ABSTRACT
Vascular co-option is a consequence of the direct interaction between perivascular cells, known as pericytes (PCs), and glioblastoma multiforme (GBM) cells (GBMcs). This process is essential for inducing changes in the pericytes' anti-tumoral and immunoreactive phenotypes. Starting from the initial stages of carcinogenesis in GBM, PCs conditioned by GBMcs undergo proliferation, acquire a pro-tumoral and immunosuppressive phenotype by expressing and secreting immunosuppressive molecules, and significantly hinder the activation of T cells, thereby facilitating tumor growth. Inhibiting the pericyte (PC) conditioning mechanisms in the GBM tumor microenvironment (TME) results in immunological activation and tumor disappearance. This underscores the pivotal role of PCs as a key cell in the TME, responsible for tumor-induced immunosuppression and enabling GBM cells to evade the immune system. Other cells within the TME, such as tumor-associated macrophages (TAMs) and microglia, have also been identified as contributors to this immunomodulation. In this paper, we will review the role of these three cell types in the immunosuppressive properties of the TME. Our conclusion is that the cellular heterogeneity of immunocompetent cells within the TME may lead to the misinterpretation of cellular lineage identification due to different reactive stages and the identification of PCs as TAMs. Consequently, novel therapies could be developed to disrupt GBM-PC interactions and/or PC conditioning through vascular co-option, thereby exposing GBMcs to the immune system.
Subject(s)
Brain Neoplasms , Pericytes , Tumor Microenvironment , Pericytes/immunology , Pericytes/pathology , Pericytes/metabolism , Humans , Tumor Microenvironment/immunology , Animals , Brain Neoplasms/immunology , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Glioma/immunology , Glioma/pathology , Glioma/metabolism , Glioblastoma/immunology , Glioblastoma/pathology , Glioblastoma/metabolism , Disease Progression , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Tumor-Associated Macrophages/pathologyABSTRACT
Resumen La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inma durez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteracio nes estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbi do, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones es tructurales y/o funcionales del cerebro subyacentes pue den ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.
Abstract The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually as sociated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical di sorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may indepen dently cause the predisposition to epilepsy and comor bid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.
ABSTRACT
The occurrence of seizures is frequent during the neonatal period due to the functional immaturity of the brain.The presence of these seizures may lead to a diagnosis of neonatal epilepsy, which is usually associated with structural alterations of the brain during neurodevelopment. Approximately 50% of people with active epilepsy have at least one comorbid medical disorder, and the existence of a comorbid process changes the course of the epilepsy. The presence of neurologic disorders preceding the onset of epilepsy indicates that underlying neurobiological alterations may independently cause the predisposition to epilepsy and comorbid processes. In this review we describe the structural and functional brain processes underlying the onset of neonatal epilepsy and its comorbidities.
La aparición de convulsiones es frecuente durante el periodo neonatal debido a las características de inmadurez funcional del cerebro es este periodo. La aparición de estas convulsiones puede llevar a un diagnóstico de epilepsia neonatal, que suele estar asociado a alteraciones estructurales del cerebro durante el neurodesarrollo. Aproximadamente el 50% de las personas con epilepsia activa padecen al menos un trastorno médico comórbido, y esto hace que cambie la evolución de la epilepsia. La presencia de trastornos neurológicos que preceden a la aparición de la epilepsia indica que alteraciones estructurales y/o funcionales del cerebro subyacentes pueden ser causa de la predisposición a padecer epilepsia y de los procesos comórbidos de manera independiente. En esta revisión describimos los procesos cerebrales estructurales y funcionales que subyacen a la aparición de epilepsia neonatal y sus comorbilidades.
Subject(s)
Epilepsy , Infant, Newborn , Humans , Epilepsy/diagnosis , Seizures/etiology , Brain , ComorbidityABSTRACT
Most of the studies on neurochemical mapping, connectivity, and physiology in the hypothalamic region were carried out in rats and under the columnar morphologic paradigm. According to the columnar model, the entire hypothalamic region lies ventrally within the diencephalon, which includes preoptic, anterior, tuberal, and mamillary anteroposterior regions, and sometimes identifying dorsal, intermediate, and ventral hypothalamic partitions. This model is weak in providing little or no experimentally corroborated causal explanation of such subdivisions. In contrast, the modern prosomeric model uses different axial assumptions based on the parallel courses of the brain floor, alar-basal boundary, and brain roof (all causally explained). This model also postulates that the hypothalamus and telencephalon jointly form the secondary prosencephalon, separately from and rostral to the diencephalon proper. The hypothalamus is divided into two neuromeric (transverse) parts called peduncular and terminal hypothalamus (PHy and THy). The classic anteroposterior (AP) divisions of the columnar hypothalamus are rather seen as dorsoventral subdivisions of the hypothalamic alar and basal plates. In this study, we offered a prosomeric immunohistochemical mapping in the rat of hypothalamic cells expressing tyrosine hydroxylase (TH), which is the enzyme that catalyzes the conversion of L-tyrosine to levodopa (L-DOPA) and a precursor of dopamine. This mapping was also combined with markers for diverse hypothalamic nuclei [agouti-related peptide (Agrp), arginine vasopressin (Avp), cocaine and amphetamine-regulated transcript (Cart), corticotropin releasing Hormone (Crh), melanin concentrating hormone (Mch), neuropeptide Y (Npy), oxytocin/neurophysin I (Oxt), proopiomelanocortin (Pomc), somatostatin (Sst), tyrosine hidroxilase (Th), and thyrotropin releasing hormone (Trh)]. TH-positive cells are particularly abundant within the periventricular stratum of the paraventricular and subparaventricular alar domains. In the tuberal region, most labeled cells are found in the acroterminal arcuate nucleus and in the terminal periventricular stratum. The dorsal retrotuberal region (PHy) contains the A13 cell group of TH-positive cells. In addition, some TH cells appear in the perimamillary and retromamillary regions. The prosomeric model proved useful for determining the precise location of TH-positive cells relative to possible origins of morphogenetic signals, thus aiding potential causal explanation of position-related specification of this hypothalamic cell type.
ABSTRACT
Resumen La neurociencia moderna aborda el problema de funcionamiento global del cerebro para poder comprender los procesos neurobiológicos que subyacen a las funciones mentales, y especialmente, a la consciencia. La actividad cerebral está basada en el intercambio de información entre neuronas a través de contactos llamados sinapsis. Las neuronas forman redes de conexión entre ellas (circuitos), que están dedicados a procesar una parcela específica de información (visual, auditiva, motora…). Los circuitos establecen redes entre ellos, combinando diferentes modalidades de información para generar lo que conocemos como actividad mental. El estudio de las conexiones entre regiones corticales, que se ha llamado conectoma, está siendo abordado mediante técnicas de neuroimagen como la resonancia magnética nuclear, que aportan datos sobre la densidad de conexiones del cerebro. La capacidad del cerebro de crear nuevas conexiones en función de la experiencia (plasticidad cerebral), sugiere que el conectoma es una estructura dinámica en constante interacción con estímulos externos e internos. La pregunta sobre si el conocimiento del conectoma de un individuo nos per mitiría predecir su conducta parece que todavía no tiene respuesta clara, porque no conocemos los parámetros físicos que ligan la complejidad de las conexiones del cerebro con la aparición de las funciones mentales y de la consciencia. Por el momento, parece que la compleja e impredecible conducta no es el simple resultado de procesos lineales de interacción neuronal. La incertidumbre prima al determinismo, lo que abre la puerta a la posibilidad de un mecanismo cuántico para explicar la consciencia.
Abstract Modern neuroscience addresses the problem of the global functioning of the brain in order to understand the neurobiological processes that underlie mental functions, and especially, consciousness. Brain activity is based on the exchange of infor mation between neurons through contacts or synapses. Neurons form networks of connection between them (circuits), which are dedicated to processing a specific type of information (visual, auditory, motor…). The circuits establish networks among themselves, combining different modalities of information to generate what we know as mental activity. The study of connections between cortical regions, which has been called connectome, is being approached through neuroimaging techniques such as nuclear magnetic resonance that provide data on the density of connections in the brain. The brain's ability to create new connections based on experience (brain plasticity) suggests that the connectome is a dynamic structure in constant interaction with external and internal stimuli. The question about whether knowledge of an individual's connectome would allow us to predict his or her behavior seems to have no clear answer yet, because we do not know the physical parameters that link the complexity of the brain's connections with the appearance of mental functions and consciousness. At the moment, it seems that the complex and unpredictable behavior is not the simple result of linear processes of neuronal interaction. Uncertainty prevails over determinism, which opens the door to the possibility of a quantum mechanism to explain consciousness.
ABSTRACT
Modern neuroscience addresses the problem of the global functioning of the brain in order to understand the neurobiological processes that underlie mental functions, and especially, consciousness. Brain activity is based on the exchange of information between neurons through contacts or synapses. Neurons form networks of connection between them (circuits), which are dedicated to processing a specific type of information (visual, auditory, motor ...). The circuits establish networks among themselves, combining different modalities of information to generate what we know as mental activity. The study of connections between cortical regions, which has been called connectome, is being approached through neuroimaging techniques such as nuclear magnetic resonance that provide data on the density of connections in the brain. The brain's ability to create new connections based on experience (brain plasticity) suggests that the connectome is a dynamic structure in constant interaction with external and internal stimuli. The question about whether knowledge of an individual's connectome would allow us to predict his or her behavior seems to have no clear answer yet, because we do not know the physical parameters that link the complexity of the brain's connections with the appearance of mental functions and consciousness. At the moment, it seems that the complex and unpredictable behavior is not the simple result of linear processes of neuronal interaction. Uncertainty prevails over determinism, which opens the door to the possibility of a quantum mechanism to explain consciousness.
La neurociencia moderna aborda el problema de funcionamiento global del cerebro para poder comprender los procesos neurobiológicos que subyacen a las funciones mentales, y especialmente, a la consciencia. La actividad cerebral está basada en el intercambio de información entre neuronas a través de contactos llamados sinapsis. Las neuronas forman redes de conexión entre ellas (circuitos), que están dedicados a procesar una parcela específica de información (visual, auditiva, motora ...). Los circuitos establecen redes entre ellos, combinando diferentes modalidades de información para generar lo que conocemos como actividad mental. El estudio de las conexiones entre regiones corticales, que se ha llamado conectoma, está siendo abordado mediante técnicas de neuroimagen como la resonancia magnética nuclear, que aportan datos sobre la densidad de conexiones del cerebro. La capacidad del cerebro de crear nuevas conexiones en función de la experiencia (plasticidad cerebral), sugiere que el conectoma es una estructura dinámica en constante interacción con estímulos externos e internos. La pregunta sobre si el conocimiento del conectoma de un individuo nos permitiría predecir su conducta parece que todavía no tiene respuesta clara, porque no conocemos los parámetros físicos que ligan la complejidad de las conexiones del cerebro con la aparición de las funciones mentales y de la consciencia. Por el momento, parece que la compleja e impredecible conducta no es el simple resultado de procesos lineales de interacción neuronal. La incertidumbre prima al determinismo, lo que abre la puerta a la posibilidad de un mecanismo cuántico para explicar la consciencia.
Subject(s)
Connectome , Neurosciences , Brain/physiology , Connectome/methods , Consciousness/physiology , Female , Humans , Male , NeuronsABSTRACT
A well-documented method and experimental design are essential to ensure the reproducibility and reliability in animal research. Experimental studies using exercise programs in animal models have experienced an exponential increase in the last decades. Complete reporting of forced wheel and treadmill exercise protocols would help to ensure the reproducibility of training programs. However, forced exercise programs are characterized by a poorly detailed methodology. Also, current guidelines do not cover the minimum data that must be included in published works to reproduce training programs. For this reason, we have carried out a systematic review to determine the reproducibility of training programs and experimental designs of published research in rodents using a forced wheel system. Having determined that most of the studies were not detailed enough to be reproducible, we have suggested guidelines for animal research using FORCED exercise wheels, which could also be applicable to any form of forced exercise.
Subject(s)
Animal Experimentation/standards , Disease Models, Animal , Exercise Test , Physical Conditioning, Animal , Animals , Exercise , Female , Humans , Humidity , Male , Mice , Rats , Reproducibility of Results , Risk , TemperatureABSTRACT
Improving exercise capacity during adolescence impacts positively on cognitive and motor functions. However, the neural mechanisms contributing to enhance physical performance during this sensitive period remain poorly understood. Such knowledge could help to optimize exercise programs and promote a healthy physical and cognitive development in youth athletes. The central dopamine system is of great interest because of its role in regulating motor behavior through the activation of D1 and D2 receptors. Thus, the aim of the present study is to determine whether D1 or D2 receptor signaling contributes to modulate the exercise capacity during adolescence and if this modulation takes place through the striatum. To test this, we used a rodent model of forced running wheel that we implemented recently to assess the exercise capacity. Briefly, rats were exposed to an 8-day period of habituation in the running wheel before assessing their locomotor performance in response to an incremental exercise test, in which the speed was gradually increased until exhaustion. We found that systemic administration of D1-like (SCH23390) and/or D2-like (raclopride) receptor antagonists prior to the incremental test reduced the duration of forced running in a dose-dependent manner. Similarly, locomotor activity in the open field was decreased by the dopamine antagonists. Interestingly, this was not the case following intrastriatal infusion of an effective dose of SCH23390, which decreased motor performance during the incremental test without disrupting the behavioral response in the open field. Surprisingly, intrastriatal delivery of raclopride failed to impact the duration of forced running. Altogether, these results indicate that the level of locomotor response to incremental loads of forced running in adolescent rats is dopamine dependent and mechanistically linked to the activation of striatal D1 and extra-striatal D2 receptors.
Subject(s)
Aging/physiology , Corpus Striatum/metabolism , Dopamine/metabolism , Physical Conditioning, Animal , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Animals , Dopamine D2 Receptor Antagonists/pharmacology , Habituation, Psychophysiologic , Male , Motor Activity , Open Field Test , Rats, Sprague-Dawley , Receptors, Dopamine D1/antagonists & inhibitorsABSTRACT
It has been demonstrated that physical activity contributes to a healthier life. However, there is a knowledge gap regarding the neural mechanisms producing these effects. One of the keystones to deal with this problem is to use training programs with equal loads of physical activity. However, irregular motor and stress responses have been found in murine exercise models. Habituation to forced exercise facilitates a complete response to a training program in all rodents, reaching the same load of physical activity among animals. Here, it was evaluated if glucose and lactate - which are stress biomarkers - are increased during the habituation to exercise. Sprague-Dawley rats received an 8-days habituation protocol with progressive increments of time and speed of running. Then, experimental and control (non-habituated) rats were subjected to an incremental test. Blood samples were obtained to determine plasmatic glucose and lactate levels before, immediately after and 30 min after each session of training. Crh and Avp mRNA expression was determined by two-step qPCR. Our results revealed that glucose and lactate levels are not increased during the habituation period and tend to decrease toward the end of the protocol. Also, Crh and Avp were not chronically activated by the habituation program. Lactate and glucose, determined after the incremental test, were higher in control rats without previous contact with the wheel, compared with habituated and wheel control rats. These results suggest that the implementation of an adaptive phase prior to forced exercise programs might avoid non-specific stress responses.
