from smaller vessels. The resultant SWI data were used to segment the hippocampal vasculature and to measure the FVD ((volume occupied by vessels)/(total volume)) for each subfield. The hippocampal fissure, along with the fimbria, granular cell layer of the dentate gyrus and cornu ammonis layers (except for CA1), showed higher micro-vascular FVD than the other parts of hippocampus. The CA1 region exhibited a significant correlation with age (R = -0.37, p < 0.05). demonstrating an overall loss of hippocampal vascularity in the normal aging process. Moreover, the vascular density reduction was more prominent than the age correlation with the volume reduction (R = -0.1, p > 0.05) of the CA1 subfield, which would suggest that vascular degeneration may precede tissue atrophy.
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Mapeo Encefálico/métodos , Óxido Ferrosoférrico/administración & dosificación , Hipocampo/irrigación sanguínea , Angiografía por Resonancia Magnética/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Voluntarios Sanos , Humanos , Masculino , Microcirculación , Persona de Mediana EdadRESUMEN
AIMS: Acetaminophen or paracetamol (PAR), the recommended antipyretic in COVID-19 and clinically used to alleviate stroke-associated hyperthermia interestingly activates cannabinoid receptor (CB1) through its AM404 metabolite, however, to date, no study reports the in vivo activation of PAR/AM404/CB1 axis in stroke. The current study deciphers the neuroprotective effect off PAR in cerebral ischemia/reperfusion (IR) rat model and unmasks its link with AM404/CB1/PI3K/Akt axis. MATERIALS AND METHODS: Animals were allocated into 5 groups: (I) sham-operated (SO), (II) IR, (III) IR + PAR (100 mg/kg), (IV) IR + PAR (100 mg/kg) + URB597; anandamide degradation inhibitor (0.3 mg/kg) and (V) IR + PAR (100 mg/kg) + AM4113; CB1 Blocker (5 mg/kg). All drugs were intraperitoneally administered at the inception of the reperfusion period. KEY FINDINGS: PAR administration alleviated the cognitive impairment in the Morris Water Maze as well as hippocampal histopathological and immunohistochemical examination of GFAP. The PAR signaling was associated with elevation of anandamide level, CB1 receptor expression and survival proteins as pS473-Akt. P(tyr202/thr204)-ERK1/2 and pS9-GSK3ß. Simultaneously, PAR increased hippocampal BDNF and ß-arrestin1 levels and decreased glutamate level. PAR restores the deranged redox milieu induced by IR Injury, by reducing lipid peroxides, myeloperoxidase activity and NF-κB and increasing NPSH, total antioxidant capacity, nitric oxide and Nrf2 levels. The pre-administration of AM4113 reversed PAR effects, while URB597 potentiated them. SIGNIFICANCE: PAR poses a significant neuroprotective effect which may be mediated, at least in part, via activation of anandamide/CB1/PI3K/Akt pathway in the IR rat model.
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Acetaminofén/farmacología , Antipiréticos/farmacología , Benzamidas/farmacología , Carbamatos/farmacología , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Daño por Reperfusión/metabolismo , Amidohidrolasas/antagonistas & inhibidores , Animales , Ácidos Araquidónicos/metabolismo , Antagonistas de Receptores de Cannabinoides/farmacología , Endocannabinoides/metabolismo , Hipocampo/irrigación sanguínea , Hipocampo/metabolismo , Hipocampo/fisiopatología , Fosfatidilinositol 3-Quinasas/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Daño por Reperfusión/fisiopatologíaRESUMEN
Our purpose is to assess the role of deep medullary veins (DMVs) in pathogenesis of MRI-visible perivascular spaces (PVS) in patients with cerebral small vessel disease (cSVD). Consecutive patients recruited in the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) were included. Susceptibility Weighted Imaging-Phase images were used to evaluate DMVs based on a brain region-based visual score. T2 weighted images were used to evaluate PVS based on the five-point score, and PVS in basal ganglia (BG-PVS), centrum semiovale (CSO-PVS) and hippocampus (H-PVS) were evaluated separately. 270 patients were included. The severity of BG-PVS, CSO-PVS and H-PVS was positively related to the increment of age (all p < 0.05). The severity of BG-PVS and H-PVS was positively related to DMVs score (both p < 0.05). Patients with more severe BG-PVS had higher Fazekas scores in both periventricle and deep white matter (both p < 0.001) and higher frequency of hypertension (p = 0.008). Patients with more severe H-PVS had higher frequency of diabetes (p < 0.001). Besides, high DMVs score was an independent risk factor for more severe BG-PVS (ß = 0.204, p = 0.001). Our results suggested that DMVs disruption might be involved in the pathogenesis of BG-PVS.
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Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Imagen por Resonancia Magnética , Anciano , Femenino , Hipocampo/irrigación sanguínea , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Objectives: Cerebral ischemia is caused by a reduction of the blood flow in a specific area in the brain, triggering cellular cascades in the tissue that result in neuronal death. This phenomenon leads to neurological decline in patients with stroke. The extent of the injury after stroke could be related to the condition of obesity. Thus, we aim to analyze the effect of obesity induced by a high fructose diet (HFD) on the brain after cerebral ischemia in rats.Methods: We induced the obesity model in female Wistar rats with 20% fructose in water for 11 weeks. We then performed cerebral ischemia surgery (2-vessel occlusion), carried out the neurological test 6, 24 and 48â h post-ischemia and analyzed the histological markers.Results: The HFD induced an obese phenotype without insulin resistance. The obese rats exhibited worse neurological performance at 6â h post-ischemia and showed neuronal loss and astroglial and microglial immunoreactivity changes in the caudate putamen, motor cortex, amygdala and hippocampus at 48â h post-ischemia. However, the most commonly affected area was the hippocampus, where we found an increase in interleukin 1ß in the blood vessels of the dentate gyrus, a remarkable disruption of MAP-2+ dendrites, a loss of brain-derived neurotrophic factor and the presence of PHF-tau. In conclusion, a HFD induces an obese phenotype and worsens the neuronal loss, inflammation and plasticity impairment in the hippocampus after cerebral ischemia.
Asunto(s)
Isquemia Encefálica/fisiopatología , Azúcares de la Dieta/administración & dosificación , Fructosa/administración & dosificación , Hipocampo/fisiopatología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Obesidad/etiología , Obesidad/fisiopatología , Animales , Femenino , Hipocampo/irrigación sanguínea , Inflamación , Ratas , Ratas WistarRESUMEN
Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response.
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Circulación Cerebrovascular , Hipocampo , Neuronas/metabolismo , Vía Perforante , Animales , Hipocampo/irrigación sanguínea , Hipocampo/metabolismo , Hiperemia/metabolismo , Masculino , Agonistas Muscarínicos/farmacología , Antagonistas Muscarínicos/farmacología , Vía Perforante/irrigación sanguínea , Vía Perforante/metabolismo , Pilocarpina/farmacología , Corteza Prefrontal/irrigación sanguínea , Corteza Prefrontal/metabolismo , Ratas , Ratas Wistar , Escopolamina/farmacologíaRESUMEN
The hippocampal formation is critically involved in learning and memory and contains a large proportion of neurons encoding aspects of the organism's spatial surroundings. In the medial entorhinal cortex (MEC), this includes grid cells with their distinctive hexagonal firing fields as well as a host of other functionally defined cell types including head direction cells, speed cells, border cells, and object-vector cells. Such spatial coding emerges from the processing of external inputs by local microcircuits. However, it remains unclear exactly how local microcircuits and their dynamics within the MEC contribute to spatial discharge patterns. In this review we focus on recent investigations of intrinsic MEC connectivity, which have started to describe and quantify both excitatory and inhibitory wiring in the superficial layers of the MEC. Although the picture is far from complete, it appears that these layers contain robust recurrent connectivity that could sustain the attractor dynamics posited to underlie grid pattern formation. These findings pave the way to a deeper understanding of the mechanisms underlying spatial navigation and memory.
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Corteza Entorrinal/irrigación sanguínea , Corteza Entorrinal/fisiología , Hipocampo/irrigación sanguínea , Células Piramidales/fisiología , Potenciales de Acción/fisiología , Animales , Humanos , Aprendizaje/fisiología , Neuronas/fisiologíaRESUMEN
Exercise is beneficial for brain health, inducing neuroplasticity and vascular plasticity in the hippocampus, which is possibly mediated by brain-derived neurotrophic factor (BDNF) levels. Here we investigated the short-term effects of exercise, to determine if a 1-week intervention is sufficient to induce brain changes. Fifteen healthy young males completed five supervised exercise training sessions over seven days. This was preceded and followed by a multi-modal magnetic resonance imaging (MRI) scan (diffusion-weighted MRI, perfusion-weighted MRI, dual-calibrated functional MRI) acquired 1 week apart, and blood sampling for BDNF. A diffusion tractography analysis showed, after exercise, a significant reduction relative to baseline in restricted fraction-an axon-specific metric-in the corpus callosum, uncinate fasciculus, and parahippocampal cingulum. A voxel-based approach found an increase in fractional anisotropy and reduction in radial diffusivity symmetrically, in voxels predominantly localised in the corpus callosum. A selective increase in hippocampal blood flow was found following exercise, with no change in vascular reactivity. BDNF levels were not altered. Thus, we demonstrate that 1 week of exercise is sufficient to induce microstructural and vascular brain changes on a group level, independent of BDNF, providing new insight into the temporal dynamics of plasticity, necessary to exploit the therapeutic potential of exercise.
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Circulación Cerebrovascular , Ejercicio Físico , Hipocampo/irrigación sanguínea , Sustancia Blanca/irrigación sanguínea , Adulto , Hipocampo/anatomía & histología , Humanos , Imagen por Resonancia Magnética , Masculino , Sustancia Blanca/anatomía & histología , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this study was to assess cerebral blood flow (CBF) and its association with self-reported symptoms in chronic traumatic brain injury (TBI). PARTICIPANTS: Sixteen participants with mild to severe TBI and persistent self-reported neurological symptoms, 6 to 72 months post-injury were included. For comparison, 16 age- and gender-matched healthy normal control participants were also included. MAIN MEASURES: Regional CBF and brain volume were assessed using pseudo-continuous Arterial Spin Labeling (PCASL) and T1-weighted data respectively. Cognitive function and self-reported symptoms were assessed in TBI participants using the national institutes of health (NIH) Toolbox Cognition Battery and Patient-Reported Outcome Measurement Information System respectively. Associations between CBF and cognitive function, symptoms were assessed. RESULTS: Global CBF and regional brain volumes were similar between groups, but region of interest (ROI) analysis revealed lower CBF bilaterally in the thalamus, hippocampus, left caudate, and left amygdala in the TBI group. Voxel-wise analysis revealed that CBF in the hippocampus, parahippocampus, rostral anterior cingulate, inferior frontal gyrus, and other temporal regions were negatively associated with self-reported anger, anxiety, and depression symptoms. Furthermore, region of interest (ROI) analysis revealed that hippocampal and rostral anterior cingulate CBF were negatively associated with symptoms of fatigue, anxiety, depression, and sleep issues. CONCLUSION: Regional CBF deficit was observed in the group with chronic TBI compared to the normal control (NC) group despite similar volume of cerebral structures. The observed negative correlation between regional CBF and affective symptoms suggests that CBF-targeted intervention may potentially improve affective symptoms and quality of life after TBI, which needs to be assessed in future studies.
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Lesiones Traumáticas del Encéfalo/fisiopatología , Lesiones Traumáticas del Encéfalo/psicología , Circulación Cerebrovascular , Giro del Cíngulo/irrigación sanguínea , Hipocampo/irrigación sanguínea , Trastornos del Humor/fisiopatología , Trastornos del Humor/psicología , Adulto , Lesiones Traumáticas del Encéfalo/complicaciones , Lesión Encefálica Crónica , Enfermedad Crónica , Cognición , Femenino , Giro del Cíngulo/fisiopatología , Hipocampo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Trastornos del Humor/etiología , Pruebas Neuropsicológicas , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/fisiopatología , Trastornos del Sueño-Vigilia/psicología , Marcadores de Spin , Resultado del TratamientoRESUMEN
Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected in rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice reveal an age-associated decline in cerebral blood flow and differential gene expression. In fact, BCAS and aging caused broadly similar effects. However, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those already present in sham aged mice. Over 30 days, BCAS in aged mice had minimal effect on either cerebral blood flow or hippocampal gene expression. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.
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Envejecimiento/genética , Perfilación de la Expresión Génica , Hipocampo/irrigación sanguínea , Hipocampo/metabolismo , Animales , Circulación Cerebrovascular/genética , Enfermedad Crónica , Regulación de la Expresión Génica , Ontología de Genes , Masculino , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
Compromise of the vascular system has important consequences on cognitive abilities and neurodegeneration. The identification of the main molecular signatures present in the blood vessels of human hippocampus could provide the basis to understand and tackle these pathologies. As direct vascular experimentation in hippocampus is problematic, we achieved this information by computationally disaggregating publicly available whole microarrays data of human hippocampal homogenates. Three conditions were analyzed: 'Young Adults', 'Aged', and 'aged with Mild Cognitive Impairment' (MCI). The genes identified were contrasted against two independent data-sets. Here we show that the endothelial cells from the Younger Group appeared in an 'activated stage'. In turn, in the Aged Group, the endothelial cells showed a significant loss of response to shear stress, changes in cell adhesion molecules, increased inflammation, brain-insulin resistance, lipidic alterations, and changes in the extracellular matrix. Some specific changes in the MCI group were also detected. Noticeably, in this study the features arisen from the Aged Group (high tortuosity, increased bifurcations, and smooth muscle proliferation), pose the need for further experimental verification to discern between the occurrence of arteriogenesis and/or vascular remodeling by capillary arterialization. This article has an associated First Person interview with the first author of the paper.
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Envejecimiento/genética , Disfunción Cognitiva/etiología , Endotelio/metabolismo , Perfilación de la Expresión Génica , Hipocampo/metabolismo , Transcriptoma , Factores de Edad , Envejecimiento/metabolismo , Empalme Alternativo , Biomarcadores , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Encéfalo/fisiopatología , Proliferación Celular , Disfunción Cognitiva/metabolismo , Biología Computacional/métodos , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Hipocampo/irrigación sanguínea , Hipocampo/fisiopatología , HumanosRESUMEN
The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer's disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer's disease, where the brain's energy supply is decreased.
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Hipocampo/irrigación sanguínea , Microcirculación/fisiología , Neocórtex/irrigación sanguínea , Corteza Visual/irrigación sanguínea , Adenosina Trifosfato/biosíntesis , Enfermedad de Alzheimer/fisiopatología , Animales , Hipoxia de la Célula/fisiología , Demencia Vascular/fisiopatología , Femenino , Hipocampo/citología , Hipocampo/diagnóstico por imagen , Hipocampo/fisiopatología , Humanos , Microscopía Intravital , Flujometría por Láser-Doppler , Masculino , Ratones , Microscopía de Fluorescencia por Excitación Multifotónica , Microvasos/diagnóstico por imagen , Microvasos/fisiología , Modelos Animales , Neocórtex/citología , Neocórtex/diagnóstico por imagen , Neocórtex/fisiopatología , Neuronas/metabolismo , Acoplamiento Neurovascular/fisiología , Fosforilación Oxidativa , Oxígeno/análisis , Oxígeno/metabolismo , Memoria Espacial/fisiología , Corteza Visual/citología , Corteza Visual/fisiopatologíaRESUMEN
Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aß) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aß plaque deposition, the primary pathophysiology of Alzheimer's disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aß plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aß plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aß plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aß plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Precursor de Proteína beta-Amiloide , Capilares/efectos de los fármacos , Disfunción Cognitiva/tratamiento farmacológico , Ácidos Cumáricos/administración & dosificación , Presenilina-1 , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Capilares/patología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Hipocampo/irrigación sanguínea , Hipocampo/efectos de los fármacos , Hipocampo/patología , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Presenilina-1/genéticaRESUMEN
Cerebrovascular lesions seen as white matter hyperintensity in MRI of elderly population caused due to micro-infracts and micro-bleeds contributes to vascular dementia. Such vascular insult caused by impairment in blood flow to specific area in brain involving small vessels can gradually worsen the pathology leading to cognitive deficits. In the present study we developed a transient model of vaso-constriction to study the impact of such pathology by bilateral injection of ET-1 (Endothelin-1; a 21 amino acid vasoconstricting peptide) into lateral ventricles of C57 mice. The impediment in cerebral blood flow decreased CD31 expression in endothelial cells lining the blood vessels around the hippocampal region, leading to memory deficits after 7 days. Activity dependent protein translation, critical for synaptic plasticity was absent in synaptoneurosomes prepared from hippocampal tissue. Further, Akt1- mTOR signaling cascade was downregulated indicating the possible cause for loss of activity dependent protein translation. However, these effects were reversed after 30 days indicating the ephemeral nature of deficits following a single vascular insult. Present study demonstrates that vasoconstriction leading to memory deficit and decline in activity dependent protein translation in hippocampus as a potential molecular mechanism impacting synaptic plasticity.
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Células Endoteliales/metabolismo , Endotelina-1/biosíntesis , Hipocampo/metabolismo , Trastornos de la Memoria/metabolismo , Sinapsis/metabolismo , Vasoconstricción , Animales , Células Endoteliales/patología , Hipocampo/irrigación sanguínea , Hipocampo/patología , Masculino , Trastornos de la Memoria/patología , Ratones , Plasticidad Neuronal , Sinapsis/patologíaRESUMEN
Blood-brain barrier (BBB) breakdown occurs in aging and neurodegenerative diseases. Although age-associated alterations have previously been described, most studies focused in male brains; hence, little is known about BBB breakdown in females. This study measured ultrastructural features in the aging female BBB using transmission electron microscopy and 3-dimensional reconstruction of cortical and hippocampal capillaries from 6- and 24-month-old female C57BL/6J mice. Aged cortical capillaries showed more changes than hippocampal capillaries. Specifically, the aged cortex showed thicker basement membrane, higher number and volume of endothelial pseudopods, decreased endothelial mitochondrial number, larger pericyte mitochondria, higher pericyte-endothelial cell contact, and increased tight junction tortuosity compared with young animals. Only increased basement membrane thickness and pericyte mitochondrial volume were observed in the aged hippocampus. Regional comparison revealed significant differences in endothelial pseudopods and tight junctions between the cortex and hippocampus of 24-month-old mice. Therefore, the aging female BBB shows region-specific ultrastructural alterations that may lead to oxidative stress and abnormal capillary blood flow and barrier stability, potentially contributing to cerebrovascular diseases, particularly in postmenopausal women.
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Envejecimiento/patología , Barrera Hematoencefálica/ultraestructura , Capilares/ultraestructura , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/ultraestructura , Hipocampo/irrigación sanguínea , Hipocampo/ultraestructura , Animales , Membrana Basal/patología , Membrana Basal/ultraestructura , Barrera Hematoencefálica/patología , Capilares/patología , Corteza Cerebral/patología , Femenino , Hipocampo/patología , Ratones Endogámicos C57BL , Microscopía Electrónica de Transmisión , Tamaño Mitocondrial , Estrés Oxidativo , Pericitos/patología , Pericitos/ultraestructura , PosmenopausiaRESUMEN
Cerebrovascular dysfunction likely contributes causally to Alzheimer's disease (AD). The strongest genetic risk factor for late-onset AD, Apolipoprotein E4 (APOE4), may act synergistically with vascular risk to cause dementia. Therefore, interventions that improve vascular health, such as exercise, may be particularly beneficial for APOE4 carriers. We assigned cognitively normal adults (65-87 years) to an aerobic exercise intervention or education only. Arterial spin labeling MRI measured hippocampal blood flow (HBF) before and after the 52-week intervention. We selected participants with hypertension at enrollment (n = 44). For APOE4 carriers, change in HBF (ΔHBF) was significantly (p = 0.006) higher for participants in the exercise intervention (4.09 mL/100g/min) than the control group (-2.08 mL/100g/min). There was no difference in ΔHBF between the control (-0.32 mL/100g/min) and exercise (-0.54 mL/100g/min) groups for non-carriers (p = 0.918). Additionally, a multiple regression showed an interaction between change in systolic blood pressure (ΔSBP) and APOE4 carrier status on ΔHBF (p = 0.035), with reductions in SBP increasing HBF for APOE4 carriers only. Aerobic exercise improved HBF for hypertensive APOE4 carriers only. Additionally, only APOE4 carriers exhibited an inverse relationship between ΔSBP and ΔHBF. This suggests exercise interventions, particularly those that lower SBP, may be beneficial for individuals at highest genetic risk of AD.ClinicalTrials.gov Identifier: NCT02000583.
Asunto(s)
Apolipoproteína E4/genética , Presión Sanguínea/fisiología , Ejercicio Físico , Hipocampo/irrigación sanguínea , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Circulación Cerebrovascular/fisiología , Disfunción Cognitiva/genética , Disfunción Cognitiva/patología , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Hipertensión/genética , Hipertensión/patología , Modelos Lineales , Imagen por Resonancia Magnética/métodos , Masculino , Marcadores de SpinRESUMEN
Microvascular damage in the hippocampus is emerging as a central cause of cognitive decline and dementia in aging. This could be a consequence of age-related decreases in vascular elasticity, exposing hippocampal capillaries to excessive cardiac-related pulsatile flow that disrupts the blood-brain barrier and the neurovascular unit. Previous studies have found altered intracranial hemodynamics in cognitive impairment and dementia, as well as negative associations between pulsatility and hippocampal volume. However, evidence linking features of the cerebral arterial flow waveform to hippocampal function is lacking. We used a high-resolution 4D flow MRI approach to estimate global representations of the time-resolved flow waveform in distal cortical arteries and in proximal arteries feeding the brain in healthy older adults. Waveform-based clustering revealed a group of individuals featuring steep systolic onset and high amplitude that had poorer hippocampus-sensitive episodic memory (p = 0.003), lower whole-brain perfusion (p = 0.001), and weaker microvascular low-frequency oscillations in the hippocampus (p = 0.035) and parahippocampal gyrus (p = 0.005), potentially indicating compromised neurovascular unit integrity. Our findings suggest that aberrant hemodynamic forces contribute to cerebral microvascular and hippocampal dysfunction in aging.
Asunto(s)
Envejecimiento , Encéfalo/irrigación sanguínea , Arterias Cerebrales/fisiología , Disfunción Cognitiva/fisiopatología , Hipocampo/fisiología , Memoria Episódica , Flujo Pulsátil , Anciano , Circulación Cerebrovascular , Femenino , Voluntarios Sanos , Hipocampo/irrigación sanguínea , Humanos , Masculino , Persona de Mediana Edad , Rigidez VascularRESUMEN
Vascular dysregulation and cholinergic basal forebrain degeneration are both early pathological events in the development of Alzheimer's disease (AD). Acetylcholine contributes to localised arterial dilatation and increased cerebral blood flow (CBF) during neurovascular coupling via activation of endothelial nitric oxide synthase (eNOS). Decreased vascular reactivity is suggested to contribute to impaired clearance of ß-amyloid (Aß) along intramural periarterial drainage (IPAD) pathways of the brain, leading to the development of cerebral amyloid angiopathy (CAA). However, the possible relationship between loss of cholinergic innervation, impaired vasoreactivity and reduced clearance of Aß from the brain has not been previously investigated. In the present study, intracerebroventricular administration of mu-saporin resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. Arterial spin labelling MRI revealed a loss of CBF response to stimulation of eNOS by the Rho-kinase inhibitor fasudil hydrochloride in the cortex of denervated mice. By contrast, the hippocampus remained responsive to drug treatment, in association with altered eNOS expression. Fasudil hydrochloride significantly increased IPAD in the hippocampus of both control and saporin-treated mice, while increased clearance from the cortex was only observed in control animals. Administration of mu-saporin in the TetOAPPSweInd mouse model of AD was associated with a significant and selective increase in Aß40-positive CAA. These findings support the importance of the interrelationship between cholinergic innervation and vascular function in the aetiology and/or progression of CAA and suggest that combined eNOS/cholinergic therapies may improve the efficiency of Aß removal from the brain and reduce its deposition as CAA.