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Sample records for cortical pyramidal neurons

  1. Chronic benzodiazepine treatment decreases spine density in cortical pyramidal neurons.

    PubMed

    Curto, Yasmina; Garcia-Mompo, Clara; Bueno-Fernandez, Clara; Nacher, Juan

    2016-02-01

    The adult brain retains a substantial capacity for synaptic reorganization, which includes a wide range of modifications from molecular to structural plasticity. Previous reports have demonstrated that the structural remodeling of excitatory neurons seems to occur in parallel to changes in GABAergic neurotransmission. The function of neuronal inhibitory networks can be modified through GABAA receptors, which have a binding site for benzodiazepines (BZ). Although BZs are among the most prescribed drugs, is not known whether they modify the structure and connectivity of pyramidal neurons. In the present study we wish to elucidate the impact of a chronic treatment of 21 days with diazepam (2mg/kg, ip), a BZ that acts as an agonist of GABAA receptors, on the structural plasticity of pyramidal neurons in the prefrontal cortex of adult mice. We have examined the density of dendritic spines and the density of axonal en passant boutons in the cingulate cortex. Although no significant changes were observed in their anxiety levels, animals treated with diazepam showed a decrease in the density of spines in the apical dendrites of pyramidal neurons. Most GFP-expressing en passant boutons in the upper layers of the cingulate cortex had an extracortical origin and no changes in their density were detected after diazepam treatment. These results indicate that the chronic potentiation of GABAergic synapses can induce the structural remodeling of postsynaptic elements in pyramidal neurons. PMID:26733301

  2. Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.

    PubMed

    Chen, Xiangdong; Shu, Shaofang; Bayliss, Douglas A

    2005-12-01

    The contributions of the hyperpolarization-activated current, I(h), to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native I(h) in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal I(h) currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating I(h) in cortical neurons at a clinically relevant concentration (5 microM); inhibition of I(h) involved a hyperpolarizing shift in half-activation voltage (DeltaV1/2 approximately -9 mV) and a decrease in maximal available current (approximately 36% inhibition, measured at -120 mV). With the slower form of I(h) expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 muM propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1-HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABA(A) and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the I(h) blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate I(h) in cortical pyramidal neurons-and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells. PMID:16093340

  3. CoREST/LSD1 control the development of pyramidal cortical neurons.

    PubMed

    Fuentes, Patricio; Cánovas, José; Berndt, F Andrés; Noctor, Stephen C; Kukuljan, Manuel

    2012-06-01

    The development of a neuron from a precursor cell comprises a complex set of steps ranging from regulation of the proliferative cycle through the acquisition of distinct morphology and functionality. How these processes are orchestrated is largely unknown. Using in utero manipulation of gene expression in the mouse embryonic cerebral cortex, we found that the transition between multipolar and bipolar stages of newborn cortical pyramidal neurons is markedly delayed by depletion of CoREST, a corepressor component of chromatin remodeling complexes. This profoundly affects the onset of their radial migration. The loss of CoREST function also perturbs the dynamics of neuronal precursor cell populations, transiently increasing the fraction of cells remaining in progenitor states, but not the acquisition of the neuronal glutamatergic fate of pyramidal cells. The function of CoREST in these processes appears to be independent of its best-known interactor, the RE-1 silencer of transcription/neural restrictive silencing factor, and requires the histone demethylase LSD1. This reveals the importance of epigenetic control in the execution of neural development programs, specifically in the cerebral cortex.

  4. Ephrin-B1 controls the columnar distribution of cortical pyramidal neurons by restricting their tangential migration.

    PubMed

    Dimidschstein, Jordane; Passante, Lara; Dufour, Audrey; van den Ameele, Jelle; Tiberi, Luca; Hrechdakian, Tatyana; Adams, Ralf; Klein, Rüdiger; Lie, Dieter Chichung; Jossin, Yves; Vanderhaeghen, Pierre

    2013-09-18

    Neurons of the cerebral cortex are organized in layers and columns. Unlike laminar patterning, the mechanisms underlying columnar organization remain largely unexplored. Here, we show that ephrin-B1 plays a key role in this process through the control of nonradial steps of migration of pyramidal neurons. In vivo gain of function of ephrin-B1 resulted in a reduction of tangential motility of pyramidal neurons, leading to abnormal neuronal clustering. Conversely, following genetic disruption of ephrin-B1, cortical neurons displayed a wider lateral dispersion, resulting in enlarged ontogenic columns. Dynamic analyses revealed that ephrin-B1 controls the lateral spread of pyramidal neurons by limiting neurite extension and tangential migration during the multipolar phase. Furthermore, we identified P-Rex1, a guanine-exchange factor for Rac3, as a downstream ephrin-B1 effector required to control migration during the multipolar phase. Our results demonstrate that ephrin-B1 inhibits nonradial migration of pyramidal neurons, thereby controlling the pattern of cortical columns.

  5. Discontinuous Galerkin finite element method for solving population density functions of cortical pyramidal and thalamic neuronal populations.

    PubMed

    Huang, Chih-Hsu; Lin, Chou-Ching K; Ju, Ming-Shaung

    2015-02-01

    Compared with the Monte Carlo method, the population density method is efficient for modeling collective dynamics of neuronal populations in human brain. In this method, a population density function describes the probabilistic distribution of states of all neurons in the population and it is governed by a hyperbolic partial differential equation. In the past, the problem was mainly solved by using the finite difference method. In a previous study, a continuous Galerkin finite element method was found better than the finite difference method for solving the hyperbolic partial differential equation; however, the population density function often has discontinuity and both methods suffer from a numerical stability problem. The goal of this study is to improve the numerical stability of the solution using discontinuous Galerkin finite element method. To test the performance of the new approach, interaction of a population of cortical pyramidal neurons and a population of thalamic neurons was simulated. The numerical results showed good agreement between results of discontinuous Galerkin finite element and Monte Carlo methods. The convergence and accuracy of the solutions are excellent. The numerical stability problem could be resolved using the discontinuous Galerkin finite element method which has total-variation-diminishing property. The efficient approach will be employed to simulate the electroencephalogram or dynamics of thalamocortical network which involves three populations, namely, thalamic reticular neurons, thalamocortical neurons and cortical pyramidal neurons.

  6. Dendritic Na(+) spikes enable cortical input to drive action potential output from hippocampal CA2 pyramidal neurons.

    PubMed

    Sun, Qian; Srinivas, Kalyan V; Sotayo, Alaba; Siegelbaum, Steven A

    2014-01-01

    Synaptic inputs from different brain areas are often targeted to distinct regions of neuronal dendritic arbors. Inputs to proximal dendrites usually produce large somatic EPSPs that efficiently trigger action potential (AP) output, whereas inputs to distal dendrites are greatly attenuated and may largely modulate AP output. In contrast to most other cortical and hippocampal neurons, hippocampal CA2 pyramidal neurons show unusually strong excitation by their distal dendritic inputs from entorhinal cortex (EC). In this study, we demonstrate that the ability of these EC inputs to drive CA2 AP output requires the firing of local dendritic Na(+) spikes. Furthermore, we find that CA2 dendritic geometry contributes to the efficient coupling of dendritic Na(+) spikes to AP output. These results provide a striking example of how dendritic spikes enable direct cortical inputs to overcome unfavorable distal synaptic locale to trigger axonal AP output and thereby enable efficient cortico-hippocampal information flow.

  7. Cerebral cortical hypoplasia with abnormal morphology of pyramidal neuron in growth-retarded mouse (grt/grt).

    PubMed

    Horiuchi-Hirose, Miwa; Saito, Shigeyoshi; Sato, Chika; Aoyama, Junya; Kobayashi, Tetsuya; Sawada, Kazuhiko

    2014-01-01

    The purpose of this study was to quantitatively characterize structural abnormalities of the cerebrum in a growth-retarded mouse (grt/grt) with a tyrosylprotein sulfotransferase 2 gene defect. Three-dimensional computed tomography (CT) images were obtained from fixed brains of male homogenous grt/grt (n=5) and heterozygous grt/+ (n=5) mice at 15 weeks of age, and volumes of representative cerebral regions were calculated on the basis of those images. Following CT measurements, cryosections of the brain were made, and immunohistochemistry for NeuN and SMI-32 was carried out. By CT-based volumetry, region-specific reductions in volumes were marked in the cerebral cortex and white matter, but not in other cerebral regions of grt/grt. When quantitatively evaluating the shape of the cerebral cortex, the frontooccipital length of the cortex was significantly smaller in grt/grt than in grt/+, whereas the cortical width was not altered in grt/grt. On the other hand, both cortical thickness and density of NeuN-immunopositive neurons in three distinctive cortical regions, i.e., the primary motor cortex, barrel field of primary somatosensory cortex and primary visual cortex, were not different between grt/grt and grt/+. By semi-quantitative immunohistochemical analysis, the intensity of SMI-32 immunostaining was significantly weaker in grt/grt than in grt/+ in the three cortical areas examined. SMI-32 staining was reduced, particularly in layer III pyramidal neurons in grt/grt, while it was sustained in multipolar neurons. The present results suggest that cerebral abnormalities in grt/grt mice are characterized by cortical hypoplasia at the frontooccipital axis with immature pyramidal neurons and insufficient development of callosal fibers.

  8. Distinct Cell- and Layer-Specific Expression Patterns and Independent Regulation of Kv2 Channel Subtypes in Cortical Pyramidal Neurons

    PubMed Central

    Bishop, Hannah I.; Guan, Dongxu; Bocksteins, Elke; Parajuli, Laxmi Kumar; Murray, Karl D.; Cobb, Melanie M.; Misonou, Hiroaki; Zito, Karen; Foehring, Robert C.

    2015-01-01

    The Kv2 family of voltage-gated potassium channel α subunits, comprising Kv2.1 and Kv2.2, mediate the bulk of the neuronal delayed rectifier K+ current in many mammalian central neurons. Kv2.1 exhibits robust expression across many neuron types and is unique in its conditional role in modulating intrinsic excitability through changes in its phosphorylation state, which affect Kv2.1 expression, localization, and function. Much less is known of the highly related Kv2.2 subunit, especially in forebrain neurons. Here, through combined use of cortical layer markers and transgenic mouse lines, we show that Kv2.1 and Kv2.2 are localized to functionally distinct cortical cell types. Kv2.1 expression is consistently high throughout all cortical layers, especially in layer (L) 5b pyramidal neurons, whereas Kv2.2 expression is primarily limited to neurons in L2 and L5a. In addition, L4 of primary somatosensory cortex is strikingly devoid of Kv2.2 immunolabeling. The restricted pattern of Kv2.2 expression persists in Kv2.1-KO mice, suggesting distinct cell- and layer-specific functions for these two highly related Kv2 subunits. Analyses of endogenous Kv2.2 in cortical neurons in situ and recombinant Kv2.2 expressed in heterologous cells reveal that Kv2.2 is largely refractory to stimuli that trigger robust, phosphorylation-dependent changes in Kv2.1 clustering and function. Immunocytochemistry and voltage-clamp recordings from outside-out macropatches reveal distinct cellular expression patterns for Kv2.1 and Kv2.2 in intratelencephalic and pyramidal tract neurons of L5, indicating circuit-specific requirements for these Kv2 paralogs. Together, these results support distinct roles for these two Kv2 channel family members in mammalian cortex. SIGNIFICANCE STATEMENT Neurons within the neocortex are arranged in a laminar architecture and contribute to the input, processing, and/or output of sensory and motor signals in a cell- and layer-specific manner. Neurons of different

  9. In Vivo Monosynaptic Excitatory Transmission between Layer 2 Cortical Pyramidal Neurons

    PubMed Central

    Jouhanneau, Jean-Sébastien; Kremkow, Jens; Dorrn, Anja L.; Poulet, James F.A.

    2015-01-01

    Summary Little is known about the properties of monosynaptic connections between identified neurons in vivo. We made multiple (two to four) two-photon targeted whole-cell recordings from neighboring layer 2 mouse somatosensory barrel cortex pyramidal neurons in vivo to investigate excitatory monosynaptic transmission in the hyperpolarized downstate. We report that pyramidal neurons form a sparsely connected (6.7% connectivity) network with an overrepresentation of bidirectional connections. The majority of unitary excitatory postsynaptic potentials were small in amplitude (<0.5 mV), with a small minority >1 mV. The coefficient of variation (CV = 0.74) could largely be explained by the presence of synaptic failures (22%). Both the CV and failure rates were reduced with increasing amplitude. The mean paired-pulse ratio was 1.15 and positively correlated with the CV. Our approach will help bridge the gap between connectivity and function and allow investigations into the impact of brain state on monosynaptic transmission and integration. PMID:26670044

  10. Dynamic FoxG1 expression coordinates the integration of multipolar pyramidal neuron precursors into the cortical plate.

    PubMed

    Miyoshi, Goichi; Fishell, Gord

    2012-06-21

    Pyramidal cells of the cerebral cortex are born in the ventricular zone and migrate through the intermediate zone to enter into the cortical plate. In the intermediate zone, these migrating precursors move tangentially and initiate the extension of their axons by transiently adopting a characteristic multipolar morphology. We observe that expression of the forkhead transcription factor FoxG1 is dynamically regulated during this transitional period. By utilizing conditional genetic strategies, we show that the downregulation of FoxG1 at the beginning of the multipolar cell phase induces Unc5D expression, the timing of which ultimately determines the laminar identity of pyramidal neurons. In addition, we demonstrate that the re-expression of FoxG1 is required for cells to transit out of the multipolar cell phase and to enter into the cortical plate. Thus, the dynamic expression of FoxG1 during migration within the intermediate zone is essential for the proper assembly of the cerebral cortex.

  11. Synaptic Conductance Estimates of the Connection Between Local Inhibitor Interneurons and Pyramidal Neurons in Layer 2/3 of a Cortical Column.

    PubMed

    Hoffmann, Jochen H O; Meyer, H S; Schmitt, Arno C; Straehle, Jakob; Weitbrecht, Trinh; Sakmann, Bert; Helmstaedter, Moritz

    2015-11-01

    Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude -0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3. PMID:25761638

  12. EPSPs Measured in Proximal Dendritic Spines of Cortical Pyramidal Neurons123

    PubMed Central

    2016-01-01

    Abstract EPSPs occur when the neurotransmitter glutamate binds to postsynaptic receptors located on small pleomorphic membrane protrusions called dendritic spines. To transmit the synaptic signal, these potentials must travel through the spine neck and the dendritic tree to reach the soma. Due to their small size, the electrical behavior of spines and their ability to compartmentalize electrical signals has been very difficult to assess experimentally. In this study, we developed a method to perform simultaneous two-photon voltage-sensitive dye recording with two-photon glutamate uncaging in order to measure the characteristics (amplitude and duration) of uncaging-evoked EPSPs in single spines on the basal dendrites of L5 pyramidal neurons in acute brain slices from CD1 control mice. We were able to record uncaging-evoked spine potentials that resembled miniature EPSPs at the soma from a wide range of spine morphologies. In proximal spines, these potentials averaged 13.0 mV (range, 6.5–30.8 mV; N = 20) for an average somatic EPSP of 0.59 mV, whereas the mean attenuation ratio (spine/soma) was found to be 25.3. Durations of spine EPSP waveforms were found to be 11.7 ms on average. Modeling studies demonstrate the important role that spine neck resistance (Rneck) plays in spine EPSP amplitudes. Simulations used to estimate Rneck by fits to voltage-sensitive dye measurements produced a mean of 179 MΩ (range, 23–420 MΩ; N = 19). Independent measurements based on fluorescence recovery after photobleaching of a cytosolic dye from spines of the same population of neurons produced a mean Rneck estimate of 204 MΩ (range, 52–521 MΩ; N = 34). PMID:27257618

  13. Basal Dendrites of Layer-III Pyramidal Neurons do not Scale with Changes in Cortical Magnification Factor in Macaque Primary Visual Cortex

    PubMed Central

    Oga, Tomofumi; Okamoto, Tsuguhisa; Fujita, Ichiro

    2016-01-01

    Neurons in the mammalian primary visual cortex (V1) are systematically arranged across the cortical surface according to the location of their receptive fields (RFs), forming a visuotopic (or retinotopic) map. Within this map, the foveal visual field is represented by a large cortical surface area, with increasingly peripheral visual fields gradually occupying smaller cortical areas. Although cellular organization in the retina, such as the spatial distribution of ganglion cells, can partially account for the eccentricity-dependent differences in the size of cortical representation, whether morphological differences exist across V1 neurons representing different eccentricities is unclear. In particular, morphological differences in dendritic field diameter might contribute to the magnified representation of the central visual field. Here, we addressed this question by measuring the basal dendritic arbors of pyramidal neurons of layer-IIIC and adjoining layer III sublayers (in the Hassler’s nomenclature) in macaque V1. We labeled layer-III pyramidal neurons at various retinotopic positions in V1 by injecting lightly fixed brain tissue with intracellular dye, and then compared dendritic morphology across regions in the retinotopic map representing 0–20° of eccentricity. The dendritic field area, total dendritic length, number of principal dendrites, branching complexity, spine density and total number of spines were all consistent across different retinotopic regions of V1. These results indicate that dendrites in layer-III pyramidal neurons are relatively homogeneous according to these morphometric parameters irrespective of their locations in this portion of the retinotopic map. The homogeneity of dendritic morphology in these neurons suggests that the emphasis of central visual field representation is not attributable to changes in the basal dendritic arbors of pyramidal neurons in layer III, but is likely the result of successive processes earlier in the

  14. Impaired Memory and Evidence of Histopathology in CA1 Pyramidal Neurons through Injection of Aβ1-42 Peptides into the Frontal Cortices of Rat

    PubMed Central

    Eslamizade, Mohammad Javad; Madjd, Zahra; Rasoolijazi, Homa; Saffarzadeh, Fatemeh; Pirhajati, Vahid; Aligholi, Hadi; Janahmadi, Mahyar; Mehdizadeh, Mehdi

    2016-01-01

    Introduction: Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, which has much benefited from animal models to find the basics of its pathophysiology. In our previous work (Haghani, Shabani, Javan, Motamedi, & Janahmadi, 2012), a non-transgenic rat model of AD was used in electrophysiological studies. However, we did not investigate the histological aspects in the mentioned study. Methods: An AD model was developed through bilateral injection of amyloid-β peptides (Aβ) into the frontal cortices. Behavioral and histological methods were used to assess alterations in the memory and (ultra)structures. Furthermore, melatonin has been administered to assess its efficacy on this AD model. Results: Passive avoidance showed a progressive decline in the memory following Aβ injection. Furthermore, Nissl staining showed that Aβ neurotoxicity caused shrinkage of the CA1 pyramidal neurons. Neurodegeneration was clearly evident from Fluoro-jade labeled neurons in Aβ treated rats. Moreover, higher NF-κB immunoreactive CA1 pyramidal neurons were remarkably observed in Aβ treated rats. Ultrastructural analysis using electron microscopy also showed the evidence of subcellular abnormalities. Melatonin treatment in this model of AD prevented Aβ-induced increased NF-κB from immunoreaction and neurodegeneration. Discussion: This study suggests that injection of Aβ into the frontal cortices results in the memory decline and histochemical disturbances in CA1 pyramidal neurons. Furthermore, melatonin can prevent several histological changes induced by Aβ. PMID:27303597

  15. Postnatal maternal separation enhances tonic GABA current of cortical layer 5 pyramidal neurons in juvenile rats and promotes genesis of GABAergic neurons in neocortical molecular layer and subventricular zone in adult rats.

    PubMed

    Feng, Mei; Sheng, Guoxia; Li, Zhongxia; Wang, Jiangping; Ren, Keming; Jin, Xiaoming; Jiang, Kewen

    2014-03-01

    Postnatal maternal separation (PMS) has been shown to be associated with an increased vulnerability to psychiatric illnesses in adulthood. However, the underlying neurological mechanisms are not well understood. Here we evaluated its effects on neurogenesis and tonic GABA currents of cortical layer 5 (L5) pyramidal neurons. PMS not only increased cell proliferation in the subventricular zone, cortical layer 1 and hippocampal dentate gyrus in the adult brain, but also promoted the newly generated cells to differentiate into GABAergic neurons, and PMS adult brain maintained higher ratios of GABAergic neurons in the survival of newly generated cells within 5 days immediately post PMS. Additionally, PMS increased the tonic currents at P7-10 and P30-35 in cortical L5 pyramidal cells. Our results suggest that the newly generated GABAergic neurons and the low GABA concentration-activated tonic currents may be involved in the development of psychiatric disorders after PMS.

  16. Validation of optical voltage reporting by the genetically encoded voltage indicator VSFP-Butterfly from cortical layer 2/3 pyramidal neurons in mouse brain slices

    PubMed Central

    Empson, Ruth M; Goulton, Chelsea; Scholtz, David; Gallero-Salas, Yasir; Zeng, Hongkui; Knöpfel, Thomas

    2015-01-01

    Understanding how behavior emerges from brain electrical activity is one of the ultimate goals of neuroscience. To achieve this goal we require methods for large-scale recording of the electrical activity of specific neuronal circuits. A very promising approach is to use optical reporting of membrane voltage transients, particularly if the voltage reporter is genetically targeted to specific neuronal populations. Targeting in this way allows population signals to be recorded and interpreted without blindness to neuronal diversity. Here, we evaluated the voltage-sensitive fluorescent protein, VSFP Butterfly 2.1, a genetically encoded voltage indicator (GEVI), for monitoring electrical activity of layer 2/3 cortical pyramidal neurons in mouse brain slices. Standard widefield fluorescence and two-photon imaging revealed robust, high signal-to-noise ratio read-outs of membrane voltage transients that are predominantly synaptic in nature and can be resolved as discrete areas of synaptically connected layer 2/3 neurons. We find that targeted expression of this GEVI in the cortex provides a flexible and promising tool for the analysis of L2/3 cortical network function. PMID:26229003

  17. In Rasmussen Encephalitis, Hemichannels Associated with Microglial Activation are linked to Cortical Pyramidal Neuron Coupling: A Possible Mechanism for Cellular Hyperexcitability

    PubMed Central

    Cepeda, Carlos; Chang, Julia W.; Owens, Geoffrey C.; Huynh, My N.; Chen, Jane Y.; Tran, Conny; Vinters, Harry V.; Levine, Michael S.; Mathern, Gary W.

    2014-01-01

    Aims Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Methods Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n=16) and non-RE (n=12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Results Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye-coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases. Conclusions In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible anti-seizure treatment for RE may involve the use of gap junction blockers. PMID:25438677

  18. Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy.

    PubMed

    Crimins, Johanna L; Rocher, Anne B; Peters, Alan; Shultz, Penny; Lewis, Jada; Luebke, Jennifer I

    2011-11-01

    Cortical neuron death is prevalent by 9 months in rTg(tau(P301L))4510 tau mutant mice (TG) and surviving pyramidal cells exhibit dendritic regression and spine loss. We used whole-cell patch-clamp recordings to investigate the impact of these marked structural changes on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs) of layer 3 pyramidal cells in frontal cortical slices from behaviorally characterized TG and non-transgenic (NT) mice at this age. Frontal lobe function of TG mice was intact following a short delay interval but impaired following a long delay interval in an object recognition test, and cortical atrophy and cell loss were pronounced. Surviving TG cells had significantly reduced dendritic diameters, total spine density, and mushroom spines, yet sEPSCs were increased and sIPSCs were unchanged in frequency. Thus, despite significant regressive structural changes, synaptic responses were not reduced in TG cells, indicating that homeostatic compensatory mechanisms occur during progressive tauopathy. Consistent with this idea, surviving TG cells were more intrinsically excitable than NT cells, and exhibited sprouting of filopodia and axonal boutons. Moreover, the neuropil in TG mice showed an increased density of asymmetric synapses, although their mean size was reduced. Taken together, these data indicate that during progressive tauopathy, cortical pyramidal cells compensate for loss of afferent input by increased excitability and establishment of new synapses. These compensatory homeostatic mechanisms may play an important role in slowing the progression of neuronal network dysfunction during neurodegenerative tauopathies.

  19. NMDA-induced glutamate and aspartate release from rat cortical pyramidal neurones: evidence for modulation by a 5-HT1A antagonist.

    PubMed Central

    Dijk, S. N.; Francis, P. T.; Stratmann, G. C.; Bowen, D. M.

    1995-01-01

    1. We have investigated an aspect of the regulation of cortical pyramidal neurone activity. Microdialysis was used to assess whether topical application of drugs (in 10 microliter) to fill a burr hole over the frontal cortex, where part of the corticostriatal pathway originates, would change concentrations of the excitatory amino acids glutamate and aspartate in the striatum of the anaesthetized rat. 2. Topical application of N-methyl-D-aspartate (NMDA, 2 and 20 mM) dose-dependently increased glutamate and aspartate concentrations in the striatum. Coapplication of tetrodotoxin (10 microM) blocked the NMDA-evoked rise in these amino acids. A calcium-free medium, perfused through the probe also blocked the rise, indicating that it was due to an exocytotic mechanism in the striatum. 3. It was hypothesized that the rise observed was due to an increase in the activity of the corticostriatal pathway. As 5-hydroxytryptamine1A (5-HT1A) receptors are enriched on cell bodies of corticostriatal neurones, a selective 5-HT1A-antagonist (WAY 100135) was coapplied with the lower dose of NMDA. Compared to NMDA alone, coapplication of 50 microM WAY 100135 significantly increased glutamate release. This effect was sensitive to tetrodotoxin and calcium-dependent. Application of 50 microM WAY 100135 alone significantly enhanced glutamate release above baseline; this was also tested at 100 microM (not significant). 4. Compared to NMDA alone, coapplication of WAY 100135 (20 microM) significantly enhanced aspartate release; the mean value was also increased (not significantly) with 50 microM. This rise was calcium-dependent, but not tetrodotoxin-sensitive. WAY 100135 (100 microM) reduced NMDA-induced aspartate release.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7582540

  20. Multisynaptic activity in a pyramidal neuron model and neural code.

    PubMed

    Ventriglia, Francesco; Di Maio, Vito

    2006-01-01

    The highly irregular firing of mammalian cortical pyramidal neurons is one of the most striking observation of the brain activity. This result affects greatly the discussion on the neural code, i.e. how the brain codes information transmitted along the different cortical stages. In fact it seems to be in favor of one of the two main hypotheses about this issue, named the rate code. But the supporters of the contrasting hypothesis, the temporal code, consider this evidence inconclusive. We discuss here a leaky integrate-and-fire model of a hippocampal pyramidal neuron intended to be biologically sound to investigate the genesis of the irregular pyramidal firing and to give useful information about the coding problem. To this aim, the complete set of excitatory and inhibitory synapses impinging on such a neuron has been taken into account. The firing activity of the neuron model has been studied by computer simulation both in basic conditions and allowing brief periods of over-stimulation in specific regions of its synaptic constellation. Our results show neuronal firing conditions similar to those observed in experimental investigations on pyramidal cortical neurons. In particular, the variation coefficient (CV) computed from the inter-spike intervals (ISIs) in our simulations for basic conditions is close to the unity as that computed from experimental data. Our simulation shows also different behaviors in firing sequences for different frequencies of stimulation. PMID:16870323

  1. Activity-dependent bidirectional regulation of GABAA receptor channels by the 5-HT4 receptor-mediated signalling in rat prefrontal cortical pyramidal neurons

    PubMed Central

    Cai, Xiang; Flores-Hernandez, Jorge; Feng, Jian; Yan, Zhen

    2002-01-01

    Emerging evidence has implicated a potential role for 5-HT4 receptors in cognition and anxiolysis. One of the main target structures of 5-HT4 receptors on ‘cognitive and emotional’ pathways is the prefrontal cortex (PFC). As GABAergic signalling plays a key role in regulating PFC functions, we examined the effect of 5-HT4 receptors on GABAA receptor channels in PFC pyramidal neurons. Application of 5-HT4 receptor agonists produced either an enhancement or a reduction of GABA-evoked currents in PFC neurons, which are both mediated by anchored protein kinase A (PKA). Although PKA phosphorylation of GABAA receptor β3 or β1 subunits leads to current enhancement or reduction respectively in heterologous expression systems, we found that β3 and β1 subunits are co-expressed in PFC pyramidal neurons. Interestingly, altering PKA activation levels can change the direction of the dual effect, switching enhancement to reduction and vice versa. In addition, increased neuronal activity in PFC slices elevated the PKA activation level, changing the enhancing effect of 5-HT4 receptors on the amplitude of GABAergic inhibitory postsynaptic currents (IPSCs) to a reduction. These results suggest that 5-HT4 receptors can modulate GABAergic signalling bidirectionally, depending on the basal PKA activation levels that are determined by neuronal activity. This modulation provides a unique and flexible mechanism for 5-HT4 receptors to dynamically regulate synaptic transmission and neuronal excitability in the PFC network. PMID:11986365

  2. Motor neuron disease with pyramidal tract dysfunction involves the cortical generators of the early somatosensory evoked potential to tibial nerve stimulation.

    PubMed

    Zanette, G; Tinazzi, M; Polo, A; Rizzuto, N

    1996-10-01

    We evaluated somatosensory evoked potentials (SEPs) to tibial nerve stimulation in 39 patients with sporadic motor neuron disease using multiple scalp derivations (earlobe reference). SEPs were altered in 22 of 29 amyotrophic lateral sclerosis (ALS) patients, whereas they were unaffected in 10 progressive muscular atrophy (PMA) patients. The main changes involved the amplitude and the field distribution of the early P40 and N37 cortical potentials with different modalities varying from a selective loss of the P40 potential (33% of tested sides) to absence of all early cortical SEPs (22% of tested sides). The later components following N50 were generally spared. The commonly used Cz-Fz montage was inadequate for detecting these alterations. Central afferent conduction was slightly affected. The selective loss of cortical SEPs and their close correlation with clinicoelectrophysiologic evidence of central motor system involvement strongly support a cortical origin of the SEP alterations in ALS. We suggest that neuronal loss in the somatosensory cortex may selectively affect the generator sites of the cortical SEPs to lower limb stimulation. PMID:8857722

  3. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.

    PubMed

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-07-07

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity.

  4. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.

    PubMed

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-01-01

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity. PMID:26151674

  5. Pyramidal Cells in Prefrontal Cortex of Primates: Marked Differences in Neuronal Structure Among Species

    PubMed Central

    Elston, Guy N.; Benavides-Piccione, Ruth; Elston, Alejandra; Manger, Paul R.; DeFelipe, Javier

    2010-01-01

    The most ubiquitous neuron in the cerebral cortex, the pyramidal cell, is characterized by markedly different dendritic structure among different cortical areas. The complex pyramidal cell phenotype in granular prefrontal cortex (gPFC) of higher primates endows specific biophysical properties and patterns of connectivity, which differ from those in other cortical regions. However, within the gPFC, data have been sampled from only a select few cortical areas. The gPFC of species such as human and macaque monkey includes more than 10 cortical areas. It remains unknown as to what degree pyramidal cell structure may vary among these cortical areas. Here we undertook a survey of pyramidal cells in the dorsolateral, medial, and orbital gPFC of cercopithecid primates. We found marked heterogeneity in pyramidal cell structure within and between these regions. Moreover, trends for gradients in neuronal complexity varied among species. As the structure of neurons determines their computational abilities, memory storage capacity and connectivity, we propose that these specializations in the pyramidal cell phenotype are an important determinant of species-specific executive cortical functions in primates. PMID:21347276

  6. The mammalian neocortex new pyramidal neuron: a new conception

    PubMed Central

    Marín-Padilla, Miguel

    2014-01-01

    The new cerebral cortex (neocortex) and the new type of pyramidal neuron are mammalian innovations that have evolved for operating their increasing motor capabilities while essentially using analogous anatomical and neural makeups. The human neocortex starts to develop in 6-week-old embryos with the establishment of a primordial cortical organization, which resembles the primitive cortices of amphibian and reptiles. From the 8th to the 15th week of age, new pyramidal neurons, of ependymal origin, are progressively incorporated within this primordial cortex forming a cellular plate that divides its components into those above it (neocortex first layer) and those below it (neocortex subplate zone). From the 16th week of age to birth and postnatally, the new pyramidal neurons continue to elongate functionally their apical dendrite by adding synaptic membrane to incorporate the needed sensory information for operating its developing motor activities. The new pyramidal neuron’ distinguishing feature is the capacity of elongating anatomically and functionally its apical dendrite (its main receptive surface) without losing its original attachment to first layer or the location of its soma and, hence, retaining its essential nature. The number of pyramidal cell functional strata established in the motor cortex increases and reflects each mammalian species motor capabilities: the hedgehog needs two pyramidal cell functional strata to carry out all its motor activities, the mouse 3, cat 4, primates 5 and humans 6. The presence of six pyramidal cell functional strata distinguish the human motor cortex from that of others primates. Homo sapiens represent a new evolutionary stage that have transformed his primate brain for operating his unique motor capabilities, such as speaking, writing, painting, sculpturing and thinking as a premotor activity. Words used in language are the motor expression of thoughts and represent sounds produced by maneuvering the column of expiratory

  7. Serotonin modulation of cortical neurons and networks

    PubMed Central

    Celada, Pau; Puig, M. Victoria; Artigas, Francesc

    2013-01-01

    The serotonergic pathways originating in the dorsal and median raphe nuclei (DR and MnR, respectively) are critically involved in cortical function. Serotonin (5-HT), acting on postsynaptic and presynaptic receptors, is involved in cognition, mood, impulse control and motor functions by (1) modulating the activity of different neuronal types, and (2) varying the release of other neurotransmitters, such as glutamate, GABA, acetylcholine and dopamine. Also, 5-HT seems to play an important role in cortical development. Of all cortical regions, the frontal lobe is the area most enriched in serotonergic axons and 5-HT receptors. 5-HT and selective receptor agonists modulate the excitability of cortical neurons and their discharge rate through the activation of several receptor subtypes, of which the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT3 subtypes play a major role. Little is known, however, on the role of other excitatory receptors moderately expressed in cortical areas, such as 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro and in vivo studies suggest that 5-HT1A and 5-HT2A receptors are key players and exert opposite effects on the activity of pyramidal neurons in the medial prefrontal cortex (mPFC). The activation of 5-HT1A receptors in mPFC hyperpolarizes pyramidal neurons whereas that of 5-HT2A receptors results in neuronal depolarization, reduction of the afterhyperpolarization and increase of excitatory postsynaptic currents (EPSCs) and of discharge rate. 5-HT can also stimulate excitatory (5-HT2A and 5-HT3) and inhibitory (5-HT1A) receptors in GABA interneurons to modulate synaptic GABA inputs onto pyramidal neurons. Likewise, the pharmacological manipulation of various 5-HT receptors alters oscillatory activity in PFC, suggesting that 5-HT is also involved in the control of cortical network activity. A better understanding of the actions of 5-HT in PFC may help to develop treatments for mood and cognitive disorders associated with an abnormal function of the frontal lobe

  8. Pyramidal Neuron Number in Layer 3 of Primary Auditory Cortex of Subjects with Schizophrenia

    PubMed Central

    Dorph-Petersen, Karl-Anton; Delevich, Kristen M.; Marcsisin, Michael J.; Zhang, Wei; Sampson, Allan R.; Gundersen, Hans Jørgen G.; Lewis, David A.; Sweet, Robert A.

    2009-01-01

    Individuals with schizophrenia demonstrate impairments of sensory processing within primary auditory cortex. We have previously identified lower densities of dendritic spines and axon boutons, and smaller mean pyramidal neuron somal volume, in layer 3 of the primary auditory cortex in subjects with schizophrenia, all of which might reflect fewer layer 3 pyramidal neurons in schizophrenia. To examine this hypothesis, we developed a robust stereological method based upon unbiased principles for estimation of total volume and pyramidal neuron numbers for each layer of a cortical area. Our method generates both a systematic, uniformly random set of mapping sections as well as a set of randomly rotated sections cut orthogonal to the pial surface, within the region of interest. We applied our approach in twelve subjects with schizophrenia, each matched to a normal comparison subject. Primary auditory cortex volume was assessed using Cavalieri’s method. The relative and absolute volume of each cortical layer and, within layer 3, the number and density of pyramidal neurons was estimated using our novel approach. Subject groups did not differ in regional volume, layer volumes, or pyramidal neuron number, although pyramidal neuron density was significantly greater in subjects with schizophrenia. These findings suggest that previously observed lower densities of dendritic spines and axon boutons reflect fewer numbers per neuron, and contribute to greater neuronal density via a reduced neuropil. Our approach represents a powerful new method for stereologic estimation of features of interest within individual layers of cerebral cortex, with applications beyond the current study. PMID:19524554

  9. Marked changes in dendritic structure and spine density precede significant neuronal death in vulnerable cortical pyramidal neuron populations in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis.

    PubMed

    Fogarty, Matthew J; Mu, Erica W H; Noakes, Peter G; Lavidis, Nickolas A; Bellingham, Mark C

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is characterised by the death of upper (corticospinal) and lower motor neurons (MNs) with progressive muscle weakness. This incurable disease is clinically heterogeneous and its aetiology remains unknown. Increased excitability of corticospinal MNs has been observed prior to symptoms in human and rodent studies. Increased excitability has been correlated with structural changes in neuronal dendritic arbors and spines for decades. Here, using a modified Golgi-Cox staining method, we have made the first longitudinal study examining the dendrites of pyramidal neurons from the motor cortex, medial pre-frontal cortex, somatosensory cortex and entorhinal cortex of hSOD1(G93A) (SOD1) mice compared to wild-type (WT) littermate controls at postnatal (P) days 8-15, 28-35, 65-75 and 120. Progressive decreases in dendritic length and spine density commencing at pre-symptomatic ages (P8-15 or P28-35) were observed in layer V pyramidal neurons within the motor cortex and medial pre-frontal cortex of SOD1 mice compared to WT mice. Spine loss without concurrent dendritic pathology was present in the pyramidal neurons of the somatosensory cortex from disease-onset (P65-75). Our results from the SOD1 model suggest that dendritic and dendritic spine changes foreshadow and underpin the neuromotor phenotypes present in ALS and may contribute to the varied cognitive, executive function and extra-motor symptoms commonly seen in ALS patients. Determining if these phenomena are compensatory or maladaptive may help explain differential susceptibility of neurons to degeneration in ALS. PMID:27488828

  10. Laminar Differences in Dendritic Structure of Pyramidal Neurons in the Juvenile Rat Somatosensory Cortex.

    PubMed

    Rojo, Concepción; Leguey, Ignacio; Kastanauskaite, Asta; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Benavides-Piccione, Ruth

    2016-06-01

    Pyramidal cell structure varies between different cortical areas and species, indicating that the cortical circuits that these cells participate in are likely to be characterized by different functional capabilities. Structural differences between cortical layers have been traditionally reported using either the Golgi method or intracellular labeling, but the structure of pyramidal cells has not previously been systematically analyzed across all cortical layers at a particular age. In the present study, we investigated the dendritic architecture of complete basal arbors of pyramidal neurons in layers II, III, IV, Va, Vb, and VI of the hindlimb somatosensory cortical region of postnatal day 14 rats. We found that the characteristics of basal dendritic morphologies are statistically different in each cortical layer. The variations in size and branching pattern that exist between pyramidal cells of different cortical layers probably reflect the particular functional properties that are characteristic of the cortical circuit in which they participate. This new set of complete basal dendritic arbors of 3D-reconstructed pyramidal cell morphologies across each cortical layer will provide new insights into interlaminar information processing in the cerebral cortex.

  11. Laminar Differences in Dendritic Structure of Pyramidal Neurons in the Juvenile Rat Somatosensory Cortex.

    PubMed

    Rojo, Concepción; Leguey, Ignacio; Kastanauskaite, Asta; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Benavides-Piccione, Ruth

    2016-06-01

    Pyramidal cell structure varies between different cortical areas and species, indicating that the cortical circuits that these cells participate in are likely to be characterized by different functional capabilities. Structural differences between cortical layers have been traditionally reported using either the Golgi method or intracellular labeling, but the structure of pyramidal cells has not previously been systematically analyzed across all cortical layers at a particular age. In the present study, we investigated the dendritic architecture of complete basal arbors of pyramidal neurons in layers II, III, IV, Va, Vb, and VI of the hindlimb somatosensory cortical region of postnatal day 14 rats. We found that the characteristics of basal dendritic morphologies are statistically different in each cortical layer. The variations in size and branching pattern that exist between pyramidal cells of different cortical layers probably reflect the particular functional properties that are characteristic of the cortical circuit in which they participate. This new set of complete basal dendritic arbors of 3D-reconstructed pyramidal cell morphologies across each cortical layer will provide new insights into interlaminar information processing in the cerebral cortex. PMID:26762857

  12. Laminar Differences in Dendritic Structure of Pyramidal Neurons in the Juvenile Rat Somatosensory Cortex

    PubMed Central

    Rojo, Concepción; Leguey, Ignacio; Kastanauskaite, Asta; Bielza, Concha; Larrañaga, Pedro; DeFelipe, Javier; Benavides-Piccione, Ruth

    2016-01-01

    Pyramidal cell structure varies between different cortical areas and species, indicating that the cortical circuits that these cells participate in are likely to be characterized by different functional capabilities. Structural differences between cortical layers have been traditionally reported using either the Golgi method or intracellular labeling, but the structure of pyramidal cells has not previously been systematically analyzed across all cortical layers at a particular age. In the present study, we investigated the dendritic architecture of complete basal arbors of pyramidal neurons in layers II, III, IV, Va, Vb, and VI of the hindlimb somatosensory cortical region of postnatal day 14 rats. We found that the characteristics of basal dendritic morphologies are statistically different in each cortical layer. The variations in size and branching pattern that exist between pyramidal cells of different cortical layers probably reflect the particular functional properties that are characteristic of the cortical circuit in which they participate. This new set of complete basal dendritic arbors of 3D-reconstructed pyramidal cell morphologies across each cortical layer will provide new insights into interlaminar information processing in the cerebral cortex. PMID:26762857

  13. A network of tufted layer 5 pyramidal neurons.

    PubMed

    Markram, H

    1997-09-01

    Tufted layer 5 (TL5) pyramidal neurons are important projection neurons from the cerebral cortex to subcortical areas. Recent and ongoing experiments aimed at understanding the computational analysis performed by a network of synaptically connected TL5 neurons are reviewed here. The experiments employed dual and triple whole-cell patch clamp recordings from visually identified and preselected neurons in brain slices of somatosensory cortex of young (14- to 16-day-old) rats. These studies suggest that a local network of TL5 neurons within a cortical module of diameter 300 microns consists of a few hundred neurons that are extensively inter-connected with reciprocal feedback from at least first-, second- and third-order target neurons. A statistical analysis of synaptic innervation suggests that this recurrent network is not randomly arranged and hence each neuron could be functionally unique. Synaptic transmission between these neurons is characterized by use-dependent synaptic depression which confers novel properties to this recurrent network of neurons. First, a range of rates of depression for different synaptic connections enable each TL5 neuron to receive a unique mixture of information about the average firing rates and the temporally correlated action potential (AP) activity in the population of presynaptic TL5 neurons. Second, each AP generated by any neuron in the network induces a change (defined as an iteration step) in the functional coupling of the neurons in the network (defined as network configuration). It is proposed that the network configuration is iterated during a stimulus to achieve an optimally orchestrated network response. Hebbian, anti-Hebbian and neuromodulatory-induced modifications of neurotransmitter release probability change the rates of synaptic depression and thereby alter the iteration step size. These data may be important to understand the dynamics of electrical activity within the network.

  14. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state

    PubMed Central

    Bellay, Timothy; Klaus, Andreas; Seshadri, Saurav; Plenz, Dietmar

    2015-01-01

    Spontaneous fluctuations in neuronal activity emerge at many spatial and temporal scales in cortex. Population measures found these fluctuations to organize as scale-invariant neuronal avalanches, suggesting cortical dynamics to be critical. Macroscopic dynamics, though, depend on physiological states and are ambiguous as to their cellular composition, spatiotemporal origin, and contributions from synaptic input or action potential (AP) output. Here, we study spontaneous firing in pyramidal neurons (PNs) from rat superficial cortical layers in vivo and in vitro using 2-photon imaging. As the animal transitions from the anesthetized to awake state, spontaneous single neuron firing increases in irregularity and assembles into scale-invariant avalanches at the group level. In vitro spike avalanches emerged naturally yet required balanced excitation and inhibition. This demonstrates that neuronal avalanches are linked to the global physiological state of wakefulness and that cortical resting activity organizes as avalanches from firing of local PN groups to global population activity. DOI: http://dx.doi.org/10.7554/eLife.07224.001 PMID:26151674

  15. Biomechanics of Single Cortical Neurons

    PubMed Central

    Bernick, Kristin B.; Prevost, Thibault P.; Suresh, Subra; Socrate, Simona

    2011-01-01

    This study presents experimental results and computational analysis of the large strain dynamic behavior of single neurons in vitro with the objective of formulating a novel quantitative framework for the biomechanics of cortical neurons. Relying on the atomic force microscopy (AFM) technique, novel testing protocols are developed to enable the characterization of neural soma deformability over a range of indentation rates spanning three orders of magnitude – 10, 1, and 0.1 μm/s. Modified spherical AFM probes were utilized to compress the cell bodies of neonatal rat cortical neurons in load, unload, reload and relaxation conditions. The cell response showed marked hysteretic features, strong non-linearities, and substantial time/rate dependencies. The rheological data were complemented with geometrical measurements of cell body morphology, i.e. cross-diameter and height estimates. A constitutive model, validated by the present experiments, is proposed to quantify the mechanical behavior of cortical neurons. The model aimed to correlate empirical findings with measurable degrees of (hyper-) elastic resilience and viscosity at the cell level. The proposed formulation, predicated upon previous constitutive model developments undertaken at the cortical tissue level, was implemented into a three-dimensional finite element framework. The simulated cell response was calibrated to the experimental measurements under the selected test conditions, providing a novel single cell model that could form the basis for further refinements. PMID:20971217

  16. Brief dopaminergic stimulations produce transient physiological changes in prefrontal pyramidal neurons.

    PubMed

    Moore, Anna R; Zhou, Wen-Liang; Potapenko, Evgeniy S; Kim, Eun-Ji; Antic, Srdjan D

    2011-01-25

    In response to food reward and other pertinent events, midbrain dopaminergic neurons fire short bursts of action potentials causing a phasic release of dopamine in the prefrontal cortex (rapid and transient increases in cortical dopamine concentration). Here we apply short (2s) iontophoretic pulses of glutamate, GABA, dopamine and dopaminergic agonists locally, onto layer 5 pyramidal neurons in brain slices of the rat medial prefrontal cortex (PFC). Unlike glutamate and GABA, brief dopaminergic pulses had negligible effects on the resting membrane potential. However, dopamine altered action potential firing in an extremely rapid (<1s) and transient (<5 min) manner, as every neuron returned to baseline in less than 5-min post-application. The physiological responses to dopamine differed markedly among individual neurons. Pyramidal neurons with a preponderance of D1-like receptor signaling respond to dopamine with a severe depression in action potential firing rate, while pyramidal neurons dominated by the D2 signaling pathway respond to dopamine with an instantaneous increase in spike production. Increasing levels of dopamine concentrations around the cell body resulted in a dose dependent response, which resembles an "inverted U curve" (Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376-384), but this effect can easily be caused by an iontophoresis current artifact. Our present data imply that one population of PFC pyramidal neurons receiving direct synaptic contacts from midbrain dopaminergic neurons would stall during the 0.5s of the phasic dopamine burst. The spillover dopamine, on the other hand, would act as a positive stimulator of cortical excitability (30% increase) to all D2-receptor carrying pyramidal cells, for the next 40s.

  17. Brief Dopaminergic Stimulations Produce Transient Physiological Changes in Prefrontal Pyramidal Neurons

    PubMed Central

    Moore, Anna R.; Zhou, Wen-Liang; Potapenko, Evgeniy S.; Kim, Eun-Ji; Antic, Srdjan D.

    2010-01-01

    In response to food reward and other pertinent events, midbrain dopaminergic neurons fire short bursts of action potentials causing a phasic release of dopamine in the prefrontal cortex (rapid and transient increases in cortical dopamine concentration). Here we apply short (2 sec) iontophoretic pulses of glutamate, GABA, dopamine and dopaminergic agonists locally, onto layer 5 pyramidal neurons in brain slices of the rat medial prefrontal cortex (PFC). Unlike glutamate and GABA, brief dopaminergic pulses had negligible effects on the resting membrane potential. However, dopamine altered action potential firing in an extremely rapid (<1s) and transient (<5min) manner, as every neuron returned to baseline in less than 5-min post-application. The physiological responses to dopamine differed markedly among individual neurons. Pyramidal neurons with a preponderance of D1-like receptor signaling respond to dopamine with a severe depression in action potential firing rate, while pyramidal neurons dominated by the D2 signaling pathway respond to dopamine with an instantaneous increase in spike production. Increasing levels of dopamine concentrations around the cell body resulted in a dose dependent response, which resembles an “inverted U curve” (Vijayraghavan et al., 2007), but this effect can easily be caused by an iontophoresis current artifact. Our present data imply that one population of PFC pyramidal neurons receiving direct synaptic contacts from midbrain dopaminergic neurons would stall during the 0.5 sec of the phasic dopamine burst. The spillover dopamine, on the other hand, would act as a positive stimulator of cortical excitability (30% increase) to all D2-receptor carrying pyramidal cells, for the next 40 seconds. PMID:21059342

  18. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons.

    PubMed

    Mardinly, A R; Spiegel, I; Patrizi, A; Centofante, E; Bazinet, J E; Tzeng, C P; Mandel-Brehm, C; Harmin, D A; Adesnik, H; Fagiolini, M; Greenberg, M E

    2016-03-17

    Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.

  19. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas.

    PubMed

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-08-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas.

  20. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas.

    PubMed

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas. PMID:25081193

  1. Branching angles of pyramidal cell dendrites follow common geometrical design principles in different cortical areas

    PubMed Central

    Bielza, Concha; Benavides-Piccione, Ruth; López-Cruz, Pedro; Larrañaga, Pedro; DeFelipe, Javier

    2014-01-01

    Unraveling pyramidal cell structure is crucial to understanding cortical circuit computations. Although it is well known that pyramidal cell branching structure differs in the various cortical areas, the principles that determine the geometric shapes of these cells are not fully understood. Here we analyzed and modeled with a von Mises distribution the branching angles in 3D reconstructed basal dendritic arbors of hundreds of intracellularly injected cortical pyramidal cells in seven different cortical regions of the frontal, parietal, and occipital cortex of the mouse. We found that, despite the differences in the structure of the pyramidal cells in these distinct functional and cytoarchitectonic cortical areas, there are common design principles that govern the geometry of dendritic branching angles of pyramidal cells in all cortical areas. PMID:25081193

  2. Generation of glutamatergic neurons from postnatal and adult subventricular zone with pyramidal-like morphology.

    PubMed

    Sequerra, Eduardo B; Miyakoshi, Leo M; Fróes, Maira M; Menezes, João R L; Hedin-Pereira, Cecilia

    2010-11-01

    The mammalian subventricular zone (SVZ) contains progenitors derived from cerebral cortex radial glia cells, which give rise to glutamatergic pyramidal neurons during embryogenesis. However, during postnatal life, SVZ generates neurons that migrate and differentiate into olfactory bulb γ-aminobutyric acid (GABA)ergic interneurons. In this work, we tested if SVZ cells are able to produce glutamatergic neurons if confronted with the embryonic cortical ventricular zone environment. Different from typical SVZ chain migration, cells from P9-P11 SVZ explants migrate into embryonic cortical slices individually, many of which radially oriented. An average of 82.5% of green fluorescent protein-positive cells were immunolabeled for neuronal marker class III β-tubulin. Invading cells differentiate into multiple morphologies, including a pyramidal-like morphotype. A subset of these cells are GABAergic; however, about 28% of SVZ-derived cells are immunoreactive for glutamate. Adult SVZ explants also give rise to glutamatergic neurons in these conditions. Taken together, our results indicate that SVZ can be a source of glutamatergic cortical neurons when submitted to proper environmental cues.

  3. Canonical Organization of Layer 1 Neuron-Led Cortical Inhibitory and Disinhibitory Interneuronal Circuits

    PubMed Central

    Lee, Alice J.; Wang, Guangfu; Jiang, Xiaolong; Johnson, Seraphina M.; Hoang, Elizabeth T.; Lanté, Fabien; Stornetta, Ruth L.; Beenhakker, Mark P.; Shen, Ying; Julius Zhu, J.

    2015-01-01

    Interneurons play a key role in cortical function and dysfunction, yet organization of cortical interneuronal circuitry remains poorly understood. Cortical Layer 1 (L1) contains 2 general GABAergic interneuron groups, namely single bouquet cells (SBCs) and elongated neurogliaform cells (ENGCs). SBCs predominantly make unidirectional inhibitory connections (SBC→) with L2/3 interneurons, whereas ENGCs frequently form reciprocal inhibitory and electric connections (ENGC↔) with L2/3 interneurons. Here, we describe a systematic investigation of the pyramidal neuron targets of L1 neuron-led interneuronal circuits in the rat barrel cortex with simultaneous octuple whole-cell recordings and report a simple organizational scheme of the interneuronal circuits. Both SBCs→ and ENGC ↔ L2/3 interneuronal circuits connect to L2/3 and L5, but not L6, pyramidal neurons. SBC → L2/3 interneuronal circuits primarily inhibit the entire dendritic–somato–axonal axis of a few L2/3 and L5 pyramidal neurons located within the same column. In contrast, ENGC ↔ L2/3 interneuronal circuits generally inhibit the distal apical dendrite of many L2/3 and L5 pyramidal neurons across multiple columns. Finally, L1 interneuron-led circuits target distinct subcellular compartments of L2/3 and L5 pyramidal neurons in a L2/3 interneuron type-dependent manner. These results suggest that L1 neurons form canonical interneuronal circuits to control information processes in both supra- and infragranular cortical layers. PMID:24554728

  4. Multilaminar networks of cortical neurons integrate common inputs from sensory thalamus.

    PubMed

    Morgenstern, Nicolás A; Bourg, Jacques; Petreanu, Leopoldo

    2016-08-01

    Neurons in the thalamorecipient layers of sensory cortices integrate thalamic and recurrent cortical input. Cortical neurons form fine-scale, functionally cotuned networks, but whether interconnected cortical neurons within a column process common thalamocortical inputs is unknown. We tested how local and thalamocortical connectivity relate to each other by analyzing cofluctuations of evoked responses in cortical neurons after photostimulation of thalamocortical axons. We found that connected pairs of pyramidal neurons in layer (L) 4 of mouse visual cortex share more inputs from the dorsal lateral geniculate nucleus than nonconnected pairs. Vertically aligned connected pairs of L4 and L2/3 neurons were also preferentially contacted by the same thalamocortical axons. Our results provide a circuit mechanism for the observed amplification of sensory responses by L4 circuits. They also show that sensory information is concurrently processed in L4 and L2/3 by columnar networks of interconnected neurons contacted by the same thalamocortical axons.

  5. Principal component and cluster analysis of layer V pyramidal cells in visual and non-visual cortical areas projecting to the primary visual cortex of the mouse.

    PubMed

    Laramée, M E; Rockland, K S; Prince, S; Bronchti, G; Boire, D

    2013-03-01

    The long-distance corticocortical connections between visual and nonvisual sensory areas that arise from pyramidal neurons located within layer V can be considered as a subpopulation of feedback connections. The purpose of the present study is to determine if layer V pyramidal neurons from visual and nonvisual sensory cortical areas that project onto the visual cortex (V1) constitute a homogeneous population of cells. Additionally, we ask whether dendritic arborization relates to the target, the sensory modality, the hierarchical level, or laterality of the source cortical area. Complete 3D reconstructions of dendritic arbors of retrogradely labeled layer V pyramidal neurons were performed for neurons of the primary auditory (A1) and somatosensory (S1) cortices and from the lateral (V2L) and medial (V2M) parts of the secondary visual cortices of both hemispheres. The morphological parameters extracted from these reconstructions were subjected to principal component analysis (PCA) and cluster analysis. The PCA showed that neurons are distributed within a continuous range of morphologies and do not form discrete groups. Nevertheless, the cluster analysis defines neuronal groups that share similar features. Each cortical area includes neurons belonging to several clusters. We suggest that layer V feedback connections within a single cortical area comprise several cell types. PMID:22426333

  6. Input transformation by dendritic spines of pyramidal neurons

    PubMed Central

    Araya, Roberto

    2014-01-01

    In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike. PMID:25520626

  7. Input transformation by dendritic spines of pyramidal neurons.

    PubMed

    Araya, Roberto

    2014-01-01

    In the mammalian brain, most inputs received by a neuron are formed on the dendritic tree. In the neocortex, the dendrites of pyramidal neurons are covered by thousands of tiny protrusions known as dendritic spines, which are the major recipient sites for excitatory synaptic information in the brain. Their peculiar morphology, with a small head connected to the dendritic shaft by a slender neck, has inspired decades of theoretical and more recently experimental work in an attempt to understand how excitatory synaptic inputs are processed, stored and integrated in pyramidal neurons. Advances in electrophysiological, optical and genetic tools are now enabling us to unravel the biophysical and molecular mechanisms controlling spine function in health and disease. Here I highlight relevant findings, challenges and hypotheses on spine function, with an emphasis on the electrical properties of spines and on how these affect the storage and integration of excitatory synaptic inputs in pyramidal neurons. In an attempt to make sense of the published data, I propose that the raison d'etre for dendritic spines lies in their ability to undergo activity-dependent structural and molecular changes that can modify synaptic strength, and hence alter the gain of the linearly integrated sub-threshold depolarizations in pyramidal neuron dendrites before the generation of a dendritic spike.

  8. Control of cortical neuronal migration by glutamate and GABA

    PubMed Central

    Luhmann, Heiko J.; Fukuda, A.; Kilb, W.

    2015-01-01

    Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca2+ transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis. PMID:25688185

  9. Control of cortical neuronal migration by glutamate and GABA.

    PubMed

    Luhmann, Heiko J; Fukuda, A; Kilb, W

    2015-01-01

    Neuronal migration in the cortex is controlled by the paracrine action of the classical neurotransmitters glutamate and GABA. Glutamate controls radial migration of pyramidal neurons by acting primarily on NMDA receptors and regulates tangential migration of inhibitory interneurons by activating non-NMDA and NMDA receptors. GABA, acting on ionotropic GABAA-rho and GABAA receptors, has a dichotomic action on radially migrating neurons by acting as a GO signal in lower layers and as a STOP signal in upper cortical plate (CP), respectively. Metabotropic GABAB receptors promote radial migration into the CP and tangential migration of interneurons. Besides GABA, the endogenous GABAergic agonist taurine is a relevant agonist controlling radial migration. To a smaller extent glycine receptor activation can also influence radial and tangential migration. Activation of glutamate and GABA receptors causes increases in intracellular Ca(2+) transients, which promote neuronal migration by acting on the cytoskeleton. Pharmacological or genetic manipulation of glutamate or GABA receptors during early corticogenesis induce heterotopic cell clusters in upper layers and loss of cortical lamination, i.e., neuronal migration disorders which can be associated with neurological or neuropsychiatric diseases. The pivotal role of NMDA and ionotropic GABA receptors in cortical neuronal migration is of major clinical relevance, since a number of drugs acting on these receptors (e.g., anti-epileptics, anesthetics, alcohol) may disturb the normal migration pattern when present during early corticogenesis.

  10. Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans

    PubMed Central

    Bianchi, Serena; Duka, Tetyana; Larsen, Michael D.; Janssen, William G. M.; Collins, Zachary; Bauernfeind, Amy L.; Schapiro, Steven J.; Baze, Wallace B.; McArthur, Mark J.; Hopkins, William D.; Wildman, Derek E.; Lipovich, Leonard; Kuzawa, Christopher W.; Jacobs, Bob; Hof, Patrick R.; Sherwood, Chet C.

    2013-01-01

    Neocortical development in humans is characterized by an extended period of synaptic proliferation that peaks in mid-childhood, with subsequent pruning through early adulthood, as well as relatively delayed maturation of neuronal arborization in the prefrontal cortex compared with sensorimotor areas. In macaque monkeys, cortical synaptogenesis peaks during early infancy and developmental changes in synapse density and dendritic spines occur synchronously across cortical regions. Thus, relatively prolonged synapse and neuronal maturation in humans might contribute to enhancement of social learning during development and transmission of cultural practices, including language. However, because macaques, which share a last common ancestor with humans ∼25 million years ago, have served as the predominant comparative primate model in neurodevelopmental research, the paucity of data from more closely related great apes leaves unresolved when these evolutionary changes in the timing of cortical development became established in the human lineage. To address this question, we used immunohistochemistry, electron microscopy, and Golgi staining to characterize synaptic density and dendritic morphology of pyramidal neurons in primary somatosensory (area 3b), primary motor (area 4), prestriate visual (area 18), and prefrontal (area 10) cortices of developing chimpanzees (Pan troglodytes). We found that synaptogenesis occurs synchronously across cortical areas, with a peak of synapse density during the juvenile period (3–5 y). Moreover, similar to findings in humans, dendrites of prefrontal pyramidal neurons developed later than sensorimotor areas. These results suggest that evolutionary changes to neocortical development promoting greater neuronal plasticity early in postnatal life preceded the divergence of the human and chimpanzee lineages. PMID:23754422

  11. PyramidalExplorer: A New Interactive Tool to Explore Morpho-Functional Relations of Human Pyramidal Neurons.

    PubMed

    Toharia, Pablo; Robles, Oscar D; Fernaud-Espinosa, Isabel; Makarova, Julia; Galindo, Sergio E; Rodriguez, Angel; Pastor, Luis; Herreras, Oscar; DeFelipe, Javier; Benavides-Piccione, Ruth

    2015-01-01

    This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron.

  12. PyramidalExplorer: A New Interactive Tool to Explore Morpho-Functional Relations of Human Pyramidal Neurons

    PubMed Central

    Toharia, Pablo; Robles, Oscar D.; Fernaud-Espinosa, Isabel; Makarova, Julia; Galindo, Sergio E.; Rodriguez, Angel; Pastor, Luis; Herreras, Oscar; DeFelipe, Javier; Benavides-Piccione, Ruth

    2016-01-01

    This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron. PMID:26778972

  13. PyramidalExplorer: A New Interactive Tool to Explore Morpho-Functional Relations of Human Pyramidal Neurons.

    PubMed

    Toharia, Pablo; Robles, Oscar D; Fernaud-Espinosa, Isabel; Makarova, Julia; Galindo, Sergio E; Rodriguez, Angel; Pastor, Luis; Herreras, Oscar; DeFelipe, Javier; Benavides-Piccione, Ruth

    2015-01-01

    This work presents PyramidalExplorer, a new tool to interactively explore and reveal the detailed organization of the microanatomy of pyramidal neurons with functionally related models. It consists of a set of functionalities that allow possible regional differences in the pyramidal cell architecture to be interactively discovered by combining quantitative morphological information about the structure of the cell with implemented functional models. The key contribution of this tool is the morpho-functional oriented design that allows the user to navigate within the 3D dataset, filter and perform Content-Based Retrieval operations. As a case study, we present a human pyramidal neuron with over 9000 dendritic spines in its apical and basal dendritic trees. Using PyramidalExplorer, we were able to find unexpected differential morphological attributes of dendritic spines in particular compartments of the neuron, revealing new aspects of the morpho-functional organization of the pyramidal neuron. PMID:26778972

  14. Dendritic spine density of prefrontal layer 6 pyramidal neurons in relation to apical dendrite sculpting by nicotinic acetylcholine receptors

    PubMed Central

    Kang, Lily; Tian, Michael K.; Bailey, Craig D. C.; Lambe, Evelyn K.

    2015-01-01

    Prefrontal layer 6 (L6) pyramidal neurons play an important role in the adult control of attention, facilitated by their strong activation by nicotinic acetylcholine receptors. These neurons in mouse association cortex are distinctive morphologically when compared to L6 neurons in primary cortical regions. Roughly equal proportions of the prefrontal L6 neurons have apical dendrites that are “long” (reaching to the pial surface) vs. “short” (terminating in the deep layers, as in primary cortical regions). This distinct prefrontal morphological pattern is established in the post-juvenile period and appears dependent on nicotinic receptors. Here, we examine dendritic spine densities in these two subgroups of prefrontal L6 pyramidal neurons under control conditions as well as after perturbation of nicotinic acetylcholine receptors. In control mice, the long neurons have significantly greater apical and basal dendritic spine density compared to the short neurons. Furthermore, manipulations of nicotinic receptors (chrna5 deletion or chronic developmental nicotine exposure) have distinct effects on these two subgroups of L6 neurons: apical spine density is significantly reduced in long neurons, and basal spine density is significantly increased in short neurons. These changes appear dependent on the α5 nicotinic subunit encoded by chrna5. Overall, the two subgroups of prefrontal L6 neurons appear positioned to integrate information either across cortex (long neurons) or within the deep layers (short neurons), and nicotinic perturbations differently alter spine density within each subgroup. PMID:26500498

  15. Dendritic and Axonal Architecture of Individual Pyramidal Neurons across Layers of Adult Human Neocortex

    PubMed Central

    Mohan, Hemanth; Verhoog, Matthijs B.; Doreswamy, Keerthi K.; Eyal, Guy; Aardse, Romy; Lodder, Brendan N.; Goriounova, Natalia A.; Asamoah, Boateng; B. Brakspear, A.B. Clementine; Groot, Colin; van der Sluis, Sophie; Testa-Silva, Guilherme; Obermayer, Joshua; Boudewijns, Zimbo S.R.M.; Narayanan, Rajeevan T.; Baayen, Johannes C.; Segev, Idan; Mansvelder, Huibert D.; de Kock, Christiaan P.J.

    2015-01-01

    The size and shape of dendrites and axons are strong determinants of neuronal information processing. Our knowledge on neuronal structure and function is primarily based on brains of laboratory animals. Whether it translates to human is not known since quantitative data on “full” human neuronal morphologies are lacking. Here, we obtained human brain tissue during resection surgery and reconstructed basal and apical dendrites and axons of individual neurons across all cortical layers in temporal cortex (Brodmann area 21). Importantly, morphologies did not correlate to etiology, disease severity, or disease duration. Next, we show that human L(ayer) 2 and L3 pyramidal neurons have 3-fold larger dendritic length and increased branch complexity with longer segments compared with temporal cortex neurons from macaque and mouse. Unsupervised cluster analysis classified 88% of human L2 and L3 neurons into human-specific clusters distinct from mouse and macaque neurons. Computational modeling of passive electrical properties to assess the functional impact of large dendrites indicates stronger signal attenuation of electrical inputs compared with mouse. We thus provide a quantitative analysis of “full” human neuron morphologies and present direct evidence that human neurons are not “scaled-up” versions of rodent or macaque neurons, but have unique structural and functional properties. PMID:26318661

  16. The pyramidal neuron in cerebral cortex following prenatal X-irradiation

    SciTech Connect

    Donoso, J.A.; Norton, S.

    1982-07-01

    Pregnant rats were subjected to whole body X-irradiation amounting to 125 R, on gestational day 15. Cortical pyramidal neurons were examined in irradiated and control offspring at 4 weeks and 4 to 6 months postnatally. All gestationally irradiated rats developed ectopic cortex located below the corpus callosum adjacent to the caudate nucleus in the forebrain. With the rapid Golgi stain, counts were made of dendritic spines on the apical dendrites of layer 5 pyramidal cells in the normally-located cortex and compared with similar neurons in the ectopias. Dendritic spines were present on all pyramidal cells but spines were more sparse on ectopic pyramidal cells. Electron microscopic examination of ectopic and layered cortex in irradiated rats showed axodendritic synapses on the spines and shafts of the dendrites and axosomatic synapses, all of which were indistinguishable morphologically from synapses in control cortex. As a result of the observations made with the light and electron microscopes, it is concluded that the ectopic cortex may contain functional cells in spite of the abnormal location of the tissue.

  17. Physiological evidence that pyramidal neurons lack functional water channels.

    PubMed

    Andrew, R David; Labron, Mark W; Boehnke, Susan E; Carnduff, Lisa; Kirov, Sergei A

    2007-04-01

    The physiological conditions that swell mammalian neurons are clinically important but contentious. Distinguishing the neuronal component of brain swelling requires viewing intact neuronal cell bodies, dendrites, and axons and measuring their changing volume in real time. Cultured or dissociated neuronal somata swell within minutes under acutely overhydrated conditions and shrink when strongly dehydrated. But paradoxically, most central nervous system (CNS) neurons do not express aquaporins, the membrane channels that conduct osmotically driven water. Using 2-photon laser scanning microscopy (2PLSM), we monitored neuronal volume under osmotic stress in real time. Specifically, the volume of pyramidal neurons in cerebral cortex and axon terminals comprising cerebellar mossy fibers was measured deep within live brain slices. The expected swelling or shrinking of the gray matter was confirmed by recording altered light transmittance and by indirectly measuring extracellular resistance over a wide osmotic range of -80 to +80 milliOsmoles (mOsm). Neurons expressing green fluorescent protein were then imaged with 2PLSM between -40 and +80 mOsm over 20 min. Surprisingly, pyramidal somata, dendrites, and spines steadfastly maintained their volume, as did the cerebellar axon terminals. This precluded a need for the neurons to acutely regulate volume, preserved their intrinsic electrophysiological stability, and confirmed that these CNS nerve cells lack functional aquaporins. Thus, whereas water easily permeates the aquaporin-rich endothelia and glia driving osmotic brain swelling, neurons tenatiously maintain their volume. However, these same neurons then swell dramatically upon oxygen/glucose deprivation or [K+]0 elevation, so prolonged depolarization (as during stroke or seizure) apparently swells neurons by opening nonaquaporin channels to water. PMID:16723408

  18. Heterogeneity of spine density in pyramidal neurons of isocortex of mongoose, Herpestes edwardsii (É. Geoffroy Saint-Hilaire 1818).

    PubMed

    Srivastava, U C; Singh, Sippy; Chauhan, Prashant

    2013-08-01

    The characteristics of pyramidal neurons within six layers of Indian gray mongoose (Herpestes edwardsii) isocortex have been investigated using Golgi and Cresyl-Violet methods. Pyramidal neurons and the cytoarchitecture of isocortex of mongoose were photographed with the help of computer aided Nikon eclipse 80i microscope whereas the lucida drawings were made by simple light microscope equipped with camera lucida. The cortical neurons exhibit marked regional differences in phenotype. The differences occur in morphology and distribution of spines within the cortical neurons not only among different species but also within an animal's brain. The present investigation aims at studying the features of pyramidal neurons and to find out the differences if any in distribution of spines in different layers (II-VI) as well as regions (Frontal, Temporal, Parietal, and Occipital) of isocortex of mongoose, which will provide information regarding importance of different layer and region. This piece of work embarks the findings that spine density shows inter-regional as well as interlaminar variations within isocortex of mongoose indicating that pyramidal cells present in varied layer and region are not equally functional and there do exists differences in activity among layers and regions. Among regions, the Temporal region possessing highest spine density contributes more toward functioning of mongoose isocortex and might play significant role in predatory nature of mongoose because this region in mammals is associated with auditory, visual perception, and object recognition. PMID:23733533

  19. Fractal dimension of apical dendritic arborization differs in the superficial and the deep pyramidal neurons of the rat cerebral neocortex.

    PubMed

    Puškaš, Nela; Zaletel, Ivan; Stefanović, Bratislav D; Ristanović, Dušan

    2015-03-01

    Pyramidal neurons of the mammalian cerebral cortex have specific structure and pattern of organization that involves the presence of apical dendrite. Morphology of the apical dendrite is well-known, but quantification of its complexity still remains open. Fractal analysis has proved to be a valuable method for analyzing the complexity of dendrite morphology. The aim of this study was to establish the fractal dimension of apical dendrite arborization of pyramidal neurons in distinct neocortical laminae by using the modified box-counting method. A total of thirty, Golgi impregnated neurons from the rat brain were analyzed: 15 superficial (cell bodies located within lamina II-III), and 15 deep pyramidal neurons (cell bodies situated within lamina V-VI). Analysis of topological parameters of apical dendrite arborization showed no statistical differences except in total dendritic length (p=0.02), indicating considerable homogeneity between the two groups of neurons. On the other hand, average fractal dimension of apical dendrite was 1.33±0.06 for the superficial and 1.24±0.04 for the deep cortical neurons, showing statistically significant difference between these two groups (p<0.001). In conclusion, according to the fractal dimension values, apical dendrites of the superficial pyramidal neurons tend to show higher structural complexity compared to the deep ones.

  20. Essential Roles for ARID1B in Dendritic Arborization and Spine Morphology of Developing Pyramidal Neurons

    PubMed Central

    Ka, Minhan; Chopra, Divyan A.; Dravid, Shashank M.

    2016-01-01

    De novo truncating mutations in ARID1B, a chromatin-remodeling gene, cause Coffin–Siris syndrome, a developmental disorder characterized by intellectual disability and speech impairment; however, how the genetic elimination leads to cognitive dysfunction remains unknown. Thus, we investigated the neural functions of ARID1B during brain development. Here, we show that ARID1B regulates dendritic differentiation in the developing mouse brain. We knocked down ARID1B expression in mouse pyramidal neurons using in utero gene delivery methodologies. ARID1B knockdown suppressed dendritic arborization of cortical and hippocampal pyramidal neurons in mice. The abnormal development of dendrites accompanied a decrease in dendritic outgrowth into layer I. Furthermore, knockdown of ARID1B resulted in aberrant dendritic spines and synaptic transmission. Finally, ARID1B deficiency led to altered expression of c-Fos and Arc, and overexpression of these factors rescued abnormal differentiation induced by ARID1B knockdown. Our results demonstrate a novel role for ARID1B in neuronal differentiation and provide new insights into the origin of cognitive dysfunction associated with developmental intellectual disability. SIGNIFICANCE STATEMENT Haploinsufficiency of ARID1B, a component of chromatin remodeling complex, causes intellectual disability. However, the role of ARID1B in brain development is unknown. Here, we demonstrate that ARID1B is required for neuronal differentiation in the developing brain, such as in dendritic arborization and synapse formation. Our findings suggest that ARID1B plays a critical role in the establishment of cognitive circuitry by regulating dendritic complexity. Thus, ARID1B deficiency may cause intellectual disability via abnormal brain wiring induced by the defective differentiation of cortical neurons. PMID:26937011

  1. Simple Method for Evaluation of Planum Temporale Pyramidal Neurons Shrinkage in Postmortem Tissue of Alzheimer Disease Patients

    PubMed Central

    Kutová, Martina; Mrzílková, Jana; Kirdajová, Denisa; Řípová, Daniela; Zach, Petr

    2014-01-01

    We measured the length of the pyramidal neurons in the cortical layer III in four subregions of the planum temporale (transitions into superior temporal gyrus, Heschl's gyrus, insular cortex, and Sylvian fissure) in control group and Alzheimer disease patients. Our hypothesis was that overall length of the pyramidal neurons would be smaller in the Alzheimer disease group compared to controls and also there would be right-left asymmetry in both the control and Alzheimer disease groups. We found pyramidal neuron length asymmetry only in controls—in the transition into the Sylvian fissure—and the rest of the subregions in the control group and Alzheimer disease patients did not show size difference. However, control-Alzheimer disease group pyramidal neuron length comparison revealed (a) no length difference in superior temporal gyrus transition area, (b) reversal of asymmetry in the insular transition area with left insular transition significantly shorter in the Alzheimer disease group compared to the control group, (c) both right and left Heschl's gyrus transitions significantly shorter in the Alzheimer disease group compared to the control group, and (d) right Sylvian fissure transition significantly shorter in the Alzheimer disease group compared to the control group. This neuronal length measurement method could supplement already existing neuropathological criteria for postmortem Alzheimer disease diagnostics. PMID:24719875

  2. Simple method for evaluation of planum temporale pyramidal neurons shrinkage in postmortem tissue of Alzheimer disease patients.

    PubMed

    Kutová, Martina; Mrzílková, Jana; Kirdajová, Denisa; Řípová, Daniela; Zach, Petr

    2014-01-01

    We measured the length of the pyramidal neurons in the cortical layer III in four subregions of the planum temporale (transitions into superior temporal gyrus, Heschl's gyrus, insular cortex, and Sylvian fissure) in control group and Alzheimer disease patients. Our hypothesis was that overall length of the pyramidal neurons would be smaller in the Alzheimer disease group compared to controls and also there would be right-left asymmetry in both the control and Alzheimer disease groups. We found pyramidal neuron length asymmetry only in controls--in the transition into the Sylvian fissure--and the rest of the subregions in the control group and Alzheimer disease patients did not show size difference. However, control-Alzheimer disease group pyramidal neuron length comparison revealed (a) no length difference in superior temporal gyrus transition area, (b) reversal of asymmetry in the insular transition area with left insular transition significantly shorter in the Alzheimer disease group compared to the control group, (c) both right and left Heschl's gyrus transitions significantly shorter in the Alzheimer disease group compared to the control group, and (d) right Sylvian fissure transition significantly shorter in the Alzheimer disease group compared to the control group. This neuronal length measurement method could supplement already existing neuropathological criteria for postmortem Alzheimer disease diagnostics.

  3. Computational Study of Subdural Cortical Stimulation: Effects of Simulating Anisotropic Conductivity on Activation of Cortical Neurons

    PubMed Central

    Seo, Hyeon; Kim, Donghyeon; Jun, Sung Chan

    2015-01-01

    Subdural cortical stimulation (SuCS) is an appealing method in the treatment of neurological disorders, and computational modeling studies of SuCS have been applied to determine the optimal design for electrotherapy. To achieve a better understanding of computational modeling on the stimulation effects of SuCS, the influence of anisotropic white matter conductivity on the activation of cortical neurons was investigated in a realistic head model. In this paper, we constructed pyramidal neuronal models (layers 3 and 5) that showed primary excitation of the corticospinal tract, and an anatomically realistic head model reflecting complex brain geometry. The anisotropic information was acquired from diffusion tensor magnetic resonance imaging (DT-MRI) and then applied to the white matter at various ratios of anisotropic conductivity. First, we compared the isotropic and anisotropic models; compared to the isotropic model, the anisotropic model showed that neurons were activated in the deeper bank during cathodal stimulation and in the wider crown during anodal stimulation. Second, several popular anisotropic principles were adapted to investigate the effects of variations in anisotropic information. We observed that excitation thresholds varied with anisotropic principles, especially with anodal stimulation. Overall, incorporating anisotropic conductivity into the anatomically realistic head model is critical for accurate estimation of neuronal responses; however, caution should be used in the selection of anisotropic information. PMID:26057524

  4. Cdk5 is required for multipolar-to-bipolar transition during radial neuronal migration and proper dendrite development of pyramidal neurons in the cerebral cortex.

    PubMed

    Ohshima, Toshio; Hirasawa, Motoyuki; Tabata, Hidenori; Mutoh, Tetsuji; Adachi, Tomoko; Suzuki, Hiromi; Saruta, Keiko; Iwasato, Takuji; Itohara, Shigeyoshi; Hashimoto, Mistuhiro; Nakajima, Kazunori; Ogawa, Masaharu; Kulkarni, Ashok B; Mikoshiba, Katsuhiko

    2007-06-01

    The mammalian cerebral cortex consists of six layers that are generated via coordinated neuronal migration during the embryonic period. Recent studies identified specific phases of radial migration of cortical neurons. After the final division, neurons transform from a multipolar to a bipolar shape within the subventricular zone-intermediate zone (SVZ-IZ) and then migrate along radial glial fibres. Mice lacking Cdk5 exhibit abnormal corticogenesis owing to neuronal migration defects. When we introduced GFP into migrating neurons at E14.5 by in utero electroporation, we observed migrating neurons in wild-type but not in Cdk5(-/-) embryos after 3-4 days. Introduction of the dominant-negative form of Cdk5 into the wild-type migrating neurons confirmed specific impairment of the multipolar-to-bipolar transition within the SVZ-IZ in a cell-autonomous manner. Cortex-specific Cdk5 conditional knockout mice showed inverted layering of the cerebral cortex and the layer V and callosal neurons, but not layer VI neurons, had severely impaired dendritic morphology. The amount of the dendritic protein Map2 was decreased in the cerebral cortex of Cdk5-deficient mice, and the axonal trajectory of cortical neurons within the cortex was also abnormal. These results indicate that Cdk5 is required for proper multipolar-to-bipolar transition, and a deficiency of Cdk5 results in abnormal morphology of pyramidal neurons. In addition, proper radial neuronal migration generates an inside-out pattern of cerebral cortex formation and normal axonal trajectories of cortical pyramidal neurons.

  5. Dendritic Spine Alterations in Neocortical Pyramidal Neurons following Postnatal Neuronal Nogo-A Knockdown

    PubMed Central

    Pradhan, A.D.; Case, A.M.; Farrer, R.G.; Tsai, S.Y.; Cheatwood, J.L.; Martin, J.L.; Kartje, G.L.

    2010-01-01

    The myelin-associated protein Nogo-A is a well-known inhibitor of axonal regeneration and compensatory plasticity, yet functions of neuronal Nogo-A are not as clear. The present study examined the effects of decreased levels of neuronal Nogo-A on dendritic spines of developing neocortical neurons. Decreased Nogo-A levels in these neurons resulted in lowered spine density and an increase in filopodial type protrusions. These results suggest a role for neuronal Nogo-A in maintaining a spine phenotype in neocortical pyramidal cells. PMID:20938157

  6. Alterations of Neocortical Pyramidal Neurons: Turning Points in the Genesis of Mental Retardation

    PubMed Central

    Granato, Alberto; De Giorgio, Andrea

    2014-01-01

    Pyramidal neurons (PNs) represent the majority of neocortical cells and their involvement in cognitive functions is decisive. Therefore, they are the most obvious target of developmental disorders characterized by mental retardation. Genetic and non-genetic forms of intellectual disability share a few basic pathogenetic signatures that result in the anomalous function of PNs. Here, we review the key mechanisms impairing these neurons and their participation in the cortical network, with special focus on experimental models of fetal exposure to alcohol. Due to the heterogeneity of PNs, some alterations affect selectively a given cell population, which may also differ depending on the considered pathology. These specific features open new possibilities for the interpretation of cognitive defects observed in mental retardation syndromes, as well as for novel therapeutic interventions. PMID:25157343

  7. Intrinsic oscillations of neocortex generated by layer 5 pyramidal neurons.

    PubMed

    Silva, L R; Amitai, Y; Connors, B W

    1991-01-25

    Rhythmic activity in the neocortex varies with different behavioral and pathological states and in some cases may encode sensory information. However, the neural mechanisms of these oscillations are largely unknown. Many pyramidal neurons in layer 5 of the neocortex showed prolonged, 5- to 12-hertz rhythmic firing patterns at threshold. Rhythmic firing was due to intrinsic membrane properties, sodium conductances were essential for rhythmicity, and calcium-dependent conductances strongly modified rhythmicity. Isolated slices of neocortex generated epochs of 4- to 10-hertz synchronized activity when N-methyl-D-aspartate receptor-mediated channels were facilitated. Layer 5 was both necessary and sufficient to produce these synchronized oscillations. Thus, synaptic networks of intrinsically rhythmic neurons in layer 5 may generate or promote certain synchronized oscillations of the neocortex.

  8. Neurotoxic effects of methamphetamine on rat hippocampus pyramidal neurons.

    PubMed

    Hori, N; Kadota, M T; Watanabe, M; Ito, Y; Akaike, N; Carpenter, D O

    2010-08-01

    Methamphetamine (MAP) is known to alter behavior and cause deficits in learning and memory. While the major site of action of MAP is on mesolimbic dopaminergic pathways, the effects on learning and memory raise the possibility of important actions in the hippocampus. We have studied electrophysiologic and morphologic effects of MAP in the CA1 region of hippocampus from young male rats chronically exposed to MAP, male rats exposed during gestation only and the effects of bath perfusion of MAP onto brain slices from control rats. Pyramidal neurons in brain slices from chronically exposed rats had reduced membrane potential and membrane resistance. Long-term potentiation (LTP) was reduced as compared to control, but when MAP was acutely perfused over control slices the amplitude of LTP was increased. LTP in young adult animals that had been gestationally exposed to MAP showed reduced LTP as compared to controls. Morphologically CA1 pyramidal neurons in chronically exposed animals showed a high prevalence of extensive blebbing of dendrites. We conclude that the NMDA receptor and the process of LTP are also targets of MAP dysfunction, at least in the hippocampus.

  9. Changes in the axonal conduction velocity of pyramidal tract neurons in the aged cat.

    PubMed

    Xi, M C; Liu, R H; Engelhardt, J K; Morales, F R; Chase, M H

    1999-01-01

    The present study was undertaken to determine whether age-dependent changes in axonal conduction velocity occur in pyramidal tract neurons. A total of 260 and 254 pyramidal tract neurons were recorded extracellularly in the motor cortex of adult control and aged cats, respectively. These cells were activated antidromically by electrical stimulation of the medullary pyramidal tract. Fast- and slow-conducting neurons were identified according to their axonal conduction velocity in both control and aged cats. While 51% of pyramidal tract neurons recorded in the control cats were fast conducting (conduction velocity greater than 20 m/s), only 26% of pyramidal tract neurons in the aged cats were fast conducting. There was a 43% decrease in the median conduction velocity for the entire population of pyramidal tract neurons in aged cats when compared with that of pyramidal tract neurons in the control cats (P < 0.001, Mann-Whitney U-test). A linear relationship between the spike duration of pyramidal tract neurons and their antidromic latency was present in both control and aged cats. However, the regression slope was significantly reduced in aged cats. This reduction was due to the appearance of a group of pyramidal tract neurons with relatively shorter spike durations but slower axonal conduction velocities in the aged cat. Sample intracellular data confirmed the above results. These observations form the basis for the following conclusions: (i) there is a decrease in median conduction velocity of pyramidal tract neurons in aged cats; (ii) the reduction in the axonal conduction velocity of pyramidal tract neurons in aged cats is due, in part, to fibers that previously belonged to the fast-conducting group and now conduct at slower velocity. PMID:10392844

  10. High-Degree Neurons Feed Cortical Computations

    PubMed Central

    Timme, Nicholas M.; Ito, Shinya; Shimono, Masanori; Yeh, Fang-Chin; Litke, Alan M.; Beggs, John M.

    2016-01-01

    Recent work has shown that functional connectivity among cortical neurons is highly varied, with a small percentage of neurons having many more connections than others. Also, recent theoretical developments now make it possible to quantify how neurons modify information from the connections they receive. Therefore, it is now possible to investigate how information modification, or computation, depends on the number of connections a neuron receives (in-degree) or sends out (out-degree). To do this, we recorded the simultaneous spiking activity of hundreds of neurons in cortico-hippocampal slice cultures using a high-density 512-electrode array. This preparation and recording method combination produced large numbers of neurons recorded at temporal and spatial resolutions that are not currently available in any in vivo recording system. We utilized transfer entropy (a well-established method for detecting linear and nonlinear interactions in time series) and the partial information decomposition (a powerful, recently developed tool for dissecting multivariate information processing into distinct parts) to quantify computation between neurons where information flows converged. We found that computations did not occur equally in all neurons throughout the networks. Surprisingly, neurons that computed large amounts of information tended to receive connections from high out-degree neurons. However, the in-degree of a neuron was not related to the amount of information it computed. To gain insight into these findings, we developed a simple feedforward network model. We found that a degree-modified Hebbian wiring rule best reproduced the pattern of computation and degree correlation results seen in the real data. Interestingly, this rule also maximized signal propagation in the presence of network-wide correlations, suggesting a mechanism by which cortex could deal with common random background input. These are the first results to show that the extent to which a neuron

  11. Effect of mescaline on single cortical neurones.

    PubMed

    Bradshaw, C M; Roberts, M H; Szabadi, E

    1971-12-01

    The effects of mescaline upon single cortical neurones were studied, using the microiontophoretic technique. Mescaline elicited excitatory and depressant responses similar to those evoked by noradrenaline (NA) and 5-hydroxytryptamine (5-HI). The responses to NA and mescaline were usually in the same direction, the neurone being either excited by both drugs or depressed by both drugs. The correlation between the effects of mescaline and 5-HT, however, was less consistent. The beta-adrenoceptor blocking agent MJ-1999 and the 5-HT antagonist methysergide were both effective in antagonizing mescaline responses.

  12. Mechanisms underlying subunit independence in pyramidal neuron dendrites

    PubMed Central

    Behabadi, Bardia F.; Mel, Bartlett W.

    2014-01-01

    Pyramidal neuron (PN) dendrites compartmentalize voltage signals and can generate local spikes, which has led to the proposal that their dendrites act as independent computational subunits within a multilayered processing scheme. However, when a PN is strongly activated, back-propagating action potentials (bAPs) sweeping outward from the soma synchronize dendritic membrane potentials many times per second. How PN dendrites maintain the independence of their voltage-dependent computations, despite these repeated voltage resets, remains unknown. Using a detailed compartmental model of a layer 5 PN, and an improved method for quantifying subunit independence that incorporates a more accurate model of dendritic integration, we first established that the output of each dendrite can be almost perfectly predicted by the intensity and spatial configuration of its own synaptic inputs, and is nearly invariant to the rate of bAP-mediated “cross-talk” from other dendrites over a 100-fold range. Then, through an analysis of conductance, voltage, and current waveforms within the model cell, we identify three biophysical mechanisms that together help make independent dendritic computation possible in a firing neuron, suggesting that a major subtype of neocortical neuron has been optimized for layered, compartmentalized processing under in-vivo–like spiking conditions. PMID:24357611

  13. An unusual population of pyramidal neurons in the anterior cingulate cortex of hominids contains the calcium-binding protein calretinin.

    PubMed

    Hof, P R; Nimchinsky, E A; Perl, D P; Erwin, J M

    2001-07-20

    In the context of an on-going comparative analysis of primate neocortex evolution, we describe the occurrence and distribution of a previously unrecognized group of pyramidal neurons, restricted to the superficial part of layer V in the anterior cingulate cortex of hominids and characterized by immunoreactivity to the calcium-binding protein, calretinin. These neurons were rare in orangutans, more numerous in gorillas and common chimpanzees, while humans had the highest numbers. These calretinin-containing pyramidal cells were not observed in the cingulate cortex of any other primate or mammalian species. This finding, together with other recent observations on the hominoid cingulate cortex, is interesting when considering primate neocortical evolution, as it indicates possible adaptive and anatomical modifications in a cortical region critical for the integration of many aspects of autonomic function, vocalization, and cognitive processes.

  14. Housing under the pyramid reduces susceptibility of hippocampal CA3 pyramidal neurons to prenatal stress in the developing rat offspring.

    PubMed

    Murthy, Krishna Dilip; George, Mitchel Constance; Ramasamy, Perumal; Mustapha, Zainal Arifin

    2013-12-01

    Mother-offspring interaction begins before birth. The foetus is particularly vulnerable to environmental insults and stress. The body responds by releasing excess of the stress hormone cortisol, which acts on glucocorticoid receptors. Hippocampus in the brain is rich in glucocorticoid receptors and therefore susceptible to stress. The stress effects are reduced when the animals are placed under a model wooden pyramid. The present study was to first explore the effects of prenatal restraint-stress on the plasma corticosterone levels and the dendritic arborisation of CA3 pyramidal neurons in the hippocampus of the offspring. Further, to test whether the pyramid environment would alter these effects, as housing under a pyramid is known to reduce the stress effects, pregnant Sprague Dawley rats were restrained for 9 h per day from gestation day 7 until parturition in a wire-mesh restrainer. Plasma corticosterone levels were found to be significantly increased. In addition, there was a significant reduction in the apical and the basal total dendritic branching points and intersections of the CA3 hippocampal pyramidal neurons. The results thus suggest that, housing in the pyramid dramatically reduces prenatal stress effects in rats.

  15. Melatonin promotes distal dendritic ramifications in layer II/III cortical pyramidal cells of rats exposed to toluene vapors.

    PubMed

    Pascual, Rodrigo; Bustamante, Carlos

    2010-10-01

    We have previously shown that toluene inhalation produces significant impairments in the basilar dendritic outgrowth of pyramidal cortical cells. This neurotoxic effect was markedly inhibited by melatonin administration at a dose of 5mg kg(-1). The present study was designed to determine whether toluene and melatonin equally affect all basilar dendritic segments or if a differential response exists between the segments. Twenty-eight male mice were weaned at postnatal day 21 (P21) and randomly assigned to either the control (C; n=10,) or toluene (T; n=18) group. Between P22-P32, male rats were placed into a glass chamber and exposed to either toluene vapors (5-000-6000 ppm) or clean air for 10 min a day. When toluene exposure ended (P32), animals were further assigned to the following experimental groups: (a) control/saline (C/S; n=10), (b) toluene/saline (T/S; n=10), or (c) toluene/melatonin 5mg kg(-1) (T/M; n=8). Melatonin or vehicle solutions were administered daily between P32 and P38. Forty-eight hours after the final toluene exposure, the animals were sacrificed, and the pyramidal cortical cells were stained using the Golgi-Cox-Sholl procedure. The number of basilar dendritic branches/order was counted using the centrifugal ordering method. The results indicate that (i) toluene inhalation significantly impairs both proximal and distal basilar dendritic ramifications (in the parietal and frontal/occipital cortices, respectively) and (ii) melatonin both protects neurons from toluene neurotoxicity in all cortical areas studied and increases the complexity of the dendritic tree above control values.

  16. Using melanopsin to study G protein signaling in cortical neurons.

    PubMed

    McGregor, K M; Bécamel, C; Marin, P; Andrade, R

    2016-09-01

    Our understanding of G protein-coupled receptors (GPCRs) in the central nervous system (CNS) has been hampered by the limited availability of tools allowing for the study of their signaling with precise temporal control. To overcome this, we tested the utility of the bistable mammalian opsin melanopsin to examine G protein signaling in CNS neurons. Specifically, we used biolistic (gene gun) approaches to transfect melanopsin into cortical pyramidal cells maintained in organotypic slice culture. Whole cell recordings from transfected neurons indicated that application of blue light effectively activated the transfected melanopsin to elicit the canonical biphasic modulation of membrane excitability previously associated with the activation of GPCRs coupling to Gαq-11 Remarkably, full mimicry of exogenous agonist concentration could be obtained with pulses as short as a few milliseconds, suggesting that their triggering required a single melanopsin activation-deactivation cycle. The resulting temporal control over melanopsin activation allowed us to compare the activation kinetics of different components of the electrophysiological response. We also replaced the intracellular loops of melanopsin with those of the 5-HT2A receptor to create a light-activated GPCR capable of interacting with the 5-HT2A receptor interacting proteins. The resulting chimera expressed weak activity but validated the potential usefulness of melanopsin as a tool for the study of G protein signaling in CNS neurons. PMID:27306679

  17. Synaptogenesis in purified cortical subplate neurons.

    PubMed

    McKellar, Claire E; Shatz, Carla J

    2009-08-01

    An ideal preparation for investigating events during synaptogenesis would be one in which synapses are sparse, but can be induced at will using a rapid, exogenous trigger. We describe a culture system of immunopurified subplate neurons in which synaptogenesis can be triggered, providing the first homogeneous culture of neocortical neurons for the investigation of synapse development. Synapses in immunopurified rat subplate neurons are sparse, and can be induced by a 48-h exposure to feeder layers of neurons and glia, an induction more rapid than any previously reported. Induced synapses are electrophysiologically functional and ultrastructurally normal. Microarray and real-time PCR experiments reveal a new program of gene expression accompanying synaptogenesis. Surprisingly few known synaptic genes are upregulated during the first 24 h of synaptogenesis; Gene Ontology annotation reveals a preferential upregulation of synaptic genes only at a later time. In situ hybridization confirms that some of the genes regulated in cultures are also expressed in the developing cortex. This culture system provides both a means of studying synapse formation in a homogeneous population of cortical neurons, and better synchronization of synaptogenesis, permitting the investigation of neuron-wide events following the triggering of synapse formation.

  18. Synaptogenesis in Purified Cortical Subplate Neurons

    PubMed Central

    Shatz, Carla J.

    2009-01-01

    An ideal preparation for investigating events during synaptogenesis would be one in which synapses are sparse, but can be induced at will using a rapid, exogenous trigger. We describe a culture system of immunopurified subplate neurons in which synaptogenesis can be triggered, providing the first homogeneous culture of neocortical neurons for the investigation of synapse development. Synapses in immunopurified rat subplate neurons are sparse, and can be induced by a 48-h exposure to feeder layers of neurons and glia, an induction more rapid than any previously reported. Induced synapses are electrophysiologically functional and ultrastructurally normal. Microarray and real-time PCR experiments reveal a new program of gene expression accompanying synaptogenesis. Surprisingly few known synaptic genes are upregulated during the first 24 h of synaptogenesis; Gene Ontology annotation reveals a preferential upregulation of synaptic genes only at a later time. In situ hybridization confirms that some of the genes regulated in cultures are also expressed in the developing cortex. This culture system provides both a means of studying synapse formation in a homogeneous population of cortical neurons, and better synchronization of synaptogenesis, permitting the investigation of neuron-wide events following the triggering of synapse formation. PMID:19029062

  19. Functional effects of distinct innervation styles of pyramidal cells by fast spiking cortical interneurons

    PubMed Central

    Kubota, Yoshiyuki; Kondo, Satoru; Nomura, Masaki; Hatada, Sayuri; Yamaguchi, Noboru; Mohamed, Alsayed A; Karube, Fuyuki; Lübke, Joachim; Kawaguchi, Yasuo

    2015-01-01

    Inhibitory interneurons target precise membrane regions on pyramidal cells, but differences in their functional effects on somata, dendrites and spines remain unclear. We analyzed inhibitory synaptic events induced by cortical, fast-spiking (FS) basket cells which innervate dendritic shafts and spines as well as pyramidal cell somata. Serial electron micrograph (EMg) reconstructions showed that somatic synapses were larger than dendritic contacts. Simulations with precise anatomical and physiological data reveal functional differences between different innervation styles. FS cell soma-targeting synapses initiate a strong, global inhibition, those on shafts inhibit more restricted dendritic zones, while synapses on spines may mediate a strictly local veto. Thus, FS cell synapses of different sizes and sites provide functionally diverse forms of pyramidal cell inhibition. DOI: http://dx.doi.org/10.7554/eLife.07919.001 PMID:26142457

  20. Effect of Anatomically Realistic Full-Head Model on Activation of Cortical Neurons in Subdural Cortical Stimulation—A Computational Study

    NASA Astrophysics Data System (ADS)

    Seo, Hyeon; Kim, Donghyeon; Jun, Sung Chan

    2016-06-01

    Electrical brain stimulation (EBS) is an emerging therapy for the treatment of neurological disorders, and computational modeling studies of EBS have been used to determine the optimal parameters for highly cost-effective electrotherapy. Recent notable growth in computing capability has enabled researchers to consider an anatomically realistic head model that represents the full head and complex geometry of the brain rather than the previous simplified partial head model (extruded slab) that represents only the precentral gyrus. In this work, subdural cortical stimulation (SuCS) was found to offer a better understanding of the differential activation of cortical neurons in the anatomically realistic full-head model than in the simplified partial-head models. We observed that layer 3 pyramidal neurons had comparable stimulation thresholds in both head models, while layer 5 pyramidal neurons showed a notable discrepancy between the models; in particular, layer 5 pyramidal neurons demonstrated asymmetry in the thresholds and action potential initiation sites in the anatomically realistic full-head model. Overall, the anatomically realistic full-head model may offer a better understanding of layer 5 pyramidal neuronal responses. Accordingly, the effects of using the realistic full-head model in SuCS are compelling in computational modeling studies, even though this modeling requires substantially more effort.

  1. Effect of Anatomically Realistic Full-Head Model on Activation of Cortical Neurons in Subdural Cortical Stimulation-A Computational Study.

    PubMed

    Seo, Hyeon; Kim, Donghyeon; Jun, Sung Chan

    2016-01-01

    Electrical brain stimulation (EBS) is an emerging therapy for the treatment of neurological disorders, and computational modeling studies of EBS have been used to determine the optimal parameters for highly cost-effective electrotherapy. Recent notable growth in computing capability has enabled researchers to consider an anatomically realistic head model that represents the full head and complex geometry of the brain rather than the previous simplified partial head model (extruded slab) that represents only the precentral gyrus. In this work, subdural cortical stimulation (SuCS) was found to offer a better understanding of the differential activation of cortical neurons in the anatomically realistic full-head model than in the simplified partial-head models. We observed that layer 3 pyramidal neurons had comparable stimulation thresholds in both head models, while layer 5 pyramidal neurons showed a notable discrepancy between the models; in particular, layer 5 pyramidal neurons demonstrated asymmetry in the thresholds and action potential initiation sites in the anatomically realistic full-head model. Overall, the anatomically realistic full-head model may offer a better understanding of layer 5 pyramidal neuronal responses. Accordingly, the effects of using the realistic full-head model in SuCS are compelling in computational modeling studies, even though this modeling requires substantially more effort. PMID:27273817

  2. Effect of Anatomically Realistic Full-Head Model on Activation of Cortical Neurons in Subdural Cortical Stimulation—A Computational Study

    PubMed Central

    Seo, Hyeon; Kim, Donghyeon; Jun, Sung Chan

    2016-01-01

    Electrical brain stimulation (EBS) is an emerging therapy for the treatment of neurological disorders, and computational modeling studies of EBS have been used to determine the optimal parameters for highly cost-effective electrotherapy. Recent notable growth in computing capability has enabled researchers to consider an anatomically realistic head model that represents the full head and complex geometry of the brain rather than the previous simplified partial head model (extruded slab) that represents only the precentral gyrus. In this work, subdural cortical stimulation (SuCS) was found to offer a better understanding of the differential activation of cortical neurons in the anatomically realistic full-head model than in the simplified partial-head models. We observed that layer 3 pyramidal neurons had comparable stimulation thresholds in both head models, while layer 5 pyramidal neurons showed a notable discrepancy between the models; in particular, layer 5 pyramidal neurons demonstrated asymmetry in the thresholds and action potential initiation sites in the anatomically realistic full-head model. Overall, the anatomically realistic full-head model may offer a better understanding of layer 5 pyramidal neuronal responses. Accordingly, the effects of using the realistic full-head model in SuCS are compelling in computational modeling studies, even though this modeling requires substantially more effort. PMID:27273817

  3. Subthreshold voltage noise of rat neocortical pyramidal neurones.

    PubMed

    Jacobson, Gilad A; Diba, Kamran; Yaron-Jakoubovitch, Anat; Oz, Yasmin; Koch, Christof; Segev, Idan; Yarom, Yosef

    2005-04-01

    Neurones are noisy elements. Noise arises from both intrinsic and extrinsic sources, and manifests itself as fluctuations in the membrane potential. These fluctuations limit the accuracy of a neurone's output but have also been suggested to play a computational role. We present a detailed study of the amplitude and spectrum of voltage noise recorded at the soma of layer IV-V pyramidal neurones in slices taken from rat neocortex. The dependence of the noise on holding potential, synaptic activity and Na+ conductance is systematically analysed. We demonstrate that voltage noise increases non-linearly as the cell depolarizes (from a standard deviation (s.d.) of 0.19 mV at -75 mV to an s.d. of 0.54 mV at -55 mV). The increase in voltage noise is accompanied by an increase in the cell impedance, due to voltage dependence of Na+ conductance. The impedance increase accounts for the majority (70%) of the voltage noise increase. The increase in voltage noise and impedance is restricted to the low-frequency range (0.2-2 Hz). At the high frequency range (5-100 Hz) the voltage noise is dominated by synaptic activity. In our slice preparation, synaptic noise has little effect on the cell impedance. A minimal model reproduces qualitatively these data. Our results imply that ion channel noise contributes significantly to membrane voltage fluctuations at the subthreshold voltage range, and that Na+ conductance plays a key role in determining the amplitude of this noise by acting as a voltage-dependent amplifier of low-frequency transients. PMID:15695244

  4. Subthreshold voltage noise of rat neocortical pyramidal neurones

    PubMed Central

    Jacobson, Gilad A; Diba, Kamran; Yaron-Jakoubovitch, Anat; Oz, Yasmin; Koch, Christof; Segev, Idan; Yarom, Yosef

    2005-01-01

    Neurones are noisy elements. Noise arises from both intrinsic and extrinsic sources, and manifests itself as fluctuations in the membrane potential. These fluctuations limit the accuracy of a neurone's output but have also been suggested to play a computational role. We present a detailed study of the amplitude and spectrum of voltage noise recorded at the soma of layer IV–V pyramidal neurones in slices taken from rat neocortex. The dependence of the noise on holding potential, synaptic activity and Na+ conductance is systematically analysed. We demonstrate that voltage noise increases non-linearly as the cell depolarizes (from a standard deviation (s.d.) of 0.19 mV at −75 mV to an s.d. of 0.54 mV at −55 mV). The increase in voltage noise is accompanied by an increase in the cell impedance, due to voltage dependence of Na+ conductance. The impedance increase accounts for the majority (70%) of the voltage noise increase. The increase in voltage noise and impedance is restricted to the low-frequency range (0.2–2 Hz). At the high frequency range (5–100 Hz) the voltage noise is dominated by synaptic activity. In our slice preparation, synaptic noise has little effect on the cell impedance. A minimal model reproduces qualitatively these data. Our results imply that ion channel noise contributes significantly to membrane voltage fluctuations at the subthreshold voltage range, and that Na+ conductance plays a key role in determining the amplitude of this noise by acting as a voltage-dependent amplifier of low-frequency transients. PMID:15695244

  5. Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons

    PubMed Central

    Kim, Sooyun; Guzman, Segundo J; Hu, Hua; Jonas, Peter

    2013-01-01

    CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic domains. In the proximal domain, action potentials initiated in the axon backpropagate actively with large amplitude and fast time course. In the distal domain, Na+ channel–mediated dendritic spikes are efficiently initiated by waveforms mimicking synaptic events. CA3 pyramidal neuron dendrites showed a high Na+-to-K+ conductance density ratio, providing ideal conditions for active backpropagation and dendritic spike initiation. Dendritic spikes may enhance the computational power of CA3 pyramidal neurons in the hippocampal network. PMID:22388958

  6. Properties of the pyramidal tract neuron system within the precentral wrist and hand area of primate motor cortex.

    PubMed

    Humphrey, D R; Corrie, W S; Rietz, R

    1978-01-01

    1. To obtain basic anatomical data that will be useful in interpreting the results of studies of primate pyramidal tract neurons (PTNs), extracellular, single-unit recording techniques were used to determine a number of the properties of the PTN population within the electrically defined, precentral wrist zone of the monkey's motor cortex. 2. Recordings were obtained from a total of 1,375 antidromically identified PT and corticospinal tract (CST) cells. A mathematical model was then used to correct the statistics of the sample for variations in the probability of unit detection, which arise from variations in neuronal size and extracellular field dimensions. 3. Both the experimentally observed and theoretically corrected results suggest that the PT projection from this cortical zone is derived principally from slowly conducting, and presumably small to medium-sized cells (an estimated 85% of the resident PTN population). 4. Both the fast and slow cell subpopulations were found to be concentrated within cortical layer V, where they tend to congregate in small, mixed clusters of 2 to 5 neurons. Estimates of the total packing density of PTNs within layer V of this cortical zone suggest that they account for only 10-20% of the neurons within this major efferent layer. 5. 70% of the slow and 82% of the fast PT neurons within this cortical area were found to send their axons into the contralateral, lateral corticospinal tract. Thus, in futur functional studies of PTNs in this cortical area, it can be assumed that three of every four neurons will in fact influence segmental cells of one category or another directly. 6. Extensive data are also presented on the incidence of axon collateral branching from PT and CST cells to the red nucleus, the medial medullary reticular formation and the cuneate nucleus. 7. Some general implications of these findings for the design of future functional studies of anatomically identified motor cortex cell systems are then discussed.

  7. Subplate Neurons: Crucial Regulators of Cortical Development and Plasticity

    PubMed Central

    Kanold, Patrick O.

    2009-01-01

    The developing cerebral cortex contains a distinct class of cells, subplate neurons, which form one of the first functional cortical circuits. Subplate neurons reside in the cortical white matter, receive thalamic inputs and project into the developing cortical plate, mostly to layer 4. Subplate neurons are present at key time points during development. Removal of subplate neurons profoundly affects cortical development. Subplate removal in visual cortex prevents the maturation of thalamocortical synapse, the maturation of inhibition in layer 4, the development of orientation selective responses in individual cortical neurons, and the formation of ocular dominance columns. In addition, monocular deprivation during development reveals that ocular dominance plasticity is paradoxical in the absence of subplate neurons. Because subplate neurons projecting to layer 4 are glutamatergic, these diverse deficits following subplate removal were hypothesized to be due to lack of feed-forward thalamic driven cortical excitation. A computational model of the developing thalamocortical pathway incorporating feed-forward excitatory subplate projections replicates both normal development and plasticity of ocular dominance as well as the effects of subplate removal. Therefore, we postulate that feed-forward excitatory projections from subplate neurons into the developing cortical plate enhance correlated activity between thalamus and layer 4 and, in concert with Hebbian learning rules in layer 4, allow maturational and plastic processes in layer 4 to commence. Thus subplate neurons are a crucial regulator of cortical development and plasticity, and damage to these neurons might play a role in the pathology of many neurodevelopmental disorders. PMID:19738926

  8. Acetaminophen Induces Apoptosis in Rat Cortical Neurons

    PubMed Central

    Posadas, Inmaculada; Santos, Pablo; Blanco, Almudena; Muñoz-Fernández, Maríangeles; Ceña, Valentín

    2010-01-01

    Background Acetaminophen (AAP) is widely prescribed for treatment of mild pain and fever in western countries. It is generally considered a safe drug and the most frequently reported adverse effect associated with acetaminophen is hepatotoxicity, which generally occurs after acute overdose. During AAP overdose, encephalopathy might develop and contribute to morbidity and mortality. Our hypothesis is that AAP causes direct neuronal toxicity contributing to the general AAP toxicity syndrome. Methodology/Principal Findings We report that AAP causes direct toxicity on rat cortical neurons both in vitro and in vivo as measured by LDH release. We have found that AAP causes concentration-dependent neuronal death in vitro at concentrations (1 and 2 mM) that are reached in human plasma during AAP overdose, and that are also reached in the cerebrospinal fluid of rats for 3 hours following i.p injection of AAP doses (250 and 500 mg/Kg) that are below those required to induce acute hepatic failure in rats. AAP also increases both neuronal cytochrome P450 isoform CYP2E1 enzymatic activity and protein levels as determined by Western blot, leading to neuronal death through mitochondrial–mediated mechanisms that involve cytochrome c release and caspase 3 activation. In addition, in vivo experiments show that i.p. AAP (250 and 500 mg/Kg) injection induces neuronal death in the rat cortex as measured by TUNEL, validating the in vitro data. Conclusions/Significance The data presented here establish, for the first time, a direct neurotoxic action by AAP both in vivo and in vitro in rats at doses below those required to produce hepatotoxicity and suggest that this neurotoxicity might be involved in the general toxic syndrome observed during patient APP overdose and, possibly, also when AAP doses in the upper dosing schedule are used, especially if other risk factors (moderate drinking, fasting, nutritional impairment) are present. PMID:21170329

  9. Location-Dependent Excitatory Synaptic Interactions in Pyramidal Neuron Dendrites

    PubMed Central

    Behabadi, Bardia F.; Polsky, Alon; Jadi, Monika; Schiller, Jackie; Mel, Bartlett W.

    2012-01-01

    Neocortical pyramidal neurons (PNs) receive thousands of excitatory synaptic contacts on their basal dendrites. Some act as classical driver inputs while others are thought to modulate PN responses based on sensory or behavioral context, but the biophysical mechanisms that mediate classical-contextual interactions in these dendrites remain poorly understood. We hypothesized that if two excitatory pathways bias their synaptic projections towards proximal vs. distal ends of the basal branches, the very different local spike thresholds and attenuation factors for inputs near and far from the soma might provide the basis for a classical-contextual functional asymmetry. Supporting this possibility, we found both in compartmental models and electrophysiological recordings in brain slices that the responses of basal dendrites to spatially separated inputs are indeed strongly asymmetric. Distal excitation lowers the local spike threshold for more proximal inputs, while having little effect on peak responses at the soma. In contrast, proximal excitation lowers the threshold, but also substantially increases the gain of distally-driven responses. Our findings support the view that PN basal dendrites possess significant analog computing capabilities, and suggest that the diverse forms of nonlinear response modulation seen in the neocortex, including uni-modal, cross-modal, and attentional effects, could depend in part on pathway-specific biases in the spatial distribution of excitatory synaptic contacts onto PN basal dendritic arbors. PMID:22829759

  10. During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons

    PubMed Central

    Brown, Adam R.; Mitchell, Scott J.; Peden, Dianne R.; Herd, Murray B.; Seifi, Mohsen; Swinny, Jerome D.; Belelli, Delia; Lambert, Jeremy J.

    2016-01-01

    As neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the α1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from α1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity. PMID:26626485

  11. Spectrotemporal processing differences between auditory cortical fast-spiking and regular-spiking neurons

    PubMed Central

    Atencio, Craig A.; Schreiner, Christoph E.

    2008-01-01

    Excitatory pyramidal neurons and inhibitory interneurons constitute the main elements of cortical circuitry and have distinctive morphologic and electrophysiological properties. Here, we differentiate them by analyzing the time course of their action potentials (APs) and characterizing their receptive field properties in auditory cortex. Pyramidal neurons have longer APs and discharge as Regular-Spiking Units (RSUs), while basket and chandelier cells, which are inhibitory interneurons, have shorter APs and are Fast-Spiking Units (FSUs). To compare these neuronal classes we stimulated cat primary auditory cortex neurons with a dynamic moving ripple stimulus and constructed single-unit spectrotemporal receptive fields (STRFs) and their associated nonlinearities. FSUs had shorter latencies, broader spectral tuning, greater stimulus specificity, and higher temporal precision than RSUs. The STRF structure of FSUs was more separable, suggesting more independence between spectral and temporal processing regimes. The nonlinearities associated with the two cell classes was indicative of higher feature selectivity for FSUs. These global functional differences between RSUs and FSUs suggest fundamental distinctions between putative excitatory and inhibitory neurons that shape auditory cortical processing. PMID:18400888

  12. Theoretical principles underlying optical stimulation of a channelrhodopsin-2 positive pyramidal neuron

    PubMed Central

    Foutz, Thomas J.; Arlow, Richard L.

    2012-01-01

    Optogenetics is an emerging field of neuromodulation that permits scaled, millisecond temporal control of the membrane dynamics of genetically targeted cells using light. Optogenetic technology has revolutionized neuroscience research; however, numerous biophysical questions remain on the optical and neuronal factors impacting the modulation of neural activity with photon-sensitive ion channels. To begin to address such questions, we developed a computational tool to explore the underlying principles of optogenetic neural stimulation. This “light-neuron” model consists of theoretical representations of the light dynamics generated by a fiber optic in brain tissue, coupled to a multicompartment cable model of a cortical pyramidal neuron embedded with channelrhodopsin-2 (ChR2) membrane dynamics. Simulations revealed that the large energies required to generate an action potential are primarily due to the limited conductivity of ChR2, and that the major determinants of stimulation threshold are the surface area of illuminated cell membrane and proximity to the light source. Our results predict that the activation threshold is sensitive to many of the properties of ChR2 (density, conductivity, and kinetics), tissue medium (scattering and absorbance), and the fiber-optic light source (diameter and numerical aperture). We also illustrate the impact of redistributing the ChR2 expression density (uniform vs. nonuniform) on the activation threshold. The model system developed in this study represents a scientific instrument to characterize the effects of optogenetic neuromodulation, as well as an engineering design tool to help guide future development of optogenetic technology. PMID:22442566

  13. Action potential initiation and propagation in rat neocortical pyramidal neurons.

    PubMed

    Stuart, G; Schiller, J; Sakmann, B

    1997-12-15

    1. Initiation and propagation of action potentials evoked by extracellular synaptic stimulation was studied using simultaneous dual and triple patch pipette recordings from different locations on neocortical layer 5 pyramidal neurons in brain slices from 4-week-old rats (P26-30) at physiological temperatures. 2. Simultaneous cell-attached and whole-cell voltage recordings from the apical trunk (up to 700 microns distal to the soma) and the soma indicated that proximal synaptic stimulation (layer 4) initiated action potentials first at the soma, whereas distal stimulation (upper layer 2/3) could initiate dendritic regenerative potentials prior to somatic action potentials following stimulation at higher intensity. 3. Somatic action potentials, once initiated, propagated back into the apical dendrites in a decremented manner which was frequency dependent. The half-width of back propagating action potentials increased and their maximum rate of rise decreased with distance from the soma, with the peak of these action potentials propagating with a conduction velocity of approximately 0.5 m s-1. 4. Back-propagation of action potentials into the dendritic tree was associated with dendritic calcium electrogenesis, which was particularly prominent during bursts of somatic action potentials. 5. When dendritic regenerative potentials were evoked prior to somatic action potentials, the more distal the dendritic recording was made from the soma the longer the time between the onset of the dendritic regenerative potential relative to somatic action potential. This suggested that dendritic regenerative potentials were initiated in the distal apical dendrites, possibly in the apical tuft. 6. At any one stimulus intensity, the initiation of dendritic regenerative potentials prior to somatic action potentials could fluctuate, and was modulated by depolarizing somatic or hyperpolarizing dendritic current injection. 7. Dendritic regenerative potentials could be initiated prior to

  14. Human cerebrospinal fluid increases the excitability of pyramidal neurons in the in vitro brain slice

    PubMed Central

    Bjorefeldt, Andreas; Andreasson, Ulf; Daborg, Jonny; Riebe, Ilse; Wasling, Pontus; Zetterberg, Henrik; Hanse, Eric

    2015-01-01

    The composition of brain extracellular fluid is shaped by a continuous exchange of substances between the cerebrospinal fluid (CSF) and interstitial fluid. The CSF is known to contain a wide range of endogenous neuromodulatory substances, but their collective influence on neuronal activity has been poorly investigated. We show here that replacing artificial CSF (aCSF), routinely used for perfusion of brain slices in vitro, with human CSF (hCSF) powerfully boosts spontaneous firing of CA1, CA3 and layer 5 pyramidal neurons in the rat brain slice. CA1 pyramidal neurons in hCSF display lowered firing thresholds, more depolarized resting membrane potentials and reduced input resistance, mimicking properties of pyramidal neurons recorded in vivo. The increased excitability of CA1 pyramidal neurons was completely occluded by intracellular application of GTPγS, suggesting that endogenous neuromodulators in hCSF act on G-protein coupled receptors to enhance excitability. We found no increase in spontaneous inhibitory synaptic transmission by hCSF, indicating a differential effect on glutamatergic and GABAergic neurons. Our findings highlight a previously unknown function of the CSF in promoting spontaneous excitatory activity, and may help to explain differences observed in the activity of pyramidal neurons recorded in vivo and in vitro. PMID:25556798

  15. Three-dimensional Quantification of Dendritic Spines from Pyramidal Neurons Derived from Human Induced Pluripotent Stem Cells.

    PubMed

    Gouder, Laura; Tinevez, Jean-Yves; Goubran-Botros, Hany; Benchoua, Alexandra; Bourgeron, Thomas; Cloëz-Tayarani, Isabelle

    2015-01-01

    Dendritic spines are small protrusions that correspond to the post-synaptic compartments of excitatory synapses in the central nervous system. They are distributed along the dendrites. Their morphology is largely dependent on neuronal activity, and they are dynamic. Dendritic spines express glutamatergic receptors (AMPA and NMDA receptors) on their surface and at the levels of postsynaptic densities. Each spine allows the neuron to control its state and local activity independently. Spine morphologies have been extensively studied in glutamatergic pyramidal cells of the brain cortex, using both in vivo approaches and neuronal cultures obtained from rodent tissues. Neuropathological conditions can be associated to altered spine induction and maturation, as shown in rodent cultured neurons and one-dimensional quantitative analysis (1). The present study describes a protocol for the 3D quantitative analysis of spine morphologies using human cortical neurons derived from neural stem cells (late cortical progenitors). These cells were initially obtained from induced pluripotent stem cells. This protocol allows the analysis of spine morphologies at different culture periods, and with possible comparison between induced pluripotent stem cells obtained from control individuals with those obtained from patients with psychiatric diseases. PMID:26484791

  16. Early postnatal migration and development of layer II pyramidal neurons in the rodent cingulate/retrosplenial cortex.

    PubMed

    Zgraggen, Eloisa; Boitard, Michael; Roman, Inge; Kanemitsu, Michiko; Potter, Gael; Salmon, Patrick; Vutskits, Laszlo; Dayer, Alexandre G; Kiss, Jozsef Z

    2012-01-01

    The cingulate and retrosplenial regions are major components of the dorsomedial (dm) limbic cortex and have been implicated in a range of cognitive functions such as emotion, attention, and spatial memory. While the structure and connectivity of these cortices are well characterized, little is known about their development. Notably, the timing and mode of migration that govern the appropriate positioning of late-born neurons remain unknown. Here, we analyzed migratory events during the early postnatal period from ventricular/subventricular zone (VZ/SVZ) to the cerebral cortex by transducing neuronal precursors in the VZ/SVZ of newborn rats/mice with Tomato/green fluorescent protein-encoding lentivectors. We have identified a pool of postmitotic pyramidal precursors in the dm part of the neonatal VZ/SVZ that migrate into the medial limbic cortex during the first postnatal week. Time-lapse imaging demonstrates that these cells migrate on radial glial fibers by locomotion and display morphological and behavioral changes as they travel through the white matter and enter into the cortical gray matter. In the granular retrosplenial cortex, these cells give rise to a Satb2+ pyramidal subtype and develop dendritic bundles in layer I. Our observations provide the first insight into the patterns and dynamics of cell migration into the medial limbic cortex. PMID:21625013

  17. The inhibitory effect of propofol on Kv2.1 potassium channel in rat parietal cortical neurons.

    PubMed

    Zhang, Yan-Zhuo; Zhang, Rui; Zeng, Xian-Zhang; Song, Chun-Yu

    2016-03-11

    Excessive K(+) efflux via activated voltage-gated K(+) channels can deplete intracellular K(+) and lead to long-lasting membrane depolarization which will promote neuronal apoptosis during ischemia/hypoxia injury. The Kv2.1 potassium channel was the major component of delayed rectifier potassium current (Ik) in pyramidal neurons in cortex and hippocampus. The neuronal protective effect of propofol has been proved. Delayed rectifier potassium current (Ik) has been shown to have close relationship with neuronal damage. The study was designed to test the inhibitory effect of propofol on Kv2.1 potassium channel in rat parietal cortical neurons. Whole-cell patch clamp recordings and Western blot analysis were used to investigate the electrophysiological function and protein expression of Kv2.1 in rat parietal cortical neurons after propofol treatment. We found that propofol concentration-dependently inhibited Ik in pyramidal neurons. Propofol also caused a downward shift of the I-V curve of Ik at 30μM concentration. Propofol significantly inhibited the expression of Kv2.1 protein level at 30μM, 50μM, 100μM concentration. In conclusion, our data showed that propofol could inhibit Ik, probably via depressing the expression of Kv2.1 protein in rat cerebral parietal cortical neurons.

  18. Cooperative Nonlinearities in Auditory Cortical Neurons

    PubMed Central

    Atencio, Craig A.; Sharpee, Tatyana O.; Schreiner, Christoph E.

    2008-01-01

    SUMMARY Cortical receptive fields represent the signal preferences of sensory neurons. Receptive fields are thought to provide a representation of sensory experience from which the cerebral cortex may make interpretations. While it is essential to determine a neuron’s receptive field, it remains unclear which features of the acoustic environment are specifically represented by neurons in the primary auditory cortex (AI). We characterized cat AI spectrotemporal receptive fields (STRFs) by finding both the spike-triggered average (STA) and stimulus dimensions that maximized the mutual information between response and stimulus. We derived a nonlinearity relating spiking to stimulus projection onto two maximally informative dimensions (MIDs). The STA was highly correlated with the first MID. Generally, the nonlinearity for the first MID was asymmetric and often monotonic in shape, while the second MID nonlinearity was symmetric and non-monotonic. The joint nonlinearity for both MIDs revealed that most first and second MIDs were synergistic, and thus should be considered conjointly. The difference between the nonlinearities suggests different possible roles for the MIDs in auditory processing. PMID:18579084

  19. IK1 channels do not contribute to the slow afterhyperpolarization in pyramidal neurons

    PubMed Central

    Wang, Kang; Mateos-Aparicio, Pedro; Hönigsperger, Christoph; Raghuram, Vijeta; Wu, Wendy W; Ridder, Margreet C; Sah, Pankaj; Maylie, Jim; Storm, Johan F; Adelman, John P

    2016-01-01

    In pyramidal neurons such as hippocampal area CA1 and basolateral amygdala, a slow afterhyperpolarization (sAHP) follows a burst of action potentials, which is a powerful regulator of neuronal excitability. The sAHP amplitude increases with aging and may underlie age related memory decline. The sAHP is due to a Ca2+-dependent, voltage-independent K+ conductance, the molecular identity of which has remained elusive until a recent report suggested the Ca2+-activated K+ channel, IK1 (KCNN4) as the sAHP channel in CA1 pyramidal neurons. The signature pharmacology of IK1, blockade by TRAM-34, was reported for the sAHP and underlying current. We have examined the sAHP and find no evidence that TRAM-34 affects either the current underling the sAHP or excitability of CA1 or basolateral amygdala pyramidal neurons. In addition, CA1 pyramidal neurons from IK1 null mice exhibit a characteristic sAHP current. Our results indicate that IK1 channels do not mediate the sAHP in pyramidal neurons. DOI: http://dx.doi.org/10.7554/eLife.11206.001 PMID:26765773

  20. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease.

    PubMed

    Spampanato, J; Gu, X; Yang, X W; Mody, I

    2008-12-01

    Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in huntingtin. A newly developed bacterial artificial chromosome transgenic mouse model (BACHD) reproduces phenotypic features of HD including predominantly neuropil-associated protein aggregation and progressive motor dysfunction with selective neurodegenerative pathology. Motor dysfunction has been shown to precede neuropathology in BACHD mice. We therefore investigated the progression of synaptic pathology in pyramidal cells and interneurons of the superficial motor cortex of BACHD mice. Whole-cell patch clamp recordings were performed on layer 2/3 primary motor cortical pyramidal cells and parvalbumin interneurons from BACHD mice at 3 months, when the mice begin to demonstrate mild motor dysfunction, and at 6 months, when the motor dysfunction is more severe. Changes in synaptic variances were detectable at 3 months, and at 6 months BACHD mice display progressive synaptic pathology in the form of reduced cortical excitation and loss of inhibition onto pyramidal cells. These results suggest that progressive alterations of the superficial cortical circuitry may contribute to the decline of motor function in BACHD mice. The synaptic pathology occurs prior to neuronal degeneration and may therefore prove useful as a target for future therapeutic design. PMID:18854207

  1. A synaptic organizing principle for cortical neuronal groups

    PubMed Central

    Perin, Rodrigo; Berger, Thomas K.; Markram, Henry

    2011-01-01

    Neuronal circuitry is often considered a clean slate that can be dynamically and arbitrarily molded by experience. However, when we investigated synaptic connectivity in groups of pyramidal neurons in the neocortex, we found that both connectivity and synaptic weights were surprisingly predictable. Synaptic weights follow very closely the number of connections in a group of neurons, saturating after only 20% of possible connections are formed between neurons in a group. When we examined the network topology of connectivity between neurons, we found that the neurons cluster into small world networks that are not scale-free, with less than 2 degrees of separation. We found a simple clustering rule where connectivity is directly proportional to the number of common neighbors, which accounts for these small world networks and accurately predicts the connection probability between any two neurons. This pyramidal neuron network clusters into multiple groups of a few dozen neurons each. The neurons composing each group are surprisingly distributed, typically more than 100 μm apart, allowing for multiple groups to be interlaced in the same space. In summary, we discovered a synaptic organizing principle that groups neurons in a manner that is common across animals and hence, independent of individual experiences. We speculate that these elementary neuronal groups are prescribed Lego-like building blocks of perception and that acquired memory relies more on combining these elementary assemblies into higher-order constructs. PMID:21383177

  2. Characteristics of intracellularly injected infragranular pyramidal neurons in cat primary auditory cortex.

    PubMed

    Ojima, H; Honda, C N; Jones, E G

    1992-01-01

    Pyramidal neurons in layers V and VI of cat primary auditory cortex (AI) were intracellularly injected with biocytin after functional characterization according to a position relative to an anteroposterior sequence of best-frequency responses. A sample of 19 completely filled neurons was analyzed, and a preliminary classification was made on the basis of dendritic morphology and axon collateral distribution. Layer V cells could be divided into two types. Cells in the upper part of layer V and projecting toward the diencephalon had a large cell body and an apical dendrite with extensive branches in layer I. These cells had few recurrent axon collaterals, and no terminal axonal bushes were formed in the vicinity of the dendritic field. Long horizontal collaterals with many boutons, however, extended in various directions parallel to the cortical surface. By contrast, cells in the lower part of layer V and sending an axon into the putamen, or without an obvious subcortical axon, had a medium soma and an apical dendrite with few branches in layer I. These cells had a dense bush of recurrent collaterals extending into layers II and III and surrounding the dendritic field, but few or no horizontal collaterals. Layer VI injected neurons were more heterogeneous. All had a thin ascending dendrite with oblique branches both ending in layer III. Axon collateral distributions varied from cell to cell. Relatively small cells with an apical dendrite that branched frequently in layers III and IV had a dense network of recurrent collaterals in the dendritic field, but virtually no horizontal collaterals. This type projected toward the diencephalon. Cells with relatively long horizontal collaterals and a weak recurrent system confined to layers V and VI had a unique arborization pattern of basal dendrites. This type may have projected to the claustrum or other cortical areas. One cell with dendritic branches restricted to layer VI had horizontal collaterals predominantly in layer

  3. Pyramidal cells make specific connections onto smooth (GABAergic) neurons in mouse visual cortex.

    PubMed

    Bopp, Rita; Maçarico da Costa, Nuno; Kampa, Björn M; Martin, Kevan A C; Roth, Morgane M

    2014-08-01

    One of the hallmarks of neocortical circuits is the predominance of recurrent excitation between pyramidal neurons, which is balanced by recurrent inhibition from smooth GABAergic neurons. It has been previously described that in layer 2/3 of primary visual cortex (V1) of cat and monkey, pyramidal cells filled with horseradish peroxidase connect approximately in proportion to the spiny (excitatory, 95% and 81%, respectively) and smooth (GABAergic, 5% and 19%, respectively) dendrites found in the neuropil. By contrast, a recent ultrastructural study of V1 in a single mouse found that smooth neurons formed 51% of the targets of the superficial layer pyramidal cells. This suggests that either the neuropil of this particular mouse V1 had a dramatically different composition to that of V1 in cat and monkey, or that smooth neurons were specifically targeted by the pyramidal cells in that mouse. We tested these hypotheses by examining similar cells filled with biocytin in a sample of five mice. We found that the average composition of the neuropil in V1 of these mice was similar to that described for cat and monkey V1, but that the superficial layer pyramidal cells do form proportionately more synapses with smooth dendrites than the equivalent neurons in cat or monkey. These distributions may underlie the distinct differences in functional architecture of V1 between rodent and higher mammals.

  4. Thalamus-derived molecules promote survival and dendritic growth of developing cortical neurons.

    PubMed

    Sato, Haruka; Fukutani, Yuma; Yamamoto, Yuji; Tatara, Eiichi; Takemoto, Makoto; Shimamura, Kenji; Yamamoto, Nobuhiko

    2012-10-31

    The mammalian neocortex is composed of various types of neurons that reflect its laminar and area structures. It has been suggested that not only intrinsic but also afferent-derived extrinsic factors are involved in neuronal differentiation during development. However, the role and molecular mechanism of such extrinsic factors are almost unknown. Here, we attempted to identify molecules that are expressed in the thalamus and affect cortical cell development. First, thalamus-specific molecules were sought by comparing gene expression profiles of the developing rat thalamus and cortex using microarrays, and by constructing a thalamus-enriched subtraction cDNA library. A systematic screening by in situ hybridization showed that several genes encoding extracellular molecules were strongly expressed in sensory thalamic nuclei. Exogenous and endogenous protein localization further demonstrated that two extracellular molecules, Neuritin-1 (NRN1) and VGF, were transported to thalamic axon terminals. Application of NRN1 and VGF to dissociated cell culture promoted the dendritic growth. An organotypic slice culture experiment further showed that the number of primary dendrites in multipolar stellate neurons increased in response to NRN1 and VGF, whereas dendritic growth of pyramidal neurons was not promoted. These molecules also increased neuronal survival of multipolar neurons. Taken together, these results suggest that the thalamus-specific molecules NRN1 and VGF play an important role in the dendritic growth and survival of cortical neurons in a cell type-specific manner. PMID:23115177

  5. Thalamus-derived molecules promote survival and dendritic growth of developing cortical neurons.

    PubMed

    Sato, Haruka; Fukutani, Yuma; Yamamoto, Yuji; Tatara, Eiichi; Takemoto, Makoto; Shimamura, Kenji; Yamamoto, Nobuhiko

    2012-10-31

    The mammalian neocortex is composed of various types of neurons that reflect its laminar and area structures. It has been suggested that not only intrinsic but also afferent-derived extrinsic factors are involved in neuronal differentiation during development. However, the role and molecular mechanism of such extrinsic factors are almost unknown. Here, we attempted to identify molecules that are expressed in the thalamus and affect cortical cell development. First, thalamus-specific molecules were sought by comparing gene expression profiles of the developing rat thalamus and cortex using microarrays, and by constructing a thalamus-enriched subtraction cDNA library. A systematic screening by in situ hybridization showed that several genes encoding extracellular molecules were strongly expressed in sensory thalamic nuclei. Exogenous and endogenous protein localization further demonstrated that two extracellular molecules, Neuritin-1 (NRN1) and VGF, were transported to thalamic axon terminals. Application of NRN1 and VGF to dissociated cell culture promoted the dendritic growth. An organotypic slice culture experiment further showed that the number of primary dendrites in multipolar stellate neurons increased in response to NRN1 and VGF, whereas dendritic growth of pyramidal neurons was not promoted. These molecules also increased neuronal survival of multipolar neurons. Taken together, these results suggest that the thalamus-specific molecules NRN1 and VGF play an important role in the dendritic growth and survival of cortical neurons in a cell type-specific manner.

  6. Cortex, cognition and the cell: new insights into the pyramidal neuron and prefrontal function.

    PubMed

    Elston, Guy N

    2003-11-01

    Arguably the most complex cortical functions are seated in human cognition, the how and why of which have been debated for centuries by theologians, philosophers and scientists alike. In his best-selling book, An Astonishing Hypothesis: A Scientific Search for the Soul, Francis Crick refined the view that these qualities are determined solely by cortical cells and circuitry. Put simply, cognition is nothing more, or less, than a biological function. Accepting this to be the case, it should be possible to identify the mechanisms that subserve cognitive processing. Since the pioneering studies of Lorent de Nó and Hebb, and the more recent studies of Fuster, Miller and Goldman-Rakic, to mention but a few, much attention has been focused on the role of persistent neural activity in cognitive processes. Application of modern technologies and modelling techniques has led to new hypotheses about the mechanisms of persistent activity. Here I focus on how regional variations in the pyramidal cell phenotype may determine the complexity of cortical circuitry and, in turn, influence neural activity. Data obtained from thousands of individually injected pyramidal cells in sensory, motor, association and executive cortex reveal marked differences in the numbers of putative excitatory inputs received by these cells. Pyramidal cells in prefrontal cortex have, on average, up to 23 times more dendritic spines than those in the primary visual area. I propose that without these specializations in the structure of pyramidal cells, and the circuits they form, human cognitive processing would not have evolved to its present state. I also present data from both New World and Old World monkeys that show varying degrees of complexity in the pyramidal cell phenotype in their prefrontal cortices, suggesting that cortical circuitry and, thus, cognitive styles are evolving independently in different species.

  7. Patterns of axon collateralization of identified supragranular pyramidal neurons in the cat auditory cortex.

    PubMed

    Ojima, H; Honda, C N; Jones, E G

    1991-01-01

    Nine pyramidal neurons in layers II and III of cat primary auditory cortex (AI) were fully reconstructed after intracellular injections of horseradish peroxidase or biocytin. Each neuron was functionally characterized according to its position relative to an anteroposterior sequence of best frequency responses. All labeled somata were in layers II or III and gave rise to typical apical and basal dendritic arbors as well as to extensive systems of axon collaterals. The primary axon of all except 1 cell entered the white matter and was probably directed toward other cortical areas ipsi- or contralaterally. Two major intracortical collateral systems emerged from the main axon in AI, one ending in the vicinity of the cell and the second at a distance. (1) Many local and recurrent collaterals, given off in layers III and V, contributed terminal branches to the formation of a columnar pattern of terminations extending superficially and deeply into the soma. The column extended through layers I-V, with some constriction in the middle portion corresponding to layer IV. (2) The axon of each cell also gave rise to 2-5 thick, long-range collaterals in layers III and/or V. These ran parallel to the pial surface for several millimeters. At several points along these long horizontal collaterals, vertically directed branches emerged to form columnar terminations, again extending through layers I-V. These columns did not overlap with that formed in the vicinity of the cell, and were situated at distances 500-1200 microns from the cell body. When viewed in the tangential plane, horizontal collaterals were oriented, on the whole, dorsoventrally with respect to the surface of the cortex. This may correspond to the organization of isofrequency bands previously described in cats. The results suggest that the major spread of excitation in AI is mediated by horizontal collaterals of pyramidal cells and that it occurs along the lines of isofrequency domains. Within the latter the

  8. Secretory function in subplate neurons during cortical development

    PubMed Central

    Kondo, Shinichi; Al-Hasani, Hannah; Hoerder-Suabedissen, Anna; Wang, Wei Zhi; Molnár, Zoltán

    2015-01-01

    Subplate cells are among the first generated neurons in the mammalian cerebral cortex and have been implicated in the establishment of cortical wiring. In rodents some subplate neurons persist into adulthood. Here we would like to highlight several converging findings which suggest a novel secretory function of subplate neurons during cortical development. Throughout the postnatal period in rodents, subplate neurons have highly developed rough endoplasmic reticulum (ER) and are under an ER stress condition. By comparing gene expression between subplate and layer 6, we found that several genes encoding secreted proteins are highly expressed in subplate neurons. One of these secreted proteins, neuroserpin, encoded by the serpini1 gene, is localized to the ER in subplate cells. We propose that subplate might influence cortical circuit formation through a transient secretory function. PMID:25859180

  9. Cholecystokinin-immunoreactive cells form symmetrical synaptic contacts with pyramidal and nonpyramidal neurons in the hippocampus.

    PubMed

    Nunzi, M G; Gorio, A; Milan, F; Freund, T F; Somogyi, P; Smith, A D

    1985-07-22

    The ultrastructural features and synaptic relationships of cholecystokinin (CCK)-immunoreactive cells of rat and cat hippocampus were studied using the unlabeled antibody immunoperoxidase technique and correlated light and electron microscopy. CCK-positive perikarya of variable shape and size were distributed in all layers and were particularly concentrated in stratum pyramidale and radiatum: the CCK-immunoreactive neurons were nonpyramidal in shape and the three most common types had the morphological features of tufted, bipolar, and multipolar cells. Electron microscopic examination revealed that all the CCK-positive boutons established symmetrical (Gray's type II) synaptic contacts with perikarya and dendrites of pyramidal and nonpyramidal neurons. The origin of some of the boutons was established by tracing fine collaterals that arose from the main axon of two CCK-immunostained cells and terminated in the stratum pyramidale; these collaterals were then examined in the electron microscope. The axon of one such neuron exhibited a course parallel to the pyramidal layer and formed pericellular nets of synaptic boutons upon the perikarya of pyramidal neurons. This pattern of axonal arborization is very similar to that of some of the basket cells, previously suggested to be the anatomical correlate for pyramidal cell inhibition. Typical dendrites of pyramidal cells also received symmetrical synaptic contacts from CCK-immunoreactive boutons, and some of these boutons could be shown to originate from a local neuron in stratum radiatum. Many CCK-immunoreactive cells received CCK-labeled boutons upon their soma and dendritic shafts. Synaptic relationship, established by multiple "en passant" boutons, was observed between CCK-positive interneurons of the stratum lacunosum-moleculare and radiatum. The soma and dendrites of the CCK-immunostained neurons also received symmetrical and asymmetrical synapses from nonimmunoreactive boutons. These results indicate that the CCK

  10. The neocortex of cetartiodactyls. II. Neuronal morphology of the visual and motor cortices in the giraffe (Giraffa camelopardalis).

    PubMed

    Jacobs, Bob; Harland, Tessa; Kennedy, Deborah; Schall, Matthew; Wicinski, Bridget; Butti, Camilla; Hof, Patrick R; Sherwood, Chet C; Manger, Paul R

    2015-09-01

    The present quantitative study extends our investigation of cetartiodactyls by exploring the neuronal morphology in the giraffe (Giraffa camelopardalis) neocortex. Here, we investigate giraffe primary visual and motor cortices from perfusion-fixed brains of three subadults stained with a modified rapid Golgi technique. Neurons (n = 244) were quantified on a computer-assisted microscopy system. Qualitatively, the giraffe neocortex contained an array of complex spiny neurons that included both "typical" pyramidal neuron morphology and "atypical" spiny neurons in terms of morphology and/or orientation. In general, the neocortex exhibited a vertical columnar organization of apical dendrites. Although there was no significant quantitative difference in dendritic complexity for pyramidal neurons between primary visual (n = 78) and motor cortices (n = 65), there was a significant difference in dendritic spine density (motor cortex > visual cortex). The morphology of aspiny neurons in giraffes appeared to be similar to that of other eutherian mammals. For cross-species comparison of neuron morphology, giraffe pyramidal neurons were compared to those quantified with the same methodology in African elephants and some cetaceans (e.g., bottlenose dolphin, minke whale, humpback whale). Across species, the giraffe (and cetaceans) exhibited less widely bifurcating apical dendrites compared to elephants. Quantitative dendritic measures revealed that the elephant and humpback whale had more extensive dendrites than giraffes, whereas the minke whale and bottlenose dolphin had less extensive dendritic arbors. Spine measures were highest in the giraffe, perhaps due to the high quality, perfusion fixation. The neuronal morphology in giraffe neocortex is thus generally consistent with what is known about other cetartiodactyls.

  11. The neocortex of cetartiodactyls. II. Neuronal morphology of the visual and motor cortices in the giraffe (Giraffa camelopardalis).

    PubMed

    Jacobs, Bob; Harland, Tessa; Kennedy, Deborah; Schall, Matthew; Wicinski, Bridget; Butti, Camilla; Hof, Patrick R; Sherwood, Chet C; Manger, Paul R

    2015-09-01

    The present quantitative study extends our investigation of cetartiodactyls by exploring the neuronal morphology in the giraffe (Giraffa camelopardalis) neocortex. Here, we investigate giraffe primary visual and motor cortices from perfusion-fixed brains of three subadults stained with a modified rapid Golgi technique. Neurons (n = 244) were quantified on a computer-assisted microscopy system. Qualitatively, the giraffe neocortex contained an array of complex spiny neurons that included both "typical" pyramidal neuron morphology and "atypical" spiny neurons in terms of morphology and/or orientation. In general, the neocortex exhibited a vertical columnar organization of apical dendrites. Although there was no significant quantitative difference in dendritic complexity for pyramidal neurons between primary visual (n = 78) and motor cortices (n = 65), there was a significant difference in dendritic spine density (motor cortex > visual cortex). The morphology of aspiny neurons in giraffes appeared to be similar to that of other eutherian mammals. For cross-species comparison of neuron morphology, giraffe pyramidal neurons were compared to those quantified with the same methodology in African elephants and some cetaceans (e.g., bottlenose dolphin, minke whale, humpback whale). Across species, the giraffe (and cetaceans) exhibited less widely bifurcating apical dendrites compared to elephants. Quantitative dendritic measures revealed that the elephant and humpback whale had more extensive dendrites than giraffes, whereas the minke whale and bottlenose dolphin had less extensive dendritic arbors. Spine measures were highest in the giraffe, perhaps due to the high quality, perfusion fixation. The neuronal morphology in giraffe neocortex is thus generally consistent with what is known about other cetartiodactyls. PMID:25048683

  12. Anatomy and physiology of the thick-tufted layer 5 pyramidal neuron

    PubMed Central

    Ramaswamy, Srikanth; Markram, Henry

    2015-01-01

    The thick-tufted layer 5 (TTL5) pyramidal neuron is one of the most extensively studied neuron types in the mammalian neocortex and has become a benchmark for understanding information processing in excitatory neurons. By virtue of having the widest local axonal and dendritic arborization, the TTL5 neuron encompasses various local neocortical neurons and thereby defines the dimensions of neocortical microcircuitry. The TTL5 neuron integrates input across all neocortical layers and is the principal output pathway funneling information flow to subcortical structures. Several studies over the past decades have investigated the anatomy, physiology, synaptology, and pathophysiology of the TTL5 neuron. This review summarizes key discoveries and identifies potential avenues of research to facilitate an integrated and unifying understanding on the role of a central neuron in the neocortex. PMID:26167146

  13. Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony.

    PubMed

    Sales-Carbonell, Carola; Rueda-Orozco, Pavel E; Soria-Gómez, Edgar; Buzsáki, György; Marsicano, Giovanni; Robbe, David

    2013-01-01

    Activation of type 1 cannabinoid receptors (CB1R) decreases GABA and glutamate release in cortical and subcortical regions, with complex outcomes on cortical network activity. To date there have been few attempts to disentangle the region- and cell-specific mechanisms underlying the effects of cannabinoids on cortical network activity in vivo. Here we addressed this issue by combining in vivo electrophysiological recordings with local and systemic pharmacological manipulations in conditional mutant mice lacking CB1R expression in different neuronal populations. First we report that cannabinoids induce hypersynchronous thalamocortical oscillations while decreasing the amplitude of faster cortical oscillations. Then we demonstrate that CB1R at striatonigral synapses (basal ganglia direct pathway) mediate the thalamocortical hypersynchrony, whereas activation of CB1R expressed in cortical glutamatergic neurons decreases cortical synchrony. Finally we show that activation of CB1 expressed in cortical glutamatergic neurons limits the cannabinoid-induced thalamocortical hypersynchrony. By reporting that CB1R activations in cortical and subcortical regions have contrasting effects on cortical synchrony, our study bridges the gap between cellular and in vivo network effects of cannabinoids. Incidentally, the thalamocortical hypersynchrony we report suggests a potential mechanism to explain the sensory "high" experienced during recreational consumption of marijuana.

  14. Striatal GABAergic and cortical glutamatergic neurons mediate contrasting effects of cannabinoids on cortical network synchrony

    PubMed Central

    Sales-Carbonell, Carola; Rueda-Orozco, Pavel E.; Soria-Gómez, Edgar; Buzsáki, György; Marsicano, Giovanni; Robbe, David

    2013-01-01

    Activation of type 1 cannabinoid receptors (CB1R) decreases GABA and glutamate release in cortical and subcortical regions, with complex outcomes on cortical network activity. To date there have been few attempts to disentangle the region- and cell-specific mechanisms underlying the effects of cannabinoids on cortical network activity in vivo. Here we addressed this issue by combining in vivo electrophysiological recordings with local and systemic pharmacological manipulations in conditional mutant mice lacking CB1R expression in different neuronal populations. First we report that cannabinoids induce hypersynchronous thalamocortical oscillations while decreasing the amplitude of faster cortical oscillations. Then we demonstrate that CB1R at striatonigral synapses (basal ganglia direct pathway) mediate the thalamocortical hypersynchrony, whereas activation of CB1R expressed in cortical glutamatergic neurons decreases cortical synchrony. Finally we show that activation of CB1 expressed in cortical glutamatergic neurons limits the cannabinoid-induced thalamocortical hypersynchrony. By reporting that CB1R activations in cortical and subcortical regions have contrasting effects on cortical synchrony, our study bridges the gap between cellular and in vivo network effects of cannabinoids. Incidentally, the thalamocortical hypersynchrony we report suggests a potential mechanism to explain the sensory “high” experienced during recreational consumption of marijuana. PMID:23269835

  15. Genetically Dissecting Cortical Neurons Involved in Epilepsy in Angelman Syndrome.

    PubMed

    Santini, Emanuela; Klann, Eric

    2016-04-01

    Epilepsy in Angelman Syndrome is thought to originate from an imbalance between local excitatory-inhibitory circuits that results in a generalized hyperexcitability. In this issue of Neuron, Judson et al. (2016) demonstrate that selective maternal deletion of Ube3a in cortical GABAergic neurons causes circuit hyperexcitability, increased seizure severity, and EEG abnormalities. PMID:27054611

  16. Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias.

    PubMed

    Foster, Vincent; Oakley, Arthur E; Slade, Janet Y; Hall, Roslyn; Polvikoski, Tuomo M; Burke, Matthew; Thomas, Alan J; Khundakar, Ahmad; Allan, Louise M; Kalaria, Raj N

    2014-09-01

    Dementia associated with cerebrovascular disease is common. It has been reported that ∼30% of elderly patients who survive stroke develop delayed dementia (post-stroke dementia), with most cases being diagnosed as vascular dementia. The pathological substrates associated with post-stroke or vascular dementia are poorly understood, particularly those associated with executive dysfunction. Three separate yet interconnecting circuits control executive function within the frontal lobe involving the dorsolateral prefrontal cortex, anterior cingulate cortex and the orbitofrontal cortex. We used stereological methods, along with immunohistological and related cell morphometric analysis, to examine densities and volumes of pyramidal neurons of the dorsolateral prefrontal cortex, anterior cingulate cortex and orbitofrontal cortex in the frontal lobe from a total of 90 elderly subjects (age range 71-98 years). Post-mortem brain tissues from post-stroke dementia and post-stroke patients with no dementia were derived from our prospective Cognitive Function After Stroke study. We also examined, in parallel, samples from ageing controls and similar age subjects pathologically diagnosed with Alzheimer's disease, mixed Alzheimer's disease and vascular dementia, and vascular dementia. We found pyramidal cell volumes in layers III and V in the dorsolateral prefrontal cortex of post-stroke and vascular dementia and, of mixed and Alzheimer's disease subjects to be reduced by 30-40% compared to post-stroke patients with no dementia and controls. There were no significant changes in neuronal volumes in either the anterior cingulate or orbitofrontal cortices. Remarkably, pyramidal neurons within the orbitofrontal cortex were also found to be smaller in size when compared to those in the other two neocortical regions. To relate the cell changes to cognitive function, we noted significant correlations between neuronal volumes and total CAMCOG, orientation and memory scores and clinical

  17. Suppressive Effects of Resveratrol Treatment on The Intrinsic Evoked Excitability of CA1 Pyramidal Neurons

    PubMed Central

    Meftahi, Gholamhossein; Ghotbedin, Zohreh; Eslamizade, Mohammad Javad; Hosseinmardi, Narges; Janahmadi, Mahyar

    2015-01-01

    Objective Resveratrol, a phytoalexin, has a wide range of desirable biological actions. Despite a growing body of evidence indicating that resveratrol induces changes in neu- ronal function, little effort, if any, has been made to investigate the cellular effect of res- veratrol treatment on intrinsic neuronal properties. Materials and Methods This experimental study was performed to examine the acute effects of resveratrol (100 µM) on the intrinsic evoked responses of rat Cornu Ammonis (CA1) pyramidal neurons in brain slices, using whole cell patch clamp re- cording under current clamp conditions. Results Findings showed that resveratrol treatment caused dramatic changes in evoked responses of pyramidal neurons. Its treatment induced a significant (P<0.05) increase in the after hyperpolarization amplitude of the first evoked action potential. Resveratrol-treated cells displayed a significantly broader action potential (AP) when compared with either control or vehicle-treated groups. In addition, the mean instantaneous firing frequency between the first two action potentials was significantly lower in resveratrol-treated neurons. It also caused a significant reduction in the time to maximum decay of AP. The rheobase current and the utilization time were both significantly greater following resveratrol treatment. Neurons exhibited a significantly depolarized voltage threshold when exposed to resveratrol. Conclusion Results provide direct electrophysiological evidence for the inhibitory effects of resveratrol on pyramidal neurons, at least in part, by reducing the evoked neural activity. PMID:26464825

  18. Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons.

    PubMed

    Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas

    2016-01-01

    There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven't been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries. PMID:27052791

  19. Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons

    NASA Astrophysics Data System (ADS)

    Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas

    2016-04-01

    There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven’t been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries.

  20. Effects of Morphology Constraint on Electrophysiological Properties of Cortical Neurons

    PubMed Central

    Zhu, Geng; Du, Liping; Jin, Lei; Offenhäusser, Andreas

    2016-01-01

    There is growing interest in engineering nerve cells in vitro to control architecture and connectivity of cultured neuronal networks or to build neuronal networks with predictable computational function. Pattern technologies, such as micro-contact printing, have been developed to design ordered neuronal networks. However, electrophysiological characteristics of the single patterned neuron haven’t been reported. Here, micro-contact printing, using polyolefine polymer (POP) stamps with high resolution, was employed to grow cortical neurons in a designed structure. The results demonstrated that the morphology of patterned neurons was well constrained, and the number of dendrites was decreased to be about 2. Our electrophysiological results showed that alterations of dendritic morphology affected firing patterns of neurons and neural excitability. When stimulated by current, though both patterned and un-patterned neurons presented regular spiking, the dynamics and strength of the response were different. The un-patterned neurons exhibited a monotonically increasing firing frequency in response to injected current, while the patterned neurons first exhibited frequency increase and then a slow decrease. Our findings indicate that the decrease in dendritic complexity of cortical neurons will influence their electrophysiological characteristics and alter their information processing activity, which could be considered when designing neuronal circuitries. PMID:27052791

  1. How cesium dialysis affects the passive properties of pyramidal neurons: implications for voltage clamp studies of persistent sodium current

    NASA Astrophysics Data System (ADS)

    Fleidervish, Ilya A.; Libman, Lior

    2008-03-01

    In order to accurately understand and model neuronal integration in the brain, we must know the biophysical properties of channels that are located far from the soma, in the axonal and dendritic membranes of central nerve cells. Reliable electrophysiological measurements in these regions are difficult to obtain, because the processes are too tiny to directly study with an electrode. One common strategy is to record with a somatic electrode that contains Cs+, to dialyze the intracellular space with this K+ channel blocker, and thereby to render the neuron electrotonically compact. Does this work? Here, we combine the experimental and modeling techniques to determine the extent to which a whole-cell voltage clamp, established with a Cs+-containing pipette in the soma of a cortical pyramidal cell, attains adequate voltage control of distal neuronal processes. We focus on the low-voltage-activated, slowly inactivating 'persistent' Na+ current (INaP), that plays a crucial role in determining neuronal excitability and synaptic integration.

  2. Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations

    PubMed Central

    Kim, Tae; Thankachan, Stephen; McKenna, James T.; McNally, James M.; Yang, Chun; Choi, Jee Hyun; Chen, Lichao; Kocsis, Bernat; Deisseroth, Karl; Strecker, Robert E.; Basheer, Radhika; McCarley, Robert W.

    2015-01-01

    Cortical gamma band oscillations (GBO, 30–80 Hz, typically ∼40 Hz) are involved in higher cognitive functions such as feature binding, attention, and working memory. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). GBO vary according to the state of arousal, are modulated by attention, and are correlated with conscious awareness. However, the subcortical cell types underlying the state-dependent control of GBO are not well understood. Here we tested the role of one cell type in the wakefulness-promoting basal forebrain (BF) region, cortically projecting GABAergic neurons containing PV, whose virally transduced fibers we found apposed cortical PV interneurons involved in generating GBO. Optogenetic stimulation of BF PV neurons in mice preferentially increased cortical GBO power by entraining a cortical oscillator with a resonant frequency of ∼40 Hz, as revealed by analysis of both rhythmic and nonrhythmic BF PV stimulation. Selective saporin lesions of BF cholinergic neurons did not alter the enhancement of cortical GBO power induced by BF PV stimulation. Importantly, bilateral optogenetic inhibition of BF PV neurons decreased the power of the 40-Hz auditory steady-state response, a read-out of the ability of the cortex to generate GBO used in clinical studies. Our results are surprising and novel in indicating that this presumptively inhibitory BF PV input controls cortical GBO, likely by synchronizing the activity of cortical PV interneurons. BF PV neurons may represent a previously unidentified therapeutic target to treat disorders involving abnormal GBO, such as schizophrenia. PMID:25733878

  3. An In Silico Agent-Based Model Demonstrates Reelin Function in Directing Lamination of Neurons during Cortical Development

    PubMed Central

    Caffrey, James R.; Hughes, Barry D.; Britto, Joanne M.; Landman, Kerry A.

    2014-01-01

    The characteristic six-layered appearance of the neocortex arises from the correct positioning of pyramidal neurons during development and alterations in this process can cause intellectual disabilities and developmental delay. Malformations in cortical development arise when neurons either fail to migrate properly from the germinal zones or fail to cease migration in the correct laminar position within the cortical plate. The Reelin signalling pathway is vital for correct neuronal positioning as loss of Reelin leads to a partially inverted cortex. The precise biological function of Reelin remains controversial and debate surrounds its role as a chemoattractant or stop signal for migrating neurons. To investigate this further we developed an in silico agent-based model of cortical layer formation. Using this model we tested four biologically plausible hypotheses for neuron motility and four biologically plausible hypotheses for the loss of neuron motility (conversion from migration). A matrix of 16 combinations of motility and conversion rules was applied against the known structure of mouse cortical layers in the wild-type cortex, the Reelin-null mutant, the Dab1-null mutant and a conditional Dab1 mutant. Using this approach, many combinations of motility and conversion mechanisms can be rejected. For example, the model does not support Reelin acting as a repelling or as a stopping signal. In contrast, the study lends very strong support to the notion that the glycoprotein Reelin acts as a chemoattractant for neurons. Furthermore, the most viable proposition for the conversion mechanism is one in which conversion is affected by a motile neuron sensing in the near vicinity neurons that have already converted. Therefore, this model helps elucidate the function of Reelin during neuronal migration and cortical development. PMID:25334023

  4. Pyramidal tract neurons receptive to different forelimb joints act differently during locomotion

    PubMed Central

    Stout, Erik E.

    2012-01-01

    During locomotion, motor cortical neurons projecting to the pyramidal tract (PTNs) discharge in close relation to strides. How their discharges vary based on the part of the body they influence is not well understood. We addressed this question with regard to joints of the forelimb in the cat. During simple and ladder locomotion, we compared the activity of four groups of PTNs with somatosensory receptive fields involving different forelimb joints: 1) 45 PTNs receptive to movements of shoulder, 2) 30 PTNs receptive to movements of elbow, 3) 40 PTNs receptive to movements of wrist, and 4) 30 nonresponsive PTNs. In the motor cortex, a relationship exists between the location of the source of afferent input and the target for motor output. On the basis of this relationship, we inferred the forelimb joint that a PTN influences from its somatosensory receptive field. We found that different PTNs tended to discharge differently during locomotion. During simple locomotion shoulder-related PTNs were most active during late stance/early swing, and upon transition from simple to ladder locomotion they often increased activity and stride-related modulation while reducing discharge duration. Elbow-related PTNs were most active during late swing/early stance and typically did not change activity, modulation, or discharge duration on the ladder. Wrist-related PTNs were most active during swing and upon transition to the ladder often decreased activity and increased modulation while reducing discharge duration. These data suggest that during locomotion the motor cortex uses distinct mechanisms to control the shoulder, elbow, and wrist. PMID:22236716

  5. Activity of pyramidal tract neurons in the cat during standing and walking on an inclined plane.

    PubMed

    Karayannidou, A; Beloozerova, I N; Zelenin, P V; Stout, E E; Sirota, M G; Orlovsky, G N; Deliagina, T G

    2009-08-01

    To keep balance when standing or walking on a surface inclined in the roll plane, the cat modifies its body configuration so that the functional length of its right and left limbs becomes different. The aim of the present study was to assess the motor cortex participation in the generation of this left/right asymmetry. We recorded the activity of fore- and hindlimb-related pyramidal tract neurons (PTNs) during standing and walking on a treadmill. A difference in PTN activity at two tilted positions of the treadmill (+/- 15 deg) was considered a positional response to surface inclination. During standing, 47% of PTNs exhibited a positional response, increasing their activity with either the contra-tilt (20%) or the ipsi-tilt (27%). During walking, PTNs were modulated in the rhythm of stepping, and tilts of the supporting surface evoked positional responses in the form of changes to the magnitude of modulation in 58% of PTNs. The contra-tilt increased activity in 28% of PTNs, and ipsi-tilt increased activity in 30% of PTNs. We suggest that PTNs with positional responses contribute to the modifications of limb configuration that are necessary for adaptation to the inclined surface. By comparing the responses to tilts in individual PTNs during standing and walking, four groups of PTNs were revealed: responding in both tasks (30%); responding only during standing (16%); responding only during walking (30%); responding in none of the tasks (24%). This diversity suggests that common and separate cortical mechanisms are used for postural adaptation to tilts during standing and walking.

  6. Dendritic integration in pyramidal neurons during network activity and disease.

    PubMed

    Palmer, Lucy M

    2014-04-01

    Neurons have intricate dendritic morphologies which come in an array of shapes and sizes. Not only do they give neurons their unique appearance, but dendrites also endow neurons with the ability to receive and transform synaptic inputs. We now have a wealth of information about the functioning of dendrites which suggests that the integration of synaptic inputs is highly dependent on both dendritic properties and neuronal input patterns. It has been shown that dendrites can perform non-linear processing, actively transforming synaptic input into Na(+) spikes, Ca(2+) plateau spikes and NMDA spikes. These membrane non-linearities can have a large impact on the neuronal output and have been shown to be regulated by numerous factors including synaptic inhibition. Many neuropathological diseases involve changes in how dendrites receive and package synaptic input by altering dendritic spine characteristics, ion channel expression and the inhibitory control of dendrites. This review focuses on the role of dendrites in integrating and transforming input and what goes wrong in the case of neuropathological diseases.

  7. A Distinct Class of Slow (∼0.2–2 Hz) Intrinsically Bursting Layer 5 Pyramidal Neurons Determines UP/DOWN State Dynamics in the Neocortex

    PubMed Central

    Gunner, David; Bao, Ying; Connelly, William M.; Isaac, John T.R.; Hughes, Stuart W.; Crunelli, Vincenzo

    2015-01-01

    During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at ∼0.2–2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca2+ medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states. PMID:25855163

  8. Kv2 subunits underlie slowly inactivating potassium current in rat neocortical pyramidal neurons.

    PubMed

    Guan, D; Tkatch, T; Surmeier, D J; Armstrong, W E; Foehring, R C

    2007-06-15

    We determined the expression of Kv2 channel subunits in rat somatosensory and motor cortex and tested for the contributions of Kv2 subunits to slowly inactivating K+ currents in supragranular pyramidal neurons. Single cell RT-PCR showed that virtually all pyramidal cells expressed Kv2.1 mRNA and approximately 80% expressed Kv2.2 mRNA. Immunocytochemistry revealed striking differences in the distribution of Kv2.1 and Kv2.2 subunits. Kv2.1 subunits were clustered and located on somata and proximal dendrites of all pyramidal cells. Kv2.2 subunits were primarily distributed on large apical dendrites of a subset of pyramidal cells from deep layers. We used two methods for isolating currents through Kv2 channels after excluding contributions from Kv1 subunits: intracellular diffusion of Kv2.1 antibodies through the recording pipette and extracellular application of rStromatoxin-1 (ScTx). The Kv2.1 antibody specifically blocked the slowly inactivating K+ current by 25-50% (at 8 min), demonstrating that Kv2.1 subunits underlie much of this current in neocortical pyramidal neurons. ScTx (300 nM) also inhibited approximately 40% of the slowly inactivating K+ current. We observed occlusion between the actions of Kv2.1 antibody and ScTx. In addition, Kv2.1 antibody- and ScTx-sensitive currents demonstrated similar recovery from inactivation and voltage dependence and kinetics of activation and inactivation. These data indicate that both agents targeted the same channels. Considering the localization of Kv2.1 and 2.2 subunits, currents from truncated dissociated cells are probably dominated by Kv2.1 subunits. Compared with Kv2.1 currents in expression systems, the Kv2.1 current in neocortical pyramidal cells activated and inactivated at relatively negative potentials and was very sensitive to holding potential.

  9. Active summation of excitatory postsynaptic potentials in hippocampal CA3 pyramidal neurons

    PubMed Central

    Urban, Nathaniel N.; Barrionuevo, German

    1998-01-01

    The manner in which the thousands of synaptic inputs received by a pyramidal neuron are summed is critical both to our understanding of the computations that may be performed by single neurons and of the codes used by neurons to transmit information. Recent work on pyramidal cell dendrites has shown that subthreshold synaptic inputs are modulated by voltage-dependent channels, raising the possibility that summation of synaptic responses is influenced by the active properties of dendrites. Here, we use somatic and dendritic whole-cell recordings to show that pyramidal cells in hippocampal area CA3 sum distal and proximal excitatory postsynaptic potentials sublinearly and actively, that the degree of nonlinearity depends on the magnitude and timing of the excitatory postsynaptic potentials, and that blockade of transient potassium channels linearizes summation. Nonlinear summation of synaptic inputs could have important implications for the computations performed by single neurons and also for the role of the mossy fiber and perforant path inputs to hippocampal area CA3. PMID:9736757

  10. Tachykinins and bombesin excite non-pyramidal neurones in rat hippocampus.

    PubMed Central

    Dreifuss, J J; Raggenbass, M

    1986-01-01

    The effects of substance P, eledoisin and physalaemin--which are structurally similar and all belong to the tachykinin family--and of bombesin, a gastrin-releasing peptide, on non-pyramidal neurones were studied using unitary extracellular recordings from rat hippocampal slices. The peptides were added to the perifusion solution, or locally applied by pressure ejection from a micropipette, at concentrations ranging from 10(-8) to 10(-6) M. 104 out of 115 non-pyramidal neurones responded to tachykinins, and 26 out of 27 responded to bombesin, by a reversible, concentration-dependent increase in firing. The responsive neurones retained their sensitivity to the tachykinins and to bombesin under the condition of synaptic blockade. A synthetic peptide known to antagonize the effects of oxytocin on hippocampal non-pyramidal neurones did not affect the excitations induced by the tachykinins or bombesin. The action of the tachykinins was not blocked by the muscarinic antagonist, atropine. These results indicate that hippocampal non-pyramidal neurones--which were previously shown to possess oxytocin receptors and mu-type opiate receptors--bear receptors for peptides of the tachykinin and of the gastrin-releasing families. The hippocampal effects of tachykinins and of bombesin, however, were not blocked by synthetic structural analogues of substance P, known to antagonize the action of these peptides on some non-nervous tissues. The possibility must be considered that brain receptors for tachykinins and for gastrin-releasing peptides may be distinct from the peripheral receptors for these peptides. PMID:2435894

  11. Magnetic Tunnel Junction Mimics Stochastic Cortical Spiking Neurons

    NASA Astrophysics Data System (ADS)

    Sengupta, Abhronil; Panda, Priyadarshini; Wijesinghe, Parami; Kim, Yusung; Roy, Kaushik

    2016-07-01

    Brain-inspired computing architectures attempt to mimic the computations performed in the neurons and the synapses in the human brain in order to achieve its efficiency in learning and cognitive tasks. In this work, we demonstrate the mapping of the probabilistic spiking nature of pyramidal neurons in the cortex to the stochastic switching behavior of a Magnetic Tunnel Junction in presence of thermal noise. We present results to illustrate the efficiency of neuromorphic systems based on such probabilistic neurons for pattern recognition tasks in presence of lateral inhibition and homeostasis. Such stochastic MTJ neurons can also potentially provide a direct mapping to the probabilistic computing elements in Belief Networks for performing regenerative tasks.

  12. Magnetic Tunnel Junction Mimics Stochastic Cortical Spiking Neurons

    PubMed Central

    Sengupta, Abhronil; Panda, Priyadarshini; Wijesinghe, Parami; Kim, Yusung; Roy, Kaushik

    2016-01-01

    Brain-inspired computing architectures attempt to mimic the computations performed in the neurons and the synapses in the human brain in order to achieve its efficiency in learning and cognitive tasks. In this work, we demonstrate the mapping of the probabilistic spiking nature of pyramidal neurons in the cortex to the stochastic switching behavior of a Magnetic Tunnel Junction in presence of thermal noise. We present results to illustrate the efficiency of neuromorphic systems based on such probabilistic neurons for pattern recognition tasks in presence of lateral inhibition and homeostasis. Such stochastic MTJ neurons can also potentially provide a direct mapping to the probabilistic computing elements in Belief Networks for performing regenerative tasks. PMID:27443913

  13. Magnetic Tunnel Junction Mimics Stochastic Cortical Spiking Neurons.

    PubMed

    Sengupta, Abhronil; Panda, Priyadarshini; Wijesinghe, Parami; Kim, Yusung; Roy, Kaushik

    2016-01-01

    Brain-inspired computing architectures attempt to mimic the computations performed in the neurons and the synapses in the human brain in order to achieve its efficiency in learning and cognitive tasks. In this work, we demonstrate the mapping of the probabilistic spiking nature of pyramidal neurons in the cortex to the stochastic switching behavior of a Magnetic Tunnel Junction in presence of thermal noise. We present results to illustrate the efficiency of neuromorphic systems based on such probabilistic neurons for pattern recognition tasks in presence of lateral inhibition and homeostasis. Such stochastic MTJ neurons can also potentially provide a direct mapping to the probabilistic computing elements in Belief Networks for performing regenerative tasks. PMID:27443913

  14. Peripheral Neuropathy Induces HCN Channel Dysfunction in Pyramidal Neurons of the Medial Prefrontal Cortex.

    PubMed

    Cordeiro Matos, Steven; Zhang, Zizhen; Séguéla, Philippe

    2015-09-23

    Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its molecular basis. The cationic current Ih mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays an important role in pain by facilitating ectopic firing and hyperexcitability in DRG neurons, however little is known regarding the role of Ih in supraspinal pain pathways. The medial prefrontal cortex (mPFC), which is reported to be involved in the affective aspects of pain, exhibits high HCN channel expression. Using the spared nerve injury (SNI) model of neuropathic pain in Long-Evans rats and patch-clamp recordings in layer II/III pyramidal neurons of the contralateral mPFC, we observed a hyperpolarizing shift in the voltage-dependent activation of Ih in SNI neurons, whereas maximal Ih remained unchanged. Accordingly, SNI mPFC pyramidal neurons exhibited increased input resistance and excitability, as well as facilitated glutamatergic mGluR5-mediated persistent firing, compared with sham neurons. Moreover, intracellular application of bromo-cAMP abolished the hyperpolarizing shift in the voltage-dependent activation of Ih observed in SNI neurons, whereas protein kinase A (PKA) inhibition further promoted this shift in both SNI and sham neurons. Behaviorally, acute HCN channel blockade by local injection of ZD7288 in the mPFC of SNI rats induced a decrease in cold allodynia. These findings suggest that changes in the cAMP/PKA axis in mPFC neurons underlie alterations to HCN channel function, which can influence descending inhibition of pain pathways in neuropathic conditions. Significance statement: Recent studies investigating the role of the medial prefrontal cortex (mPFC) in neuropathic pain have led to an increased awareness of how affective and cognitive factors can influence pain perception. It is therefore imperative that we advance our understanding of the involvement of supraspinal

  15. Early phenotype expression of cortical neurons: evidence that a subclass of migrating neurons have callosal axons.

    PubMed Central

    Schwartz, M L; Rakic, P; Goldman-Rakic, P S

    1991-01-01

    The use of [3H]thymidine labeling in combination with various axonal transport tracers has revealed that a subset of migrating neurons in the fetal monkey cerebrum issue axons to the opposite cerebral hemisphere while still migrating to their final positions in the cortical plate. Other cortical neurons with the same "birthdate" (i.e., that underwent their last round of DNA synthesis on the same day) are not retrogradely labeled by tracer injections of the opposite hemisphere. These findings suggest that the cardinal distinction between projection and local circuit neurons may be specified in postmitotic neurons before they acquire their final positions in the cortex. Images PMID:1705036

  16. Early phenotype expression of cortical neurons: Evidence that a subclass of migrating neurons have callosal axons

    SciTech Connect

    Schwartz, M.L.; Rakic, P.; Goldman-Rakic, P.S. )

    1991-02-15

    The use of ({sup 3}H)thymidine labeling in combination with various axonal transport tracers has revealed that a subset of migrating neurons in the fetal monkey cerebrum issue axons to the opposite cerebral hemisphere while still migrating to their final positions in the cortical plate. Other cortical neurons with the same birthdate (i.e., that underwent their last round of DNA synthesis on the same day) are not retrogradely labeled by tracer injections of the opposite hemisphere. These findings suggest that the cardinal distinction between projection and local circuit neurons may be specified in postmitotic neurons before they acquire their final positions in the cortex.

  17. Distinct profiles of myelin distribution along single axons of pyramidal neurons in the neocortex.

    PubMed

    Tomassy, Giulio Srubek; Berger, Daniel R; Chen, Hsu-Hsin; Kasthuri, Narayanan; Hayworth, Kenneth J; Vercelli, Alessandro; Seung, H Sebastian; Lichtman, Jeff W; Arlotta, Paola

    2014-04-18

    Myelin is a defining feature of the vertebrate nervous system. Variability in the thickness of the myelin envelope is a structural feature affecting the conduction of neuronal signals. Conversely, the distribution of myelinated tracts along the length of axons has been assumed to be uniform. Here, we traced high-throughput electron microscopy reconstructions of single axons of pyramidal neurons in the mouse neocortex and built high-resolution maps of myelination. We find that individual neurons have distinct longitudinal distribution of myelin. Neurons in the superficial layers displayed the most diversified profiles, including a new pattern where myelinated segments are interspersed with long, unmyelinated tracts. Our data indicate that the profile of longitudinal distribution of myelin is an integral feature of neuronal identity and may have evolved as a strategy to modulate long-distance communication in the neocortex.

  18. Preferential localization of muscarinic M1 receptor on dendritic shaft and spine of cortical pyramidal cells and its anatomical evidence for volume transmission.

    PubMed

    Yamasaki, Miwako; Matsui, Minoru; Watanabe, Masahiko

    2010-03-24

    Acetylcholine (ACh) plays important roles for higher brain functions, including arousal, attention, and cognition. These effects are mediated largely by muscarinic acetylcholine receptors (mAChRs). However, it remains inconclusive whether the mode of ACh-mAChR signaling is synaptic, so-called "wired," transmission mediated by ACh released into the synaptic cleft, or nonsynaptic, so-called "volume," transmission by ambient ACh. To address this issue, we examined cellular and subcellular distribution of M(1), the most predominant mAChR subtype in the cerebral cortex and hippocampus, and pursued its anatomical relationship with cholinergic varicosities in these regions of adult mice. M(1) was highly expressed in glutamatergic pyramidal neurons, whereas it was low or undetectable in various GABAergic interneuron subtypes. M(1) was preferentially distributed on the extrasynaptic membrane of pyramidal cell dendrites and spines. Cholinergic varicosities often made direct contact to pyramidal cell dendrites and synapses. At such contact sites, however, synapse-like specialization was infrequent, and no particular accumulation was found at around contact sites for both M(1) and presynpatic active zone protein Bassoon. These features contrasted with those of the glutamatergic system, in which AMPA receptor GluA2 and metabotropic receptor mGluR5 were recruited to the synaptic or perisynaptic membrane, respectively, and Bassoon was highly accumulated in the presynaptic terminals. These results suggest that M(1) is so positioned to sense ambient ACh released from cholinergic varicosities at variable distances, and to enhance the synaptic efficacy and excitability of pyramidal cells. These molecular-anatomical arrangements will provide the evidence for volume transmission, at least in M(1)-mediated cortical cholinergic signaling.

  19. De novo expression of neurokinin-1 receptors by spinoparabrachial lamina I pyramidal neurons following a peripheral nerve lesion.

    PubMed

    Saeed, Abeer W; Ribeiro-da-Silva, Alfredo

    2013-06-01

    Lamina I of the spinal dorsal horn is a major site of integration and transmission to higher centers of nociceptive information from the periphery. One important primary afferent population that transmits such information to the spinal cord expresses substance P (SP). These fibers terminate in contact with lamina I projection neurons that express the SP receptor, also known as the neurokinin-1 receptor (NK-1r). Three types of lamina I projection neurons have been described: multipolar, fusiform, and pyramidal. Most neurons of the first two types are thought to be nociceptive and express the NK-1r, whereas most pyramidal neurons are nonnociceptive and do not express the NK-1r. In this immunocytochemical and behavioral study, we induced a neuropathic pain-like condition in the rat by means of a polyethylene cuff placed around in the sciatic nerve. We document that this lesion led to a de novo expression of NK-1r on pyramidal neurons as well as a significant increase in SP-immunoreactive innervation onto these neurons. These phenotypic changes were evident at the time of onset of neuropathic pain-related behavior. Additionally, we show that, after a noxious stimulus (intradermal capsaicin injection), these NK-1r on pyramidal neurons were internalized, providing evidence that these neurons become responsive to peripheral noxious stimulation. We suggest that the changes following nerve lesion in the phenotype and innervation pattern of pyramidal neurons are of significance for neuropathic pain and/or limb temperature regulation.

  20. Cortical cell and neuron density estimates in one chimpanzee hemisphere.

    PubMed

    Collins, Christine E; Turner, Emily C; Sawyer, Eva Kille; Reed, Jamie L; Young, Nicole A; Flaherty, David K; Kaas, Jon H

    2016-01-19

    The density of cells and neurons in the neocortex of many mammals varies across cortical areas and regions. This variability is, perhaps, most pronounced in primates. Nonuniformity in the composition of cortex suggests regions of the cortex have different specializations. Specifically, regions with densely packed neurons contain smaller neurons that are activated by relatively few inputs, thereby preserving information, whereas regions that are less densely packed have larger neurons that have more integrative functions. Here we present the numbers of cells and neurons for 742 discrete locations across the neocortex in a chimpanzee. Using isotropic fractionation and flow fractionation methods for cell and neuron counts, we estimate that neocortex of one hemisphere contains 9.5 billion cells and 3.7 billion neurons. Primary visual cortex occupies 35 cm(2) of surface, 10% of the total, and contains 737 million densely packed neurons, 20% of the total neurons contained within the hemisphere. Other areas of high neuron packing include secondary visual areas, somatosensory cortex, and prefrontal granular cortex. Areas of low levels of neuron packing density include motor and premotor cortex. These values reflect those obtained from more limited samples of cortex in humans and other primates. PMID:26729880

  1. Cortical cell and neuron density estimates in one chimpanzee hemisphere.

    PubMed

    Collins, Christine E; Turner, Emily C; Sawyer, Eva Kille; Reed, Jamie L; Young, Nicole A; Flaherty, David K; Kaas, Jon H

    2016-01-19

    The density of cells and neurons in the neocortex of many mammals varies across cortical areas and regions. This variability is, perhaps, most pronounced in primates. Nonuniformity in the composition of cortex suggests regions of the cortex have different specializations. Specifically, regions with densely packed neurons contain smaller neurons that are activated by relatively few inputs, thereby preserving information, whereas regions that are less densely packed have larger neurons that have more integrative functions. Here we present the numbers of cells and neurons for 742 discrete locations across the neocortex in a chimpanzee. Using isotropic fractionation and flow fractionation methods for cell and neuron counts, we estimate that neocortex of one hemisphere contains 9.5 billion cells and 3.7 billion neurons. Primary visual cortex occupies 35 cm(2) of surface, 10% of the total, and contains 737 million densely packed neurons, 20% of the total neurons contained within the hemisphere. Other areas of high neuron packing include secondary visual areas, somatosensory cortex, and prefrontal granular cortex. Areas of low levels of neuron packing density include motor and premotor cortex. These values reflect those obtained from more limited samples of cortex in humans and other primates.

  2. Retinoic acid from the meninges regulates cortical neuron generation.

    PubMed

    Siegenthaler, Julie A; Ashique, Amir M; Zarbalis, Konstantinos; Patterson, Katelin P; Hecht, Jonathan H; Kane, Maureen A; Folias, Alexandra E; Choe, Youngshik; May, Scott R; Kume, Tsutomu; Napoli, Joseph L; Peterson, Andrew S; Pleasure, Samuel J

    2009-10-30

    Extrinsic signals controlling generation of neocortical neurons during embryonic life have been difficult to identify. In this study we demonstrate that the dorsal forebrain meninges communicate with the adjacent radial glial endfeet and influence cortical development. We took advantage of Foxc1 mutant mice with defects in forebrain meningeal formation. Foxc1 dosage and loss of meninges correlated with a dramatic reduction in both neuron and intermediate progenitor production and elongation of the neuroepithelium. Several types of experiments demonstrate that retinoic acid (RA) is the key component of this secreted activity. In addition, Rdh10- and Raldh2-expressing cells in the dorsal meninges were either reduced or absent in the Foxc1 mutants, and Rdh10 mutants had a cortical phenotype similar to the Foxc1 null mutants. Lastly, in utero RA treatment rescued the cortical phenotype in Foxc1 mutants. These results establish RA as a potent, meningeal-derived cue required for successful corticogenesis.

  3. Stress-induced remodeling of hippocampal CA3 pyramidal neurons.

    PubMed

    McEwen, Bruce S

    2016-08-15

    The discovery of steroid hormone receptors in brain regions that mediate virtually every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as determining the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neurogenesis leading to neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. The two Brain Research papers noted in this review played an important role in triggering these advances. This article is part of a Special Issue entitled SI:50th Anniversary Issue. PMID:26740399

  4. Potential Synaptic Connectivity of Different Neurons onto Pyramidal Cells in a 3D Reconstruction of the Rat Hippocampus

    PubMed Central

    Ropireddy, Deepak; Ascoli, Giorgio A.

    2011-01-01

    Most existing connectomic data and ongoing efforts focus either on individual synapses (e.g., with electron microscopy) or on regional connectivity (tract tracing). An individual pyramidal cell (PC) extends thousands of synapses over macroscopic distances (∼cm). The contrasting requirements of high-resolution and large field of view make it too challenging to acquire the entire synaptic connectivity for even a single typical cortical neuron. Light microscopy can image whole neuronal arbors and resolve dendritic branches. Analyzing connectivity in terms of close spatial appositions between axons and dendrites could thus bridge the opposite scales, from synaptic level to whole systems. In the mammalian cortex, structural plasticity of spines and boutons makes these “potential synapses” functionally relevant to learning capability and memory capacity. To date, however, potential synapses have only been mapped in the surrounding of a neuron and relative to its local orientation rather than in a system-level anatomical reference. Here we overcome this limitation by estimating the potential connectivity of different neurons embedded into a detailed 3D reconstruction of the rat hippocampus. Axonal and dendritic trees were oriented with respect to hippocampal cytoarchitecture according to longitudinal and transversal curvatures. We report the potential connectivity onto PC dendrites from the axons of a dentate granule cell, three CA3 PCs, one CA2 PC, and 13 CA3b interneurons. The numbers, densities, and distributions of potential synapses were analyzed in each sub-region (e.g., CA3 vs. CA1), layer (e.g., oriens vs. radiatum), and septo-temporal location (e.g., dorsal vs. ventral). The overall ratio between the numbers of actual and potential synapses was ∼0.20 for the granule and CA3 PCs. All potential connectivity patterns are strikingly dependent on the anatomical location of both pre-synaptic and post-synaptic neurons. PMID:21779242

  5. Rich-Club Organization in Effective Connectivity among Cortical Neurons.

    PubMed

    Nigam, Sunny; Shimono, Masanori; Ito, Shinya; Yeh, Fang-Chin; Timme, Nicholas; Myroshnychenko, Maxym; Lapish, Christopher C; Tosi, Zachary; Hottowy, Pawel; Smith, Wesley C; Masmanidis, Sotiris C; Litke, Alan M; Sporns, Olaf; Beggs, John M

    2016-01-20

    The performance of complex networks, like the brain, depends on how effectively their elements communicate. Despite the importance of communication, it is virtually unknown how information is transferred in local cortical networks, consisting of hundreds of closely spaced neurons. To address this, it is important to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512-electrode array (60 μm spacing) to record spontaneous activity at 20 kHz from up to 500 neurons simultaneously in slice cultures of mouse somatosensory cortex for 1 h at a time. We applied a previously validated version of transfer entropy to quantify information transfer. Similar to in vivo reports, we found an approximately lognormal distribution of firing rates. Pairwise information transfer strengths also were nearly lognormally distributed, similar to reports of synaptic strengths. Some neurons transferred and received much more information than others, which is consistent with previous predictions. Neurons with the highest outgoing and incoming information transfer were more strongly connected to each other than chance, thus forming a "rich club." We found similar results in networks recorded in vivo from rodent cortex, suggesting the generality of these findings. A rich-club structure has been found previously in large-scale human brain networks and is thought to facilitate communication between cortical regions. The discovery of a small, but information-rich, subset of neurons within cortical regions suggests that this population will play a vital role in communication, learning, and memory. Significance statement: Many studies have focused on communication networks between cortical brain regions. In contrast, very few studies have examined communication networks within a cortical region. This is the first study to combine such a large number of neurons (several

  6. Rich-Club Organization in Effective Connectivity among Cortical Neurons

    PubMed Central

    Shimono, Masanori; Ito, Shinya; Yeh, Fang-Chin; Timme, Nicholas; Myroshnychenko, Maxym; Lapish, Christopher C.; Tosi, Zachary; Hottowy, Pawel; Smith, Wesley C.; Masmanidis, Sotiris C.; Litke, Alan M.; Sporns, Olaf; Beggs, John M.

    2016-01-01

    The performance of complex networks, like the brain, depends on how effectively their elements communicate. Despite the importance of communication, it is virtually unknown how information is transferred in local cortical networks, consisting of hundreds of closely spaced neurons. To address this, it is important to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512-electrode array (60 μm spacing) to record spontaneous activity at 20 kHz from up to 500 neurons simultaneously in slice cultures of mouse somatosensory cortex for 1 h at a time. We applied a previously validated version of transfer entropy to quantify information transfer. Similar to in vivo reports, we found an approximately lognormal distribution of firing rates. Pairwise information transfer strengths also were nearly lognormally distributed, similar to reports of synaptic strengths. Some neurons transferred and received much more information than others, which is consistent with previous predictions. Neurons with the highest outgoing and incoming information transfer were more strongly connected to each other than chance, thus forming a “rich club.” We found similar results in networks recorded in vivo from rodent cortex, suggesting the generality of these findings. A rich-club structure has been found previously in large-scale human brain networks and is thought to facilitate communication between cortical regions. The discovery of a small, but information-rich, subset of neurons within cortical regions suggests that this population will play a vital role in communication, learning, and memory. SIGNIFICANCE STATEMENT Many studies have focused on communication networks between cortical brain regions. In contrast, very few studies have examined communication networks within a cortical region. This is the first study to combine such a large number of neurons (several

  7. Selective neurofilament (SMI-32, FNP-7 and N200) expression in subpopulations of layer V pyramidal neurons in vivo and in vitro.

    PubMed

    Voelker, Courtney C J; Garin, Nathalie; Taylor, Jeremy S H; Gähwiler, Beat H; Hornung, Jean-Pierre; Molnár, Zoltán

    2004-11-01

    There are two main types of layer V pyramidal neurons in rat cortex. Type I neurons have tufted apical dendrites extending into layer I, produce bursts of action potentials and project to subcortical targets (spinal cord, superior colliculus and pontine nuclei). Type II neurons have apical dendrites, which arborize in layers II-IV, do not produce bursts of action potentials and project to ipsilateral and contralateral cortex. The specific expression of different genes and proteins in these two distinct layer V neurons is unknown. To distinguish between distinct subpopulations, fluorescent microspheres were injected into subcortical targets (labeling type I neurons) or primary somatosensory cortex (labeling type II neurons) of adult rats. After transport, cortical sections were processed for immunohistochemistry using various antibodies. This study demonstrated that antigens recognized by SMI-32, N200 and FNP-7 antibodies were only expressed in subcortical (type I)--but not in contralateral (type II)--projecting neurons. NR1, NR2a/b, PLCbeta1, BDNF, NGF and TrkB antigens were highly expressed in all neuronal subpopulations examined. Organotypic culture experiments demonstrated that the development of neurofilament expression and laminar specificity does not depend on the presence of the subcortical targets. This study suggests specific markers for the subcortical projecting layer V neuron subpopulations.

  8. Pyramidal Neurons in Rat Prefrontal Cortex Projecting to Ventral Tegmental Area and Dorsal Raphe Nucleus Express 5-HT2A Receptors

    PubMed Central

    Vázquez-Borsetti, Pablo; Cortés, Roser

    2009-01-01

    The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotics modulate cortico-limbic circuits mainly through subcortical D2 receptor blockade, whereas second generation (atypical) antipsychotics preferentially target cortical 5-HT receptors. Anatomical and functional evidence supports a PFC-based control of the brainstem monoaminergic nuclei. Using a combination of retrograde tracing experiments and in situ hybridization we report that a substantial proportion of PFC pyramidal neurons projecting to the dorsal raphe (DR) and/or ventral tegmental area (VTA) express 5-HT2A receptors. Cholera-toxin B application into the DR and the VTA retrogradely labeled projection neurons in the medial PFC (mPFC) and in orbitofrontal cortex (OFC). In situ hybridization of 5-HT2A receptor mRNA in the same tissue sections labeled a large neuronal population in mPFC and OFC. The percentage of DR-projecting neurons expressing 5-HT2A receptor mRNA was ∼60% in mPFC and ∼75% in OFC (n = 3). Equivalent values for VTA-projecting neurons were ∼55% in both mPFC and ventral OFC. Thus, 5-HT2A receptor activation/blockade in PFC may have downstream effects on dopaminergic and serotonergic systems via direct descending pathways. Atypical antipsychotics may distally modulate monoaminergic cells through PFC 5-HT2A receptor blockade, presumably decreasing the activity of neurons receiving direct cortical inputs. PMID:19029064

  9. On learning time delays between the spikes from different input neurons in a biophysical model of a pyramidal neuron.

    PubMed

    Koutsou, Achilleas; Bugmann, Guido; Christodoulou, Chris

    2015-10-01

    Biological systems are able to recognise temporal sequences of stimuli or compute in the temporal domain. In this paper we are exploring whether a biophysical model of a pyramidal neuron can detect and learn systematic time delays between the spikes from different input neurons. In particular, we investigate whether it is possible to reinforce pairs of synapses separated by a dendritic propagation time delay corresponding to the arrival time difference of two spikes from two different input neurons. We examine two subthreshold learning approaches where the first relies on the backpropagation of EPSPs (excitatory postsynaptic potentials) and the second on the backpropagation of a somatic action potential, whose production is supported by a learning-enabling background current. The first approach does not provide a learning signal that sufficiently differentiates between synapses at different locations, while in the second approach, somatic spikes do not provide a reliable signal distinguishing arrival time differences of the order of the dendritic propagation time. It appears that the firing of pyramidal neurons shows little sensitivity to heterosynaptic spike arrival time differences of several milliseconds. This neuron is therefore unlikely to be able to learn to detect such differences.

  10. Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide

    PubMed Central

    Scullion, Sarah; Brown, Jon T.; Randall, Andrew D.

    2015-01-01

    ABSTRACT Accumulation of beta‐amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ‐overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2–5 h treatment with an oligomeric preparation of synthetic human Aβ 1–42 peptide. Whole cell current clamp recordings were compared between Aβ‐(500 nM) and vehicle‐(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub‐threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated “sag”. Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra‐threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after‐hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:25515596

  11. Intrinsic excitability changes induced by acute treatment of hippocampal CA1 pyramidal neurons with exogenous amyloid β peptide.

    PubMed

    Tamagnini, Francesco; Scullion, Sarah; Brown, Jon T; Randall, Andrew D

    2015-07-01

    Accumulation of beta-amyloid (Aβ) peptides in the human brain is a canonical pathological hallmark of Alzheimer's disease (AD). Recent work in Aβ-overexpressing transgenic mice indicates that increased brain Aβ levels can be associated with aberrant epileptiform activity. In line with this, such mice can also exhibit altered intrinsic excitability (IE) of cortical and hippocampal neurons: these observations may relate to the increased prevalence of seizures in AD patients. In this study, we examined what changes in IE are produced in hippocampal CA1 pyramidal cells after 2-5 h treatment with an oligomeric preparation of synthetic human Aβ 1-42 peptide. Whole cell current clamp recordings were compared between Aβ-(500 nM) and vehicle-(DMSO 0.05%) treated hippocampal slices obtained from mice. The soluble Aβ treatment did not produce alterations in sub-threshold intrinsic properties, including membrane potential, input resistance, and hyperpolarization activated "sag". Similarly, no changes were noted in the firing profile evoked by 500 ms square current supra-threshold stimuli. However, Aβ 500 nM treatment resulted in the hyperpolarization of the action potential (AP) threshold. In addition, treatment with Aβ at 500 nM depressed the after-hyperpolarization that followed both a single AP or 50 Hz trains of a number of APs between 5 and 25. These data suggest that acute exposure to soluble Aβ oligomers affects IE properties of CA1 pyramidal neurons differently from outcomes seen in transgenic models of amyloidopathy. However, in both chronic and acute models, the IE changes are toward hyperexcitability, reinforcing the idea that amyloidopathy and increased incidence in seizures might be causally related in AD patients.

  12. The spatio-temporal characteristics of action potential initiation in layer 5 pyramidal neurons: a voltage imaging study

    PubMed Central

    Popovic, Marko A; Foust, Amanda J; McCormick, David A; Zecevic, Dejan

    2011-01-01

    Abstract The spatial pattern of Na+ channel clustering in the axon initial segment (AIS) plays a critical role in tuning neuronal computations, and changes in Na+ channel distribution have been shown to mediate novel forms of neuronal plasticity in the axon. However, immunocytochemical data on channel distribution may not directly predict spatio-temporal characteristics of action potential initiation, and prior electrophysiological measures are either indirect (extracellular) or lack sufficient spatial resolution (intracellular) to directly characterize the spike trigger zone (TZ). We took advantage of a critical methodological improvement in the high sensitivity membrane potential imaging (Vm imaging) technique to directly determine the location and length of the spike TZ as defined in functional terms. The results show that in mature axons of mouse cortical layer 5 pyramidal cells, action potentials initiate in a region ∼20 μm in length centred between 20 and 40 μm from the soma. From this region, the AP depolarizing wave invades initial nodes of Ranvier within a fraction of a millisecond and propagates in a saltatory fashion into axonal collaterals without failure at all physiologically relevant frequencies. We further demonstrate that, in contrast to the saltatory conduction in mature axons, AP propagation is non-saltatory (monotonic) in immature axons prior to myelination. PMID:21669974

  13. Neurochemical phenotype of corticocortical connections in the macaque monkey: quantitative analysis of a subset of neurofilament protein-immunoreactive projection neurons in frontal, parietal, temporal, and cingulate cortices

    NASA Technical Reports Server (NTRS)

    Hof, P. R.; Nimchinsky, E. A.; Morrison, J. H.; Bloom, F. E. (Principal Investigator)

    1995-01-01

    The neurochemical characteristics of the neuronal subsets that furnish different types of corticocortical connections have been only partially determined. In recent years, several cytoskeletal proteins have emerged as reliable markers to distinguish subsets of pyramidal neurons in the cerebral cortex of primates. In particular, previous studies using an antibody to nonphosphorylated neurofilament protein (SMI-32) have revealed a consistent degree of regional and laminar specificity in the distribution of a subpopulation of pyramidal cells in the primate cerebral cortex. The density of neurofilament protein-immunoreactive neurons was shown to vary across corticocortical pathways in macaque monkeys. In the present study, we have used the antibody SMI-32 to examine further and to quantify the distribution of a subset of corticocortically projecting neurons in a series of long ipsilateral corticocortical pathways in comparison to short corticocortical, commissural, and limbic connections. The results demonstrate that the long association pathways interconnecting the frontal, parietal, and temporal neocortex have a high representation of neurofilament protein-enriched pyramidal neurons (45-90%), whereas short corticocortical, callosal, and limbic pathways are characterized by much lower numbers of such neurons (4-35%). These data suggest that different types of corticocortical connections have differential representation of highly specific neuronal subsets that share common neurochemical characteristics, thereby determining regional and laminar cortical patterns of morphological and molecular heterogeneity. These differences in neuronal neurochemical phenotype among corticocortical circuits may have considerable influence on cortical processing and may be directly related to the type of integrative function subserved by each cortical pathway. Finally, it is worth noting that neurofilament protein-immunoreactive neurons are dramatically affected in the course of

  14. Changes in cortical thickness in the frontal lobes in schizophrenia are a result of thinning of pyramidal cell layers.

    PubMed

    Williams, M R; Chaudhry, R; Perera, S; Pearce, R K B; Hirsch, S R; Ansorge, O; Thom, M; Maier, M

    2013-02-01

    Decreased cortical thickness and reduced activity as measured by fMRI in the grey matter of the subgenual cingulate cortex have been reported in schizophrenia and bipolar disorder, and cortical grey matter loss has been reliably reported in the frontal and temporal lobes in schizophrenia. The aim of this study was to examine the thickness of each of the six cortical layers in the subgenual cingulate cortex, five frontal lobe and four temporal lobe gyri. We examined two separate cohorts. Cohort 1 examines the subgenual cingulate cortex (SCC) in schizophrenia (n = 10), bipolar disorder (n = 15) and major depressive disorder (n = 20) against control subjects (n = 19). Cohort two examines frontal and temporal gyri in schizophrenia (n = 16), major depressive disorder (n = 6) against matched controls (n = 32). The cohorts were selected with identical clinical criteria, but underwent different tissue processing to contrast the effect of chemical treatment on tissue shrinkage. Measurements of layer I-VI thickness were taken from cresyl-violet- and haematoxylin-stained sections in cohort one and from cresyl-violet- and H&E-stained sections in cohort two. SCC cortical thickness decreased in male subjects with bipolar disorder (p = 0.048), and male schizophrenia cases showed a specific decrease in the absolute thickness of layer V (p = 0.003). Compared to controls, the relative thickness of layer V in the crown of the SCC decreased in schizophrenia (p < 0.001). A significant decrease in total cortical thickness was observed across the frontal lobe in schizophrenia (p < 0.0001), with specific pyramidal layer thinning in layers III (p = 0.0001) and V (p = 0.005). There was no effect of lateralization. No changes were noted in temporal lobe cortical thickness. This study demonstrates diminished pyramidal layer thickness resulting in decreased frontal lobe thickness in schizophrenia.

  15. Synchronized dynamics of cortical neurons with time-delay feedback

    PubMed Central

    Landsman, Alexandra S; Schwartz, Ira B

    2007-01-01

    The dynamics of three mutually coupled cortical neurons with time delays in the coupling are explored numerically and analytically. The neurons are coupled in a line, with the middle neuron sending a somewhat stronger projection to the outer neurons than the feedback it receives, to model for instance the relay of a signal from primary to higher cortical areas. For a given coupling architecture, the delays introduce correlations in the time series at the time-scale of the delay. It was found that the middle neuron leads the outer ones by the delay time, while the outer neurons are synchronized with zero lag times. Synchronization is found to be highly dependent on the synaptic time constant, with faster synapses increasing both the degree of synchronization and the firing rate. Analysis shows that pre-synaptic input during the inter-spike interval stabilizes the synchronous state, even for arbitrarily weak coupling, and independent of the initial phase. The finding may be of significance to synchronization of large groups of cells in the cortex that are spatially distanced from each other. PMID:17908335

  16. Coordinated scaling of cortical and cerebellar numbers of neurons.

    PubMed

    Herculano-Houzel, Suzana

    2010-01-01

    While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species - an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of four different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora), Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble.

  17. Coordinated Scaling of Cortical and Cerebellar Numbers of Neurons

    PubMed Central

    Herculano-Houzel, Suzana

    2010-01-01

    While larger brains possess concertedly larger cerebral cortices and cerebella, the relative size of the cerebral cortex increases with brain size, but relative cerebellar size does not. In the absence of data on numbers of neurons in these structures, this discrepancy has been used to dispute the hypothesis that the cerebral cortex and cerebellum function and have evolved in concert and to support a trend towards neocorticalization in evolution. However, the rationale for interpreting changes in absolute and relative size of the cerebral cortex and cerebellum relies on the assumption that they reflect absolute and relative numbers of neurons in these structures across all species – an assumption that our recent studies have shown to be flawed. Here I show for the first time that the numbers of neurons in the cerebral cortex and cerebellum are directly correlated across 19 mammalian species of four different orders, including humans, and increase concertedly in a similar fashion both within and across the orders Eulipotyphla (Insectivora), Rodentia, Scandentia and Primata, such that on average a ratio of 3.6 neurons in the cerebellum to every neuron in the cerebral cortex is maintained across species. This coordinated scaling of cortical and cerebellar numbers of neurons provides direct evidence in favor of concerted function, scaling and evolution of these brain structures, and suggests that the common notion that equates cognitive advancement with neocortical expansion should be revisited to consider in its stead the coordinated scaling of neocortex and cerebellum as a functional ensemble. PMID:20300467

  18. Spontaneous cortical activity in awake monkeys composed of neuronal avalanches.

    PubMed

    Petermann, Thomas; Thiagarajan, Tara C; Lebedev, Mikhail A; Nicolelis, Miguel A L; Chialvo, Dante R; Plenz, Dietmar

    2009-09-15

    Spontaneous neuronal activity is an important property of the cerebral cortex but its spatiotemporal organization and dynamical framework remain poorly understood. Studies in reduced systems--tissue cultures, acute slices, and anesthetized rats--show that spontaneous activity forms characteristic clusters in space and time, called neuronal avalanches. Modeling studies suggest that networks with this property are poised at a critical state that optimizes input processing, information storage, and transfer, but the relevance of avalanches for fully functional cerebral systems has been controversial. Here we show that ongoing cortical synchronization in awake rhesus monkeys carries the signature of neuronal avalanches. Negative LFP deflections (nLFPs) correlate with neuronal spiking and increase in amplitude with increases in local population spike rate and synchrony. These nLFPs form neuronal avalanches that are scale-invariant in space and time and with respect to the threshold of nLFP detection. This dimension, threshold invariance, describes a fractal organization: smaller nLFPs are embedded in clusters of larger ones without destroying the spatial and temporal scale-invariance of the dynamics. These findings suggest an organization of ongoing cortical synchronization that is scale-invariant in its three fundamental dimensions--time, space, and local neuronal group size. Such scale-invariance has ontogenetic and phylogenetic implications because it allows large increases in network capacity without a fundamental reorganization of the system.

  19. Neurofilament-labeled pyramidal neurons and astrocytes are deficient in DNA methylation marks in Alzheimer's disease.

    PubMed

    Phipps, Andrew J; Vickers, James C; Taberlay, Phillippa C; Woodhouse, Adele

    2016-09-01

    There is increasing evidence that epigenetic alterations may play a role in Alzheimer's disease (AD); yet, there is little information regarding epigenetic modifications in specific cell types. We assessed DNA methylation (5-methylcytosine [5mC]) and hydroxymethylation (5-hydroxymethylcytosine [5hmC]) marks specifically in neuronal and glial cell types in the inferior temporal gyrus of human AD cases and age-matched controls. Interestingly, neurofilament (NF)-labeled pyramidal neurons that are vulnerable to AD pathology are deficient in extranuclear 5mC in AD cases compared with controls. We also found that fewer astrocytes exhibited nuclear 5mC and 5hmC marks in AD cases compared with controls. However, there were no alterations in 5mC and 5hmC in disease-resistant calretinin interneurons or microglia in AD, and there was no alteration in the density of 5mC- or 5hmC-labeled nuclei in near-plaque versus plaque-free regions in late-AD cases. 5mC and 5hmC were present in a high proportion of neurofibrillary tangles, suggesting no loss of DNA methylation marks in tangle bearing neurons. We provide evidence that epigenetic dysregulation may be occurring in astrocytes and NF-positive pyramidal neurons in AD. PMID:27459923

  20. Enhancement of an outwardly rectifying chloride channel in hippocampal pyramidal neurons after cerebral ischemia.

    PubMed

    Li, Jianguo; Chang, Quanzhong; Li, Xiaoming; Li, Xiawen; Qiao, Jiantian; Gao, Tianming

    2016-08-01

    Cerebral ischemia induces delayed, selective neuronal death in the CA1 region of the hippocampus. The underlying molecular mechanisms remain unclear, but it is known that apoptosis is involved in this process. Chloride efflux has been implicated in the progression of apoptosis in various cell types. Using both the inside-out and whole-cell configurations of the patch-clamp technique, the present study characterized an outwardly rectifying chloride channel (ORCC) in acutely dissociated pyramid neurons in the hippocampus of adult rats. The channel had a nonlinear current-voltage relationship with a conductance of 42.26±1.2pS in the positive voltage range and 18.23±0.96pS in the negative voltage range, indicating an outward rectification pattern. The channel is Cl(-) selective, and the open probability is voltage-dependent. It can be blocked by the classical Cl(-) channel blockers DIDS, SITS, NPPB and glibenclamide. We examined the different changes in ORCC activity in CA1 and CA3 pyramidal neurons at 6, 24 and 48h after transient forebrain ischemia. In the vulnerable CA1 neurons, ORCC activity was persistently enhanced after ischemic insult, whereas in the invulnerable CA3 neurons, no significant changes occurred. Further analysis of channel kinetics suggested that multiple openings are a major contributor to the increase in channel activity after ischemia. Pharmacological blockade of the ORCC partly attenuated cell death in the hippocampal neurons. We propose that the enhanced activity of ORCC might contribute to selective neuronal damage in the CA1 region after cerebral ischemia, and that ORCC may be a therapeutic target against ischemia-induced cell death. PMID:27181516

  1. Ultrastructural characteristics of human adult and infant cerebral cortical neurons.

    PubMed Central

    Ong, W Y; Garey, L J

    1991-01-01

    Biopsy specimens of human cerebral cortex from three adults and two infants were studied by correlating their light microscopic features in semithin sections with their ultrastructural characteristics. There was good tissue preservation, due to a minimum delay between obtaining the specimens and fixation. Pyramidal cells had a prominent apical dendrite, fine heterochromatin clumps in the nucleus and generally small numbers of cytoplasmic organelles, except for numerous free ribosomes in some of the large pyramids of Layers III to VI. Non-pyramidal cells lacked an apical dendrite and were further classified, on size and ultrastructure, into small, medium and large types. Large numbers of asymmetrical and symmetrical synapses were present in the neuropil but very few axosomatic synapses were found in the human cerebral cortex compared with subhuman primates and other mammals. Some symmetrical synapses were characterised by the presence of wide pre- and postsynaptic densities. The same general features of the adult cortex were also encountered in the infant, with certain exceptions. Many of the infant neurons had less densely packed heterochromatin, but greater numbers of free ribosomes, compared with the adult, and lipofuscin was absent. There was a total absence of myelinated fibres from the infant cortex; more large diameter dendrites were present than in the adult and axosomatic synapses were commoner. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 Fig. 9 Fig. 10 Fig. 11 Fig. 12 Fig. 13 Fig. 14 Fig. 15 PMID:2050578

  2. Comparative morphology of three types of projection-identified pyramidal neurons in the superficial layers of cat visual cortex.

    PubMed

    Matsubara, J A; Chase, R; Thejomayen, M

    1996-02-26

    The morphology and dendritic organization of corticocortical neurons in the superficial layers of area 18 that project to area 17 were studied by intracellular injection of lucifer yellow in the fixed-slice preparation. This corticocortical population contains primarily standard pyramidal cells, but occasional nonpyramidal, modified, fusiform, star, and inverted pyramidal cells were also seen. All cell types were present throughout layer 2 and in the upper and middle parts of layer 3. Standard pyramidal cells were found exclusively in lower layer 3. The mean somatic area of the area 17 projecting neurons was 251 microns 2. The width of basal dendritic fields was correlated to cell size for standard pyramidal cells but not for the other cell types. Next, the morphology and dendritic organization of the area 17 projecting neurons were compared to the pyramidal cells of the local horizontal patch networks and of the callosal system. The depth profile of the area 17 projecting and callosal pyramidal groups was virtually identical, peaking at 400 microns from the pial surface, whereas the local patch pyramidal group peaked at 281 microns. The local patch, area 17 projecting, and callosal pyramidal cells displayed increasingly larger mean somatic areas and basilar dendritic field width measurements. The number of basal dendritic branch points was greatest for callosal cells, and it was indistinguishable between local patch and area 17 projecting neurons. In the tangential plane, circular dendritic fields were observed on all callosal cells, but they were found on only approximately half of the local patch and area 17 projecting neurons. The remaining local patch and area 17 projecting neurons displayed mediolaterally and anteroposteriorly elongated basal dendritic fields, respectively. PMID:8866848

  3. Neuronal gap junctions play a role in the secondary neuronal death following controlled cortical impact.

    PubMed

    Belousov, Andrei B; Wang, Yongfu; Song, Ji-Hoon; Denisova, Janna V; Berman, Nancy E; Fontes, Joseph D

    2012-08-22

    In the mammalian CNS, excessive release of glutamate and overactivation of glutamate receptors are responsible for the secondary (delayed) neuronal death following neuronal injury, including ischemia, traumatic brain injury (TBI) and epilepsy. Recent studies in mice showed a critical role for neuronal gap junctions in NMDA receptor-mediated excitotoxicity and ischemia-mediated neuronal death. Here, using controlled cortical impact (CCI) in adult mice, as a model of TBI, and Fluoro-Jade B staining for analysis of neuronal death, we set to determine whether neuronal gap junctions play a role in the CCI-mediated secondary neuronal death. We report that 24h post-CCI, substantial neuronal death is detected in a number of brain regions outside the injury core, including the striatum. The striatal neuronal death is reduced both in wild-type mice by systemic administration of mefloquine (a relatively selective blocker of neuronal gap junctions) and in knockout mice lacking connexin 36 (neuronal gap junction protein). It is also reduced by inactivation of group II metabotropic glutamate receptors (with LY341495) which, as reported previously, control the rapid increase in neuronal gap junction coupling following different types of neuronal injury. The results suggest that neuronal gap junctions play a critical role in the CCI-induced secondary neuronal death. PMID:22781494

  4. Cortical neurons exposed to glutamate rapidly leak preloaded chromium 51

    SciTech Connect

    Maulucci-Gedde, M.; Choi, D.W.

    1987-05-01

    The acute toxic effects of excess glutamate exposure on cortical neurons in culture was followed using a novel adaptation of the /sup 51/Cr efflux assay. Although the acute, sodium-dependent phase of glutamate neurotoxicity may contribute to several acute disease settings, including sustained seizures and stroke, functional aspects of the phenomenon have not been previously studied. We report here that the earliest morphologic sign of glutamate neurotoxicity, neuronal swelling, is accompanied by a large efflux of complexed /sup 51/Cr from preloaded neurons in the first hour after exposure, and that this efflux is detectable as early as 15 min after the onset of glutamate exposure. We suggest that this pathological burst of /sup 51/Cr may result from glutamate-induced leakiness of neuronal cell membranes.

  5. Membrane Potential Dynamics of CA1 Pyramidal Neurons during Hippocampal Ripples in Awake Mice.

    PubMed

    Hulse, Brad K; Moreaux, Laurent C; Lubenov, Evgueniy V; Siapas, Athanassios G

    2016-02-17

    Ripples are high-frequency oscillations associated with population bursts in area CA1 of the hippocampus that play a prominent role in theories of memory consolidation. While spiking during ripples has been extensively studied, our understanding of the subthreshold behavior of hippocampal neurons during these events remains incomplete. Here, we combine in vivo whole-cell and multisite extracellular recordings to characterize the membrane potential dynamics of identified CA1 pyramidal neurons during ripples. We find that the subthreshold depolarization during ripples is uncorrelated with the net excitatory input to CA1, while the post-ripple hyperpolarization varies proportionately. This clarifies the circuit mechanism keeping most neurons silent during ripples. On a finer timescale, the phase delay between intracellular and extracellular ripple oscillations varies systematically with membrane potential. Such smoothly varying delays are inconsistent with models of intracellular ripple generation involving perisomatic inhibition alone. Instead, they suggest that ripple-frequency excitation leading inhibition shapes intracellular ripple oscillations.

  6. Cortical neuronal cytoskeletal changes associated with FIV infection

    NASA Technical Reports Server (NTRS)

    Jacobson, S.; Henriksen, S. J.; Prospero-Garcia, O.; Phillips, T. R.; Elder, J. H.; Young, W. G.; Bloom, F. E.; Fox, H. S.

    1997-01-01

    HIV-1 infection is often complicated by central nervous system (CNS) dysfunction. Degenerative neuronal changes as well as neuronal loss have been documented in individuals with AIDS. Feline immunodeficiency virus (FIV) infection of cats provides a model for both the immune and the central nervous system manifestations of HIV infection of humans. In this study we have examined neurons in the frontal cortex of feline immunodeficiency virus-infected cats and controls for immunoreactivity with SMI 32, an antibody recognizing a non-phosphorylated epitope on neurofilaments. We noted a significant increase in the number of immunoreactive pyramidal cells in infected animals compared to controls. The changes seen in the neuronal cytoskeleton as a consequence of the inoculation with FIV were similar to those seen in humans undergoing the normal aging process as well as those suffering from neurological diseases, including Alzheimer's and dementia pugilistica. The changes we noted in the feline brain were also similar to that reported in animals with traumatic injuries or with spontaneously occurring or induced motor neuron diseases, suggesting that the increase in reactivity represents a deleterious effect of FIV on the central nervous system.

  7. Calmodulin Suppresses Synaptotagmin-2 Transcription in Cortical Neurons*

    PubMed Central

    Pang, Zhiping P.; Xu, Wei; Cao, Peng; Südhof, Thomas C.

    2010-01-01

    Calmodulin (CaM) is a ubiquitous Ca2+ sensor protein that plays a pivotal role in regulating innumerable neuronal functions, including synaptic transmission. In cortical neurons, most neurotransmitter release is triggered by Ca2+ binding to synaptotagmin-1; however, a second delayed phase of release, referred to as asynchronous release, is triggered by Ca2+ binding to an unidentified secondary Ca2+ sensor. To test whether CaM could be the enigmatic Ca2+ sensor for asynchronous release, we now use in cultured neurons short hairpin RNAs that suppress expression of ∼70% of all neuronal CaM isoforms. Surprisingly, we found that in synaptotagmin-1 knock-out neurons, the CaM knockdown caused a paradoxical rescue of synchronous release, instead of a block of asynchronous release. Gene and protein expression studies revealed that both in wild-type and in synaptotagmin-1 knock-out neurons, the CaM knockdown altered expression of >200 genes, including that encoding synaptotagmin-2. Synaptotagmin-2 expression was increased several-fold by the CaM knockdown, which accounted for the paradoxical rescue of synchronous release in synaptotagmin-1 knock-out neurons by the CaM knockdown. Interestingly, the CaM knockdown primarily activated genes that are preferentially expressed in caudal brain regions, whereas it repressed genes in rostral brain regions. Consistent with this correlation, quantifications of protein levels in adult mice uncovered an inverse relationship of CaM and synaptotagmin-2 levels in mouse forebrain, brain stem, and spinal cord. Finally, we employed molecular replacement experiments using a knockdown rescue approach to show that Ca2+ binding to the C-lobe but not the N-lobe of CaM is required for suppression of synaptotagmin-2 expression in cortical neurons. Our data describe a previously unknown, Ca2+/CaM-dependent regulatory pathway that controls the expression of synaptic proteins in the rostral-caudal neuraxis. PMID:20729199

  8. Rich club neurons dominate Information Transfer in local cortical networks

    NASA Astrophysics Data System (ADS)

    Nigam, Sunny; Shimono, Masanori; Sporns, Olaf; Beggs, John

    2015-03-01

    The performance of complex networks depends on how they route their traffic. It is unknown how information is transferred in local cortical networks of hundreds of closely-spaced neurons. To address this, it is necessary to record simultaneously from hundreds of neurons at a spacing that matches typical axonal connection distances, and at a temporal resolution that matches synaptic delays. We used a 512 electrode array (60 μm spacing) to record spontaneous activity at 20 kHz, simultaneously from up to 700 neurons in slice cultures of mouse somatosensory cortex for 1 hr at a time. We used transfer entropy to quantify directed information transfer (IT) between pairs of neurons. We found an approximately lognormal distribution of firing rates as reported in in-vivo. Pairwise information transfer strengths also were nearly lognormally distributed, similar to synaptic strengths. 20% of the neurons accounted for 70% of the total IT coming into, and going out of the network and were defined as rich nodes. These rich nodes were more densely and strongly connected to each other expected by chance, forming a rich club. This highly uneven distribution of IT has implications for the efficiency and robustness of local cortical networks, and gives clues to the plastic processes that shape them. JSPS.

  9. Loss of Hippocampal CA3 Pyramidal Neurons in Mice Lacking STAM1

    PubMed Central

    Yamada, Mitsuhiro; Takeshita, Toshikazu; Miura, Shigeto; Murata, Kazuko; Kimura, Yutaka; Ishii, Naoto; Nose, Masato; Sakagami, Hiroyuki; Kondo, Hisatake; Tashiro, Fumi; Miyazaki, Jun-Ichi; Sasaki, Hidetada; Sugamura, Kazuo

    2001-01-01

    STAM1, a member of the STAM (signal transducing adapter molecule) family, has a unique structure containing a Src homology 3 domain and ITAM (immunoreceptor tyrosine-based activation motif). STAM1 was previously shown to be associated with the Jak2 and Jak3 tyrosine kinases and to be involved in the regulation of intracellular signal transduction mediated by interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro. Here we generated mice lacking STAM1 by using homologous recombination with embryonic stem cells. STAM1−/− mice were morphologically indistinguishable from their littermates at birth. However, growth retardation in the third week after birth was observed for the STAM1−/− mice. Unexpectedly, despite the absence of STAM1, hematopoietic cells, including T- and B-lymphocyte and other hematopoietic cell populations, developed normally and responded well to several cytokines, including IL-2 and GM-CSF. However, histological analyses revealed the disappearance of hippocampal CA3 pyramidal neurons in STAM1−/− mice. Furthermore, we observed that primary hippocampal neurons derived from STAM1−/− mice are vulnerable to cell death induced by excitotoxic amino acids or an NO donor. These data suggest that STAM1 is dispensable for cytokine-mediated signaling in lymphocytes but may be involved in the survival of hippocampal CA3 pyramidal neurons. PMID:11340172

  10. A Method for High Fidelity Optogenetic Control of Individual Pyramidal Neurons In vivo

    PubMed Central

    Cooper, Donald C.

    2013-01-01

    Optogenetic methods have emerged as a powerful tool for elucidating neural circuit activity underlying a diverse set of behaviors across a broad range of species. Optogenetic tools of microbial origin consist of light-sensitive membrane proteins that are able to activate (e.g., channelrhodopsin-2, ChR2) or silence (e.g., halorhodopsin, NpHR) neural activity ingenetically-defined cell types over behaviorally-relevant timescales. We first demonstrate a simple approach for adeno-associated virus-mediated delivery of ChR2 and NpHR transgenes to the dorsal subiculum and prelimbic region of the prefrontal cortex in rat. Because ChR2 and NpHR are genetically targetable, we describe the use of this technology to control the electrical activity of specific populations of neurons (i.e., pyramidal neurons) embedded in heterogeneous tissue with high temporal precision. We describe herein the hardware, custom software user interface, and procedures that allow for simultaneous light delivery and electrical recording from transduced pyramidal neurons in an anesthetized in vivo preparation. These light-responsive tools provide the opportunity for identifying the causal contributions of different cell types to information processing and behavior. PMID:24022017

  11. Loss of Sleep Affects the Ultrastructure of Pyramidal Neurons in the Adolescent Mouse Frontal Cortex

    PubMed Central

    de Vivo, Luisa; Nelson, Aaron B.; Bellesi, Michele; Noguti, Juliana; Tononi, Giulio; Cirelli, Chiara

    2016-01-01

    Study Objective: The adolescent brain may be uniquely affected by acute sleep deprivation (ASD) and chronic sleep restriction (CSR), but direct evidence is lacking. We used electron microscopy to examine how ASD and CSR affect pyramidal neurons in the frontal cortex of adolescent mice, focusing on mitochondria, endosomes, and lysosomes that together perform most basic cellular functions, from nutrient intake to prevention of cellular stress. Methods: Adolescent (1-mo-old) mice slept (S) or were sleep deprived (ASD, with novel objects and running wheels) during the first 6–8 h of the light period, chronically sleep restricted (CSR) for > 4 days (using novel objects, running wheels, social interaction, forced locomotion, caffeinated water), or allowed to recover sleep (RS) for ∼32 h after CSR. Ultrastructural analysis of 350 pyramidal neurons was performed (S = 82; ASD = 86; CSR = 103; RS = 79; 4 to 5 mice/group). Results: Several ultrastructural parameters differed in S versus ASD, S versus CSR, CSR versus RS, and S versus RS, although the different methods used to enforce wake may have contributed to some of the differences between short and long sleep loss. Differences included larger cytoplasmic area occupied by mitochondria in CSR versus S, and higher number of secondary lysosomes in CSR versus S and RS. We also found that sleep loss may unmask interindividual differences not obvious during baseline sleep. Moreover, using a combination of 11 ultrastructural parameters, we could predict in up to 80% of cases whether sleep or wake occurred at the single cell level. Conclusions: Ultrastructural analysis may be a powerful tool to identify which cellular organelles, and thus which cellular functions, are most affected by sleep and sleep loss. Citation: de Vivo L, Nelson AB, Bellesi M, Noguti J, Tononi G, Cirelli C. Loss of sleep affects the ultrastructure of pyramidal neurons in the adolescent mouse frontal cortex. SLEEP 2016;39(4):861–874. PMID:26715225

  12. Persistent Sodium Current Drives Conditional Pacemaking in CA1 Pyramidal Neurons under Muscarinic Stimulation

    PubMed Central

    Yamada-Hanff, Jason

    2013-01-01

    Hippocampal CA1 pyramidal neurons are normally quiescent but can fire spontaneously when stimulated by muscarinic agonists. In brain slice recordings from mouse CA1 pyramidal neurons, we examined the ionic basis of this activity using interleaved current-clamp and voltage-clamp experiments. Both in control and after muscarinic stimulation, the steady-state current–voltage curve was dominated by inward TTX-sensitive persistent sodium current (INaP) that activated near −75 mV and increased steeply with depolarization. In control, total membrane current was net outward (hyperpolarizing) near −70 mV so that cells had a stable resting potential. Muscarinic stimulation activated a small nonselective cation current so that total membrane current near −70 mV shifted to become barely net inward (depolarizing). The small depolarization triggers regenerative activation of INaP, which then depolarizes the cell from −70 mV to spike threshold. We quantified the relative contributions of INaP, hyperpolarization-activated cation current (Ih), and calcium current to pacemaking by using the cell's own firing as a voltage command along with specific blockers. TTX-sensitive sodium current was substantial throughout the entire interspike interval, increasing as the membrane potential approached threshold, while both Ih and calcium current were minimal. Thus, spontaneous activity is driven primarily by activation of INaP in a positive feedback loop starting near −70 mV and providing increasing inward current to threshold. These results show that the pacemaking “engine” from INaP is an inherent property of CA1 pyramidal neurons that can be engaged or disengaged by small shifts in net membrane current near −70 mV, as by muscarinic stimulation. PMID:24048831

  13. Activation of 5‐HT2A receptors by TCB‐2 induces recurrent oscillatory burst discharge in layer 5 pyramidal neurons of the mPFC in vitro

    PubMed Central

    Spindle, Michael S.; Thomas, Mark P.

    2014-01-01

    Abstract The medial prefrontal cortex (mPFC) is a region of neocortex that plays an integral role in several cognitive processes which are abnormal in schizophrenic patients. As with other cortical regions, large‐bodied layer 5 pyramidal neurons serve as the principle subcortical output of microcircuits of the mPFC. The coexpression of both inhibitory serotonin 5‐HT1A receptors on the axon initial segments, and excitatory 5‐HT2A receptors throughout the somatodendritic compartments, by layer 5 pyramidal neurons allows serotonin to provide potent top–down regulation of input–output relationships within cortical microcircuits. Application of 5‐HT2A agonists has previously been shown to enhance synaptic input to layer 5 pyramidal neurons, as well as increase the gain in neuronal firing rate in response to increasing depolarizing current steps. Using whole‐cell patch‐clamp recordings obtained from layer 5 pyramidal neurons of the mPFC of C57/bl6 mice, the aim of our present study was to investigate the modulation of long‐term spike trains by the selective 5‐HT2A agonist TCB‐2. We found that in the presence of synaptic blockers, TCB‐2 induced recurrent oscillatory bursting (ROB) after 15–20 sec of tonic spiking in 7 of the 14 cells. In those seven cells, ROB discharge was accurately predicted by the presence of a voltage sag in response to a hyperpolarizing current injection. This effect was reversed by 5–10 min of drug washout and ROB discharge was inhibited by both synaptic activity and coapplication of the 5‐HT2A/2C antagonist ketanserin. While the full implications of this work are not yet understood, it may provide important insight into serotonergic modulation of cortical networks. PMID:24844635

  14. Enhanced Sensitivity to Rapid Input Fluctuations by Nonlinear Threshold Dynamics in Neocortical Pyramidal Neurons.

    PubMed

    Mensi, Skander; Hagens, Olivier; Gerstner, Wulfram; Pozzorini, Christian

    2016-02-01

    The way in which single neurons transform input into output spike trains has fundamental consequences for network coding. Theories and modeling studies based on standard Integrate-and-Fire models implicitly assume that, in response to increasingly strong inputs, neurons modify their coding strategy by progressively reducing their selective sensitivity to rapid input fluctuations. Combining mathematical modeling with in vitro experiments, we demonstrate that, in L5 pyramidal neurons, the firing threshold dynamics adaptively adjust the effective timescale of somatic integration in order to preserve sensitivity to rapid signals over a broad range of input statistics. For that, a new Generalized Integrate-and-Fire model featuring nonlinear firing threshold dynamics and conductance-based adaptation is introduced that outperforms state-of-the-art neuron models in predicting the spiking activity of neurons responding to a variety of in vivo-like fluctuating currents. Our model allows for efficient parameter extraction and can be analytically mapped to a Generalized Linear Model in which both the input filter--describing somatic integration--and the spike-history filter--accounting for spike-frequency adaptation--dynamically adapt to the input statistics, as experimentally observed. Overall, our results provide new insights on the computational role of different biophysical processes known to underlie adaptive coding in single neurons and support previous theoretical findings indicating that the nonlinear dynamics of the firing threshold due to Na+-channel inactivation regulate the sensitivity to rapid input fluctuations. PMID:26907675

  15. Enhanced Sensitivity to Rapid Input Fluctuations by Nonlinear Threshold Dynamics in Neocortical Pyramidal Neurons

    PubMed Central

    Mensi, Skander; Hagens, Olivier; Gerstner, Wulfram; Pozzorini, Christian

    2016-01-01

    The way in which single neurons transform input into output spike trains has fundamental consequences for network coding. Theories and modeling studies based on standard Integrate-and-Fire models implicitly assume that, in response to increasingly strong inputs, neurons modify their coding strategy by progressively reducing their selective sensitivity to rapid input fluctuations. Combining mathematical modeling with in vitro experiments, we demonstrate that, in L5 pyramidal neurons, the firing threshold dynamics adaptively adjust the effective timescale of somatic integration in order to preserve sensitivity to rapid signals over a broad range of input statistics. For that, a new Generalized Integrate-and-Fire model featuring nonlinear firing threshold dynamics and conductance-based adaptation is introduced that outperforms state-of-the-art neuron models in predicting the spiking activity of neurons responding to a variety of in vivo-like fluctuating currents. Our model allows for efficient parameter extraction and can be analytically mapped to a Generalized Linear Model in which both the input filter—describing somatic integration—and the spike-history filter—accounting for spike-frequency adaptation—dynamically adapt to the input statistics, as experimentally observed. Overall, our results provide new insights on the computational role of different biophysical processes known to underlie adaptive coding in single neurons and support previous theoretical findings indicating that the nonlinear dynamics of the firing threshold due to Na+-channel inactivation regulate the sensitivity to rapid input fluctuations. PMID:26907675

  16. Active dendrites regulate the impact of gliotransmission on rat hippocampal pyramidal neurons.

    PubMed

    Ashhad, Sufyan; Narayanan, Rishikesh

    2016-06-01

    An important consequence of gliotransmission, a signaling mechanism that involves glial release of active transmitter molecules, is its manifestation as N-methyl-d-aspartate receptor (NMDAR)-dependent slow inward currents in neurons. However, the intraneuronal spatial dynamics of these events or the role of active dendrites in regulating their amplitude and spatial spread have remained unexplored. Here, we used somatic and/or dendritic recordings from rat hippocampal pyramidal neurons and demonstrate that a majority of NMDAR-dependent spontaneous slow excitatory potentials (SEP) originate at dendritic locations and are significantly attenuated through their propagation across the neuronal arbor. We substantiated the astrocytic origin of SEPs through paired neuron-astrocyte recordings, where we found that specific infusion of inositol trisphosphate (InsP3) into either distal or proximal astrocytes enhanced the amplitude and frequency of neuronal SEPs. Importantly, SEPs recorded after InsP3 infusion into distal astrocytes exhibited significantly slower kinetics compared with those recorded after proximal infusion. Furthermore, using neuron-specific infusion of pharmacological agents and morphologically realistic conductance-based computational models, we demonstrate that dendritically expressed hyperpolarization-activated cyclic-nucleotide-gated (HCN) and transient potassium channels play critical roles in regulating the strength, kinetics, and compartmentalization of neuronal SEPs. Finally, through the application of subtype-specific receptor blockers during paired neuron-astrocyte recordings, we provide evidence that GluN2B- and GluN2D-containing NMDARs predominantly mediate perisomatic and dendritic SEPs, respectively. Our results unveil an important role for active dendrites in regulating the impact of gliotransmission on neurons and suggest astrocytes as a source of dendritic plateau potentials that have been implicated in localized plasticity and place cell

  17. Broadband macroscopic cortical oscillations emerge from intrinsic neuronal response failures.

    PubMed

    Goldental, Amir; Vardi, Roni; Sardi, Shira; Sabo, Pinhas; Kanter, Ido

    2015-01-01

    Broadband spontaneous macroscopic neural oscillations are rhythmic cortical firing which were extensively examined during the last century, however, their possible origination is still controversial. In this work we show how macroscopic oscillations emerge in solely excitatory random networks and without topological constraints. We experimentally and theoretically show that these oscillations stem from the counterintuitive underlying mechanism-the intrinsic stochastic neuronal response failures (NRFs). These NRFs, which are characterized by short-term memory, lead to cooperation among neurons, resulting in sub- or several- Hertz macroscopic oscillations which coexist with high frequency gamma oscillations. A quantitative interplay between the statistical network properties and the emerging oscillations is supported by simulations of large networks based on single-neuron in-vitro experiments and a Langevin equation describing the network dynamics. Results call for the examination of these oscillations in the presence of inhibition and external drives. PMID:26578893

  18. Broadband macroscopic cortical oscillations emerge from intrinsic neuronal response failures

    PubMed Central

    Goldental, Amir; Vardi, Roni; Sardi, Shira; Sabo, Pinhas; Kanter, Ido

    2015-01-01

    Broadband spontaneous macroscopic neural oscillations are rhythmic cortical firing which were extensively examined during the last century, however, their possible origination is still controversial. In this work we show how macroscopic oscillations emerge in solely excitatory random networks and without topological constraints. We experimentally and theoretically show that these oscillations stem from the counterintuitive underlying mechanism—the intrinsic stochastic neuronal response failures (NRFs). These NRFs, which are characterized by short-term memory, lead to cooperation among neurons, resulting in sub- or several- Hertz macroscopic oscillations which coexist with high frequency gamma oscillations. A quantitative interplay between the statistical network properties and the emerging oscillations is supported by simulations of large networks based on single-neuron in-vitro experiments and a Langevin equation describing the network dynamics. Results call for the examination of these oscillations in the presence of inhibition and external drives. PMID:26578893

  19. Spiking neural networks for cortical neuronal spike train decoding.

    PubMed

    Fang, Huijuan; Wang, Yongji; He, Jiping

    2010-04-01

    Recent investigation of cortical coding and computation indicates that temporal coding is probably a more biologically plausible scheme used by neurons than the rate coding used commonly in most published work. We propose and demonstrate in this letter that spiking neural networks (SNN), consisting of spiking neurons that propagate information by the timing of spikes, are a better alternative to the coding scheme based on spike frequency (histogram) alone. The SNN model analyzes cortical neural spike trains directly without losing temporal information for generating more reliable motor command for cortically controlled prosthetics. In this letter, we compared the temporal pattern classification result from the SNN approach with results generated from firing-rate-based approaches: conventional artificial neural networks, support vector machines, and linear regression. The results show that the SNN algorithm can achieve higher classification accuracy and identify the spiking activity related to movement control earlier than the other methods. Both are desirable characteristics for fast neural information processing and reliable control command pattern recognition for neuroprosthetic applications. PMID:19922291

  20. Self-organization and neuronal avalanches in networks of dissociated cortical neurons.

    PubMed

    Pasquale, V; Massobrio, P; Bologna, L L; Chiappalone, M; Martinoia, S

    2008-06-01

    Dissociated cortical neurons from rat embryos cultured onto micro-electrode arrays exhibit characteristic patterns of electrophysiological activity, ranging from isolated spikes in the first days of development to highly synchronized bursts after 3-4 weeks in vitro. In this work we analyzed these features by considering the approach proposed by the self-organized criticality theory: we found that networks of dissociated cortical neurons also generate spontaneous events of spreading activity, previously observed in cortical slices, in the form of neuronal avalanches. Choosing an appropriate time scale of observation to detect such neuronal avalanches, we studied the dynamics by considering the spontaneous activity during acute recordings in mature cultures and following the development of the network. We observed different behaviors, i.e. sub-critical, critical or super-critical distributions of avalanche sizes and durations, depending on both the age and the development of cultures. In order to clarify this variability, neuronal avalanches were correlated with other statistical parameters describing the global activity of the network. Criticality was found in correspondence to medium synchronization among bursts and high ratio between bursting and spiking activity. Then, the action of specific drugs affecting global bursting dynamics (i.e. acetylcholine and bicuculline) was investigated to confirm the correlation between criticality and regulated balance between synchronization and variability in the bursting activity. Finally, a computational model of neuronal network was developed in order to interpret the experimental results and understand which parameters (e.g. connectivity, excitability) influence the distribution of avalanches. In summary, cortical neurons preserve their capability to self-organize in an effective network even when dissociated and cultured in vitro. The distribution of avalanche features seems to be critical in those cultures displaying

  1. An Augmented Two-Layer Model Captures Nonlinear Analog Spatial Integration Effects in Pyramidal Neuron Dendrites

    PubMed Central

    JADI, MONIKA P.; BEHABADI, BARDIA F.; POLEG-POLSKY, ALON; SCHILLER, JACKIE; MEL, BARTLETT W.

    2014-01-01

    In pursuit of the goal to understand and eventually reproduce the diverse functions of the brain, a key challenge lies in reverse engineering the peculiar biology-based “technology” that underlies the brain’s remarkable ability to process and store information. The basic building block of the nervous system is the nerve cell, or “neuron,” yet after more than 100 years of neurophysiological study and 60 years of modeling, the information processing functions of individual neurons, and the parameters that allow them to engage in so many different types of computation (sensory, motor, mnemonic, executive, etc.) remain poorly understood. In this paper, we review both historical and recent findings that have led to our current understanding of the analog spatial processing capabilities of dendrites, the major input structures of neurons, with a focus on the principal cell type of the neocortex and hippocampus, the pyramidal neuron (PN). We encapsulate our current understanding of PN dendritic integration in an abstract layered model whose spatially sensitive branch-subunits compute multidimensional sigmoidal functions. Unlike the 1-D sigmoids found in conventional neural network models, multidimensional sigmoids allow the cell to implement a rich spectrum of nonlinear modulation effects directly within their dendritic trees. PMID:25554708

  2. Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation.

    PubMed

    Chua, Yansong; Morrison, Abigail

    2016-01-01

    The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be

  3. Effects of Calcium Spikes in the Layer 5 Pyramidal Neuron on Coincidence Detection and Activity Propagation

    PubMed Central

    Chua, Yansong; Morrison, Abigail

    2016-01-01

    The role of dendritic spiking mechanisms in neural processing is so far poorly understood. To investigate the role of calcium spikes in the functional properties of the single neuron and recurrent networks, we investigated a three compartment neuron model of the layer 5 pyramidal neuron with calcium dynamics in the distal compartment. By performing single neuron simulations with noisy synaptic input and occasional large coincident input at either just the distal compartment or at both somatic and distal compartments, we show that the presence of calcium spikes confers a substantial advantage for coincidence detection in the former case and a lesser advantage in the latter. We further show that the experimentally observed critical frequency phenomenon, in which action potentials triggered by stimuli near the soma above a certain frequency trigger a calcium spike at distal dendrites, leading to further somatic depolarization, is not exhibited by a neuron receiving realistically noisy synaptic input, and so is unlikely to be a necessary component of coincidence detection. We next investigate the effect of calcium spikes in propagation of spiking activities in a feed-forward network (FFN) embedded in a balanced recurrent network. The excitatory neurons in the network are again connected to either just the distal, or both somatic and distal compartments. With purely distal connectivity, activity propagation is stable and distinguishable for a large range of recurrent synaptic strengths if the feed-forward connections are sufficiently strong, but propagation does not occur in the absence of calcium spikes. When connections are made to both the somatic and the distal compartments, activity propagation is achieved for neurons with active calcium dynamics at a much smaller number of neurons per pool, compared to a network of passive neurons, but quickly becomes unstable as the strength of recurrent synapses increases. Activity propagation at higher scaling factors can be

  4. Probabilistic Identification of Cerebellar Cortical Neurones across Species

    PubMed Central

    Van Dijck, Gert; Van Hulle, Marc M.; Heiney, Shane A.; Blazquez, Pablo M.; Meng, Hui; Angelaki, Dora E.; Arenz, Alexander; Margrie, Troy W.; Mostofi, Abteen; Edgley, Steve; Bengtsson, Fredrik; Ekerot, Carl-Fredrik; Jörntell, Henrik; Dalley, Jeffrey W.; Holtzman, Tahl

    2013-01-01

    Despite our fine-grain anatomical knowledge of the cerebellar cortex, electrophysiological studies of circuit information processing over the last fifty years have been hampered by the difficulty of reliably assigning signals to identified cell types. We approached this problem by assessing the spontaneous activity signatures of identified cerebellar cortical neurones. A range of statistics describing firing frequency and irregularity were then used, individually and in combination, to build Gaussian Process Classifiers (GPC) leading to a probabilistic classification of each neurone type and the computation of equi-probable decision boundaries between cell classes. Firing frequency statistics were useful for separating Purkinje cells from granular layer units, whilst firing irregularity measures proved most useful for distinguishing cells within granular layer cell classes. Considered as single statistics, we achieved classification accuracies of 72.5% and 92.7% for granular layer and molecular layer units respectively. Combining statistics to form twin-variate GPC models substantially improved classification accuracies with the combination of mean spike frequency and log-interval entropy offering classification accuracies of 92.7% and 99.2% for our molecular and granular layer models, respectively. A cross-species comparison was performed, using data drawn from anaesthetised mice and decerebrate cats, where our models offered 80% and 100% classification accuracy. We then used our models to assess non-identified data from awake monkeys and rabbits in order to highlight subsets of neurones with the greatest degree of similarity to identified cell classes. In this way, our GPC-based approach for tentatively identifying neurones from their spontaneous activity signatures, in the absence of an established ground-truth, nonetheless affords the experimenter a statistically robust means of grouping cells with properties matching known cell classes. Our approach therefore

  5. Synergistic Regulation of Glutamatergic Transmission by Serotonin and Norepinephrine Reuptake Inhibitors in Prefrontal Cortical Neurons*

    PubMed Central

    Yuen, Eunice Y.; Qin, Luye; Wei, Jing; Liu, Wenhua; Liu, Aiyi; Yan, Zhen

    2014-01-01

    The monoamine system in the prefrontal cortex has been implicated in various mental disorders and has been the major target of anxiolytics and antidepressants. Clinical studies show that serotonin and norepinephrine reuptake inhibitors (SNRIs) produce better therapeutic effects than single selective reuptake inhibitors, but the underlying mechanisms are largely unknown. Here, we found that low dose SNRIs, by acting on 5-HT1A and α2-adrenergic receptors, synergistically reduced AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents and AMPAR surface expression in prefrontal cortex pyramidal neurons via a mechanism involving Rab5/dynamin-mediated endocytosis of AMPARs. The synergistic effect of SNRIs on AMPARs was blocked by inhibition of activator of G protein signaling 3, a G protein modulator that prevents reassociation of Gi protein α subunit and prolongs the βγ-mediated signaling pathway. Moreover, the depression of AMPAR-mediated excitatory postsynaptic currents by SNRIs required p38 kinase activity, which was increased by 5-HT1A and α2-adrenergic receptor co-activation in an activator of G protein signaling 3-dependent manner. These results have revealed a potential mechanism for the synergy between the serotonin and norepinephrine systems in the regulation of glutamatergic transmission in cortical neurons. PMID:25056951

  6. In vivo administration of epidermal growth factor and its homologue attenuates developmental maturation of functional excitatory synapses in cortical GABAergic neurons.

    PubMed

    Nagano, Tadasato; Namba, Hisaaki; Abe, Yuichi; Aoki, Hiroyuki; Takei, Nobuyuki; Nawa, Hiroyuki

    2007-01-01

    The ErbB1 ligand family includes epidermal growth factor (EGF), transforming growth factor-alpha (TGFalpha), heparin-binding EGF-like growth factor, amphiregulin and betacellulin. Previously, we demonstrated that TGFalpha decreases alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in cultured neocortical gamma-aminobutyric acid (GABA) neurons. In the present study, we examined in vivo effects of EGF and TGFalpha in the mouse neocortex using electrophysiological and biochemical techniques. In mouse neonates, subcutaneously administered EGF penetrated the blood-brain barrier and activated ErbB1 in the neocortex. Daily administration of EGF or TGFalpha attenuates developmental increases in expression of the AMPA receptor subunits (GluR1 and GluR2/3) in the neocortex of postnatal mice. Immunohistochemistry revealed that the reduction in AMPA receptor expression was significant in the GABAergic neurons, especially those positive for parvalbumin. Using cortical slices prepared from EGF-treated mice, we recorded miniature excitatory postsynaptic currents (mEPSCs) in both GABAergic and pyramidal neurons. Subchronic treatment with EGF decreased the amplitude and frequency of mEPSCs in GABAergic neurons, but its effects were negligible on pyramidal neurons. We conclude that EGF or other ErbB1 ligand(s) attenuates a developmental increase in AMPA receptor expression and function in cortical GABAergic neurons.

  7. Activation of Ih and TTX-sensitive sodium current at subthreshold voltages during CA1 pyramidal neuron firing.

    PubMed

    Yamada-Hanff, Jason; Bean, Bruce P

    2015-10-01

    We used dynamic clamp and action potential clamp techniques to explore how currents carried by tetrodotoxin-sensitive sodium channels and HCN channels (Ih) regulate the behavior of CA1 pyramidal neurons at resting and subthreshold voltages. Recording from rat CA1 pyramidal neurons in hippocampal slices, we found that the apparent input resistance and membrane time constant were strongly affected by both conductances, with Ih acting to decrease apparent input resistance and time constant and sodium current acting to increase both. We found that both Ih and sodium current were active during subthreshold summation of artificial excitatory postsynaptic potentials (EPSPs) generated by dynamic clamp, with Ih dominating at less depolarized voltages and sodium current at more depolarized voltages. Subthreshold sodium current-which amplifies EPSPs-was most effectively recruited by rapid voltage changes, while Ih-which blunts EPSPs-was maximal for slow voltage changes. The combined effect is to selectively amplify rapid EPSPs. We did similar experiments in mouse CA1 pyramidal neurons, doing voltage-clamp experiments using experimental records of action potential firing of CA1 neurons previously recorded in awake, behaving animals as command voltages to quantify flow of Ih and sodium current at subthreshold voltages. Subthreshold sodium current was larger and subthreshold Ih was smaller in mouse neurons than in rat neurons. Overall, the results show opposing effects of subthreshold sodium current and Ih in regulating subthreshold behavior of CA1 neurons, with subthreshold sodium current prominent in both rat and mouse CA1 pyramidal neurons and additional regulation by Ih in rat neurons.

  8. Transcranial electric stimulation entrains cortical neuronal populations in rats

    PubMed Central

    Ozen, Simal; Sirota, Anton; Belluscio, Mariano A.; Anastassiou, Costas A.; Stark, Eran; Koch, Christof; Buzsáki, György

    2010-01-01

    Low intensity electric fields have been suggested to affect the ongoing neuronal activity in vitro and in human studies. However, the physiological mechanism of how weak electrical fields affect and interact with intact brain activity is not well understood. We performed in vivo extracellular and intracellular recordings from the neocortex and hippocampus of anaesthetized rats and extracellular recordings in behaving rats. Electric fields were generated by sinusoid patterns at slow frequency (0.8, 1.25 or 1.7 Hz) via electrodes placed on the surface of the skull or the dura. Transcranial electric stimulation (TES) reliably entrained neurons in widespread cortical areas, including the hippocampus. The percentage of TES phase-locked neurons increased with stimulus intensity and depended on the behavioral state of the animal. TES-induced voltage gradient, as low as 1 mV/mm at the recording sites, was sufficient to phase-bias neuronal spiking. Intracellular recordings showed that both spiking and subthreshold activity were under the combined influence of TES forced fields and network activity. We suggest that TES in chronic preparations may be used for experimental and therapeutic control of brain activity. PMID:20739569

  9. Major Vault Protein is Expressed along the Nucleus–Neurite Axis and Associates with mRNAs in Cortical Neurons

    PubMed Central

    Paspalas, Constantinos D.; Perley, Casey C.; Venkitaramani, Deepa V.; Goebel-Goody, Susan M.; Zhang, YongFang; Kurup, Pradeep; Mattis, Joanna H.

    2009-01-01

    Major Vault Protein (MVP), the main constituent of the vault ribonucleoprotein particle, is highly conserved in eukaryotic cells and upregulated in a variety of tumors. Vaults have been speculated to function as cargo transporters in several cell lines, yet no work to date has characterized the protein in neurons. Here we first describe the cellular and subcellular expression of MVP in primate and rodent cerebral cortex, and in cortical neurons in vitro. In prefrontal, somatosensory and hippocampal cortices, MVP was predominantly expressed in pyramidal neurons. Immunogold labeled free and attached ribosomes, and structures reminiscent of vaults on the rough endoplasmic reticulum and the nuclear envelope. The nucleus was immunoreactive in association with nucleopores. Axons and particularly principal dendrites expressed MVP along individual microtubules, and in pre- and postsynaptic structures. Synapses were not labeled. Colocalization with microtubule-associated protein-2, tubulin, tau, and phalloidin was observed in neurites and growth cones in culture. Immunoprecipitation coupled with reverse transcription PCR showed that MVP associates with mRNAs that are known to be translated in response to synaptic activity. Taken together, our findings provide the first characterization of neuronal MVP along the nucleus–neurite axis and may offer new insights into its possible function(s) in the brain. PMID:19029061

  10. A Transgenic Mouse Model Reveals Fast Nicotinic Transmission in Hippocampal Pyramidal Neurons

    PubMed Central

    Grybko, Michael J.; Hahm, Eu-teum; Perrine, Wesley; Parnes, Jason A.; Chick, Wallace S.; Sharma, Geeta; Finger, Thomas E.; Vijayaraghavan, Sukumar

    2011-01-01

    The relative contribution, to brain cholinergic signaling, by synaptic- and diffusion-based mechanisms remains to be elucidated. In this study, we examined the prevalence of fast nicotinic signaling in the hippocampus. We describe a mouse model where cholinergic axons are labeled with the tauGFP fusion protein driven by the choline acetyltransferase (ChAT) promoter. The model provides for the visualization of individual cholinergic axons at greater resolution than other available models and techniques, even in thick, live, slices. Combining calcium imaging and electrophysiology, we demonstrate that local stimulation of visualized cholinergic fibers results in rapid EPSCs mediated by the activation of α7-subunit containing nicotinic receptors (α7-nAChRs) on CA3 pyramidal neurons. These responses were blocked by the α7-nAChR antagonist methyllycaconitine (MLA) and potentiated by the receptor specific allosteric modulator 1-(5-chloro-2,4- dimethoxy-phenyl)-3-(5-methyl-isoxanol-3-yl)-urea (PNU-120596). Our results suggest, for the first time, that synaptic nAChRs can modulate pyramidal cell plasticity and development. Fast nicotinic transmission might play a greater role in cholinergic signaling than previously assumed. We provide a model for the examination of synaptic properties of basal forebrain cholinergic innervation in the brain. PMID:21501254

  11. Repeated transcranial magnetic stimulation prevents kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons.

    PubMed

    Shojaei, A; Semnanian, S; Janahmadi, M; Moradi-Chameh, H; Firoozabadi, S M; Mirnajafi-Zadeh, J

    2014-11-01

    The mechanisms underlying antiepileptic or antiepileptogenic effects of repeated transcranial magnetic stimulation (rTMS) are poorly understood. In this study, we investigated the effect of rTMS applied during rapid amygdala kindling on some electrophysiological properties of hippocampal CA1 pyramidal neurons. Male Wistar rats were kindled by daily electrical stimulation of the basolateral amygdala in a semi-rapid manner (12 stimulations/day) until they achieved stage-5 seizure. One group (kindled+rTMS (KrTMS)) of animals received rTMS (1Hz for 4min) 5min after termination of daily kindling stimulations. Twenty four hours following the last kindling stimulation electrophysiological properties of hippocampal CA1 pyramidal neurons were investigated using whole-cell patch-clamp technique. Amygdala kindling significantly depolarized the resting membrane potential and increased the input resistance, spontaneous firing activity, number of evoked spikes and half-width of the first evoked spike. Kindling also decreased the first-spike latency and amplitude significantly. Application of rTMS during kindling somehow prevented the development of seizures and protected CA1 pyramidal neurons of hippocampus against deleterious effect of kindling on both passive and active neuronal electrophysiological properties. Interestingly, application of rTMS alone enhanced the excitability of CA1 pyramidal neurons significantly. Based on the results of our study, it may be suggested that rTMS exerts its anticonvulsant effect, in part, through preventing the amygdala kindling-induced changes in electrophysiological properties of hippocampal CA1 pyramidal neurons. It seems that rTMS exerts protective effects on the neural circuits involved in spreading the seizures from the focus to other parts of the brain.

  12. Pyramidal neurons in the septal and temporal CA1 field of the human and hedgehog tenrec hippocampus.

    PubMed

    Liagkouras, Ioannis; Michaloudi, Helen; Batzios, Christos; Psaroulis, Dimitrios; Georgiadis, Marios; Künzle, Heinz; Papadopoulos, Georgios C

    2008-07-01

    The present study examines comparatively the cellular density of disector-counted/Nissl-stained CA1 pyramidal neurons and the morphometric characteristics (dendritic number/length, spine number/density and Sholl-counted dendritic branch points/20 microm) of the basal and apical dendritic systems of Golgi-impregnated CA1 neurons, in the septal and temporal hippocampus of the human and hedgehog tenrec brain. The obtained results indicate that in both hippocampal parts the cellular density of the CA1 pyramidal neurons is lower in human than in tenrec. However, while the human pyramidal cell density is higher in the septal hippocampal part than in the temporal one, in the tenrec the density of these cells is higher in the temporal part. The dendritic tree of the CA1 pyramidal cells, more developed in the septal than in temporal hippocampus in both species studied, is in general more complex in the human hippocampus. The basal and the apical dendritic systems exhibit species related morphometric differences, while dendrites of different orders exhibit differences in their number and length, and in their spine density. Finally, in both species, as well as hippocampal parts and dendritic systems, changes of dendritic morphometric features along ascending dendritic orders fluctuate in a similar way, as do the number of dendritic branch points in relation to the distance from the neuron soma.

  13. ERK1/2 Activation Is Necessary for BDNF to Increase Dendritic Spine Density in Hippocampal CA1 Pyramidal Neurons

    ERIC Educational Resources Information Center

    Alonso, Mariana; Medina, Jorge H.; Pozzo-Miller, Lucas

    2004-01-01

    Brain-derived neurotrophic factor (BDNF) is a potent modulator of synaptic transmission and plasticity in the CNS, acting both pre- and postsynaptically. We demonstrated recently that BDNF/TrkB signaling increases dendritic spine density in hippocampal CA1 pyramidal neurons. Here, we tested whether activation of the prominent ERK (MAPK) signaling…

  14. PKC activators enhance GABAergic neurotransmission and paired-pulse facilitation in hippocampal CA1 pyramidal neurons.

    PubMed

    Xu, C; Liu, Q-Y; Alkon, D L

    2014-05-30

    Bryostatin-1, a potent agonist of protein kinase C (PKC), has recently been found to enhance spatial learning and long-term memory in rats, mice, rabbits and the nudibranch Hermissenda, and to exert profound neuroprotective effects on Alzheimer's disease (AD) in transgenic mice. However, details of the mechanistic effects of bryostatin on learning and memory remain unclear. To address this issue, whole-cell recording, a dual-recording approach and extracellular recording techniques were performed on young (2-4months) Brown-Norway rats. We found that bath-applied bryostatin-1 significantly increased the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). The firing rate of GABAergic interneurons significantly was also increased as recorded with a loosely-attached extracellular recording configuration. Simultaneous recordings from communicating cell pairs of interneuron and pyramidal neuron revealed unique activity-dependent properties of GABAergic synapses. Furthermore, the bryostatin-induced increase of the frequency and amplitude of IPSCs was blocked by methionine enkephalin which selectively suppressed the excitability of interneurons. Pretreatment with RO-32-0432, a relatively specific PKCα antagonist, blocked the effect of bryostatin on sIPSCs. Finally, bryostatin increased paired-pulse ratio of GABAergic synapses that lasted for at least 20min while pretreatment with RO-32-0432 significantly reduced the ratio. In addition, 8-[2-(2-pentyl-cyclopropylmethl)-cyclopropyl]-octanoic acid (DCP-LA), a selective PKCε activator, also increased the frequency and amplitude of sIPSCs. Taken together, these results suggest that bryostatin enhances GABAergic neurotransmission in pyramidal neurons by activating the PKCα & ε-dependent pathway and by a presynaptic mechanism with excitation of GABAergic interneurons. These effects of bryostatin on GABAergic transmissions and modifiability may contribute to the improvement of learning and memory

  15. Sex differences in GABABR-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex

    PubMed Central

    de Velasco, Ezequiel Marron Fernandez; Hearing, Matthew; Xia, Zhilian; Victoria, Nicole C.; Luján, Rafael; Wickman, Kevin

    2015-01-01

    The medial prefrontal cortex (mPFC) has been implicated in multiple disorders characterized by clear sex differences, including schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, and drug addiction. These sex differences likely represent underlying differences in connectivity and/or the balance of neuronal excitability within the mPFC. Recently, we demonstrated that signaling via the metabotropic γ-aminobutyric acid receptor (GABABR) and G proteingated inwardly-rectifying K+ (GIRK/Kir3) channels modulates the excitability of the key output neurons of the mPFC, the layer 5/6 pyramidal neurons. Here, we report a sex difference in the GABABR-GIRK signaling pathway in these neurons. Specifically, GABABR-dependent GIRK currents recorded in the prelimbic region of the mPFC were larger in adolescent male mice than in female counterparts. Interestingly, this sex difference was not observed in layer 5/6 pyramidal neurons of the adjacent infralimbic cortex, nor was it seen in young adult mice. The sex difference in GABABR-GIRK signaling is not attributable to different expression levels of signaling pathway components, but rather to a phosphorylation-dependent trafficking mechanism. Thus, sex differences related to some diseases associated with altered mPFC function may be explained in part by sex differences in GIRK-dependent signaling in mPFC pyramidal neurons. PMID:25843643

  16. Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth.

    PubMed

    De Zio, Daniela; Molinari, Francesca; Rizza, Salvatore; Gatta, Lucia; Ciotti, Maria Teresa; Salvatore, Anna Maria; Mathiassen, Søs Grønbæk; Cwetsch, Andrzej W; Filomeni, Giuseppe; Rosano, Giuseppe; Ferraro, Elisabetta

    2015-11-01

    The establishment of neuronal polarity and axonal outgrowth are key processes affecting neuronal migration and synapse formation, their impairment likely leading to cognitive deficits. Here we have found that the apoptotic protease activating factor 1 (Apaf1), apart from its canonical role in apoptosis, plays an additional function in cortical neurons, where its deficiency specifically impairs axonal growth. Given the central role played by centrosomes and microtubules in the polarized extension of the axon, our data suggest that Apaf1-deletion affects axonal outgrowth through an impairment of centrosome organization. In line with this, centrosomal protein expression, as well as their centrosomal localization proved to be altered upon Apaf1-deletion. Strikingly, we also found that Apaf1-loss affects trans-Golgi components and leads to a robust activation of AMP-dependent protein kinase (AMPK), this confirming the stressful conditions induced by Apaf1-deficiency. Since AMPK hyper-phosphorylation is known to impair a proper axon elongation, our finding contributes to explain the effect of Apaf1-deficiency on axogenesis. We also discovered that the signaling pathways mediating axonal growth and involving glycogen synthase kinase-3β, liver kinase B1, and collapsing-response mediator protein-2 are altered in Apaf1-KO neurons. Overall, our results reveal a novel non-apoptotic role for Apaf1 in axonal outgrowth, suggesting that the neuronal phenotype due to Apaf1-deletion could not only be fully ascribed to apoptosis inhibition, but might also be the result of defects in axogenesis. The discovery of new molecules involved in axonal elongation has a clinical relevance since it might help to explain neurological abnormalities occurring during early brain development. PMID:25975226

  17. Ibuprofen augments bilirubin toxicity in rat cortical neuronal culture.

    PubMed

    Berns, Monika; Toennessen, Margit; Koehne, Petra; Altmann, Rodica; Obladen, Michael

    2009-04-01

    Premature infants are at risk for bilirubin-associated brain damage. In cell cultures bilirubin causes neuronal apoptosis and necrosis. Ibuprofen is used to close the ductus arteriosus, and is often given when hyperbilirubinemia is at its maximum. Ibuprofen is known to interfere with bilirubin-albumin binding. We hypothesized that bilirubin toxicity to cultured rat embryonic cortical neurons is augmented by coincubation with ibuprofen. Incubation with ibuprofen above a concentration of 125 microg/mL reduced cell viability, measured by methylthiazole tetrazolium reduction, to 68% of controls (p < 0.05). Lactate dehydrogenase (LDH) release increased from 29 to 38% (p < 0.01). The vehicle solution did not affect cell viability. Coincubation with 10 microM unconjugated bilirubin (UCB)/human serum albumin in a molar ratio of 3:1 and 250 microg/mL ibuprofen caused additional loss of cell viability and increased LDH release (p < 0.01), DNA fragmentation, and activated caspase-3. Preincubation with the pan-caspase inhibitor z-val-ala-asp-fluoromethyl ketone abolished ibuprofen- and UCB-induced DNA fragmentation. The study demonstrates that bilirubin in low concentration of 10 microM reduces neuron viability and ibuprofen increases this effect. Apoptosis is the underlying cell death mechanism.

  18. Effects of 810 nm laser on mouse primary cortical neurons

    NASA Astrophysics Data System (ADS)

    Kharkwal, Gitika B.; Sharma, Sulbha K.; Huang, Ying-Ying; De Taboada, Luis; McCarthy, Thomas; Hamblin, Michael R.

    2011-03-01

    In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from mouse embryonic brains. Neurons were irradiated with light dose of 0.03, 0.3, 3, 10 and 30 J/cm2 and intracellular levels of reactive oxygen species, nitric oxide and calcium were measured. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluence. ROS was induced significantly by light at all light doses. Nitric oxide levels also showed an increase on treatment with light. The results of the present study suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling process which in turn may be responsible for the biomodulatory effects of the low level laser. At higher fluences beneficial mediators are reduced but potentially harmful mediators are increased thus offering an explanation for the biphasic dose response.

  19. Density of voltage-gated potassium channels is a bifurcation parameter in pyramidal neurons

    PubMed Central

    Robinson, Hugh P. C.; Århem, Peter

    2014-01-01

    Several types of intrinsic dynamics have been identified in brain neurons. Type 1 excitability is characterized by a continuous frequency-stimulus relationship and, thus, an arbitrarily low frequency at threshold current. Conversely, Type 2 excitability is characterized by a discontinuous frequency-stimulus relationship and a nonzero threshold frequency. In previous theoretical work we showed that the density of Kv channels is a bifurcation parameter, such that increasing the Kv channel density in a neuron model transforms Type 1 excitability into Type 2 excitability. Here we test this finding experimentally, using the dynamic clamp technique on Type 1 pyramidal cells in rat cortex. We found that increasing the density of slow Kv channels leads to a shift from Type 1 to Type 2 threshold dynamics, i.e., a distinct onset frequency, subthreshold oscillations, and reduced latency to first spike. In addition, the action potential was resculptured, with a narrower spike width and more pronounced afterhyperpolarization. All changes could be captured with a two-dimensional model. It may seem paradoxical that an increase in slow K channel density can lead to a higher threshold firing frequency; however, this can be explained in terms of bifurcation theory. In contrast to previous work, we argue that an increased outward current leads to a change in dynamics in these neurons without a rectification of the current-voltage curve. These results demonstrate that the behavior of neurons is determined by the global interactions of their dynamical elements and not necessarily simply by individual types of ion channels. PMID:25339708

  20. Low Concentrations of the Solvent Dimethyl Sulphoxide Alter Intrinsic Excitability Properties of Cortical and Hippocampal Pyramidal Cells

    PubMed Central

    Brown, Jonathan T.; Randall, Andrew D.

    2014-01-01

    Dimethylsulfoxide (DMSO) is a widely used solvent in biology. It has many applications perhaps the most common of which is in aiding the preparation of drug solutions from hydrophobic chemical entities. Recent studies have suggested that this molecule may be able to induce apoptosis in neural tissues urging caution regarding its introduction into humans, for example as part of stem cell transplants. Here we have used in vitro electrophysiological methods applied to murine brain slices to examine whether a few hours treatment with 0.05% DMSO (a concentration regarded by many as innocuous) alters intrinsic excitability properties of neurones. We investigated pyramidal neurones in two distinct brain regions, namely area CA1 of the hippocampus and layer 2 of perirhinal cortex. In the former there was no effect on resting potential but input resistance was decreased by DMSO pre-treatment. In line with this action potential count for any level of depolarizing current stimulus was reduced by ∼25% following DMSO treatment. Ih-mediated “sag” was also increased in CA1 pyramids and action potential waveform analysis demonstrated that DMSO treatment moved action potential threshold towards resting potential. In perirhinal cortex a decreased action potential output for various depolarizing current stimuli was also seen. In these cells action potential threshold was unaltered by DMSO but a significant increase in action potential width was apparent. These data indicate that pre-treatment with this widely employed solvent can elicit multifaceted neurophysiological changes in mammalian neurones at concentrations below those frequently encountered in the published literature. PMID:24647720

  1. Synaptic Conductances during Interictal Discharges in Pyramidal Neurons of Rat Entorhinal Cortex

    PubMed Central

    Amakhin, Dmitry V.; Ergina, Julia L.; Chizhov, Anton V.; Zaitsev, Aleksey V.

    2016-01-01

    In epilepsy, the balance of excitation and inhibition underlying the basis of neural network activity shifts, resulting in neuronal network hyperexcitability and recurrent seizure-associated discharges. Mechanisms involved in ictal and interictal events are not fully understood, in particular, because of controversial data regarding the dynamics of excitatory and inhibitory synaptic conductances. In the present study, we estimated AMPAR-, NMDAR-, and GABAA R-mediated conductances during two distinct types of interictal discharge (IID) in pyramidal neurons of rat entorhinal cortex in cortico-hippocampal slices. Repetitively emerging seizure-like events and IIDs were recorded in high extracellular potassium, 4-aminopyridine, and reduced magnesium-containing solution. An original procedure for estimating synaptic conductance during IIDs was based on the differences among the current-voltage characteristics of the synaptic components. The synaptic conductance dynamics obtained revealed that the first type of IID is determined by activity of GABAA R channels with depolarized reversal potential. The second type of IID is determined by the interplay between excitation and inhibition, with early AMPAR and prolonged depolarized GABAA R and NMDAR-mediated components. The study then validated the contribution of these components to IIDs by intracellular pharmacological isolation. These data provide new insights into the mechanisms of seizures generation, development, and cessation. PMID:27790093

  2. ToF-SIMS cluster ion imaging of hippocampal CA1 pyramidal rat neurons

    NASA Astrophysics Data System (ADS)

    Francis, J. T.; Nie, H.-Y.; Taylor, A. R.; Walzak, M. J.; Chang, W. H.; MacFabe, D. F.; Lau, W. M.

    2008-12-01

    Recent studies have demonstrated the power of time-of-flight secondary ion mass spectrometry (ToF-SIMS) cluster ion imaging to characterize biological structures, such as that of the rat central nervous system. A large number of the studies to date have been carried out on the "structural scale" imaging several mm 2 using mounted thin sections. In this work, we present our ToF-SIMS cluster ion imaging results on hippocampal rat brain neurons, at the cellular and sub-cellular levels. As a part of an ongoing investigation to examine gut linked metabolic factors in autism spectrum disorders using a novel rat model, we have observed a possible variation in hippocampal Cornu ammonis 1 (CA1) pyramidal neuron geometry in thin, paraformaldehyde fixed brain sections. However, the fixation process alters the tissue matrix such that much biochemical information appears to be lost. In an effort to preserve as much as possible this original information, we have established a protocol using unfixed thin brain sections, along with low dose, 500 eV Cs + pre-sputtering that allows imaging down to the sub-cellular scale with minimal sample preparation.

  3. Maternal mobile phone exposure alters intrinsic electrophysiological properties of CA1 pyramidal neurons in rat offspring.

    PubMed

    Razavinasab, Moazamehosadat; Moazzami, Kasra; Shabani, Mohammad

    2016-06-01

    Some studies have shown that exposure to electromagnetic field (EMF) may result in structural damage to neurons. In this study, we have elucidated the alteration in the hippocampal function of offspring Wistar rats (n = 8 rats in each group) that were chronically exposed to mobile phones during their gestational period by applying behavioral, histological, and electrophysiological tests. Rats in the EMF group were exposed to 900 MHz pulsed-EMF irradiation for 6 h/day. Whole cell recordings in hippocampal pyramidal cells in the mobile phone groups did show a decrease in neuronal excitability. Mobile phone exposure was mostly associated with a decrease in the number of action potentials fired in spontaneous activity and in response to current injection in both male and female groups. There was an increase in the amplitude of the afterhyperpolarization (AHP) in mobile phone rats compared with the control. The results of the passive avoidance and Morris water maze assessment of learning and memory performance showed that phone exposure significantly altered learning acquisition and memory retention in male and female rats compared with the control rats. Light microscopy study of brain sections of the control and mobile phone-exposed rats showed normal morphology.Our results suggest that exposure to mobile phones adversely affects the cognitive performance of both female and male offspring rats using behavioral and electrophysiological techniques.

  4. An arithmetic rule for spatial summation of excitatory and inhibitory inputs in pyramidal neurons

    PubMed Central

    Hao, Jiang; Wang, Xu-dong; Dan, Yang; Poo, Mu-ming; Zhang, Xiao-hui

    2009-01-01

    Dendritic integration of excitatory and inhibitory inputs is critical for neuronal computation, but the underlying rules remain to be elucidated. Based on realistic modeling and experiments in rat hippocampal slices, we derived a simple arithmetic rule for spatial summation of concurrent excitatory glutamatergic inputs (E) and inhibitory GABAergic inputs (I). The somatic response can be well approximated as the sum of the excitatory postsynaptic potential (EPSP), the inhibitory postsynaptic potential (IPSP), and a nonlinear term proportional to their product (k*EPSP*IPSP), where the coefficient k reflects the strength of shunting effect. The k value shows a pronounced asymmetry in its dependence on E and I locations. For I on the dendritic trunk, k decays rapidly with E–I distance for proximal Es, but remains largely constant for distal Es, indicating a uniformly high shunting efficacy for all distal Es. For I on an oblique branch, the shunting effect is restricted mainly within the branch, with the same proximal/distal asymmetry. This asymmetry can be largely attributed to cable properties of the dendrite. Further modeling studies showed that this rule also applies to the integration of multiple coincident Es and Is. Thus, this arithmetic rule offers a simple analytical tool for studying E–I integration in pyramidal neurons that incorporates the location specificity of GABAergic shunting inhibition. PMID:19955407

  5. Comparison of activity of individual pyramidal tract neurons during balancing, locomotion, and scratching.

    PubMed

    Beloozerova, Irina N; Sirota, Mikhail G; Orlovsky, Grigori N; Deliagina, Tatiana G

    2006-04-25

    Neuronal mechanisms of the spinal cord, brainstem, and cerebellum play a key role in the control of complex automatic motor behaviors-postural corrections, stepping, and scratching, whereas the role of the motor cortex is less clear. To assess this role, we recorded fore and hind limb-related pyramidal tract neurons (PTNs) in the cat during postural corrections and during locomotion; hind limb PTNs were also tested during scratching. The activity of nearly all PTNs was modulated in the rhythm of each of these motor patterns. The discharge frequency, averaged over the PTN population, was similar in different motor tasks, whereas the degree of frequency modulation was larger during locomotion. In individual PTNs, a correlation between analogous discharge characteristics (frequency or its modulation) in different tasks was very low, suggesting that input signals to PTNs in these tasks have a substantially different origin. In about a half of PTNs, their activity in different tasks was timed to the analogous (flexor/extensor) parts of the cycle, suggesting that these PTNs perform similar functions in these tasks (e.g., control of the value of muscle activity). In another half of PTNs, their activity was timed to opposite parts of the cycle in different tasks. These PTNs seem to perform different motor functions in different tasks, or their targets are active in different parts of the cycle in these tasks, or their effects are not directly related to the control of motor output (e.g., they modulate transmission of afferent signals).

  6. Plasticity-dependent, full detonation at hippocampal mossy fiber–CA3 pyramidal neuron synapses

    PubMed Central

    Vyleta, Nicholas P; Borges-Merjane, Carolina; Jonas, Peter

    2016-01-01

    Mossy fiber synapses on CA3 pyramidal cells are 'conditional detonators' that reliably discharge postsynaptic targets. The 'conditional' nature implies that burst activity in dentate gyrus granule cells is required for detonation. Whether single unitary excitatory postsynaptic potentials (EPSPs) trigger spikes in CA3 neurons remains unknown. Mossy fiber synapses exhibit both pronounced short-term facilitation and uniquely large post-tetanic potentiation (PTP). We tested whether PTP could convert mossy fiber synapses from subdetonator into detonator mode, using a recently developed method to selectively and noninvasively stimulate individual presynaptic terminals in rat brain slices. Unitary EPSPs failed to initiate a spike in CA3 neurons under control conditions, but reliably discharged them after induction of presynaptic short-term plasticity. Remarkably, PTP switched mossy fiber synapses into full detonators for tens of seconds. Plasticity-dependent detonation may be critical for efficient coding, storage, and recall of information in the granule cell–CA3 cell network. DOI: http://dx.doi.org/10.7554/eLife.17977.001 PMID:27780032

  7. Three-dimensional localization of neurons in cortical tetrode recordings

    PubMed Central

    Victor, Jonathan D.; Ohiorhenuan, Ifije; Schmid, Anita M.; Hu, Qin

    2011-01-01

    The recording radius and spatial selectivity of an extracellular probe are important for interpreting neurophysiological recordings but are rarely measured. Moreover, an analysis of the recording biophysics of multisite probes (e.g., tetrodes) can provide for source characterization and localization of spiking single units, but this capability has remained largely unexploited. Here we address both issues quantitatively. Advancing a tetrode (≈40-μm contact separation, tetrahedral geometry) in 5- to 10-μm steps, we repeatedly recorded extracellular action potentials (EAPs) of single neurons in the visual cortex. Using measured spatial variation of EAPs, the tetrodes' measured geometry, and a volume conductor model of the cortical tissue, we solved the inverse problem of estimating the location and the size of the equivalent dipole model of the spike generator associated with each neuron. Half of the 61 visual neurons were localized within a radius of ≈100 μm and 95% within ≈130 μm around the tetrode tip (i.e., a large fraction was much further than previously thought). Because of the combined angular sensitivity of the tetrode's leads, location uncertainty was less than one-half the cell's distance. We quantified the spatial dependence of the probability of cell isolation, the isolated fraction, and the dependence of the recording radius on probe size and equivalent dipole size. We also reconstructed the spatial configuration of sets of simultaneously recorded neurons to demonstrate the potential use of 3D dipole localization for functional anatomy. Finally, we found that the dipole moment vector, surprisingly, tended to point toward the probe, leading to the interpretation that the equivalent dipole represents a “local lobe” of the dendritic arbor. PMID:21613581

  8. Ketamine-induced apoptosis in cultured rat cortical neurons

    SciTech Connect

    Takadera, Tsuneo . E-mail: t-takadera@hokuriku-u.ac.jp; Ishida, Akira; Ohyashiki, Takao

    2006-01-15

    Recent data suggest that anesthetic drugs cause neurodegeneration during development. Ketamine is frequently used in infants and toddlers for elective surgeries. The purpose of this study is to determine whether glycogen synthase kinase-3 (GSK-3) is involved in ketamine-induced apoptosis. Ketamine increased apoptotic cell death with morphological changes which were characterized by cell shrinkage, nuclear condensation or fragmentation. In addition, insulin growth factor-1 completely blocked the ketamine-induced apoptotic cell death. Ketamine decreased Akt phosphorylation. GSK-3 is known as a downstream target of Akt. The selective inhibitors of GSK-3 prevented the ketamine-induced apoptosis. Moreover, caspase-3 activation was accompanied by the ketamine-induced cell death and inhibited by the GSK-3 inhibitors. These results suggest that activation of GSK-3 is involved in ketamine-induced apoptosis in rat cortical neurons.

  9. Simultaneous visualization of cortical barrels and horseradish peroxidase-injected layer 5b vibrissa neurones in the rat.

    PubMed Central

    Ito, M

    1992-01-01

    1. Using diaminobenzidine (DAB) as a chromagen, horseradish peroxidase-injected neurones and cytochrome oxidase-stained barrels were visualized simultaneously in the rat vibrissa cortex. Neurones were initially tested during extracellular recording for responses to whisker deflections. This was followed by intracellular injection of the soma with horseradish peroxidase (HRP) and histological processing to visualize the HRP-stained neurone in an incubation solution which contained, in addition to DAB, cytochrome C for cytochrome oxidase (CO) reaction of the barrels. 2. Recording and intracellular staining were made in layer 5b under urethane anaesthesia. CO-stained barrels were observed in layer 4. Physiologically and morphologically characterized neurones were mostly large pyramidal neurones that responded to more than one whisker and displayed transient-type responses. 3. In tangential sections, the apical dendrite of the HRP-filled neurone was followed from the soma level upward as it ascended through the barrelfield in layer 4. The cross-section of the apical dendrite was found in the periphery of the CO-stained barrel. Using the apical dendrite as a guide, the basal dendritic field of the layer 5b pyramidal neurone was aligned on the pattern of layer 4 barrels. The soma was seen to project basal dendrites in all directions, involving one or two neighbouring barrels/columns. 4. In sixteen neurones examined in tangential sections, a complete spatial tuning map constructed by measuring sensitivity of the neurone to different whiskers could be compared to the basal dendritic field in relation to the pattern of overlying layer 4 barrels. The mean receptive field size in terms of the number of effective whiskers was 5.8 whereas the mean dendritic field size in terms of the number of barrels/columns involved was 2.2. In addition to the well-documented role of intracortical connectivity in elaboration of multi-whisker receptor fields in the cortical neurones, the role

  10. Human temporal cortical single neuron activity during working memory maintenance.

    PubMed

    Zamora, Leona; Corina, David; Ojemann, George

    2016-06-01

    The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two

  11. Human temporal cortical single neuron activity during working memory maintenance.

    PubMed

    Zamora, Leona; Corina, David; Ojemann, George

    2016-06-01

    The Working Memory model of human memory, first introduced by Baddeley and Hitch (1974), has been one of the most influential psychological constructs in cognitive psychology and human neuroscience. However the neuronal correlates of core components of this model have yet to be fully elucidated. Here we present data from two studies where human temporal cortical single neuron activity was recorded during tasks differentially affecting the maintenance component of verbal working memory. In Study One we vary the presence or absence of distracting items for the entire period of memory storage. In Study Two we vary the duration of storage so that distractors filled all, or only one-third of the time the memory was stored. Extracellular single neuron recordings were obtained from 36 subjects undergoing awake temporal lobe resections for epilepsy, 25 in Study one, 11 in Study two. Recordings were obtained from a total of 166 lateral temporal cortex neurons during performance of one of these two tasks, 86 study one, 80 study two. Significant changes in activity with distractor manipulation were present in 74 of these neurons (45%), 38 Study one, 36 Study two. In 48 (65%) of those there was increased activity during the period when distracting items were absent, 26 Study One, 22 Study Two. The magnitude of this increase was greater for Study One, 47.6%, than Study Two, 8.1%, paralleling the reduction in memory errors in the absence of distracters, for Study One of 70.3%, Study Two 26.3% These findings establish that human lateral temporal cortex is part of the neural system for working memory, with activity during maintenance of that memory that parallels performance, suggesting it represents active rehearsal. In 31 of these neurons (65%) this activity was an extension of that during working memory encoding that differed significantly from the neural processes recorded during overt and silent language tasks without a recent memory component, 17 Study one, 14 Study two

  12. Selection and parameterization of cortical neurons for neuroprosthetic control

    NASA Astrophysics Data System (ADS)

    Wahnoun, Remy; He, Jiping; Helms Tillery, Stephen I.

    2006-06-01

    When designing neuroprosthetic interfaces for motor function, it is crucial to have a system that can extract reliable information from available neural signals and produce an output suitable for real life applications. Systems designed to date have relied on establishing a relationship between neural discharge patterns in motor cortical areas and limb movement, an approach not suitable for patients who require such implants but who are unable to provide proper motor behavior to initially tune the system. We describe here a method that allows rapid tuning of a population vector-based system for neural control without arm movements. We trained highly motivated primates to observe a 3D center-out task as the computer played it very slowly. Based on only 10-12 s of neuronal activity observed in M1 and PMd, we generated an initial mapping between neural activity and device motion that the animal could successfully use for neuroprosthetic control. Subsequent tunings of the parameters led to improvements in control, but the initial selection of neurons and estimated preferred direction for those cells remained stable throughout the remainder of the day. Using this system, we have observed that the contribution of individual neurons to the overall control of the system is very heterogeneous. We thus derived a novel measure of unit quality and an indexing scheme that allowed us to rate each neuron's contribution to the overall control. In offline tests, we found that fewer than half of the units made positive contributions to the performance. We tested this experimentally by having the animals control the neuroprosthetic system using only the 20 best neurons. We found that performance in this case was better than when the entire set of available neurons was used. Based on these results, we believe that, with careful task design, it is feasible to parameterize control systems without any overt behaviors and that subsequent control system design will be enhanced with

  13. Slow Bursting Neurons of Mouse Cortical Layer 6b Are Depolarized by Hypocretin/Orexin and Major Transmitters of Arousal

    PubMed Central

    Wenger Combremont, Anne-Laure; Bayer, Laurence; Dupré, Anouk; Mühlethaler, Michel; Serafin, Mauro

    2016-01-01

    Neurons firing spontaneously in bursts in the absence of synaptic transmission have been previously recorded in different layers of cortical brain slices. It has been suggested that such neurons could contribute to the generation of alternating UP and DOWN states, a pattern of activity seen during slow-wave sleep. Here, we show that in layer 6b (L6b), known from our previous studies to contain neurons highly responsive to the wake-promoting transmitter hypocretin/orexin (hcrt/orx), there is a set of neurons, endowed with distinct intrinsic properties, which displayed a strong propensity to fire spontaneously in rhythmic bursts. In response to small depolarizing steps, they responded with a delayed firing of action potentials which, upon higher depolarizing steps, invariably inactivated and were followed by a depolarized plateau potential and a depolarizing afterpotential. These cells also displayed a strong hyperpolarization-activated rectification compatible with the presence of an Ih current. Most L6b neurons with such properties were able to fire spontaneously in bursts. Their bursting activity was of intrinsic origin as it persisted not only in presence of blockers of ionotropic glutamatergic and GABAergic receptors but also in a condition of complete synaptic blockade. However, a small number of these neurons displayed a mix of intrinsic bursting and synaptically driven recurrent UP and DOWN states. Most of the bursting L6b neurons were depolarized and excited by hcrt/orx through a direct postsynaptic mechanism that led to tonic firing and eventually inactivation. Similarly, they were directly excited by noradrenaline, histamine, dopamine, and neurotensin. Finally, the intracellular injection of these cells with dye and their subsequent Neurolucida reconstruction indicated that they were spiny non-pyramidal neurons. These results lead us to suggest that the propensity for slow rhythmic bursting of this set of L6b neurons could be directly impeded by hcrt

  14. Exogenous Reelin modifies the migratory behavior of neurons depending on cortical location.

    PubMed

    Britto, Joanne M; Tait, Karen J; Lee, Ean Phing; Gamble, Robin S; Hattori, Mitsuharu; Tan, Seong-Seng

    2014-11-01

    Malformations of cortical development can arise when projection neurons generated in the germinal zones fail to migrate properly into the cortical plate. This process is critically dependent on the Reelin glycoprotein, which when absent leads to an inversion of cortical layers and blurring of borders. Reelin has other functions including supporting neuron migration and maintaining their trajectories; however, the precise role on glial fiber-dependent or -independent migration of neurons remains controversial. In this study, we wish to test the hypothesis that migrating cortical neurons at different levels of the cortical wall have differential responses to Reelin. We exposed neurons migrating across the cortical wall to exogenous Reelin and monitored their migratory behavior using time-lapse imaging. Our results show that, in the germinal zones, exogenous Reelin retarded neuron migration and altered their trajectories. This behavior is in contrast to the response of neurons located in the intermediate zone (IZ), possibly because Reelin receptors are not expressed in this zone. In the reeler cortex, Reelin receptors are expressed in the IZ and exposure to exogenous Reelin was able to rescue the migratory defect. These studies demonstrate that migrating neurons have nonequivalent responses to Reelin depending on their location within the cortical wall. PMID:23749873

  15. Exogenous Reelin modifies the migratory behavior of neurons depending on cortical location.

    PubMed

    Britto, Joanne M; Tait, Karen J; Lee, Ean Phing; Gamble, Robin S; Hattori, Mitsuharu; Tan, Seong-Seng

    2014-11-01

    Malformations of cortical development can arise when projection neurons generated in the germinal zones fail to migrate properly into the cortical plate. This process is critically dependent on the Reelin glycoprotein, which when absent leads to an inversion of cortical layers and blurring of borders. Reelin has other functions including supporting neuron migration and maintaining their trajectories; however, the precise role on glial fiber-dependent or -independent migration of neurons remains controversial. In this study, we wish to test the hypothesis that migrating cortical neurons at different levels of the cortical wall have differential responses to Reelin. We exposed neurons migrating across the cortical wall to exogenous Reelin and monitored their migratory behavior using time-lapse imaging. Our results show that, in the germinal zones, exogenous Reelin retarded neuron migration and altered their trajectories. This behavior is in contrast to the response of neurons located in the intermediate zone (IZ), possibly because Reelin receptors are not expressed in this zone. In the reeler cortex, Reelin receptors are expressed in the IZ and exposure to exogenous Reelin was able to rescue the migratory defect. These studies demonstrate that migrating neurons have nonequivalent responses to Reelin depending on their location within the cortical wall.

  16. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'. PMID:27574304

  17. Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states.

    PubMed

    Lecrux, C; Hamel, E

    2016-10-01

    Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as 'neurovascular coupling (NVC)'. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states.This article is part of the themed issue 'Interpreting BOLD: a dialogue between cognitive and cellular neuroscience'.

  18. Apoptosis of Hippocampal Pyramidal Neurons Is Virus Independent in a Mouse Model of Acute Neurovirulent Picornavirus Infection

    PubMed Central

    Buenz, Eric J.; Sauer, Brian M.; LaFrance-Corey, Reghann G.; Deb, Chandra; Denic, Aleksandar; German, Christopher L.; Howe, Charles L.

    2009-01-01

    Many viruses, including picornaviruses, have the potential to infect the central nervous system (CNS) and stimulate a neuroinflammatory immune response, especially in infants and young children. Cognitive deficits associated with CNS picornavirus infection result from injury and death of neurons that may occur due to direct viral infection or during the immune responses to virus in the brain. Previous studies have concluded that apoptosis of hippocampal neurons during picornavirus infection is a cell-autonomous event triggered by direct neuronal infection. However, these studies assessed neuron death at time points late in infection and during infections that lead to either death of the host or persistent viral infection. In contrast, many neurovirulent picornavirus infections are acute and transient, with rapid clearance of virus from the host. We provide evidence of hippocampal pathology in mice acutely infected with the Theiler’s murine encephalomyelitis picornavirus. We found that CA1 pyramidal neurons exhibited several hallmarks of apoptotic death, including caspase-3 activation, DNA fragmentation, and chromatin condensation within 72 hours of infection. Critically, we also found that many of the CA1 pyramidal neurons undergoing apoptosis were not infected with virus, indicating that neuronal cell death during acute picornavirus infection of the CNS occurs in a non–cell-autonomous manner. These observations suggest that therapeutic strategies other than antiviral interventions may be useful for neuroprotection during acute CNS picornavirus infection. PMID:19608874

  19. Apoptosis of hippocampal pyramidal neurons is virus independent in a mouse model of acute neurovirulent picornavirus infection.

    PubMed

    Buenz, Eric J; Sauer, Brian M; Lafrance-Corey, Reghann G; Deb, Chandra; Denic, Aleksandar; German, Christopher L; Howe, Charles L

    2009-08-01

    Many viruses, including picornaviruses, have the potential to infect the central nervous system (CNS) and stimulate a neuroinflammatory immune response, especially in infants and young children. Cognitive deficits associated with CNS picornavirus infection result from injury and death of neurons that may occur due to direct viral infection or during the immune responses to virus in the brain. Previous studies have concluded that apoptosis of hippocampal neurons during picornavirus infection is a cell-autonomous event triggered by direct neuronal infection. However, these studies assessed neuron death at time points late in infection and during infections that lead to either death of the host or persistent viral infection. In contrast, many neurovirulent picornavirus infections are acute and transient, with rapid clearance of virus from the host. We provide evidence of hippocampal pathology in mice acutely infected with the Theiler's murine encephalomyelitis picornavirus. We found that CA1 pyramidal neurons exhibited several hallmarks of apoptotic death, including caspase-3 activation, DNA fragmentation, and chromatin condensation within 72 hours of infection. Critically, we also found that many of the CA1 pyramidal neurons undergoing apoptosis were not infected with virus, indicating that neuronal cell death during acute picornavirus infection of the CNS occurs in a non-cell-autonomous manner. These observations suggest that therapeutic strategies other than antiviral interventions may be useful for neuroprotection during acute CNS picornavirus infection. PMID:19608874

  20. Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits.

    PubMed

    Oh, M Matthew; Simkin, Dina; Disterhoft, John F

    2016-01-01

    Aging-related cognitive deficits have been attributed to dysfunction of neurons due to failures at synaptic or intrinsic loci, or both. Given the importance of the hippocampus for successful encoding of memory and that the main output of the hippocampus is via the CA1 pyramidal neurons, much of the research has been focused on identifying the aging-related changes of these CA1 pyramidal neurons. We and others have discovered that the postburst afterhyperpolarization (AHP) following a train of action potentials is greatly enlarged in CA1 pyramidal neurons of aged animals. This enlarged postburst AHP is a significant factor in reducing the intrinsic excitability of these neurons, and thus limiting their activity in the neural network during learning. Based on these data, it has largely been thought that aging-related cognitive deficits are attributable to reduced activity of pyramidal neurons. However, recent in vivo and ex vivo studies provide compelling evidence that aging-related deficits could also be due to a converse change in CA3 pyramidal neurons, which show increased activity with aging. In this review, we will incorporate these recent findings and posit that an interdependent dynamic dysfunctional change occurs within the hippocampal network, largely due to altered intrinsic excitability in CA1 and CA3 hippocampal pyramidal neurons, which ultimately leads to the aging-related cognitive deficits. PMID:27375440

  1. Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits

    PubMed Central

    Oh, M. Matthew; Simkin, Dina; Disterhoft, John F.

    2016-01-01

    Aging-related cognitive deficits have been attributed to dysfunction of neurons due to failures at synaptic or intrinsic loci, or both. Given the importance of the hippocampus for successful encoding of memory and that the main output of the hippocampus is via the CA1 pyramidal neurons, much of the research has been focused on identifying the aging-related changes of these CA1 pyramidal neurons. We and others have discovered that the postburst afterhyperpolarization (AHP) following a train of action potentials is greatly enlarged in CA1 pyramidal neurons of aged animals. This enlarged postburst AHP is a significant factor in reducing the intrinsic excitability of these neurons, and thus limiting their activity in the neural network during learning. Based on these data, it has largely been thought that aging-related cognitive deficits are attributable to reduced activity of pyramidal neurons. However, recent in vivo and ex vivo studies provide compelling evidence that aging-related deficits could also be due to a converse change in CA3 pyramidal neurons, which show increased activity with aging. In this review, we will incorporate these recent findings and posit that an interdependent dynamic dysfunctional change occurs within the hippocampal network, largely due to altered intrinsic excitability in CA1 and CA3 hippocampal pyramidal neurons, which ultimately leads to the aging-related cognitive deficits. PMID:27375440

  2. Dendritic branching angles of pyramidal cells across layers of the juvenile rat somatosensory cortex.

    PubMed

    Leguey, Ignacio; Bielza, Concha; Larrañaga, Pedro; Kastanauskaite, Asta; Rojo, Concepción; Benavides-Piccione, Ruth; DeFelipe, Javier

    2016-09-01

    The characterization of the structural design of cortical microcircuits is essential for understanding how they contribute to function in both health and disease. Since pyramidal neurons represent the most abundant neuronal type and their dendritic spines constitute the major postsynaptic elements of cortical excitatory synapses, our understanding of the synaptic organization of the neocortex largely depends on the available knowledge regarding the structure of pyramidal cells. Previous studies have identified several apparently common rules in dendritic geometry. We study the dendritic branching angles of pyramidal cells across layers to further shed light on the principles that determine the geometric shapes of these cells. We find that the dendritic branching angles of pyramidal cells from layers II-VI of the juvenile rat somatosensory cortex suggest common design principles, despite the particular morphological and functional features that are characteristic of pyramidal cells in each cortical layer. J. Comp. Neurol. 524:2567-2576, 2016. © 2016 Wiley Periodicals, Inc.

  3. Dendritic branching angles of pyramidal cells across layers of the juvenile rat somatosensory cortex.

    PubMed

    Leguey, Ignacio; Bielza, Concha; Larrañaga, Pedro; Kastanauskaite, Asta; Rojo, Concepción; Benavides-Piccione, Ruth; DeFelipe, Javier

    2016-09-01

    The characterization of the structural design of cortical microcircuits is essential for understanding how they contribute to function in both health and disease. Since pyramidal neurons represent the most abundant neuronal type and their dendritic spines constitute the major postsynaptic elements of cortical excitatory synapses, our understanding of the synaptic organization of the neocortex largely depends on the available knowledge regarding the structure of pyramidal cells. Previous studies have identified several apparently common rules in dendritic geometry. We study the dendritic branching angles of pyramidal cells across layers to further shed light on the principles that determine the geometric shapes of these cells. We find that the dendritic branching angles of pyramidal cells from layers II-VI of the juvenile rat somatosensory cortex suggest common design principles, despite the particular morphological and functional features that are characteristic of pyramidal cells in each cortical layer. J. Comp. Neurol. 524:2567-2576, 2016. © 2016 Wiley Periodicals, Inc. PMID:26850576

  4. Decreased Lin7b Expression in Layer 5 Pyramidal Neurons May Contribute to Impaired Corticostriatal Connectivity in Huntington Disease

    PubMed Central

    Zucker, Birgit; Kama, Jibrin A.; Kuhn, Alexandre; Thu, Doris; Orlando, Lianna R.; Dunah, Anthone W.; Gokce, Ozgun; Taylor, David M.; Lambeck, Johann; Friedrich, Bernd; Lindenberg, Katrin S.; Faull, Richard L.M.; Weiller, Cornelius; Young, Anne B.; Luthi-Carter, Ruth

    2010-01-01

    Motor dysfunction, cognitive impairment and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine-related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1 and lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the lin7 homolog b, (lin7b, also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. lin7b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD. PMID:20720508

  5. Alterations in cortical thickness and neuronal density in the frontal cortex of Albert Einstein.

    PubMed

    Anderson, B; Harvey, T

    1996-06-01

    Neuronal density, neuron size, and the number of neurons under 1 mm2 of cerebral cortical surface area were measured in the right pre-frontal cortex of Albert Einstein and five elderly control subjects. Measurement of neuronal density used the optical dissector technique on celloidin-embedded cresyl violet-stained sections. The neurons counted provided a systematic random sample for the measurement of cell body cross-sectional area. Einstein's cortex did not differ from the control subjects in the number of neurons under 1 mm2 of cerebral cortex or in mean neuronal size. Because Einstein's cortex was thinner than the controls he had a greater neuronal density.

  6. Modulation of neuronal activity and plasma membrane properties with low-power millimeter waves in organotypic cortical slices

    NASA Astrophysics Data System (ADS)

    Pikov, Victor; Arakaki, Xianghong; Harrington, Michael; Fraser, Scott E.; Siegel, Peter H.

    2010-08-01

    As millimeter waves (MMWs) are being increasingly used in communications and military applications, their potential effects on biological tissue has become an important issue for scientific inquiry. Specifically, several MMW effects on the whole-nerve activity were reported, but the underlying neuronal changes remain unexplored. This study used slices of cortical tissue to evaluate the MMW effects on individual pyramidal neurons under conditions mimicking their in vivo environment. The applied levels of MMW power are three orders of magnitude below the existing safe limit for human exposure of 1 mW cm-2. Surprisingly, even at these low power levels, MMWs were able to produce considerable changes in neuronal firing rate and plasma membrane properties. At the power density approaching 1 µW cm-2, 1 min of MMW exposure reduced the firing rate to one third of the pre-exposure level in four out of eight examined neurons. The width of the action potentials was narrowed by MMW exposure to 17% of the baseline value and the membrane input resistance decreased to 54% of the baseline value across all neurons. These effects were short lasting (2 min or less) and were accompanied by MMW-induced heating of the bath solution at 3 °C. Comparison of these results with previously published data on the effects of general bath heating of 10 °C indicated that MMW-induced effects cannot be fully attributed to heating and may involve specific MMW absorption by the tissue. Blocking of the intracellular Ca2+-mediated signaling did not significantly alter the MMW-induced neuronal responses suggesting that MMWs interacted directly with the neuronal plasma membrane. The presented results constitute the first demonstration of direct real-time monitoring of the impact of MMWs on nervous tissue at a microscopic scale. Implication of these findings for the therapeutic modulation of neuronal excitability is discussed.

  7. IgLON cell adhesion molecules are shed from the cell surface of cortical neurons to promote neuronal growth.

    PubMed

    Sanz, Ricardo; Ferraro, Gino B; Fournier, Alyson E

    2015-02-13

    Matrix metalloproteinases and a disintegrin and metalloproteinases are members of the zinc endopeptidases, which cleave components of the extracellular matrix as well as cell surface proteins resulting in degradation or release of biologically active fragments. Surface ectodomain shedding affects numerous biological processes, including survival, axon outgrowth, axon guidance, and synaptogenesis. In this study, we evaluated the role of metalloproteinases in regulating cortical neurite growth. We found that treatment of mature cortical neurons with pan-metalloproteinase inhibitors or with tissue inhibitors of metalloproteinase-3 reduced neurite outgrowth. Through mass spectrometry, we characterized the metalloproteinase-sensitive cell surface proteome of mature cortical neurons. Members of the IgLON family of glycosylphosphatidylinositol-anchored neural cell adhesion molecules were identified and validated as proteins that were shed from the surface of mature cortical neurons in a metalloproteinase-dependent manner. Introduction of two members of the IgLON family, neurotrimin and NEGR1, in early embryonic neurons was sufficient to confer sensitivity to metalloproteinase inhibitors in neurite outgrowth assays. Outgrowth experiments on immobilized IgLON proteins revealed a role for all IgLON family members in promoting neurite extension from cortical neurons. Together, our findings support a role for metalloproteinase-dependent shedding of IgLON family members in regulating neurite outgrowth from mature cortical neurons.

  8. Differential emotional experience induces elevated spine densities on basal dendrites of pyramidal neurons in the anterior cingulate cortex of Octodon degus.

    PubMed

    Helmeke, C; Poeggel, G; Braun, K

    2001-01-01

    It appears likely that, in analogy to the synaptic development of sensory and motor cortices, which critically depends on sensory or motor stimulation (Rosenzweig and Bennett, 1996), the synaptic development of limbic cortical regions are modulated by early postnatal cognitive and emotional experiences. The very first postnatal experience, which takes place in a confined and stable familial environment, is the interaction of the newborn individual with the parents and siblings (Gray, 1958). The aim of this quantitative morphological study was to analyze the impact of different degrees of juvenile emotional experience on the synaptic development in a limbic cortical area, the dorsal anterior cingulate cortex, a region which is involved in the perception and regulation of emotions. We study the precocious trumpet-tailed rat (Octodon degus) as the animal model, because, like human babies, this species is born with functional visual and acoustic systems and the pups are therefore capable of detecting even subtle environmental changes immediately after birth (Reynolds and Wright, 1979; Poeggel and Braun, 1996; Braun et al., 2000; Ovtscharoff and Braun, 2001). The results demonstrate that already a subtle disturbance of the familial environment such as handling induced significantly elevated spine densities on the basal dendrites of layer III cortical pyramidal neurons. More severe disturbances of the emotional environment, such as periodic parental deprivation with or without subsequent chronic social isolation, resulted in an elevation of spine densities of similar magnitude as seen after handling and in addition, altered spine densities confined to specific dendritic segments were observed in these groups. These observations unveil the remarkable sensitivity of the dorsal anterior cingulate cortex towards environmental influences and behavioral experiences during phases of postnatal development. The behavioral consequences of these experience-induced synaptic changes

  9. C3G regulates cortical neuron migration, preplate splitting and radial glial cell attachment.

    PubMed

    Voss, Anne K; Britto, Joanne M; Dixon, Mathew P; Sheikh, Bilal N; Collin, Caitlin; Tan, Seong-Seng; Thomas, Tim

    2008-06-01

    Neuronal migration is integral to the development of the cerebral cortex and higher brain function. Cortical neuron migration defects lead to mental disorders such as lissencephaly and epilepsy. Interaction of neurons with their extracellular environment regulates cortical neuron migration through cell surface receptors. However, it is unclear how the signals from extracellular matrix proteins are transduced intracellularly. We report here that mouse embryos lacking the Ras family guanine nucleotide exchange factor, C3G (Rapgef1, Grf2), exhibit a cortical neuron migration defect resulting in a failure to split the preplate into marginal zone and subplate and a failure to form a cortical plate. C3G-deficient cortical neurons fail to migrate. Instead, they arrest in a multipolar state and accumulate below the preplate. The basement membrane is disrupted and radial glial processes are disorganised and lack attachment in C3G-deficient brains. C3G is activated in response to reelin in cortical neurons, which, in turn, leads to activation of the small GTPase Rap1. In C3G-deficient cells, Rap1 GTP loading in response to reelin stimulation is reduced. In conclusion, the Ras family regulator C3G is essential for two aspects of cortex development, namely radial glial attachment and neuronal migration.

  10. Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation.

    PubMed

    Tokuda, Kazuhiro; Izumi, Yukitoshi; Zorumski, Charles F

    2011-07-01

    Using an antibody against 5α-reduced neurosteroids, predominantly allopregnanolone, we found that immunostaining in the CA1 region of rat hippocampal slices was confined to pyramidal neurons. This neurosteroid staining was increased following 15 min administration of 60 mm but not 20 mm ethanol, and the enhancement was blocked by finasteride and dutasteride, selective inhibitors of 5α-reductase, a key enzyme required for allopregnanolone synthesis. Consistent with a prior report indicating that N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation can promote steroid production, we observed that D-2-amino-5-phosphonovalerate (APV), a competitive NMDAR antagonist, blocked the effects of 60 mm ethanol on staining. We previously reported that 60 mm ethanol inhibits the induction of long-term potentiation (LTP), a cellular model for memory formation, in the CA1 region. In the present study, LTP inhibition by 60 mm ethanol was also overcome by both the 5α-reductase inhibitors and by APV. Furthermore, the effects of ethanol on neurosteroid production and LTP were mimicked by a low concentration of NMDA (1 μm), and the ability of NMDA to inhibit LTP and to enhance neurosteroid staining was reversed by finasteride and dutasteride, as well as by APV. These results indicate that ethanol paradoxically enhances GABAergic neurosteroid production by activation of unblocked NMDARs and that acute LTP inhibition by ethanol represents a form of NMDAR-mediated metaplasticity. PMID:21734282

  11. Development and Maturation of Embryonic Cortical Neurons Grafted into the Damaged Adult Motor Cortex

    PubMed Central

    Ballout, Nissrine; Frappé, Isabelle; Péron, Sophie; Jaber, Mohamed; Zibara, Kazem; Gaillard, Afsaneh

    2016-01-01

    Injury to the human central nervous system can lead to devastating consequences due to its poor ability to self-repair. Neural transplantation aimed at replacing lost neurons and restore functional circuitry has proven to be a promising therapeutical avenue. We previously reported in adult rodent animal models with cortical lesions that grafted fetal cortical neurons could effectively re-establish specific patterns of projections and synapses. The current study was designed to provide a detailed characterization of the spatio-temporal in vivo development of fetal cortical transplanted cells within the lesioned adult motor cortex and their corresponding axonal projections. We show here that as early as 2 weeks after grafting, cortical neuroblasts transplanted into damaged adult motor cortex developed appropriate projections to cortical and subcortical targets. Grafted cells initially exhibited characteristics of immature neurons, which then differentiated into mature neurons with appropriate cortical phenotypes where most were glutamatergic and few were GABAergic. All cortical subtypes identified with the specific markers CTIP2, Cux1, FOXP2, and Tbr1 were generated after grafting as evidenced with BrdU co-labeling. The set of data provided here is of interest as it sets biological standards for future studies aimed at replacing fetal cells with embryonic stem cells as a source of cortical neurons. PMID:27536221

  12. Low-intensity repetitive magnetic stimulation lowers action potential threshold and increases spike firing in layer 5 pyramidal neurons in vitro.

    PubMed

    Tang, Alexander D; Hong, Ivan; Boddington, Laura J; Garrett, Andrew R; Etherington, Sarah; Reynolds, John N J; Rodger, Jennifer

    2016-10-29

    Repetitive transcranial magnetic stimulation (rTMS) has become a popular method of modulating neural plasticity in humans. Clinically, rTMS is delivered at high intensities to modulate neuronal excitability. While the high-intensity magnetic field can be targeted to stimulate specific cortical regions, areas adjacent to the targeted area receive stimulation at a lower intensity and may contribute to the overall plasticity induced by rTMS. We have previously shown that low-intensity rTMS induces molecular and structural plasticity in vivo, but the effects on membrane properties and neural excitability have not been investigated. Here we investigated the acute effect of low-intensity repetitive magnetic stimulation (LI-rMS) on neuronal excitability and potential changes on the passive and active electrophysiological properties of layer 5 pyramidal neurons in vitro. Whole-cell current clamp recordings were made at baseline prior to subthreshold LI-rMS (600 pulses of iTBS, n=9 cells from 7 animals) or sham (n=10 cells from 9 animals), immediately after stimulation, as well as 10 and 20min post-stimulation. Our results show that LI-rMS does not alter passive membrane properties (resting membrane potential and input resistance) but hyperpolarises action potential threshold and increases evoked spike-firing frequency. Increases in spike firing frequency were present throughout the 20min post-stimulation whereas action potential (AP) threshold hyperpolarization was present immediately after stimulation and at 20min post-stimulation. These results provide evidence that LI-rMS alters neuronal excitability of excitatory neurons. We suggest that regions outside the targeted region of high-intensity rTMS are susceptible to neuromodulation and may contribute to rTMS-induced plasticity. PMID:27568058

  13. Kv1.2 mediates heterosynaptic modulation of direct cortical synaptic inputs in CA3 pyramidal cells

    PubMed Central

    Hyun, Jung Ho; Eom, Kisang; Lee, Kyu-Hee; Bae, Jin Young; Bae, Yong Chul; Kim, Myoung-Hwan; Kim, Sooyun; Ho, Won-Kyung; Lee, Suk-Ho

    2015-01-01

    A short high frequency stimulation of mossy fibres (MFs) induces long-term potentiation (LTP) of direct cortical or perforant path (PP) synaptic inputs in hippocampal CA3 pyramidal cells (CA3-PCs). However, the cellular mechanism underlying this heterosynaptic modulation remains elusive. Previously, we reported that repetitive somatic firing at 10 Hz downregulates Kv1.2 in the CA3-PCs. Here, we show that MF inputs induce similar somatic firing and downregulation of Kv1.2 in the CA3-PCs. The effect of Kv1.2 downregulation was specific to PP synaptic inputs that arrive at distal apical dendrites. We found that the somatodendritic expression of Kv1.2 is polarized to distal apical dendrites. Compartmental simulations based on this finding suggested that passive normalization of synaptic inputs and polarized distributions of dendritic ionic channels may facilitate the activation of dendritic Na+ channels preferentially at distal apical dendrites. Indeed, partial block of dendritic Na+ channels using 10 nm tetrodotoxin brought back the enhanced PP-evoked excitatory postsynaptic potentials (PP-EPSPs) to the baseline level. These results indicate that activity-dependent downregulation of Kv1.2 in CA3-PCs mediates MF-induced heterosynaptic LTP of PP-EPSPs by facilitating activation of Na+ channels at distal apical dendrites. PMID:26047212

  14. Neurochemical, morphologic, and laminar characterization of cortical projection neurons in the cingulate motor areas of the macaque monkey

    NASA Technical Reports Server (NTRS)

    Nimchinsky, E. A.; Hof, P. R.; Young, W. G.; Morrison, J. H.; Bloom, F. E. (Principal Investigator)

    1996-01-01

    The primate cingulate gyrus contains multiple cortical areas that can be distinguished by several neurochemical features, including the distribution of neurofilament protein-enriched pyramidal neurons. In addition, connectivity and functional properties indicate that there are multiple motor areas in the cortex lining the cingulate sulcus. These motor areas were targeted for analysis of potential interactions among regional specialization, connectivity, and cellular characteristics such as neurochemical profile and morphology. Specifically, intracortical injections of retrogradely transported dyes and intracellular injection were combined with immunocytochemistry to investigate neurons projecting from the cingulate motor areas to the putative forelimb region of the primary motor cortex, area M1. Two separate groups of neurons projecting to area M1 emanated from the cingulate sulcus, one anterior and one posterior, both of which furnished commissural and ipsilateral connections with area M1. The primary difference between the two populations was laminar origin, with the anterior projection originating largely in deep layers, and the posterior projection taking origin equally in superficial and deep layers. With regard to cellular morphology, the anterior projection exhibited more morphologic diversity than the posterior projection. Commissural projections from both anterior and posterior fields originated largely in layer VI. Neurofilament protein distribution was a reliable tool for localizing the two projections and for discriminating between them. Comparable proportions of the two sets of projection neurons contained neurofilament protein, although the density and distribution of the total population of neurofilament protein-enriched neurons was very different in the two subareas of origin. Within a projection, the participating neurons exhibited a high degree of morphologic heterogeneity, and no correlation was observed between somatodendritic morphology and

  15. Hippocampal CA1 pyramidal neurons of Mecp2 mutant mice show a dendritic spine phenotype only in the presymptomatic stage.

    PubMed

    Chapleau, Christopher A; Boggio, Elena Maria; Calfa, Gaston; Percy, Alan K; Giustetto, Maurizio; Pozzo-Miller, Lucas

    2012-01-01

    Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations in MECP2, is the leading cause of intellectual disabilities in women. Neurons in Mecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus of Mecp2(tm1.1Jae) male mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1 stratum radiatum of symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomatic Mecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

  16. Hippocampal pyramidal neurons switch from a multipolar migration mode to a novel "climbing" migration mode during development.

    PubMed

    Kitazawa, Ayako; Kubo, Ken-ichiro; Hayashi, Kanehiro; Matsunaga, Yuki; Ishii, Kazuhiro; Nakajima, Kazunori

    2014-01-22

    The hippocampus plays important roles in brain functions. Despite the importance of hippocampal functions, recent analyses of neuronal migration have mainly been performed on the cerebral neocortex, and the cellular mechanisms responsible for the formation of the hippocampus are not yet completely understood. Moreover, why a prolonged time is required for hippocampal neurons to complete their migration has been unexplainable for several decades. We analyzed the migratory profile of neurons in the developing mouse hippocampal CA1 region and found that the hippocampal pyramidal neurons generated near the ventricle became postmitotic multipolar cells and accumulated in the multipolar cell accumulation zone (MAZ) in the late stage of development. The hippocampal neurons passed through the pyramidal layer by a unique mode of migration. Their leading processes were highly branched and made contact with many radial fibers. Time-lapse imaging revealed that the migrating cells changed their scaffolds from the original radial fibers to other radial fibers, and as a result they proceed in a zigzag manner, with long intervals. The migrating cells in the hippocampus reminded us of "rock climbers" that instead of using their hands to pull up their bodies were using their leading processes to pull up their cell bodies. Because this mode of migration had never been described, we called it the "climbing" mode. The change from the "climbing" mode in the hippocampus to the "locomotion" mode in the neocortex may have contributed to the brain expansion during evolution.

  17. Layer 5 Pyramidal Neurons' Dendritic Remodeling and Increased Microglial Density in Primary Motor Cortex in a Murine Model of Facial Paralysis.

    PubMed

    Urrego, Diana; Troncoso, Julieta; Múnera, Alejandro

    2015-01-01

    This work was aimed at characterizing structural changes in primary motor cortex layer 5 pyramidal neurons and their relationship with microglial density induced by facial nerve lesion using a murine facial paralysis model. Adult transgenic mice, expressing green fluorescent protein in microglia and yellow fluorescent protein in projecting neurons, were submitted to either unilateral section of the facial nerve or sham surgery. Injured animals were sacrificed either 1 or 3 weeks after surgery. Two-photon excitation microscopy was then used for evaluating both layer 5 pyramidal neurons and microglia in vibrissal primary motor cortex (vM1). It was found that facial nerve lesion induced long-lasting changes in the dendritic morphology of vM1 layer 5 pyramidal neurons and in their surrounding microglia. Dendritic arborization of the pyramidal cells underwent overall shrinkage. Apical dendrites suffered transient shortening while basal dendrites displayed sustained shortening. Moreover, dendrites suffered transient spine pruning. Significantly higher microglial cell density was found surrounding vM1 layer 5 pyramidal neurons after facial nerve lesion with morphological bias towards the activated phenotype. These results suggest that facial nerve lesions elicit active dendrite remodeling due to pyramidal neuron and microglia interaction, which could be the pathophysiological underpinning of some neuropathic motor sequelae in humans.

  18. Euchromatin histone methyltransferase 1 regulates cortical neuronal network development

    PubMed Central

    Bart Martens, Marijn; Frega, Monica; Classen, Jessica; Epping, Lisa; Bijvank, Elske; Benevento, Marco; van Bokhoven, Hans; Tiesinga, Paul; Schubert, Dirk; Nadif Kasri, Nael

    2016-01-01

    Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome. PMID:27767173

  19. Reward-timing-dependent bidirectional modulation of cortical microcircuits during optical single-neuron operant conditioning.

    PubMed

    Hira, Riichiro; Ohkubo, Fuki; Masamizu, Yoshito; Ohkura, Masamichi; Nakai, Junichi; Okada, Takashi; Matsuzaki, Masanori

    2014-11-24

    Animals rapidly adapt to environmental change. To reveal how cortical microcircuits are rapidly reorganized when an animal recognizes novel reward contingency, we conduct two-photon calcium imaging of layer 2/3 motor cortex neurons in mice and simultaneously reinforce the activity of a single cortical neuron with water delivery. Here we show that when the target neuron is not relevant to a pre-trained forelimb movement, the mouse increases the target neuron activity and the number of rewards delivered during 15-min operant conditioning without changing forelimb movement behaviour. The reinforcement bidirectionally modulates the activity of subsets of non-target neurons, independent of distance from the target neuron. The bidirectional modulation depends on the relative timing between the reward delivery and the neuronal activity, and is recreated by pairing reward delivery and photoactivation of a subset of neurons. Reward-timing-dependent bidirectional modulation may be one of the fundamental processes in microcircuit reorganization for rapid adaptation.

  20. Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1.

    PubMed

    Barnabé-Heider, Fanie; Wasylnka, Julie A; Fernandes, Karl J L; Porsche, Christian; Sendtner, Michael; Kaplan, David R; Miller, Freda D

    2005-10-20

    Precursor cells of the embryonic cortex sequentially generate neurons and then glial cells, but the mechanisms regulating this neurogenic-to-gliogenic transition are unclear. Using cortical precursor cultures, which temporally mimic this in vivo differentiation pattern, we demonstrate that cortical neurons synthesize and secrete the neurotrophic cytokine cardiotrophin-1, which activates the gp130-JAK-STAT pathway and is essential for the timed genesis of astrocytes in vitro. Our data indicate that a similar phenomenon also occurs in vivo. In utero electroporation of neurotrophic cytokines in the environment of embryonic cortical precursors causes premature gliogenesis, while acute perturbation of gp130 in cortical precursors delays the normal timed appearance of astrocytes. Moreover, the neonatal cardiotrophin-1-/- cortex contains fewer astrocytes. Together, these results describe a neural feedback mechanism; newly born neurons produce cardiotrophin-1, which instructs multipotent cortical precursors to generate astrocytes, thereby ensuring that gliogenesis does not occur until neurogenesis is largely complete. PMID:16242406

  1. Evidence for neuroprotective effect of sulbutiamine against oxygen-glucose deprivation in rat hippocampal CA1 pyramidal neurons.

    PubMed

    Kwag, Jeehyun; Majid, Aman Shah Abdul; Kang, Kui Dong

    2011-01-01

    Hippocampus is one of the earliest brain regions that gets affected by ischemia, however, no pharmacological therapy exists yet that can fully counteract the ischemic damage. Here we study the effect of sulbutiamine, a synthetic thiamine analogue that can cross the blood-brain barrier easily, on hippocampal neurons under an in vitro model of ischemia, oxygen-glucose deprivation (OGD). We find that exposure to OGD in the presence of sulbutiamine significantly increases neuronal viability and enhances electrophysiological properties such as excitatory synaptic transmissions and intrinsic neuronal membrane input resistance in a concentration-dependent manner. Overall, here we report, for the first time, the neuroprotective evidence of sulbutiamine on hippocampal CA1 pyramidal neurons under OGD, which may have beneficial implications as a possible therapeutic agent/substance against ischemic insult. PMID:22040892

  2. Dysplastic neocortex and subcortical heterotopias in methylazoxymethanol-treated rats: an intracellular study of identified pyramidal neurones.

    PubMed

    Sancini, G; Franceschetti, S; Battaglia, G; Colacitti, C; Di Luca, M; Spreafico, R; Avanzini, G

    1998-05-01

    Intracellular recordings were obtained using biocytin-filled electrodes from 78 neurones located in both dysplastic neocortex and subcortical heterotopic aggregates in a model of neuronal migration disorder induced in rats by means of a double methylazoxymethanol injection given on embryonic day 15. Both regular spiking and intrinsically bursting pyramidal neurones were found in all of the examined structures and were synaptically activated by subcortical stimulation. In a neuronal subpopulation (22%) located in the neocortex as well as in the subcortical heterotopic aggregates, the injection of depolarising current pulses elicited aberrant firing patterns, consisting of repetitive bursts of APs that gradually increased in duration and eventually merged in a long-lasting discharge. The gradual development of this 'excessive' bursting behaviour suggests a progressive run-down of the slow components of the hyperpolarising afterpotential. PMID:9792622

  3. Stability and plasticity of intrinsic membrane properties in hippocampal CA1 pyramidal neurons: effects of internal anions

    PubMed Central

    Kaczorowski, Catherine Cook; Disterhoft, John; Spruston, Nelson

    2007-01-01

    CA1 pyramidal neurons from animals that have acquired hippocampal tasks show increased neuronal excitability, as evidenced by a reduction in the postburst afterhyperpolarization (AHP). Studies of AHP plasticity require stable long-term recordings, which are affected by the intracellular solutions potassium methylsulphate (KMeth) or potassium gluconate (KGluc). Here we show immediate and gradual effects of these intracellular solutions on measurement of the AHP and basic membrane properties, and on the induction of AHP plasticity in CA1 pyramidal neurons from rat hippocampal slices. The AHP measured immediately after establishing whole-cell recordings was larger with KMeth than with KGluc. In general, the AHP in KMeth was comparable to the AHP measured in the perforated-patch configuration. However, KMeth induced time-dependent changes in the intrinsic membrane properties of CA1 pyramidal neurons. Specifically, input resistance progressively increased by 70% after 50 min; correspondingly, the current required to trigger an action potential and the fast afterdepolarization following action potentials gradually decreased by about 50%. Conversely, these measures were stable in KGluc. We also demonstrate that activity-dependent plasticity of the AHP occurs with physiologically relevant stimuli in KGluc. AHPs triggered with theta-burst firing every 30 s were progressively reduced, whereas AHPs elicited every 150 s were stable. Blockade of the apamin-sensitive AHP current (IAHP) was insufficient to block AHP plasticity, suggesting that plasticity is manifested through changes in the apamin-insensitive slow AHP current (sIAHP). These changes were observed in the presence of synaptic blockers, and therefore reflect changes in the intrinsic properties of the neurons. However, no AHP plasticity was observed using KMeth. In summary, these data show that KMeth produces time-dependent changes in basic membrane properties and prevents or obscures activity-dependent reduction of

  4. The electrical activity of hippocampal pyramidal neuron is subjected to descending control by the brain orexin/hypocretin system.

    PubMed

    Riahi, Esmail; Arezoomandan, Reza; Fatahi, Zahra; Haghparast, Abbas

    2015-03-01

    The hippocampus receives sparse orexinergic innervation from the lateral hypothalamus and expresses a high level of orexin receptor. The function of orexin receptor in the regulation of hippocampal neural activity has never been investigated. In this study, in vivo single unit recording was performed in urethane-anesthetized rats. After 15 min of baseline recording from pyramidal neuron within the CA1 region of the dorsal hippocampus, i.c.v. injection of orexin-A 0.5 nmol, SB334867 400 nmol, a selective orexin receptor 1 antagonist, saline, or DMSO, or microinjection of carbachol 250 nmol or saline into the ipsilateral lateral hypothalamus were performed using a Hamilton microsyringe, and the spontaneous firing activity continued to be recorded for 25 min. Results showed that orexin administration into the lateral cerebral ventricle excited 6 out of 8 neurons and inhibited 1 neuron. Chemical stimulation of the lateral hypothalamus by carbachol excited 9 out of 13 hippocampal neurons and inhibited 3 neurons. On the other hand, i.c.v. injection of the SB334867, caused reductions in the firing activity of 6 out of 10 neurons and increases in 4 additional neurons. It seems that orexin neurotransmission in the hippocampus mostly elicits an excitatory response, whereas blockade of orexin receptor has an inhibitory effect. Further studies need to be done to elucidate the underlying mechanism of orexin action on hippocampal neurons.

  5. Changes in Neuronal Excitability by Activated Microglia: Differential Na(+) Current Upregulation in Pyramid-Shaped and Bipolar Neurons by TNF-α and IL-18.

    PubMed

    Klapal, Lars; Igelhorst, Birte A; Dietzel-Meyer, Irmgard D

    2016-01-01

    Microglia are activated during pathological events in the brain and are capable of releasing various types of inflammatory cytokines. Here, we demonstrate that the addition of 5% microglia activated by 1 μg/ml lipopolysaccharides (LPS) to hippocampal cultures upregulates Na(+) current densities (INavD) of bipolar as well as pyramid-shaped neurons, thereby increasing their excitability. Deactivation of microglia by the addition of 10 ng/ml transforming growth factor-β (TGF-β) decreases INavD below control levels suggesting that the residual activated microglial cells influence neuronal excitability in control cultures. Preincubation of hippocampal cultures with 10 ng/ml tumor necrosis factor-α (TNF-α), a major cytokine released by activated microglia, upregulated INavD significantly by ~30% in bipolar cells, whereas in pyramid-shaped cells, the upregulation only reached an increase of ~14%. Incubation of the cultures with antibodies against either TNF-receptor 1 or 2 blocked the upregulation of INavD in bipolar cells, whereas in pyramid-shaped cells, increases in INavD were exclusively blocked by antibodies against TNF-receptor 2, suggesting that both cell types respond differently to TNF-α exposure. Since additional cytokines, such as interleukin-18 (IL-18), are released from activated microglia, we tested potential effects of IL-18 on INavD in both cell types. Exposure to 5-10 ng/ml IL-18 for 4 days increased INavD in both pyramid-shaped as well as bipolar neurons, albeit the dose-response curves were shifted to lower concentrations in bipolar cells. Our results suggest that by secretion of cytokines, microglial cells upregulate Na(+) current densities in bipolar and pyramid-shaped neurons to some extent differentially. Depending on the exact cytokine composition and concentration released, this could change the balance between the activity of inhibitory bipolar and excitatory pyramid-shaped cells. Since bipolar cells show a larger upregulation of

  6. Changes in Neuronal Excitability by Activated Microglia: Differential Na+ Current Upregulation in Pyramid-Shaped and Bipolar Neurons by TNF-α and IL-18

    PubMed Central

    Klapal, Lars; Igelhorst, Birte A.; Dietzel-Meyer, Irmgard D.

    2016-01-01

    Microglia are activated during pathological events in the brain and are capable of releasing various types of inflammatory cytokines. Here, we demonstrate that the addition of 5% microglia activated by 1 μg/ml lipopolysaccharides (LPS) to hippocampal cultures upregulates Na+ current densities (INavD) of bipolar as well as pyramid-shaped neurons, thereby increasing their excitability. Deactivation of microglia by the addition of 10 ng/ml transforming growth factor-β (TGF-β) decreases INavD below control levels suggesting that the residual activated microglial cells influence neuronal excitability in control cultures. Preincubation of hippocampal cultures with 10 ng/ml tumor necrosis factor-α (TNF-α), a major cytokine released by activated microglia, upregulated INavD significantly by ~30% in bipolar cells, whereas in pyramid-shaped cells, the upregulation only reached an increase of ~14%. Incubation of the cultures with antibodies against either TNF-receptor 1 or 2 blocked the upregulation of INavD in bipolar cells, whereas in pyramid-shaped cells, increases in INavD were exclusively blocked by antibodies against TNF-receptor 2, suggesting that both cell types respond differently to TNF-α exposure. Since additional cytokines, such as interleukin-18 (IL-18), are released from activated microglia, we tested potential effects of IL-18 on INavD in both cell types. Exposure to 5–10 ng/ml IL-18 for 4 days increased INavD in both pyramid-shaped as well as bipolar neurons, albeit the dose–response curves were shifted to lower concentrations in bipolar cells. Our results suggest that by secretion of cytokines, microglial cells upregulate Na+ current densities in bipolar and pyramid-shaped neurons to some extent differentially. Depending on the exact cytokine composition and concentration released, this could change the balance between the activity of inhibitory bipolar and excitatory pyramid-shaped cells. Since bipolar cells show a larger upregulation of

  7. Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression

    PubMed Central

    Simkin, Dina; Hattori, Shoai; Ybarra, Natividad; Musial, Timothy F.; Buss, Eric W.; Richter, Hannah; Oh, M. Matthew

    2015-01-01

    Aging-related impairments in hippocampus-dependent cognition have been attributed to maladaptive changes in the functional properties of pyramidal neurons within the hippocampal subregions. Much evidence has come from work on CA1 pyramidal neurons, with CA3 pyramidal neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing in the hippocampal circuit. Here, we use whole-cell current-clamp to demonstrate that aged rat (29–32 months) CA3 pyramidal neurons fire significantly more action potentials (APs) during theta-burst frequency stimulation and that this is associated with faster AP repolarization (i.e., narrower AP half-widths and enlarged fast afterhyperpolarization). Using a combination of patch-clamp physiology, pharmacology, Western blot analyses, immunohistochemistry, and array tomography, we demonstrate that these faster AP kinetics are mediated by enhanced function and expression of Kv4.2/Kv4.3 A-type K+ channels, particularly within the perisomatic compartment, of CA3 pyramidal neurons. Thus, our study indicates that inhibition of these A-type K+ channels can restore the intrinsic excitability properties of aged CA3 pyramidal neurons to a young-like state. SIGNIFICANCE STATEMENT Age-related learning deficits have been attributed, in part, to altered hippocampal pyramidal neuronal function with normal aging. Much evidence has come from work on CA1 neurons, with CA3 neurons receiving comparatively less attention despite its age-related hyperactivation being postulated to interfere with spatial processing. Hence, we conducted a series of experiments to identify the cellular mechanisms that underlie the hyperexcitability reported in the CA3 region. Contrary to CA1 neurons, we demonstrate that postburst afterhyperpolarization is not altered with aging and that aged CA3 pyramidal neurons are able to fire significantly more action potentials and that this is associated with

  8. The protective role of ascorbic acid on hippocampal CA1 pyramidal neurons in a rat model of maternal lead exposure.

    PubMed

    Sepehri, Hamid; Ganji, Farzaneh

    2016-07-01

    Oxidative stress is a major pathogenic mechanism of lead neurotoxicity. The antioxidant ascorbic acid protects hippocampal pyramidal neurons against cell death during congenital lead exposure; however, critical functions like synaptic transmission, integration, and plasticity depend on preservation of dendritic and somal morphology. This study was designed to examine if ascorbic acid also protects neuronal morphology during developmental lead exposure. Timed pregnant rats were divided into four treatment groups: (1) control, (2) 100mg/kg ascorbic acid once a day via gavage, (3) 0.05% lead acetate in drinking water, and (4) 0.05% lead+100mg/kg oral ascorbic acid. Brains of eight male pups (P25) per treatment group were processed for Golgi staining. Changes in hippocampal CA1 pyramidal neurons' somal size were estimated by cross-sectional area and changes in dendritic arborization by Sholl's analysis. One-way ANOVA was used to compare results among treatment groups. Lead-exposed pups exhibited a significant decrease in somal size compared to controls (P<0.01) that was reversed by cotreatment with ascorbic acid. Sholl's analysis revealed a significant increase in apical dendritic branch points near cell body (P<0.05) and a decreased total dendritic length in both apical and basal dendritic trees of CA1 neurons (P<0.05). Ascorbic acid significantly but only partially reversed the somal and dendritic damage caused by developmental lead exposure. Oxidative stress thus contributes to lead neurotoxicity but other pathogenic mechanisms are also involved.

  9. Drp1 levels constitutively regulate mitochondrial dynamics and cell survival in cortical neurons

    PubMed Central

    Uo, Takuma; Dworzak, Jenny; Kinoshita, Chizuru; Inman, Denise M.; Kinoshita, Yoshito; Horner, Philip J.; Morrison, Richard S.

    2009-01-01

    Mitochondria exist as dynamic networks that are constantly remodeled through the opposing actions of fusion and fission proteins. Changes in the expression of these proteins alter mitochondrial shape and size, and may promote or inhibit the propagation of apoptotic signals. Using mitochondrially targeted EGFP or DsRed2 to identify mitochondria, we observed a short, distinctly tubular mitochondrial morphology in postnatal cortical neurons in culture and in retinal ganglion cells in vivo, whereas longer, highly interconnected mitochondrial networks were detected in cortical astrocytes in vitro and non-neuronal cells in the retina in vivo. Differential expression patterns of fusion and fission proteins, in part, appear to determine these morphological differences as neurons expressed markedly high levels of Drp1 and OPA1 proteins compared to non-neuronal cells. This finding was corroborated using optic tissue samples. Moreover, cortical neurons expressed several splice variants of Drp1 including a neuron-specific isoform which incorporates exon 3. Knockdown or dominant negative interference of endogenous Drp1 significantly increased mitochondrial length in both neurons and non-neuronal cells, but caused cell death only in cortical neurons. Conversely, depletion of the fusion protein, Mfn2, but not Mfn1, caused extensive mitochondrial fission and cell death. Thus, Drp1 and Mfn2 in normal cortical neurons not only regulate mitochondrial morphology, but are also required for cell survival. The present findings point to unique patterns of Drp1 expression and selective vulnerability to reduced levels of Drp1 expression/activity in neurons, and demonstrate that the regulation of mitochondrial dynamics must be tightly regulated in neurons. PMID:19445933

  10. Calcium-activated afterhyperpolarizations regulate synchronization and timing of epileptiform bursts in hippocampal CA3 pyramidal neurons.

    PubMed

    Fernández de Sevilla, David; Garduño, Julieta; Galván, Emilio; Buño, Washington

    2006-12-01

    Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca(2+)-activated K(+)-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg(2+)-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO(4) reduced burst frequency. Block of GABA(A-B) inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity. PMID:16971683

  11. Rab, Arf, and Arl-Regulated Membrane Traffic in Cortical Neuron Migration.

    PubMed

    Tang, Bor Luen

    2016-07-01

    The migration of projection neurons from its birthplace in the subventricular zone to their final destination in the cortical plate is a complex process that requires a series of highly coordinated cellular events. Amongst the key factors involved in the processes are modulators of cytoskeletal dynamics, as well as cellular membrane traffic. Members of the small GTPases family responsible for the latter process, the Rabs and Arfs, have been recently implicated in cortical neuron migration. Rab5 and Rab11, which are key modulators of endocytosis and endocytic recycling respectively, ensure proper surface expression and distribution of N-cadherin, a key adhesion protein that tethers migrating neurons to the radial glia fiber tracts during pia-directed migration. Rab7, which is associated with lysosomal biogenesis and function, is important for the final step of terminal translocation when N-cadherin is downregulated by lysosomal degradation. Arf6 activity, which is known to be important in neuronal processes outgrowth, may negatively impact the multipolar-bipolar transition of cortical neurons undergoing radial migration, but the downstream effector of Arf6 in this regard is not yet known. In addition to the above, members of the Arl family which have been recently shown to be important in radial glia scaffold formation, would also be important for cortical neuron migration. In this short review, we discuss recent advances in our understanding of the importance of membrane traffic regulated by the Rab, Arf, and Arl family members in cortical neuron migration.

  12. Rab, Arf, and Arl-Regulated Membrane Traffic in Cortical Neuron Migration.

    PubMed

    Tang, Bor Luen

    2016-07-01

    The migration of projection neurons from its birthplace in the subventricular zone to their final destination in the cortical plate is a complex process that requires a series of highly coordinated cellular events. Amongst the key factors involved in the processes are modulators of cytoskeletal dynamics, as well as cellular membrane traffic. Members of the small GTPases family responsible for the latter process, the Rabs and Arfs, have been recently implicated in cortical neuron migration. Rab5 and Rab11, which are key modulators of endocytosis and endocytic recycling respectively, ensure proper surface expression and distribution of N-cadherin, a key adhesion protein that tethers migrating neurons to the radial glia fiber tracts during pia-directed migration. Rab7, which is associated with lysosomal biogenesis and function, is important for the final step of terminal translocation when N-cadherin is downregulated by lysosomal degradation. Arf6 activity, which is known to be important in neuronal processes outgrowth, may negatively impact the multipolar-bipolar transition of cortical neurons undergoing radial migration, but the downstream effector of Arf6 in this regard is not yet known. In addition to the above, members of the Arl family which have been recently shown to be important in radial glia scaffold formation, would also be important for cortical neuron migration. In this short review, we discuss recent advances in our understanding of the importance of membrane traffic regulated by the Rab, Arf, and Arl family members in cortical neuron migration. PMID:26587959

  13. Afferent inputs to cortical fast-spiking interneurons organize pyramidal cell network oscillations at high-gamma frequencies (60-200 Hz).

    PubMed

    Suffczynski, Piotr; Crone, Nathan E; Franaszczuk, Piotr J

    2014-12-01

    High-gamma activity, ranging in frequency between ∼60 Hz and 200 Hz, has been observed in local field potential, electrocorticography, EEG and magnetoencephalography signals during cortical activation, in a variety of functional brain systems. The origin of these signals is yet unknown. Using computational modeling, we show that a cortical network model receiving thalamic input generates high-gamma responses comparable to those observed in local field potential recorded in monkey somatosensory cortex during vibrotactile stimulation. These high-gamma oscillations appear to be mediated mostly by an excited population of inhibitory fast-spiking interneurons firing at high-gamma frequencies and pacing excitatory regular-spiking pyramidal cells, which fire at lower rates but in phase with the population rhythm. The physiological correlates of high-gamma activity, in this model of local cortical circuits, appear to be similar to those proposed for hippocampal ripples generated by subsets of interneurons that regulate the discharge of principal cells. PMID:25210164

  14. Enhancement of Synaptic Potentials in Rabbit CA1 Pyramidal Neurons Following Classical Conditioning

    NASA Astrophysics Data System (ADS)

    Loturco, Joseph J.; Coulter, Douglas A.; Alkon, Daniel L.

    1988-03-01

    A synaptic potential elicited by high-frequency stimulation of the Schaffer collaterals was enhanced in hippocampal CA1 pyramidal cells from rabbits that were classically conditioned relative to cells from control rabbits. In addition, confirming previous reports, the after-hyperpolarization was reduced in cells from conditioned animals. We suggest that reduced after-hyperpolarization and enhanced synaptic responsiveness in cells from conditioned animals work in concert to contribute to the functioning of hippocampal CA1 pyramidal cells during classical conditioning.

  15. Reelin and cofilin cooperate during the migration of cortical neurons: a quantitative morphological analysis.

    PubMed

    Chai, Xuejun; Zhao, Shanting; Fan, Li; Zhang, Wei; Lu, Xi; Shao, Hong; Wang, Shaobo; Song, Lingzhen; Failla, Antonio Virgilio; Zobiak, Bernd; Mannherz, Hans G; Frotscher, Michael

    2016-03-15

    In reeler mutant mice, which are deficient in reelin (Reln), the lamination of the cerebral cortex is disrupted. Reelin signaling induces phosphorylation of LIM kinase 1, which phosphorylates the actin-depolymerizing protein cofilin in migrating neurons. Conditional cofilin mutants show neuronal migration defects. Thus, both reelin and cofilin are indispensable during cortical development. To analyze the effects of cofilin phosphorylation on neuronal migration we used in utero electroporation to transfect E14.5 wild-type cortical neurons with pCAG-EGFP plasmids encoding either a nonphosphorylatable form of cofilin 1 (cofilin(S3A)), a pseudophosphorylated form (cofilin(S3E)) or wild-type cofilin 1 (cofilin(WT)). Wild-type controls and reeler neurons were transfected with pCAG-EGFP. Real-time microscopy and histological analyses revealed that overexpression of cofilin(WT) and both phosphomutants induced migration defects and morphological abnormalities of cortical neurons. Of note, reeler neurons and cofilin(S3A)- and cofilin(S3E)-transfected neurons showed aberrant backward migration towards the ventricular zone. Overexpression of cofilin(S3E), the pseudophosphorylated form, partially rescued the migration defect of reeler neurons, as did overexpression of Limk1. Collectively, the results indicate that reelin and cofilin cooperate in controlling cytoskeletal dynamics during neuronal migration.

  16. Amyloid precursor protein expression and processing are differentially regulated during cortical neuron differentiation

    PubMed Central

    Bergström, Petra; Agholme, Lotta; Nazir, Faisal Hayat; Satir, Tugce Munise; Toombs, Jamie; Wellington, Henrietta; Strandberg, Joakim; Bontell, Thomas Olsson; Kvartsberg, Hlin; Holmström, Maria; Boreström, Cecilia; Simonsson, Stina; Kunath, Tilo; Lindahl, Anders; Blennow, Kaj; Hanse, Eric; Portelius, Erik; Wray, Selina; Zetterberg, Henrik

    2016-01-01

    Amyloid precursor protein (APP) and its cleavage product amyloid β (Aβ) have been thoroughly studied in Alzheimer’s disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. α-Cleaved soluble APP (sAPPα) was secreted early during differentiation, from neuronal progenitors, while β-cleaved soluble APP (sAPPβ) was first secreted after deep-layer neurons had formed. Short Aβ peptides, including Aβ1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as Aβ1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by Aβ1-40/42, is associated with mature neuronal phenotypes. PMID:27383650

  17. Low level laser therapy reduces oxidative stress in cortical neurons in vitro

    NASA Astrophysics Data System (ADS)

    Huang, Ying-Ying; Tedford, Clark E.; McCarthy, Thomas; Hamblin, Michael R.

    2012-03-01

    It is accepted that the mechanisms of low level laser therapy (LLLT) involves photons that are absorbed in the mitochondria of cells and lead to increase of mitochondrial metabolism resulting in more electron transport, increase of mitochondrial membrane potential, and more ATP production. Intracellular calcium changes are seen that correlate with mitochondrial stimulation. The situation with two other intermediates is more complex however: reactive oxygen species (ROS) and nitric oxide (NO). Evidence exists that low levels of ROS are produced by LLLT in normal cells that can be beneficial by (for instance) activating NF-kB. However high fluences of light can produce large amounts of ROS that can damage the cells. In oxidatively stressed cells the situation may be different. We exposed primary cultured cortical neurons to hydrogen peroxide (H2O2) or cobalt chloride (CoCl2) oxidative insults in the presence or absence of LLLT (810-nm laser at 0.3 or 3 J/cm2). Cell viability of cortical neurons was determined by lactate dehydrogenase assay. ROS in neurons was detected using an ROS probe, MitoRox with confocal microscopy. Results showed that LLLT dose-dependently reversed ROS production and protected cortical neurons against H2O2 or CoCl2 induced oxidative injury in cultured cortical neurons. Conclusion: LLLT can protect cortical neurons against oxidative stress by reversing the levels of ROS.

  18. MEC-17 deficiency leads to reduced α-tubulin acetylation and impaired migration of cortical neurons.

    PubMed

    Li, Lei; Wei, Dan; Wang, Qiong; Pan, Jing; Liu, Rong; Zhang, Xu; Bao, Lan

    2012-09-12

    Neuronal migration is a fundamental process during the development of the cerebral cortex and is regulated by cytoskeletal components. Microtubule dynamics can be modulated by posttranslational modifications to tubulin subunits. Acetylation of α-tubulin at lysine 40 is important in regulating microtubule properties, and this process is controlled by acetyltransferase and deacetylase. MEC-17 is a newly discovered α-tubulin acetyltransferase that has been found to play a major role in the acetylation of α-tubulin in different species in vivo. However, the physiological function of MEC-17 during neural development is largely unknown. Here, we report that MEC-17 is critical for the migration of cortical neurons in the rat. MEC-17 was strongly expressed in the cerebral cortex during development. MEC-17 deficiency caused migratory defects in the cortical projection neurons and interneurons, and perturbed the transition of projection neurons from the multipolar stage to the unipolar/bipolar stage in the intermediate zone of the cortex. Furthermore, knockdown of α-tubulin deacetylase HDAC6 or overexpression of tubulin(K40Q) to mimic acetylated α-tubulin could reduce the migratory and morphological defects caused by MEC-17 deficiency in cortical projection neurons. Thus, MEC-17, which regulates the acetylation of α-tubulin, appears to control the migration and morphological transition of cortical neurons. This finding reveals the importance of MEC-17 and α-tubulin acetylation in cortical development.

  19. Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics

    PubMed Central

    Handel, Adam E.; Chintawar, Satyan; Lalic, Tatjana; Whiteley, Emma; Vowles, Jane; Giustacchini, Alice; Argoud, Karene; Sopp, Paul; Nakanishi, Mahito; Bowden, Rory; Cowley, Sally; Newey, Sarah; Akerman, Colin; Ponting, Chris P.; Cader, M. Zameel

    2016-01-01

    Induced pluripotent stem cell (iPSC)-derived cortical neurons potentially present a powerful new model to understand corticogenesis and neurological disease. Previous work has established that differentiation protocols can produce cortical neurons, but little has been done to characterize these at cellular resolution. In particular, it is unclear to what extent in vitro two-dimensional, relatively disordered culture conditions recapitulate the development of in vivo cortical layer identity. Single-cell multiplex reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) was used to interrogate the expression of genes previously implicated in cortical layer or phenotypic identity in individual cells. Totally, 93.6% of single cells derived from iPSCs expressed genes indicative of neuronal identity. High proportions of single neurons derived from iPSCs expressed glutamatergic receptors and synaptic genes. And, 68.4% of iPSC-derived neurons expressing at least one layer marker could be assigned to a laminar identity using canonical cortical layer marker genes. We compared single-cell RNA-seq of our iPSC-derived neurons to available single-cell RNA-seq data from human fetal and adult brain and found that iPSC-derived cortical neurons closely resembled primary fetal brain cells. Unexpectedly, a subpopulation of iPSC-derived neurons co-expressed canonical fetal deep and upper cortical layer markers. However, this appeared to be concordant with data from primary cells. Our results therefore provide reassurance that iPSC-derived cortical neurons are highly similar to primary cortical neurons at the level of single cells but suggest that current layer markers, although effective, may not be able to disambiguate cortical layer identity in all cells. PMID:26740550

  20. Excitatory cortical neurons with multipolar shape establish neuronal polarity by forming a tangentially oriented axon in the intermediate zone.

    PubMed

    Hatanaka, Yumiko; Yamauchi, Kenta

    2013-01-01

    The formation of axon-dendrite polarity is crucial for neuron to make the proper information flow within the brain. Although the processes of neuronal polarity formation have been extensively studied using neurons in dissociated culture, the corresponding developmental processes in vivo are still unclear. Here, we illuminate the initial steps of morphological polarization of excitatory cortical neurons in situ, by sparsely labeling their neuroepithelial progenitors using in utero electroporation and then examining their neuronal progeny in brain sections and in slice cultures. Morphological analysis showed that an axon-like long tangential process formed in progeny cells in the intermediate zone (IZ). Time-lapse imaging analysis using slice culture revealed that progeny cells with multipolar shape, after alternately extending and retracting their short processes for several hours, suddenly elongated a long process tangentially. These cells then transformed into a bipolar shape, extending a pia-directed leading process, and migrated radially leaving the tangential process behind, which gave rise to an "L-shaped" axon. Our findings suggest that neuronal polarity in these cells is established de novo from a nonpolarized stage in vivo and indicate that excitatory cortical neurons with multipolar shape in the IZ initiate axon outgrowth before radial migration into the cortical plate. PMID:22267309

  1. Excitatory cortical neurons with multipolar shape establish neuronal polarity by forming a tangentially oriented axon in the intermediate zone.

    PubMed

    Hatanaka, Yumiko; Yamauchi, Kenta

    2013-01-01

    The formation of axon-dendrite polarity is crucial for neuron to make the proper information flow within the brain. Although the processes of neuronal polarity formation have been extensively studied using neurons in dissociated culture, the corresponding developmental processes in vivo are still unclear. Here, we illuminate the initial steps of morphological polarization of excitatory cortical neurons in situ, by sparsely labeling their neuroepithelial progenitors using in utero electroporation and then examining their neuronal progeny in brain sections and in slice cultures. Morphological analysis showed that an axon-like long tangential process formed in progeny cells in the intermediate zone (IZ). Time-lapse imaging analysis using slice culture revealed that progeny cells with multipolar shape, after alternately extending and retracting their short processes for several hours, suddenly elongated a long process tangentially. These cells then transformed into a bipolar shape, extending a pia-directed leading process, and migrated radially leaving the tangential process behind, which gave rise to an "L-shaped" axon. Our findings suggest that neuronal polarity in these cells is established de novo from a nonpolarized stage in vivo and indicate that excitatory cortical neurons with multipolar shape in the IZ initiate axon outgrowth before radial migration into the cortical plate.

  2. Recombinant Probes Reveal Dynamic Localization of CaMKIIα within Somata of Cortical Neurons

    PubMed Central

    Mora, Rudy J.; Roberts, Richard W.

    2013-01-01

    In response to NMDA receptor stimulation, CaMKIIα moves rapidly from a diffuse distribution within the shafts of neuronal dendrites to a clustered postsynaptic distribution. However, less is known about CaMKIIα localization and trafficking within neuronal somata. Here we use a novel recombinant probe capable of labeling endogenous CaMKIIα in living rat neurons to examine its localization and trafficking within the somata of cortical neurons. This probe, which was generated using an mRNA display selection, binds to endogenous CaMKIIα at high affinity and specificity following expression in rat cortical neurons in culture. In ∼45% of quiescent cortical neurons, labeled clusters of CaMKIIα 1–4 μm in diameter were present. Upon exposure to glutamate and glycine, CaMKIIα clusters disappeared in a Ca2+-dependent manner within seconds. Moreover, minutes after the removal of glutamate and glycine, the clusters returned to their original configuration. The clusters, which also appear in cortical neurons in sections taken from mouse brains, contain actin and disperse upon exposure to cytochalasin D, an actin depolymerizer. In conclusion, within the soma, CaMKII localizes and traffics in a manner that is distinct from its localization and trafficking within the dendrites. PMID:24005308

  3. Response of cat cortical neurons to position and movement of the femur.

    PubMed

    Aloisi, A M; Decchi, B; Fontani, G; Rossi, A; Carli, G

    1996-01-01

    The contribution of joint afferents to the response of cortical neurons in area 3a to mechanical stimulation of the contralateral hindlimb was evaluated in cats anesthetized with sodium pentobarbital and paralyzed with pancuronium bromide. The hindlimb projection to the pericruciate cortex was established by recording the evoked potentials to electrical stimulation of the sciatic nerve and some of its branches, the bicepssemitendinosus and the quadratus femoris. Out of 169 neurons, 63 responded exclusively to cutaneous stimuli (superficial), whereas the others could be activated by local pressure of hindlimb muscles and/or by joint rotation (deep). Deep neurons were classified as slowly adapting (SA) or rapidly adapting (RA) units. In the neurons responding exclusively to joint rotation, the site of the receptive field could not be identified with certainty. In 13 deep neurons, their firing was affected by rotation of multiple joints of the contralateral hindlimb. In an attempt to identify the source of activation of cortical neurons, partial denervations and muscle disconnections were performed in five animals to isolate and stimulate the hip capsule. In these preparations, in 14 of 15 cortical neurons the source of activation was localized in the periarticular muscles, with no response to mechanical stimulation of the joint capsule. Only one neuron (SA) could be selectively excited by punctate pressure on the hip capsule. Our results suggest that in neurons of area 3a of the cat, the information about the position of the femur relies mainly on muscle afferents.

  4. Caloric restriction stimulates autophagy in rat cortical neurons through neuropeptide Y and ghrelin receptors activation

    PubMed Central

    Carmo-Silva, Sara; Botelho, Mariana; de Almeida, Luís Pereira; Cavadas, Cláudia

    2016-01-01

    Caloric restriction is an anti-aging intervention known to extend lifespan in several experimental models, at least in part, by stimulating autophagy. Caloric restriction increases neuropeptide Y (NPY) in the hypothalamus and plasma ghrelin, a peripheral gut hormone that acts in hypothalamus to modulate energy homeostasis. NPY and ghrelin have been shown to be neuroprotective in different brain areas and to induce several physiological modifications similar to those induced by caloric restriction. However, the effect of NPY and ghrelin in autophagy in cortical neurons is currently not known. Using a cell culture of rat cortical neurons we investigate the involvement of NPY and ghrelin in caloric restriction-induced autophagy. We observed that a caloric restriction mimetic cell culture medium stimulates autophagy in rat cortical neurons and NPY or ghrelin receptor antagonists blocked this effect. On the other hand, exogenous NPY or ghrelin stimulate autophagy in rat cortical neurons. Moreover, NPY mediates the stimulatory effect of ghrelin on autophagy in rat cortical neurons. Since autophagy impairment occurs in aging and age-related neurodegenerative diseases, NPY and ghrelin synergistic effect on autophagy stimulation may suggest a new strategy to delay aging process. PMID:27441412

  5. Distributions of Cells and Neurons across the Cortical Sheet in Old World Macaques.

    PubMed

    Turner, Emily C; Young, Nicole A; Reed, Jamie L; Collins, Christine E; Flaherty, David K; Gabi, Mariana; Kaas, Jon H

    2016-01-01

    According to previous research, cell and neuron densities vary across neocortex in a similar manner across primate taxa. Here, we provide a more extensive examination of this effect in macaque monkeys. We separated neocortex from the underlying white matter in 4 macaque monkey hemispheres (1 Macaca nemestrina, 2 Macaca radiata, and 1 Macaca mulatta), manually flattened the neocortex, and divided it into smaller tissue pieces for analysis. The number of cells and neurons were determined for each piece across the cortical sheet using flow cytometry. Primary visual cortex had the most densely packed neurons and primary motor cortex had the least densely packed neurons. With respect to differences in brain size between cases, there was little variability in the total cell and neuron numbers within specific areas, and overall trends were similar to what has been previously described in Old World baboons and other primates. The average hemispheric total cell number per hemisphere ranged from 2.9 to 3.7 billion, while the average total neuron number ranged from 1.3 to 1.7 billion neurons. The visual cortex neuron densities were predictably higher, ranging from 18.2 to 34.7 million neurons/cm2 in macaques, in comparison to a range of 9.3-17.7 million neurons/cm2 across cortex as a whole. The results support other evidence that neuron surface densities vary across the cortical sheet in a predictable pattern within and across primate taxa. PMID:27547956

  6. Mechanism of soluble beta-amyloid 25-35 neurotoxicity in primary cultured rat cortical neurons.

    PubMed

    Wang, Yong; Liu, Lili; Hu, Weimin; Li, Guanglai

    2016-04-01

    This study aimed to determine the effects of different concentrations of soluble beta-amyloid 25-35 (Aβ25-35) on cell viability, calcium overload, and PI3K-p85 expression in cultured cortical rat neurons. Primary cultured cerebral cortical neurons of newborn rats were divided randomly into six groups. Five groups were treated with soluble Aβ25-35 at concentrations of 10nmol/L, 100nmol/L, 1μmol/L, 10μmol/L, or 30μmol/L. Cell Counting Kit-8 staining was used to measure cell viability, laser-scanning confocal imaging was used to detect changes in intracellular free calcium concentration, and western blot assay was used to measure neuronal PI3K-p85 expression. Soluble Aβ25-35 was found to reduce cell viability and induce calcium overload in primary cultured rat cerebral cortical neurons, in a concentration-dependent manner. At certain concentrations, soluble Aβ25-35 also increased neuronal PI3K-p85 expression. These findings reveal that soluble Aβ25-35 reduces the viability of cultured cerebral cortical rat neurons. The neurotoxicity mechanism may involve calcium overload and disruption of insulin signal transduction pathways. PMID:26940239

  7. Mechanism of soluble beta-amyloid 25-35 neurotoxicity in primary cultured rat cortical neurons.

    PubMed

    Wang, Yong; Liu, Lili; Hu, Weimin; Li, Guanglai

    2016-04-01

    This study aimed to determine the effects of different concentrations of soluble beta-amyloid 25-35 (Aβ25-35) on cell viability, calcium overload, and PI3K-p85 expression in cultured cortical rat neurons. Primary cultured cerebral cortical neurons of newborn rats were divided randomly into six groups. Five groups were treated with soluble Aβ25-35 at concentrations of 10nmol/L, 100nmol/L, 1μmol/L, 10μmol/L, or 30μmol/L. Cell Counting Kit-8 staining was used to measure cell viability, laser-scanning confocal imaging was used to detect changes in intracellular free calcium concentration, and western blot assay was used to measure neuronal PI3K-p85 expression. Soluble Aβ25-35 was found to reduce cell viability and induce calcium overload in primary cultured rat cerebral cortical neurons, in a concentration-dependent manner. At certain concentrations, soluble Aβ25-35 also increased neuronal PI3K-p85 expression. These findings reveal that soluble Aβ25-35 reduces the viability of cultured cerebral cortical rat neurons. The neurotoxicity mechanism may involve calcium overload and disruption of insulin signal transduction pathways.

  8. Expression profile analysis of vulnerable CA1 pyramidal neurons in young-middle aged Ts65Dn mice

    PubMed Central

    Alldred, Melissa J.; Lee, Sang Han; Petkova, Eva; Ginsberg, Stephen D.

    2014-01-01

    Down syndrome (DS) is the most prevalent cause of intellectual disability (ID). Individuals with DS show a variety of cognitive deficits, most notably in hippocampal learning and memory, and display pathological hallmarks of Alzheimer's disease (AD), with neurodegeneration of cholinergic basal forebrain (CBF) neurons. Elucidation of the molecular and cellular underpinnings of neuropathology has been assessed via gene expression analysis in a relevant animal model, termed the Ts65Dn mouse. The Ts65Dn mouse is a segmental trisomy model of DS which mimics DS/AD pathology, notably age-related cognitive dysfunction and degeneration of basal forebrain cholinergic neurons (BFCNs). To determine expression level changes, molecular fingerprinting of Cornu Ammonis 1 (CA1) pyramidal neurons was performed in adult (4-9 month old) Ts65Dn mice, at the initiation of BFCN degeneration. To quantitate transcriptomic changes during this early time period, laser capture microdissection (LCM), terminal continuation (TC) RNA amplification, custom-designed microarray analysis, and subsequent validation of individual transcripts by qPCR and protein analysis via immunoblotting was performed. Results indicate significant alterations within CA1 pyramidal neurons of Ts65Dn mice compared to normal disomic (2N) littermates, notably in the downregulation of neurotrophins and their cognate neurotrophin receptors among other classes of transcripts relevant to neurodegeneration. These results of this single population gene expression analysis at the time of septohippocampal deficits in a trisomic mouse model shed light on a vulnerable circuit that may cause the AD-like pathology invariably seen in DS that could help to identify mechanisms of degeneration, and provide novel gene targets for therapeutic interventions. PMID:25131634

  9. Effects of Maternal Marginal Iodine Deficiency on Dendritic Morphology in the Hippocampal CA1 Pyramidal Neurons in Rat Offspring.

    PubMed

    Min, Hui; Wang, Yi; Dong, Jing; Wang, Yuan; Yu, Ye; Shan, Zhongyan; Xi, Qi; Teng, Weiping; Chen, Jie

    2016-06-01

    Although the salt iodization programmes are taken to control iodine deficiency (ID), some regions are still suffering from marginal ID. During pregnancy, marginal ID frequently leads to subtle insufficiency of thyroid hormones, characterized as low serum T4 levels. Therefore, the present research was to explore the effects of maternal marginal ID exposure on dendritic arbor growth in the hippocampal CA1 region and the underlying mechanisms. We established Wistar rat models with ID diet during pregnancy and lactation. The overall daily iodine intakes of the rats were estimated as 7.0, 5.0 and 1.5 μg/day in the control, marginal ID and severe ID groups, respectively. To study the morphological alterations of pyramidal neurons, Golgi-Cox procedure was conducted in the hippocampus. Sholl analyses demonstrated a slight decrease in the total length and branching numbers of basal dendrites on postnatal day (PN) 7, PN14 and PN21 in marginal ID group relative to the controls. However, there was no overt morphological change observed in apical dendrites. Immunofluorescence and Western blot analysis indicated that phosphorylation of MAP2, stathmin and JNK1 was down-regulated in marginal ID group. We speculate that the pups treated with maternal marginal ID subjected to subtle changes in dendritic growth of CA1 pyramidal neurons, which may be associated with the dysregulation of MAP2 and stathmin in a JNK1-dependent manner. PMID:27017219

  10. Properties of BK-type Ca(+) (+)-dependent K(+) channel currents in medial prefrontal cortex pyramidal neurons in rats of different ages.

    PubMed

    Książek, Aneta; Ladno, Wioletta; Szulczyk, Bartłomiej; Grzelka, Katarzyna; Szulczyk, Paweł

    2013-01-01

    The medial prefrontal cortex (PFC) is involved in cognitive functions, which undergo profound changes during adolescence. This alteration of the PFC function derives from neuron activity, which, in turn, may depend on age-dependent properties and the expression of neuronal ion channels. BK-type channels are involved in controlling both the Ca(+) (+) ion concentration in the cell interior and cell excitability. The purpose of this study was to test the properties of BK currents in the medial PFC pyramidal neurons of young (18- to 22-day-old), adolescent (38- to 42-day-old), and adult (60- to 65-day-old) rats. Whole-cell currents evoked by depolarizing voltage steps were recorded from dispersed medial PFC pyramidal neurons. A selective BK channel blocker - paxilline (10 μM) - irreversibly decreased the non-inactivating K(+) current in neurons that were isolated from the young and adult rats. This current was not significantly affected by paxilline in the neurons obtained from adolescent rats. The properties of single-channel K(+) currents were recorded from the soma of dispersed medial PFC pyramidal neurons in the cell-attached configuration. Of the K(+) channel currents that were recorded, ~90% were BK and leak channel currents. The BK-type channel currents were dependent on the Ca(+) (+) concentration and the voltage and were inhibited by paxilline. The biophysical properties of the BK channel currents did not differ among the pyramidal neurons isolated from young, adolescent, and adult rats. Among all of the recorded K(+) channel currents, 38.9, 12.7, and 21.1% were BK-type channel currents in the neurons isolated from the young, adolescent, and adult rats, respectively. Furthermore, application of paxilline effectively prolonged the half-width of the action potential in pyramidal neurons in slices isolated from young and adult rats but not in neurons isolated from adolescent rats. We conclude that the availability of BK channel currents decreases in medial PFC

  11. Properties of BK-type Ca++-dependent K+ channel currents in medial prefrontal cortex pyramidal neurons in rats of different ages

    PubMed Central

    Książek, Aneta; Ładno, Wioletta; Szulczyk, Bartłomiej; Grzelka, Katarzyna; Szulczyk, Paweł

    2013-01-01

    The medial prefrontal cortex (PFC) is involved in cognitive functions, which undergo profound changes during adolescence. This alteration of the PFC function derives from neuron activity, which, in turn, may depend on age-dependent properties and the expression of neuronal ion channels. BK-type channels are involved in controlling both the Ca++ ion concentration in the cell interior and cell excitability. The purpose of this study was to test the properties of BK currents in the medial PFC pyramidal neurons of young (18- to 22-day-old), adolescent (38- to 42-day-old), and adult (60- to 65-day-old) rats. Whole-cell currents evoked by depolarizing voltage steps were recorded from dispersed medial PFC pyramidal neurons. A selective BK channel blocker – paxilline (10 μM) – irreversibly decreased the non-inactivating K+ current in neurons that were isolated from the young and adult rats. This current was not significantly affected by paxilline in the neurons obtained from adolescent rats. The properties of single-channel K+ currents were recorded from the soma of dispersed medial PFC pyramidal neurons in the cell-attached configuration. Of the K+ channel currents that were recorded, ~90% were BK and leak channel currents. The BK-type channel currents were dependent on the Ca++ concentration and the voltage and were inhibited by paxilline. The biophysical properties of the BK channel currents did not differ among the pyramidal neurons isolated from young, adolescent, and adult rats. Among all of the recorded K+ channel currents, 38.9, 12.7, and 21.1% were BK-type channel currents in the neurons isolated from the young, adolescent, and adult rats, respectively. Furthermore, application of paxilline effectively prolonged the half-width of the action potential in pyramidal neurons in slices isolated from young and adult rats but not in neurons isolated from adolescent rats. We conclude that the availability of BK channel currents decreases in medial PFC pyramidal

  12. In utero electroporation followed by primary neuronal culture for studying gene function in subset of cortical neurons.

    PubMed

    Rice, Heather; Suth, Seiyam; Cavanaugh, William; Bai, Jilin; Young-Pearse, Tracy L

    2010-10-08

    In vitro study of primary neuronal cultures allows for quantitative analyses of neurite outgrowth. In order to study how genetic alterations affect neuronal process outgrowth, shRNA or cDNA constructs can be introduced into primary neurons via chemical transfection or viral transduction. However, with primary cortical cells, a heterogeneous pool of cell types (glutamatergic neurons from different layers, inhibitory neurons, glial cells) are transfected using these methods. The use of in utero electroporation to introduce DNA constructs in the embryonic rodent cortex allows for certain subsets of cells to be targeted: while electroporation of early embryonic cortex targets deep layers of the cortex, electroporation at late embryonic timepoints targets more superficial layers. Further, differential placement of electrodes across the heads of individual embryos results in the targeting of dorsal-medial versus ventral-lateral regions of the cortex. Following electroporation, transfected cells can be dissected out, dissociated, and plated in vitro for quantitative analysis of neurite outgrowth. Here, we provide a step-by-step method to quantitatively measure neuronal process outgrowth in subsets of cortical cells. The basic protocol for in utero electroporation has been described in detail in two other JoVE articles from the Kriegstein lab. We will provide an overview of our protocol for in utero electroporation, focusing on the most important details, followed by a description of our protocol that applies in utero electroporation to the study of gene function in neuronal process outgrowth.

  13. Expression of brain-derived neurotrophic factor in cortical neurons is regulated by striatal target area.

    PubMed

    Canals, J M; Checa, N; Marco, S; Akerud, P; Michels, A; Pérez-Navarro, E; Tolosa, E; Arenas, E; Alberch, J

    2001-01-01

    Changes in BDNF expression after different types of brain insults are related to neuroprotection, stimulation of sprouting, and synaptic reorganization. In the cerebral cortex, an autocrine-paracrine mechanism for BDNF has been proposed because the distribution patterns of BDNF and TrkB expression are almost identical. Moreover, cortical BDNF is anterogradely transported to the striatum, suggesting a role of BDNF in the functional interaction between the two brain regions. Here we have examined the expression of this neurotrophin in the cerebral cortex after various striatal lesions. Intrastriatal injection of quinolinate, kainate, 3-nitropropionic acid, or colchicine increased BDNF mRNA levels in cerebral cortex. In contrast, stimulation of neuronal activity in the striatum did not change cortical BDNF expression. Both excitatory amino acids increased BDNF expression in neurons of cortical layers II/III, V, and VI that project to the striatum. Moreover, grafting a BDNF-secreting cell line prevented both the loss of striatal neurons and the cortical upregulation of BDNF induced by excitotoxins. Because retrograde transport in the corticostriatal pathway was intact after striatal lesions, our results suggest that striatal damage upregulates endogenous BDNF in corticostriatal neurons by a transneuronal mechanism, which may constitute a protective mechanism for striatal and/or cortical cells.

  14. GVS-111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons.

    PubMed

    Pelsman, Alejandra; Hoyo-Vadillo, Carlos; Gudasheva, Tatiana A; Seredenin, Sergei B; Ostrovskaya, Rita U; Busciglio, Jorge

    2003-05-01

    The neuroprotective activity of a novel N-acylprolyl-containing dipeptide analog of the nootropic 2-oxo-1-pyrrolidine acetamide (Piracetam) designated as GVS-111 (DVD-111/Noopept) was tested in two in vitro models of neuronal degeneration mediated by oxidative stress: normal human cortical neurons treated with H(2)O(2), and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H(2)O(2) for 1h resulted in morphological and structural changes consistent with neuronal apoptosis and in the degeneration of more than 60% of the neurons present in the culture. GVS-111 significantly increased neuronal survival after H(2)O(2)-treatment displaying a dose-dependent neuroprotective activity from 10nM to 100 microM, and an IC(50) value of 1.21+/-0.07 microM. GVS-111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H(2)O(2) or FeSO(4), suggesting an antioxidant mechanism of action. GVS-111 exhibited significantly higher neuroprotection compared to the standard cognition enhancer Piracetam, or to the antioxidants Vitamin E, propyl gallate and N-tert-butyl-2-sulpho-phenylnitrone (s-PBN). In DS cortical cultures, chronic treatment with GVS-111 significantly reduced the appearance of degenerative changes and enhanced neuronal survival. The results suggest that the neuroprotective effect of GVS-111 against oxidative damage and its potential nootropic activity may present a valuable therapeutic combination for the treatment of mental retardation and chronic neurodegenerative disorders. PMID:12711349

  15. Extraction and analysis of neuron firing signals from deep cortical video microscopy

    SciTech Connect

    Kerekes, Ryan A; Blundon, Jay

    2014-01-01

    We introduce a method for extracting and analyzing neuronal activity time signals from video of the cortex of a live animal. The signals correspond to the firing activity of individual cortical neurons. Activity signals are based on the changing fluorescence of calcium indicators in the cells over time. We propose a cell segmentation method that relies on a user-specified center point, from which the signal extraction method proceeds. A stabilization approach is used to reduce tissue motion in the video. The extracted signal is then processed to flatten the baseline and detect action potentials. We show results from applying the method to a cortical video of a live mouse.

  16. Diminished Perisomatic GABAergic Terminals on Cortical Neurons Adjacent to Amyloid Plaques

    PubMed Central

    Garcia-Marin, Virginia; Blazquez-Llorca, Lidia; Rodriguez, José-Rodrigo; Boluda, Susana; Muntane, Gerard; Ferrer, Isidro; DeFelipe, Javier

    2009-01-01

    One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought. PMID:19949482

  17. Expression of constitutively active erythropoietin receptor in pyramidal neurons of cortex and hippocampus boosts higher cognitive functions in mice

    PubMed Central

    2011-01-01

    Background Erythropoietin (EPO) and its receptor (EPOR) are expressed in the developing brain and their transcription is upregulated in adult neurons and glia upon injury or neurodegeneration. We have shown neuroprotective effects and improved cognition in patients with neuropsychiatric diseases treated with EPO. However, the critical EPO targets in brain are unknown, and separation of direct and indirect effects has remained difficult, given the role of EPO in hematopoiesis and brain oxygen supply. Results Here we demonstrate that mice with transgenic expression of a constitutively active EPOR isoform (cEPOR) in pyramidal neurons of cortex and hippocampus exhibit enhancement of spatial learning, cognitive flexibility, social memory, and attentional capacities, accompanied by increased impulsivity. Superior cognitive performance is associated with augmented long-term potentiation of cEPOR expressing neurons in hippocampal slices. Conclusions Active EPOR stimulates neuronal plasticity independent of any hematopoietic effects and in addition to its neuroprotective actions. This property of EPOR signaling should be exploited for defining novel strategies to therapeutically enhance cognitive performance in disease conditions. PMID:21527022

  18. Disrupted ERK signaling during cortical development leads to abnormal progenitor proliferation, neuronal and network excitability and behavior, modeling human neuro-cardio-facial-cutaneous and related syndromes.

    PubMed

    Pucilowska, Joanna; Puzerey, Pavel A; Karlo, J Colleen; Galán, Roberto F; Landreth, Gary E

    2012-06-20

    Genetic disorders arising from copy number variations in the ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases or mutations in their upstream regulators that result in neuro-cardio-facial-cutaneous syndromes are associated with developmental abnormalities, cognitive deficits, and autism. We developed murine models of these disorders by deleting the ERKs at the beginning of neurogenesis and report disrupted cortical progenitor generation and proliferation, which leads to altered cytoarchitecture of the postnatal brain in a gene-dose-dependent manner. We show that these changes are due to ERK-dependent dysregulation of cyclin D1 and p27(Kip1), resulting in cell cycle elongation, favoring neurogenic over self-renewing divisions. The precocious neurogenesis causes premature progenitor pool depletion, altering the number and distribution of pyramidal neurons. Importantly, loss of ERK2 alters the intrinsic excitability of cortical neurons and contributes to perturbations in global network activity. These changes are associated with elevated anxiety and impaired working and hippocampal-dependent memory in these mice. This study provides a novel mechanistic insight into the basis of cortical malformation which may provide a potential link to cognitive deficits in individuals with altered ERK activity.

  19. TETRAMETHRIN AND DDT INHIBIT SPONTANEOUS FIRING IN CORTICAL NEURONAL NETWORKS

    EPA Science Inventory

    The insecticidal and neurotoxic effects of pyrethroids result from prolonged sodium channel inactivation, which causes alterations in neuronal firing and communication. Previously, we determined the relative potencies of 11 type I and type II pyrethroid insecticides using microel...

  20. Automated evolutionary optimization of ion channel conductances and kinetics in models of young and aged rhesus monkey pyramidal neurons.

    PubMed

    Rumbell, Timothy H; Draguljić, Danel; Yadav, Aniruddha; Hof, Patrick R; Luebke, Jennifer I; Weaver, Christina M

    2016-08-01

    Conductance-based compartment modeling requires tuning of many parameters to fit the neuron model to target electrophysiological data. Automated parameter optimization via evolutionary algorithms (EAs) is a common approach to accomplish this task, using error functions to quantify differences between model and target. We present a three-stage EA optimization protocol for tuning ion channel conductances and kinetics in a generic neuron model with minimal manual intervention. We use the technique of Latin hypercube sampling in a new way, to choose weights for error functions automatically so that each function influences the parameter search to a similar degree. This protocol requires no specialized physiological data collection and is applicable to commonly-collected current clamp data and either single- or multi-objective optimization. We applied the protocol to two representative pyramidal neurons from layer 3 of the prefrontal cortex of rhesus monkeys, in which action potential firing rates are significantly higher in aged compared to young animals. Using an idealized dendritic topology and models with either 4 or 8 ion channels (10 or 23 free parameters respectively), we produced populations of parameter combinations fitting the target datasets in less than 80 hours of optimization each. Passive parameter differences between young and aged models were consistent with our prior results using simpler models and hand tuning. We analyzed parameter values among fits to a single neuron to facilitate refinement of the underlying model, and across fits to multiple neurons to show how our protocol will lead to predictions of parameter differences with aging in these neurons. PMID:27106692

  1. Baicalein reverts L-valine-induced persistent sodium current up-modulation in primary cortical neurons.

    PubMed

    Caioli, Silvia; Candelotti, Elena; Pedersen, Jens Z; Saba, Luana; Antonini, Alessia; Incerpi, Sandra; Zona, Cristina

    2016-04-01

    L-valine is a branched-chain amino acid (BCAA) largely used as dietary integrator by athletes and involved in some inherited rare diseases such as maple syrup urine disease. This pathology is caused by an altered BCAA metabolism with the accumulation of toxic keto acids in tissues and body fluids with consequent severe neurological symptoms. In animal models of BCAA accumulation, increased oxidative stress levels and lipid peroxidation have been reported. The aim of this study was to analyze both whether high BCAA concentrations in neurons induce reactive oxygen species (ROS) production and whether, by performing electrophysiological recordings, the neuronal functional properties are modified. Our results demonstrate that in primary cortical cultures, a high dose of valine increases ROS production and provokes neuronal hyperexcitability because the action potential frequencies and the persistent sodium current amplitudes increase significantly compared to non-treated neurons. Since Baicalein, a flavone obtained from the Scutellaria root, has been shown to act as a strong antioxidant with neuroprotective effects, we evaluated its possible antioxidant activity in primary cortical neurons chronically exposed to L-valine. The preincubation of cortical neurons with Baicalein prevents the ROS production and is able to revert both the neuronal hyperexcitability and the increase of the persistent sodium current, indicating a direct correlation between the ROS production and the altered physiological parameters. In conclusion, our data show that the electrophysiological alterations of cortical neurons elicited by high valine concentration are due to the increase in ROS production, suggesting much caution in the intake of BCAA dietary integrators. PMID:26721313

  2. Baicalein reverts L-valine-induced persistent sodium current up-modulation in primary cortical neurons.

    PubMed

    Caioli, Silvia; Candelotti, Elena; Pedersen, Jens Z; Saba, Luana; Antonini, Alessia; Incerpi, Sandra; Zona, Cristina

    2016-04-01

    L-valine is a branched-chain amino acid (BCAA) largely used as dietary integrator by athletes and involved in some inherited rare diseases such as maple syrup urine disease. This pathology is caused by an altered BCAA metabolism with the accumulation of toxic keto acids in tissues and body fluids with consequent severe neurological symptoms. In animal models of BCAA accumulation, increased oxidative stress levels and lipid peroxidation have been reported. The aim of this study was to analyze both whether high BCAA concentrations in neurons induce reactive oxygen species (ROS) production and whether, by performing electrophysiological recordings, the neuronal functional properties are modified. Our results demonstrate that in primary cortical cultures, a high dose of valine increases ROS production and provokes neuronal hyperexcitability because the action potential frequencies and the persistent sodium current amplitudes increase significantly compared to non-treated neurons. Since Baicalein, a flavone obtained from the Scutellaria root, has been shown to act as a strong antioxidant with neuroprotective effects, we evaluated its possible antioxidant activity in primary cortical neurons chronically exposed to L-valine. The preincubation of cortical neurons with Baicalein prevents the ROS production and is able to revert both the neuronal hyperexcitability and the increase of the persistent sodium current, indicating a direct correlation between the ROS production and the altered physiological parameters. In conclusion, our data show that the electrophysiological alterations of cortical neurons elicited by high valine concentration are due to the increase in ROS production, suggesting much caution in the intake of BCAA dietary integrators.

  3. Specific Targeting of the Basolateral Amygdala to Projectionally Defined Pyramidal Neurons in Prelimbic and Infralimbic Cortex123

    PubMed Central

    Ferreira, Ashley N.

    2016-01-01

    Abstract Adjacent prelimbic (PL) and infralimbic (IL) regions in the medial prefrontal cortex have distinct roles in emotional learning. A complete mechanistic understanding underlying this dichotomy remains unclear. Here we explored targeting of specific PL and IL neurons by the basolateral amygdala (BLA), a limbic structure pivotal in pain and fear processing. In mice, we used retrograde labeling, brain-slice recordings, and adenoviral optogenetics to dissect connectivity of ascending BLA input onto PL and IL neurons projecting to the periaqueductal gray (PAG) or the amygdala. We found differential targeting of BLA projections to PL and IL cortex. Activating BLA projections evoked excitatory and inhibitory responses in cortico-PAG (CP) neurons in layer 5 (L5) of both PL and IL cortex. However, all inhibitory responses were polysynaptic and monosynaptic BLA input was stronger to CP neurons in IL cortex. Conversely, the BLA preferentially targeted corticoamygdalar (CA) neurons in layer 2 (L2) of PL over IL cortex. We also reveal that BLA input is projection specific by showing preferential targeting of L5 CP neurons over neighboring L3/5 CA neurons in IL cortex. We conclude by showing that BLA input is laminar-specific by producing stronger excitatory responses CA neurons in L3/5 compared with L2 in IL cortex. Collectively, this study reveals differential targeting of the BLA to PL and IL cortex, which depends both on laminar location and projection target of cortical neurons. Overall, our findings should have important implications for understanding the processing of pain and fear input by the PL and IL cortex. PMID:27022632

  4. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication

    PubMed Central

    Jiang, Zhiwu; Gu, Liming; Chen, Yanxia

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  5. Influenza Virus Induces Inflammatory Response in Mouse Primary Cortical Neurons with Limited Viral Replication.

    PubMed

    Wang, Gefei; Li, Rui; Jiang, Zhiwu; Gu, Liming; Chen, Yanxia; Dai, Jianping; Li, Kangsheng

    2016-01-01

    Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i.) but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy. PMID:27525278

  6. Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia

    PubMed Central

    Gonzalez-Burgos, Guillermo; Cho, Raymond Y; Lewis, David A

    2015-01-01

    Cognitive deficits are a core clinical feature of schizophrenia but respond poorly to available medications. Thus, understanding the neural basis of these deficits is crucial for the development of new therapeutic interventions. The types of cognitive processes affected in schizophrenia are thought to depend on the precisely timed transmission of information in cortical regions via synchronous oscillations at gamma band frequency. Here, we review 1) data from clinical studies suggesting that induction of frontal cortex gamma oscillations during tasks that engage cognitive or complex perceptual functions is attenuated in schizophrenia, 2) findings from basic neuroscience studies highlighting the features of parvalbumin-positive (PV) interneurons that are critical for gamma oscillation production and 3) results from recent postmortem human brain studies providing additional molecular bases for PV interneuron alterations in prefrontal cortical circuitry in schizophrenia. PMID:25863358

  7. Inhibitory Circuits in Cortical Layer 5

    PubMed Central

    Naka, Alexander; Adesnik, Hillel

    2016-01-01

    Inhibitory neurons play a fundamental role in cortical computation and behavior. Recent technological advances, such as two photon imaging, targeted in vivo recording, and molecular profiling, have improved our understanding of the function and diversity of cortical interneurons, but for technical reasons most work has been directed towards inhibitory neurons in the superficial cortical layers. Here we review current knowledge specifically on layer 5 (L5) inhibitory microcircuits, which play a critical role in controlling cortical output. We focus on recent work from the well-studied rodent barrel cortex, but also draw on evidence from studies in primary visual cortex and other cortical areas. The diversity of both deep inhibitory neurons and their pyramidal cell targets make this a challenging but essential area of study in cortical computation and sensory processing. PMID:27199675

  8. Induction of plasminogen in rat hippocampal pyramidal neurons by kainic acid.

    PubMed

    Matsuoka, Y; Kitamura, Y; Taniguchi, T

    1998-08-14

    Tissue plasminogen activator (tPA) is used to treat acute stroke, but tPA- and plasminogen-gene-deficient mice exhibit resistance to neurodegeneration. Thus, it is unclear whether the tPA-plasminogen system, an extracellular proteolytic cascade plays a helpful or harmful role, and whether plasminogen is induced by neurodegeneration. In the CA3, kainic acid (KA)-injection caused neuronal damage after 6 h, and almost all of the neurons were lost after 7 days. Plasminogen mRNA was strongly induced 6 h after injection, then gradually decreased, and was very weak at 2 days after injection. Plasminogen protein was expressed after 6 h and localized in abnormally shaped neurons. The in vivo expression of plasminogen was synchronous with morphological changes in neurons. These results suggest that the expression of plasminogen induced by KA-injection may disrupt of neuron-extracellular matrix interaction and thereby contribute to cell death in neurons in the hippocampus.

  9. Differential cycling rates of Kv4.2 channels in proximal and distal dendrites of hippocampal CA1 pyramidal neurons

    PubMed Central

    Nestor, Michael W.; Hoffman, Dax A.

    2010-01-01

    The heterogeneous expression of voltage-gated channels in dendrites suggests that neurons perform local microdomain computations at different regions. It has been shown that A-type K+ channels have a non-uniform distribution along the primary apical dendrite in CA1 pyramidal neurons, increasing with distance from the soma. Kv4.2 channels, which are responsible for the somatodendritic A-type K+ current in CA1 pyramidal neurons, shape local synaptic input and regulate the back-propagation of APs into dendrites. Experiments were performed to test the hypothesis that Kv4.2 channels are differentially trafficked at different regions along the apical dendrite during basal activity and upon stimulation in CA1 neurons. Proximal (50–150 µm from the soma, primary and oblique) and distal (>200 µm) apical dendrites were selected. The fluorescence recovery after photobleaching (FRAP) technique was used to measure basal cycling rates of EGFP-tagged Kv4.2 (Kv4.2g). We found that the cycling rate of Kv4.2 channels was one order of magnitude slower at both primary and oblique dendrites between 50–150 µm from the soma. Kv4.2 channel cycling increased significantly at 200–250 µm from the soma. Expression of a Kv4.2 mutant lacking a phosphorylation site for protein kinase-A (Kv4.2gS552A) abolished this distance-dependent change in channel cycling; demonstrating that phosphorylation by PKA underlies the increased mobility in distal dendrites. Neuronal stimulation by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) treatment increased cycling of Kv4.2 channels significantly at distal sites only. This activity-dependent increase in Kv4.2 cycling at distal dendrites was blocked by expression of Kv4.2gS552A. These results indicate that distance-dependent Kv4.2 mobility is regulated by activity-dependent phosphorylation of Kv4.2 by PKA. PMID:21472817

  10. Tangential migration of glutamatergic neurons and cortical patterning during development: Lessons from Cajal-Retzius cells.

    PubMed

    Barber, Melissa; Pierani, Alessandra

    2016-08-01

    Tangential migration is a mode of cell movement, which in the developing cerebral cortex, is defined by displacement parallel to the ventricular surface and orthogonal to the radial glial fibers. This mode of long-range migration is a strategy by which distinct neuronal classes generated from spatially and molecularly distinct origins can integrate to form appropriate neural circuits within the cortical plate. While it was previously believed that only GABAergic cortical interneurons migrate tangentially from their origins in the subpallial ganglionic eminences to integrate in the cortical plate, it is now known that transient populations of glutamatergic neurons also adopt this mode of migration. These include Cajal-Retzius cells (CRs), subplate neurons (SPs), and cortical plate transient neurons (CPTs), which have crucial roles in orchestrating the radial and tangential development of the embryonic cerebral cortex in a noncell-autonomous manner. While CRs have been extensively studied, it is only in the last decade that the molecular mechanisms governing their tangential migration have begun to be elucidated. To date, the mechanisms of SPs and CPTs tangential migration remain unknown. We therefore review the known signaling pathways, which regulate parameters of CRs migration including their motility, contact-redistribution and adhesion to the pial surface, and discuss this in the context of how CR migration may regulate their signaling activity in a spatial and temporal manner. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 847-881, 2016.

  11. Regulation of Cerebral Cortical Size and Neuron Number by Fibroblast Growth Factors: Implications for Autism

    ERIC Educational Resources Information Center

    Vaccarino, Flora M.; Grigorenko, Elena L.; Smith, Karen Muller; Stevens, Hanna E.

    2009-01-01

    Increased brain size is common in children with autism spectrum disorders. Here we propose that an increased number of cortical excitatory neurons may underlie the increased brain volume, minicolumn pathology and excessive network excitability, leading to sensory hyper-reactivity and seizures, which are often found in autism. We suggest that…

  12. mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion

    PubMed Central

    Zhu, Jie; Huang, Jui-Yen; Yu, Dinghui; Justice, Nicholas J.; Lu, Hui-Chen

    2013-01-01

    The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions. PMID:23940572

  13. Simultaneous measurement of neuronal activity and cortical hemodynamics by unshielded magnetoencephalography and near-infrared spectroscopy

    NASA Astrophysics Data System (ADS)

    Seki, Yusuke; Miyashita, Tsuyoshi; Kandori, Akihiko; Maki, Atsushi; Koizumi, Hideaki

    2012-10-01

    The correlation between neuronal activity and cortical hemodynamics, namely, neurovascular coupling (NVC), is important to shed light on the mechanism of a variety of brain functions or neuronal diseases. NVC can be studied by simultaneously measuring neuronal activity and cortical hemodynamics. Consequently, noninvasive measurements of the NVC have been widely studied using both electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). However, electromagnetic interference between EEG and fMRI is still a major problem. On the other hand, near-infrared spectroscopy (NIRS) is another promising tool for detecting cortical hemodynamics because it can be combined with EEG or magnetoencephalography (MEG) without any electromagnetic interference. Accordingly, in the present study, a simultaneous measurement system-combining an unshielded MEG using a two-dimensional gradiometer based on a low-T superconducting quantum interference device (SQUID) and an NIRS using nonmagnetic thin probes-was developed. This combined system was used to simultaneously measure both an auditory-evoked magnetic field and blood flow change in the auditory cortex. It was experimentally demonstrated that the combined unshielded MEG/NIRS system can simultaneously measure neuronal activity and cortical hemodynamics.

  14. Arctigenin protects cultured cortical neurons from glutamate-induced neurodegeneration by binding to kainate receptor.

    PubMed

    Jang, Young P; Kim, So R; Choi, Young H; Kim, Jinwoong; Kim, Sang G; Markelonis, George J; Oh, Tae H; Kim, Young C

    2002-04-15

    We previously reported that arctigenin, a lignan isolated from the bark of Torreya nucifera, showed significant neuroprotective activity against glutamate-induced toxicity in primary cultured rat cortical cells. In this study, the mode of action of arctigenin was investigated using primary cultures of rat cortical cells as an in vitro system. Arctigenin significantly attenuated glutamate-induced neurotoxicity when added prior to or after an excitotoxic glutamate challenge. The lignan protected cultured neuronal cells more selectively from neurotoxicity induced by kainic acid than by N-methyl-D-aspartate. The binding of [(3)H]-kainate to its receptors was significantly inhibited by arctigenin in a competitive manner. Furthermore, arctigenin directly scavenged free radicals generated by excess glutamate and successfully reduced the level of cellular peroxide in cultured neurons. These results suggest that arctigenin exerted significant neuroprotective effects on glutamate-injured primary cultures of rat cortical cells by directly binding to kainic acid receptors and partly scavenging of free radicals.

  15. Coconut oil attenuates the effects of amyloid-β on cortical neurons in vitro.

    PubMed

    Nafar, Firoozeh; Mearow, Karen M

    2014-01-01

    Dietary supplementation has been studied as an approach to ameliorating deficits associated with aging and neurodegeneration. We undertook this pilot study to investigate the effects of coconut oil supplementation directly on cortical neurons treated with amyloid-β (Aβ) peptide in vitro. Our results indicate that neuron survival in cultures co-treated with coconut oil and Aβ is rescued compared to cultures exposed only to Aβ. Coconut oil co-treatment also attenuates Aβ-induced mitochondrial alterations. The results of this pilot study provide a basis for further investigation of the effects of coconut oil, or its constituents, on neuronal survival focusing on mechanisms that may be involved.

  16. Slow cortical rhythms: from single-neuron electrophysiology to whole-brain imaging in vivo.

    PubMed

    Olcese, Umberto; Faraguna, Ugo

    2015-01-01

    The slow cortical oscillation is the major brain rhythm occurring during sleep, and has been the object of thorough investigation for over thirty years. Despite all these efforts, the function and the neuronal mechanisms behind slow cortical rhythms remain only partially understood. In this review we will provide an overview of the techniques available for the in vivo study of slow cortical oscillations in animal models. Our goal is to provide an up to date resource for the selection of the best experimental strategies to study specific aspects of slow oscillations. We will cover both traditional, population-level electrophysiological approaches (electroencephalography - EEG, local field potentials) as well as more recent techniques, such as two photon calcium imaging and optogenetics. Overall, we believe that new breakthroughs in our understanding of slow cortical rhythms will require the integration of different techniques, to bridge the gap between different spatio-temporal scales and go from a correlative to a causal level of analysis. PMID:26742663

  17. Sex differences in GABA(B)R-GIRK signaling in layer 5/6 pyramidal neurons of the mouse prelimbic cortex.

    PubMed

    Marron Fernandez de Velasco, Ezequiel; Hearing, Matthew; Xia, Zhilian; Victoria, Nicole C; Luján, Rafael; Wickman, Kevin

    2015-08-01

    The medial prefrontal cortex (mPFC) has been implicated in multiple disorders characterized by clear sex differences, including schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, depression, and drug addiction. These sex differences likely represent underlying differences in connectivity and/or the balance of neuronal excitability within the mPFC. Recently, we demonstrated that signaling via the metabotropic γ-aminobutyric acid receptor (GABABR) and G protein-gated inwardly-rectifying K(+) (GIRK/Kir3) channels modulates the excitability of the key output neurons of the mPFC, the layer 5/6 pyramidal neurons. Here, we report a sex difference in the GABABR-GIRK signaling pathway in these neurons. Specifically, GABABR-dependent GIRK currents recorded in the prelimbic region of the mPFC were larger in adolescent male mice than in female counterparts. Interestingly, this sex difference was not observed in layer 5/6 pyramidal neurons of the adjacent infralimbic cortex, nor was it seen in young adult mice. The sex difference in GABABR-GIRK signaling is not attributable to different expression levels of signaling pathway components, but rather to a phosphorylation-dependent trafficking mechanism. Thus, sex differences related to some diseases associated with altered mPFC function may be explained in part by sex differences in GIRK-dependent signaling in mPFC pyramidal neurons. PMID:25843643

  18. DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons.

    PubMed

    Wei, Jing; Graziane, Nicholas M; Gu, Zhenglin; Yan, Zhen

    2015-11-13

    Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state.

  19. DISC1 Protein Regulates γ-Aminobutyric Acid, Type A (GABAA) Receptor Trafficking and Inhibitory Synaptic Transmission in Cortical Neurons.

    PubMed

    Wei, Jing; Graziane, Nicholas M; Gu, Zhenglin; Yan, Zhen

    2015-11-13

    Association studies have suggested that Disrupted-in-Schizophrenia 1 (DISC1) confers a genetic risk at the level of endophenotypes that underlies many major mental disorders. Despite the progress in understanding the significance of DISC1 at neural development, the mechanisms underlying DISC1 regulation of synaptic functions remain elusive. Because alterations in the cortical GABA system have been strongly linked to the pathophysiology of schizophrenia, one potential target of DISC1 that is critically involved in the regulation of cognition and emotion is the GABAA receptor (GABAAR). We found that cellular knockdown of DISC1 significantly reduced GABAAR-mediated synaptic and whole-cell current, whereas overexpression of wild-type DISC1, but not the C-terminal-truncated DISC1 (a schizophrenia-related mutant), significantly increased GABAAR currents in pyramidal neurons of the prefrontal cortex. These effects were accompanied by DISC1-induced changes in surface GABAAR expression. Moreover, the regulation of GABAARs by DISC1 knockdown or overexpression depends on the microtubule motor protein kinesin 1 (KIF5). Our results suggest that DISC1 exerts an important effect on GABAergic inhibitory transmission by regulating KIF5/microtubule-based GABAAR trafficking in the cortex. The knowledge gained from this study would shed light on how DISC1 and the GABA system are linked mechanistically and how their interactions are critical for maintaining a normal mental state. PMID:26424793

  20. Interplay of environmental signals and progenitor diversity on fate specification of cortical GABAergic neurons

    PubMed Central

    Romcy-Pereira, Rodrigo N.

    2015-01-01

    Cortical GABAergic interneurons constitute an extremely diverse population of cells organized in a well-defined topology of precisely interconnected cells. They play a crucial role regulating inhibitory-excitatory balance in brain circuits, gating sensory perception, and regulating spike timing to brain oscillations during distinct behaviors. Dysfunctions in the establishment of proper inhibitory circuits have been associated to several brain disorders such as autism, epilepsy, and schizophrenia. In the rodent adult cortex, inhibitory neurons are generated during the second gestational week from distinct progenitor lineages located in restricted domains of the ventral telencephalon. However, only recently, studies have revealed some of the mechanisms generating the heterogeneity of neuronal subtypes and their modes of integration in brain networks. Here we will discuss some the events involved in the production of cortical GABAergic neuron diversity with focus on the interaction between intrinsically driven genetic programs and environmental signals during development. PMID:25972784

  1. A physiological correlate of the Pulfrich effect in cortical neurons of the cat.

    PubMed

    Carney, T; Paradiso, M A; Freeman, R D

    1989-01-01

    When a swinging pendulum is viewed with a light-attenuating filter before one eye, the pendulum bob is perceived to move in an elliptical path in depth. It is believed that the filter causes this illusion, the Pulfrich effect, by delaying processing of the image in the filtered eye relative to that of the unfiltered eye. We sought a physiological correlate of this effect by studying binocular integration in cortical neurons of cats while they viewed moving stimuli. Special attention was focused on single unit disparity tuning because it is widely believed that depth perception is related to the responses of disparity selective neurons in visual cortex. We found that placing a filter before one of the cat's eyes produced a temporal delay in the cortical response. The temporal delay was always associated with a shift in the neuron's spatial disparity tuning. The observed temporal delays and disparity shifts are comparable with the magnitude of the Pulfrich effect in humans.

  2. MicroRNA targeting of CoREST controls polarization of migrating cortical neurons.

    PubMed

    Volvert, Marie-Laure; Prévot, Pierre-Paul; Close, Pierre; Laguesse, Sophie; Pirotte, Sophie; Hemphill, James; Rogister, Florence; Kruzy, Nathalie; Sacheli, Rosalie; Moonen, Gustave; Deiters, Alexander; Merkenschlager, Matthias; Chariot, Alain; Malgrange, Brigitte; Godin, Juliette D; Nguyen, Laurent

    2014-05-22

    The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.

  3. Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity

    SciTech Connect

    Huang, Y.-N.; Wu, C.-H.; Lin, T.-C.; Wang, J.-Y.

    2009-11-01

    The impairment of cognitive and motor functions in humans and animals caused by methamphetamine (METH) administration underscores the importance of METH toxicity in cortical neurons. The heme oxygenase-1 (HO-1) exerts a cytoprotective effect against various neuronal injures; however, it remains unclear whether HO-1 is involved in METH-induced toxicity. We used primary cortical neuron/glia cocultures to explore the role of HO-1 in METH-induced toxicity. Exposure of cultured cells to various concentrations of METH (0.1, 0.5, 1, 3, 5, and 10 mM) led to cytotoxicity in a concentration-dependent manner. A METH concentration of 5 mM, which caused 50% of neuronal death and glial activation, was chosen for subsequent experiments. RT-PCR and Western blot analysis revealed that METH significantly induced HO-1 mRNA and protein expression, both preceded cell death. Double and triple immunofluorescence staining further identified HO-1-positive cells as activated astrocytes, microglia, and viable neurons, but not dying neurons. Inhibition of the p38 mitogen-activated protein kinase pathway significantly blocked HO-1 induction by METH and aggravated METH neurotoxicity. Inhibition of HO activity using tin protoporphyrine IX significantly reduced HO activity and exacerbated METH neurotoxicity. However, prior induction of HO-1 using cobalt protoporphyrine IX partially protected neurons from METH toxicity. Taken together, our results suggest that induction of HO-1 by METH via the p38 signaling pathway may be protective, albeit insufficient to completely protect cortical neurons from METH toxicity.

  4. Deleterious impacts of a 900-MHz electromagnetic field on hippocampal pyramidal neurons of 8-week-old Sprague Dawley male rats.

    PubMed

    Şahin, Arzu; Aslan, Ali; Baş, Orhan; İkinci, Ayşe; Özyılmaz, Cansu; Sönmez, Osman Fikret; Çolakoğlu, Serdar; Odacı, Ersan

    2015-10-22

    Children are at potential risk due to their intense use of mobile phones. We examined 8-week-old rats because this age of the rats is comparable with the preadolescent period in humans. The number of pyramidal neurons in the cornu ammonis of the Sprague Dawley male rat (8-weeks old, weighing 180-250 g) hippocampus following exposure to a 900 MHz (MHz) electromagnetic field (EMF) were examined. The study consisted of control (CN-G), sham exposed (SHM-EG) and EMF exposed (EMF-EG) groups with 6 rats in each. The EMF-EG rats were exposed to 900 MHz EMF (1h/day for 30 days) in an EMF jar. The SHM-EG rats were placed in the EMF jar but not exposed to the EMF (1h/day for 30 days). The CN-G rats were not placed into the exposure jar and were not exposed to the EMF during the study period. All animals were sacrificed at the end of the experiment, and their brains were removed for histopathological and stereological analysis. The number of pyramidal neurons in the cornu ammonis of the hippocampus was estimated on Cresyl violet stained sections of the brain using the optical dissector counting technique. Histopathological evaluations were also performed on these sections. Histopathological observation showed abundant cells with abnormal, black or dark blue cytoplasm and shrunken morphology among the normal pyramidal neurons. The largest lateral ventricles were observed in the EMF-EG sections compared to those from the other groups. Stereological analyses showed that the total number of pyramidal neurons in the cornu ammonis of the EMF-EG rats was significantly lower than those in the CN-G (p<0.05) and the SHM-EG (p<0.05). In conclusion, our results suggest that pyramidal neuron loss and histopathological changes in the cornu ammonis of 8-week-old male rats may be due to the 900-MHz EMF exposure.

  5. Effect of chronic ethanol treatment in vivo on excitability in mouse cortical neurones in vitro

    PubMed Central

    Ibbotson, T; Field, M J; Boden, P R

    1997-01-01

    The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post-withdrawal. This ethanol-induced increase in seizure rating was unaffected by carbamazepine (30 mg kg−1) but significantly reduced at a higher concentration (130 mg kg−1). Intracellular recordings were made from cortical layer II neurones in vitro from control mice and from mice following chronic ethanol ingestion. Evoked synaptic potentials were generated in these neurones through intralaminar stimulation. Neurones from control mice displayed an evoked potential consisting of a fast excitatory postsynaptic potential (e.p.s.p.) mediated by AMPA-type glutamate receptors and an inhibitory postsynaptic potential (i.p.s.p.) mediated via GABAA receptors. Application of pentylenetetrazole (PTZ) or bicuculline onto these neurones inhibited the i.p.s.p., caused a large increase in both the amplitude and duration of the e.p.s.p. and initiated spontaneous excitatory activity. The resulting large evoked e.p.s.p. was mediated via both NMDA- and AMPA-type glutamate receptors. Most neurones (77%) from ethanol treated mice displayed an evoked potential which comprised a large e.p.s.p. and no i.p.s.p. The e.p.s.p. consisted of several distinct components and in addition these neurones displayed spontaneous paroxysmal depolarizing shifts. This multi-component e.p.s.p. was mediated through both NMDA- and AMPA-type glutamate receptors. A population (23%) of neurones from ethanol treated mice exhibited evoked potentials which possessed both inhibitory and excitatory components and these neurones were effectively identical to those obtained from control mice. Carbamazepine reduced the duration of the e.p.s.p. in neurones from ethanol treated mice and in PTZ

  6. The role of extracellular conductivity profiles in compartmental models for neurons: particulars for layer 5 pyramidal cells.

    PubMed

    Wang, Kai; Riera, Jorge; Enjieu-Kadji, Herve; Kawashima, Ryuta

    2013-07-01

    With the rapid increase in the number of technologies aimed at observing electric activity inside the brain, scientists have felt the urge to create proper links between intracellular- and extracellular-based experimental approaches. Biophysical models at both physical scales have been formalized under assumptions that impede the creation of such links. In this work, we address this issue by proposing a multicompartment model that allows the introduction of complex extracellular and intracellular resistivity profiles. This model accounts for the geometrical and electrotonic properties of any type of neuron through the combination of four devices: the integrator, the propagator, the 3D connector, and the collector. In particular, we applied this framework to model the tufted pyramidal cells of layer 5 (PCL5) in the neocortex. Our model was able to reproduce the decay and delay curves of backpropagating action potentials (APs) in this type of cell with better agreement with experimental data. We used the voltage drops of the extracellular resistances at each compartment to approximate the local field potentials generated by a PCL5 located in close proximity to linear microelectrode arrays. Based on the voltage drops produced by backpropagating APs, we were able to estimate the current multipolar moments generated by a PCL5. By adding external current sources in parallel to the extracellular resistances, we were able to create a sensitivity profile of PCL5 to electric current injections from nearby microelectrodes. In our model for PCL5, the kinetics and spatial profile of each ionic current were determined based on a literature survey, and the geometrical properties of these cells were evaluated experimentally. We concluded that the inclusion of the extracellular space in the compartmental models of neurons as an extra electrotonic medium is crucial for the accurate simulation of both the propagation of the electric potentials along the neuronal dendrites and the

  7. The role of extracellular conductivity profiles in compartmental models for neurons: particulars for layer 5 pyramidal cells.

    PubMed

    Wang, Kai; Riera, Jorge; Enjieu-Kadji, Herve; Kawashima, Ryuta

    2013-07-01

    With the rapid increase in the number of technologies aimed at observing electric activity inside the brain, scientists have felt the urge to create proper links between intracellular- and extracellular-based experimental approaches. Biophysical models at both physical scales have been formalized under assumptions that impede the creation of such links. In this work, we address this issue by proposing a multicompartment model that allows the introduction of complex extracellular and intracellular resistivity profiles. This model accounts for the geometrical and electrotonic properties of any type of neuron through the combination of four devices: the integrator, the propagator, the 3D connector, and the collector. In particular, we applied this framework to model the tufted pyramidal cells of layer 5 (PCL5) in the neocortex. Our model was able to reproduce the decay and delay curves of backpropagating action potentials (APs) in this type of cell with better agreement with experimental data. We used the voltage drops of the extracellular resistances at each compartment to approximate the local field potentials generated by a PCL5 located in close proximity to linear microelectrode arrays. Based on the voltage drops produced by backpropagating APs, we were able to estimate the current multipolar moments generated by a PCL5. By adding external current sources in parallel to the extracellular resistances, we were able to create a sensitivity profile of PCL5 to electric current injections from nearby microelectrodes. In our model for PCL5, the kinetics and spatial profile of each ionic current were determined based on a literature survey, and the geometrical properties of these cells were evaluated experimentally. We concluded that the inclusion of the extracellular space in the compartmental models of neurons as an extra electrotonic medium is crucial for the accurate simulation of both the propagation of the electric potentials along the neuronal dendrites and the

  8. Hbp1 regulates the timing of neuronal differentiation during cortical development by controlling cell cycle progression.

    PubMed

    Watanabe, Naoki; Kageyama, Ryoichiro; Ohtsuka, Toshiyuki

    2015-07-01

    In the developing mammalian brain, neural stem cells (NSCs) initially expand the progenitor pool by symmetric divisions. NSCs then shift from symmetric to asymmetric division and commence neurogenesis. Although the precise mechanisms regulating the developmental timing of this transition have not been fully elucidated, gradual elongation in the length of the cell cycle and coinciding accumulation of determinants that promote neuronal differentiation might function as a biological clock that regulates the onset of asymmetric division and neurogenesis. We conducted gene expression profiling of embryonic NSCs in the cortical regions and found that expression of high mobility group box transcription factor 1 (Hbp1) was upregulated during neurogenic stages. Induced conditional knockout mice of Hbp1, generated by crossing with Nestin-CreER(T2) mice, exhibited a remarkable dilatation of the telencephalic vesicles with a tangentially expanded ventricular zone and a thinner cortical plate containing reduced numbers of neurons. In these Hbp1-deficient mouse embryos, neural stem/progenitor cells continued to divide with a shorter cell cycle length. Moreover, downstream target genes of the Wnt signaling, such as cyclin D1 (Ccnd1) and c-jun (Jun), were upregulated in the germinal zone of the cortical regions. These results indicate that Hbp1 plays a crucial role in regulating the timing of cortical neurogenesis by elongating the cell cycle and that it is essential for normal cortical development.

  9. Rapid Bidirectional Reorganization of Cortical Microcircuits

    PubMed Central

    Albieri, Giorgia; Barnes, Samuel J.; de Celis Alonso, Benito; Cheetham, Claire E.J.; Edwards, Clarissa E.; Lowe, Andrew S.; Karunaratne, Harini; Dear, John P.; Lee, Kalok C.; Finnerty, Gerald T.

    2015-01-01

    Mature neocortex adapts to altered sensory input by changing neural activity in cortical circuits. The underlying cellular mechanisms remain unclear. We used blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to show reorganization in somatosensory cortex elicited by altered whisker sensory input. We found that there was rapid expansion followed by retraction of whisker cortical maps. The cellular basis for the reorganization in primary somatosensory cortex was investigated with paired electrophysiological recordings in the periphery of the expanded whisker representation. During map expansion, the chance of finding a monosynaptic connection between pairs of pyramidal neurons increased 3-fold. Despite the rapid increase in local excitatory connectivity, the average strength and synaptic dynamics did not change, which suggests that new excitatory connections rapidly acquire the properties of established excitatory connections. During map retraction, entire excitatory connections between pyramidal neurons were lost. In contrast, connectivity between pyramidal neurons and fast spiking interneurons was unchanged. Hence, the changes in local excitatory connectivity did not occur in all circuits involving pyramidal neurons. Our data show that pyramidal neurons are recruited to and eliminated from local excitatory networks over days. These findings suggest that the local excitatory connectome is dynamic in mature neocortex. PMID:24836895

  10. Spatial Parkin Translocation and Degradation of Damaged Mitochondria Via Mitophagy in Live Cortical Neurons

    PubMed Central

    Cai, Qian; Zakaria, Hesham Mostafa; Simone, Anthony; Sheng, Zu-Hang

    2012-01-01

    Summary Mitochondria are essential for neuronal survival and function. Proper degradation of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control. Recent studies have indicated that PINK1/Parkin-mediated pathways ensure mitochondrial integrity and function [1–8]. Translocation of Parkin to damaged mitochondria induces mitophagy in many non-neuronal cell types [9–16]. However, evidence showing Parkin translocation in primary neurons is controversial [9,15,17,18], leaving unanswered questions as to how and where Parkin-mediated mitophagy occurs in neurons. Here, we report the unique process of dissipating mitochondrial Δψm-induced and Parkin-mediated mitophagy in mature cortical neurons. Compared with non-neuronal cells, neuronal mitophagy is a much slower and compartmentally restricted process, coupled with reduced anterograde mitochondrial transport. Parkin-targeted mitochondria are accumulated in the somatodendritic regions where mature lysosomes are predominantly located. Time-lapse imaging shows dynamic formation and elimination of Parkin- and LC3-ring like structures surrounding depolarized mitochondria through the autophagy-lysosomal pathway in the soma. Knocking down Parkin in neurons impairs the elimination of dysfunctional mitochondria. Thus, our study provides neuronal evidence for dynamic and spatial Parkin-mediated mitophagy, which will help us understand whether altered mitophagy contributes to pathogenesis of several major neurodegenerative diseases characterized by mitochondrial dysfunction and impaired transport. PMID:22342752

  11. Graphene Oxide Nanosheets Disrupt Lipid Composition, Ca(2+) Homeostasis, and Synaptic Transmission in Primary Cortical Neurons.

    PubMed

    Bramini, Mattia; Sacchetti, Silvio; Armirotti, Andrea; Rocchi, Anna; Vázquez, Ester; León Castellanos, Verónica; Bandiera, Tiziano; Cesca, Fabrizia; Benfenati, Fabio

    2016-07-26

    Graphene has the potential to make a very significant impact on society, with important applications in the biomedical field. The possibility to engineer graphene-based medical devices at the neuronal interface is of particular interest, making it imperative to determine the biocompatibility of graphene materials with neuronal cells. Here we conducted a comprehensive analysis of the effects of chronic and acute exposure of rat primary cortical neurons to few-layer pristine graphene (GR) and monolayer graphene oxide (GO) flakes. By combining a range of cell biology, microscopy, electrophysiology, and "omics" approaches we characterized the graphene-neuron interaction from the first steps of membrane contact and internalization to the long-term effects on cell viability, synaptic transmission, and cell metabolism. GR/GO flakes are found in contact with the neuronal membrane, free in the cytoplasm, and internalized through the endolysosomal pathway, with no significant impact on neuron viability. However, GO exposure selectively caused the inhibition of excitatory transmission, paralleled by a reduction in the number of excitatory synaptic contacts, and a concomitant enhancement of the inhibitory activity. This was accompanied by induction of autophagy, altered Ca(2+) dynamics, and a downregulation of some of the main players in the regulation of Ca(2+) homeostasis in both excitatory and inhibitory neurons. Our results show that, although graphene exposure does not impact neuron viability, it does nevertheless have important effects on neuronal transmission and network functionality, thus warranting caution when planning to employ this material for neurobiological applications. PMID:27359048

  12. Correlated activity of cortical neurons survives extensive removal of feedforward sensory input

    PubMed Central

    Shapcott, Katharine A.; Schmiedt, Joscha T.; Saunders, Richard C.; Maier, Alexander; Leopold, David A.; Schmid, Michael C.

    2016-01-01

    A fundamental property of brain function is that the spiking activity of cortical neurons is variable and that some of this variability is correlated between neurons. Correlated activity not due to the stimulus arises from shared input but the neuronal circuit mechanisms that result in these noise correlations are not fully understood. Here we tested in the visual system if correlated variability in mid-level area V4 of visual cortex is altered following extensive lesions of primary visual cortex (V1). To this end we recorded longitudinally the neuronal correlations in area V4 of two behaving macaque monkeys before and after a V1 lesion while the monkeys fixated a grey screen. We found that the correlations of neuronal activity survived the lesions in both monkeys. In one monkey, the correlation of multi-unit spiking signals was strongly increased in the first week post-lesion, while in the second monkey, correlated activity was slightly increased, but not greater than some week-by-week fluctuations observed. The typical drop-off of inter-neuronal correlations with cortical distance was preserved after the lesion. Therefore, as V4 noise correlations remain without feedforward input from V1, these results suggest instead that local and/or feedback input seem to be necessary for correlated activity. PMID:27721468

  13. Amino acids modify thalamo-cortical response transformation expressed by neurons of the ventrobasal complex.

    PubMed

    Vahle-Hinz, C; Hicks, T P; Gottschaldt, K M

    1994-02-21

    The hypothesis has been tested that inhibitory mechanisms, active spatially and temporally between the input and the output of thalamic neurons, determine the nature of the information transmitted to the cerebral cortex. To enable this assessment, in barbiturate-anesthetized cats and urethane-anesthetized rats juxtacellular recordings were performed together with microiontophoretic ejection of transmitter agonists and antagonists. The effects of these drugs were studied on responses evoked by mechanical stimulation of cutaneous receptive fields (RFs) of neurons in the thalamic ventrobasal complex (VB). Neurons from different parts of the VB were investigated: 29 units were located medially, in the ventral posteromedial nucleus (VPM; facial RFs), and 11 units were located laterally, in the ventral posterolateral nucleus (VPL; forepaw and body RFs). A further eleven VB units had no detectable RF. Twenty-six neurons were tested with electrical stimulation of the somatosensory cortex (SI), 17 of these being identified as thalamo-cortical relay neurons and 5 being classified as presumed interneurons; the remaining 4 could not be activated. Four additional recordings were from trigemino-thalamic or thalamo-cortical fibers. For the quantitative assessment of the neurons' input and output, neuronal activity was induced by feedback-controlled, mechanical trapezoidal and/or sinusoidal stimuli applied to sinus hairs, fur or skin and the numbers of prepotentials and soma spikes were compared in peristimulus time histograms (PSTHs) generated simultaneously for both types of signal from 'DC' recordings. Iontophoretic administration of excitatory amino acids (EAAs) or bicuculline methiodide (BMI) increased output-input ratios in 87% of the cases tested, due to a higher rate of conversion of prepotentials into soma spikes taking place. In cases of neurons exhibiting a sustained-to-transient response pattern, changes to sustained-to-sustained patterns were demonstrated. Tests with

  14. Forebrain-specific deletion of Cdk5 in pyramidal neurons results in mania-like behavior and cognitive impairment

    PubMed Central

    Su, Susan C.; Rudenko, Andrii; Cho, Sukhee; Tsai, Li-Huei

    2013-01-01

    Cyclin-dependent kinase 5 (Cdk5) is associated with synaptic plasticity and cognitive function. Previous reports have demonstrated that Cdk5 is necessary for memory formation, although others have reported Cdk5 conditional knockout mouse models exhibiting enhanced learning and memory. Furthermore, how Cdk5 acts in specific cell populations to affect behavior and cognitive outcomes remains unclear. Here we conduct a behavioral characterization of a forebrain-specific Cdk5 conditional knockout mouse model under the αCaMKII promoter, in which Cdk5 is ablated in excitatory pyramidal neurons of the forebrain. The Cdk5 conditional knockouts exhibit hyperactivitiy in the open field, reduced anxiety, and reduced behavioral despair. Moreover, the Cdk5 conditional knockouts also display impaired spatial learning in the Morris water maze and are severely impaired in contextual fear memory, which correspond to deficits in synaptic transmission. Remarkably, the hyperactivity of the Cdk5 conditional knockouts can be ameliorated by the administration of lithium chloride, an inhibitor of GSK3β signaling. Collectively, our data reveal that Cdk5 ablation from forebrain excitatory neurons results in deleterious effects on emotional and cognitive behavior and highlight a key role for Cdk5 in regulating the GSK3β signaling pathway. PMID:23850563

  15. Selective regulation of neurosteroid biosynthesis under ketamine-induced apoptosis of cortical neurons in vitro.

    PubMed

    Li, Jianli; Yu, Yang; Wang, Bei; Wu, Honghai; Xue, Gai; Hou, Yanning

    2016-02-01

    Numerous studies have suggested that ketamine administration can induce neuroapoptosis in primary cultured cortical neurons. Neurosteroids modulate neuronal function and serve important roles in the central nervous system, however the role of neurosteroids in neuroapoptosis induced by ketamine remains to be elucidated. The present study aimed to explore whether neurosteroidogenesis was a pivotal mechanism for neuroprotection against ketamine-induced neuroapoptosis, and whether it may be selectively regulated under ketamine-induced neuroapoptosis conditions in primary cultured cortical neurons. To study this hypothesis, the effect of ketamine exposure on neurosteroidogenesis in primary cultured cortical neurons was investigated. Cholesterol, a substrate involved in the synthesis of neurosteroids, was added to the culture medium, and neurosteroids were quantified using high-performance liquid chromatography-tandem mass spectrometry analysis. The data demonstrated that cholesterol blocked ketamine-induced neuroapoptosis by promoting the synthesis of various neurosteroids, and the pathway of neurosteroid testosterone conversion into estradiol was inhibited by ketamine exposure. These data suggest that endogenous neurosteroids biosynthesis is critical for neuroprotection against ketamine-induced neuroapoptosis and inhibiting the biosynthesis of neuroprotective-neurosteroid estradiol is of notable importance for ketamine-induced neuroapoptosis. PMID:26709052

  16. Dynamics of Cortical Neuronal Ensembles Transit from Decision Making to Storage for Later Report

    PubMed Central

    Ponce-Alvarez, Adrián; Nácher, Verónica; Luna, Rogelio; Riehle, Alexa

    2012-01-01

    Decisions based on sensory evaluation during single trials may depend on the collective activity of neurons distributed across brain circuits. Previous studies have deepened our understanding of how the activity of individual neurons relates to the formation of a decision and its storage for later report. However, little is known about how decision-making and decision maintenance processes evolve in single trials. We addressed this problem by studying the activity of simultaneously recorded neurons from different somatosensory and frontal lobe cortices of monkeys performing a vibrotactile discrimination task. We used the hidden Markov model to describe the spatiotemporal pattern of activity in single trials as a sequence of firing rate states. We show that the animal's decision was reliably maintained in frontal lobe activity through a selective state sequence, initiated by an abrupt state transition, during which many neurons changed their activity in a concomitant way, and for which both latency and variability depended on task difficulty. Indeed, transitions were more delayed and more variable for difficult trials compared with easy trials. In contrast, state sequences in somatosensory cortices were weakly decision related, had less variable transitions, and were not affected by the difficulty of the task. In summary, our results suggest that the decision process and its subsequent maintenance are dynamically linked by a cascade of transient events in frontal lobe cortices. PMID:22933781

  17. Activation of 5-HT2A/2C receptors reduces the excitability of cultured cortical neurons.

    PubMed

    Hu, Lingli; Liu, Chunhua; Dang, Minyan; Luo, Bin; Guo, Yiping; Wang, Haitao

    2016-10-01

    The abundant forebrain serotonergic projections are believed to modulate the activities of cortical neurons. 5-HT2 receptor among multiple subtypes of serotonin receptors contributes to the modulation of excitability, synaptic transmissions and plasticity. In the present study, whole-cell patch-clamp recording was adopted to examine whether activation of 5-HT2A/2C receptors would have any impact on the excitability of cultured cortical neurons. We found that 2,5-Dimethoxy-4-iodoamphetamine (DOI), a selective 5-HT2A/2C receptor agonist, rapidly and reversibly depressed spontaneous action potentials mimicking the effect of serotonin. The decreased excitability was also observed for current-evoked firing. Additionally DOI increased neuronal input resistance. Hyperpolarization-activated cyclic nucleotide-gated cationic channels (HCN) did not account for the inhibition of spontaneous firing. The synaptic contribution was ruled out in that DOI augmented excitation and attenuated inhibition to actually favor an increase in the excitability. Our findings revealed that activation of 5-HT2A/2C receptors reduces neuronal excitability, which would deepen our understanding of serotonergic modulation of cortical activities. PMID:27585751

  18. Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

    NASA Astrophysics Data System (ADS)

    He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

    2005-03-01

    Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

  19. ACTIVITY-DEPENDENT STRUCTURAL PLASTICITY AFTER AVERSIVE EXPERIENCES IN AMYGDALA AND AUDITORY CORTEX PYRAMIDAL NEURONS

    PubMed Central

    Gruene, Tina; Flick, Katelyn; Rendall, Sam; Cho, Jin Hyung; Gray, Jesse; Shansky, Rebecca

    2016-01-01

    The brain is highly plastic and undergoes changes in response to many experiences. Learning especially can induce structural remodeling of dendritic spines, which is thought to relate to memory formation. Classical Pavlovian fear conditioning (FC) traditionally pairs an auditory cue with an aversive footshock, and has been widely used to study neural processes underlying associative learning and memory. Past research has found dendritic spine changes after FC in several structures. But, due to heterogeneity of cells within brain structures and limitations of traditional neuroanatomical techniques, it is unclear if all cells included in analyses were actually active during learning processes, even if known circuits are isolated. In this study, we employed a novel approach to analyze structural plasticity explicitly in neurons activated by exposure to either cued or uncued footshocks. We used male and female Arc-dVenus transgenic mice, which express the Venus fluorophore driven by the activity-related Arc promoter, to identify neurons that were active during either scenario. We then targeted fluorescent microinjections to Arc+ and neighboring Arc− neurons in the basolateral area of the amygdala (BLA) and auditory association cortex (TeA). In both BLA and TeA, Arc+ neurons had reduced thin and mushroom spine densities compared to Arc− neurons. This effect was present in males and females alike and also in both cued and uncued shock groups. Overall, this study adds to our understanding of how neuronal activity affects structural plasticity, and represents a methodological advance in the ways we can directly relate structural changes to experience-related neural activity. PMID:27155146

  20. Activity-dependent structural plasticity after aversive experiences in amygdala and auditory cortex pyramidal neurons.

    PubMed

    Gruene, Tina; Flick, Katelyn; Rendall, Sam; Cho, Jin Hyung; Gray, Jesse; Shansky, Rebecca

    2016-07-22

    The brain is highly plastic and undergoes changes in response to many experiences. Learning especially can induce structural remodeling of dendritic spines, which is thought to relate to memory formation. Classical Pavlovian fear conditioning (FC) traditionally pairs an auditory cue with an aversive footshock, and has been widely used to study neural processes underlying associative learning and memory. Past research has found dendritic spine changes after FC in several structures. But, due to heterogeneity of cells within brain structures and limitations of traditional neuroanatomical techniques, it is unclear if all cells included in analyses were actually active during learning processes, even if known circuits are isolated. In this study, we employed a novel approach to analyze structural plasticity explicitly in neurons activated by exposure to either cued or uncued footshocks. We used male and female Arc-dVenus transgenic mice, which express the Venus fluorophore driven by the activity-related Arc promoter, to identify neurons that were active during either scenario. We then targeted fluorescent microinjections to Arc+ and neighboring Arc- neurons in the basolateral area of the amygdala (BLA) and auditory association cortex (TeA). In both BLA and TeA, Arc+ neurons had reduced thin and mushroom spine densities compared to Arc- neurons. This effect was present in males and females alike and also in both cued and uncued shock groups. Overall, this study adds to our understanding of how neuronal activity affects structural plasticity, and represents a methodological advance in the ways we can directly relate structural changes to experience-related neural activity.

  1. Activity-dependent structural plasticity after aversive experiences in amygdala and auditory cortex pyramidal neurons.

    PubMed

    Gruene, Tina; Flick, Katelyn; Rendall, Sam; Cho, Jin Hyung; Gray, Jesse; Shansky, Rebecca

    2016-07-22

    The brain is highly plastic and undergoes changes in response to many experiences. Learning especially can induce structural remodeling of dendritic spines, which is thought to relate to memory formation. Classical Pavlovian fear conditioning (FC) traditionally pairs an auditory cue with an aversive footshock, and has been widely used to study neural processes underlying associative learning and memory. Past research has found dendritic spine changes after FC in several structures. But, due to heterogeneity of cells within brain structures and limitations of traditional neuroanatomical techniques, it is unclear if all cells included in analyses were actually active during learning processes, even if known circuits are isolated. In this study, we employed a novel approach to analyze structural plasticity explicitly in neurons activated by exposure to either cued or uncued footshocks. We used male and female Arc-dVenus transgenic mice, which express the Venus fluorophore driven by the activity-related Arc promoter, to identify neurons that were active during either scenario. We then targeted fluorescent microinjections to Arc+ and neighboring Arc- neurons in the basolateral area of the amygdala (BLA) and auditory association cortex (TeA). In both BLA and TeA, Arc+ neurons had reduced thin and mushroom spine densities compared to Arc- neurons. This effect was present in males and females alike and also in both cued and uncued shock groups. Overall, this study adds to our understanding of how neuronal activity affects structural plasticity, and represents a methodological advance in the ways we can directly relate structural changes to experience-related neural activity. PMID:27155146

  2. Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis.

    PubMed

    Coleman, Leon G; Oguz, Ipek; Lee, Joohwi; Styner, Martin; Crews, Fulton T

    2012-09-01

    Ethanol treatment on postnatal day seven (P7) causes robust brain cell death and is a model of late gestational alcohol exposure (Ikonomidou et al., 2000). To investigate the long-term effects of P7 ethanol treatment on adult brain, mice received either two doses of saline or ethanol on P7 (2.5 g/kg, s.c., 2 h apart) and were assessed as adults (P82) for brain volume (using postmortem MRI) and cellular architecture (using immunohistochemistry). Adult mice that received P7 ethanol had reduced MRI total brain volume (4%) with multiple brain regions being reduced in both males and females. Immunohistochemistry indicated reduced frontal cortical parvalbumin immunoreactive (PV + IR) interneurons (18-33%) and reduced Cux1+IR layer II pyramidal neurons (15%) in both sexes. Interestingly, markers of adult hippocampal neurogenesis differed between sexes, with only ethanol treated males showing increased doublecortin and Ki67 expression (52 and 57% respectively) in the dentate gyrus, consistent with increased neurogenesis compared to controls. These findings suggest that P7 ethanol treatment causes persistent reductions in adult brain volume and frontal cortical neurons in both males and females. Increased adult neurogenesis in males, but not females, is consistent with differential adaptive responses to P7 ethanol toxicity between the sexes. One day of ethanol exposure, e.g. P7, causes persistent adult brain dysmorphology.

  3. Distribution of pyramidal cells associated with perineuronal nets in the neocortex of rat.

    PubMed

    Alpár, Alán; Gärtner, Ulrich; Härtig, Wolfgang; Brückner, Gert

    2006-11-20

    Perineuronal nets are lattice-like accumulations of extracellular matrix components around the cell body and perisomatic portion of certain neurons. Whereas interneurons associated to this specific neuron-associated sheath have been elaborately classified, less effort has been undertaken to describe the occurrence of perineuronal nets around pyramidal neurons. Our aim was to give a detailed and comparative description of the occurrence of net-associated pyramidal cells throughout the rat neocortex as well as to systematically and comparatively analyze the relation of main projection types of principal neurons to the presence of perineuronal nets. The present study revealed that perineuronal nets stained with WFA were associated rather rarely to pyramidal cells compared to interneurons in layers II/III and V/VI of rat neocortex. However, their frequency was considerably different between various cortical areas with a maximum in visual cortex and with a minimum in secondary motor cortices. Further analysis revealed that neuron-associated matrix sheaths around principal cells were more common in the primary than in the secondary fields of corresponding areas and they were more numerous in infra-than in supragranular layers in most regions. Subfields of cortical areas also differed regarding the occurrence of net-associated principal cells, and the subtlety of cortical representation seemed to correlate with the frequency of perineuronal nets around pyramidal neurons in the primary somatosensory cortex. It appears that net-associated pyramidal cells do not have a projection pattern restricted to distinct target regions. Rather a functional heterogeneity of the pyramidal cell population contributing to specific intra-or subcortical projections is suggested.

  4. Transient Receptor Potential Vanilloid 4 Inhibits γ-Aminobutyric Acid-Activated Current in Hippocampal Pyramidal Neurons

    PubMed Central

    Hong, Zhiwen; Tian, Yujing; Qi, Mengwen; Li, Yingchun; Du, Yimei; Chen, Lei; Liu, Wentao; Chen, Ling

    2016-01-01

    The balance between excitatory and inhibitory neurotransmitter systems is crucial for the modulation of neuronal excitability in the central nervous system (CNS). The activation of transient receptor potential vanilloid 4 (TRPV4) is reported to enhance the response of hippocampal glutamate receptors, but whether the inhibitory neurotransmitter system can be regulated by TRPV4 remains unknown. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Here, we show that application of transient receptor potential vanilloid 4 (TRPV4) synthetic (GSK1016790A or 4α-PDD) or endogenous agonist (5,6-EET) inhibited GABA-activated current (IGABA) in hippocampal CA1 pyramidal neurons, which was blocked by specific antagonists of TRPV4 and of GABAA receptors. GSK1016790A increased the phosphorylated AMP-activated protein kinase (p-AMPK) and decreased the phosphorylated protein kinase B (p-Akt) protein levels, which was attenuated by removing extracellular calcium or by a calcium/calmodulin-dependent protein kinase kinase-β antagonist. GSK1016790A-induced decrease of p-Akt protein level was sensitive to an AMPK antagonist. GSK1016790A-inhibited IGABA was blocked by an AMPK antagonist or a phosphatidyl inositol 3 kinase (PI3K) agonist. GSK1016790A-induced inhibition of IGABA was also significantly attenuated by a protein kinase C (PKC) antagonist but was unaffected by protein kinase A or calcium/calmodulin-dependent protein kinase II antagonist. We conclude that activation of TRPV4 inhibits GABAA receptor, which may be mediated by activation of AMPK and subsequent down-regulation of PI3K/Akt signaling and activation of PKC signaling. Inhibition of GABAA receptors may account for the neuronal hyperexcitability caused by TRPV4 activation. PMID:27616980

  5. Transient Receptor Potential Vanilloid 4 Inhibits γ-Aminobutyric Acid-Activated Current in Hippocampal Pyramidal Neurons

    PubMed Central

    Hong, Zhiwen; Tian, Yujing; Qi, Mengwen; Li, Yingchun; Du, Yimei; Chen, Lei; Liu, Wentao; Chen, Ling

    2016-01-01

    The balance between excitatory and inhibitory neurotransmitter systems is crucial for the modulation of neuronal excitability in the central nervous system (CNS). The activation of transient receptor potential vanilloid 4 (TRPV4) is reported to enhance the response of hippocampal glutamate receptors, but whether the inhibitory neurotransmitter system can be regulated by TRPV4 remains unknown. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Here, we show that application of transient receptor potential vanilloid 4 (TRPV4) synthetic (GSK1016790A or 4α-PDD) or endogenous agonist (5,6-EET) inhibited GABA-activated current (IGABA) in hippocampal CA1 pyramidal neurons, which was blocked by specific antagonists of TRPV4 and of GABAA receptors. GSK1016790A increased the phosphorylated AMP-activated protein kinase (p-AMPK) and decreased the phosphorylated protein kinase B (p-Akt) protein levels, which was attenuated by removing extracellular calcium or by a calcium/calmodulin-dependent protein kinase kinase-β antagonist. GSK1016790A-induced decrease of p-Akt protein level was sensitive to an AMPK antagonist. GSK1016790A-inhibited IGABA was blocked by an AMPK antagonist or a phosphatidyl inositol 3 kinase (PI3K) agonist. GSK1016790A-induced inhibition of IGABA was also significantly attenuated by a protein kinase C (PKC) antagonist but was unaffected by protein kinase A or calcium/calmodulin-dependent protein kinase II antagonist. We conclude that activation of TRPV4 inhibits GABAA receptor, which may be mediated by activation of AMPK and subsequent down-regulation of PI3K/Akt signaling and activation of PKC signaling. Inhibition of GABAA receptors may account for the neuronal hyperexcitability caused by TRPV4 activation.

  6. Transient Receptor Potential Vanilloid 4 Inhibits γ-Aminobutyric Acid-Activated Current in Hippocampal Pyramidal Neurons.

    PubMed

    Hong, Zhiwen; Tian, Yujing; Qi, Mengwen; Li, Yingchun; Du, Yimei; Chen, Lei; Liu, Wentao; Chen, Ling

    2016-01-01

    The balance between excitatory and inhibitory neurotransmitter systems is crucial for the modulation of neuronal excitability in the central nervous system (CNS). The activation of transient receptor potential vanilloid 4 (TRPV4) is reported to enhance the response of hippocampal glutamate receptors, but whether the inhibitory neurotransmitter system can be regulated by TRPV4 remains unknown. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Here, we show that application of transient receptor potential vanilloid 4 (TRPV4) synthetic (GSK1016790A or 4α-PDD) or endogenous agonist (5,6-EET) inhibited GABA-activated current (I GABA) in hippocampal CA1 pyramidal neurons, which was blocked by specific antagonists of TRPV4 and of GABAA receptors. GSK1016790A increased the phosphorylated AMP-activated protein kinase (p-AMPK) and decreased the phosphorylated protein kinase B (p-Akt) protein levels, which was attenuated by removing extracellular calcium or by a calcium/calmodulin-dependent protein kinase kinase-β antagonist. GSK1016790A-induced decrease of p-Akt protein level was sensitive to an AMPK antagonist. GSK1016790A-inhibited I GABA was blocked by an AMPK antagonist or a phosphatidyl inositol 3 kinase (PI3K) agonist. GSK1016790A-induced inhibition of I GABA was also significantly attenuated by a protein kinase C (PKC) antagonist but was unaffected by protein kinase A or calcium/calmodulin-dependent protein kinase II antagonist. We conclude that activation of TRPV4 inhibits GABAA receptor, which may be mediated by activation of AMPK and subsequent down-regulation of PI3K/Akt signaling and activation of PKC signaling. Inhibition of GABAA receptors may account for the neuronal hyperexcitability caused by TRPV4 activation. PMID:27616980

  7. Inhibition of microRNA 128 promotes excitability of cultured cortical neuronal networks

    PubMed Central

    McSweeney, K. Melodi; Gussow, Ayal B.; Bradrick, Shelton S.; Dugger, Sarah A.; Gelfman, Sahar; Wang, Quanli; Petrovski, Slavé; Frankel, Wayne N.; Boland, Michael J.; Goldstein, David B.

    2016-01-01

    Cultured neuronal networks monitored with microelectrode arrays (MEAs) have been used widely to evaluate pharmaceutical compounds for potential neurotoxic effects. A newer application of MEAs has been in the development of in vitro models of neurological disease. Here, we directly evaluated the utility of MEAs to recapitulate in vivo phenotypes of mature microRNA-128 (miR-128) deficiency, which causes fatal seizures in mice. We show that inhibition of miR-128 results in significantly increased neuronal activity in cultured neuronal networks derived from primary mouse cortical neurons. These results support the utility of MEAs in developing in vitro models of neuroexcitability disorders, such as epilepsy, and further suggest that MEAs provide an effective tool for the rapid identification of microRNAs that promote seizures when dysregulated. PMID:27516621

  8. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.

    PubMed

    La Fata, Giorgio; Gärtner, Annette; Domínguez-Iturza, Nuria; Dresselaers, Tom; Dawitz, Julia; Poorthuis, Rogier B; Averna, Michele; Himmelreich, Uwe; Meredith, Rhiannon M; Achsel, Tilmann; Dotti, Carlos G; Bagni, Claudia

    2014-12-01

    Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity.

  9. Foxp1 Regulates Cortical Radial Migration and Neuronal Morphogenesis in Developing Cerebral Cortex

    PubMed Central

    Li, Xue; Xiao, Jian; Fröhlich, Henning; Tu, Xiaomeng; Li, Lianlian; Xu, Yue; Cao, Huateng; Qu, Jia; Rappold, Gudrun A.; Chen, Jie-Guang

    2015-01-01

    FOXP1 is a member of FOXP subfamily transcription factors. Mutations in FOXP1 gene have been found in various development-related cognitive disorders. However, little is known about the etiology of these symptoms, and specifically the function of FOXP1 in neuronal development. Here, we report that suppression of Foxp1 expression in mouse cerebral cortex led to a neuronal migration defect, which was rescued by overexpression of Foxp1. Mice with Foxp1 knockdown exhibited ectopic neurons in deep layers of the cortex postnatally. The neuronal differentiation of Foxp1-downregulated cells was normal. However, morphological analysis showed that the neurons with Foxp1 deficiency had an inhibited axonal growth in vitro and a weakened transition from multipolar to bipolar in vivo. Moreover, we found that the expression of Foxp1 modulated the dendritic maturation of neurons at a late postnatal date. Our results demonstrate critical roles of Foxp1 in the radial migration and morphogenesis of cortical neurons during development. This study may shed light on the complex relationship between neuronal development and the related cognitive disorders. PMID:26010426

  10. Similar PDK1-AKT-mTOR pathway activation in balloon cells and dysmorphic neurons of type II focal cortical dysplasia with refractory epilepsy.

    PubMed

    Lin, Yuan-xiang; Lin, Kun; Kang, De-zhi; Liu, Xin-xiu; Wang, Xing-fu; Zheng, Shu-fa; Yu, Liang-hong; Lin, Zhang-ya

    2015-05-01

    Dysmorphic neurons and balloon cells constitute the neuropathological hallmarks of type II focal cortical dysplasias (FCDs) with refractory epilepsy. The genesis of these cells may be critical to the histological findings in type II FCD. Recent work has shown enhanced activation of the mTOR cascade in both balloon cells and dysmorphic neurons, suggesting a common pathogenesis for these two neuropathological hallmarks. A direct comparative analysis of balloon cells and dysmorphic neurons might identify a molecular link between balloon cells and dysmorphic neurons. Here, we addressed whether PDK1-AKT-mTOR activation differentiates balloon cells from dysmorphic neurons. We used immunohistochemistry with antibodies against phosphorylated (p)-PDK1 (Ser241), p-AKT (Thr308), p-AKT (Ser473), p-mTOR (Ser2448), p-P70S6K (Thr229), and p-p70S6 kinase (Thr389) in balloon cells compared with dysmorphic neurons. Strong or moderate staining for components of the PDK1-AKT-mTOR signaling pathway was observed in both balloon cells and dysmorphic neurons. However, only a few pyramidal neurons displayed weak staining in control group (perilesional neocortex and histologically normal neocortex). Additionally, p-PDK1 (Ser241) and p-AKT (Thr308) staining in balloon cells were stronger than in dysmorphic neurons, whereas p-P70S6K (Thr229) and p-p70S6 kinase (Thr389) staining in balloon cells was weaker than in dysmorphic neurons. In balloon cells, p-AKT (Ser473) and p-mTOR (Ser2448) staining was comparable with the staining in dysmorphic neurons. Our data support the previously suggested pathogenic relationship between balloon cells and dysmorphic neurons concerning activation of the PDK1-AKT-mTOR, which may play important roles in the pathogenesis of type II FCD. Differential expression of some components of the PDK1-AKT-mTOR pathway between balloon cells and dysmorphic neurons may result from cell-specific gene expression.

  11. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons.

    PubMed

    Hack, Iris; Hellwig, Sabine; Junghans, Dirk; Brunne, Bianka; Bock, Hans H; Zhao, Shanting; Frotscher, Michael

    2007-11-01

    Reelin, its lipoprotein receptors [very low density lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (ApoER2; also known as Lrp8)], and the cytoplasmic adaptor protein disabled 1 (Dab1) are important for the correct formation of layers in the cerebral cortex. Reeler mice lacking the reelin protein show altered radial neuronal migration resulting in an inversion of cortical layers. ApoER2 Vldlr double-knockout mutants and Dab1 mutants show a reeler-like phenotype, whereas milder phenotypes are found if only one of the two lipoprotein receptors for reelin is absent. However, the precise role of the individual reelin receptors in neuronal migration remained unclear. In the study reported here, we performed fate mapping of newly generated cortical neurons in single and double receptor mutants using bromodeoxyuridine-labeling and layer-specific markers. We present evidence for divergent roles of the two reelin receptors Vldlr and ApoER2, with Vldlr mediating a stop signal for migrating neurons and ApoER2 being essential for the migration of late generated neocortical neurons.

  12. Juxtasomal Biocytin Labeling to Study the Structure-function Relationship of Individual Cortical Neurons

    PubMed Central

    de Haan, Roel; Pieneman, Anton W.; de Kock, Christiaan P.J.

    2014-01-01

    The cerebral cortex is characterized by multiple layers and many distinct cell-types that together as a network are responsible for many higher cognitive functions including decision making, sensory-guided behavior or memory. To understand how such intricate neuronal networks perform such tasks, a crucial step is to determine the function (or electrical activity) of individual cell types within the network, preferentially when the animal is performing a relevant cognitive task. Additionally, it is equally important to determine the anatomical structure of the network and the morphological architecture of the individual neurons to allow reverse engineering the cortical network. Technical breakthroughs available today allow recording cellular activity in awake, behaving animals with the valuable option of post hoc identifying the recorded neurons. Here, we demonstrate the juxtasomal biocytin labeling technique, which involves recording action potential spiking in the extracellular (or loose-patch) configuration using conventional patch pipettes. The juxtasomal recording configuration is relatively stable and applicable across behavioral conditions, including anesthetized, sedated, awake head-fixed, and even in the freely moving animal. Thus, this method allows linking cell-type specific action potential spiking during animal behavior to reconstruction of the individual neurons and ultimately, the entire cortical microcircuit. In this video manuscript, we show how individual neurons in the juxtasomal configuration can be labeled with biocytin in the urethane-anaesthetized rat for post hoc identification and morphological reconstruction. PMID:24638127

  13. TRPV1 Activation in Primary Cortical Neurons Induces Calcium-Dependent Programmed Cell Death.

    PubMed

    Song, Juhyun; Lee, Jun Hong; Lee, Sung Ho; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

    2013-03-01

    Transient receptor potential cation channel, subfamily V, member 1 (TRPV1, also known as vanilloid receptor 1) is a receptor that detects capsaicin, a pungent component of chili peppers, and noxious heat. Although its function in the primary nociceptor as a pain receptor is well established, whether TRPV1 is expressed in the brain is still under debate. In this study, the responses of primary cortical neurons were investigated. Here, we report that 1) capsaicin induces caspase-3-dependent programmed cell death, which coincides with increased production of nitric oxide and peroxynitrite ; that 2) the prolonged capsaicin treatment induces a steady increase in the degree of capase-3 activation, which is prevented by the removal of capsaicin; 3) and that blocking calcium entry and calcium-mediated signaling prevents capsaicin-induced cell death. These results indicate that cortical neurons express TRPV1 whose prolonged activation causes cell death. PMID:23585723

  14. Effect of low frequency repetitive transcranial magnetic stimulation on kindling-induced changes in electrophysiological properties of rat CA1 pyramidal neurons.

    PubMed

    Moradi Chameh, Homeira; Janahmadi, Mahyar; Semnanian, Saeed; Shojaei, Amir; Mirnajafi-Zadeh, Javad

    2015-05-01

    In this study, the effect of repetitive transcranial magnetic stimulation (rTMS) on the kindling induced changes in electrophysiological firing properties of hippocampal CA1 pyramidal neurons was investigated. Male Wistar rats were kindled by daily electrical stimulation of the basolateral amygdala in a semi-rapid manner (12 stimulations/day) until they achieved stage-5 seizure. One group (kindled+rTMS (KrTMS)) of animals received rTMS (240 pulses at 1 Hz) at 5 min after termination of daily kindling stimulations. Twenty-four hours following the last kindling stimulation electrophysiological properties of hippocampal CA1 pyramidal neurons were investigated using a whole-cell patch clamp technique, under current clamp condition. Amygdala kindling significantly decreased the adaptation index, post-afterhyperpolarization, rheobase current, utilization time, and delay to the first rebound spike. It also caused an increase in the voltage sag, number of rebound spikes and number of evoked action potential. Results of the present study revealed that application of rTMS following kindling stimulations had antiepileptogenic effects. In addition, application of rTMS prevented hyperexcitability of CA1 pyramidal neurons induced by kindling and conserved the normal neuronal firing.

  15. Synaptic relationships between a multipolar stellate cell and a pyramidal neuron in the rat visual cortex. A combined Golgi-electron microscope study.

    PubMed

    Peters, A; Proskauer, C C

    1980-04-01

    Two synapsing and impregnated neurons in the rat visual cortex have been examined by a combined Golgi-electron microscope technique in which the Golgi precipitate is replaced by gold particles. One of the neurons is a stellate cell with smooth dendrites and a well impregnated axon, while the other is a layer III pyramidal neuron. Light microscopy showed some boutons from the axonal plexus of the stellate cell closely apposed to the soma and dendrites of the pyramid and it was predicted that synapses were present at these sites. An electron microscopic examination of serial thin sections, in which the profiles of the impregnated neurons are marked by their content of gold particles, showed most of these predicted synapses to exist. Indeed, axon terminals of the stellate cell formed five symmetric synapses with the cell body of the pyramid, one with the apical dendritic shaft and three with basal dendrites. Reasons are given for believing these synapses to be inhibitory. In addition, it was found that one of the axon terminals of the stellate cell synapsed with one of that cell's own dendrites. The significance of this finding is discussed.

  16. Cortical neuron activation induced by electromagnetic stimulation: a quantitative analysis via modelling and simulation.

    PubMed

    Wu, Tiecheng; Fan, Jie; Lee, Kim Seng; Li, Xiaoping

    2016-02-01

    Previous simulation works concerned with the mechanism of non-invasive neuromodulation has isolated many of the factors that can influence stimulation potency, but an inclusive account of the interplay between these factors on realistic neurons is still lacking. To give a comprehensive investigation on the stimulation-evoked neuronal activation, we developed a simulation scheme which incorporates highly detailed physiological and morphological properties of pyramidal cells. The model was implemented on a multitude of neurons; their thresholds and corresponding activation points with respect to various field directions and pulse waveforms were recorded. The results showed that the simulated thresholds had a minor anisotropy and reached minimum when the field direction was parallel to the dendritic-somatic axis; the layer 5 pyramidal cells always had lower thresholds but substantial variances were also observed within layers; reducing pulse length could magnify the threshold values as well as the variance; tortuosity and arborization of axonal segments could obstruct action potential initiation. The dependence of the initiation sites on both the orientation and the duration of the stimulus implies that the cellular excitability might represent the result of the competition between various firing-capable axonal components, each with a unique susceptibility determined by the local geometry. Moreover, the measurements obtained in simulation intimately resemble recordings in physiological and clinical studies, which seems to suggest that, with minimum simplification of the neuron model, the cable theory-based simulation approach can have sufficient verisimilitude to give quantitatively accurate evaluation of cell activities in response to the externally applied field. PMID:26719168

  17. Bidirectional plasticity of excitatory postsynaptic potential (EPSP)-spike coupling in CA1 hippocampal pyramidal neurons.

    PubMed

    Daoudal, Gael; Hanada, Yasuhiro; Debanne, Dominique

    2002-10-29

    Integration of synaptic excitation to generate an action potential (excitatory postsynaptic potential-spike coupling or E-S coupling) determines the neuronal output. Bidirectional synaptic plasticity is well established in the hippocampus, but whether active synaptic integration can display potentiation and depression remains unclear. We show here that synaptic depression is associated with an N-methyl-d-aspartate receptor-dependent and long-lasting depression of E-S coupling. E-S depression is input-specific and is expressed in the presence of gamma-aminobutyric acid type A and B receptor antagonists. In single neurons, E-S depression is observed without modification of postsynaptic passive properties. We conclude that a decrease in intrinsic excitability underlies E-S depression and is synergic with glutamatergic long-term depression.

  18. The release of glutamate from cortical neurons regulated by BDNF via the TrkB/Src/PLC-γ1 pathway.

    PubMed

    Zhang, Zitao; Fan, Jin; Ren, Yongxin; Zhou, Wei; Yin, Guoyong

    2013-01-01

    The brain-derived neurotrophic factor (BDNF) participates in the regulation of cortical neurons by influencing the release of glutamate. However, the specific mechanisms are unclear. Hence, we isolated and cultured the cortical neurons of Sprague Dawley rats. Specific inhibitors of TrkB, Src, PLC-γ1, Akt, and MEK1/2 (i.e., K252a, PP2, U73122, LY294002, and PD98059, respectively) were used to treat cortical neurons and to detect the glutamate release from cortical neurons stimulated with BDNF. BDNF significantly increased glutamate release, and simultaneously enhanced phosphorylation levels of TrkB, Src, PLC-γ, Akt, and Erk1/2. For BDNF-stimulated cortical neurons, K252a inhibited glutamate release and inhibited the phosphorylation levels of TrkB, Src, PLC-γ, Erk1/2, and Akt (P < 0.05). PP2 reduced the glutamate release from BDNF-stimulated cortical neurons (P < 0.05) and inhibited the phosphorylation levels of TrkB and PLC-γ1 (P < 0.05). However, PP2 had no effect on the phosphorylation levels of Erk1/2 or Akt (P > 0.05). U73122 inhibited the glutamate release from BDNF-stimulated cortical neurons, but had no influence on the phosphorylation levels of TrkB, Src, Erk1/2, or Akt (P > 0.05). LY294002 and PD98059 did not affect the BDNF-stimulated glutamate release and did not inhibit the phosphorylation levels of TrkB, Src, or PLC-γ1. In summary, BDNF stimulated the glutamate release from cortical neurons via the TrkB/Src/PLC-γ1 signaling pathway.

  19. Simple Cortical and Thalamic Neuron Models for Digital Arithmetic Circuit Implementation

    PubMed Central

    Nanami, Takuya; Kohno, Takashi

    2016-01-01

    Trade-off between reproducibility of neuronal activities and computational efficiency is one of crucial subjects in computational neuroscience and neuromorphic engineering. A wide variety of neuronal models have been studied from different viewpoints. The digital spiking silicon neuron (DSSN) model is a qualitative model that focuses on efficient implementation by digital arithmetic circuits. We expanded the DSSN model and found appropriate parameter sets with which it reproduces the dynamical behaviors of the ionic-conductance models of four classes of cortical and thalamic neurons. We first developed a four-variable model by reducing the number of variables in the ionic-conductance models and elucidated its mathematical structures using bifurcation analysis. Then, expanded DSSN models were constructed that reproduce these mathematical structures and capture the characteristic behavior of each neuron class. We confirmed that statistics of the neuronal spike sequences are similar in the DSSN and the ionic-conductance models. Computational cost of the DSSN model is larger than that of the recent sophisticated Integrate-and-Fire-based models, but smaller than the ionic-conductance models. This model is intended to provide another meeting point for above trade-off that satisfies the demand for large-scale neuronal network simulation with closer-to-biology models. PMID:27242397

  20. Dendritic sodium spikes are required for long-term potentiation at distal synapses on hippocampal pyramidal neurons

    PubMed Central

    Kim, Yujin; Hsu, Ching-Lung; Cembrowski, Mark S; Mensh, Brett D; Spruston, Nelson

    2015-01-01

    Dendritic integration of synaptic inputs mediates rapid neural computation as well as longer-lasting plasticity. Several channel types can mediate dendritically initiated spikes (dSpikes), which may impact information processing and storage across multiple timescales; however, the roles of different channels in the rapid vs long-term effects of dSpikes are unknown. We show here that dSpikes mediated by Nav channels (blocked by a low concentration of TTX) are required for long-term potentiation (LTP) in the distal apical dendrites of hippocampal pyramidal neurons. Furthermore, imaging, simulations, and buffering experiments all support a model whereby fast Nav channel-mediated dSpikes (Na-dSpikes) contribute to LTP induction by promoting large, transient, localized increases in intracellular calcium concentration near the calcium-conducting pores of NMDAR and L-type Cav channels. Thus, in addition to contributing to rapid neural processing, Na-dSpikes are likely to contribute to memory formation via their role in long-lasting synaptic plasticity. DOI: http://dx.doi.org/10.7554/eLife.06414.001 PMID:26247712

  1. PLD1 participates in BDNF-induced signalling in cortical neurons

    PubMed Central

    Ammar, Mohamed Raafet; Thahouly, Tamou; Hanauer, André; Stegner, David; Nieswandt, Bernhard; Vitale, Nicolas

    2015-01-01

    The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1−/− neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons. PMID:26437780

  2. PLD1 participates in BDNF-induced signalling in cortical neurons.

    PubMed

    Ammar, Mohamed Raafet; Thahouly, Tamou; Hanauer, André; Stegner, David; Nieswandt, Bernhard; Vitale, Nicolas

    2015-01-01

    The brain-derived neurotrophic factor BDNF plays a critical role in neuronal development and the induction of L-LTP at glutamatergic synapses in several brain regions. However, the cellular and molecular mechanisms underlying these BDNF effects have not been firmly established. Using in vitro cultures of cortical neurons from knockout mice for Pld1 and Rsk2, BDNF was observed to induce a rapid RSK2-dependent activation of PLD and to stimulate BDNF ERK1/2-CREB and mTor-S6K signalling pathways, but these effects were greatly reduced in Pld1(-/-) neurons. Furthermore, phospho-CREB did not accumulate in the nucleus, whereas overexpression of PLD1 amplified the BDNF-dependent nuclear recruitment of phospho-ERK1/2 and phospho-CREB. This BDNF retrograde signalling was prevented in cells silenced for the scaffolding protein PEA15, a protein which complexes with PLD1, ERK1/2, and RSK2 after BDNF treatment. Finally PLD1, ERK1/2, and RSK2 partially colocalized on endosomal structures, suggesting that these proteins are part of the molecular module responsible for BDNF signalling in cortical neurons. PMID:26437780

  3. Aberrant neuronal avalanches in cortical tissue removed from juvenile epilepsy patients.

    PubMed

    Hobbs, Jon P; Smith, Jodi L; Beggs, John M

    2010-12-01

    Some forms of epilepsy may arise as a result of pathologic interactions among neurons. Many forms of collective activity have been identified, including waves, spirals, oscillations, synchrony, and neuronal avalanches. All these emergent activity patterns have been hypothesized to show pathologic signatures associated with epilepsy. Here, the authors used 60-channel multielectrode arrays to record neuronal avalanches in cortical tissue removed from juvenile epilepsy patients. For comparison, they also recorded activity in rat cortical slices. The authors found that some human tissue removed from epilepsy patients exhibited prolonged periods of hyperactivity not seen in rat slices. In addition, they found a positive correlation between the branching parameter, a measure of network gain, and firing rate in human slices during periods of hyperactivity. This relationship was not present in rat slices. The authors suggest that this positive correlation between the branching parameter and the firing rate is part of a positive feedback loop and may contribute to some forms of epilepsy. These results also indicate that neuronal avalanches are abnormally regulated in slices removed from pediatric epilepsy patients.

  4. Neuronal avalanches imply maximum dynamic range in cortical networks at criticality.

    PubMed

    Shew, Woodrow L; Yang, Hongdian; Petermann, Thomas; Roy, Rajarshi; Plenz, Dietmar

    2009-12-01

    Spontaneous neuronal activity is a ubiquitous feature of cortex. Its spatiotemporal organization reflects past input and modulates future network output. Here we study whether a particular type of spontaneous activity is generated by a network that is optimized for input processing. Neuronal avalanches are a type of spontaneous activity observed in superficial cortical layers in vitro and in vivo with statistical properties expected from a network operating at "criticality." Theory predicts that criticality and, therefore, neuronal avalanches are optimal for input processing, but until now, this has not been tested in experiments. Here, we use cortex slice cultures grown on planar microelectrode arrays to demonstrate that cortical networks that generate neuronal avalanches benefit from a maximized dynamic range, i.e., the ability to respond to the greatest range of stimuli. By changing the ratio of excitation and inhibition in the cultures, we derive a network tuning curve for stimulus processing as a function of distance from criticality in agreement with predictions from our simulations. Our findings suggest that in the cortex, (1) balanced excitation and inhibition establishes criticality, which maximizes the range of inputs that can be processed, and (2) spontaneous activity and input processing are unified in the context of critical phenomena.

  5. Chronic LPS exposure produces changes in intrinsic membrane properties and a sustained IL-beta-dependent increase in GABAergic inhibition in hippocampal CA1 pyramidal neurons.

    PubMed

    Hellstrom, Ian C; Danik, Marc; Luheshi, Giamal N; Williams, Sylvain

    2005-01-01

    Chronic inflammation has been reported to be a significant factor in the induction and progression of a number of chronic neurological disorders including Alzheimer's disease and Down syndrome. It is believed that inflammation may promote synaptic dysfunction, an effect that is mediated in part by pro-inflammatory cytokines such as interleukin-1beta (IL-1beta). However, the role of IL-1beta and other cytokines in synaptic transmission is still poorly understood. In this study, we have investigated how synaptic transmission and neuronal excitability in hippocampal pyramidal neurons are affected by chronic inflammation induced by exposing organotypic slices to the bacterial cell-wall product lipopolysaccharide (LPS). We report that CA1 pyramidal neurons recorded in whole cell from slices previously exposed to LPS for 7 days had resting membrane potential and action potential properties similar to those of the controls. However, they had significantly lower membrane resistance and a more elevated action potential threshold, and displayed a slower frequency of action potential discharge. Moreover, the amplitude of pharmacologically isolated postsynaptic gamma-aminobutyric acid (GABA)ergic potentials, but not excitatory glutamatergic postsynaptic potentials, was significantly larger following chronic LPS exposure. Interestingly, co-incubation of the IL-1 receptor antagonist (IL-1Ra) concurrently with LPS prevented the increase in GABAergic transmission, but not the reduction in intrinsic neuronal excitability. Finally, we confirmed that LPS dramatically increased IL-1beta, and IL-1beta-dependent IL-6 levels in the culture medium for 2 days before returning to baseline. We conclude that CA1 pyramidal neurons in slices chronically exposed to LPS show a persistent decrease in excitability due to a combined decrease in intrinsic membrane excitability and an enhancement in synaptic GABAergic input, the latter being dependent on IL-1beta. Therefore, chronic inflammation in

  6. A reservoir of time constants for memory traces in cortical neurons.

    PubMed

    Bernacchia, Alberto; Seo, Hyojung; Lee, Daeyeol; Wang, Xiao-Jing

    2011-03-01

    According to reinforcement learning theory of decision making, reward expectation is computed by integrating past rewards with a fixed timescale. In contrast, we found that a wide range of time constants is available across cortical neurons recorded from monkeys performing a competitive game task. By recognizing that reward modulates neural activity multiplicatively, we found that one or two time constants of reward memory can be extracted for each neuron in prefrontal, cingulate and parietal cortex. These timescales ranged from hundreds of milliseconds to tens of seconds, according to a power law distribution, which is consistent across areas and reproduced by a 'reservoir' neural network model. These neuronal memory timescales were weakly, but significantly, correlated with those of monkey's decisions. Our findings suggest a flexible memory system in which neural subpopulations with distinct sets of long or short memory timescales may be selectively deployed according to the task demands.

  7. Inhibitory control of linear and supralinear dendritic excitation in CA1 pyramidal neurons.

    PubMed

    Müller, Christina; Beck, Heinz; Coulter, Douglas; Remy, Stefan

    2012-09-01

    The transformation of dendritic excitatory synaptic inputs to axonal action potential output is the fundamental computation performed by all principal neurons. We show that in the hippocampus this transformation is potently controlled by recurrent inhibitory microcircuits. However, excitatory input on highly excitable dendritic branches could resist inhibitory control by generating strong dendritic spikes and trigger precisely timed action potential output. Furthermore, we show that inhibition-sensitive branches can be transformed into inhibition-resistant, strongly spiking branches by intrinsic plasticity of branch excitability. In addition, we demonstrate that the inhibitory control of spatially defined dendritic excitation is strongly regulated by network activity patterns. Our findings suggest that dendritic spikes may serve to transform correlated branch input into reliable and temporally precise output even in the presence of inhibition.

  8. Additivity of Pyrethroid Actions on Sodium Influx in Cortical Neurons in Cerebrocortical Neurons in Primary Culture

    EPA Science Inventory

    BACKGROUND: Pyrethroid insecticides bind to voltage-gated sodium channels and modify their gating kinetics, thereby disrupting neuronal function. Although previous work has tested the additivity of pyrethroids in vivo, this has not been assessed directly at the primary molecular ...

  9. The PPARβ/δ Agonist GW0742 Induces Early Neuronal Maturation of Cortical Post-Mitotic Neurons: Role of PPARβ/δ in Neuronal Maturation.

    PubMed

    Benedetti, Elisabetta; Di Loreto, Silvia; D'Angelo, Barbara; Cristiano, Loredana; d'Angelo, Michele; Antonosante, Andrea; Fidoamore, Alessia; Golini, Raffaella; Cinque, Benedetta; Cifone, Maria Grazia; Ippoliti, Rodolfo; Giordano, Antonio; Cimini, Annamaria

    2016-03-01

    Increasing evidences support that signaling lipids participate in synaptic plasticity and cell survival, and that the lipid signaling is closely associated with neuronal differentiation, learning, and memory and with pathologic events, such as epilepsy and Alzheimer's disease. The Peroxisome Proliferator-Activated Receptors (PPAR) are strongly involved in the fatty acid cell signaling, as many of the natural lypophylic compounds are PPAR ligands. We have previously shown that PPARβ/δ is the main isotype present in cortical neuron primary cultures and that during neuronal maturation, PPARβ/δ is gradually increased and activated. To get more insight into the molecular mechanism by which PPARβ/δ may be involved in neuronal maturation processes, in this work a specific PPARβ/δ agonist, GW0742 was used administered alone or in association with a specific PPARβ/δ antagonist, the GSK0660, and the parameters involved in neuronal differentiation and maturation were assayed. The data obtained demonstrated the strong involvement of PPARβ/δ in neuronal maturation, triggering the agonist an anticipation of neuronal differentiation, and the antagonist abolishing the observed effects. These effects appear to be mediated by the activation of BDNF pathway.

  10. Online stimulus optimization rapidly reveals multidimensional selectivity in auditory cortical neurons.

    PubMed

    Chambers, Anna R; Hancock, Kenneth E; Sen, Kamal; Polley, Daniel B

    2014-07-01

    Neurons in sensory brain regions shape our perception of the surrounding environment through two parallel operations: decomposition and integration. For example, auditory neurons decompose sounds by separately encoding their frequency, temporal modulation, intensity, and spatial location. Neurons also integrate across these various features to support a unified perceptual gestalt of an auditory object. At higher levels of a sensory pathway, neurons may select for a restricted region of feature space defined by the intersection of multiple, independent stimulus dimensions. To further characterize how auditory cortical neurons decompose and integrate multiple facets of an isolated sound, we developed an automated procedure that manipulated five fundamental acoustic properties in real time based on single-unit feedback in awake mice. Within several minutes, the online approach converged on regions of the multidimensional stimulus manifold that reliably drove neurons at significantly higher rates than predefined stimuli. Optimized stimuli were cross-validated against pure tone receptive fields and spectrotemporal receptive field estimates in the inferior colliculus and primary auditory cortex. We observed, from midbrain to cortex, increases in both level invariance and frequency selectivity, which may underlie equivalent sparseness of responses in the two areas. We found that onset and steady-state spike rates increased proportionately as the stimulus was tailored to the multidimensional receptive field. By separately evaluating the amount of leverage each sound feature exerted on the overall firing rate, these findings reveal interdependencies between stimulus features as well as hierarchical shifts in selectivity and invariance that may go unnoticed with traditional approaches. PMID:24990917

  11. Clinacanthus nutans Protects Cortical Neurons Against Hypoxia-Induced Toxicity by Downregulating HDAC1/6.

    PubMed

    Tsai, Hsin-Da; Wu, Jui-Sheng; Kao, Mei-Han; Chen, Jin-Jer; Sun, Grace Y; Ong, Wei-Yi; Lin, Teng-Nan

    2016-09-01

    Many population-based epidemiological studies have unveiled an inverse correlation between intake of herbal plants and incidence of stroke. C. nutans is a traditional herbal medicine widely used for snake bite, viral infection and cancer in Asian countries. However, its role in protecting stroke damage remains to be studied. Despite of growing evidence to support epigenetic regulation in the pathogenesis and recovery of stroke, a clear understanding of the underlying molecular mechanisms is still lacking. In the present study, primary cortical neurons were subjected to in vitro oxygen-glucose deprivation (OGD)-reoxygenation and hypoxic neuronal death was used to investigate the interaction between C. nutans and histone deacetylases (HDACs). Using pharmacological agents (HDAC inhibitor/activator), loss-of-function (HDAC siRNA) and gain-of-function (HDAC plasmid) approaches, we demonstrated an early induction of HDAC1/2/3/8 and HDAC6 in neurons after OGD insult. C. nutans extract selectively inhibited HDAC1 and HDAC6 expression and attenuated neuronal death. Results of reporter analysis further revealed that C. nutans suppressed HDAC1 and HDAC6 transcription. Besides ameliorating neuronal death, C. nutans also protected astrocytes and endothelial cells from hypoxic-induced cell death. In summary, results support ability for C. nutans to suppress post-hypoxic HDACs activation and mitigate against OGD-induced neuronal death. This study further opens a new avenue for the use of herbal medicines to regulate epigenetic control of brain injury. PMID:27165113

  12. Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

    PubMed Central

    Zhao, Yaqian; Huang, Guowei; Chen, Shuang; Gou, Yun; Dong, Zhiping; Zhang, Xumei

    2016-01-01

    Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level. PMID:27455253

  13. Lactate Modulates the Activity of Primary Cortical Neurons through a Receptor-Mediated Pathway

    PubMed Central

    Bozzo, Luigi; Puyal, Julien; Chatton, Jean-Yves

    2013-01-01

    Lactate is increasingly described as an energy substrate of the brain. Beside this still debated metabolic role, lactate may have other effects on brain cells. Here, we describe lactate as a neuromodulator, able to influence the activity of cortical neurons. Neuronal excitability of mouse primary neurons was monitored by calcium imaging. When applied in conjunction with glucose, lactate induced a decrease in the spontaneous calcium spiking frequency of neurons. The effect was reversible and concentration dependent (IC50 ∼4.2 mM). To test whether lactate effects are dependent on energy metabolism, we applied the closely related substrate pyruvate (5 mM) or switched to different glucose concentrations (0.5 or 10 mM). None of these conditions reproduced the effect of lactate. Recently, a Gi protein-coupled receptor for lactate called HCA1 has been introduced. To test if this receptor is implicated in the observed lactate sensitivity, we incubated cells with pertussis toxin (PTX) an inhibitor of Gi-protein. PTX prevented the decrease of neuronal activity by L-lactate. Moreover 3,5-dyhydroxybenzoic acid, a specific agonist of the HCA1 receptor, mimicked the action of lactate. This study indicates that lactate operates a negative feedback on neuronal activity by a receptor-mediated mechanism, independent from its intracellular metabolism. PMID:23951229

  14. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

    PubMed

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  15. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice

    PubMed Central

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  16. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

    PubMed

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  17. Cell Signaling Mechanisms by which Geniposide Regulates Insulin- Degrading Enzyme Expression in Primary Cortical Neurons.

    PubMed

    Zhang, Yonglan; Xia, Zhining; Liu, Jianhui; Yin, Fei

    2015-01-01

    An increasing number of studies have demonstrated that insulin-degrading enzyme (IDE) plays an essential role in both the degradation and its activity of β-amyloid (Aβ). Therefore, the regulation of IDE expression and/or modification of IDE-dependent actions are two emerging strategies for the treatment of Alzheimer's disease (AD). We previously observed that geniposide, a novel agonist of glucagon-like peptide 1 receptor (GLP-1R), could attenuate Aβ-induced neurotoxicity by regulating the expression of IDE in primary cortical neurons. However, the signal transduction mechanisms underlying this effect were not elucidated. The present study, therefore examined and explored the cell signaling transduction and molecular mechanisms by which geniposide induces the expression of IDE in primary cortical neurons. The current study revealed that LY294002 (an inhibitor for phosphatidyl inositol 3-kinase, PI3K), PP1 (inhibitor for c-Src), GW9662 (antagonist for peroxisome proliferator-activated receptor γ, PPARγ), H89 (an inhibitor for protein kinase A, PKA) and AG1478 (an antagonist for epidermal growth factor receptor, EGFR) prohibited the up-regulation of IDE induced by geniposide in primary cortical neurons. Further, geniposide also enhanced the phosphorylation of PPARγ and accelerated the release of phosphorylated FoxO1 (forkhead box O1) from nuclear fraction to the cytosol. Moreover, geniposide directly activated the activity of IDE promoter in PC12 cells, which confirmed the presence of the GLP-1 receptor. Taken together, our findings reveal for the first time the cell signaling transduction pathway of geniposide regulating the expression of IDE in neurons.

  18. Ethanol upregulates NMDA receptor subunit gene expression in human embryonic stem cell-derived cortical neurons.

    PubMed

    Xiang, Yangfei; Kim, Kun-Yong; Gelernter, Joel; Park, In-Hyun; Zhang, Huiping

    2015-01-01

    Chronic alcohol consumption may result in sustained gene expression alterations in the brain, leading to alcohol abuse or dependence. Because of ethical concerns of using live human brain cells in research, this hypothesis cannot be tested directly in live human brains. In the present study, we used human embryonic stem cell (hESC)-derived cortical neurons as in vitro cellular models to investigate alcohol-induced expression changes of genes involved in alcohol metabolism (ALDH2), anti-apoptosis (BCL2 and CCND2), neurotransmission (NMDA receptor subunit genes: GRIN1, GRIN2A, GRIN2B, and GRIN2D), calcium channel activity (ITPR2), or transcriptional repression (JARID2). hESCs were differentiated into cortical neurons, which were characterized by immunostaining using antibodies against cortical neuron-specific biomarkers. Ethanol-induced gene expression changes were determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). After a 7-day ethanol (50 mM) exposure followed by a 24-hour ethanol withdrawal treatment, five of the above nine genes (including all four NMDA receptor subunit genes) were highly upregulated (GRIN1: 1.93-fold, P = 0.003; GRIN2A: 1.40-fold, P = 0.003; GRIN2B: 1.75-fold, P = 0.002; GRIN2D: 1.86-fold, P = 0.048; BCL2: 1.34-fold, P = 0.031), and the results of GRIN1, GRIN2A, and GRIN2B survived multiple comparison correction. Our findings suggest that alcohol responsive genes, particularly NMDA receptor genes, play an important role in regulating neuronal function and mediating chronic alcohol consumption-induced neuroadaptations.

  19. Taste-Guided Decisions Differentially Engage Neuronal Ensembles across Gustatory Cortices

    PubMed Central

    MacDonald, Christopher J.; Meck, Warren H.; Simon, Sidney A.; Nicolelis, Miguel A.L.

    2009-01-01

    Much remains to be understood about the differential contributions from primary and secondary sensory cortices to sensory guided decision making. To address this issue we simultaneously recorded activity from neuronal ensembles in primary (gustatory cortex – GC) and secondary gustatory (orbitofrontal cortex – OFC) cortices while rats made a taste-guided decision between two response alternatives. We found that before animals commenced a response guided by a tastant cue, GC ensembles contained more information than OFC about the response alternative about to be selected. Thereafter, while the animal’s response was underway the response selective information in ensembles from both regions increased, albeit to a greater degree in OFC. In GC, this increase depends on a representation of the taste cue guiding the animal‘s response. The increase in the OFC also depends on the taste cue guiding and other features of the response such as its spatiomotor properties and the behavioral context under which it is executed. Each of these latter features is encoded by different ensembles of OFC neurons that are recruited at specific times throughout the response selection process. These results indicate that during a taste-guided decision task both primary and secondary gustatory cortices dynamically encode different types of information. PMID:19741134

  20. Physiological approaches to understanding molecular actions on dorsolateral prefrontal cortical neurons underlying higher cognitive processing

    PubMed Central

    WANG, Min; ARNSTEN, Amy F.T.

    2015-01-01

    Revealing how molecular mechanisms influence higher brain circuits in primates will be essential for understanding how genetic insults lead to increased risk of cognitive disorders. Traditionally, modulatory influences on higher cortical circuits have been examined using lesion techniques, where a brain region is depleted of a particular transmitter to determine how its loss impacts cognitive function. For example, depletion of catecholamines or acetylcholine from the dorsolateral prefrontal cortex produces striking deficits in working memory abilities. More directed techniques have utilized direct infusions of drug into a specific cortical site to try to circumvent compensatory changes that are common following transmitter depletion. The effects of drug on neuronal firing patterns are often studied using iontophoresis, where a minute amount of drug is moved into the brain using a tiny electrical current, thus minimizing the fluid flow that generally disrupts neuronal recordings. All of these approaches can be compared to systemic drug administration, which remains a key arena for the development of effective therapeutics for human cognitive disorders. Most recently, viral techniques are being developed to be able to manipulate proteins for which there is no developed pharmacology, and to allow optogenetic manipulations in primate cortex. As the association cortices greatly expand in brain evolution, research in nonhuman primates is particularly important for understanding the modulatory regulation of our highest order cognitive operations. PMID:26646567

  1. Physiological approaches to understanding molecular actions on dorsolateral prefrontal cortical neurons underlying higher cognitive processing.

    PubMed

    Wang, Min; Arnsten, Amy F T

    2015-11-18

    Revealing how molecular mechanisms influence higher brain circuits in primates will be essential for understanding how genetic insults lead to increased risk of cognitive disorders. Traditionally, modulatory influences on higher cortical circuits have been examined using lesion techniques, where a brain region is depleted of a particular transmitter to determine how its loss impacts cognitive function. For example, depletion of catecholamines or acetylcholine from the dorsolateral prefrontal cortex produces striking deficits in working memory abilities. More directed techniques have utilized direct infusions of drug into a specific cortical site to try to circumvent compensatory changes that are common following transmitter depletion. The effects of drug on neuronal firing patterns are often studied using iontophoresis, where a minute amount of drug is moved into the brain using a tiny electrical current, thus minimizing the fluid flow that generally disrupts neuronal recordings. All of these approaches can be compared to systemic drug administration, which remains a key arena for the development of effective therapeutics for human cognitive disorders. Most recently, viral techniques are being developed to be able to manipulate proteins for which there is no developed pharmacology, and to allow optogenetic manipulations in primate cortex. As the association cortices greatly expand in brain evolution, research in nonhuman primates is particularly important for understanding the modulatory regulation of our highest order cognitive operations. PMID:26646567

  2. TFP5 prevents 1-methyl-4-phenyl pyridine ion-induced neurotoxicity in mouse cortical neurons

    PubMed Central

    Zhang, Qi-Shan; Liao, Yuan-Gao; Ji, Zhong; Gu, Yong; Jiang, Hai-Shan; Xie, Zuo-Shan; Pan, Su-Yue; Hu, Ya-Fang

    2016-01-01

    The present study aimed to investigate the protective effect of a modified p5 peptide, TFP5, on 1-methyl-4-phenyl pyridine ion (MPP+)-induced neurotoxicity in cortical neurons and explore the therapeutic effect of TFP5 on Parkinson's disease (PD). MPP+ was applied to a primary culture of mouse cortical neurons to establish the cell model of PD. Neurons were divided into four groups: Control, model (MPP+), scrambled peptide (Scb) (Scb + MPP+) and TFP5 (TFP5 + MPP+) groups. Pretreatment with Scb or TFP5 was applied to the latter two groups, respectively, for 3 h, while phosphate-buffered saline was applied to the control and model groups. MPP+ was then applied to all groups, with the exception of the control group, and neurons were cultured for an additional 24 h. Neuron viability was evaluated using a Cell Counting kit-8 (CCK8) assay. To explore the mechanism underlying the protective effects of TFP5, the expression levels of p35, p25 and phosphorylated myocyte enhancer factor 2 (p-MEF2D) were determined by western blotting. Fluorescence microscopy showed that TFP5 was able to pass through cell membranes and distribute around the nucleus. CCK8 assay showed that neuronal apoptosis was dependent on MPP+ concentration and exposure time. Cell viability decreased significantly in the model group compared with the control group (55±7 vs. 100±0%; P<0.01), and increased significantly in the TFP5 group compared with the model group (98±2 vs. 55±5%; P<0.01) and Scb group (98±2 vs. 54±4%; P<0.01). Scb exhibited no protective effect. Western blotting results showed that MPP+ induced p25 and p-MEF2D expression, TFP5 and Scb did not affect MPP+-induced p25 expression, but TFP5 reduced MPP+-induced p-MEF2D expression. In summary, TFP5 protects against MPP+-induced neurotoxicity in mouse cortical neurons, possibly through inhibiting the MPP+-induced formation and elevated kinase activity of a cyclin-dependent kinase 5/p25 complex.

  3. TFP5 prevents 1-methyl-4-phenyl pyridine ion-induced neurotoxicity in mouse cortical neurons

    PubMed Central

    Zhang, Qi-Shan; Liao, Yuan-Gao; Ji, Zhong; Gu, Yong; Jiang, Hai-Shan; Xie, Zuo-Shan; Pan, Su-Yue; Hu, Ya-Fang

    2016-01-01

    The present study aimed to investigate the protective effect of a modified p5 peptide, TFP5, on 1-methyl-4-phenyl pyridine ion (MPP+)-induced neurotoxicity in cortical neurons and explore the therapeutic effect of TFP5 on Parkinson's disease (PD). MPP+ was applied to a primary culture of mouse cortical neurons to establish the cell model of PD. Neurons were divided into four groups: Control, model (MPP+), scrambled peptide (Scb) (Scb + MPP+) and TFP5 (TFP5 + MPP+) groups. Pretreatment with Scb or TFP5 was applied to the latter two groups, respectively, for 3 h, while phosphate-buffered saline was applied to the control and model groups. MPP+ was then applied to all groups, with the exception of the control group, and neurons were cultured for an additional 24 h. Neuron viability was evaluated using a Cell Counting kit-8 (CCK8) assay. To explore the mechanism underlying the protective effects of TFP5, the expression levels of p35, p25 and phosphorylated myocyte enhancer factor 2 (p-MEF2D) were determined by western blotting. Fluorescence microscopy showed that TFP5 was able to pass through cell membranes and distribute around the nucleus. CCK8 assay showed that neuronal apoptosis was dependent on MPP+ concentration and exposure time. Cell viability decreased significantly in the model group compared with the control group (55±7 vs. 100±0%; P<0.01), and increased significantly in the TFP5 group compared with the model group (98±2 vs. 55±5%; P<0.01) and Scb group (98±2 vs. 54±4%; P<0.01). Scb exhibited no protective effect. Western blotting results showed that MPP+ induced p25 and p-MEF2D expression, TFP5 and Scb did not affect MPP+-induced p25 expression, but TFP5 reduced MPP+-induced p-MEF2D expression. In summary, TFP5 protects against MPP+-induced neurotoxicity in mouse cortical neurons, possibly through inhibiting the MPP+-induced formation and elevated kinase activity of a cyclin-dependent kinase 5/p25 complex. PMID:27698762

  4. Passive Synaptic Normalization and Input Synchrony-Dependent Amplification of Cortical Feedback in Thalamocortical Neuron Dendrites

    PubMed Central

    Connelly, William M.; Crunelli, Vincenzo

    2016-01-01

    significantly increase the influence of corticothalamic feedback on sensory information transfer. SIGNIFICANCE STATEMENT Neurons in first-order thalamic nuclei transmit sensory information from the periphery to the cortex. However, the numerically dominant synaptic input to thalamocortical neurons comes from the cortex, which provides a strong, activity-dependent modulatory feedback influence on information flow through the thalamus. Here, we reveal how individual quantal-sized corticothalamic EPSPs propagate within thalamocortical neuron dendrites and how different spatial and temporal input patterns are integrated by these cells. We find that thalamocortical neurons have voltage- and synchrony-dependent postsynaptic mechanisms, involving NMDA receptors and T-type Ca2+ channels that allow nonlinear amplification of integrated corticothalamic EPSPs. These mechanisms significantly increase the responsiveness of thalamocortical neurons to cortical excitatory input and broaden the “modulatory” influence exerted by corticothalamic synapses. PMID:27030759

  5. Deleterious impacts of a 900-MHz electromagnetic field on hippocampal pyramidal neurons of 8-week-old Sprague Dawley male rats.

    PubMed

    Şahin, Arzu; Aslan, Ali; Baş, Orhan; İkinci, Ayşe; Özyılmaz, Cansu; Sönmez, Osman Fikret; Çolakoğlu, Serdar; Odacı, Ersan

    2015-10-22

    Children are at potential risk due to their intense use of mobile phones. We examined 8-week-old rats because this age of the rats is comparable with the preadolescent period in humans. The number of pyramidal neurons in the cornu ammonis of the Sprague Dawley male rat (8-weeks old, weighing 180-250 g) hippocampus following exposure to a 900 MHz (MHz) electromagnetic field (EMF) were examined. The study consisted of control (CN-G), sham exposed (SHM-EG) and EMF exposed (EMF-EG) groups with 6 rats in each. The EMF-EG rats were exposed to 900 MHz EMF (1h/day for 30 days) in an EMF jar. The SHM-EG rats were placed in the EMF jar but not exposed to the EMF (1h/day for 30 days). The CN-G rats were not placed into the exposure jar and were not exposed to the EMF during the study period. All animals were sacrificed at the end of the experiment, and their brains were removed for histopathological and stereological analysis. The number of pyramidal neurons in the cornu ammonis of the hippocampus was estimated on Cresyl violet stained sections of the brain using the optical dissector counting technique. Histopathological evaluations were also performed on these sections. Histopathological observation showed abundant cells with abnormal, black or dark blue cytoplasm and shrunken morphology among the normal pyramidal neurons. The largest lateral ventricles were observed in the EMF-EG sections compared to those from the other groups. Stereological analyses showed that the total number of pyramidal neurons in the cornu ammonis of the EMF-EG rats was significantly lower than those in the CN-G (p<0.05) and the SHM-EG (p<0.05). In conclusion, our results suggest that pyramidal neuron loss and histopathological changes in the cornu ammonis of 8-week-old male rats may be due to the 900-MHz EMF exposure. PMID:26239913

  6. Comparison of spike parameters from optically identified GABAergic and glutamatergic neurons in sparse cortical cultures

    PubMed Central

    Weir, Keiko; Blanquie, Oriane; Kilb, Werner; Luhmann, Heiko J.; Sinning, Anne

    2015-01-01

    Primary neuronal cultures share many typical features with the in vivo situation, including similarities in distinct electrical activity patterns and synaptic network interactions. Here, we use multi-electrode array (MEA) recordings from spontaneously active cultures of wildtype and glutamic acid decarboxylase 67 (GAD67)-green fluorescent protein (GFP) transgenic mice to evaluate which spike parameters differ between GABAergic interneurons and principal, putatively glutamatergic neurons. To analyze this question we combine MEA recordings with optical imaging in sparse cortical cultures to assign individual spikes to visually-identified single neurons. In our culture system, excitatory and inhibitory neurons are present at a similar ratio as described in vivo, and spike waveform characteristics and firing patterns are fully developed after 2 weeks in vitro. Spike amplitude, but not other spike waveform parameters, correlated with the distance between the recording electrode and the location of the assigned neuron’s soma. Cluster analysis of spike waveform properties revealed no particular cell population that may be assigned to putative inhibitory or excitatory neurons. Moreover, experiments in primary cultures from transgenic GAD67-GFP mice, which allow optical identification of GABAergic interneurons and thus unambiguous assignment of extracellular signals, did not reveal any significant difference in spike timing and spike waveform parameters between inhibitory and excitatory neurons. Despite of our detailed characterization of spike waveform and temporal spiking properties we could not identify an unequivocal electrical parameter to discriminate between individual excitatory and inhibitory neurons in vitro. Our data suggest that under in vitro conditions cellular classifications of single neurons on the basis of their extracellular firing properties should be treated with caution. PMID:25642167

  7. Near infrared radiation rescues mitochondrial dysfunction in cortical neurons after oxygen-glucose deprivation.

    PubMed

    Yu, Zhanyang; Liu, Ning; Zhao, Jianhua; Li, Yadan; McCarthy, Thomas J; Tedford, Clark E; Lo, Eng H; Wang, Xiaoying

    2015-04-01

    Near infrared radiation (NIR) is known to penetrate and affect biological systems in multiple ways. Recently, a series of experimental studies suggested that low intensity NIR may protect neuronal cells against a wide range of insults that mimic diseases such as stroke, brain trauma and neurodegeneration. However, the potential molecular mechanisms of neuroprotection with NIR remain poorly defined. In this study, we tested the hypothesis that low intensity NIR may attenuate hypoxia/ischemia-induced mitochondrial dysfunction in neurons. Primary cortical mouse neuronal cultures were subjected to 4 h oxygen-glucose deprivation followed by reoxygenation for 2 h, neurons were then treated with a 2 min exposure to 810-nm NIR. Mitochondrial function markers including MTT reduction and mitochondria membrane potential were measured at 2 h after treatment. Neurotoxicity was quantified 20 h later. Our results showed that 4 h oxygen-glucose deprivation plus 20 h reoxygenation caused 33.8 ± 3.4 % of neuron death, while NIR exposure significantly reduced neuronal death to 23.6 ± 2.9 %. MTT reduction rate was reduced to 75.9 ± 2.7 % by oxygen-glucose deprivation compared to normoxic controls, but NIR exposure significantly rescued MTT reduction to 87.6 ± 4.5 %. Furthermore, after oxygen-glucose deprivation, mitochondria membrane potential was reduced to 48.9 ± 4.39 % of normoxic control, while NIR exposure significantly ameliorated this reduction to 89.6 ± 13.9 % of normoxic control. Finally, NIR significantly rescued OGD-induced ATP production decline at 20 min after NIR. These findings suggest that low intensity NIR can protect neurons against oxygen-glucose deprivation by rescuing mitochondrial function and restoring neuronal energetics.

  8. Spatiotemporal SERT expression in cortical map development.

    PubMed

    Chen, Xiaoning; Petit, Emilie I; Dobrenis, Kostantin; Sze, Ji Ying

    2016-09-01

    The cerebral cortex is organized into morphologically distinct areas that provide biological frameworks underlying perception, cognition, and behavior. Profiling mouse and human cortical transcriptomes have revealed temporal-specific differential gene expression modules in distinct neocortical areas during cortical map establishment. However, the biological roles of spatiotemporal gene expression in cortical patterning and how cortical topographic gene expression is regulated are largely unknown. Here, we characterize temporal- and spatial-defined expression of serotonin (5-HT) transporter (SERT) in glutamatergic neurons during sensory map development in mice. SERT is transiently expressed in glutamatergic thalamic neurons projecting to sensory cortices and in pyramidal neurons in the prefrontal cortex (PFC) and hippocampus (HPC) during the period that lays down the basic functional neural circuits. We previously identified that knockout of SERT in the thalamic neurons blocks 5-HT uptake by their thalamocortical axons, resulting in excessive 5-HT signaling that impairs sensory map architecture. In contrast, here we show that selective SERT knockout in the PFC and HPC neurons does not perturb sensory map patterning. These data suggest that transient SERT expression in specific glutamatergic neurons provides area-specific instructions for cortical map patterning. Hence, genetic and pharmacological manipulations of this SERT function could illuminate the fundamental genetic programming of cortex-specific maps and biological roles of temporal-specific cortical topographic gene expression in normal development and mental disorders. PMID:27282696

  9. Paired associative transspinal and transcortical stimulation produces plasticity in human cortical and spinal neuronal circuits.

    PubMed

    Dixon, Luke; Ibrahim, Mohamed M; Santora, Danielle; Knikou, Maria

    2016-08-01

    Anatomical, physiological, and functional connectivity exists between the neurons of the primary motor cortex (M1) and spinal cord. Paired associative stimulation (PAS) produces enduring changes in M1, based on the Hebbian principle of associative plasticity. The present study aimed to establish neurophysiological changes in human cortical and spinal neuronal circuits by pairing noninvasive transspinal stimulation with transcortical stimulation via transcranial magnetic stimulation (TMS). We delivered paired transspinal and transcortical stimulation for 40 min at precise interstimulus intervals, with TMS being delivered after (transspinal-transcortical PAS) or before (transcortical-transspinal PAS) transspinal stimulation. Transspinal-transcortical PAS markedly decreased intracortical inhibition, increased intracortical facilitation and M1 excitability with concomitant decreases of motor threshold, and reduced the soleus Hoffmann's reflex (H-reflex) low frequency-mediated homosynaptic depression. Transcortical-transspinal PAS did not affect intracortical circuits, decreased M1 excitability, and reduced the soleus H-reflex-paired stimulation pulses' mediated postactivation depression. Both protocols affected the excitation threshold of group Ia afferents and motor axons. These findings clearly indicate that the pairing of transspinal with transcortical stimulation produces cortical and spinal excitability changes based on the timing interval and functional network interactions between the two associated inputs. This new PAS paradigm may constitute a significant neuromodulation method with physiological impact, because it can be used to alter concomitantly excitability of intracortical circuits, corticospinal neurons, and spinal inhibition in humans. PMID:27281748

  10. Amyloid beta-peptide disrupts carbachol-induced muscarinic cholinergic signal transduction in cortical neurons.

    PubMed

    Kelly, J F; Furukawa, K; Barger, S W; Rengen, M R; Mark, R J; Blanc, E M; Roth, G S; Mattson, M P

    1996-06-25

    Cholinergic pathways serve important functions in learning and memory processes, and deficits in cholinergic transmission occur in Alzheimer disease (AD). A subset of muscarinic cholinergic receptors are linked to G-proteins that activate phospholipase C, resulting in the liberation of inositol trisphosphate and Ca2+ release from intracellular stores. We now report that amyloid beta-peptide (Abeta), which forms plaques in the brain in AD, impairs muscarinic receptor activation of G proteins in cultured rat cortical neurons. Exposure of rodent fetal cortical neurons to Abeta25-35 and Abeta1-40 resulted in a concentration and time-dependent attenuation of carbachol-induced GTPase activity without affecting muscarinic receptor ligand binding parameters. Downstream events in the signal transduction cascade were similarly attenuated by Abeta. Carbachol-induced accumulation of inositol phosphates (IP, IP2, IP3, and IP4) was decreased and calcium imaging studies revealed that carbachol-induced release of calcium was severely impaired in neurons pretreated with Abeta. Muscarinic cholinergic signal transduction was disrupted with subtoxic levels of exposure to AP. The effects of Abeta on carbachol-induced GTPase activity and calcium release were attenuated by antioxidants, implicating free radicals in the mechanism whereby Abeta induced uncoupling of muscarinic receptors. These data demonstrate that Abeta disrupts muscarinic receptor coupling to G proteins that mediate induction of phosphoinositide accumulation and calcium release, findings that implicate Abeta in the impairment of cholinergic transmission that occurs in AD. PMID:8692890

  11. Information capacity and transmission are maximized in balanced cortical networks with neuronal avalanches.

    PubMed

    Shew, Woodrow L; Yang, Hongdian; Yu, Shan; Roy, Rajarshi; Plenz, Dietmar

    2011-01-01

    The repertoire of neural activity patterns that a cortical network can produce constrains the ability of the network to transfer and process information. Here, we measured activity patterns obtained from multisite local field potential recordings in cortex cultures, urethane-anesthetized rats, and awake macaque monkeys. First, we quantified the information capacity of the pattern repertoire of ongoing and stimulus-evoked activity using Shannon entropy. Next, we quantified the efficacy of information transmission between stimulus and response using mutual information. By systematically changing the ratio of excitation/inhibition (E/I) in vitro and in a network model, we discovered that both information capacity and information transmission are maximized at a particular intermediate E/I, at which ongoing activity emerges as neuronal avalanches. Next, we used our in vitro and model results to correctly predict in vivo information capacity and interactions between neuronal groups during ongoing activity. Close agreement between our experiments and model suggest that neuronal avalanches and peak information capacity arise because of criticality and are general properties of cortical networks with balanced E/I.

  12. Contrasting roles for parvalbumin-expressing inhibitory neurons in two forms of adult visual cortical plasticity

    PubMed Central

    Kaplan, Eitan S; Cooke, Sam F; Komorowski, Robert W; Chubykin, Alexander A; Thomazeau, Aurore; Khibnik, Lena A; Gavornik, Jeffrey P; Bear, Mark F

    2016-01-01

    The roles played by cortical inhibitory neurons in experience-dependent plasticity are not well understood. Here we evaluate the participation of parvalbumin-expressing (PV+) GABAergic neurons in two forms of experience-dependent modification of primary visual cortex (V1) in adult mice: ocular dominance (OD) plasticity resulting from monocular deprivation and stimulus-selective response potentiation (SRP) resulting from enriched visual experience. These two forms of plasticity are triggered by different events but lead to a similar increase in visual cortical response. Both also require the NMDA class of glutamate receptor (NMDAR). However, we find that PV+ inhibitory neurons in V1 play a critical role in the expression of SRP and its behavioral correlate of familiarity recognition, but not in the expression of OD plasticity. Furthermore, NMDARs expressed within PV+ cells, reversibly inhibited by the psychotomimetic drug ketamine, play a critical role in SRP, but not in the induction or expression of adult OD plasticity. DOI: http://dx.doi.org/10.7554/eLife.11450.001 PMID:26943618

  13. Lamin B1 protein is required for dendrite development in primary mouse cortical neurons

    PubMed Central

    Giacomini, Caterina; Mahajani, Sameehan; Ruffilli, Roberta; Marotta, Roberto; Gasparini, Laura

    2016-01-01

    Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, and mouse and human loss-of-function mutations in lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, whereas deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced, and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus, possibly due to delocalization of nuclear pore complexes (NPCs) at the nuclear envelope. Taken together, these data highlight a previously unrecognized role of lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution. PMID:26510501

  14. TFP5, a peptide derived from p35, a Cdk5 neuronal activator, rescues cortical neurons from glucose toxicity.

    PubMed

    Binukumar, B K; Zheng, Ya-Li; Shukla, Varsha; Amin, Niranjana D; Grant, Philip; Pant, Harish C

    2014-01-01

    Multiple lines of evidence link the incidence of diabetes to the development of Alzheimer's disease (AD). Patients with diabetes have a 50 to 75% increased risk of developing AD. Cyclin dependent kinase 5 (Cdk5) is a serine/threonine protein kinase, which forms active complexes with p35 or p39, found principally in neurons and in pancreatic β cells. Recent studies suggest that Cdk5 hyperactivity is a possible link between neuropathology seen in AD and diabetes. Previously, we identified P5, a truncated 24-aa peptide derived from the Cdk5 activator p35, later modified as TFP5, so as to penetrate the blood-brain barrier after intraperitoneal injections in AD model mice. This treatment inhibited abnormal Cdk5 hyperactivity and significantly rescued AD pathology in these mice. The present study explores the potential of TFP5 peptide to rescue high glucose (HG)-mediated toxicity in rat embryonic cortical neurons. HG exposure leads to Cdk5-p25 hyperactivity and oxidative stress marked by increased reactive oxygen species production, and decreased glutathione levels and superoxide dismutase activity. It also induces hyperphosphorylation of tau, neuroinflammation as evident from the increased expression of inflammatory cytokines like TNF-α, IL-1β, and IL-6, and apoptosis. Pretreatment of cortical neurons with TFP5 before HG exposure inhibited Cdk5-p25 hyperactivity and significantly attenuated oxidative stress by decreasing reactive oxygen species levels, while increasing superoxide dismutase activity and glutathione. Tau hyperphosphorylation, inflammation, and apoptosis induced by HG were also considerably reduced by pretreatment with TFP5. These results suggest that TFP5 peptide may be a novel candidate for type 2 diabetes therapy. PMID:24326517

  15. Neuroprotection with metformin and thymoquinone against ethanol-induced apoptotic neurodegeneration in prenatal rat cortical neurons

    PubMed Central

    2012-01-01

    Background Exposure to ethanol during early development triggers severe neuronal death by activating multiple stress pathways and causes neurological disorders, such as fetal alcohol effects or fetal alcohol syndrome. This study investigated the effect of ethanol on intracellular events that predispose developing neurons for apoptosis via calcium-mediated signaling. Although the underlying molecular mechanisms of ethanol neurotoxicity are not completely determined, mitochondrial dysfunction, altered calcium homeostasis and apoptosis-related proteins have been implicated in ethanol neurotoxicity. The present study was designed to evaluate the neuroprotective mechanisms of metformin (Met) and thymoquinone (TQ) during ethanol toxicity in rat prenatal cortical neurons at gestational day (GD) 17.5. Results We found that Met and TQ, separately and synergistically, increased cell viability after ethanol (100 mM) exposure for 12 hours and attenuated the elevation of cytosolic free calcium [Ca2+]c. Furthermore, Met and TQ maintained normal physiological mitochondrial transmembrane potential (ΔψM), which is typically lowered by ethanol exposure. Increased cytosolic free [Ca2+]c and lowered mitochondrial transmembrane potential after ethanol exposure significantly decreased the expression of a key anti-apoptotic protein (Bcl-2), increased expression of Bax, and stimulated the release of cytochrome-c from mitochondria. Met and TQ treatment inhibited the apoptotic cascade by increasing Bcl-2 expression. These compounds also repressed the activation of caspase-9 and caspase-3 and reduced the cleavage of PARP-1. Morphological conformation of cell death was assessed by TUNEL, Fluoro-Jade-B, and PI staining. These staining methods demonstrated more cell death after ethanol treatment, while Met, TQ or Met plus TQ prevented ethanol-induced apoptotic cell death. Conclusion These findings suggested that Met and TQ are strong protective agents against ethanol-induced neuronal

  16. Rhythmic Cortical Neurons Increase their Oscillations and Sculpt Basal Ganglia Signaling During Motor Learning

    PubMed Central

    Day, Nancy F.; Nick, Teresa A.

    2014-01-01

    The function and modulation of neural circuits underlying motor skill may involve rhythmic oscillations (Feller, 1999; Marder and Goaillard, 2006; Churchland et al., 2012). In the proposed pattern generator for birdsong, the cortical nucleus HVC, the frequency and power of oscillatory bursting during singing increases with development (Crandall et al., 2007; Day et al., 2009). We examined the maturation of cellular activity patterns that underlie these changes. Single unit ensemble recording combined with antidromic identification (Day et al., 2011) was used to study network development in anesthetized zebra finches. Autocovariance quantified oscillations within single units. A subset of neurons oscillated in the theta/alpha/mu/beta range (8–20 Hz), with greater power in adults compared to juveniles. Across the network, the normalized oscillatory power in the 8–20 Hz range was greater in adults than juveniles. In addition, the correlated activity between rhythmic neuron pairs increased with development. We next examined the functional impact of the oscillators on the output neurons of HVC. We found that the firing of oscillatory neurons negatively correlated with the activity of cortico-basal ganglia neurons (HVCXs), which project to Area X (the song basal ganglia). If groups of oscillators work together to tonically inhibit and precisely control the spike timing of adult HVCXs with coordinated release from inhibition, then the activity of HVCXs in juveniles should be decreased relative to adults due to uncorrelated, tonic inhibition. Consistent with this hypothesis, HVCXs had lower activity in juveniles. These data reveal network changes that shape cortical-to-basal ganglia signaling during motor learning. PMID:23776169

  17. Interplay between kinesin-1 and cortical dynein during axonal outgrowth and microtubule organization in Drosophila neurons.

    PubMed

    del Castillo, Urko; Winding, Michael; Lu, Wen; Gelfand, Vladimir I

    2015-12-28

    In this study, we investigated how microtubule motors organize microtubules in Drosophila neurons. We showed that, during the initial stages of axon outgrowth, microtubules display mixed polarity and minus-end-out microtubules push the tip of the axon, consistent with kinesin-1 driving outgrowth by sliding antiparallel microtubules. At later stages, the microtubule orientation in the axon switches from mixed to uniform polarity with plus-end-out. Dynein knockdown prevents this rearrangement and results in microtubules of mixed orientation in axons and accumulation of microtubule minus-ends at axon tips. Microtubule reorganization requires recruitment of dynein to the actin cortex, as actin depolymerization phenocopies dynein depletion, and direct recruitment of dynein to the membrane bypasses the actin requirement. Our results show that cortical dynein slides 'minus-end-out' microtubules from the axon, generating uniform microtubule arrays. We speculate that differences in microtubule orientation between axons and dendrites could be dictated by differential activity of cortical dynein.

  18. Self-wiring in neural nets of point-like cortical neurons fails to reproduce cytoarchitectural differences.

    PubMed

    Gafarov, Fail M

    2006-06-01

    We propose a model for description of activity-dependent evolution and self-wiring between binary neurons. Specifically, this model can be used for investigation of growth of neuronal connectivity in the developing neocortex. By using computational simulations with appropriate training pattern sequences, we show that long-term memory can be encoded in neuronal connectivity and that the external stimulations form part of the functioning neocortical circuit. It is proposed that such binary neuron representations of point-like cortical neurons fail to reproduce cytoarchitectural differences of the neocortical organization, which has implications for inadequacies of compartmental models.

  19. Expression of Nampt in Hippocampal and Cortical Excitatory Neurons Is Critical for Cognitive Function

    PubMed Central

    Stein, Liana Roberts; Wozniak, David F.; Dearborn, Joshua T.; Kubota, Shunsuke; Apte, Rajendra S.; Izumi, Yukitoshi; Zorumski, Charles F.

    2014-01-01

    Nicotinamide adenine dinucleotide (NAD+) is an enzyme cofactor or cosubstrate in many essential biological pathways. To date, the primary source of neuronal NAD+ has been unclear. NAD+ can be synthesized from several different precursors, among which nicotinamide is the substrate predominantly used in mammals. The rate-limiting step in the NAD+ biosynthetic pathway from nicotinamide is performed by nicotinamide phosphoribosyltransferase (Nampt). Here, we tested the hypothesis that neurons use intracellular Nampt-mediated NAD+ biosynthesis by generating and evaluating mice lacking Nampt in forebrain excitatory neurons (CaMKIIαNampt−/− mice). CaMKIIαNampt−/− mice showed hippocampal and cortical atrophy, astrogliosis, microgliosis, and abnormal CA1 dendritic morphology by 2–3 months of age. Importantly, these histological changes occurred with altered intrahippocampal connectivity and abnormal behavior; including hyperactivity, some defects in motor skills, memory impairment, and reduced anxiety, but in the absence of impaired sensory processes or long-term potentiation of the Schaffer collateral pathway. These results clearly demonstrate that forebrain excitatory neurons mainly use intracellular Nampt-mediated NAD+ biosynthesis to mediate their survival and function. Studying this particular NAD+ biosynthetic pathway in these neurons provides critical insight into their vulnerability to pathophysiological stimuli and the development of therapeutic and preventive interventions for their preservation. PMID:24760840

  20. 14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

    SciTech Connect

    Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shigong

    2014-07-18

    Highlights: • 14,15-EET inhibits OGD-induced apoptosis in cortical neurons. • Mitochondrial biogenesis of cortical neurons is promoted by 14,15-EET. • 14,15-EET preserves mitochondrial function of cortical neurons under OGD. • CREB mediates effect of 14,15-EET on mitochondrial biogenesis and function. - Abstract: 14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen–glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1.

  1. Facilitatory effect of docosahexaenoic acid on N-methyl-D-aspartate response in pyramidal neurones of rat cerebral cortex.

    PubMed Central

    Nishikawa, M; Kimura, S; Akaike, N

    1994-01-01

    1. The effect of docosahexaenoic acid (DHA) on N-methyl-D-aspartic acid (NMDA) responses in the presence of glycine was investigated in pyramidal neurons acutely dissociated from rat cerebral cortex in whole-cell and single channel configurations. 2. DHA potentiated the NMDA-induced response but reduced the non-NMDA (kainate-induced) response in a concentration-dependent manner at a holding potential of -60 mV under voltage-clamp conditions. 3. Arachidonic acid (AA) also potentiated the NMDA-induced response in a manner similar to DHA. Oleic acid caused a slight potentiation. However, other polyunsaturated and saturated fatty acids had no such effects. 4. The facilitatory action of DHA on the NMDA-induced response was not affected by adding inhibitors of cyclo-oxygenase, lipoxygenase or phospholipase A2, suggesting that DHA may exert its facilitatory effect directly on the NMDA receptor. 5. The facilitatory action of DHA was observed in the presence of a saturating dose of NMDA. Moreover, a detailed analysis of the NMDA receptor-operated single channel currents revealed that, in the presence of DHA, the open probability of the channel increased without changing the conductance, indicating that DHA may act by binding directly to a novel site on the NMDA receptor or by altering the lipid environment of the NMDA receptor and thereby potentiating the response to NMDA. 6. The results are discussed in terms of the possibility that DHA may play an important role in the genesis of long-term potentiation, at least that involving the activation of NMDA receptors. PMID:7514666

  2. Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome

    PubMed Central

    Wood, Lydia; Shepherd, Gordon M. G.

    2010-01-01

    Motor and cognitive functions are severely impaired in Rett syndrome (RTT). Here, we examined local synaptic circuits of layer 2/3 (L2/3) pyramidal neurons in motor-frontal cortex of male hemizygous MeCP2-null mice at 3–4 weeks of age. We mapped local excitatory input to L2/3 neurons using glutamate uncaging and laser scanning photostimulation, and compared synaptic input maps recorded from MeCP2-null and wild type (WT) mice. Local excitatory input was significantly reduced in the mutants. The strongest phenotype was observed for lateral (horizontal, intralaminar) inputs, that is, L2/3→2/3 inputs, which showed a large reduction in MeCP2−/y animals. Neither the amount of local inhibitory input to these L2/3 pyramidal neurons nor their intrinsic electrophysiological properties differed by genotype. Our findings provide further evidence that excitatory networks are selectively reduced in RTT. We discuss our findings in the context of recently published parallel studies using selective MeCP2 knockdown in individual L2/3 neurons. PMID:20138994

  3. Acute Seizures in Old Age Leads to a Greater Loss of CA1 Pyramidal Neurons, an Increased Propensity for Developing Chronic TLE and a Severe Cognitive Dysfunction.

    PubMed

    Hattiangady, Bharathi; Kuruba, Ramkumar; Shetty, Ashok K

    2011-02-01

    The aged population displays an enhanced risk for developing acute seizure (AS) activity. However, it is unclear whether AS activity in old age would result in a greater magnitude of hippocampal neurodegeneration and inflammation, and an increased predilection for developing chronic temporal lobe epilepsy (TLE) and cognitive dysfunction. Therefore, we addressed these issues in young-adult (5-months old) and aged (22-months old) F344 rats after three-hours of AS activity, induced through graded intraperitoneal injections of kainic acid (KA), and terminated through a diazepam injection. During the three-hours of AS activity, both young adult and aged groups exhibited similar numbers of stage-V motor seizures but the numbers of stage-IV motor seizures were greater in the aged group. In both age groups, three-hour AS activity induced degeneration of 50-55% of neurons in the dentate hilus, 22-32% of neurons in the granule cell layer and 49-52% neurons in the CA3 pyramidal cell layer without showing any interaction between the age and AS activity. However, degeneration of neurons in the CA1 pyramidal cell layer showed a clear interaction between the age and AS activity (12% in the young adult group and 56% in the aged group), suggesting that an advanced age makes the CA1 pyramidal neurons more susceptible to die with AS activity. The extent of inflammation measured through the numbers of activated microglial cells was similar between the two age groups. Interestingly, the predisposition for developing chronic TLE at 2-3 months after AS activity was 60% for young adult rats but 100% for aged rats. Moreover, both frequency & intensity of spontaneous recurrent seizures in the chronic phase after AS activity were 6-12 folds greater in aged rats than in young adult rats. Furthermore, aged rats lost their ability for spatial learning even in a scrupulous eleven-session water maze learning paradigm after AS activity, in divergence from young adult rats which retained the

  4. Prenatal Exposure to Benzo(a)pyrene Impairs Later-Life Cortical Neuronal Function

    PubMed Central

    McCallister, Monique M.; Maguire, Mark; Ramesh, Aramandla; Aimin, Qiao; Liu, Sheng; Khoshbouei, Habibeh; Aschner, Michael; Ebner, Ford F.; Hood, Darryl B.

    2009-01-01

    Prenatal exposure to environmental contaminants, such as Benzo(a)pyrene [B(a)P] has been shown to impair brain development. The overarching hypothesis of our work is that glutamate receptor subunit expression is crucial for cortical evoked responses and that prenatal B(a)P exposure modulates the temporal developmental expression of glutamatergic receptor subunits in the somatosensory cortex. To characterize prenatal B(a)P exposure on the development of cortical function, pregnant Long Evans rats were exposed to low-level B(a)P (300μg/kg BW) by oral gavage on gestational days 14 to 17. At this exposure dose, there was no significant effect of B(a)P on 1) the number of pups born per litter, 2) the pre-weaning growth curves and 3) initial and final brain to body weight ratios. Control and B(a)P-exposed offspring were profiled for B(a)P metabolites in plasma and whole brain during the pre-weaning period. No detectable levels of metabolites were found in the control offspring. However, a time-dependent decrease in total metabolite concentration was observed in B(a)P-exposed offspring. On PND100-120, cerebrocortical mRNA expression was determined for the glutamatergic NMDA receptor subunit (NR2B) in control and B(a)P-exposed offspring. Neural activity was also recorded from neurons in primary somatic sensory (barrel) cortex. Semiquantitative PCR from B(a)P-exposed offspring revealed a significant 50% reduction in NR2B mRNA expression in B(a)P-exposed offspring relative to controls. Recordings from B(a)P-exposed offspring revealed that N-methyl-D-aspartate (NMDA) receptor -dependent neuronal activity in barrel cortex evoked by whisker stimulation was also significantly reduced (70%) as compared to controls. Analysis showed that the greatest deficit in cortical neuronal responses occurred in the shorter latency epochs from 5-20ms post-stimulus. The results suggest that in utero exposure to benzo(a)pyrene results in diminished mRNA expression of the NMDA NR2B receptor

  5. Run-down of the GABAA response under experimental ischaemia in acutely dissociated CA1 pyramidal neurones of the rat.

    PubMed Central

    Harata, N; Wu, J; Ishibashi, H; Ono, K; Akaike, N

    1997-01-01

    1. The effect of experimental ischaemia on the response to gamma-aminobutyric acid (GABA) was assessed in acutely dissociated CA1 pyramidal neurones of rats, using the patch-clamp technique. 2. Rapid application of 3 x 10(-5) M GABA induced a bicuculline-sensitive inward Cl- current (IGABA) at a holding potential (Vh) of -44 mV. The peak amplitude of IGABA showed a time-dependent decrease (run-down) when it was recorded with the conventional whole-cell mode without internal ATP. The run-down was not observed when the intracellular ATP concentration ([ATP]i) was maintained by the nystatin-perforated recording with an intracellular Na+ concentration ([Na+]i) of 0 mM. 3. When [Na+]i was increased to more than 30 mM, the IGABA run-down was observed even with the nystatin-perforated recording. 4. The IGABA run-down observed at 60 mM [Na+]i with the nystatin method was further enhanced under experimental ischaemia without changes in the reversal potential of IGABA. The enhanced run-down was suppressed by application of the Na+,K(+)-ATPase inhibitors, ouabain and SPAI-1. 5. IGABA run-down during ischaemia was also accompanied by an outward holding current and a concomitant increase in intracellular free Ca2+ concentration ([Ca2+]i) in 48.5% of the neurones. The outward current was a Ca(2+)-activated K+ current, which was blocked by 3 x 10(-7) M charybdotoxin. 6. In the inside-out mode of the single-channel analysis, GABA activated three subconductance states with conductances of 33.4, 22.7 and 15.2 pS. Reduction of ATP concentration from 2 to 0 mM on the intracellular side suppressed the channel activities, while an increase in Ca2+ concentration from 0.7 x 10(-9) to 1.1 x 10(-6) M had no effect. 7. These results suggest that ischaemia induces the run-down of the postsynaptic GABA response at the GABAA receptor level, and that this run-down is triggered by a decrease in [ATP]i. Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:9161985

  6. Isolation and propagation of primary human and rodent embryonic neural progenitor cells and cortical neurons

    PubMed Central

    Darbinyan, Armine; Kaminski, Rafal; White, Martyn K; Darbinian, Nune; Khalili, Kamel

    2014-01-01

    Summary The research on human neural progenitor cells holds great potential for the understanding the molecular programs that control differentiation of cells of glial and neuronal lineages and pathogenetic mechanisms of neurological diseases. Stem cell technologies provide also opportunities for pharmaceutical industry to develop new approaches for regenerative medicine. Here we describe the protocol for isolation and maintenance of neural progenitor cells and cortical neurons using human fetal brain tissue. This protocol can be successfully adapted for preparation of rodent neural and oligodendrocyte progenitor cells. While several methods for isolation of neural and ologodendrocyte progenitors from rodent brain tissue have been described, including techniques which use gene transfer and magnetisc resonsnce beads, few methods are focused on derivation of human oligodendrocyte progenitor cells. Development of human culture provides the most physiologically relevent system for investigation of mechanisms which regulate function of oligodendrocyte, specifically of human origin. PMID:23975820

  7. Neuronal avalanches organize as nested theta- and beta/gamma-oscillations during development of cortical layer 2/3.

    PubMed

    Gireesh, Elakkat D; Plenz, Dietmar

    2008-05-27

    Maturation of the cerebral cortex involves the spontaneous emergence of distinct patterns of neuronal synchronization, which regulate neuronal differentiation, synapse formation, and serve as a substrate for information processing. The intrinsic activity patterns that characterize the maturation of cortical layer 2/3 are poorly understood. By using microelectrode array recordings in vivo and in vitro, we show that this development is marked by the emergence of nested - and beta/gamma-oscillations that require NMDA- and GABA(A)-mediated synaptic transmission. The oscillations organized as neuronal avalanches, i.e., they were synchronized across cortical sites forming diverse and millisecond-precise spatiotemporal patterns that distributed in sizes according to a power law with a slope of -1.5. The correspondence between nested oscillations and neuronal avalanches required activation of the dopamine D(1) receptor. We suggest that the repetitive formation of neuronal avalanches provides an intrinsic template for the selective linking of external inputs to developing superficial layers.

  8. Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling.

    PubMed

    Pacary, Emilie; Heng, Julian; Azzarelli, Roberta; Riou, Philippe; Castro, Diogo; Lebel-Potter, Mélanie; Parras, Carlos; Bell, Donald M; Ridley, Anne J; Parsons, Maddy; Guillemot, François

    2011-03-24

    Little is known of the intracellular machinery that controls the motility of newborn neurons. We have previously shown that the proneural protein Neurog2 promotes the migration of nascent cortical neurons by inducing the expression of the atypical Rho GTPase Rnd2. Here, we show that another proneural factor, Ascl1, promotes neuronal migration in the cortex through direct regulation of a second Rnd family member, Rnd3. Both Rnd2 and Rnd3 promote neuronal migration by inhibiting RhoA signaling, but they control distinct steps of the migratory process, multipolar to bipolar transition in the intermediate zone and locomotion in the cortical plate, respectively. Interestingly, these divergent functions directly result from the distinct subcellular distributions of the two Rnd proteins. Because Rnd proteins also regulate progenitor divisions and neurite outgrowth, we propose that proneural factors, through spatiotemporal regulation of Rnd proteins, integrate the process of neuronal migration with other events in the neurogenic program. PMID:21435554

  9. Proneural transcription factors regulate different steps of cortical neuron migration through Rnd-mediated inhibition of RhoA signaling.

    PubMed

    Pacary, Emilie; Heng, Julian; Azzarelli, Roberta; Riou, Philippe; Castro, Diogo; Lebel-Potter, Mélanie; Parras, Carlos; Bell, Donald M; Ridley, Anne J; Parsons, Maddy; Guillemot, François

    2011-03-24

    Little is known of the intracellular machinery that controls the motility of newborn neurons. We have previously shown that the proneural protein Neurog2 promotes the migration of nascent cortical neurons by inducing the expression of the atypical Rho GTPase Rnd2. Here, we show that another proneural factor, Ascl1, promotes neuronal migration in the cortex through direct regulation of a second Rnd family member, Rnd3. Both Rnd2 and Rnd3 promote neuronal migration by inhibiting RhoA signaling, but they control distinct steps of the migratory process, multipolar to bipolar transition in the intermediate zone and locomotion in the cortical plate, respectively. Interestingly, these divergent functions directly result from the distinct subcellular distributions of the two Rnd proteins. Because Rnd proteins also regulate progenitor divisions and neurite outgrowth, we propose that proneural factors, through spatiotemporal regulation of Rnd proteins, integrate the process of neuronal migration with other events in the neurogenic program.

  10. Golli Myelin Basic Proteins Modulate Voltage-Operated Ca(++) Influx and Development in Cortical and Hippocampal Neurons.

    PubMed

    Vt, Cheli; DA, Santiago González; V, Spreuer; V, Handley; At, Campagnoni; Pm, Paez

    2016-10-01

    The golli proteins, products of the myelin basic protein gene, are widely expressed in oligodendrocyte progenitor cells and neurons during the postnatal development of the brain. While golli appears to be important for oligodendrocyte migration and differentiation, its function in neuronal development is completely unknown. We have found that golli proteins function as new and novel modulators of voltage-operated Ca(++) channels (VOCCs) in neurons. In vitro, golli knock-out (KO) neurons exhibit decreased Ca(++) influx after plasma membrane depolarization and a substantial maturational delay. Increased expression of golli proteins enhances L-type Ca(++) entry and processes outgrowth in cortical neurons, and pharmacological activation of L-type Ca(++) channels stimulates maturation and prevents cell death in golli-KO neurons. In situ, Ca(++) influx mediated by L-type VOCCs was significantly decreased in cortical and hippocampal neurons of the golli-KO brain. These Ca(++) alterations affect cortical and hippocampal development and the proliferation and survival of neural progenitor cells during the postnatal development of the golli-KO brain. The CA1/3 sections and the dentate gyrus of the hippocampus were reduced in the golli-KO mice as well as the density of dendrites in the somatosensory cortex. Furthermore, the golli-KO mice display abnormal behavior including deficits in episodic memory and reduced anxiety. Because of the expression of the golli proteins within neurons in learning and memory centers of the brain, this work has profound implication in neurodegenerative diseases and neurological disorders.

  11. Imaging separation of neuronal from vascular effects of cocaine on rat cortical brain in vivo

    SciTech Connect

    Yuan, Z.; Du, C.; Yuan, Z.; Luo, Z.; Volkow, N.D.; Pan, Y.; Du, C.

    2010-09-08

    MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod2 fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30 {micro}m, 10 Hz) and over a large field of view (3 x 5 mm{sup 2}). We apply it to assess cocaine's effects in rat cortical brain and show an immediate decrease 3.5 {+-} 0.9 min, phase (1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot 7.1 {+-} 0.2 min, phase (2) lasting over 20 min whereas Ca{sup 2+} increased immediately (peaked at t = 4.1 {+-} 0.4 min) and remained elevated. This enabled us to identify a delay (2.9 {+-} 0.5 min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI).

  12. Imaging separation of neuronal from vascular effects of cocaine on rat cortical brain in vivo

    PubMed Central

    Yuan, Zhijia; Luo, Zhongchi; Volkow, Nora D.; Pan, Yingtian; Du, Congwu

    2010-01-01

    MRI techniques to study brain function assume coupling between neuronal activity, metabolism and flow. However, recent evidence of physiological uncoupling between neuronal and cerebrovascular events highlights the need for methods to simultaneously measure these three properties. We report a multimodality optical approach that integrates dual-wavelength laser speckle imaging (measures changes in blood flow, blood volume and hemoglobin oxygenation), digital-frequency-ramping optical coherence tomography (images quantitative 3D vascular network) and Rhod2 fluorescence (images intracellular calcium for measure of neuronal activity) at high spatiotemporal resolutions (30μm, 10Hz) and over a large field of view (3 × 5mm2). We apply it to assess cocaine’s effects in rat cortical brain and show an immediate decrease (3.5 ± 0.9min, phase 1) in the oxygen content of hemoglobin and the cerebral blood flow followed by an overshoot (7.1 ± 0.2min, phase 2) lasting over 20min whereas Ca2+ increased immediately (peaked at t=4.1 ± 0.4min) and remained elevated. This enabled us to identify a delay (2.9 ± 0.5min) between peak neuronal and vascular responses in phase 2. The ability of this multimodality optical approach for simultaneous imaging at high spatiotemporal resolutions permits us to distinguish the vascular versus cellular changes of the brain, thus complimenting other neuroimaging modalities for brain functional studies (e. g., PET, fMRI). PMID:20804849

  13. Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

    PubMed

    Ohtaka-Maruyama, Chiaki; Okado, Haruo

    2015-01-01

    Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis. PMID:26733777

  14. Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development

    PubMed Central

    Ohtaka-Maruyama, Chiaki; Okado, Haruo

    2015-01-01

    Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis. PMID:26733777

  15. FMRP regulates multipolar to bipolar transition affecting neuronal migration and cortical circuitry.

    PubMed

    La Fata, Giorgio; Gärtner, Annette; Domínguez-Iturza, Nuria; Dresselaers, Tom; Dawitz, Julia; Poorthuis, Rogier B; Averna, Michele; Himmelreich, Uwe; Meredith, Rhiannon M; Achsel, Tilmann; Dotti, Carlos G; Bagni, Claudia

    2014-12-01

    Deficiencies in fragile X mental retardation protein (FMRP) are the most common cause of inherited intellectual disability, fragile X syndrome (FXS), with symptoms manifesting during infancy and early childhood. Using a mouse model for FXS, we found that Fmrp regulates the positioning of neurons in the cortical plate during embryonic development, affecting their multipolar-to-bipolar transition (MBT). We identified N-cadherin, which is crucial for MBT, as an Fmrp-regulated target in embryonic brain. Furthermore, spontaneous network activity and high-resolution brain imaging revealed defects in the establishment of neuronal networks at very early developmental stages, further confirmed by an unbalanced excitatory and inhibitory network. Finally, reintroduction of Fmrp or N-cadherin in the embryo normalized early postnatal neuron activity. Our findings highlight the critical role of Fmrp in the developing cerebral cortex and might explain some of the clinical features observed in patients with FXS, such as alterations in synaptic communication and neuronal network connectivity. PMID:25402856

  16. Molecular Pathways Underlying Projection Neuron Production and Migration during Cerebral Cortical Development.

    PubMed

    Ohtaka-Maruyama, Chiaki; Okado, Haruo

    2015-01-01

    Glutamatergic neurons of the mammalian cerebral cortex originate from radial glia (RG) progenitors in the ventricular zone (VZ). During corticogenesis, neuroblasts migrate toward the pial surface using two different migration modes. One is multipolar (MP) migration with random directional movement, and the other is locomotion, which is a unidirectional movement guided by the RG fiber. After reaching their final destination, the neurons finalize their migration by terminal translocation, which is followed by maturation via dendrite extension to initiate synaptogenesis and thereby complete neural circuit formation. This switching of migration modes during cortical development is unique in mammals, which suggests that the RG-guided locomotion mode may contribute to the evolution of the mammalian neocortical 6-layer structure. Many factors have been reported to be involved in the regulation of this radial neuronal migration process. In general, the radial migration can be largely divided into four steps; (1) maintenance and departure from the VZ of neural progenitor cells, (2) MP migration and transition to bipolar cells, (3) RG-guided locomotion, and (4) terminal translocation and dendrite maturation. Among these, many different gene mutations or knockdown effects have resulted in failure of the MP to bipolar transition (step 2), suggesting that it is a critical step, particularly in radial migration. Moreover, this transition occurs at the subplate layer. In this review, we summarize recent advances in our understanding of the molecular mechanisms underlying each of these steps. Finally, we discuss the evolutionary aspects of neuronal migration in corticogenesis.

  17. Cortical neurons of bats respond best to echoes from nearest targets when listening to natural biosonar multi-echo streams

    PubMed Central

    Beetz, M. Jerome; Hechavarría, Julio C.; Kössl, Manfred

    2016-01-01

    Bats orientate in darkness by listening to echoes from their biosonar calls, a behaviour known as echolocation. Recent studies showed that cortical neurons respond in a highly selective manner when stimulated with natural echolocation sequences that contain echoes from single targets. However, it remains unknown how cortical neurons process echolocation sequences containing echo information from multiple objects. In the present study, we used echolocation sequences containing echoes from three, two or one object separated in the space depth as stimuli to study neuronal activity in the bat auditory cortex. Neuronal activity was recorded with multi-electrode arrays placed in the dorsal auditory cortex, where neurons tuned to target-distance are found. Our results show that target-distance encoding neurons are mostly selective to echoes coming from the closest object, and that the representation of echo information from distant objects is selectively suppressed. This suppression extends over a large part of the dorsal auditory cortex and may override possible parallel processing of multiple objects. The presented data suggest that global cortical suppression might establish a cortical “default mode” that allows selectively focusing on close obstacle even without active attention from the animals. PMID:27786252

  18. Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

    PubMed

    Khodr, Christina E; Chen, Lihua; Dave, Sonya; Al-Harthi, Lena; Hu, Xiu-Ti

    2016-10-01

    Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K(+) influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca(2+) influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca(2+) potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca(2+) influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca(2+) dysregulation in the mPFC.

  19. Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons.

    PubMed

    Khodr, Christina E; Chen, Lihua; Dave, Sonya; Al-Harthi, Lena; Hu, Xiu-Ti

    2016-10-01

    Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca(2+) channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca(2+) potentials (Ca(2+) influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K(+) influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca(2+) influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca(2+) potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca(2+) influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca(2+) dysregulation in the mPFC. PMID:27326669

  20. Basal forebrain neurons suppress amygdala kindling via cortical but not hippocampal cholinergic projections in rats.

    PubMed

    Ferencz, I; Leanza, G; Nanobashvili, A; Kokaia, M; Lindvall, O

    2000-06-01

    Intraventricular administration of the immunotoxin 192 IgG-saporin in rats has been shown to cause a selective loss of cholinergic afferents to the hippocampus and cortical areas, and to facilitate seizure development in hippocampal kindling. Here we demonstrate that this lesion also accelerates seizure progression when kindling is induced by electrical stimulations in the amygdala. However, whereas intraventricular 192 IgG-saporin facilitated the development of the initial stages of hippocampal kindling, the same lesion promoted the late stages of amygdala kindling. To explore the role of various parts of the basal forebrain cholinergic system in amygdala kindling, selective lesions of the cholinergic projections to either hippocampus or cortex were produced by intraparenchymal injections of 192 IgG-saporin into medial septum/vertical limb of the diagonal band or nucleus basalis, respectively. Cholinergic denervation of the cortical regions caused acceleration of amygdala kindling closely resembling that observed after the more widespread lesion induced by intraventricular 192 IgG-saporin. In contrast, removal of the cholinergic input to the hippocampus had no effect on the development of amygdala kindling. These data indicate that basal forebrain cholinergic neurons suppress kindling elicited from amygdala, and that this dampening effect is mediated via cortical but not hippocampal projections.

  1. Neuroprotective effect of the endogenous neural peptide apelin in cultured mouse cortical neurons

    SciTech Connect

    Zeng, Xiang Jun; Yu, Shan Ping; Zhang, Like; Wei, Ling

    2010-07-01

    The adipocytokine apelin and its G protein-coupled APJ receptor were initially isolated from a bovine stomach and have been detected in the brain and cardiovascular system. Recent studies suggest that apelin can protect cardiomyocytes from ischemic injury. Here, we investigated the effect of apelin on apoptosis in mouse primary cultures of cortical neurons. Exposure of the cortical cultures to a serum-free medium for 24 h induced nuclear fragmentation and apoptotic death; apelin-13 (1.0-5.0 nM) markedly prevented the neuronal apoptosis. Apelin neuroprotective effects were mediated by multiple mechanisms. Apelin-13 reduced serum deprivation (SD)-induced ROS generation, mitochondria depolarization, cytochrome c release and activation of caspase-3. Apelin-13 prevented SD-induced changes in phosphorylation status of Akt and ERK1/2. In addition, apelin-13 attenuated NMDA-induced intracellular Ca{sup 2+} accumulation. These results indicate that apelin is an endogenous neuroprotective adipocytokine that may block apoptosis and excitotoxic death via cellular and molecular mechanisms. It is suggested that apelins may be further explored as a potential neuroprotective reagent for ischemia-induced brain damage.

  2. Effect of nano-hydroxyapatite on the axonal guidance growth of rat cortical neurons.

    PubMed

    Liu, Meili; Zhou, Gang; Song, Wei; Li, Ping; Liu, Haifeng; Niu, Xufeng; Fan, Yubo

    2012-05-21

    Nanomaterials such as carbon nanotubes (CNT) can improve axonal connecting in a target direction during regeneration, however, it is limited by the neurotoxicity of CNT. Here we investigate the possible protective effect of nano-hydroxyapatite (n-HA) against nerve injury, as well as CNT in cultured rat cortical neurons. In this study the nanomaterials were characterized by X-Ray diffractometry (XRD) and atomic force microscopy (AFM) analysis. Our results showed that axonal migration and extension were increased significantly after n-HA treatment by immunocytochemistry assay. The patch clamp assay results showed that n-HA acts protectively after nerve injury, which inhibited the average amplitude and frequency of excitatory postsynaptic currents (EPSCs). n-HA is not neurotoxic for the electrophysiology activity of cells. To find the effect of n-HA on axonal guidance growth in the cultured cortical neurons, Netrin 1, one of the axonal guidance cues, was determined by RT-PCR and western blot assay. Compared to the control group, n-HA down-regulated the mRNA level of netrin 1, and moreover, the expression of netrin 1 decreased significantly in the cells. n-HA caused the axonal guidance growth to be mediated by netrin 1 during nerve regeneration. Therefore, the data from the present study provided a new approach for the therapy or prevention of nerve injury. PMID:22504488

  3. TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons

    SciTech Connect

    Shirakawa, Hisashi; Yamaoka, Tomoko; Sanpei, Kazuaki; Sasaoka, Hirotoshi; Nakagawa, Takayuki; Kaneko, Shuji

    2008-12-26

    Transient receptor potential vanilloid 1 (TRPV1) functions as a polymodal nociceptor and is activated by several vanilloids, including capsaicin, protons and heat. Although TRPV1 channels are widely distributed in the brain, their roles remain unclear. Here, we investigated the roles of TRPV1 in cytotoxic processes using TRPV1-expressing cultured rat cortical neurons. Capsaicin induced severe neuronal death with apoptotic features, which was completely inhibited by the TRPV1 antagonist capsazepine and was dependent on extracellular Ca{sup 2+} influx. Interestingly, nifedipine, a specific L-type Ca{sup 2+} channel blocker, attenuated capsaicin cytotoxicity, even when applied 2-4 h after the capsaicin. ERK inhibitor PD98059 and several antioxidants, but not the JNK and p38 inhibitors, attenuated capsaicin cytotoxicity. Together, these data indicate that TRPV1 activation triggers apoptotic cell death of rat cortical cultures via L-type Ca{sup 2+} channel opening, Ca{sup 2+} influx, ERK phosphorylation, and reactive oxygen species production.

  4. Selective α4β2 nicotinic acetylcholine receptor agonists target epigenetic mechanisms in cortical GABAergic neurons.

    PubMed

    Maloku, Ekrem; Kadriu, Bashkim; Zhubi, Adrian; Dong, Erbo; Pibiri, Fabio; Satta, Rosalba; Guidotti, Alessandro

    2011-06-01

    Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD(67)) expression. Here we explored the impact of synthetic α(4)β(2) and α(7) nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at α(4)β(2) and a lower affinity full agonist at α(7) neuronal nAChR, injected in doses of 1-5 mg/kg/s.c. twice daily for 5 days, elicited a 30-40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD(67) mRNA and protein. This upregulation of GAD(67) was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP(2) binding to GAD(67) promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD(67) expression were obtained after administration of A-85380, an agonist that binds to α(4)β(2) but has negligible affinity for α(3)β(4) or α(7) subtypes containing nAChR. In contrast, PNU-282987, an agonist of the homomeric α(7) nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD(67) expression. The present study suggests that the α(4)β(2) nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the α(7) nAChR agonists.

  5. Generation of human cortical neurons from a new immortal fetal neural stem cell line

    SciTech Connect

    Cacci, E.; Villa, A.; Parmar, M.; Cavallaro, M.; Mandahl, N.; Lindvall, O.; Martinez-Serrano, A.; Kokaia, Z. . E-mail: Zaal.Kokaia@med.lu.se

    2007-02-01

    Isolation and expansion of neural stem cells (NSCs) of human origin are crucial for successful development of cell therapy approaches in neurodegenerative diseases. Different epigenetic and genetic immortalization strategies have been established for long-term maintenance and expansion of these cells in vitro. Here we report the generation of a new, clonal NSC (hc-NSC) line, derived from human fetal cortical tissue, based on v-myc immortalization. Using immunocytochemistry, we show that these cells retain the characteristics of NSCs after more than 50 passages. Under proliferation conditions, when supplemented with epidermal and basic fibroblast growth factors, the hc-NSCs expressed neural stem/progenitor cell markers like nestin, vimentin and Sox2. When growth factors were withdrawn, proliferation and expression of v-myc and telomerase were dramatically reduced, and the hc-NSCs differentiated into glia and neurons (mostly glutamatergic and GABAergic, as well as tyrosine hydroxylase-positive, presumably dopaminergic neurons). RT-PCR analysis showed that the hc-NSCs retained expression of Pax6, Emx2 and Neurogenin2, which are genes associated with regionalization and cell commitment in cortical precursors during brain development. Our data indicate that this hc-NSC line could be useful for exploring the potential of human NSCs to replace dead or damaged cortical cells in animal models of acute and chronic neurodegenerative diseases. Taking advantage of its clonality and homogeneity, this cell line will also be a valuable experimental tool to study the regulatory role of intrinsic and extrinsic factors in human NSC biology.

  6. Convergence of sensory inputs upon projection neurons of somatosensory cortex.

    PubMed

    Zarzecki, P; Wiggin, D M

    1982-01-01

    Cortico-cortical neurons and pyramidal tract neurons of the cat were tested for convergent inputs from forelimb afferents. Neurons were recorded in cortical areas 1, 2, and 3a. Consideration was given to both suprathreshold and subthreshold inputs evoked by electrical stimulation of forelimb nerves. Individual cortico-cortical neurons and also pyramidal tract neurons were characterized by convergence of multiple somatosensory inputs from different regions of skin, from several muscle groups, and between group I deep afferents and low threshold cutaneous afferents. Certain patterns of afferent input varied with cytoarchitectonic area. There was, however, no difference between area 3a and areas 1-2 in the incidence of cross-modality convergence in the form of input from cutaneous and also deep nerves. Many of the inputs were subthreshold. Arguments are presented that these inputs, though subthreshold, must be considered for a role in cortical information processing. The convergent nature of the sensory inputs is discussed in relation to the proposed specificities of cortical columns. The patterns of afferent inputs reaching cortico-cortical neurons seem to be appropriate for them to have a role in the formation of sensory fields of motor cortex neurons. PT neurons of somatosensory cortex have possible roles as modifiers of ascending sensory systems, however, the convergent input which these PT neurons receive argues against a simple relationship between the modality of peripheral stimuli influencing them and the modality of the ascending tract neurons under their descending control. PMID:7140889

  7. In Utero Electroporation: Assay System for Migration of Cerebral Cortical Neurons

    NASA Astrophysics Data System (ADS)

    Tabata, Hidenori; Nakajima, Kazunori

    During the development of the cerebral cortex, the majority of cortical neurons are generated in the ventricular zone (VZ) facing the lateral ventricle and then migrate toward the pial surface to form the highly organized 6-layered cerebral cortex. Detailed profiles of these processes and their molecular mechanisms had been largely unknown because of the absence of an efficient assay system. The in vivo electroporation system was initially devised for use within chick embryos (Funahashi et al., 1999; Itasaki et al., 1999; Momose et al., 1999; Muramatsu et al., 1997), and we and other groups have used that system as a basis for developing an in utero electroporation system, which allows plasmid DNA to be introduced into cortical progenitor cells in developing mouse embryos in the uterus (Fukuchi-Shimogori and Grove, 2001; Saito and Nakatsuji, 2001; Tabata and Nakajima, 2001; Takahashi et al., 2002). In utero electroporation of other sites in the brain, including the hippocampus (Navarro-Quiroga et al., 2007), cerebral basal ganglia (Borrell et al., 2005; Nakahira et al., 2006), cortical hem (Takiguchi-Hayashi et al., 2004), and dorsal thalamus (Bonnin et al., 2007), has recently been reported. Introducing green fluorescent protein (GFP) enables the entire processes of migration and layer formation to be visualized (Ajioka and Nakajima, 2005; Sasaki et al., 2008; Tabata and Nakajima, 2002, 2003), and the role of any gene involved in these processes can be easily assessed by overexpressing the proteins or their mutants (Ohshima et al., 2007), or by knocking down the genes by the RNA interference technique (Bai et al., 2003). Furthermore, the Tet-On/Off system and/or other plasmid- vector-based technologies will expand the potential of the analyses. In this section we review the principles and methods of gene transfer into the cortical wall of mouse embryos by means of the in utero electroporation system.

  8. Inhibition of Phosphodiesterase 10A Increases the Responsiveness of Striatal Projection Neurons to Cortical Stimulation.

    PubMed

    Threlfell, Sarah; Sammut, Stephen; Menniti, Frank S; Schmidt, Christopher J; West, Anthony R

    2009-03-01

    The cyclic nucleotide phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium-sized spiny projection neurons (MSNs), apparently playing a critical role in the regulation of both cGMP and cAMP signaling cascades. Genetic disruption or pharmacological inhibition of PDE10A reverses behavioral abnormalities associated with subcortical hyperdopaminergia. Here, we investigate the effect of PDE10A inhibition on the activity of MSNs using single-unit extracellular recordings performed in the dorsal striatum of anesthetized rats. Antidromic stimulation of the substantia nigra pars reticulata was used to identify striatonigral (SNr+) MSNs. Intrastriatal infusion of the selective PDE10A inhibitors papaverine or TP-10 [2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid] by reverse microdialysis did not affect spontaneous firing but robustly increased measures of cortically evoked spike activity in a stimulus intensity-dependent manner. Systemic administration of TP-10 also increased cortically evoked spike activity in a stimulus intensity- and dose-dependent manner. A robust increase in cortically evoked activity was apparent in SNr- MSNs (primarily striatopallidal). It is interesting that TP-10 administration did not affect cortically evoked activity in SNr+ MSNs. However, TP-10 administration increased the incidence of antidromically activated (i.e., SNr+) MSNs. These findings indicate that inhibition of striatal PDE10A activity increases the responsiveness of MSNs to depolarizing stimuli. Furthermore, given the lack of effect of TP-10 on SNr+ MSNs, we speculate that PDE10A inhibition may have a greater facilitatory effect on corticostriatal synaptic activity in striatopallidal MSNs. These data support further investigation of selective targeting of PDE signaling pathways in MSN subpopulations because this may represent a promising novel approach for treating brain disorders involving dysfunctional glutamatergic

  9. Cortical Efferents Lacking Mutant huntingtin Improve Striatal Neuronal Activity and Behavior in a Conditional Mouse Model of Huntington's Disease

    PubMed Central

    Estrada-Sánchez, Ana María; Burroughs, Courtney L.; Cavaliere, Stephen; Barton, Scott J.; Chen, Shirley; Yang, X. William

    2015-01-01

    Abnormal electrophysiological activity in the striatum, which receives dense innervation from the cerebral cortex, is believed to set the stage for the behavioral phenotype observed in Huntington's disease (HD), a neurodegenerative condition caused by mutation of the huntingtin (mhtt) protein. However, cortical involvement is far from clear. To determine whether abnormal striatal processing can be explained by mhtt alone (cell-autonomous model) or by mhtt in the corticostriatal projection cell–cell interaction model, we used BACHD/Emx1–Cre (BE) mice, a conditional HD model in which full-length mhtt is genetically reduced in cortical output neurons, including those that project to the striatum. Animals were assessed beginning at 20 weeks of age for at least the next 40 weeks, a range over which presymptomatic BACHD mice become symptomatic. Both open-field and nest-building behavior deteriorated progressively in BACHD mice relative to both BE and wild-type (WT) mice. Neuronal activity patterns in the dorsal striatum, which receives input from the primary motor cortex (M1), followed a similar age progression because BACHD activity changed more rapidly than either BE or WT mice. However, in the M1, BE neuronal activity differed significantly from both WT and BACHD. Although abnormal cortical activity in BE mice likely reflects input from mhtt-expressing afferents, including cortical interneurons, improvements in BE striatal activity and behavior suggest a critical role for mhtt in cortical output neurons in shaping the onset and progression of striatal dysfunction. PMID:25762686

  10. Voltage-clamp analysis of the potentiation of the slow Ca2+-activated K+ current in hippocampal pyramidal neurons.

    PubMed

    Borde, M; Bonansco, C; Fernández de Sevilla, D; Le Ray, D; Buño, W

    2000-01-01

    Exploring the principles that govern activity-dependent changes in excitability is an essential step to understand the function of the nervous system, because they act as a general postsynaptic control mechanism that modulates the flow of synaptic signals. We show an activity-dependent potentiation of the slow Ca2+-activated K+ current (sl(AHP)) which induces sustained decreases in the excitability in CA1 pyramidal neurons. We analyzed the sl(AHP) using the slice technique and voltage-clamp recordings with sharp or patch-electrodes. Using sharp electrodes-repeated activation with depolarizing pulses evoked a prolonged (8-min) potentiation of the amplitude (171%) and duration (208%) of the sl(AHP). Using patch electrodes, early after entering the whole-cell configuration (<20 min), responses were as those reported above. However, although the sl(AHP) remained unchanged, its potentiation was markedly reduced in later recordings, suggesting that the underlying mechanisms were rapidly eliminated by intracellular dialysis. Inhibition of L-type Ca2+ current by nifedipine (20 microM) markedly reduced the sl(AHP) (79%) and its potentiation (55%). Ryanodine (20 microM) that blocks the release of intracellular Ca2+ also reduced sl(AHP) (29%) and its potentiation (25%). The potentiation of the sl(AHP) induced a marked and prolonged (>50%; approximately equals 8 min) decrease in excitability. The results suggest that sl(AHP) is potentiated as a result of an increased intracellular Ca2+ concentration ([Ca2+]i) following activation of voltage-gated L-type Ca2+ channels, aided by the subsequent release of Ca2+ from intracellular stores. Another possibility is that repeated activation increases the Ca2+-binding capacity of the channels mediating the sl(AHP). This potentiation of the sl(AHP) could be relevant in hippocampal physiology, because the changes in excitability it causes may regulate the induction threshold of the long-term potentiation of synaptic efficacy. Moreover, the

  11. Complementary Functional Organization of Neuronal Activity Patterns in the Perirhinal, Lateral Entorhinal, and Medial Entorhinal Cortices

    PubMed Central

    Keene, Christopher S.; Bladon, John; McKenzie, Sam; Liu, Cindy D.; O'Keefe, Joseph

    2016-01-01

    It is commonly conceived that the cortical areas of the hippocampal region are functionally divided into the perirhinal cortex (PRC) and the lateral entorhinal cortex (LEC), which selectively process object information; and the medial entorhinal cortex (MEC), which selectively processes spatial information. Contrary to this notion, in rats performing a task that demands both object and spatial information processing, single neurons in PRC, LEC, and MEC, including those in both superficial and deep cortical areas and in grid, border, and head direction cells of MEC, have a highly similar range of selectivity to object and spatial dimensions of the task. By contrast, representational similarity analysis of population activity reveals a key distinction in the organization of information in these areas, such that PRC and LEC populations prioritize object over location information, whereas MEC populations prioritize location over object information. These findings bring to the hippocampal system a growing emphasis on population analyses as a powerful tool for characterizing neural representations supporting cognition and memory. SIGNIFICANCE STATEMENT Contrary to the common view that brain regions in the “what” and “where” streams distinctly process object and spatial cues, respectively, we found that both streams encode both object and spatial information but distinctly organize memories for objects and space. Specifically, perirhinal cortex and lateral entorhinal cortex represent objects and, within the object-specific representations, the locations where they occur. Conversely, medial entorhinal cortex represents relevant locations and, within those spatial representations, the objects that occupy them. Furthermore, these findings reach beyond simple notions of perirhinal cortex and lateral entorhinal cortex neurons as object detectors and MEC neurons as position detectors, and point to a more complex organization of memory representations within the medial

  12. Maximal variability of phase synchrony in cortical networks with neuronal avalanches.

    PubMed

    Yang, Hongdian; Shew, Woodrow L; Roy, Rajarshi; Plenz, Dietmar

    2012-01-18

    Ongoing interactions among cortical neurons often manifest as network-level synchrony. Understanding the spatiotemporal dynamics of such spontaneous synchrony is important because it may (1) influence network response to input, (2) shape activity-dependent microcircuit structure, and (3) reveal fundamental network properties, such as an imbalance of excitation (E) and inhibition (I). Here we delineate the spatiotemporal character of spontaneous synchrony in rat cortex slice cultures and a computational model over a range of different E-I conditions including disfacilitated (antagonized AMPA, NMDA receptors), unperturbed, and disinhibited (antagonized GABA(A) receptors). Local field potential was recorded with multielectrode arrays during spontaneous burst activity. Synchrony among neuronal groups was quantified based on phase-locking among recording sites. As network excitability was increased from low to high, we discovered three phenomena at an intermediate excitability level: (1) onset of synchrony, (2) maximized variability of synchrony, and (3) neuronal avalanches. Our computational model predicted that these three features occur when the network operates near a unique balanced E-I condition called "criticality." These results were invariant to changes in the measurement spatial extent, spatial resolution, and frequency bands. Our findings indicate that moderate average synchrony, which is required to avoid pathology, occurs over a limited range of E-I conditions and emerges together with maximally variable synchrony. If variable synchrony is detrimental to cortical function, this is a cost paid for moderate average synchrony. However, if variable synchrony is beneficial, then by operating near criticality the cortex may doubly benefit from moderate mean and maximized variability of synchrony.

  13. The Dynamic Brain: From Spiking Neurons to Neural Masses and Cortical Fields

    PubMed Central

    Deco, Gustavo; Jirsa, Viktor K.; Robinson, Peter A.; Breakspear, Michael; Friston, Karl

    2008-01-01

    The cortex is a complex system, characterized by its dynamics and architecture, which underlie many functions such as action, perception, learning, language, and cognition. Its structural architecture has been studied for more than a hundred years; however, its dynamics have been addressed much less thoroughly. In this paper, we review and integrate, in a unifying framework, a variety of computational approaches that have been used to characterize the dynamics of the cortex, as evidenced at different levels of measurement. Computational models at different space–time scales help us understand the fundamental mechanisms that underpin neural processes and relate these processes to neuroscience data. Modeling at the single neuron level is necessary because this is the level at which information is exchanged between the computing elements of the brain; the neurons. Mesoscopic models tell us how neural elements interact to yield emergent behavior at the level of microcolumns and cortical columns. Macroscopic models can inform us about whole brain dynamics and interactions between large-scale neural systems such as cortical regions, the thalamus, and brain stem. Each level of description relates uniquely to neuroscience data, from single-unit recordings, through local field potentials to functional magnetic resonance imaging (fMRI), electroencephalogram (EEG), and magnetoencephalogram (MEG). Models of the cortex can establish which types of large-scale neuronal networks can perform computations and characterize their emergent properties. Mean-field and related formulations of dynamics also play an essential and complementary role as forward models that can be inverted given empirical data. This makes dynamic models critical in integrating theory and experiments. We argue that elaborating principled and informed models is a prerequisite for grounding empirical neuroscience in a cogent theoretical framework, commensurate with the achievements in the physical sciences

  14. Functional topography of single cortical cells: an intracellular approach combined with optical imaging.

    PubMed

    Buzás, P; Eysel, U T; Kisvárday, Z F

    1998-11-01

    Pyramidal cells mediating long-range corticocortical connections have been assumed to play an important role in visual perceptual mechanisms [C.D. Gilbert, Horizontal integration and cortical dynamics, Neuron 9 (1992) 1-13]. However, no information is available as yet on the specificity of individual pyramidal cells with respect to functional maps, e.g., orientation map. Here, we show a combination of techniques with which the functional topography of single pyramidal neurons can be explored in utmost detail. To this end, we used optical imaging of intrinsic signals followed by intracellular recording and staining with biocytin in vivo. The axonal and dendritic trees of the labelled neurons were reconstructed in three dimensions and aligned with corresponding functional orientation maps. The results indicate that, contrary to the sharp orientation tuning of neurons shown by the recorded spike activity, the efferent connections (axon terminal distribution) of the same pyramidal cells were found to terminate at a much broader range of orientations.

  15. Enhanced intrinsic excitability and EPSP-spike coupling accompany enriched environment-induced facilitation of LTP in hippocampal CA1 pyramidal neurons.

    PubMed

    Malik, Ruchi; Chattarji, Sumantra

    2012-03-01

    Environmental enrichment (EE) is a well-established paradigm for studying naturally occurring changes in synaptic efficacy in the hippocampus that underlie experience-induced modulation of learning and memory in rodents. Earlier research on the effects of EE on hippocampal plasticity focused on long-term potentiation (LTP). Whereas many of these studies investigated changes in synaptic weight, little is known about potential contributions of neuronal excitability to EE-induced plasticity. Here, using whole-cell recordings in hippocampal slices, we address this gap by analyzing the impact of EE on both synaptic plasticity and intrinsic excitability of hippocampal CA1 pyramidal neurons. Consistent with earlier reports, EE increased contextual fear memory and dendritic spine density on CA1 cells. Furthermore, EE facilitated LTP at Schaffer collateral inputs to CA1 pyramidal neurons. Analysis of the underlying causes for enhanced LTP shows EE to increase the frequency but not amplitude of miniature excitatory postsynaptic currents. However, presynaptic release probability, assayed using paired-pulse ratios and use-dependent block of N-methyl-d-aspartate receptor currents, was not affected. Furthermore, CA1 neurons fired more action potentials (APs) in response to somatic depolarization, as well as during the induction of LTP. EE also reduced spiking threshold and after-hyperpolarization amplitude. Strikingly, this EE-induced increase in excitability caused the same-sized excitatory postsynaptic potential to fire more APs. Together, these findings suggest that EE may enhance the capacity for plasticity in CA1 neurons, not only by strengthening synapses but also by enhancing their efficacy to fire spikes-and the two combine to act as an effective substrate for amplifying LTP.

  16. Orbitofrontal cortical neurons encode expectation-driven initiation of reward-seeking.

    PubMed

    Moorman, David E; Aston-Jones, Gary

    2014-07-30

    Adaptive execution and inhibition of behavior are guided by the activity of neuronal populations across multiple frontal cortical areas. The rodent medial prefrontal cortex has been well studied with respect to these behaviors, influencing behavioral execution/inhibition based on context. Other frontal regions, in particular the orbitofrontal cortex (OFC), are critical in directing behavior to obtain rewards, but the relationship between OFC neuronal activity and response execution or inhibition has been poorly characterized. In particular, little is known about OFC with respect to extinction learning, an important example of context-guided response inhibition. Here, we recorded the activity of OFC neurons while rats performed a discriminative-stimulus (DS)-driven sucrose-seeking task followed by multiple days of extinction of the DS. OFC neuronal activity was maximally responsive (1) to reward-predicting stimuli (RS) that triggered a lever press (i.e., lever-response initiation) and (2) during reward-well approach in pursuit of sucrose (i.e., well-response initiation). RS presentation that was not followed by a lever press or RS presentation during extinction produced weak activation, as did nonrewarded stimulus (NS) presentation regardless of response (press or withhold) or session (DS-sucrose or extinction). Activity related to nonrewarded well entry was minor, and activity was significantly inhibited during reward consumption. Finally, OFC neuronal activity switched selectivity to track rewarded behaviors when the RS/NS contingencies were reversed. Thus, rather than signaling variables related to extinction or response inhibition, activity in OFC was strongest at the initiation of multiple components of reward-seeking behavior, most prominently when valid reward-predicting cues drove these behaviors. PMID:25080585

  17. Orbitofrontal Cortical Neurons Encode Expectation-Driven Initiation of Reward-Seeking

    PubMed Central

    Aston-Jones, Gary

    2014-01-01

    Adaptive execution and inhibition of behavior are guided by the activity of neuronal populations across multiple frontal cortical areas. The rodent medial prefrontal cortex has been well studied with respect to these behaviors, influencing behavioral execution/inhibition based on context. Other frontal regions, in particular the orbitofrontal cortex (OFC), are critical in directing behavior to obtain rewards, but the relationship between OFC neuronal activity and response execution or inhibition has been poorly characterized. In particular, little is known about OFC with respect to extinction learning, an important example of context-guided response inhibition. Here, we recorded the activity of OFC neurons while rats performed a discriminative-stimulus (DS)-driven sucrose-seeking task followed by multiple days of extinction of the DS. OFC neuronal activity was maximally responsive (1) to reward-predicting stimuli (RS) that triggered a lever press (i.e., lever-response initiation) and (2) during reward-well approach in pursuit of sucrose (i.e., well-response initiation). RS presentation that was not followed by a lever press or RS presentation during extinction produced weak activation, as did nonrewarded stimulus (NS) presentation regardless of response (press or withhold) or session (DS-sucrose or extinction). Activity related to nonrewarded well entry was minor, and activity was significantly inhibited during reward consumption. Finally, OFC neuronal activity switched selectivity to track rewarded behaviors when the RS/NS contingencies were reversed. Thus, rather than signaling variables related to extinction or response inhibition, activity in OFC was strongest at the initiation of multiple components of reward-seeking behavior, most prominently when valid reward-predicting cues drove these behaviors. PMID:25080585

  18. Graded defragmentation of cortical neuronal firing during recovery of consciousness in rats.

    PubMed

    Vizuete, J A; Pillay, S; Ropella, K M; Hudetz, A G

    2014-09-01

    State-dependent neuronal firing patterns reflect changes in ongoing information processing and cortical function. A disruption of neuronal coordination has been suggested as the neural correlate of anesthesia. Here, we studied the temporal correlation patterns of ongoing spike activity, during a stepwise reduction of the volatile anesthetic desflurane, in the cerebral cortex of freely moving rats. We hypothesized that the recovery of consciousness from general anesthesia is accompanied by specific changes in the spatiotemporal pattern and correlation of neuronal activity. Sixty-four contact microelectrode arrays were chronically implanted in the primary visual cortex (contacts spanning 1.4-mm depth and 1.4-mm width) for recording of extracellular unit activity at four steady-state levels of anesthesia (8-2% desflurane) and wakefulness. Recovery of consciousness was defined as the regaining of the righting reflex (near 4%). High-intensity firing (HI) periods were segmented using a threshold (200-ms) representing the minimum in the neurons' bimodal interspike interval histogram under anesthesia. We found that the HI periods were highly fragmented in deep anesthesia and gradually transformed to a near-continuous firing pattern at wakefulness. As the anesthetic was withdrawn, HI periods became longer and increasingly correlated among the units both locally and across remote recording sites. Paradoxically, in 4 of 8 animals, HI correlation was also high at the deepest level of anesthesia (8%) when local field potentials (LFP) were burst-suppressed. We conclude that recovery from desflurane anesthesia is accompanied by a graded defragmentation of neuronal activity in the cerebral cortex. Hypersynchrony during deep anesthesia is an exception that occurs only with LFP burst suppression.

  19. Dynamics of Elongation Factor 2 Kinase Regulation in Cortical Neurons in Response to Synaptic Activity

    PubMed Central

    Kenney, Justin W.; Sorokina, Oksana; Genheden, Maja; Sorokin, Anatoly

    2015-01-01

    The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca2+/CaM-dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca2+-coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca2+ with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons. PMID:25698741

  20. Use of cortical neuronal networks for in vitro material biocompatibility testing.

    PubMed

    Charkhkar, Hamid; Frewin, Christopher; Nezafati, Maysam; Knaack, Gretchen L; Peixoto, Nathalia; Saddow, Stephen E; Pancrazio, Joseph J

    2014-03-15

    Neural interfaces aim to restore neurological function lost during disease or injury. Novel implantable neural interfaces increasingly capitalize on novel materials to achieve microscale coupling with the nervous system. Like any biomedical device, neural interfaces should consist of materials that exhibit biocompatibility in accordance with the international standard ISO10993-5, which describes in vitro testing involving fibroblasts where cytotoxicity serves as the main endpoint. In the present study, we examine the utility of living neuronal networks as functional assays for in vitro material biocompatibility, particularly for materials that comprise implantable neural interfaces. Embryonic mouse cortical tissue was cultured to form functional networks where spontaneous action potentials, or spikes, can be monitored non-invasively using a substrate-integrated microelectrode array. Taking advantage of such a platform, we exposed established positive and negative control materials to the neuronal networks in a consistent method with ISO 10993-5 guidance. Exposure to the negative controls, gold and polyethylene, did not significantly change the neuronal activity whereas the positive controls, copper and polyvinyl chloride (PVC), resulted in reduction of network spike rate. We also compared the functional assay with an established cytotoxicity measure using L929 fibroblast cells. Our findings indicate that neuronal networks exhibit enhanced sensitivity to positive control materials. In addition, we assessed functional neurotoxicity of tungsten, a common microelectrode material, and two conducting polymer formulations that have been used to modify microelectrode properties for in vivo recording and stimulation. These data suggest that cultured neuronal networks are a useful platform for evaluating the functional toxicity of materials intended for implantation in the nervous system.

  1. Potential protection of green tea polyphenols against 1800 MHz electromagnetic radiation-induced injury on rat cortical neurons.

    PubMed

    Liu, Mei-Li; Wen, Jian-Qiang; Fan, Yu-Bo

    2011-10-01

    Radiofrequency electromagnetic fields (EMF) are harmful to public health, but the certain anti-irradiation mechanism is not clear yet. The present study was performed to investigate the possible protective effects of green tea polyphenols against electromagnetic radiation-induced injury in the cultured rat cortical neurons. In this study, green tea polyphenols were used in the cultured cortical neurons exposed to 1800 MHz EMFs by the mobile phone. We found that the mobile phone irradiation for 24 h induced marked neuronal cell death in the MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide) and TUNEL (TdT mediated biotin-dUTP nicked-end labeling) assay, and protective effects of green tea polyphenols on the injured cortical neurons were demonstrated by testing the content of Bcl-2 Assaciated X protein (Bax) in the immunoprecipitation assay and Western blot assay. In our study results, the mobile phone irradiation-induced increases in the content of active Bax were inhibited significantly by green tea polyphenols, while the contents of total Bax had no marked changes after the treatment of green tea polyphenols. Our results suggested a neuroprotective effect of green tea polyphenols against the mobile phone irradiation-induced injury on the cultured rat cortical neurons.

  2. EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages.

    PubMed

    Gu, Da-Min; Lu, Pei-Hua; Zhang, Ke; Wang, Xiang; Sun, Min; Chen, Guo-Qian; Wang, Qiong

    2015-02-13

    In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. PMID:25582778

  3. Assortment of GABAergic plasticity in the cortical interneuron melting pot.

    PubMed

    Méndez, Pablo; Bacci, Alberto

    2011-01-01

    Cortical structures of the adult mammalian brain are characterized by a spectacular diversity of inhibitory interneurons, which use GABA as neurotransmitter. GABAergic neurotransmission is fundamental for integrating and filtering incoming information and dictating postsynaptic neuronal spike timing, therefore providing a tight temporal code used by each neuron, or ensemble of neurons, to perform sophisticated computational operations. However, the heterogeneity of cortical GABAergic cells is associated to equally diverse properties governing intrinsic excitability as well as strength, dynamic range, spatial extent, anatomical localization, and molecular components of inhibitory synaptic connections that they form with pyramidal neurons. Recent studies showed that similarly to their excitatory (glutamatergic) counterparts, also inhibitory synapses can undergo activity-dependent changes in their strength. Here, some aspects related to plasticity and modulation of adult cortical and hippocampal GABAergic synaptic transmission will be reviewed, aiming at providing a fresh perspective towards the elucidation of the role played by specific cellular elements of cortical microcircuits during both physiological and pathological operations.

  4. Green Tea Polyphenols Attenuated Glutamate Excitotoxicity via Antioxidative and Antiapoptotic Pathway in the Primary Cultured Cortical Neurons.

    PubMed

    Cong, Lin; Cao, Chang; Cheng, Yong; Qin, Xiao-Yan

    2016-01-01

    Green tea polyphenols are a natural product which has antioxidative and antiapoptotic effects. It has been shown that glutamate excitotoxicity induced oxidative stress is linked to neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In this study we explored the neuroprotective effect of green teen polyphenols against glutamate excitotoxicity in the primary cultured cortical neurons. We found that green tea polyphenols protected against glutamate induced neurotoxicity in the cortical neurons as measured by MTT and TUNEL assays. Green tea polyphenols were then showed to inhibit the glutamate induced ROS release and SOD activity reduction in the neurons. Furthermore, our results demonstrated that green tea polyphenols restored the dysfunction of mitochondrial pro- or antiapoptotic proteins Bax, Bcl-2, and caspase-3 caused by glutamate. Interestingly, the neuroprotective effect of green tea polyphenols was abrogated when the neurons were incubated with siBcl-2. Taken together, these results demonstrated that green tea polyphenols protected against glutamate excitotoxicity through antioxidative and antiapoptotic pathways.

  5. Bidirectional Regulation of Innate and Learned Behaviors That Rely on Frequency Discrimination by Cortical Inhibitory Neurons.

    PubMed

    Aizenberg, Mark; Mwilambwe-Tshilobo, Laetitia; Briguglio, John J; Natan, Ryan G; Geffen, Maria N

    2015-12-01

    The ability to discriminate tones of different frequencies is fundamentally important for everyday hearing. While neurons in the primary auditory cortex (AC) respond differentially to tones of different frequencies, whether and how AC regulates auditory behaviors that rely on frequency discrimination remains poorly understood. Here, we find that the level of activity of inhibitory neurons in AC controls frequency specificity in innate and learned auditory behaviors that rely on frequency discrimination. Photoactivation of parvalbumin-positive interneurons (PVs) improved the ability of the mouse to detect a shift in tone frequency, whereas photosuppression of PVs impaired the performance. Furthermore, photosuppression of PVs during discriminative auditory fear conditioning increased generalization of conditioned response across tone frequencies, whereas PV photoactivation preserved normal specificity of learning. The observed changes in behavioral performance were correlated with bidirectional changes in the magnitude of tone-evoked responses, consistent with predictions of a model of a coupled excitatory-inhibitory cortical network. Direct photoactivation of excitatory neurons, which did not change tone-evoked response magnitude, did not affect behavioral performance in either task. Our results identify a new function for inhibition in the auditory cortex, demonstrating that it can improve or impair acuity of innate and learned auditory behaviors that rely on frequency discrimination. PMID:26629746

  6. Cultured Cortical Neurons Can Perform Blind Source Separation According to the Free-Energy Principle.

    PubMed

    Isomura, Takuya; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2015-12-01

    Blind source separation is the computation underlying the cocktail party effect--a partygoer can distinguish a particular talker's voice from the ambient noise. Early studies indicated that the brain might use blind source separation as a signal processing strategy for sensory perception and numerous mathematical models have been proposed; however, it remains unclear how the neural networks extract particular sources from a complex mixture of inputs. We discovered that neurons in cultures of dissociated rat cortical cells could learn to represent particular sources while filtering out other signals. Specifically, the distinct classes of neurons in the culture learned to respond to the distinct sources after repeating training stimulation. Moreover, the neural network structures changed to reduce free energy, as predicted by the free-energy principle, a candidate unified theory of learning and memory, and by Jaynes' principle of maximum entropy. This implicit learning can only be explained by some form of Hebbian plasticity. These results are the first in vitro (as opposed to in silico) demonstration of neural networks performing blind source separation, and the first formal demonstration of neuronal self-organization under the free energy principle. PMID:26690814

  7. Reaction-diffusion waves in neuronal tissue and the window of cortical excitability

    NASA Astrophysics Data System (ADS)

    Dahlem, M. A.; Müller, S. C.

    2004-07-01

    Spreading depression (SD) is a dynamic wave phenomenon occurring in all gray matter regions of the central nervous systems (CNS). It is characterized by a sudden breakdown of neuronal activity and accompanied by a massive influx and efflux of ions across the membrane of neurons. The retina is a constituent of the CNS in which one can easily observe the dynamic behavior of the SD wave fronts, because SD changes the optical properties of the tissue. There is ample evidence that SD belongs to the self-organization processes due to the coupling of reaction with diffusion in excitable medium. It is assumed that the occurrence of SD is associated with some neurological symptoms of migraine with aura. A frequently reported aura symptom is a traveling visual blind region (scotoma) with a preceding figure of scintillating line segments. The characteristic form and development of the scotoma suggests that the underlying phenomenon is a wave propagating through the primary visual cortex, most likely the cortical spreading depression. In this article we discuss similarities between SD waves and the migraine aura on the basis of properties of reaction-diffusion waves known from other excitable media. In particular, the propagation velocities, the shape and the dynamics of the waves are compared with each other. We find that the assumption of the neuronal tissue to be in a state of only weak excitability explains some properties of the migraine aura, such as the confined appearance and its propagation with a stable velocity.

  8. Assessment of general anaesthetic cytotoxicity in murine cortical neurones in dissociated culture.

    PubMed

    Campbell, Laura L; Tyson, Jennifer A; Stackpole, Emily E; Hokenson, Kristen E; Sherrill, Hanna; McKeon, Jeanne E; Kim, Sarah A; Edmands, Scott D; Suarez, Cristina; Hall, Adam C

    2011-04-28

    General anaesthetics are proposed to cause unconsciousness by modulating neuronal excitability in the mammalian brain through mechanisms that include enhancement of inhibitory GABA(A) receptor currents and suppression of excitatory glutamate receptor responses. Both intravenous and volatile agents may produce neurotoxic effects during early postnatal rodent brain development through similar mechanisms. In the following study, we investigated anaesthetic cytotoxicity in primary cortical neurones and glia from postnatal day 2-8 mice. Cultures at 4-20 days in vitro were exposed to combinations of ketamine (100 μM to 3 mM), nitrous oxide (75%, v/v) and/or isoflurane (1.5-5%, v/v) for 6-12 h. Neuronal survival and cell death were measured via microtubule associated protein 2 immunoassay and lactate dehydrogenase release assays, respectively. Clinically relevant anaesthetic concentrations of ketamine, nitrous oxide and isoflurane had no significant neurotoxic effects individually or when given as anaesthetic cocktails, even with up to 12 h exposure. This lack of neurotoxicity was observed regardless of whether cultures were prepared from postnatal day 0-2 or day 8 mice, and was also unaffected by number of days in vitro (DIV 4-20). Significant neurotoxic effects were only observed at supraclinical concentrations (e.g. 1-3 mM ketamine). Our study suggests that neurotoxicity previously reported in vivo is not due to direct cytotoxicity of anaesthetic agents, but results from other impacts of the anaesthetised state during early brain development. PMID:21277931