ABSTRACT
PURPOSE: Acute ischemic stroke induces deoxyhemoglobin accumulation around the ischemic region while activating endothelial nitric oxide synthase (eNOS) coupling and the subsequent release of nitric oxide (NO). Because deoxyhemoglobin is a natural NO spin trap, its interplay with NO could be prominent during acute stroke. Its interaction with NO has been shown to induce overt paramagnetic signals in vitro; our goal was to investigate whether this interplay can be detected using MRI. METHODS: To verify the in vivo image effects using the deoxyhemoglobin-NO interaction during acute stroke, eNOS states were manipulated in an animal model of acute ischemia, and the susceptibility signals, cerebral perfusion, and infarction were assessed noninvasively via MR susceptibility weighted imaging (SWI). RESULTS: Occlusion of the right middle cerebral artery increased eNOS coupling and susceptibility signals in the ischemic cortex while abolishing regional cerebral blood flow. Pharmacological eNOS blockage led to weakened susceptibility signals in the ischemic cortex as well as worsened tissue survival. Consistently, abolishment of eNOS coupling through genetic editing reduced the regional susceptibility signals in the ischemic cortex, causing large infarcts. CONCLUSION: Upregulation of eNOS during acute ischemia sustains tissue viability through the interaction between NO and deoxyhemoglobin. This interplay can be traced in vivo using SWI and can be considered a sensitive marker revealing the delicate oxygenation status of the ischemic tissue, therefore, guiding the management of acute stroke in clinical settings.
Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke , Animals , Brain Ischemia/diagnostic imaging , Magnetic Resonance Spectroscopy , Nitric Oxide Synthase Type III , Stroke/diagnostic imagingABSTRACT
BACKGROUND: Adipose tissue is closely related to bone mass, bone quality, and bone fractures, but the connection between fat and bone is complex and gender-related. Fat-water magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are very useful tools for identifying tissue fat. PURPOSE: To assess gender interactions between bone mineral density (BMD), bone marrow fat, and body mass index (BMI) in the elderly using fat-water MRI and MRS. STUDY TYPE: Prospective/cohort. POPULATION: Sixty-six women and 38 men (mean age, 62.3 years; range, 50-75 years), Asian. FIELD STRENGTH: A 1.5T MR equipped with a body and spine array coil. STEAM MRS and T2 * Dixon were performed. ASSESSMENT: Vertebral bone marrow fat ratio (MFR), BMI, and BMD were measured. Correlations between these variables and differences in bone density in MFR were assessed between participants, divided into three groups based on bone density. STATISTICAL TESTS: Multiple regression; Pearson tests; analysis of covariance; analysis of variance. RESULTS: Multiple regression analysis identified gender, vertebral bone MFR, and BMI as significant predictors of vertebral BMD (P < 0.001). Among the women, vertebral BMD was negatively correlated with vertebral MFR (P = 0.011), but among the men, it was positively correlated with BMI (P = 0.048), although this relationship was confounded by age and MFR. Moreover, vertebral bone marrow fat and BMI were indeed statistically uncorrelated in the elderly (P = 0.357 in women; P = 0.961 in men). DATA CONCLUSION: We found gender interactions between fat and bone in the elderly. Higher bone marrow fat was correlated with lower trabecular BMD in older women but not in men. On the other hand, the positive correlation between BMI and BMD was more pronounced in men than in women. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1382-1389.
Subject(s)
Bone Density , Water , Adipose Tissue/diagnostic imaging , Aged , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Prospective Studies , SpineABSTRACT
Spinocerebellar ataxia (SCA) is a hereditary neurodegenerative disease. We have generated SCA17 transgenic mice bearing human TBP with 109 CAG repeats under the Purkinje cell-specific L7/pcp2 promoter. These mice recapitulate the patients' phenotypes and are suitable for the study of the SCA17 pathomechanism. Magnetic resonance imaging (MRI) and immunostainings were performed to identify the neuroimaging spectrum during disease progression. The results indicate that despite an overall normal appearance at birth, postnatal brain damage takes place rapidly in SCA17. Cerebellar atrophy, fourth-ventricle enlargement, and reduced cerebellar N-acetylaspartate levels were detected at the presymptomatic stage, when the mice were juvenile. The aberrations, which included reductions in body weight; cerebral size; striatal size; and the mean, radial, and axial diffusivities of the cerebellum, became more salient as the disease progressed to the old, late-symptomatic stage. Phosphorylated H2A histone family, member X (γH2AX) immunostaining revealed that the cerebellum underwent severe cell senescence in the old stage while the striatum appeared relatively unaffected by aging. Morphometric analysis indicated that the cerebellar atrophy occurred in all subregions with aging. The data establish that the SCA17 mouse brain appears normal at birth but becomes aberrant at the presymptomatic/juvenile stage. More widespread deficits add to the pathological spectrum at the old stage. The study provides information for the expression and expansion of L7/pcp2 promoter and implies the disease progression of SCA17 patients.
Subject(s)
Brain/pathology , Spinocerebellar Ataxias/pathology , Animals , Disease Models, Animal , Disease Progression , Humans , Magnetic Resonance Imaging , Mice , Mice, Transgenic , Neuroimaging/methodsABSTRACT
OBJECTIVE: Huntington disease (HD) is an inherited neurodegenerative disease caused by the mutant huntingtin gene (mHTT), which harbors expanded CAG repeats. We previously reported that the brain vessel density is higher in mice and patients with HD than in controls. The present study determines whether vascular function is altered in HD and characterizes the underlying mechanism. METHODS: The brain vessel density and vascular reactivity (VR) to carbogen challenge of HD mice were monitored by 3D ΔR2 -mMRA and blood oxygenation level-dependent (BOLD)/flow-sensitive alternating inversion recovery (FAIR) magnetic resonance imaging (MRI), respectively. The amount of vascular endothelial growth factor (VEGF)-A and the pericyte coverage were determined by immunohistochemistry and enzyme-linked immunosorbent assay in human and mouse brain sections, primary mouse astrocytes and pericytes, and human astrocytes derived from induced pluripotent stem cells. RESULTS: Expression of mHTT in astrocytes and neurons is sufficient to increase the brain vessel density in HD mice. BOLD and FAIR MRI revealed gradually impaired VR to carbogen in HD mice. Astrocytes from HD mice and patients contained more VEGF-A, which triggers proliferation of endothelial cells and may be responsible for the augmented neurovascular changes. Moreover, an astrocytic inflammatory response, which reduces the survival of pericytes through an IκB kinase-dependent pathway, mediates the low pericyte coverage of blood vessels in HD brains. INTERPRETATION: Our findings suggest that the inflammation-prone HD astrocytes provide less pericyte coverage by promoting angiogenesis and reducing the number of pericytes and that these changes can explain the inferior VR in HD mice. The resultant impaired VR might hinder cerebral hemodynamics and increase brain atrophy during HD progression.
Subject(s)
Astrocytes/metabolism , Blood Vessels/metabolism , Brain/blood supply , Huntington Disease/metabolism , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Nuclear Proteins/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Animals , Astrocytes/pathology , Blood Vessels/pathology , Blood Vessels/physiopathology , Brain/metabolism , Brain/pathology , Cells, Cultured , Female , Humans , Huntingtin Protein , Huntington Disease/pathology , Huntington Disease/physiopathology , Induced Pluripotent Stem Cells/metabolism , Magnetic Resonance Angiography , Magnetic Resonance Imaging , Male , Mice , Mice, Transgenic , Middle Aged , Pericytes/pathologyABSTRACT
Decreased cerebral blood volume/flow (CBV/CBF) contributes to negative blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signals. But it is still strongly debated whether these negative BOLD or CBV/CBF signals are indicative of decreased or increased neuronal activity. The fidelity of Ca(2+) signals in reflecting neuronal excitation is well documented. However, the roles of Ca(2+) signals and Ca(2+)-dependent activity in negative fMRI signals have never been explored; an understanding of this is essential to unraveling the underlying mechanisms and correctly interpreting the hemodynamic response of interest. The present study utilized a nociception-induced negative CBV fMRI response as a model. Ca(2+) signals were investigated in vivo using Mn(2+)-enhanced MRI (MEMRI), and the downstream Ca(2+)-dependent signaling was investigated using phosphorylated cAMP response-element-binding (pCREB) immunohistology. The results showed that nociceptive stimulation led to (1) striatal CBV decreases, (2) Ca(2+) increases via the nigrostriatal pathway, and (3) substantial expression of pCREB in substantia nigra dopaminergic neurons and striatal neurons. Interestingly, the striatal negative fMRI response was abolished by blocking substantia nigra activity but was not affected by blocking the striatal activity. This suggests the importance of input activity other than output in triggering the negative CBV signals. These findings indicate that the striatal negative CBV fMRI signals are associated with Ca(2+) increases and Ca(2+)-dependent signaling along the nigrostriatal pathway. The obtained data reveal a new brain road map in response to nociceptive stimulation of hemodynamic changes in association with Ca(2+) signals within the dopaminergic system.
Subject(s)
Brain Mapping , Brain/blood supply , Brain/physiology , Calcium/metabolism , Cerebrovascular Circulation/physiology , Animals , Blood Volume , Hemodynamics/physiology , Image Processing, Computer-Assisted , Immunohistochemistry , Magnetic Resonance Imaging , Male , Nociception/physiology , Rats , Rats, Sprague-DawleyABSTRACT
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is associated with high mortality and neurological deficits, and concurrent hyperglycemia usually worsens clinical outcomes. Aquaporin-4 (AQP-4) is important in cerebral water movement. Our aim was to investigate the role of AQP-4 in hyperglycemic ICH. METHODS: Hyperglycemia was induced by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg) in adult Sprague-Dawley male rats. ICH was induced by stereotaxic infusion of collagenase/heparin into the right striatum. One set of rats was repeatedly monitored by MRI at 1, 4, and 7 days after ICH induction so as to acquire information on the formation of hematoma and edema. Another set of rats was killed and brains were examined for differences in the degree of hemorrhage and edema, water content, blood-brain barrier destruction, and AQP-4 expression. RESULTS: Hyperglycemia ICH rats exhibited increased brain water content, more severe blood-brain barrier destruction, and greater vasogenic edema as seen on diffusion-weighted MRI. Significant downregulation of AQP-4 was observed in STZ-treated rats after ICH as compared with non-STZ-treated rats. Apoptosis was greater on day 1 after ICH in STZ-treated rats. CONCLUSIONS: The expression of AQP-4 in the brain is downregulated in hyperglycemic rats as compared with normoglycemic rats after ICH. This change is accompanied by increased vasogenic brain edema and more severe blood-brain barrier destruction.
Subject(s)
Aquaporin 4/physiology , Cerebral Hemorrhage/epidemiology , Cerebral Hemorrhage/physiopathology , Diffusion Magnetic Resonance Imaging , Down-Regulation/physiology , Hyperglycemia/epidemiology , Hyperglycemia/physiopathology , Animals , Aquaporin 4/genetics , Brain Edema/epidemiology , Brain Edema/pathology , Cerebral Hemorrhage/chemically induced , Collagenases/administration & dosage , Collagenases/adverse effects , Comorbidity , Disease Models, Animal , Hematoma/epidemiology , Hematoma/pathology , Heparin/administration & dosage , Heparin/adverse effects , Hyperglycemia/chemically induced , Incidence , Infusions, Intraventricular , Injections, Intraperitoneal , Male , Rats , Rats, Sprague-Dawley , Streptozocin/administration & dosage , Streptozocin/adverse effectsABSTRACT
Nonmotor manifestations determine the life quality of patients with Parkinson's disease (PD). Identification of the nonmotor symptoms in PD as definite changes will represent a milestone in its diagnosis. Outcome measures that characterize nonmotor manifestations with specificity for dopaminergic deficiency are essential to that goal. Pain is a prevalent sensory disturbance in PD patients. The prevalence was reported to be up to 83%. Nociceptive stimuli under normal conditions elicit decreases in cerebral blood volume (CBV) in the striatum via dopaminergic neurotransmission. This nociception-induced CBV response is potentially to be defined as a characteristic of the pain symptom of PD. To validate this concept, steady-state CBV-weighted functional magnetic resonance imaging with iron oxide nanoparticles was employed to measure CBV changes in parkinsonian rats. Tyrosine hydroxylase immunohistology was used to identify the dopaminergic integrity to corroborate the imaging findings. Additional experiments that tested pain responses in parkinsonism were also carried out. The results revealed that the lesioned striatum exhibited a weakened CBV decrease in response to the nociceptive stimulus. This weakened CBV response occurred mainly in areas with dopaminergic denervation. A strong correspondence was observed between the distributions of the nociception-induced CBV responses and dopaminergic innervation. The persisting CBV signals in the striatum were abolished by the D2/D3 antagonist eticlopride. The findings of these behavioral, neuroimaging, immunohistological, and pharmacological experiments demonstrate that pain in a rat model of PD can be characterized by nociception induced striatal CBV signal changes with specificity for dopaminergic dysfunction.
Subject(s)
Brain/physiopathology , Dopamine/metabolism , Magnetic Resonance Imaging/methods , Nociceptive Pain/physiopathology , Parkinsonian Disorders/physiopathology , Animals , Blood Volume/drug effects , Blood Volume/physiology , Blood Volume Determination/methods , Brain/drug effects , Cerebrovascular Circulation/drug effects , Cerebrovascular Circulation/physiology , Dopamine Antagonists/pharmacology , Ferric Compounds , Functional Laterality , Immunohistochemistry , Male , Metal Nanoparticles , Oxidopamine , Rats, Wistar , Salicylamides/pharmacology , Tyrosine 3-Monooxygenase/metabolismABSTRACT
In this work, we report a monodisperse bifunctional nanoparticle system, MIO@SiO2 -RITC, as an MRI contrast agent [core, manganese iron oxide (MIO); shell, amorphous silica conjugated with rhodamine B isothiocyanate (RITC)]. It was prepared by thermal decomposition and modified microemulsion methods. The nanoparticles with varying iron to manganese ratios displayed different saturated magnetizations and relaxivities. In vivo MRI of rats injected intravenously with MIO@SiO2-RITC nanoparticles exhibited enhancement of the T1 contrast in brain tissue, in particular a time-delayed enhancement in the hippocampus, pituitary gland, striatum and cerebellum. This is attributable to the gradual degradation of MIO@SiO2-RITC nanoparticles in the liver, resulting in the slow release of manganese(II) [Mn(II)] into the blood pool and, subsequently, accumulation in the brain tissue. Thus, T1-weighted contrast enhancement was clearly detected in the anatomic structure of the brain as time progressed. In addition, T2*-weighted images of the liver showed a gradual darkening effect. Here, we demonstrate the concept of the slow release of Mn(II) for neuroimaging. This new nanoparticle-based manganese contrast agent allows one simple intravenous injection (rather than multiple infusions) of Mn(II) precursor, and results in delineation of the detailed anatomic neuroarchitecture in MRI; hence, this provides the advantage of the long-term study of neural function.
Subject(s)
Brain/metabolism , Ferric Compounds , Magnetic Resonance Imaging , Manganese , Nanoparticles , Silicon Dioxide , Animals , Cell Death , Computer Simulation , Liver/physiology , Manganese/blood , Mice , Microscopy, Fluorescence , NIH 3T3 Cells , Nanoparticles/ultrastructure , Rats , Rhodamines/metabolism , Time FactorsABSTRACT
The coupling between neuronal activity and vascular responses is controlled by the neurovascular unit (NVU), which comprises multiple cell types. Many different types of dysfunction in these cells may impair the proper control of vascular responses by the NVU. Magnetic resonance imaging, which is the most powerful tool available to investigate neurovascular structures or functions, will be discussed in the present article in relation to its applications and discoveries. Because aberrant angiogenesis and vascular remodeling have been increasingly reported as being implicated in brain pathogenesis, this review article will refer to this hallmark event when suitable.
Subject(s)
Brain Diseases/pathology , Brain/blood supply , Cerebrovascular Circulation , Brain/metabolism , Brain Diseases/physiopathology , Humans , Magnetic Resonance Imaging , Neovascularization, Pathologic/pathologyABSTRACT
Functional magnetic resonance imaging (fMRI) has revolutionized investigations of brain functions. Increases in fMRI signals are usually correlated with neuronal activation, but diverse explanations have been proposed for negative fMRI responses, including decreases in neuronal activity, the vascular-steal effect, and large increases in oxygen consumption. These possible scenarios, although encompassing a wide range of potential neurovascular responses, cannot yet be used to interpret certain types of negative fMRI signals. Recent studies have found that intravenous injection of dopamine D(2) receptor (D2DR) agonist reduced the hemodynamic responses in the caudate-putamen (CPu); however, whether endogenous dopaminergic neurotransmission contributes to fMRI signals remains obscure. Since it has been suggested that the D2DR is involved in pain modulation, and the CPu shows equivocal fMRI signals during noxious stimulation, the present study established an animal model based on graded electrical stimulation to elicit different levels of nociception, and aimed to determine whether nociception-induced endogenous dopaminergic neurotransmission is sufficient to generate negative fMRI responses. Our results from cerebral blood volume (CBV)-weighted fMRI, Fos immunohistochemistry, and electrophysiological recording demonstrated a salient bilateral CBV decreases associated with heightened neuronal activity in the CPu induced by unilateral noxious electrical stimulation. In addition, preinjection of D2DR antagonist reduced the observed CBV decreases. Our findings reveal the role of the D2DR in regulating striatal vascular responses and suggest that endogenous neurotransmission-induced CBV decreases underlie negative fMRI signals. Hence, the influence of endogenous neurotransmission should be considered when interpreting fMRI data, especially in an area involved in strong vasoactive neurotransmission.
Subject(s)
Magnetic Resonance Imaging/methods , Synaptic Transmission/physiology , Animals , Brain/physiology , Brain Mapping/methods , Electric Stimulation/methods , Male , Pain Measurement/methods , Rats , Rats, WistarABSTRACT
Gout is one of the most painful disease conditions. The central mechanism of pain processing in this condition remains elusive. Cerebral blood volume (CBV) responses are faithful correlates of brain activity changes; the application of CBV-weighted functional magnetic resonance imaging (fMRI) may shed light on the issue of interest. Transient receptor potential vanilloid 1 (TRPV1) is a critical ion channel expressed both peripherally in nociceptors and centrally in the brain. Whether TRPV1 plays a critical role in gout pain was also explored. Results showed that, in rats with gouty arthritis, noxious stimulation induced CBV increases in the primary somatosensory cortex and thalamus. These increases were correlated with up-regulated TRPV1 protein expression and pain behavior. Selective blockage of central TRPV1 channel activity by intrathecal administration of AMG9810 reversed the induced pain, and abolished the induced CBV increase in thalamocortical regions. The findings support that TRPV1 activation in the central pain pathway is crucial to the augmentation of pain in gouty conditions. This new information supports the development of TRPV1-based drugs for treating gout pain, while fMRI can be useful for repeated evaluation of brain activity changes induced by gout.
Subject(s)
Arthritis, Gouty/diagnostic imaging , Magnetic Resonance Imaging , Somatosensory Cortex/diagnostic imaging , TRPV Cation Channels/metabolism , Acute Disease , Animals , Behavior, Animal , Cerebral Blood Volume , Disease Models, Animal , Inflammation/pathology , Nociception , Pain , Rats , TRPV Cation Channels/antagonists & inhibitorsABSTRACT
Nociceptive neuronal activation in subcortical regions has not been well investigated in functional magnetic resonance imaging (fMRI) studies. The present report aimed to use the blood oxygenation level-dependent (BOLD) fMRI technique to map nociceptive responses in both subcortical and cortical regions by employing a refined data processing method, the atlas registration-based event-related (ARBER) analysis technique. During fMRI acquisition, 5% formalin (50 mul) was injected into the left hindpaw to induce nociception. ARBER was then used to normalize the data among rats, and images were analyzed using automatic selection of the atlas-based region of interest. It was found that formalin-induced nociceptive processing increased BOLD signals in both cortical and subcortical regions. The cortical activation was distributed over the cingulate, motor, somatosensory, insular, and visual cortices, and the subcortical activation involved the caudate putamen, hippocampus, periaqueductal gray, superior colliculus, thalamus, and hypothalamus. With the aid of ARBER, the present study revealed a detailed activation pattern that possibly indicated the recruitment of various parts of the nociceptive system. The results also demonstrated the utilization of ARBER in establishing an fMRI-based whole-brain nociceptive map. The formalin induced nociceptive images may serve as a template of central nociceptive responses, which can facilitate the future use of fMRI in evaluation of new drugs and preclinical therapies for pain.
Subject(s)
Brain Mapping/methods , Brain/physiology , Evoked Potentials/physiology , Magnetic Resonance Imaging/methods , Pain Measurement/methods , Animals , Male , Rats , Rats, WistarABSTRACT
RATIONALE: Manganese (Mn2+)-enhanced magnetic resonance imaging (MEMRI) is an emerging in vivo MR approach for pharmacological research. One new application of MEMRI in this area is to characterize functional changes of a specific neural circuit that is essential to the central effects of a drug challenge. OBJECTIVES: To develop and validate such use of MEMRI in neuropharmacology, the current study applied MEMRI to visualize functional changes within a multisynaptic pathway originating from fasciculus retroflexus (FR) that is central to a commonly abused psychostimulant, methamphetamine (MA). METHODS: Twelve rats were injected intraperitoneally with MA (10 mg/kg) or saline every 2 h for a total of four injections. After 6 days, Mn2+ was injected into the habenular nucleus (FR origin) of all animals, and MEMRI was repeatedly performed at certain points in time over 48 h. The evolution of Mn2+-induced signal enhancement was assessed across the FR tract, the ventral tegmental area (VTA), the striatum, the nucleus accumbens, and the prefrontal cortex (PFC), in both MA-injected animals and controls. RESULTS: MA treatment was found to affect the complexity and efficiency of Mn2+ uptake in the VTA, via the FR tract, with significantly increased Mn2+ accumulation in the VTA, the dorsomedial part of the striatum, and the PFC. CONCLUSIONS: MEMRI successfully visualizes disruptions in the multisynaptic pathway as the consequences of repeated MA exposure. MEMRI is potentially an important method in the future to investigate functional changes within a specific pathway under the influences of pharmacological agents, given its excellent functional, in vivo, spatial, and temporal properties.
Subject(s)
Central Nervous System Stimulants/pharmacology , Manganese/pharmacokinetics , Methamphetamine/pharmacology , Neural Pathways/drug effects , Neurons/drug effects , Neurotoxicity Syndromes/metabolism , Animals , Cations, Divalent , Contrast Media , Corpus Striatum/pathology , Habenula/metabolism , Image Enhancement/methods , Magnetic Resonance Imaging , Male , Neural Pathways/metabolism , Neurons/metabolism , Neurons/pathology , Neurotoxicity Syndromes/pathology , Nucleus Accumbens/metabolism , Prefrontal Cortex/metabolism , Rats , Rats, Sprague-Dawley , Synapses/metabolism , Ventral Tegmental Area/metabolismABSTRACT
Immune-responsive neurons in the brainstem, primarily in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), contribute to a significant drive on forebrain nuclei responsible for brain-mediated host defense responses. The current study investigated the relative contribution of brainstem-derived ascending pathways to forebrain immune-responsive nuclei in the rat by means of retrograde tract tracing and c-Fos immunohistochemistry. Fluorogold was iontophoresed into the bed nucleus of stria terminalis (BST), central nucleus of the amygdala (CEA), paraventricular nucleus of the hypothalamus (PVN), and the pontine lateral parabrachial nucleus (PBL; an important component of ascending viscerosensensory pathways) followed 2 weeks later by intraperitoneal injection of lipopolysaccharide (LPS, 0.1 mg/kg) or saline. The NTS and VLM provide immune-responsive input to all four regions, via direct, predominantly catecholaminergic, projections to the PVN, the lateral BST, and the CEA, and mostly non-catecholaminergic projections to the PBL. The PBL provides a major LPS-activated input to the BST and CEA. The pattern of LPS-activated catecholaminergic projections from the VLM and NTS to the forebrain is characterized by a strong predominance of VLM input to the PVN, whereas the NTS provides a greater contribution to the BST. These findings indicate that direct and indirect pathways originate in the caudal brainstem that propagate immune-related information from the periphery with multiple levels of processing en route to the forebrain nuclei, which may allow for integration of brain responses to infection.
Subject(s)
Amygdala/cytology , Medulla Oblongata/cytology , Neural Pathways/cytology , Paraventricular Hypothalamic Nucleus/cytology , Septal Nuclei/cytology , Amygdala/immunology , Amygdala/metabolism , Animals , Fluorescent Dyes/metabolism , Immunohistochemistry , Lipopolysaccharides/immunology , Male , Medulla Oblongata/immunology , Medulla Oblongata/metabolism , Neural Pathways/immunology , Neural Pathways/metabolism , Neuroimmunomodulation/immunology , Neuroimmunomodulation/physiology , Paraventricular Hypothalamic Nucleus/immunology , Paraventricular Hypothalamic Nucleus/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Sprague-Dawley , Septal Nuclei/immunology , Septal Nuclei/metabolism , Visceral Afferents/cytology , Visceral Afferents/immunology , Visceral Afferents/metabolismABSTRACT
Postischemic angiogenesis is an important recovery mechanism. Both arteries and veins are upregulated during angiogenesis, but eventually there are more angiogenic veins than arteries in terms of number and length. It is critical to understand how the veins are modulated after ischemia and then transitioned into angiogenic vessels during the proangiogenic stage to finally serve as a restorative strength to the injured area. Using a rat model of transient focal cerebral ischemia, the hypercapnic blood oxygen level-dependent (BOLD) response was used to evaluate vascular reactivity, while the hyperoxic BOLD and tissue oxygen level-dependent (TOLD) responses were used to evaluate the vascular functionality at 1, 3, and 7days after ischemia. Vessel-like venous signals appeared on R2* maps on days 3 and 7, but not on day 1. The large hypercapnic BOLD responses on days 3 and 7 indicated that these areas have high vascular reactivity. The temporal correlation between vascular reactivity and the immunoreactivity to desmin and VEGF further indicates that the integrity of vascular reactivity is associated with the pericyte coverage as regulated by the VEGF level. Vascular functionality remained low on days 1, 3, and 7, as reflected by the small hyperoxic BOLD and large hyperoxic TOLD responses, indicating the low oxygen consumption of the ischemic tissues. These functional changes in proangiogenic veins may be critical for angiogenesis.
Subject(s)
Brain Ischemia/physiopathology , Cerebral Veins/physiopathology , Cerebrovascular Circulation , Magnetic Resonance Angiography/methods , Neovascularization, Physiologic/physiology , Vascular Remodeling , Animals , Brain Ischemia/pathology , Cerebral Veins/pathology , Male , Rats , Rats, Sprague-Dawley , Recovery of Function , Reperfusion , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
White matter tracts are important for the trafficking of neural progenitor cells (NPCs) in both normal and pathological conditions, but the underlying mechanism is not clear. The directionality of white matter is advantageous for molecules or cells to distribute over a long distance, but this feature is unlikely solely responsible for efficient migration. The present study hypothesizes that the efficient migration of NPCs into white matter is under the influences of neurochemical attractionCXCL12/CXCR4 signaling, a major mechanism underlying the targeted migration of NPCs. To test this view, the present study investigated the effects of CXCL12 administration into the corpus callosum (CC) on the migratory behavior of transplanted NPCs. A living animal tracking platform based on MRI and a magnetic cell labeling technique was employed. The NPCs were magnetically labeled and then transplanted at the right end of the CC. CXCL12 was infused continuously at the left end. Migration of NPCs was monitored repeatedly over a 7-day course using 3D gradient echo T2*-weighted imaging. It was found that, CXCL12 induced NPCs to migrate up to 1,881 µm from the graft whereas the spontaneous migration was mere 200 µm. CXCL12 induced migration that was nine times as efficient in the speed. The results indicate that the CXCL12/CXCR4 signaling may be a mechanism via which NPCs efficiently migrate along the white matter tracts. The study also presents a potential strategy for facilitating the targeted migration in NPC therapy for brain disorders.
Subject(s)
Cell Movement/physiology , Chemokine CXCL12/metabolism , Neural Stem Cells/physiology , Receptors, CXCR4/metabolism , Signal Transduction/physiology , White Matter/physiology , Analysis of Variance , Animals , Cell Differentiation/drug effects , Cell Movement/drug effects , Cells, Cultured , Chemokine CXCL12/pharmacology , Embryo, Mammalian , Female , Flow Cytometry , Host Cell Factor C1/drug effects , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Male , Mice , Mice, Inbred C57BL , Neural Stem Cells/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Time Factors , White Matter/cytologyABSTRACT
The bed nucleus of the stria terminalis (BNST) is interconnected with the amygdala that is implicated in memory modulation. In view of the innervation of this structure by the hippocampus and brain stem noradrenergic nuclei, this study examined the role of BNST noradrenergic activity in acquisition, formation and expression of spatial memory. Male Wistar rats with indwelling cannulae in the BNST were trained on a spatial navigation task in the Morris water maze. Groups of rats received intra-BNST infusion of vehicle, norepinephrine, prazosin or both drugs shortly before or after each daily training session, or shortly before retention tests. Results showed that pre- or posttraining infusion of 1.0 microg prazosin impaired acquisition and retention, but the treatment had no effect on a cued response task. Posttraining infusion of 1.0 microg norepinephrine enhanced acquisition and retention, and this enhancing effect was blocked by simultaneous infusion of 0.3 microg prazosin. Pretest intra-BNST of prazosin or norepinephrine at a dose of 1.0 microg did not impair expression of the spatial navigation memory. These findings suggest that the BNST noradrengergic function is involved in modulating acquisition and formation of spatial memory that engage the hippocampus.
Subject(s)
Adrenergic alpha-Antagonists/administration & dosage , Maze Learning/drug effects , Maze Learning/physiology , Prazosin/administration & dosage , Retention, Psychology/drug effects , Septal Nuclei/physiology , Adrenergic alpha-Agonists/administration & dosage , Animals , Cues , Dose-Response Relationship, Drug , Drug Administration Schedule , Male , Memory/drug effects , Norepinephrine/administration & dosage , Rats , Rats, Wistar , Septal Nuclei/drug effects , SwimmingABSTRACT
The targeted migration of neural stem/progenitor cells (NSPCs) is a prerequisite for the use of stem cell therapy in the treatment of pathologies. This migration is regulated mainly by C-X-C motif chemokine 12 (CXCL12). Therefore, promotion of the migratory responses of grafted cells by upregulating CXCL12 signaling has been proposed as a strategy for improving the efficacy of such cell therapies. However, the effects of this strategy on brain tumors have not yet been examined in vivo. The aim of the present study was thus to elucidate the effects of grafted rat green fluorescent protein (GFP)-labeled NSPCs (GFP-NSPCs) with CXCL12 enhancement on a model of spontaneous rat brain tumor induced by N-ethyl-N-nitrosourea. T2-weighted magnetic resonance imaging was applied to determine the changes in tumor volume and morphology over time. Postmortem histology was performed to confirm the tumor pathology, expression levels of CXCL12 and C-X-C chemokine receptor type 4, and the fate of GFP-NSPCs. The results showed that the tumor volume and hypointense areas of T2-weighted images were both significantly increased in animals treated with combined NSPC transplantation and CXCL12 induction, but not in control animals or in those with tumors that received only one of the treatments. GFP-NSPCs appear to migrate toward tumors with CXCL12 enhancement and differentiate uniquely into a neuronal lineage. These findings suggest that CXCL12 is an effective chemoattractant that facilitates exogenous NSPC migration toward brain tumors and that CXCL12 and NSPC can act synergistically to promote tumor progression with severe hemorrhage.
ABSTRACT
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin commonly used to produce an animal model of Parkinson's disease. Previous studies have suggested a critical role for neuronal nitric oxide (NO) synthase- (nNOS-) derived NO in the pathogenesis of MPTP. However, NO activity is difficult to assess in vivo due to its extremely short biological half-life, and so in vivo evidence of NO involvement in MPTP neurotoxicity remains scarce. In the present study, we utilized flow-sensitive alternating inversion recovery sequences, in vivo localized proton magnetic resonance spectroscopy, and diffusion-weighted imaging to, respectively, assess the hemodynamics, metabolism, and cytotoxicity induced by MPTP. The role of NO in MPTP toxicity was clarified further by administering a selective nNOS inhibitor, 7-nitroindazole (7-NI), intraperitoneally to some of the experimental animals prior to MPTP challenge. The transient increase in cerebral blood flow (CBF) in the cortex and striatum induced by systemic injection of MPTP was completely prevented by pretreatment with 7-NI. We provide the first in vivo evidence of increased nNOS activity in acute MPTP-induced neurotoxicity. Although the observed CBF change may be independent of the toxicogenesis of MPTP, this transient hyperperfusion state may serve as an early indicator of neuroinflammation.
Subject(s)
MPTP Poisoning/enzymology , MPTP Poisoning/physiopathology , Magnetic Resonance Imaging , Neurotoxins/toxicity , Nitric Oxide Synthase Type I/metabolism , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Cerebrovascular Circulation/drug effects , Male , Rats , Rats, Sprague-Dawley , Regional Blood Flow/drug effects , Time Factors , Toxicity Tests, AcuteABSTRACT
The ability to evaluate the cerebral microvascular structure and function is crucial for investigating pathological processes in brain disorders. Previous angiographic methods based on blood oxygen level-dependent (BOLD) contrast offer appropriate visualization of the cerebral vasculature, but these methods remain to be optimized in order to extract more comprehensive information. This study aimed to integrate the advantages of BOLD MRI in both structural and functional vascular assessments. The BOLD contrast was manipulated by a carbogen challenge, and signal changes in gradient-echo images were computed to generate ΔR2* maps. Simultaneously, a functional index representing the regional cerebral blood volume was derived by normalizing the ΔR2* values of a given region to those of vein-filled voxels of the sinus. This method is named 3D gas ΔR2*-mMRA (microscopic MRA). The advantages of using 3D gas ΔR2*-mMRA to observe the microvasculature include the ability to distinguish air-tissue interfaces, a high vessel-to-tissue contrast, and not being affected by damage to the blood-brain barrier. A stroke model was used to demonstrate the ability of 3D gas ΔR2*-mMRA to provide information about poststroke revascularization at 3 days after reperfusion. However, this technique has some limitations that cannot be overcome and hence should be considered when it is applied, such as magnifying vessel sizes and predominantly revealing venous vessels.