RESUMEN
Visualizing nerve cells has been fundamental for the systematic description of brain structure and function in humans and other species. Different approaches aimed to unravel the morphological features of neuron types and diversity. The inherent complexity of the human nervous tissue and the need for proper histological processing have made studying human dendrites and spines challenging in postmortem samples. In this study, we used Golgi data and open-source software for 3D image reconstruction of human neurons from the cortical amygdaloid nucleus to show different dendrites and pleomorphic spines at different angles. Procedures required minimal equipment and generated high-quality images for differently shaped cells. We used the "single-section" Golgi method adapted for the human brain to engender 3D reconstructed images of the neuronal cell body and the dendritic ramification by adopting a neuronal tracing procedure. In addition, we elaborated 3D reconstructions to visualize heterogeneous dendritic spines using a supervised machine learning-based algorithm for image segmentation. These tools provided an additional upgrade and enhanced visual display of information related to the spatial orientation of dendritic branches and for dendritic spines of varied sizes and shapes in these human subcortical neurons. This same approach can be adapted for other techniques, areas of the central or peripheral nervous system, and comparative analysis between species.
Asunto(s)
Dendritas , Corteza Olfatoria , Humanos , Dendritas/fisiología , Imagenología Tridimensional , Neuronas , Programas Informáticos , Espinas Dendríticas/fisiologíaRESUMEN
Macroautophagy (hereafter "autophagy") is a lysosomal degradation pathway that is important for learning and memory, suggesting critical roles for autophagy at the neuronal synapse. Little is known, however, about the molecular details of how autophagy is regulated with synaptic activity. Here, we used live-cell confocal microscopy to define the autophagy pathway in primary hippocampal neurons under various paradigms of synaptic activity. We found that synaptic activity regulates the motility of autophagic vacuoles (AVs) in dendrites. Stimulation of synaptic activity dampens AV motility, whereas silencing synaptic activity induces AV motility. Activity-dependent effects on dendritic AV motility are local and reversible. Importantly, these effects are compartment specific, occurring in dendrites and not in axons. Most strikingly, synaptic activity increases the presence of degradative autolysosomes in dendrites and not in axons. On the basis of our findings, we propose a model whereby synaptic activity locally controls AV dynamics and function within dendrites that may regulate the synaptic proteome.
Asunto(s)
Autofagia , Movimiento Celular , Dendritas/fisiología , Hipocampo/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Vacuolas/fisiología , Animales , Autofagosomas/fisiología , Axones/fisiología , Hipocampo/citología , Lisosomas/fisiología , Ratones , Neuronas/citología , Ratas , Ratas Sprague-DawleyRESUMEN
In spiking neural P (SN P) systems, neurons are interconnected by means of synapses, and they use spikes to communicate with each other. However, in biology, the complex structure of dendritic tree is also an important part in the communication scheme between neurons since these structures are linked to advanced neural process such as learning and memory formation. In this work, we present a new variant of the SN P systems inspired by diverse dendrite and axon phenomena such as dendritic feedback, dendritic trunk, dendritic delays and axonal delays, respectively. This new variant is referred to as a spiking neural P system with dendritic and axonal computation (DACSN P system). Specifically, we include experimentally proven biological features in the current SN P systems to reduce the computational complexity of the soma by providing it with stable firing patterns through dendritic delays, dendritic feedback and axonal delays. As a consequence, the proposed DACSN P systems use the minimum number of synapses and neurons with simple and homogeneous standard spiking rules. Here, we study the computational capabilities of a DACSN P system. In particular, we prove that DACSN P systems with dendritic and axonal behavior are universal as both number-accepting/generating devices. In addition, we constructed a small universal SN P system using 39 neurons with standard spiking rules to compute any Turing computable function.
Asunto(s)
Retroalimentación , Modelos Neurológicos , Redes Neurales de la Computación , Sinapsis/fisiología , Potenciales de Acción , Axones/fisiología , Dendritas/fisiología , Humanos , Tiempo de ReacciónRESUMEN
The establishment of polarity is crucial for the physiology and wiring of neurons. Therefore, monitoring the axo-dendritic specification allows the mechanisms and signals associated with development, growth, and disease to be explored. Here, we describe major and minor steps to study polarity acquisition, using primary cultures of hippocampal neurons isolated from embryonic rat hippocampi, for in vitro monitoring. Furthermore, we use in utero electroporated, GFP-expressing embryonic mouse brains for visualizing cortical neuron migration and polarization in situ. Some underreported after-protocol steps are also included. For complete details on the use and execution of this protocol, please refer to Wilson et al. (2020).
Asunto(s)
Polaridad Celular/fisiología , Neuronas/metabolismo , Cultivo Primario de Células/métodos , Animales , Axones/fisiología , Células Cultivadas , Dendritas/fisiología , Electroporación , Hipocampo/metabolismo , Ratones , Neurogénesis , Neuronas/fisiología , RatasRESUMEN
A general agreement in psycholinguistics claims that syntax and meaning are unified precisely and very quickly during online sentence processing. Although several theories have advanced arguments regarding the neurocomputational bases of this phenomenon, we argue that these theories could potentially benefit by including neurophysiological data concerning cortical dynamics constraints in brain tissue. In addition, some theories promote the integration of complex optimization methods in neural tissue. In this paper we attempt to fill these gaps introducing a computational model inspired in the dynamics of cortical tissue. In our modeling approach, proximal afferent dendrites produce stochastic cellular activations, while distal dendritic branches-on the other hand-contribute independently to somatic depolarization by means of dendritic spikes, and finally, prediction failures produce massive firing events preventing formation of sparse distributed representations. The model presented in this paper combines semantic and coarse-grained syntactic constraints for each word in a sentence context until grammatically related word function discrimination emerges spontaneously by the sole correlation of lexical information from different sources without applying complex optimization methods. By means of support vector machine techniques, we show that the sparse activation features returned by our approach are well suited-bootstrapping from the features returned by Word Embedding mechanisms-to accomplish grammatical function classification of individual words in a sentence. In this way we develop a biologically guided computational explanation for linguistically relevant unification processes in cortex which connects psycholinguistics to neurobiological accounts of language. We also claim that the computational hypotheses established in this research could foster future work on biologically-inspired learning algorithms for natural language processing applications.
Asunto(s)
Vías Aferentes/fisiología , Simulación por Computador , Lingüística/métodos , Neocórtex/fisiología , Red Nerviosa/fisiología , Percepción del Habla/fisiología , Dendritas/fisiología , HumanosRESUMEN
Life experiences at early ages, such as physical activity in childhood and adolescence, can result in long-lasting brain effects able to reduce future risk of brain disorders and to enhance lifelong brain functions. However, how early physical exercise promotes these effects remains unclear. A possible hypothesis is that physical exercise increases the expression of neurotrophic factors and stimulates neuronal growth, resulting in a neural reserve to be used at later ages. Basing our study on this hypothesis, we evaluated the absolute number and morphology of neuronal cells, as well as the expression of growth, proliferation and survival proteins (BDNF, Akt, mTOR, p70S6K, ERK and CREB) in the cerebral cortex and hippocampal formation throughout of a sedentary period of rats who were physically active during youth. To do this, male Wistar rats were submitted to an aerobic exercise protocol from the 21st to the 60th postnatal days (P21-P60), and evaluated at 0 (P60), 30 (P90) and 60 (P120) days after the last exercise session. Results showed that juvenile exercise increased, and maintained elevated, the number of cortical and hippocampal neuronal cells and dendritic arborization, when evaluated at the above post-exercise ages. Hippocampal BDNF levels and cortical mTOR expression were found to be increased at P60, but were restored to control levels at P90 and P120. Overall, these findings indicate that, despite the short-term effects on growth and survival proteins, early exercise induces long-lasting morphological changes in cortical and hippocampal neurons even during a sedentary period of rats.
Asunto(s)
Corteza Cerebral/citología , Hipocampo/citología , Plasticidad Neuronal/fisiología , Neuronas/citología , Condicionamiento Físico Animal/fisiología , Hormona Adrenocorticotrópica/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Forma de la Célula/fisiología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Corticosterona/metabolismo , Dendritas/fisiología , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Neuronas/metabolismo , Neuronas/fisiología , Ratas , Ratas Wistar , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Microtubules (MTs) are long cylindrical structures of the cytoskeleton that control cell division, intracellular transport, and the shape of cells. MTs also form bundles, which are particularly prominent in neurons, where they help define axons and dendrites. MTs are bio-electrochemical transistors that form nonlinear electrical transmission lines. However, the electrical properties of most MT structures remain largely unknown. Here we show that bundles of brain MTs spontaneously generate electrical oscillations and bursts of electrical activity similar to action potentials. Under intracellular-like conditions, voltage-clamped MT bundles displayed electrical oscillations with a prominent fundamental frequency at 39 Hz that progressed through various periodic regimes. The electrical oscillations represented, in average, a 258% change in the ionic conductance of the MT structures. Interestingly, voltage-clamped membrane-permeabilized neurites of cultured mouse hippocampal neurons were also capable of both, generating electrical oscillations, and conducting the electrical signals along the length of the structure. Our findings indicate that electrical oscillations are an intrinsic property of brain MT bundles, which may have important implications in the control of various neuronal functions, including the gating and regulation of cytoskeleton-regulated excitable ion channels and electrical activity that may aid and extend to higher brain functions such as memory and consciousness.
Asunto(s)
Potenciales de Acción/fisiología , Axones/fisiología , Encéfalo/metabolismo , Dendritas/fisiología , Microtúbulos/fisiología , Neuronas/fisiología , Animales , Axones/metabolismo , Células Cultivadas , Dendritas/metabolismo , Conductividad Eléctrica , Fenómenos Electrofisiológicos , Ratones , Microtúbulos/metabolismo , Neuronas/metabolismo , RatasRESUMEN
Action potentials (APs) in nigral dopaminergic neurons often exhibit two separate components: the first reflecting spike initiation in the dendritically located axon initial segment (AIS) and the second the subsequent dendro-somatic spike. These components are separated by a notch in the ascending phase of the somatic extracellular waveform and in the temporal derivative of the somatic intracellular waveform. Still, considerable variability exists in the presence and magnitude of the notch across neurons. To systematically address the contribution of AIS, dendritic and somatic compartments to shaping the two-component APs, we modeled APs of previously in vivo electrophysiologically characterized and 3D-reconstructed male mouse and rat dopaminergic neurons. A parsimonious two-domain model, with high (AIS) and lower (dendro-somatic) Na+ conductance, reproduced the notch in the temporal derivatives, but not in the extracellular APs, regardless of morphology. The notch was only revealed when somatic active currents were reduced, constraining the model to three domains. Thus, an initial AIS spike is followed by an actively generated spike by the axon-bearing dendrite (ABD), in turn followed mostly passively by the soma. The transition from being a source compartment for the AIS spike to a source compartment for the ABD spike satisfactorily explains the extracellular somatic notch. Larger AISs and thinner ABD (but not soma-to-AIS distance) accentuate the AIS component. We conclude that variability in AIS size and ABD caliber explains variability in AP extracellular waveform and separation of AIS and dendro-somatic components, given the presence of at least three functional domains with distinct excitability characteristics.SIGNIFICANCE STATEMENT Midbrain dopamine neurons make an important contribution to circuits mediating motivation and movement. Understanding the basic rules that govern the electrical activity of single dopaminergic neurons is therefore essential to reveal how they ultimately contribute to movement and motivation as well as what goes wrong in associated disorders. Our computational study focuses on the generation and propagation of action potentials and shows that different morphologies and excitability characteristics of the cell body, dendrites and proximal axon can explain the diversity of action potentials shapes in this population. These compartments likely make differential contributions both to normal dopaminergic signaling and could potentially underlie pathological dopaminergic signaling implicated in addiction, schizophrenia, Parkinson's disease, and other disorders.
Asunto(s)
Potenciales de Acción/fisiología , Simulación por Computador , Neuronas Dopaminérgicas/fisiología , Modelos Neurológicos , Sustancia Negra/fisiología , Animales , Axones/fisiología , Dendritas/fisiología , Neuronas Dopaminérgicas/citología , Masculino , Ratones , Ratas , Sustancia Negra/citologíaRESUMEN
Preservation of a balance between synaptic excitation and inhibition is critical for normal brain function. A number of homeostatic cellular mechanisms have been suggested to play a role in maintaining this balance, including long-term plasticity of GABAergic inhibitory synapses. Many previous studies have demonstrated a coupling of postsynaptic spiking with modification of perisomatic inhibition. Here, we demonstrate that activation of NMDA-type glutamate receptors leads to input-specific long-term potentiation of dendritic inhibition mediated by somatostatin-expressing interneurons. This form of plasticity is expressed postsynaptically and requires both CaMKIIα and the ß2 subunit of the GABA-A receptor. Importantly, this process may function to preserve dendritic inhibition, as genetic deletion of NMDAR signaling results in a selective weakening of dendritic inhibition. Overall, our results reveal a new mechanism for linking excitatory and inhibitory input in neuronal dendrites and provide novel insight into the homeostatic regulation of synaptic transmission in cortical circuits.
Asunto(s)
Dendritas/fisiología , Potenciación a Largo Plazo/fisiología , Proteínas del Tejido Nervioso/fisiología , Inhibición Neural/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Ácido gamma-Aminobutírico/fisiología , Animales , Señalización del Calcio/fisiología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/fisiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Piramidales/fisiología , Receptores de GABA-A/fisiologíaRESUMEN
During aging, the brain undergoes changes that impair cognitive capacity and circuit plasticity, including a marked decrease in production of adult-born hippocampal neurons. It is unclear whether development and integration of those new neurons are also affected by age. Here, we show that adult-born granule cells (GCs) in aging mice are scarce and exhibit slow development, but they display a remarkable potential for structural plasticity. Retrovirally labeled 3-week-old GCs in middle-aged mice were small, underdeveloped, and disconnected. Neuronal development and integration were accelerated by voluntary exercise or environmental enrichment. Similar effects were observed via knockdown of Lrig1, an endogenous negative modulator of neurotrophin receptors. Consistently, blocking neurotrophin signaling by Lrig1 overexpression abolished the positive effects of exercise. These results demonstrate an unparalleled degree of plasticity in the aging brain mediated by neurotrophins, whereby new GCs remain immature until becoming rapidly recruited to the network by activity.
Asunto(s)
Envejecimiento , Hipocampo/metabolismo , Plasticidad Neuronal/fisiología , Animales , Calbindinas/metabolismo , Proteínas de Unión al ADN , Dendritas/fisiología , Giro Dentado/metabolismo , Femenino , Técnicas In Vitro , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal , Factores de Crecimiento Nervioso/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/fisiología , Proteínas Nucleares/metabolismo , Técnicas de Placa-Clamp , Condicionamiento Físico Animal , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de SeñalRESUMEN
The formation of synaptic connections during nervous system development requires the precise control of dendrite growth and synapse formation. Although glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 are expressed in the forebrain, the role of this system in the hippocampus remains unclear. Here, we investigated the consequences of GFRα1 deficiency for the development of hippocampal connections. Analysis of conditional Gfra1 knockout mice shows a reduction in dendritic length and complexity, as well as a decrease in postsynaptic density specializations and in the synaptic localization of postsynaptic proteins in hippocampal neurons. Gain- and loss-of-function assays demonstrate that the GDNF-GFRα1 complex promotes dendritic growth and postsynaptic differentiation in cultured hippocampal neurons. Finally, in vitro assays revealed that GDNF-GFRα1-induced dendrite growth and spine formation are mediated by NCAM signaling. Taken together, our results indicate that the GDNF-GFRα1 complex is essential for proper hippocampal circuit development.
Asunto(s)
Dendritas/fisiología , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Hipocampo/crecimiento & desarrollo , Moléculas de Adhesión de Célula Nerviosa/fisiología , Neurogénesis/genética , Plasticidad Neuronal/genética , Animales , Diferenciación Celular/genética , Células Cultivadas , Embrión de Mamíferos , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Receptores del Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Hipocampo/citología , Hipocampo/metabolismo , Ratones , Ratones Noqueados , Complejos Multiproteicos/fisiología , Red Nerviosa/crecimiento & desarrollo , Red Nerviosa/metabolismo , Neuronas/fisiología , Unión Proteica , Ratas , Ratas WistarRESUMEN
Findings showing that neonatal lesions of the forebrain dopaminergic system in rodents lead to juvenile locomotor hyperactivity and learning deficits have been taken as evidence of face validity for the attention deficit hyperactivity disorder. However, the core cognitive and physiological intermediate phenotypes underlying this rodent syndrome remain unknown. Here we show that early postnatal dopaminergic lesions cause long-lasting deficits in exploitation of shelter, social and nutritional resources, and an imbalanced exploratory behavior, where nondirected local exploration is exacerbated, whereas sophisticated search behaviors involving sequences of goal directed actions are degraded. Importantly, some behavioral deficits do not diminish after adolescence but instead worsen or mutate, particularly those related to the exploration of wide and spatially complex environments. The in vivo electrophysiological recordings and morphological reconstructions of striatal medium spiny neurons reveal corticostriatal alterations associated to the behavioral phenotype. More specifically, an attenuation of corticostriatal functional connectivity, affecting medial prefrontal inputs more markedly than cingulate and motor inputs, is accompanied by a contraction of the dendritic arbor of striatal projection neurons in this animal model. Thus, dopaminergic neurons are essential during postnatal development for the functional and structural maturation of corticostriatal connections. From a bottom-up viewpoint, our findings suggest that neuropsychiatric conditions presumably linked to developmental alterations of the dopaminergic system should be evaluated for deficits in foraging decision making, alterations in the recruitment of corticostriatal circuits during foraging tasks, and structural disorganization of the frontostriatal connections.
Asunto(s)
Corteza Cerebral/fisiopatología , Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Conducta Exploratoria/fisiología , Animales , Animales Recién Nacidos , Corteza Cerebral/crecimiento & desarrollo , Corteza Cerebral/patología , Cuerpo Estriado/patología , Dendritas/patología , Dendritas/fisiología , Modelos Animales de Enfermedad , Electrodos Implantados , Inmunohistoquímica , Ratones , Actividad Motora/fisiología , Vías Nerviosas/crecimiento & desarrollo , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Oxidopamina , Fenotipo , Conducta Social , Conducta Espacial/fisiologíaRESUMEN
Previous work has shown a reduction of apical dendritic length and spine density in neurons from the CA1 hippocampus subfield of spontaneously hypertensive rats (SHRs). These abnormalities are prevented by treatment for 2 weeks with 17ß-estradiol. In view of the fact that diabetes and hypertension are comorbid diseases, we have now studied the effect of Streptozotocin-induced diabetes on the dendritic tree and spines of CA1 hippocampus neurons, and also compared the regulation of these parameters by 17ß-estradiol in diabetic and normoglycemic SHR. Twenty-week-old male SHR received i.v. 40-mg/kg Streptozotocin or vehicle and studied 1 month afterward. A group of normoglycemic and hyperglycemic SHR also received s.c. a single 17ß-estradiol pellet or vehicle for 2weeks. Hippocampus sections were impregnated with silver nitrate following a modified Golgi's method and the arbor of CA1 pyramidal neurons analyzed by Sholl's method. 17ß-Estradiol treatment of normoglycemic SHR reversed the reduced length of apical dendrites, the low spine density and additionally decreased blood pressure (BP). Diabetic SHR showed increased length of apical and basal dendrites but reduced spine density compared to normoglycemic SHR. Diabetes also decreased BP of SHR. Treatment with 17ß-estradiol of diabetic SHR enhanced dendritic length, increased dendritic spine density and further decreased BP. Thus, changes of cytoarchitecture of CA1 neurons due to 17ß-estradiol treatment of normoglycemic SHR persisted after diabetes induction. A decrease of BP may also contribute to the central effects of 17ß-estradiol in SHR diabetic rats.
Asunto(s)
Región CA1 Hipocampal/efectos de los fármacos , Dendritas/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Estradiol/farmacología , Fármacos Neuroprotectores/farmacología , Células Piramidales/efectos de los fármacos , Animales , Presión Sanguínea/efectos de los fármacos , Región CA1 Hipocampal/patología , Región CA1 Hipocampal/fisiopatología , Dendritas/patología , Dendritas/fisiología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/patología , Hipertensión/fisiopatología , Masculino , Fotomicrografía , Células Piramidales/patología , Células Piramidales/fisiopatología , Ratas Endogámicas SHRRESUMEN
Brain activity contains three fundamental aspects: (a) The physiological aspect, covering all kinds of processes that involve matter and/or energy; (b) the mental unconscious aspect, consisting of dynamical patterns (i.e., frequency, amplitude and phase-modulated waves) embodied in neural activity. These patterns are variously operated (transmitted, stored, combined, matched, amplified, erased, etc), forming cognitive and emotional unconscious processes and (c) the mental conscious aspect, consisting of feelings experienced in the first-person perspective and cognitive functions grounded in feelings, as memory formation, selection of the focus of attention, voluntary behavior, aesthetical appraisal and ethical judgment. Triple-aspect monism (TAM) is a philosophical theory that provides a model of the relation of the three aspects. Spatially distributed neuronal dendritic potentials generate amplitude-modulated waveforms transmitted to the extracellular medium and adjacent astrocytes, prompting the formation of large waves in the astrocyte network, which are claimed to both integrate distributed information and instantiate feelings. According to the valence of the feeling, the large wave feeds back on neuronal synapses, modulating (reinforcing or depressing) cognitive and behavioral functions.
Asunto(s)
Encéfalo/fisiología , Estado de Conciencia/fisiología , Modelos Neurológicos , Filosofía , Astrocitos/fisiología , Conducta/fisiología , Evolución Biológica , Cognición/fisiología , Dendritas/fisiología , Emociones/fisiología , Retroalimentación Fisiológica/fisiología , Humanos , Procesos Mentales/fisiologíaRESUMEN
The Down syndrome cell adhesion molecule (DSCAM) is required for regulation of cell number, soma spacing, and cell type-specific dendrite avoidance in many types of retinal ganglion and amacrine cells. In this study we assay the organization of cells making up the outer plexiform layer of the retina in the absence of Dscam. Some types of OFF bipolar cells, type 3b and type 4 bipolar cells, had defects in dendrite arborization in the Dscam mutant retina, whereas other cell types appeared similar to wild type. The cone synapses that these cells project their dendrites to were intact, as visualized by electron microscopy, and had a distribution and density that was not significantly different from that of wild type. The spacing of type 3b bipolar cell dendrites was further analyzed by Voronoi domain analysis, density recovery profiling (DRP) analysis, and nearest neighbor analysis. Spacing was found to be significantly different when wild-type and mutant type 3b bipolar cell dendrites were compared. Defects in arborization of these bipolar cells could not be attributed to the disorganization of inner plexiform layer cells that occurs in the Dscam mutant retina or an increase in cell number, as they arborized when Dscam was targeted in retinal ganglion cells only or in the bax null retina. Localization of DSCAM was assayed and the protein was localized near to cone synapses in mouse, macaque, and ground squirrel retinas. DSCAM protein was detected in several types of bipolar cells, including type 3b and type 4 bipolar cells.
Asunto(s)
Células Fotorreceptoras Retinianas Conos/citología , Células Fotorreceptoras Retinianas Conos/fisiología , Sinapsis/fisiología , Animales , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Recuento de Células , Dendritas/fisiología , Femenino , Macaca , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Electrónica , Mutación , Retina/citología , Retina/fisiopatología , Células Bipolares de la Retina/citología , Células Bipolares de la Retina/fisiología , Sciuridae , Especificidad de la Especie , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Neuronal connectivity and synaptic remodeling are fundamental substrates for higher brain functions. Understanding their dynamics in the mammalian allocortex emerges as a critical step to tackle the cellular basis of cognitive decline that occurs during normal aging and in neurodegenerative disorders. In this work we have designed a novel approach to assess alterations in the dynamics of functional and structural connectivity elicited by chronic cell-autonomous overexpression of the human amyloid precursor protein (hAPP). We have taken advantage of the fact that the hippocampus continuously generates new dentate granule cells (GCs) to probe morphofunctional development of GCs expressing different variants of hAPP in a healthy background. hAPP was expressed together with a fluorescent reporter in neural progenitor cells of the dentate gyrus of juvenile mice by retroviral delivery. Neuronal progeny was analyzed several days post infection (dpi). Amyloidogenic cleavage products of hAPP such as the ß-C terminal fragment (ß-CTF) induced a substantial reduction in glutamatergic connectivity at 21 dpi, at which time new GCs undergo active growth and synaptogenesis. Interestingly, this effect was transient, since the strength of glutamatergic inputs was normal by 35 dpi. This delay in glutamatergic synaptogenesis was paralleled by a decrease in dendritic length with no changes in spine density, consistent with a protracted dendritic development without alterations in synapse formation. Finally, similar defects in newborn GC development were observed by overexpression of α-CTF, a non-amyloidogenic cleavage product of hAPP. These results indicate that hAPP can elicit protracted dendritic development independently of the amyloidogenic processing pathway.
Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Dendritas/metabolismo , Hipocampo/citología , Neurogénesis , Precursor de Proteína beta-Amiloide/genética , Animales , Dendritas/fisiología , Giro Dentado/citología , Giro Dentado/crecimiento & desarrollo , Giro Dentado/fisiología , Potenciales Postsinápticos Excitadores , Femenino , Hipocampo/crecimiento & desarrollo , Hipocampo/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/citología , Red Nerviosa/crecimiento & desarrollo , Red Nerviosa/fisiología , Células Receptoras Sensoriales/citología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/fisiologíaRESUMEN
Dendritic arborization of neurons is regulated by brain-derived neurotrophic factor (BDNF) together with its receptor, TrkB. Endocytosis is required for dendritic branching and regulates TrkB signaling, but how postendocytic trafficking determines the neuronal response to BDNF is not well understood. The monomeric GTPase Rab11 regulates the dynamics of recycling endosomes and local delivery of receptors to specific dendritic compartments. We investigated whether Rab11-dependent trafficking of TrkB in dendrites regulates BDNF-induced dendritic branching in rat hippocampal neurons. We report that TrkB in dendrites is a cargo for Rab11 endosomes and that both Rab11 and its effector, MyoVb, are required for BDNF/TrkB-induced dendritic branching. In addition, BDNF induces the accumulation of Rab11-positive endosomes and GTP-bound Rab11 in dendrites and the expression of a constitutively active mutant of Rab11 is sufficient to increase dendritic branching by increasing TrkB localization in dendrites and enhancing sensitization to endogenous BDNF. We propose that Rab11-dependent dendritic recycling provides a mechanism to retain TrkB in dendrites and to increase local signaling to regulate arborization.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Dendritas/efectos de los fármacos , Endosomas/efectos de los fármacos , Proteínas de Unión al GTP/metabolismo , Neuronas/citología , Análisis de Varianza , Animales , Anticuerpos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Carbazoles/farmacología , Células Cultivadas , Dendritas/fisiología , Dendritas/ultraestructura , Embrión de Mamíferos , Endocitosis/efectos de los fármacos , Endosomas/ultraestructura , Inhibidores Enzimáticos/farmacología , Femenino , Proteínas de Unión al GTP/genética , Proteínas de Unión al GTP/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Guanosina Trifosfato/metabolismo , Hipocampo/citología , Alcaloides Indólicos/farmacología , Masculino , Microscopía Confocal , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación/genética , Miosinas/metabolismo , Neuronas/efectos de los fármacos , ARN Interferente Pequeño/farmacología , Ratas , Receptor trkB/metabolismo , Tiazolidinas/farmacología , TransfecciónRESUMEN
The cortical layer 1 contains mainly small interneurons, which have traditionally been classified according to their axonal morphology. The dendritic morphology of these cells, however, has received little attention and remains ill defined. Very little is known about how the dendritic morphology and spatial distribution of these cells may relate to functional neuronal properties. We used biocytin labeling and whole cell patch clamp recordings, associated with digital reconstruction and quantitative morphological analysis, to assess correlations between dendritic morphology, spatial distribution and membrane properties of rat layer 1 neurons. A total of 106 cells were recorded, labeled and subjected to morphological analysis. Based on the quantitative patterns of their dendritic arbor, cells were divided into four major morphotypes: horizontal, radial, ascendant, and descendant cells. Descendant cells exhibited a highly distinct spatial distribution in relation to other morphotypes, suggesting that they may have a distinct function in these cortical circuits. A significant difference was also found in the distribution of firing patterns between each morphotype and between the neuronal populations of each sublayer. Passive membrane properties were, however, statistically homogeneous among all subgroups. We speculate that the differences observed in active membrane properties might be related to differences in the synaptic input of specific types of afferent fibers and to differences in the computational roles of each morphotype in layer 1 circuits. Our findings provide new insights into dendritic morphology and neuronal spatial distribution in layer 1 circuits, indicating that variations in these properties may be correlated with distinct physiological functions.
Asunto(s)
Animales , Ratas , Potenciales de Acción/fisiología , Tamaño de la Célula , Interneuronas/citología , Neuronas/citología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Dendritas/fisiología , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Sinapsis/fisiologíaRESUMEN
The vertebrate retina has a very high dynamic range. This is due to the concerted action of its diverse cell types. Ganglion cells, which are the output cells of the retina, have to preserve this high dynamic range to convey it to higher brain areas. Experimental evidence shows that the firing response of ganglion cells is strongly correlated with their total dendritic area and only weakly correlated with their dendritic branching complexity. On the other hand, theoretical studies with simple neuron models claim that active and large dendritic trees enhance the dynamic range of single neurons. Theoretical models also claim that electrical coupling between ganglion cells via gap junctions enhances their collective dynamic range. In this work we use morphologically reconstructed multi-compartmental ganglion cell models to perform two studies. In the first study we investigate the relationship between single ganglion cell dynamic range and number of dendritic branches/total dendritic area for both active and passive dendrites. Our results support the claim that large and active dendrites enhance the dynamic range of a single ganglion cell and show that total dendritic area has stronger correlation with dynamic range than with number of dendritic branches. In the second study we investigate the dynamic range of a square array of ganglion cells with passive or active dendritic trees coupled with each other via dendrodendritic gap junctions. Our results suggest that electrical coupling between active dendritic trees enhances the dynamic range of the ganglion cell array in comparison with both the uncoupled case and the coupled case with cells with passive dendrites. The results from our detailed computational modeling studies suggest that the key properties of the ganglion cells that endow them with a large dynamic range are large and active dendritic trees and electrical coupling via gap junctions.
Asunto(s)
Dendritas/fisiología , Sinapsis Eléctricas/fisiología , Uniones Comunicantes/fisiología , Células Ganglionares de la Retina/fisiología , Potenciales de Acción/fisiología , Ambystoma , Animales , Células Cultivadas , Potenciales de la Membrana/fisiología , Modelos Neurológicos , Neuronas/citología , Neuronas/fisiologíaRESUMEN
Stress leads to secretion of the adrenal steroid hormone corticosterone (CORT). The aim of this study was to determine the effects of chronic CORT administration on auditory and visual fear conditioning. Male Sprague-Dawley rats received CORT (400 mg/ml) in their drinking water for 10 consecutive days; this treatment induces stress levels of serum CORT. CORT impaired fear conditioning (F((1,28)) = 11.52, p < 0.01) and extinction (F((1,28)) = 4.86, p < 0.05) of auditory fear learning, but did not affect visual fear conditioning. In addition, we analyzed the CORT effects on the neuronal morphology of the inferior colliculus (flat neurons, auditory mesencephalon, a key brain area for auditory processing) and superior colliculus (wide-field neurons, related to visual processing) by Golgi stain. CORT decreased dendritic arborization of inferior colliculus neurons by approximately 50%, but did not affect superior colliculus neurons. Thus, CORT had more deleterious effects on the auditory fear processing than the visual system in the brain.