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PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.
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Astrocitos , Clozapina , Animales , Clozapina/metabolismo , Clozapina/farmacología , Fluorodesoxiglucosa F18/metabolismo , Glucosa/metabolismo , Ácido Glutámico/metabolismo , Ácido Glutámico/farmacología , Humanos , Masculino , Tomografía de Emisión de Positrones , Ratas , Ratas WistarRESUMEN
Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.
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Encéfalo/metabolismo , Ambiente , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/prevención & control , Plasticidad Neuronal/fisiología , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Animales Recién Nacidos , Femenino , Hipoxia-Isquemia Encefálica/psicología , Lactancia/metabolismo , Lactancia/psicología , Masculino , Aprendizaje por Laberinto/fisiología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Enfermedades Neurodegenerativas/psicología , Tomografía de Emisión de Positrones/métodos , Embarazo , Efectos Tardíos de la Exposición Prenatal/psicología , Ratas , Ratas WistarRESUMEN
BACKGROUND AND PURPOSE: Hypoxia and cerebral ischemia (HI) events are capable of triggering important changes in brain metabolism, including glucose metabolism abnormalities, which may be related to the severity of the insult. Using positron emission microtomography (microPET) with [18F]fluorodeoxyglucose (18F-FDG), this study proposes to assess abnormalities of brain glucose metabolism in adult rats previously submitted to the neonatal HI model. We hypothesize that cerebral metabolic outcomes will be associated with cognitive deficits and magnitude of brain injury. METHODS: Seven-day-old rats were subjected to an HI model, induced by permanent occlusion of the right common carotid artery and systemic hypoxia. 18F-FDG-microPET was used to assess regional and whole brain glucose metabolism in rats at 60 postnatal days (PND 60). An interregional cross-correlation matrix was utilized to construct metabolic brain networks (MBN). Rats were also subjected to the Morris Water Maze (MWM) to evaluate spatial memory and their brains were processed for volumetric evaluation. RESULTS: Brain glucose metabolism changes were observed in adult rats after neonatal HI insult, limited to the right brain hemisphere. However, not all HI animals exhibited significant cerebral hypometabolism. Hippocampal glucose metabolism was used to stratify HI animals into HI hypometabolic (HI-h) and HI non-hypometabolic (HI non-h) groups. The HI-h group had drastic MBN disturbance, cognitive deficit, and brain tissue loss, concomitantly. Conversely, HI non-h rats had normal brain glucose metabolism and brain tissue preserved, but also presented MBN changes and spatial memory impairment. Furthermore, data showed that brain glucose metabolism correlated with cognitive deficits and brain volume outcomes. CONCLUSIONS: Our findings demonstrated that long-term changes in MBN drive memory impairments in adult rats subjected to neonatal hypoxic ischemia, using in vivo imaging microPET-FDG. The MBN analyses identified glucose metabolism abnormalities in HI non-h animals, which were not detected by conventional 18F-FDG standardized uptake value (SUVr) measurements. These animals exhibited a metabolic brain signature that may explain the cognitive deficit even with no identifiable brain damage.
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Encéfalo/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Trastornos de la Memoria/metabolismo , Red Nerviosa/metabolismo , Animales , Encéfalo/diagnóstico por imagen , Modelos Animales de Enfermedad , Glucosa/metabolismo , Hipoxia-Isquemia Encefálica/complicaciones , Hipoxia-Isquemia Encefálica/diagnóstico por imagen , Masculino , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/etiología , Red Nerviosa/diagnóstico por imagen , Tomografía de Emisión de Positrones , Ratas , Ratas WistarRESUMEN
Sepsis is characterized by a severe and disseminated inflammation. In the central nervous system, sepsis promotes synaptic dysfunction and permanent cognitive impairment. Besides sepsis-induced neuronal dysfunction, glial cell response has been gaining considerable attention with microglial activation as a key player. By contrast, astrocytes' role during acute sepsis is still underexplored. Astrocytes are specialized immunocompetent cells involved in brain surveillance. In this context, the potential communication between the peripheral immune system and astrocytes during acute sepsis still remains unclear. We hypothesized that peripheral blood mononuclear cell (PBMC) mediators are able to affect the brain during an episode of acute sepsis. With this in mind, we first performed a data-driven transcriptome analysis of blood from septic patients to identify common features among independent clinical studies. Our findings evidenced pronounced impairment in energy-related signaling pathways in the blood of septic patients. Since astrocytes are key for brain energy homeostasis, we decided to investigate the communication between PBMC mediators and astrocytes in a rat model of acute sepsis, induced by cecal ligation and perforation (CLP). In the CLP animals, we identified widespread in vivo brain glucose hypometabolism. Ex vivo analyses demonstrated astrocyte reactivity along with reduced glutamate uptake capacity during sepsis. Also, by exposing cultured astrocytes to mediators released by PBMCs from CLP animals, we reproduced the energetic failure observed in vivo. Finally, by pharmacologically inhibiting phosphoinositide 3-kinase (PI3K), a central metabolic pathway downregulated in the blood of septic patients and reduced in the CLP rat brain, we mimicked the PBMC mediators effect on glutamate uptake but not on glucose metabolism. These results suggest that PBMC mediators are capable of directly mediating astrocyte reactivity and contribute to the brain energetic failure observed in acute sepsis. Moreover, the evidence of PI3K participation in this process indicates a potential target for therapeutic modulation.
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Astrocitos/metabolismo , Leucocitos Mononucleares/metabolismo , Sepsis/fisiopatología , Adulto , Animales , Encéfalo/metabolismo , Sistema Nervioso Central/metabolismo , Bases de Datos Genéticas , Modelos Animales de Enfermedad , Femenino , Ácido Glutámico/metabolismo , Humanos , Inflamación/metabolismo , Leucocitos Mononucleares/fisiología , Masculino , Neuronas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Ratas , Ratas Wistar , Sepsis/genética , Transducción de Señal/fisiologíaRESUMEN
Large changes to brain structure (e.g., from damage or disease) can explain alterations in behavior. It is therefore plausible that smaller structural differences in healthy samples can be used to better understand and predict individual differences in behavior. Despite the brain's multivariate and distributed structure-to-function mapping, most studies have used univariate analyses of individual structural brain measures. Here we used a multivariate approach in a multimodal data set composed of volumetric, surface-based, diffusion-based, and functional resting-state MRI measures to predict reliable individual differences in risk and intertemporal preferences. We show that combining twelve brain structure measures led to better predictions across tasks than using any individual measure, and by examining model coefficients, we visualize the relative contribution of different brain measures from different brain regions. Using a multivariate approach to brain structure-to-function mapping that combines across many brain structure properties, along with reliably measured behavior phenotypes, may increase out-of-sample prediction accuracies and insight into neural underpinnings. Furthermore, this methodological approach may be useful to improve predictions and neural insight across basic, translational, and clinical research fields.
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Episodic memory decline is a major signature of both normal and pathological aging. Many neural regions have been implicated in the processes subserving both episodic memory and typical aging decline. Here, we demonstrate that the cerebellum is causally involved episodic memory under aging. We show that a 12-day neurostimulation program delivered to the right cerebellum led to improvements in episodic memory performance under healthy aging that long outlast the stimulation period - healthy elderly individuals show episodic memory improvement both immediately after the intervention program and in a 4-month follow-up. These results demonstrate the causal relevance of the cerebellum in processes associated with long-term episodic memory, potentially highlighting its role in regulating and maintaining cognitive processing. Moreover, they point to the importance of non-pharmacological interventions that prevent or diminish cognitive decline in healthy aging.
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Disfunción Cognitiva , Memoria Episódica , Humanos , Anciano , Envejecimiento/fisiología , Cognición , CerebeloRESUMEN
Deciding how to manipulate an object to fulfill a goal requires accessing different types of object-related information. How these different types of information are integrated and represented in the brain is still an open question. Here, we focus on examining two types of object-related information-tool-gesture knowledge (i.e., how to manipulate an object), and tool-gesture production (i.e., the actual manipulation of an object). We show a double dissociation between tool-gesture knowledge and tool-gesture production: Patient FP presents problems in pantomiming tool use in the context of a spared ability to perform judgments about an object's manipulation, whereas Patient LS can pantomime tool use, but is impaired at performing manipulation judgments. Moreover, we compared the location of the lesions in FP and LS with those sustained by two classic ideomotor apraxic patients (IMA), using a cortical thickness approach. Patient FP presented lesions in common with our classic IMA that included the left inferior parietal lobule (IPL), and specifically the supramarginal gyrus, the left parietal operculum, the left premotor cortex and the left inferior frontal gyrus, whereas Patient LS and our classic IMA patients presented common lesions in regions of the superior parietal lobule (SPL), motor areas (as primary somatosensory cortex, premotor cortex and primary motor cortex), and frontal areas. Our results show that tool-gesture production and tool-gesture knowledge can be behaviorally and neurally doubly dissociated and put strong constraints on extant theories of action and object recognition and use.
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Apraxias , Gestos , Mapeo Encefálico , Humanos , Imagen por Resonancia Magnética , Lóbulo ParietalRESUMEN
Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light-dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.
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Ansiedad/inducido químicamente , Glucosa/metabolismo , Metilfenidato/farmacología , Corteza Prefrontal/efectos de los fármacos , Animales , Ansiedad/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Homeostasis/efectos de los fármacos , Masculino , Redes y Vías Metabólicas/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas WistarRESUMEN
The spatial coordinate system in which a stimulus representation is embedded is known as its reference frame. Every visual representation has a reference frame [1], and the visual system uses a variety of reference frames to efficiently code visual information [e.g., 1-5]. The representation of faces in early stages of visual processing depends on retino-centered reference frames, but little is known about the reference frames that code the high-level representations used to make judgements about faces. Here, we focus on a rare and striking disorder of face perception-hemi-prosopometamorphopsia (hemi-PMO)-to investigate these reference frames. After a left splenium lesion, Patient A.D. perceives features on the right side of faces as if they had melted. The same features were distorted when faces were presented in either visual field, at different in-depth rotations, and at different picture-plane orientations including upside-down. A.D.'s results indicate faces are aligned to a view- and orientation-independent face template encoded in a face-centered reference frame, that these face-centered representations are present in both the left and right hemisphere, and that the representations of the left and right halves of a face are dissociable.