RESUMEN
The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs1-4. The human EC continues to develop during childhood5, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+RELN+ cells6,7. Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood.
Asunto(s)
Movimiento Celular , Neuronas , Lóbulo Temporal , Animales , Preescolar , Humanos , Lactante , Corteza Entorrinal/citología , Corteza Entorrinal/fisiología , Eminencia Ganglionar/citología , Interneuronas/citología , Interneuronas/fisiología , Macaca mulatta , Neuronas/citología , Neuronas/fisiología , Análisis de Expresión Génica de una Sola Célula , Lóbulo Temporal/citología , Lóbulo Temporal/crecimiento & desarrolloRESUMEN
New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day, whereas other studies find many fewer putative new neurons. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18-77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.
Asunto(s)
Hipocampo/citología , Neurogénesis , Neuronas/citología , Adolescente , Adulto , Anciano , Animales , Animales Recién Nacidos , Recuento de Células , Proliferación Celular , Niño , Preescolar , Giro Dentado/citología , Giro Dentado/embriología , Epilepsia/patología , Femenino , Desarrollo Fetal , Voluntarios Sanos , Hipocampo/anatomía & histología , Hipocampo/embriología , Humanos , Lactante , Macaca mulatta , Masculino , Persona de Mediana Edad , Células-Madre Neurales/citología , Adulto JovenRESUMEN
Adult hippocampal neurogenesis was originally discovered in rodents. Subsequent studies identified the adult neural stem cells and found important links between adult neurogenesis and plasticity, behavior, and disease. However, whether new neurons are produced in the human dentate gyrus (DG) during healthy aging is still debated. We and others readily observe proliferating neural progenitors in the infant hippocampus near immature cells expressing doublecortin (DCX), but the number of such cells decreases in children and few, if any, are present in adults. Recent investigations using dual antigen retrieval find many cells stained by DCX antibodies in adult human DG. This has been interpreted as evidence for high rates of adult neurogenesis, even at older ages. However, most of these DCX-labeled cells have mature morphology. Furthermore, studies in the adult human DG have not found a germinal region containing dividing progenitor cells. In this Dual Perspectives article, we show that dual antigen retrieval is not required for the detection of DCX in multiple human brain regions of infants or adults. We review prior studies and present new data showing that DCX is not uniquely expressed by newly born neurons: DCX is present in adult amygdala, entorhinal and parahippocampal cortex neurons despite being absent in the neighboring DG. Analysis of available RNA-sequencing datasets supports the view that DG neurogenesis is rare or absent in the adult human brain. To resolve the conflicting interpretations in humans, it is necessary to identify and visualize dividing neuronal precursors or develop new methods to evaluate the age of a neuron at the single-cell level.
Asunto(s)
Hipocampo/citología , Hipocampo/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Adulto , Diferenciación Celular/fisiología , Niño , Humanos , Plasticidad Neuronal/fisiologíaRESUMEN
The neocortex of primates, including humans, contains more abundant and diverse inhibitory neurons compared with rodents, but the molecular foundations of these observations are unknown. Through integrative gene coexpression analysis, we determined a consensus transcriptional profile of GABAergic neurons in mid-gestation human neocortex. By comparing this profile to genes expressed in GABAergic neurons purified from neonatal mouse neocortex, we identified conserved and distinct aspects of gene expression in these cells between the species. We show here that the calcium-binding protein secretagogin (SCGN) is robustly expressed by neocortical GABAergic neurons derived from caudal ganglionic eminences (CGE) and lateral ganglionic eminences during human but not mouse brain development. Through electrophysiological and morphometric analyses, we examined the effects of SCGN expression on GABAergic neuron function and form. Forced expression of SCGN in CGE-derived mouse GABAergic neurons significantly increased total neurite length and arbor complexity following transplantation into mouse neocortex, revealing a molecular pathway that contributes to morphological differences in these cells between rodents and primates.
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Neuronas GABAérgicas/metabolismo , Neocórtex/embriología , Neurogénesis/fisiología , Secretagoginas/metabolismo , Animales , Humanos , Interneuronas/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuritas/metabolismo , TranscriptomaRESUMEN
Glucocorticoid stress hormones (GCs) are well known for being anti-inflammatory, but some reports suggest that GCs can also augment aspects of inflammation during acute brain injury. Because the GC receptor (GR) is ubiquitously expressed throughout the brain, it is difficult to know which cell types might mediate these unusual "proinflammatory" GC actions. We examined this with cell type-specific deletion or overexpression of GR in mice experiencing seizure or ischemia. Counter to their classical anti-inflammatory actions, GR signaling in myeloid cells increased Iba-1 and CD68 staining as well as nuclear p65 levels in the injured tissue. GCs also reduced levels of occludin, claudin 5, and caveolin 1, proteins central to blood-brain-barrier integrity; these effects required GR in endothelial cells. Finally, GCs compromised neuron survival, an effect mediated by GR in myeloid and endothelial cells to a greater extent than by neuronal GR.
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Lesiones Encefálicas/patología , Corticosterona/metabolismo , Encefalitis/patología , Células Mieloides/metabolismo , Transducción de Señal/fisiología , Análisis de Varianza , Animales , Infarto Encefálico/etiología , Infarto Encefálico/prevención & control , Lesiones Encefálicas/inducido químicamente , Lesiones Encefálicas/tratamiento farmacológico , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Corticosterona/administración & dosificación , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis/tratamiento farmacológico , Encefalitis/etiología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Ácido Kaínico/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptor TIE-2 , Receptores de Glucocorticoides/genética , Transducción de Señal/efectos de los fármacos , Quinasa de Factor Nuclear kappa BRESUMEN
BACKGROUND/AIMS: Stress exacerbates neuron loss in many CNS injuries via the actions of adrenal glucocorticoid (GC) hormones. For some injuries, this GC endangerment of neurons is accompanied by greater immune cell activation in the CNS, a surprising outcome given the potent immunosuppressive properties of GCs. METHODS: To determine whether the effects of GCs on inflammation contribute to neuron death or result from it, we tested whether nonsteroidal anti-inflammatory drugs could protect neurons from GCs during kainic acid excitotoxicity in adrenalectomized male rats. We next measured GC effects on (1) chemokine production (CCL2 and CINC-1), (2) signals that suppress immune activation (CX3CL1, CD22, CD200, and TGF-ß), and (3) NF-κB activity. RESULTS: Concurrent treatment with minocycline, but not indomethacin, prevented GC endangerment. GCs did not substantially affect CCL2, CINC-1, or baseline NF-κB activity, but they did suppress CX3CL1, CX3CR1, and CD22 expression in the hippocampus - factors that normally restrain inflammatory responses. CONCLUSIONS: These findings demonstrate that cellular inflammation is not necessarily suppressed by GCs in the injured hippocampus; instead, GCs may worsen hippocampal neuron death, at least in part by increasing the neurotoxicity of CNS inflammation.
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Agonistas de Aminoácidos Excitadores/toxicidad , Glucocorticoides/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Ácido Kaínico/toxicidad , Adrenalectomía , Animales , Antiinflamatorios no Esteroideos/farmacología , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Quimiocinas/metabolismo , Relación Dosis-Respuesta a Droga , Hipocampo/patología , Indometacina/farmacología , Masculino , Minociclina/farmacología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Neuronas/efectos de los fármacos , Neuronas/inmunología , Neuronas/patología , Fármacos Neuroprotectores/farmacología , Ratas Sprague-DawleyRESUMEN
Throughout the life of the adult songbird, neurons are recruited into brain regions important for song learning. Movies captured by Shvedov et al. demonstrate this dynamic process in the live animal, revealing the mechanisms of neuronal migration in the adult brain.
Asunto(s)
Pájaros Cantores , Animales , Pájaros Cantores/fisiología , Vocalización Animal/fisiología , Aprendizaje/fisiología , Encéfalo/fisiología , Neuronas/fisiologíaRESUMEN
The paralaminar nucleus of the amygdala (PL) comprises neurons that exhibit delayed maturation. PL neurons are born during gestation but mature during adolescent ages, differentiating into excitatory neurons. These late-maturing PL neurons contribute to the increase in size and cell number of the amygdala between birth and adulthood. However, the function of the PL upon maturation is unknown, as the region has only recently begun to be characterized in detail. In this study, we investigated key defining features of the adult mouse PL; the intrinsic morpho-electric properties of its neurons, and its input and output circuit connectivity. We identify two subtypes of excitatory neurons in the PL based on unsupervised clustering of electrophysiological properties. These subtypes are defined by differential action potential firing properties and dendritic architecture, suggesting divergent functional roles. We further uncover major axonal inputs to the adult PL from the main olfactory network and basolateral amygdala. We also find that axonal outputs from the PL project reciprocally to these inputs and to diverse targets including the amygdala, frontal cortex, hippocampus, hypothalamus, and brainstem. Thus, the adult mouse PL is centrally placed to play a major role in the integration of olfactory sensory information, to coordinate affective and autonomic behavioral responses to salient odor stimuli.
Asunto(s)
Amígdala del Cerebelo , Neuronas , Animales , Ratones , Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/citología , Neuronas/fisiología , Masculino , Ratones Endogámicos C57BL , Potenciales de Acción/fisiología , Femenino , Vías Nerviosas/fisiología , Ratones Transgénicos , Dendritas/fisiologíaRESUMEN
The paralaminar nucleus of the amygdala (PL) is comprised of neurons which exhibit delayed maturation. PL neurons are born during gestation but mature during adolescent ages, differentiating into excitatory neurons. The PL is prominent in the adult amygdala, contributing to its increased neuron number and relative size compared to childhood. However, the function of the PL is unknown, as the region has only recently begun to be characterized in detail. In this study, we investigated key defining features of the adult PL; the intrinsic morpho-electric properties of its neurons, and its input and output connectivity. We identify two subtypes of excitatory neurons in the PL based on unsupervised clustering of electrophysiological properties. These subtypes are defined by differential action potential firing properties and dendritic architecture, suggesting divergent functional roles. We further uncover major axonal inputs to the adult PL from the main olfactory network and basolateral amygdala. We also find that axonal outputs from the PL project reciprocally to major inputs, and to diverse targets including the amygdala, frontal cortex, hippocampus, hypothalamus, and brainstem. Thus, the adult PL is centrally placed to play a major role in the integration of olfactory sensory information, likely coordinating affective and autonomic behavioral responses to salient odor stimuli. Significance Statement: Mammalian amygdala development includes a growth period from childhood to adulthood, believed to support emotional and social learning. This amygdala growth is partly due to the maturation of neurons during adolescence in the paralaminar amygdala. However, the functional properties of these neurons are unknown. In our recent studies, we characterized the paralaminar amygdala in the mouse. Here, we investigate the properties of the adult PL in the mouse, revealing the existence of two neuronal subtypes that may play distinct functional roles in the adult brain. We further reveal the brain-wide input and output connectivity of the PL, indicating that the PL combines olfactory cues for emotional processing and delivers information to regions associated with reward and autonomic states.
RESUMEN
The human amygdala paralaminar nucleus (PL) contains many immature excitatory neurons that undergo prolonged maturation from birth to adulthood. We describe a previously unidentified homologous PL region in mice that contains immature excitatory neurons and has previously been considered part of the amygdala intercalated cell clusters or ventral endopiriform cortex. Mouse PL neurons are born embryonically, not from postnatal neurogenesis, despite a subset retaining immature molecular and morphological features in adults. During juvenile-adolescent ages (P21-P35), the majority of PL neurons undergo molecular, structural, and physiological maturation, and a subset of excitatory PL neurons migrate into the adjacent endopiriform cortex. Alongside these changes, PL neurons develop responses to aversive and appetitive olfactory stimuli. The presence of this homologous region in both humans and mice points to the significance of this conserved mechanism of neuronal maturation and migration during adolescence, a key time period for amygdala circuit maturation and related behavioral changes.
Asunto(s)
Complejo Nuclear Basolateral , Células-Madre Neurales , Adolescente , Humanos , Adulto , Animales , Ratones , Neuronas , Amígdala del Cerebelo , AfectoRESUMEN
The human amygdala is critical for emotional learning, valence coding, and complex social interactions, all of which mature throughout childhood, puberty, and adolescence. Across these ages, the amygdala paralaminar nucleus (PL) undergoes significant structural changes including increased numbers of mature neurons. The PL contains a large population of immature excitatory neurons at birth, some of which may continue to be born from local progenitors. These progenitors disappear rapidly in infancy, but the immature neurons persist throughout childhood and adolescent ages, indicating that they develop on a protracted timeline. Many of these late-maturing neurons settle locally within the PL, though a small subset appear to migrate into neighboring amygdala subnuclei. Despite its prominent growth during postnatal life and possible contributions to multiple amygdala circuits, the function of the PL remains unknown. PL maturation occurs predominately during late childhood and into puberty when sex hormone levels change. Sex hormones can promote developmental processes such as neuron migration, dendritic outgrowth, and synaptic plasticity, which appear to be ongoing in late-maturing PL neurons. Collectively, we describe how the growth of late-maturing neurons occurs in the right time and place to be relevant for amygdala functions and neuropsychiatric conditions.
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Amígdala del Cerebelo , Neurogénesis , Adolescente , Niño , Humanos , Recién Nacido , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , PubertadRESUMEN
Terreros-Roncal et al. investigated the impacts of human neurodegeneration on immunostainings assumed to be associated with neurogenesis. However, the study provides no evidence that putative proliferating cells are linked to neurogenesis, that multipolar nestin+ astrocytes are progenitors, or that mature-looking doublecortin+ neurons are adult-born. Their histology-marker expression differs from what is observed in species where adult hippocampal neurogenesis is well documented.
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Hipocampo , Enfermedades Neurodegenerativas , Neurogénesis , Adulto , Astrocitos , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Humanos , Enfermedades Neurodegenerativas/metabolismo , Neurogénesis/fisiología , Neuronas/fisiologíaRESUMEN
Although the anti-inflammatory actions of glucocorticoids (GCs) are well established, evidence has accumulated showing that proinflammatory GC effects can occur in the brain, in a poorly understood manner. Using electrophoretic mobility shift assay, real-time PCR, and immunoblotting, we investigated the ability of varying concentrations of corticosterone (CORT, the GC of rats) to modulate lipopolysaccharide (LPS)-induced activation of NF-κB (nuclear factor κB), expression of anti- and proinflammatory factors and of the MAP (mitogen-activated protein) kinase family [ERK (extracellular signal-regulated kinase), p38, and JNK/SAPK (c-Jun N-terminal protein kinase/stress-activated protein kinase)], and AKT. In the frontal cortex, elevated CORT levels were proinflammatory, exacerbating LPS effects on NF-κB, MAP kinases, and proinflammatory gene expression. Milder proinflammatory GCs effects occurred in the hippocampus. In the absence of LPS, elevated CORT levels increased basal activation of ERK1/2, p38, SAPK/JNK, and AKT in both regions. These findings suggest that GCs do not uniformly suppress neuroinflammation and can even enhance it at multiple levels in the pathway linking LPS exposure to inflammation.
Asunto(s)
Corticosterona/farmacología , Lóbulo Frontal/metabolismo , Hipocampo/metabolismo , Transducción de Señal/efectos de los fármacos , Análisis de Varianza , Animales , Western Blotting , Corticosterona/sangre , Relación Dosis-Respuesta a Droga , Ensayo de Cambio de Movilidad Electroforética , Lóbulo Frontal/efectos de los fármacos , Glucocorticoides/farmacología , Hipocampo/efectos de los fármacos , Inflamación/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Lipopolisacáridos/farmacología , Masculino , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/fisiología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Studies of individuals with autism spectrum disorder (ASD) have revealed a strong multigenic basis with the identification of hundreds of ASD susceptibility genes. ASD is characterized by social deficits and a range of other phenotypes, implicating complex genetics and involvement of a variety of brain regions. However, how mutations and mis-expression of select gene sets are associated with the behavioral components of ASD remains unknown. We reasoned that for genes to be associated with ASD core behaviors they must be: (1) expressed in brain regions relevant to ASD social behaviors and (2) expressed during the ASD susceptible window of brain development. METHODS: Focusing on the amygdala, a brain region whose dysfunction has been highly implicated in the social component of ASD, we mined publicly available gene expression databases to identify ASD-susceptibility genes expressed during human and mouse amygdala development. We found that a large cohort of known ASD susceptibility genes is expressed in the developing human and mouse amygdala. We further performed analysis of single-nucleus RNA-seq (snRNA-seq) data from microdissected amygdala tissue from five ASD and five control human postmortem brains ranging in age from 4 to 20 years to elucidate cell type specificity of amygdala-expressed genes and their dysregulation in ASD. RESULTS: Our analyses revealed that of the high-ranking ASD susceptibility genes, 80 are expressed in both human and mouse amygdala during fetal to early postnatal stages of development. Our human snRNA-seq analyses revealed cohorts of genes with altered expression in the ASD amygdala postnatally, especially within excitatory neurons, with dysregulated expression of seven genes predicted from our datamining pipeline. LIMITATIONS: We were limited by the ages for which we were able to obtain human tissue; therefore, the results from our datamining pipeline approach will require validation, to the extent possible, in human tissue from earlier developmental stages. CONCLUSIONS: Our pipeline narrows down the number of amygdala-expressed genes possibly involved in the social pathophysiology of ASD. Our human single-nucleus gene expression analyses revealed that ASD is characterized by changes in gene expression in specific cell types in the early postnatal amygdala.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Trastorno del Espectro Autista/etiología , Biomarcadores , Susceptibilidad a Enfermedades , Alelos , Amígdala del Cerebelo/fisiopatología , Animales , Trastorno del Espectro Autista/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Biología Computacional/métodos , Bases de Datos Genéticas , Expresión Génica , Perfilación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Ratones , Transducción de Señal , TranscriptomaRESUMEN
The human early postnatal brain contains late migratory streams of immature interneurons that are directed to cortex and other focal brain regions. However, such migration is not observed in rodent brain, and whether other small animal models capture this aspect of human brain development is unclear. Here, we investigated whether the gyrencephalic ferret cortex possesses human-equivalent postnatal streams of doublecortin positive (DCX+) young neurons. We mapped DCX+ cells in the brains of ferrets at P20 (analogous to human term gestation), P40, P65, and P90. In addition to the rostral migratory stream, we identified three populations of young neurons with migratory morphology at P20 oriented toward: (a) prefrontal cortex, (b) dorsal posterior sigmoid gyrus, and (c) occipital lobe. These three neuronal collections were all present at P20 and became extinguished by P90 (equivalent to human postnatal age 2 years). DCX+ cells in such collections all expressed GAD67, identifying them as interneurons, and they variously expressed the subtype markers SP8 and secretagogin (SCGN). SCGN+ interneurons appeared in thick sections to be oriented from white matter toward multiple cortical regions, and persistent SCGN-expressing cells were observed in cortex. These findings indicate that ferret is a suitable animal model to study the human-relevant process of late postnatal cortical interneuron integration into multiple regions of cortex.
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Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Hurones/anatomía & histología , Interneuronas/citología , Animales , Encéfalo/metabolismo , Caspasa 3/metabolismo , Movimiento Celular , Proteínas de Dominio Doblecortina , Proteína Doblecortina , Hurones/metabolismo , Humanos , Interneuronas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Neuropéptidos/metabolismo , Secretagoginas/metabolismo , Sustancia Blanca/citología , Sustancia Blanca/crecimiento & desarrollo , Sustancia Blanca/metabolismoRESUMEN
The human amygdala grows during childhood, and its abnormal development is linked to mood disorders. The primate amygdala contains a large population of immature neurons in the paralaminar nuclei (PL), suggesting protracted development and possibly neurogenesis. Here we studied human PL development from embryonic stages to adulthood. The PL develops next to the caudal ganglionic eminence, which generates inhibitory interneurons, yet most PL neurons express excitatory markers. In children, most PL cells are immature (DCX+PSA-NCAM+), and during adolescence many transition into mature (TBR1+VGLUT2+) neurons. Immature PL neurons persist into old age, yet local progenitor proliferation sharply decreases in infants. Using single nuclei RNA sequencing, we identify the transcriptional profile of immature excitatory neurons in the human amygdala between 4-15 years. We conclude that the human PL contains excitatory neurons that remain immature for decades, a possible substrate for persistent plasticity at the interface of the hippocampus and amygdala.
Asunto(s)
Desarrollo del Adolescente/fisiología , Complejo Nuclear Basolateral/crecimiento & desarrollo , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Adolescente , Adulto , Anciano , Complejo Nuclear Basolateral/citología , Núcleo Celular/genética , Niño , Preescolar , Feto , Hipocampo/fisiología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Plasticidad Neuronal/fisiología , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Adulto JovenRESUMEN
The walls of the cerebral ventricles in the developing embryo harbor the primary neural stem cells from which most neurons and glia derive. In many vertebrates, neurogenesis continues postnatally and into adulthood in this region. Adult neurogenesis at the ventricle has been most extensively studied in organisms with small brains, such as reptiles, birds, and rodents. In reptiles and birds, these progenitor cells give rise to young neurons that migrate into many regions of the forebrain. Neurogenesis in adult rodents is also relatively widespread along the lateral ventricles, but migration is largely restricted to the rostral migratory stream into the olfactory bulb. Recent work indicates that the wall of the lateral ventricle is highly regionalized, with progenitor cells giving rise to different types of neurons depending on their location. In species with larger brains, young neurons born in these spatially specified domains become dramatically separated from potential final destinations. Here we hypothesize that the increase in size and topographical complexity (e.g., intervening white matter tracts) in larger brains may severely limit the long-term contribution of new neurons born close to, or in, the ventricular wall. We compare the process of adult neuronal birth, migration, and integration across species with different brain sizes, and discuss how early regional specification of progenitor cells may interact with brain size and affect where and when new neurons are added.
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Encéfalo/anatomía & histología , Encéfalo/fisiología , Neurogénesis/fisiología , Células Madre Adultas/fisiología , Animales , Humanos , Células-Madre Neurales/fisiología , Tamaño de los ÓrganosAsunto(s)
Glucocorticoides/fisiología , Inmunidad Celular/fisiología , Inmunidad Innata/fisiología , Macrófagos/fisiología , Animales , Glucocorticoides/efectos adversos , Glucocorticoides/farmacología , Humanos , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Macrófagos/inmunología , Receptor Toll-Like 2/efectos de los fármacosRESUMEN
GABAergic cortical interneurons, derived from the embryonic medial and caudal ganglionic eminences (MGE and CGE), are functionally and morphologically diverse. Inroads have been made in understanding the roles of distinct cortical interneuron subgroups, however, there are still many mechanisms to be worked out that may contribute to the development and maturation of different types of GABAergic cells. Moreover, altered GABAergic signaling may contribute to phenotypes of autism, schizophrenia and epilepsy. Specific Cre-driver lines have begun to parcel out the functions of unique interneuron subgroups. Despite the advances in mouse models, it is often difficult to efficiently study GABAergic cortical interneuron progenitors with molecular approaches in vivo. One important technique used to study the cell autonomous programming of these cells is transplantation of MGE cells into host cortices. These transplanted cells migrate extensively, differentiate, and functionally integrate. In addition, MGE cells can be efficiently transduced with lentivirus immediately prior to transplantation, allowing for a multitude of molecular approaches. Here we detail a protocol to efficiently transduce MGE cells before transplantation for in vivo analysis, using available Cre-driver lines and Cre-dependent expression vectors. This approach is advantageous because it combines precise genetic manipulation with the ability of these cells to disperse after transplantation, permitting greater cell-type specific resolution in vivo.
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Trasplante de Células/métodos , Neuronas GABAérgicas/trasplante , Interneuronas/fisiología , Interneuronas/virología , Eminencia Media/fisiología , Eminencia Media/virología , Animales , Femenino , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/fisiología , Neuronas GABAérgicas/virología , Células HEK293 , Humanos , Interneuronas/citología , Interneuronas/trasplante , Lentivirus/genética , Eminencia Media/citología , Eminencia Media/trasplante , Ratones , Células-Madre Neurales/citología , Embarazo , Transducción de Señal , Transducción GenéticaRESUMEN
OBJECTIVES: Relapse management is a crucial component of multiple sclerosis (MS) care. High-dose corticosteroids (CSs) are used to dampen inflammation, which is thought to hasten the recovery of MS relapse. A diversity of mechanisms drive the heterogeneous clinical response to exogenous CSs in patients with MS. Preclinical research is beginning to provide important insights into how CSs work, both in terms of intended and unintended effects. In this article we discuss cellular, systemic, and clinical characteristics that might contribute to intended and unintended CS effects when utilizing supraphysiological doses in clinical practice. The goal of this article is to consider recent insights about CS mechanisms of action in the context of MS. METHODS: We reviewed relevant preclinical and clinical studies on the desirable and undesirable effects of high-dose corticosteroids used in MS care. RESULTS: Preclinical studies reviewed suggest that corticosteroids may act in unpredictable ways in the context of autoimmune conditions. The precise timing, dosage, duration, cellular exposure, and background CS milieu likely contribute to their clinical heterogeneity. CONCLUSION: It is difficult to predict when patients will respond favorably to CSs, both in terms of therapeutic response and tolerability profile. There are specific cellular, systemic, and clinical characteristics that might merit further consideration when utilizing CSs in clinical practice, and these should be explored in a translational setting.