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1.
Proc Natl Acad Sci U S A ; 120(31): e2308798120, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37487074

RESUMEN

Mammalian infants depend on parental care for survival, with numerous consequences for their behavioral development. We investigated the epigenetic and neurodevelopmental mechanisms mediating the impact of early biparental care on development of alloparenting behavior, or caring for offspring that are not one's own. We find that receiving high parental care early in life leads to slower epigenetic aging of both sexes and widespread male-specific differential expression of genes related to synaptic transmission and autism in the nucleus accumbens. Examination of parental care composition indicates that high-care fathers promote a male-specific increase in excitatory synapses and increases in pup retrieval behavior as juveniles. Interestingly, females raised by high-care fathers have the opposite behavioral response and display fewer pup retrievals. These results support the concept that neurodevelopmental trajectories are programmed by different features of early-life parental care and reveal that male neurodevelopmental processes are uniquely sensitive to care by fathers.


Asunto(s)
Conducta Animal , Padre , Humanos , Femenino , Animales , Masculino , Conducta Animal/fisiología , Conducta Materna/fisiología , Núcleo Accumbens , Padres , Conducta Paterna , Arvicolinae/fisiología
2.
J Neurosci ; 43(41): 6872-6883, 2023 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-37648449

RESUMEN

The acoustic environment an animal experiences early in life shapes the structure and function of its auditory system. This process of experience-dependent development is thought to be primarily orchestrated by potentiation and depression of synapses, but plasticity of intrinsic voltage dynamics may also contribute. Here, we show that in juvenile male and female zebra finches, neurons in a cortical-level auditory area, the caudal mesopallium (CM), can rapidly change their firing dynamics. This plasticity was only observed in birds that were reared in a complex acoustic and social environment, which also caused increased expression of the low-threshold potassium channel Kv1.1 in the plasma membrane and endoplasmic reticulum (ER). Intrinsic plasticity depended on activity, was reversed by blocking low-threshold potassium currents, and was prevented by blocking intracellular calcium signaling. Taken together, these results suggest that Kv1.1 is rapidly mobilized to the plasma membrane by activity-dependent elevation of intracellular calcium. This produces a shift in the excitability and temporal integration of CM neurons that may be permissive for auditory learning in complex acoustic environments during a crucial period for the development of vocal perception and production.SIGNIFICANCE STATEMENT Neurons can change not only the strength of their connections to other neurons, but also how they integrate synaptic currents to produce patterns of action potentials. In contrast to synaptic plasticity, the mechanisms and functional roles of intrinisic plasticity remain poorly understood. We found that neurons in the zebra finch auditory cortex can rapidly shift their spiking dynamics within a few minutes in response to intracellular stimulation. This plasticity involves increased conductance of a low-threshold potassium current associated with the Kv1.1 channel, but it only occurs in birds reared in a rich acoustic environment. Thus, auditory experience regulates a mechanism of neural plasticity that allows neurons to rapidly adapt their firing dynamics to stimulation.


Asunto(s)
Corteza Auditiva , Pinzones , Animales , Masculino , Femenino , Corteza Auditiva/fisiología , Pinzones/fisiología , Neuronas/fisiología , Potenciales de Acción , Potasio , Vocalización Animal/fisiología , Estimulación Acústica , Plasticidad Neuronal/fisiología , Percepción Auditiva/fisiología
3.
Genes Dev ; 29(14): 1535-51, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26220996

RESUMEN

CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that CaV3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional CaV3.2 channels primarily incorporate into synapses, replace existing CaV3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCaV3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCaV3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of CaV3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.


Asunto(s)
Canales de Calcio/genética , Canales de Calcio/metabolismo , Epilepsia Tipo Ausencia/fisiopatología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/genética , Canales de Calcio Tipo T/metabolismo , Epilepsia Tipo Ausencia/genética , Regulación de la Expresión Génica , Humanos , Mutación , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal/efectos de los fármacos , Sinapsis/metabolismo
4.
Eur J Neurosci ; 50(4): 2707-2721, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30888721

RESUMEN

Nicotine-craving progressively increases, or incubates, over abstinence following extended access self-administration. While not yet examined for nicotine, the incubation of cocaine-seeking is accompanied by changes in synaptic plasticity in the nucleus accumbens. Here, we determined whether such changes also accompany enhanced nicotine-seeking following extended access self-administration and abstinence, and whether exercise, a potential intervention for nicotine addiction, may exert its efficacy by normalizing these changes. Given that in humans, tobacco/nicotine use begins during adolescence, we used an adolescent-onset model. Nicotine-seeking was assessed in male rats following extended access nicotine or saline self-administration (23-hr/day, 10 days) and 10 days of abstinence, conditions known to induce the incubation of nicotine-seeking, using a within-session extinction/cue-induced reinstatement procedure. A subset of rats had 2-hr/day access to a running wheel during abstinence. Ultrastructural alterations of synapses in the nucleus accumbens core and shell were examined using electron microscopy. Nicotine-seeking was elevated following extended access self-administration and abstinence (in sedentary group), and levels of seeking were associated with an increase in the density of asymmetric (excitatory) and symmetric (inhibitory) synapses onto dendrites in the core, as well as longer asymmetric synapses onto spines, a marker of synaptic potentiation, in both the core and shell. Exercise normalized each of these changes; however, in the shell, exercise and nicotine similarly increased the synapse length. Together, these findings indicate an association between nicotine-seeking and synaptic plasticity in the nucleus accumbens, particularly the core, and indicate that the efficacy of exercise to reduce nicotine-seeking may be mediated by reversing these adaptations.


Asunto(s)
Comportamiento de Búsqueda de Drogas , Plasticidad Neuronal , Condicionamiento Físico Animal , Síndrome de Abstinencia a Sustancias/patología , Sinapsis/patología , Tabaquismo/patología , Tabaquismo/psicología , Animales , Espinas Dendríticas/patología , Extinción Psicológica , Masculino , Núcleo Accumbens/patología , Ratas , Ratas Sprague-Dawley , Autoadministración , Cese del Hábito de Fumar , Sinapsis/ultraestructura
5.
J Neurosci ; 37(44): 10541-10553, 2017 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-28951447

RESUMEN

Brief monocular deprivation (MD) shifts ocular dominance and reduces the density of thalamic synapses in layer 4 of the mouse primary visual cortex (V1). We found that microglial lysosome content is also increased as a result of MD. Previous studies have shown that the microglial fractalkine receptor CX3CR1 is involved in synaptic development and hippocampal plasticity. We therefore tested the hypothesis that neuron-to-microglial communication via CX3CR1 is an essential component of visual cortical development and plasticity in male mice. Our data show that CX3CR1 is not required for normal development of V1 responses to visual stimulation, multiple forms of experience-dependent plasticity, or the synapse loss that accompanies MD in layer 4. By ruling out an essential role for fractalkine signaling, our study narrows the search for understanding how microglia respond to active synapse modification in the visual cortex.SIGNIFICANCE STATEMENT Microglia in the visual cortex respond to monocular deprivation with increased lysosome content, but signaling through the fractalkine receptor CX3CR1 is not an essential component in the mechanisms of visual cortical development or experience-dependent synaptic plasticity.


Asunto(s)
Potenciales Evocados Visuales/fisiología , Microglía/metabolismo , Plasticidad Neuronal/fisiología , Receptores de Quimiocina/deficiencia , Corteza Visual/crecimiento & desarrollo , Corteza Visual/metabolismo , Animales , Receptor 1 de Quimiocinas CX3C , Comunicación Celular/fisiología , Cuerpos Geniculados/crecimiento & desarrollo , Cuerpos Geniculados/metabolismo , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Técnicas de Cultivo de Órganos , Visión Monocular/fisiología
6.
Dev Dyn ; 246(11): 956-962, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28598521

RESUMEN

BACKGROUND: Spinal motor nerves are essential for relaying information between the central and peripheral nervous systems. Perturbations to cell types that comprise these nerves may impair rapid and efficient transmission of action potentials and alter nerve function. Identifying ultrastructural changes resulting from defects to these cellular components via transmission electron microscopy (TEM) can provide valuable insight into nerve function and disease. However, efficiently locating spinal motor nerves in adult zebrafish for TEM is challenging and time-consuming. Because of this, we developed a protocol that allows us to quickly and precisely locate spinal motor nerve roots in adult zebrafish for TEM processing. RESULTS: Following fixation, a transverse slab of adult zebrafish dissected from the trunk region was mounted in embedding media, sectioned, and secondary fixation with osmium tetroxide performed. Transverse sections containing motor nerves were selected for TEM ultrathin sectioning and imaging. CONCLUSIONS: We developed an efficient protocol for locating spinal motor nerves in adult zebrafish to allow for ultrastructural characterization. Although our work focuses on spinal motor nerves, this protocol may be useful for efficiently identifying other discrete, repeated structures within the developing and mature nervous system that are difficult to find via traditional, whole organism TEM processing. Developmental Dynamics 246:956-962, 2017. © 2017 Wiley Periodicals, Inc.


Asunto(s)
Microscopía Electrónica de Transmisión/métodos , Raíces Nerviosas Espinales/ultraestructura , Animales , Técnicas Histológicas/métodos , Pez Cebra/anatomía & histología
7.
J Neurosci ; 33(48): 18792-805, 2013 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-24285886

RESUMEN

The C1 neurons, located in the rostral ventrolateral medulla (VLM), are activated by pain, hypotension, hypoglycemia, hypoxia, and infection, as well as by psychological stress. Prior work has highlighted the ability of these neurons to increase sympathetic tone, hence peripheral catecholamine release, probably via their direct excitatory projections to sympathetic preganglionic neurons. In this study, we use channelrhodopsin-2 (ChR2) optogenetics to test whether the C1 cells are also capable of broadly activating the brain's noradrenergic system. We selectively expressed ChR2(H134R) in rostral VLM catecholaminergic neurons by injecting Cre-dependent adeno-associated viral vectors into the brain of adult dopamine-ß-hydroxylase (DßH)(Cre/0) mice. Most ChR2-expressing VLM neurons (75%) were immunoreactive for phenylethanolamine N-methyl transferease, thus were C1 cells, and most of the ChR2-positive axonal varicosities were immunoreactive for vesicular glutamate transporter-2 (78%). We produced light microscopic evidence that the axons of rostral VLM (RVLM) catecholaminergic neurons contact locus coeruleus, A1, and A2 noradrenergic neurons, and ultrastructural evidence that these contacts represent asymmetric synapses. Using optogenetics in tissue slices, we show that RVLM catecholaminergic neurons activate the locus coeruleus as well as A1 and A2 noradrenergic neurons monosynaptically by releasing glutamate. In conclusion, activation of RVLM catecholaminergic neurons, predominantly C1 cells, by somatic or psychological stresses has the potential to increase the firing of both peripheral and central noradrenergic neurons.


Asunto(s)
Tronco Encefálico/fisiología , Ácido Glutámico/fisiología , Locus Coeruleus/fisiología , Neuronas/fisiología , Sistema Nervioso Simpático/fisiología , Sinapsis/fisiología , Animales , Tronco Encefálico/citología , Channelrhodopsins , Dependovirus/genética , Dopamina beta-Hidroxilasa/genética , Fenómenos Electrofisiológicos/genética , Fenómenos Electrofisiológicos/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Vectores Genéticos , Técnicas In Vitro , Locus Coeruleus/química , Bulbo Raquídeo/citología , Bulbo Raquídeo/fisiología , Ratones , Microscopía Electrónica , Microscopía Fluorescente , Optogenética , Sistema Nervioso Parasimpático/fisiología , Estimulación Luminosa , Proteína 2 de Transporte Vesicular de Glutamato/metabolismo
8.
Neurobiol Dis ; 62: 44-55, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24051276

RESUMEN

Altered GABA-mediated inhibition is proposed to play a role in the pathogenesis of epilepsy. Previous studies have demonstrated a loss of somatostatin-containing GABAergic interneurons innervating granule cells in epileptic animals. However, the reorganization of synapses between interneurons and granule cells has not been investigated. We studied synapse organization in an animal model of temporal lobe epilepsy (TLE) using continuous hippocampal stimulation. The distribution of axon terminals and inhibitory synapses on granule cell dendrites was studied using a combination of immunohistochemistry and pre-embedding electron microscopy techniques. A whole-cell patch-clamp technique was applied to study the functional changes in GABAergic input from different interneurons. In epileptic animals, the density of cholecystokinin (CCK)-immunoreactive (IR) fibers and α2 subunit containing GABAA receptors in the inner molecular layer of the dentate gyrus was reduced. Quantitative immuno-electron microscopy study revealed that the ratio of CCK-containing symmetric synapses to the total symmetric synapses was reduced. The frequency of GABAergic synaptic currents (sIPSC) was decreased and their amplitude was increased. The inhibitory effect of the activation of cannabinoid 1 (CB1) receptors was also reduced in epileptic animals. Isolation of CCK- and parvalbumin (PV)-containing GABAergic inputs by N- and P/Q-type calcium channel blockers respectively suggested that GABA release from CCK-containing interneurons was selectively reduced in epileptic rats. This study found that there was a loss of CCK-containing GABAergic synapses to granule cells both morphologically and functionally. These studies add to our understanding of the mechanisms that contribute to altering GABAergic inhibition of granule cells in TLE.


Asunto(s)
Colecistoquinina/metabolismo , Giro Dentado/metabolismo , Epilepsia del Lóbulo Temporal/metabolismo , Interneuronas/fisiología , Terminales Presinápticos/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Giro Dentado/fisiopatología , Giro Dentado/ultraestructura , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/fisiopatología , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Terminales Presinápticos/ultraestructura , Subunidades de Proteína/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Receptores de GABA-A/metabolismo
9.
eNeuro ; 11(3)2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38538082

RESUMEN

Rodent models, such as mice and rats, are commonly used to examine retinal ganglion cell damage in eye diseases. However, as nocturnal animals, rodent retinal structures differ from primates, imposing significant limitations in studying retinal pathology. Tree shrews (Tupaia belangeri) are small, diurnal paraprimates that exhibit superior visual acuity and color vision compared with mice. Like humans, tree shrews have a dense retinal nerve fiber layer (RNFL) and a thick ganglion cell layer (GCL), making them a valuable model for investigating optic neuropathies. In this study, we applied high-resolution visible-light optical coherence tomography to characterize the tree shrew retinal structure in vivo and compare it with that of humans and mice. We quantitatively characterize the tree shrew's retinal layer structure in vivo, specifically examining the sublayer structures within the inner plexiform layer (IPL) for the first time. Next, we conducted a comparative analysis of retinal layer structures among tree shrews, mice, and humans. We then validated our in vivo findings in the tree shrew inner retina using ex vivo confocal microscopy. The in vivo and ex vivo analyses of the shrew retina build the foundation for future work to accurately track and quantify the retinal structural changes in the IPL, GCL, and RNFL during the development and progression of human optic diseases.


Asunto(s)
Tupaia , Tupaiidae , Humanos , Ratones , Animales , Ratas , Musarañas , Retina/diagnóstico por imagen , Células Ganglionares de la Retina/patología
10.
IEEE Trans Med Imaging ; 43(8): 2769-2777, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38517719

RESUMEN

We seek to develop techniques for high-resolution imaging of the tree shrew retina for visualizing and parameterizing retinal ganglion cell (RGC) axon bundles in vivo. We applied visible-light optical coherence tomography fibergraphy (vis-OCTF) and temporal speckle averaging (TSA) to visualize individual RGC axon bundles in the tree shrew retina. For the first time, we quantified individual RGC bundle width, height, and cross-sectional area and applied vis-OCT angiography (vis-OCTA) to visualize the retinal microvasculature in tree shrews. Throughout the retina, as the distance from the optic nerve head (ONH) increased from 0.5 mm to 2.5 mm, bundle width increased by 30%, height decreased by 67%, and cross-sectional area decreased by 36%. We also showed that axon bundles become vertically elongated as they converge toward the ONH. Ex vivo confocal microscopy of retinal flat-mounts immunostained with Tuj1 confirmed our in vivo vis-OCTF findings.


Asunto(s)
Axones , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Tupaiidae , Animales , Tomografía de Coherencia Óptica/métodos , Células Ganglionares de la Retina/citología , Axones/fisiología
11.
Anesthesiology ; 118(5): 1086-97, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23411726

RESUMEN

BACKGROUND: General anesthetics induce apoptotic neurodegeneration in the developing mammalian brain. General anesthesia (GA) also causes significant disturbances in mitochondrial morphogenesis during intense synaptogenesis. Mitochondria are dynamic organelles that undergo remodeling via fusion and fission. The fine balance between these two opposing processes determines mitochondrial morphometric properties, allowing for their regeneration and enabling normal functioning. As mitochondria are exquisitely sensitive to anesthesia-induced damage, we examined how GA affects mitochondrial fusion/fission. METHODS: Seven-day-old rat pups received anesthesia containing a sedative dose of midazolam followed by a combined nitrous oxide and isoflurane anesthesia for 6 h. RESULTS: GA causes 30% upregulation of reactive oxygen species (n = 3-5 pups/group), accompanied by a 2-fold downregulation of an important scavenging enzyme, superoxide dismutase (n = 6 pups/group). Reactive oxygen species upregulation is associated with impaired mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The imbalance between fission and fusion is due to acute sequestration of the main fission protein, dynamin-related protein 1, from the cytoplasm to mitochondria, and its oligomerization on the outer mitochondrial membrane. These are necessary steps in the formation of the ring-like structures that are required for mitochondrial fission. The fission is further promoted by GA-induced 40% downregulation of cytosolic mitofusin-2, a protein necessary for maintaining the opposing process, mitochondrial fusion (n = 6 pups/group). CONCLUSIONS: Early exposure to GA causes acute reactive oxygen species upregulation and disturbs the fine balance between mitochondrial fission and fusion, leading to excessive fission and disturbed mitochondrial morphogenesis. These effects may play a causal role in GA-induced developmental neuroapoptosis.


Asunto(s)
Anestesia General/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Dinámicas Mitocondriales/efectos de los fármacos , Animales , Western Blotting , Encéfalo/patología , Catalasa/metabolismo , Citoplasma/metabolismo , Regulación hacia Abajo/fisiología , Dinaminas/biosíntesis , Dinaminas/genética , GTP Fosfohidrolasas , Homeostasis/fisiología , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Proteínas Mitocondriales/biosíntesis , Proteínas Mitocondriales/genética , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Fracciones Subcelulares/metabolismo , Superóxido Dismutasa/metabolismo
12.
Front Neuroanat ; 17: 1150747, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37007643

RESUMEN

Introduction: The visual signals evoked at the retinal ganglion cells are modified and modulated by various synaptic inputs that impinge on lateral geniculate nucleus cells before they are sent to the cortex. The selectivity of geniculate inputs for clustering or forming microcircuits on discrete dendritic segments of geniculate cell types may provide the structural basis for network properties of the geniculate circuitry and differential signal processing through the parallel pathways of vision. In our study, we aimed to reveal the patterns of input selectivity on morphologically discernable relay cell types and interneurons in the mouse lateral geniculate nucleus. Methods: We used two sets of Scanning Blockface Electron Microscopy (SBEM) image stacks and Reconstruct software to manually reconstruct of terminal boutons and dendrite segments. First, using an unbiased terminal sampling (UTS) approach and statistical modeling, we identified the criteria for volume-based sorting of geniculate boutons into their putative origins. Geniculate terminal boutons that were sorted in retinal and non-retinal categories based on previously described mitochondrial morphology, could further be sorted into multiple subpopulations based on their bouton volume distributions. Terminals deemed non-retinal based on the morphological criteria consisted of five distinct subpopulations, including small-sized putative corticothalamic and cholinergic boutons, two medium-sized putative GABAergic inputs, and a large-sized bouton type that contains dark mitochondria. Retinal terminals also consisted of four distinct subpopulations. The cutoff criteria for these subpopulations were then applied to datasets of terminals that synapse on reconstructed dendrite segments of relay cells or interneurons. Results: Using a network analysis approach, we found an almost complete segregation of retinal and cortical terminals on putative X-type cell dendrite segments characterized by grape-like appendages and triads. On these cells, interneuron appendages intermingle with retinal and other medium size terminals to form triads within glomeruli. In contrast, a second, presumed Y-type cell displayed dendrodendritic puncta adherentia and received all terminal types without a selectivity for synapse location; these were not engaged in triads. Furthermore, the contribution of retinal and cortical synapses received by X-, Y- and interneuron dendrites differed such that over 60% of inputs to interneuron dendrites were from the retina, as opposed to 20% and 7% to X- and Y-type cells, respectively. Conclusion: The results underlie differences in network properties of synaptic inputs from distinct origins on geniculate cell types.

13.
Nat Neurosci ; 26(3): 470-480, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36732641

RESUMEN

The thalamus is the main gateway for sensory information from the periphery to the mammalian cerebral cortex. A major conundrum has been the discrepancy between the thalamus's central role as the primary feedforward projection system into the neocortex and the sparseness of thalamocortical synapses. Here we use new methods, combining genetic tools and scalable tissue expansion microscopy for whole-cell synaptic mapping, revealing the number, density and size of thalamic versus cortical excitatory synapses onto individual layer 2/3 (L2/3) pyramidal cells (PCs) of the mouse primary visual cortex. We find that thalamic inputs are not only sparse, but remarkably heterogeneous in number and density across individual dendrites and neurons. Most surprising, despite their sparseness, thalamic synapses onto L2/3 PCs are smaller than their cortical counterparts. Incorporating these findings into fine-scale, anatomically faithful biophysical models of L2/3 PCs reveals how individual neurons with sparse and weak thalamocortical synapses, embedded in small heterogeneous neuronal ensembles, may reliably 'read out' visually driven thalamic input.


Asunto(s)
Neocórtex , Tálamo , Ratones , Animales , Tálamo/fisiología , Neuronas/fisiología , Sinapsis/fisiología , Células Piramidales , Mamíferos
14.
bioRxiv ; 2023 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-37293064

RESUMEN

We seek to develop techniques for high-resolution imaging of the tree shrew retina for visualizing and parameterizing retinal ganglion cell (RGC) axon bundles in vivo. We applied visible-light optical coherence tomography fibergraphy (vis-OCTF) and temporal speckle averaging (TSA) to visualize individual RGC axon bundles in the tree shrew retina. For the first time, we quantified individual RGC bundle width, height, and cross-sectional area and applied vis-OCT angiography (vis-OCTA) to visualize the retinal microvasculature in tree shrews. Throughout the retina, as the distance from the optic nerve head (ONH) increased from 0.5 mm to 2.5 mm, bundle width increased by 30%, height decreased by 67%, and cross-sectional area decreased by 36%. We also showed that axon bundles become vertically elongated as they converge toward the ONH. Ex vivo confocal microscopy of retinal flat-mounts immunostained with Tuj1 confirmed our in vivo vis-OCTF findings.

15.
J Exp Med ; 220(12)2023 12 04.
Artículo en Inglés | MEDLINE | ID: mdl-37733279

RESUMEN

A key process in central sensory circuit development involves activity-dependent pruning of exuberant terminals. Here, we studied gustatory terminal field maturation in the postnatal mouse nucleus of the solitary tract (NST) during normal development and in mice where their mothers were fed a low NaCl diet for a limited period soon after conception. Pruning of terminal fields of gustatory nerves in controls involved the complement system and is likely driven by NaCl-elicited taste activity. In contrast, offspring of mothers with an early dietary manipulation failed to prune gustatory terminal fields even though peripheral taste activity developed normally. The ability to prune in these mice was rescued by activating myeloid cells postnatally, and conversely, pruning was arrested in controls with the loss of myeloid cell function. The altered pruning and myeloid cell function appear to be programmed before the peripheral gustatory system is assembled and corresponds to the embryonic period when microglia progenitors derived from the yolk sac migrate to and colonize the brain.


Asunto(s)
Microglía , Cloruro de Sodio , Animales , Ratones , Embarazo , Femenino , Gusto , Dieta , Encéfalo
16.
J Neurosci ; 30(29): 9670-82, 2010 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-20660250

RESUMEN

Monocular lid closure (MC) causes a profound shift in the ocular dominance (OD) of neurons in primary visual cortex (V1). Anatomical studies in both cat and mouse V1 suggest that large-scale structural rearrangements of eye-specific thalamocortical (TC) axons in response to MC occur much more slowly than the shift in OD. Consequently, there has been considerable debate as to whether the plasticity of TC synapses, which transmit competing visual information from each eye to V1, contributes to the early functional consequences of MC or is simply a feature of long-term deprivation. Here, we used quantitative immuno-electron microscopy to examine the possibility that alterations of TC synapses occur rapidly enough to impact OD after brief MC. The effect of short-term deprivation on TC synaptic structure was examined in male C57BL/6 mice that underwent 3 and 7 d of MC or monocular retinal inactivation (MI) with tetrodotoxin. The data show that 3 d of MC is sufficient to induce substantial remodeling of TC synapses. In contrast, 3 d of MI, which alters TC activity but does not shift OD, does not significantly affect the structure of TC synapses. Our results support the hypothesis that the rapid plasticity of TC synapses is a key step in the sequence of events that shift OD in visual cortex.


Asunto(s)
Plasticidad Neuronal/fisiología , Regeneración/fisiología , Sinapsis/fisiología , Sinapsis/ultraestructura , Tálamo/fisiología , Corteza Visual/fisiología , Animales , Biomarcadores/análisis , Potenciales Evocados Visuales , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Neuronas , Lóbulo Occipital/química , Lóbulo Occipital/citología , Lóbulo Occipital/ultraestructura , Sinapsis/química , Proteína 2 de Transporte Vesicular de Glutamato/análisis , Vías Visuales/fisiología
17.
J Cell Biol ; 175(4): 541-6, 2006 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-17101697

RESUMEN

Alzheimer's Disease (AD) is defined histopathologically by extracellular beta-amyloid (Abeta) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which Abeta lies upstream of tau, but the steps that connect Abeta to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular Abeta in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar Abeta42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar Abeta40, and microtubules were insensitive to fibrillar Abeta. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible Abeta.


Asunto(s)
Péptidos beta-Amiloides/farmacología , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Neurofibrillas/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Proteínas tau/metabolismo , Enfermedad de Alzheimer/patología , Animales , Células COS , Chlorocebus aethiops , Humanos , Ratones , Microscopía Fluorescente , Neurofibrillas/ultraestructura , Fosforilación/efectos de los fármacos , Estructura Cuaternaria de Proteína/efectos de los fármacos , Ratas , Proteínas tau/química
18.
J Comp Neurol ; 529(10): 2558-2575, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33458823

RESUMEN

Ventroposterior medialis parvocellularis (VPMP) nucleus of the primate thalamus receives direct input from the nucleus of the solitary tract, whereas the homologous thalamic structure in the rodent does not. To reveal whether the synaptic circuitries in these nuclei lend evidence for conservation of design principles in the taste thalamus across species or across sensory thalamus in general, we characterized the ultrastructural and molecular properties of the VPMP in a close relative of primates, the tree shrew (Tupaia belangeri), and compared these to known properties of the taste thalamus in rodent, and the visual thalamus in mammals. Electron microscopy analysis to categorize the synaptic inputs in the VPMP revealed that the largest-size terminals contained many vesicles and formed large synaptic zones with thick postsynaptic density on multiple, medium-caliber dendrite segments. Some formed triads within glomerular arrangements. Smaller-sized terminals contained dark mitochondria; most formed a single asymmetric or symmetric synapse on small-diameter dendrites. Immuno-EM experiments revealed that the large-size terminals contained VGLUT2, whereas the small-size terminal populations contained VGLUT1 or ChAT. These findings provide evidence that the morphological and molecular characteristics of synaptic circuitry in the tree shrew VPMP are similar to that in nonchemical sensory thalamic nuclei. Furthermore, the results indicate that all primary sensory nuclei of the thalamus in higher mammals share a structural template for processing thalamocortical sensory information. In contrast, substantial morphological and molecular differences in rodent versus tree shrew taste nuclei suggest a fundamental divergence in cellular processing mechanisms of taste input in these two species.


Asunto(s)
Núcleos Talámicos Posteriores/fisiología , Núcleos Talámicos Posteriores/ultraestructura , Percepción del Gusto/fisiología , Tupaiidae/anatomía & histología , Tupaiidae/fisiología , Animales , Inmunohistoquímica , Microscopía Electrónica de Transmisión , Neuronas/ultraestructura
19.
eNeuro ; 7(5)2020.
Artículo en Inglés | MEDLINE | ID: mdl-32958478

RESUMEN

Despite decades of discussion in the neuroanatomical literature, the role of the synaptic "spinule" in synaptic development and function remains elusive. Canonically, spinules are finger-like projections that emerge from postsynaptic spines and can become enveloped by presynaptic boutons. When a presynaptic bouton encapsulates a spinule in this manner, the membrane apposition between the spinule and surrounding bouton can be significantly larger than the membrane interface at the synaptic active zone. Hence, spinules may represent a mechanism for extrasynaptic neuronal communication and/or may function as structural "anchors" that increase the stability of cortical synapses. Yet despite their potential to impact synaptic function, we have little information on the percentages of developing and adult cortical bouton populations that contain spinules, the percentages of these cortical spinule-bearing boutons (SBBs) that contain spinules from distinct neuronal/glial origins, or whether the onset of activity or cortical plasticity are correlated with increased prevalence of cortical SBBs. Here, we employed 2D and 3D electron microscopy to determine the prevalence of spinules in excitatory presynaptic boutons at key developmental time points in the primary visual cortex (V1) of female and male ferrets. We find that the prevalence of SBBs in V1 increases across postnatal development, such that ∼25% of excitatory boutons in late adolescent ferret V1 contain spinules. In addition, we find that a majority of spinules within SBBs at later developmental time points emerge from postsynaptic spines and adjacent boutons/axons, suggesting that synaptic spinules may enhance synaptic stability and allow for axo-axonal communication in mature sensory cortex.


Asunto(s)
Terminales Presinápticos , Sinapsis , Animales , Axones , Femenino , Hurones , Masculino , Microscopía Electrónica , Neuronas
20.
J Neurosci ; 27(46): 12641-50, 2007 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-18003843

RESUMEN

In animal models of temporal lobe epilepsy (TLE), neurosteroid sensitivity of GABA(A) receptors on dentate granule cells (DGCs) is diminished; the molecular mechanism underlying this phenomenon remains unclear. The current study investigated a mechanism for loss of neurosteroid sensitivity of synaptic GABA(A) receptors in TLE. Synaptic currents recorded from DGCs of epileptic animals (epileptic DGCs) were less frequent, larger in amplitude, and less sensitive to allopregnanolone modulation than those recorded from DGCs of control animals (control DGCs). Synaptic currents recorded from epileptic DGCs were less sensitive to diazepam and had altered sensitivity to benzodiazepine inverse agonist RO 15-4513 (ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5alpha][1,4]benzodiazepine-3-carboxylate) and furosemide than those recorded from control DGCs. Properties of synaptic currents recorded from epileptic DGCs appeared similar to those of recombinant receptors containing the alpha4 subunit. Expression of the alpha4 subunit and its colocalization with the synaptic marker GAD65 was increased in epileptic DGCs. Location of the alpha4 subunit in relation to symmetric (inhibitory) synapses on soma and dendrites of control and epileptic DGCs was examined with postembedding immunogold electron microscopy. The alpha4 immunogold labeling was present more commonly within the synapse in epileptic DGCs compared with control DGCs, in which the subunit was extrasynaptic. These studies demonstrate that, in epileptic DGCs, the neurosteroid modulation of synaptic currents is diminished and alpha4 subunit-containing receptors are present at synapses and participate in synaptic transmission. These changes may facilitate seizures in epileptic animals.


Asunto(s)
Epilepsia del Lóbulo Temporal/metabolismo , Hipocampo/metabolismo , Inhibición Neural/genética , Receptores de GABA-A/metabolismo , Esteroides/metabolismo , Sinapsis/metabolismo , Animales , Benzodiazepinas/farmacología , Modelos Animales de Enfermedad , Resistencia a Medicamentos/efectos de los fármacos , Resistencia a Medicamentos/genética , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/fisiopatología , Glutamato Descarboxilasa/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Masculino , Inhibición Neural/efectos de los fármacos , Pregnanolona/metabolismo , Pregnanolona/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Receptores de GABA-A/genética , Esteroides/farmacología , Sinapsis/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , Ácido gamma-Aminobutírico/metabolismo
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