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Sample records for cortical pyramidal neurons

  1. Quantitative analysis of cortical pyramidal neurons after corpus callosotomy.

    PubMed

    Jacobs, Bob; Creswell, Johanna; Britt, Jonathan P; Ford, Kevin L; Bogen, Joseph E; Zaidel, Eran

    2003-07-01

    This study quantitatively explored the dendritic/spine extent of supragranular pyramidal neurons across several cortical areas in two adult male subjects who had undergone a callosotomy several decades before death. In all cortical areas, there were numerous atypical, supragranular pyramidal neurons with elongated "tap root" basilar dendrites. These atypical cells could be associated with an underlying epileptic condition and/or could represent a compensatory mechanism in response to deafferentation after callosotomy.

  2. Pyramidal Neurons Are Not Generalizable Building Blocks of Cortical Networks

    PubMed Central

    Luebke, Jennifer I.

    2017-01-01

    A key challenge in cortical neuroscience is to gain a comprehensive understanding of how pyramidal neuron heterogeneity across different areas and species underlies the functional specialization of individual neurons, networks, and areas. Comparative studies have been important in this endeavor, providing data relevant to the question of which of the many inherent properties of individual pyramidal neurons are necessary and sufficient for species-specific network and areal function. In this mini review, the importance of pyramidal neuron structural properties for signaling are outlined, followed by a summary of our recent work comparing the structural features of mouse (C57/BL6 strain) and rhesus monkey layer 3 (L3) pyramidal neurons in primary visual and frontal association cortices and their implications for neuronal and areal function. Based on these and other published data, L3 pyramidal neurons plausibly might be considered broadly “generalizable” from one area to another in the mouse neocortex due to their many similarities, but major differences in the properties of these neurons in diverse areas in the rhesus monkey neocortex rules this out in the primate. Further, fundamental differences in the dendritic topology of mouse and rhesus monkey pyramidal neurons highlight the implausibility of straightforward scaling and/or extrapolation from mouse to primate neurons and cortical networks. PMID:28326020

  3. Variations in Acetylcholinesterase Activity within Human Cortical Pyramidal Neurons Across Age and Cognitive Trajectories.

    PubMed

    Janeczek, Monica; Gefen, Tamar; Samimi, Mehrnoosh; Kim, Garam; Weintraub, Sandra; Bigio, Eileen; Rogalski, Emily; Mesulam, M-Marsel; Geula, Changiz

    2017-03-01

    We described an extensive network of cortical pyramidal neurons in the human brain with abundant acetylcholinesterase (AChE) activity. Emergence of these neurons during childhood/adolescence, attainment of highest density in early adulthood, and virtual absence in other species led us to hypothesize involvement of AChE within these neurons in higher cortical functions. The current study quantified the density and staining intensity of these neurons using histochemical procedures. Few faintly stained AChE-positive cortical pyramidal neurons were observed in children/adolescents. These neurons attained their highest density and staining intensity in young adulthood. Compared with the young adult group, brains of cognitively normal elderly displayed no significant change in numerical density but a significant decrease in staining intensity of AChE-positive cortical pyramidal neurons. Brains of elderly above age 80 with unusually preserved memory performance (SuperAgers) showed significantly lower staining intensity and density of these neurons when compared with same-age peers. Conceivably, low levels of AChE activity could enhance the impact of acetylcholine on pyramidal neurons to counterbalance other involutional factors that mediate the decline of memory capacity during average aging. We cannot yet tell if elderly with superior memory capacity have constitutively low neuronal AChE levels or if this feature reflects adaptive neuroplasticity.

  4. EPSPs Measured in Proximal Dendritic Spines of Cortical Pyramidal Neurons.

    PubMed

    Acker, Corey D; Hoyos, Erika; Loew, Leslie M

    2016-01-01

    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 R eck estimate of 204 MΩ (range, 52-521 MΩ; N = 34).

  5. Alterations of cortical pyramidal neurons in mice lacking high-affinity nicotinic receptors

    PubMed Central

    Ballesteros-Yáñez, Inmaculada; Benavides-Piccione, Ruth; Bourgeois, Jean-Pierre; Changeux, Jean-Pierre; DeFelipe, Javier

    2010-01-01

    The neuronal nicotinic acetylcholine receptors (nAChRs) are allosteric membrane proteins involved in multiple cognitive processes, including attention, learning, and memory. The most abundant form of heterooligomeric nAChRs in the brain contains the β2- and α4- subunits and binds nicotinic agonists with high affinity. In the present study, we investigated in the mouse the consequences of the deletion of one of the nAChR components: the β2-subunit (β2−/−) on the microanatomy of cortical pyramidal cells. Using an intracellular injection method, complete basal dendritic arbors of 650 layer III pyramidal neurons were sampled from seven cortical fields, including primary sensory, motor, and associational areas, in both β2−/− and WT animals. We observed that the pyramidal cell phenotype shows significant quantitative differences among different cortical areas in mutant and WT mice. In WT mice, the density of dendritic spines was rather similar in all cortical fields, except in the prelimbic/infralimbic cortex, where it was significantly higher. In the absence of the β2-subunit, the most significant reduction in the density of spines took place in this high-order associational field. Our data suggest that the β2-subunit is involved in the dendritic morphogenesis of pyramidal neurons and, in particular, in the circuits that contribute to the high-order functional connectivity of the cerebral cortex. PMID:20534523

  6. [Electrical excitability of the apical dendrites of mammalian cortical pyramidal neurons].

    PubMed

    Fan, Shih-Fang

    2012-12-25

    The electrical excitability of the dendrites of the cortical neurons was first studied on the apical dendrites of the pyramidal neurons. Professor ZHANG Xiang-Tong (H-T Chang) made important contributions in the fifties of last century on this topic. Through numerous studies later on, it has been established that the electrical excitability of dendrites of different types of neurons, even different dendrites in the same neuron is different. For the apical dendrites of the cortical pyramidal neurons, neither a single nor a train of repetitive action potentials with constant frequency can reach its terminal portion. However, some of the burst repetitive responses with non-constant frequency of the apical dendrite elicited by direct current injected into the soma may reach the terminal portion. This may be due to: (1) the calcium ion concentration in the apical dendrite is increased by the burst activities, which, in turn, increases the electrical excitability of the apical dendrite and /or (2) some retrograde collaterals of axon of the activated soma reach the apical dendrite and release neurotransmitter glutamate, which changes the properties of the voltage-gated ion channels in the apical dendrite. Low electrical excitability of the apical dendrites seems to be essential for the processing of numerous income signals to the terminal portion of the apical dendrites.

  7. State and location dependence of action potential metabolic cost in cortical pyramidal neurons.

    PubMed

    Hallermann, Stefan; de Kock, Christiaan P J; Stuart, Greg J; Kole, Maarten H P

    2012-06-03

    Action potential generation and conduction requires large quantities of energy to restore Na(+) and K(+) ion gradients. We investigated the subcellular location and voltage dependence of this metabolic cost in rat neocortical pyramidal neurons. Using Na(+)/K(+) charge overlap as a measure of action potential energy efficiency, we found that action potential initiation in the axon initial segment (AIS) and forward propagation into the axon were energetically inefficient, depending on the resting membrane potential. In contrast, action potential backpropagation into dendrites was efficient. Computer simulations predicted that, although the AIS and nodes of Ranvier had the highest metabolic cost per membrane area, action potential backpropagation into the dendrites and forward propagation into axon collaterals dominated energy consumption in cortical pyramidal neurons. Finally, we found that the high metabolic cost of action potential initiation and propagation down the axon is a trade-off between energy minimization and maximization of the conduction reliability of high-frequency action potentials.

  8. Potassium channels control the interaction between active dendritic integration compartments in layer 5 cortical pyramidal neurons

    PubMed Central

    Harnett, Mark T.; Xu, Ning-Long; Magee, Jeffrey C.; Williams, Stephen R.

    2013-01-01

    Active dendritic synaptic integration enhances the computational power of neurons. Such nonlinear processing generates an object-localization signal in the apical dendritic tuft of layer 5B cortical pyramidal neurons during sensory-motor behaviour. Here we employ electrophysiological and optical approaches in brain-slices and behaving animals to investigate how excitatory synaptic input to this distal dendritic compartment influences neuronal output. We find that active dendritic integration throughout the apical dendritic tuft is highly compartmentalized by voltage-gated potassium (KV) channels. A high-density of both transient and sustained KV channels was observed in all apical dendritic compartments. These channels potently regulated the interaction between apical dendritic tuft, trunk, and axo-somatic integration zones to control neuronal output in vitro as well as the engagement of dendritic nonlinear processing in vivo during sensory-motor behaviour. Thus, KV channels dynamically tune the interaction between active dendritic integration compartments in layer 5B pyramidal neurons to shape behaviourally relevant neuronal computations. PMID:23931999

  9. Impact of calcium-activated potassium channels on NMDA spikes in cortical layer 5 pyramidal neurons

    PubMed Central

    Bock, Tobias

    2016-01-01

    Active electrical events play an important role in shaping signal processing in dendrites. As these events are usually associated with an increase in intracellular calcium, they are likely to be under the control of calcium-activated potassium channels. Here, we investigate the impact of calcium-activated potassium channels on N-methyl-d-aspartate (NMDA) receptor-dependent spikes, or NMDA spikes, evoked by glutamate iontophoresis onto basal dendrites of cortical layer 5 pyramidal neurons. We found that small-conductance calcium-activated potassium channels (SK channels) act to reduce NMDA spike amplitude but at the same time, also decrease the iontophoretic current required for their generation. This SK-mediated decrease in NMDA spike threshold was dependent on R-type voltage-gated calcium channels and indicates a counterintuitive, excitatory effect of SK channels on NMDA spike generation, whereas the capacity of SK channels to suppress NMDA spike amplitude is in line with the expected inhibitory action of potassium channels on dendritic excitability. Large-conductance calcium-activated potassium channels had no significant impact on NMDA spikes, indicating that these channels are either absent from basal dendrites or not activated by NMDA spikes. These experiments reveal complex and opposing interactions among NMDA receptors, SK channels, and voltage-gated calcium channels in basal dendrites of cortical layer 5 pyramidal neurons during NMDA spike generation, which are likely to play an important role in regulating the way these neurons integrate the thousands of synaptic inputs they receive. PMID:26936985

  10. Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models

    PubMed Central

    Weaver, Christina M.; Rocher, Anne B.; Rodriguez, Alfredo; Crimins, Johanna L.; Dickstein, Dara L.; Wearne, Susan L.; Hof, Patrick R.

    2011-01-01

    In neurodegenerative disorders, such as Alzheimer’s disease, neuronal dendrites and dendritic spines undergo significant pathological changes. Because of the determinant role of these highly dynamic structures in signaling by individual neurons and ultimately in the functionality of neuronal networks that mediate cognitive functions, a detailed understanding of these changes is of paramount importance. Mutant murine models, such as the Tg2576 APP mutant mouse and the rTg4510 tau mutant mouse have been developed to provide insight into pathogenesis involving the abnormal production and aggregation of amyloid and tau proteins, because of the key role that these proteins play in neurodegenerative disease. This review showcases the multidimensional approach taken by our collaborative group to increase understanding of pathological mechanisms in neurodegenerative disease using these mouse models. This approach includes analyses of empirical 3D morphological and electrophysiological data acquired from frontal cortical pyramidal neurons using confocal laser scanning microscopy and whole-cell patch-clamp recording techniques, combined with computational modeling methodologies. These collaborative studies are designed to shed insight on the repercussions of dystrophic changes in neocortical neurons, define the cellular phenotype of differential neuronal vulnerability in relevant models of neurodegenerative disease, and provide a basis upon which to develop meaningful therapeutic strategies aimed at preventing, reversing, or compensating for neurodegenerative changes in dementia. PMID:20177698

  11. High fidelity optogenetic control of individual prefrontal cortical pyramidal neurons in vivo

    PubMed Central

    Cooper, Donald C

    2012-01-01

    Precise spatial and temporal manipulation of neural activity in specific genetically defined cell populations is now possible with the advent of optogenetics. The emerging field of optogenetics consists of a set of naturally-occurring and engineered light-sensitive membrane proteins that are able to activate (e.g. channelrhodopsin-2, ChR2) or silence (e.g. halorhodopsin, NpHR) neural activity. Here we demonstrate the technique and the feasibility of using novel adeno-associated viral (AAV) tools to activate (AAV-CaMKllα-ChR2-eYFP) or silence (AAV-CaMKllα-eNpHR3.0-eYFP) neural activity of rat prefrontal cortical prelimbic (PL) pyramidal neurons  in vivo.  In vivo single unit extracellular recording of ChR2-transduced pyramidal neurons showed that delivery of brief (10 ms) blue (473 nm) light-pulse trains up to 20 Hz via a custom fiber optic-coupled recording electrode (optrode) induced spiking with high fidelity at 20 Hz for the duration of recording (up to two hours in some cases). To silence spontaneously active neurons, we transduced them with the NpHR construct and administered continuous green (532 nm) light to completely inhibit action potential activity for up to 10 seconds with 100% fidelity in most cases. These versatile photosensitive tools, combined with optrode recording methods, provide experimental control over activity of genetically defined neurons and can be used to investigate the functional relationship between neural activity and complex cognitive behavior. PMID:24555016

  12. High fidelity optogenetic control of individual prefrontal cortical pyramidal neurons in vivo.

    PubMed

    Nakamura, Shinya; Baratta, Michael V; Pomrenze, Matthew B; Dolzani, Samuel D; Cooper, Donald C

    2012-01-01

    Precise spatial and temporal manipulation of neural activity in specific genetically defined cell populations is now possible with the advent of optogenetics. The emerging field of optogenetics consists of a set of naturally-occurring and engineered light-sensitive membrane proteins that are able to activate (e.g. channelrhodopsin-2, ChR2) or silence (e.g. halorhodopsin, NpHR) neural activity. Here we demonstrate the technique and the feasibility of using novel adeno-associated viral (AAV) tools to activate (AAV-CaMKllα-ChR2-eYFP) or silence (AAV-CaMKllα-eNpHR3.0-eYFP) neural activity of rat prefrontal cortical prelimbic (PL) pyramidal neurons  in vivo.  In vivo single unit extracellular recording of ChR2-transduced pyramidal neurons showed that delivery of brief (10 ms) blue (473 nm) light-pulse trains up to 20 Hz via a custom fiber optic-coupled recording electrode (optrode) induced spiking with high fidelity at 20 Hz for the duration of recording (up to two hours in some cases). To silence spontaneously active neurons, we transduced them with the NpHR construct and administered continuous green (532 nm) light to completely inhibit action potential activity for up to 10 seconds with 100% fidelity in most cases. These versatile photosensitive tools, combined with optrode recording methods, provide experimental control over activity of genetically defined neurons and can be used to investigate the functional relationship between neural activity and complex cognitive behavior.

  13. 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.

  14. Kv1 channels control spike threshold dynamics and spike timing in cortical pyramidal neurones

    PubMed Central

    Higgs, Matthew H; Spain, William J

    2011-01-01

    Abstract Previous studies showed that cortical pyramidal neurones (PNs) have a dynamic spike threshold that functions as a high-pass filter, enhancing spike timing in response to high-frequency input. While it is commonly assumed that Na+ channel inactivation is the primary mechanism of threshold accommodation, the possible role of K+ channel activation in fast threshold changes has not been well characterized. The present study tested the hypothesis that low-voltage activated Kv1 channels affect threshold dynamics in layer 2–3 PNs, using α-dendrotoxin (DTX) or 4-aminopyridine (4-AP) to block these conductances. We found that Kv1 blockade reduced the dynamic changes of spike threshold in response to a variety of stimuli, including stimulus-evoked synaptic input, current steps and ramps of varied duration, and noise. Analysis of the responses to noise showed that Kv1 channels increased the coherence of spike output with high-frequency components of the stimulus. A simple model demonstrates that a dynamic spike threshold can account for this effect. Our results show that the Kv1 conductance is a major mechanism that contributes to the dynamic spike threshold and precise spike timing of cortical PNs. PMID:21911608

  15. Homeostatic regulation of synaptic excitability: tonic GABAA receptor currents replace Ih in cortical pyramidal neurons of HCN1 knockout mice

    PubMed Central

    Chen, Xiangdong; Shu, Shaofang; Schwartz, Lauren C.; Sun, Chengsan; Kapur, Jaideep; Bayliss, Douglas A.

    2010-01-01

    Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (Ih) that serves to limit temporal summation of synaptic inputs. In HCN1 knockout mice, as expected, Ih is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABAA current in these cells that could be attributed to selective up-regulation of GABAA α5 subunit expression in the cortex of HCN1 knockout mice. Strikingly, despite diminished Ih, baseline sub-linear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knockout mice; however, blocking tonic GABAA currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knockout mice than in those cells from wild type mice. Increasing tonic GABAA receptor conductance in the context of reduced Ih, using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knockout mice. These data indicate that up-regulation of α5 subunit-mediated GABAA receptor tonic current compensates quantitatively for loss of dendritic Ih in cortical pyramidal neurons from HCN1 knockout mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo. PMID:20164346

  16. Reproductive experience modified dendritic spines on cortical pyramidal neurons to enhance sensory perception and spatial learning in rats

    PubMed Central

    Chen, Jeng-Rung; Lim, Seh Hong; Chung, Sin-Cun; Lee, Yee-Fun; Wang, Yueh-Jan; Tseng, Guo-Fang; Wang, Tsyr-Jiuan

    2016-01-01

    Behavioral adaptations during motherhood are aimed at increasing reproductive success. Alterations of hormones during motherhood could trigger brain morphological changes to underlie behavioral alterations. Here we investigated whether motherhood changes a rat’s sensory perception and spatial memory in conjunction with cortical neuronal structural changes. Female rats of different statuses, including virgin, pregnant, lactating, and primiparous rats were studied. Behavioral test showed that the lactating rats were most sensitive to heat, while rats with motherhood and reproduction experience outperformed virgin rats in a water maze task. By intracellular dye injection and computer-assisted 3-dimensional reconstruction, the dendritic arbors and spines of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons were revealed for closer analysis. The results showed that motherhood and reproductive experience increased dendritic spines but not arbors or the lengths of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons. In addition, lactating rats had a higher incidence of spines than pregnant or primiparous rats. The increase of dendritic spines was coupled with increased expression of the glutamatergic postsynaptic marker protein (PSD-95), especially in lactating rats. On the basis of the present results, it is concluded that motherhood enhanced rat sensory perception and spatial memory and was accompanied by increases in dendritic spines on output neurons of the somatosensory cortex and CA1 hippocampus. The effect was sustained for at least 6 weeks after the weaning of the pups. PMID:27784858

  17. Reproductive experience modified dendritic spines on cortical pyramidal neurons to enhance sensory perception and spatial learning in rats.

    PubMed

    Chen, Jeng-Rung; Lim, Seh Hong; Chung, Sin-Cun; Lee, Yee-Fun; Wang, Yueh-Jan; Tseng, Guo-Fang; Wang, Tsyr-Jiuan

    2017-01-27

    Behavioral adaptations during motherhood are aimed at increasing reproductive success. Alterations of hormones during motherhood could trigger brain morphological changes to underlie behavioral alterations. Here we investigated whether motherhood changes a rat's sensory perception and spatial memory in conjunction with cortical neuronal structural changes. Female rats of different statuses, including virgin, pregnant, lactating, and primiparous rats were studied. Behavioral test showed that the lactating rats were most sensitive to heat, while rats with motherhood and reproduction experience outperformed virgin rats in a water maze task. By intracellular dye injection and computer-assisted 3-dimensional reconstruction, the dendritic arbors and spines of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons were revealed for closer analysis. The results showed that motherhood and reproductive experience increased dendritic spines but not arbors or the lengths of the layer III and V pyramidal neurons of the somatosensory cortex and CA1 hippocampal pyramidal neurons. In addition, lactating rats had a higher incidence of spines than pregnant or primiparous rats. The increase of dendritic spines was coupled with increased expression of the glutamatergic postsynaptic marker protein (PSD-95), especially in lactating rats. On the basis of the present results, it is concluded that motherhood enhanced rat sensory perception and spatial memory and was accompanied by increases in dendritic spines on output neurons of the somatosensory cortex and CA1 hippocampus. The effect was sustained for at least 6 weeks after the weaning of the pups.

  18. 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.

  19. Branch specific and spike-order specific action potential invasion in basal, oblique, and apical dendrites of cortical pyramidal neurons

    PubMed Central

    Zhou, Wen-Liang; Short, Shaina M.; Rich, Matthew T.; Oikonomou, Katerina D.; Singh, Mandakini B.; Sterjanaj, Enas V.; Antic, Srdjan D.

    2014-01-01

    Abstract. In neocortical pyramidal neurons, action potentials (APs) propagate from the axon into the dendritic tree to influence distal synapses. Traditionally, AP backpropagation was studied in the thick apical trunk. Here, we used the principles of optical imaging developed by Cohen to investigate AP invasion into thin dendritic branches (basal, oblique, and tuft) of prefrontal cortical L5 pyramidal neurons. Multisite optical recordings from neighboring dendrites revealed a clear dichotomy between two seemingly equal dendritic branches belonging to the same cell (“sister branches”). We documented the variable efficacy of AP invasion in basal and oblique branches by revealing their AP voltage waveforms. Using fast multisite calcium imaging, we found that trains of APs are filtered differently between two apical tuft branches. Although one dendritic branch passes all spikes in an AP train, another branch belonging to the same neuron, same cortical layer, and same path distance from the cell body, experiences only one spike. Our data indicate that the vast differences in dendritic voltage and calcium transients, detected in dendrites of pyramidal neurons, arise from a nonuniform distribution of A-type K+ conductance, an aggregate number of branch points in the path of the AP propagation and minute differences in dendritic diameter. PMID:26157997

  20. Investigating spike backpropagation induced Ca2+ influx in models of hippocampal and cortical pyramidal neurons.

    PubMed

    Marsálek, P; Santamaría, F

    1998-01-01

    We modeled the influx of calcium ions into dendrites following active backpropagation of spike trains in a dendritic tree, using compartmental models of anatomically reconstructed pyramidal cells in a GENESIS program. Basic facts of ion channel densities in pyramidal cells were taken into account. The time scale of the backpropagating spike train development was longer than in previous models. We also studied the relationship between intracellular calcium dynamics and membrane voltage. Comparisons were made between two pyramidal cell prototypes and in simplified model. Our results show that: (1) sodium and potassium channels are enough to explain regenerative backpropagating spike trains; (2) intracellular calcium concentration changes are consistent in the range of milliseconds to seconds; (3) the simulations support several experimental observations in both hippocampal and neocortical cells. No additional parameter search optimization was necessary. Compartmental models can be used for investigating the biology of neurons, and then simplified for constructing neural networks.

  1. Three-dimensional spatial modeling of spines along dendritic networks in human cortical pyramidal neurons

    PubMed Central

    Larrañaga, Pedro; Benavides-Piccione, Ruth; Fernaud-Espinosa, Isabel; DeFelipe, Javier; Bielza, Concha

    2017-01-01

    We modeled spine distribution along the dendritic networks of pyramidal neurons in both basal and apical dendrites. To do this, we applied network spatial analysis because spines can only lie on the dendritic shaft. We expanded the existing 2D computational techniques for spatial analysis along networks to perform a 3D network spatial analysis. We analyzed five detailed reconstructions of adult human pyramidal neurons of the temporal cortex with a total of more than 32,000 spines. We confirmed that there is a spatial variation in spine density that is dependent on the distance to the cell body in all dendrites. Considering the dendritic arborizations of each pyramidal cell as a group of instances of the same observation (the neuron), we used replicated point patterns together with network spatial analysis for the first time to search for significant differences in the spine distribution of basal dendrites between different cells and between all the basal and apical dendrites. To do this, we used a recent variant of Ripley’s K function defined to work along networks. The results showed that there were no significant differences in spine distribution along basal arbors of the same neuron and along basal arbors of different pyramidal neurons. This suggests that dendritic spine distribution in basal dendritic arbors adheres to common rules. However, we did find significant differences in spine distribution along basal versus apical networks. Therefore, not only do apical and basal dendritic arborizations have distinct morphologies but they also obey different rules of spine distribution. Specifically, the results suggested that spines are more clustered along apical than in basal dendrites. Collectively, the results further highlighted that synaptic input information processing is different between these two dendritic domains. PMID:28662210

  2. Three-dimensional spatial modeling of spines along dendritic networks in human cortical pyramidal neurons.

    PubMed

    Anton-Sanchez, Laura; Larrañaga, Pedro; Benavides-Piccione, Ruth; Fernaud-Espinosa, Isabel; DeFelipe, Javier; Bielza, Concha

    2017-01-01

    We modeled spine distribution along the dendritic networks of pyramidal neurons in both basal and apical dendrites. To do this, we applied network spatial analysis because spines can only lie on the dendritic shaft. We expanded the existing 2D computational techniques for spatial analysis along networks to perform a 3D network spatial analysis. We analyzed five detailed reconstructions of adult human pyramidal neurons of the temporal cortex with a total of more than 32,000 spines. We confirmed that there is a spatial variation in spine density that is dependent on the distance to the cell body in all dendrites. Considering the dendritic arborizations of each pyramidal cell as a group of instances of the same observation (the neuron), we used replicated point patterns together with network spatial analysis for the first time to search for significant differences in the spine distribution of basal dendrites between different cells and between all the basal and apical dendrites. To do this, we used a recent variant of Ripley's K function defined to work along networks. The results showed that there were no significant differences in spine distribution along basal arbors of the same neuron and along basal arbors of different pyramidal neurons. This suggests that dendritic spine distribution in basal dendritic arbors adheres to common rules. However, we did find significant differences in spine distribution along basal versus apical networks. Therefore, not only do apical and basal dendritic arborizations have distinct morphologies but they also obey different rules of spine distribution. Specifically, the results suggested that spines are more clustered along apical than in basal dendrites. Collectively, the results further highlighted that synaptic input information processing is different between these two dendritic domains.

  3. The influence of phospho-τ on dendritic spines of cortical pyramidal neurons in patients with Alzheimer's disease.

    PubMed

    Merino-Serrais, Paula; Benavides-Piccione, Ruth; Blazquez-Llorca, Lidia; Kastanauskaite, Asta; Rábano, Alberto; Avila, Jesús; DeFelipe, Javier

    2013-06-01

    The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer's disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer's disease is likely to depend on the relative number of neurons that have well developed tangles.

  4. The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease

    PubMed Central

    Merino-Serrais, Paula; Benavides-Piccione, Ruth; Blazquez-Llorca, Lidia; Kastanauskaite, Asta; Rábano, Alberto; Avila, Jesús

    2013-01-01

    The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer’s disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer’s disease is likely to depend on the relative number of neurons that have well developed tangles. PMID:23715095

  5. Transition from Initial Hypoactivity to Hyperactivity in Cortical Layer V Pyramidal Neurons after Traumatic Brain Injury In Vivo.

    PubMed

    Ping, Xingjie; Jin, Xiaoming

    2016-02-15

    Traumatic brain injury (TBI) often results in structural damage and a loss of neurons that is commonly accompanied by early changes in neuronal electrical activity. Loss of neuronal activity has been hypothesized to contribute to post-traumatic epileptogenesis through the regulation of homeostatic plasticity. The existence of activity loss in cortical neurons after TBI and its subsequent transition into hyperactivity over time is not well characterized, however, particularly in models of TBI in vivo. In the current study, changes in neuronal activity in the primary motor cortex after moderate controlled cortical impact (CCI) in mice were studied using a single-unit recording technique in vivo. Recordings were made at different time points after CCI from cortical layer V pyramidal neurons that were within 1-2 mm from the anterior edge of the injured foci. Within 1-4 h after CCI, the frequency of spontaneous single-unit activity depressed significantly, with the mean firing frequency decreasing from 2.59 ± 0.18 Hz in the sham group to 1.05 ± 0.20 Hz of the injured group. The firing frequencies recovered to the normal level at 1 day and 7 days post-CCI, but became significantly higher at 3 days and 14 days post-CCI. The results suggest that TBI caused initial loss of activity in neurons of the perilesional cortical region, which was followed by compensatory recovery and enhancement of activity. These time-dependent changes in neuronal activity may contribute to the development of hyperexcitability through homeostatic activity regulation.

  6. 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

  7. Basal Dendritic Morphology of Cortical Pyramidal Neurons in Williams Syndrome: Prefrontal Cortex and Beyond.

    PubMed

    Hrvoj-Mihic, Branka; Hanson, Kari L; Lew, Caroline H; Stefanacci, Lisa; Jacobs, Bob; Bellugi, Ursula; Semendeferi, Katerina

    2017-01-01

    Williams syndrome (WS) is a unique neurodevelopmental disorder with a specific behavioral and cognitive profile, which includes hyperaffiliative behavior, poor social judgment, and lack of social inhibition. Here we examined the morphology of basal dendrites on pyramidal neurons in the cortex of two rare adult subjects with WS. Specifically, we examined two areas in the prefrontal cortex (PFC)-the frontal pole (Brodmann area 10) and the orbitofrontal cortex (Brodmann area 11)-and three areas in the motor, sensory, and visual cortex (BA 4, BA 3-1-2, BA 18). The findings suggest that the morphology of basal dendrites on the pyramidal neurons is altered in the cortex of WS, with differences that were layer-specific, more prominent in PFC areas, and displayed an overall pattern of dendritic organization that differentiates WS from other disorders. In particular, and unlike what was expected based on typically developing brains, basal dendrites in the two PFC areas did not display longer and more branched dendrites compared to motor, sensory and visual areas. Moreover, dendritic branching, dendritic length, and the number of dendritic spines differed little within PFC and between the central executive region (BA 10) and BA 11 that is part of the orbitofrontal region involved into emotional processing. In contrast, the relationship between the degree of neuronal branching in supra- versus infra-granular layers was spared in WS. Although this study utilized tissue held in formalin for a prolonged period of time and the number of neurons available for analysis was limited, our findings indicate that WS cortex, similar to that in other neurodevelopmental disorders such as Down syndrome, Rett syndrome, Fragile X, and idiopathic autism, has altered morphology of basal dendrites on pyramidal neurons, which appears more prominent in selected areas of the PFC. Results were examined from developmental perspectives and discussed in the context of other neurodevelopmental disorders

  8. D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons

    PubMed Central

    Wang, Yun; Goldman-Rakic, Patricia S.

    2004-01-01

    The efficacy of antipsychotics in the treatment of schizophrenia depends on their ability to block dopamine (DA) D2 receptors. D2 receptor excitatory mediation of glutamatergic receptors has been implicated in in vivo studies. However, D2 receptor enhancement of glutamatergic transmission has rarely been reported in slice recordings. Instead, D2 receptor depression of both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) action was obtained in previous slice studies. To obtain insight into this paradox, we examined DA's actions on synaptic responses of layer V pyramidal cells to minimal extracellular stimulation in layer III of ferret prefrontal cortical slices under NMDA and γ-aminobutyric acid type A blockade. This experimental design models the proposed hypofunction of NMDA receptor and γ-aminobutyric acid type A deficiency in schizophrenia. We found that DA and D2 receptor agonists promoted burst firing in a subset of pyramidal cells, which was reversed by haloperidol, a D2 antagonist and a D3 agonist, compounds having antipsychotic efficacy. In contrast, a D4 antagonist, which has not proven clinically effective, was not effective in blocking DA-promoted bursts. These results revealed excitatory effects of DA mediated mainly via D2 receptors, potentially providing a cellular mechanism for the D2 antagonism in treating schizophrenia. PMID:15051874

  9. Immediate Effects of Repetitive Magnetic Stimulation on Single Cortical Pyramidal Neurons

    PubMed Central

    Banerjee, Jineta; Sorrell, Mary E.; Celnik, Pablo A.; Pelled, Galit

    2017-01-01

    Repetitive Transcranial Magnetic Stimulation (rTMS) has been successfully used as a non-invasive therapeutic intervention for several neurological disorders in the clinic as well as an investigative tool for basic neuroscience. rTMS has been shown to induce long-term changes in neuronal circuits in vivo. Such long-term effects of rTMS have been investigated using behavioral, imaging, electrophysiological, and molecular approaches, but there is limited understanding of the immediate effects of TMS on neurons. We investigated the immediate effects of high frequency (20 Hz) rTMS on the activity of cortical neurons in an effort to understand the underlying cellular mechanisms activated by rTMS. We used whole-cell patch-clamp recordings in acute rat brain slices and calcium imaging of cultured primary neurons to examine changes in neuronal activity and intracellular calcium respectively. Our results indicate that each TMS pulse caused an immediate and transient activation of voltage gated sodium channels (9.6 ± 1.8 nA at -45 mV, p value < 0.01) in neurons. Short 500 ms 20 Hz rTMS stimulation induced action potentials in a subpopulation of neurons, and significantly increased the steady state current of the neurons at near threshold voltages (at -45 mV: before TMS: I = 130 ± 17 pA, during TMS: I = 215 ± 23 pA, p value = 0.001). rTMS stimulation also led to a delayed increase in intracellular calcium (153.88 ± 61.94% increase from baseline). These results show that rTMS has an immediate and cumulative effect on neuronal activity and intracellular calcium levels, and suggest that rTMS may enhance neuronal responses when combined with an additional motor, sensory or cognitive stimulus. Thus, these results could be translated to optimize rTMS protocols for clinical as well as basic science applications. PMID:28114421

  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 Central

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

    2015-01-01

    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. 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. © The Author 2015. Published by Oxford University Press.

  13. Selective Alterations in Postsynaptic Markers of Chandelier Cell Inputs to Cortical Pyramidal Neurons in Subjects with Schizophrenia

    PubMed Central

    Cruz, Dianne A.; Weaver, Cassandra; Lovallo, Emily M.; Melchitzky, Darlene S.; Lewis, David A.

    2009-01-01

    Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (dlPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABAA receptor α2 subunit is increased in postsynaptic AIS. To understand the nature and functional significance of these alterations, we determined the density, laminar distribution and length of AIS immunoreactive for ankryin-G and βIV spectrin, two proteins involved in the regulation of synapse structure and ion channel clustering at AIS, in dlPFC area 46 from 14 matched triads of subjects with schizophrenia or major depressive disorder (MDD) and normal comparison subjects. The density of ankyrin-G-immunoreactive (IR) AIS in the superficial, but not in the deep, cortical layers was significantly decreased by 15-19% in the subjects with schizophrenia relative to the other subject groups. In contrast, no group differences were present in the density of βIV spectrin-IR AIS. The length of labeled AIS did not differ across subject groups for either ankyrin-G or βIV spectrin. The density of ankyrin-G-IR AIS was not altered in the dlPFC of macaque monkeys chronically exposed to antipsychotic medications. Given the important role of ankyrin-G in the recruitment and stabilization of sodium channels and other integral membrane proteins to AIS, our findings suggest that these processes are selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia. PMID:19322171

  14. 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

  15. Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons.

    PubMed

    Marek, Gerard J

    2017-08-23

    Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2A receptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

  16. 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

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

    PubMed

    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 retino

  18. MGluR-Mediated Calcium Waves that Invade the Soma Regulate Firing in Layer V Medial Prefrontal Cortical Pyramidal Neurons

    PubMed Central

    Hagenston, Anna M.; Fitzpatrick, John S.; Yeckel, Mark F.

    2010-01-01

    Factors that influence the activity of prefrontal cortex (PFC) pyramidal neurons are likely to play an important role in working memory function. One such factor may be the release of Ca2+ from intracellular stores. Here we investigate the hypothesis that metabotropic glutamate receptors (mGluRs)-mediated waves of internally released Ca2+ can regulate the intrinsic excitability and firing patterns of PFC pyramidal neurons. Synaptic or focal pharmacological activation of mGluRs triggered Ca2+waves in the dendrites and somata of layer V medial PFC pyramidal neurons. These Ca2+ waves often evoked a transient SK-mediated hyperpolarization followed by a prolonged depolarization that respectively decreased and increased neuronal excitability. Generation of the hyperpolarization depended on whether the Ca2+wave invaded or came near to the soma. The depolarization also depended on the extent of Ca2+ wave propagation. We tested factors that influence the propagation of Ca2+ waves into the soma. Stimulating more synapses, increasing inositol trisphosphate concentration near the soma, and priming with physiological trains of action potentials all enhanced the amplitude and likelihood of evoking somatic Ca2+waves. These results suggest that mGluR-mediated Ca2+waves may regulate firing patterns of PFC pyramidal neurons engaged by working memory, particularly under conditions that favor the propagation of Ca2+ waves into the soma. PMID:17573372

  19. Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons.

    PubMed

    Shah, Mala M; Anderson, Anne E; Leung, Victor; Lin, Xiaodi; Johnston, Daniel

    2004-10-28

    The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurons in chronic epilepsy. Discerning the mechanisms underlying signal integration within EC neurons is essential for understanding network excitability alterations involving the hippocampus during epilepsy. Twenty-four hours following a single seizure episode when there were no behavioral or electrographic seizures, we found enhanced spontaneous activity still present in the rat EC in vivo and in vitro. The increased excitability was accompanied by a profound reduction in I(h) in EC layer III neurons and a significant decline in HCN1 and HCN2 subunits that encode for h channels. Consequently, dendritic excitability was enhanced, resulting in increased neuronal firing despite hyperpolarized membrane potentials. The loss of I(h) and the increased neuronal excitability persisted for 1 week following seizures. Our results suggest that dendritic I(h) plays an important role in determining the excitability of EC layer III neurons and their associated neural networks.

  20. 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

  1. Distinct Physiological Effects of Dopamine D4 Receptors on Prefrontal Cortical Pyramidal Neurons and Fast-Spiking Interneurons.

    PubMed

    Zhong, Ping; Yan, Zhen

    2016-01-01

    Dopamine D4 receptor (D4R), which is strongly linked to neuropsychiatric disorders, such as attention-deficit hyperactivity disorder and schizophrenia, is highly expressed in pyramidal neurons and GABAergic interneurons in prefrontal cortex (PFC). In this study, we examined the impact of D4R on the excitability of these 2 neuronal populations. We found that D4R activation decreased the frequency of spontaneous action potentials (sAPs) in PFC pyramidal neurons, whereas it induced a transient increase followed by a decrease of sAP frequency in PFC parvalbumin-positive (PV+) interneurons. D4R activation also induced distinct effects in both types of PFC neurons on spontaneous excitatory and inhibitory postsynaptic currents, which drive the generation of sAP. Moreover, dopamine substantially decreased sAP frequency in PFC pyramidal neurons, but markedly increased sAP frequency in PV+ interneurons, and both effects were partially mediated by D4R activation. In the phencyclidine model of schizophrenia, the decreasing effect of D4R on sAP frequency in both types of PFC neurons was attenuated, whereas the increasing effect of D4R on sAP in PV+ interneurons was intact. These results suggest that D4R activation elicits distinct effects on synaptically driven excitability in PFC projection neurons versus fast-spiking interneurons, which are differentially altered in neuropsychiatric disorder-related conditions.

  2. Fractal Analysis of Aggregates of Non-Uniformly Sized Particles: AN Application to Macaque Monkey Cortical Pyramidal Neurons

    NASA Astrophysics Data System (ADS)

    Henry, B. I.; Hof, P. R.; Rothnie, P.; Wearne, S. L.

    A variant of the cumulative mass method is developed for measuring the multi-fractal dimension spectrum of three-dimensional aggregates composed of particles of different sizes. The method is applied to measuring the mass fractal dimensions of pyramidal neurons of the prefrontal cortex of macaque monkeys, digitized with standard 3-dimensional tracing software. Fractal dimension estimates obtained from our approach are found to be useful for distinguishing two functionally different neuronal types which are visually similar.

  3. Altered excitatory and inhibitory inputs to striatal medium-sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease.

    PubMed

    Indersmitten, Tim; Tran, Conny H; Cepeda, Carlos; Levine, Michael S

    2015-04-01

    The Q175 knockin mouse model of Huntington's disease (HD) carries a CAG trinucleotide expansion of the human mutant huntingtin allele in its native mouse genomic context and recapitulates the genotype more closely than transgenic models. In this study we examined the progression of changes in intrinsic membrane properties and excitatory and inhibitory synaptic transmission, using whole cell patch-clamp recordings of medium-sized spiny neurons (MSNs) in the dorsolateral striatum and cortical pyramidal neurons (CPNs) in layers 2/3 of the primary motor cortex in brain slices from heterozygous (Q175(+/-)) and homozygous (Q175(+/+)) mice. Input resistance in MSNs from Q175(+/+) and Q175(+/-) mice was significantly increased compared with wild-type (WT) littermates beginning at 2 mo. Furthermore, the frequency of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was significantly reduced in MSNs from Q175(+/+) and Q175(+/-) mice compared with WTs beginning at 7 mo. In contrast, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and IPSC-to-EPSC ratios were increased in MSNs from Q175(+/+) mice beginning at 2 mo. Morphologically, significant decreases in spine density of MSNs from Q175(+/-) and Q175(+/+) mice occurred at 7 and 12 mo. In CPNs, sIPSC frequencies and IPSC-to-EPSC ratios were significantly increased in Q175(+/-) mice compared with WTs at 12 mo. There were no changes in intrinsic membrane properties or morphology. In summary, we show a number of alterations in electrophysiological and morphological properties of MSNs in Q175 mice that are similar to other HD mouse models. However, unlike other models, CPN inhibitory activity is increased in Q175(+/-) mice, indicating reduced cortical excitability.

  4. Micro RNA detection in long-term fixed tissue of cortical glutamatergic pyramidal neurons after targeted laser-capture neuroanatomical microdissection.

    PubMed

    Herai, Roberto R; Stefanacci, Lisa; Hrvoj-Mihic, Branka; Chailangkarn, Thanathom; Hanson, Kari; Semendeferi, Katerina; Muotri, Alysson R

    2014-09-30

    Formalin fixation (FF) is the standard and most common method for preserving postmortem brain tissue. FF stabilizes cellular morphology and tissue architecture, and can be used to study the distinct morphologic and genetic signatures of different cell types. Although the procedure involved in FF degrades messenger RNA over time, an alternative approach is to use small RNAs (sRNAs) for genetic analysis associated with cell morphology. Although genetic analysis is carried out on fresh or frozen tissue, there is limited availability or impossibility on targeting specific cell populations, respectively. The goal of this study is to detect miRNA and other classes of sRNA stored in formalin or in paraffin embedded for over decades. Two brain samples, one formed by a mixed population of cortical and subcortical cells, and one formed by pyramidal shaped cells collected by laser-capture microdissection, were subjected to sRNA sequencing. Performing bioinformatics analysis over the sequenced sRNA from brain tissue, we detected several classes of sRNA, such as miRNAs that play key roles in brain neurodevelopmental and maintenance pathways, and hsa-mir-155 expression in neurons. Comparison with existing method: Our method is the first to combine the approaches for: laser-capture of pyramidal neurons from long-term formalin-fixed brain; extract sRNA from laser-captured pyramidal neurons; apply a suite of bioinformatics tools to detect miRNA and other classes of sRNAs on sequenced samples having high levels of RNA degradation. This is the first study to show that sRNA can be rescued from laser-captured FF pyramidal neurons. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Cortical Overexpression of Neuronal Calcium Sensor-1 Induces Functional Plasticity in Spinal Cord Following Unilateral Pyramidal Tract Injury in Rat

    PubMed Central

    Yip, Ping K.; Wong, Liang-Fong; Sears, Thomas A.; Yáñez-Muñoz, Rafael J.; McMahon, Stephen B.

    2010-01-01

    Following trauma of the adult brain or spinal cord the injured axons of central neurons fail to regenerate or if intact display only limited anatomical plasticity through sprouting. Adult cortical neurons forming the corticospinal tract (CST) normally have low levels of the neuronal calcium sensor-1 (NCS1) protein. In primary cultured adult cortical neurons, the lentivector-induced overexpression of NCS1 induces neurite sprouting associated with increased phospho-Akt levels. When the PI3K/Akt signalling pathway was pharmacologically inhibited the NCS1-induced neurite sprouting was abolished. The overexpression of NCS1 in uninjured corticospinal neurons exhibited axonal sprouting across the midline into the CST-denervated side of the spinal cord following unilateral pyramidotomy. Improved forelimb function was demonstrated behaviourally and electrophysiologically. In injured corticospinal neurons, overexpression of NCS1 induced axonal sprouting and regeneration and also neuroprotection. These findings demonstrate that increasing the levels of intracellular NCS1 in injured and uninjured central neurons enhances their intrinsic anatomical plasticity within the injured adult central nervous system. PMID:20585375

  6. Subpopulations of somatostatin-immunoreactive non-pyramidal neurons in the amygdala and adjacent external capsule project to the basal forebrain: evidence for the existence of GABAergic projection neurons in the cortical nuclei and basolateral nuclear complex

    PubMed Central

    McDonald, Alexander J.; Mascagni, Franco; Zaric, Violeta

    2012-01-01

    The hippocampus and amygdala are key structures of the limbic system whose connections include reciprocal interactions with the basal forebrain (BF). The hippocampus receives both cholinergic and GABAergic afferents from the medial septal area of the BF. Hippocampal projections back to the medial septal area arise from non-pyramidal GABAergic neurons that express somatostatin (SOM), calbindin (CB), and neuropeptide Y (NPY). Recent experiments in our lab have demonstrated that the basolateral amygdala, like the hippocampus, receives both cholinergic and GABAergic afferents from the BF. These projections arise from neurons in the substantia innominata (SI) and ventral pallidum (VP). It remained to be determined, however, whether the amygdala has projections back to the BF that arise from GABAergic non-pyramidal neurons. This question was investigated in the present study by combining Fluorogold (FG) retrograde tract tracing with immunohistochemistry for GABAergic non-pyramidal cell markers, including SOM, CB, NPY, parvalbumin, calretinin, and glutamic acid decarboxylase (GAD). FG injections into the BF produced a diffuse array of retrogradely labeled neurons in many nuclei of the amygdala. The great majority of amygdalar FG+ neurons did not express non-pyramidal cell markers. However, a subpopulation of non-pyramidal SOM+ neurons, termed “long-range non-pyramidal neurons” (LRNP neurons), in the external capsule, basolateral amygdala, and cortical and medial amygdalar nuclei were FG+. About one-third of the SOM+ LRNP neurons were CB+ or NPY+, and one-half were GAD+. It remains to be determined if these inhibitory amygdalar projections to the BF, like those from the hippocampus, are important for regulating synchronous oscillations in the amygdalar-BF network. PMID:22837739

  7. 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

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

    2015-07-29

    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. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  8. Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons.

    PubMed

    Inagaki, Tsuyoshi; Begum, Tahamina; Reza, Faruque; Horibe, Shoko; Inaba, Mie; Yoshimura, Yumiko; Komatsu, Yukio

    2008-06-01

    High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca2+ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca2+ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.

  9. Properties of voltage-gated potassium currents in nucleated patches from large layer 5 cortical pyramidal neurons of the rat

    PubMed Central

    Bekkers, John M

    2000-01-01

    Voltage-gated potassium currents were studied in nucleated outside-out patches obtained from large layer 5 pyramidal neurons in acute slices of sensorimotor cortex from 13- to 15-day-old Wistar rats (22–25 °C).Two main types of current were found, an A-current (IA) and a delayed rectifier current (IK), which were blocked by 4-aminopyridine (5 mm) and tetraethylammonium (30 mm), respectively.Recovery from inactivation was mono-exponential (for IA) or bi-exponential (for IK) and strongly voltage dependent. Both IA and IK could be almost fully inactivated by depolarising prepulses of sufficient duration. Steady-state inactivation curves were well fitted by the Boltzmann equation with half-maximal voltage (V½) and slope factor (k) values of −81.6 mV and −6.7 mV for IA, and −66.6 mV and −9.2 mV for IK. Peak activation curves were described by the Boltzmann equation with V½ and k values of −18.8 mV and 16.6 mV for IA, and −9.6 mV and 13.2 mV for IK.IA inactivated mono-exponentially during a depolarising test pulse, with a time constant (∼7 ms) that was weakly dependent on membrane potential. IK inactivated bi-exponentially with time constants (∼460 ms, ∼4.2 s) that were also weakly voltage dependent. The time to peak of both IA and IK depended strongly on membrane potential. The kinetics of IA and IK were described by a Hodgkin-Huxley-style equation of the form mNh, where N was 3 for IA and 1 for IK.These results provide a basis for understanding the role of voltage-gated potassium currents in the firing properties of large layer 5 pyramidal neurons of the rat neocortex. PMID:10856115

  10. GM2 ganglioside and pyramidal neuron dendritogenesis.

    PubMed

    Walkley, S U; Siegel, D A; Dobrenis, K

    1995-11-01

    GM2 ganglioside, although scarce in normal adult brain, is the predominant ganglioside accumulating in several types of lysosomal disorders, most notably Tay-Sachs disease. Pyramidal neurons of cerebral cortex in Tay-Sachs, as well as many other types of neuronal storage disorders, are known to exhibit a phenomenon believed unique to storage disorders: growth of ectopic dendrites. Recent studies have shown that a common metabolic abnormality shared by storage diseases with ectopic dendrite growth is the abnormal accumulation of GM2 ganglioside. The correlation between increased levels of GM2 and the presence of ectopic dendrites has been found in both ganglioside and nonganglioside storage disorders, the latter including sphingomyelin-cholesterol lipidosis, mucopolysaccharidosis, and alpha-mannosidosis. Quantitative HPTLC analysis has shown that increases in GM2 occur in proportion to the incidence of ectopic dendrite growth, whereas other gangliosides, including GM1, lack similar increases. Immunocytochemical studies of all nonganglioside storage diseases which exhibit ectopic dendritogenesis have revealed heightened GM2 ganglioside-immunoreactivity in the cortical pyramidal cell population, whereas nerurons in normal adult brain exhibit little or no staining for this ganglioside. Further, studies examining disease development have consistently shown that accumulation of GM2 ganglioside precedes growth of ectopic dendrites, indicating that it is not simply occurring secondary to new membrane production. These findings have prompted an examination for a similar relationship between GM2 ganglioside and dendritogenesis in cortical neurons of normal developing brain. Results show that GM2 ganglioside-immunoreactivity is consistently elevated in immature neurons during the period when they are undergoing active dendritic initiation, but this staining diminishes dramatically as the dendritic trees of these cells mature. Collectively, these studies on diseased and normal

  11. Requirement of cannabinoid CB(1) receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections.

    PubMed

    Wu, Chia-Shan; Zhu, Jie; Wager-Miller, Jim; Wang, Shan; O'Leary, Dennis; Monory, Krisztina; Lutz, Beat; Mackie, Ken; Lu, Hui-Chen

    2010-09-01

    A role for endocannabinoid signaling in neuronal morphogenesis as the brain develops has recently been suggested. Here we used the developing somatosensory circuit as a model system to examine the role of endocannabinoid signaling in neural circuit formation. We first show that a deficiency in cannabinoid receptor type 1 (CB(1)R), but not G-protein-coupled receptor 55 (GPR55), leads to aberrant fasciculation and pathfinding in both corticothalamic and thalamocortical axons despite normal target recognition. Next, we localized CB(1)R expression to developing corticothalamic projections and found little if any expression in thalamocortical axons, using a newly established reporter mouse expressing GFP in thalamocortical projections. A similar thalamocortical projection phenotype was observed following removal of CB(1)R from cortical principal neurons, clearly demonstrating that CB(1)R in corticothalamic axons was required to instruct their complimentary connections, thalamocortical axons. When reciprocal thalamic and cortical connections meet, CB(1)R-containing corticothalamic axons are intimately associated with elongating thalamocortical projections containing DGLβ, a 2-arachidonoyl glycerol (2-AG) synthesizing enzyme. Thus, 2-AG produced in thalamocortical axons and acting at CB(1)Rs on corticothalamic axons is likely to modulate axonal patterning. The presence of monoglyceride lipase, a 2-AG degrading enzyme, in both thalamocortical and corticothalamic tracts probably serves to restrict 2-AG availability. In summary, our study provides strong evidence that endocannabinoids are a modulator for the proposed 'handshake' interactions between corticothalamic and thalamocortical axons, especially for fasciculation. These findings are important in understanding the long-term consequences of alterations in CB(1)R activity during development, a potential etiology for the mental health disorders linked to prenatal cannabis use.

  12. Nociceptive Processing by Anterior Cingulate Pyramidal Neurons

    PubMed Central

    Shyu, Bai-Chuang; Sikes, Robert W.; Vogt, Brent A.

    2010-01-01

    Although the cingulate cortex is frequently activated in acute human pain studies, postsynaptic responses are not known nor are links between nociceptive afferents, neuronal responses, and outputs to other structures. Intracellular potentials were recorded from neurobiotin-injected, pyramidal neurons in anterior cingulate area 24b following noxious stimulation of the sciatic nerve in anesthetized rabbits. Layer IIIc pyramids had extensive and horizontally oriented basal dendrites in layer IIIc where nociceptive afferents terminate. They had the longest excitatory postsynaptic potentials (EPSPs; 545 ms) that were modulated with hyperpolarizing currents. Pyramids in layer V had an intermediate tuft of oblique apical dendrites in layer IIIc that were 150–350 μm from somata in layer Va and 351–550 μm in layer Vb. Although average EPSP durations were short in layers II–IIIab (222 ± 31), Va (267 ± 65), and Vb (159 ± 31), there were five neurons in layers IIIab–Va that had EPSP durations lasting >300 ms (548 ± 63 ms). Neurons in layers IIIc, Va, and Vb had the highest amplitude EPSPs (6.25, 6.84 ± 0.58, and 6.4 ± 0.47 mV, respectively), whereas those in layers II–IIIab were 5 ± 0.56 mV. Nociceptive responses in layer Vb were complex and some had initial inhibitory postsynaptic potentials with shorter-duration EPSPs. Layers II–IIIab had dye-coupled pyramids and EPSPs in these layers had short durations (167 ± 33 ms) compared with those in layers IIIc–Va (487 ± 28 ms). In conclusion there are two populations of anterior cingulate cortex pyramids with EPSPs of significantly different durations, although their dendritic morphologies do not predict EPSP duration. Short-duration EPSPs are thalamic-mediated, nociceptive responses lasting ≤200 ms. Longer, “integrative” EPSPs are >350 ms and are likely modulated by intracortical axon collateral discharges. These findings suggest that links between nociception and projections to cortical and motor

  13. 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.

  14. 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

  15. TRH regulates action potential shape in cerebral cortex pyramidal neurons.

    PubMed

    Rodríguez-Molina, Víctor; Patiño, Javier; Vargas, Yamili; Sánchez-Jaramillo, Edith; Joseph-Bravo, Patricia; Charli, Jean-Louis

    2014-07-07

    Thyrotropin releasing hormone (TRH) is a neuropeptide with a wide neural distribution and a variety of functions. It modulates neuronal electrophysiological properties, including resting membrane potential, as well as excitatory postsynaptic potential and spike frequencies. We explored, with whole-cell patch clamp, TRH effect on action potential shape in pyramidal neurons of the sensorimotor cortex. TRH reduced spike and after hyperpolarization amplitudes, and increased spike half-width. The effect varied with dose, time and cortical layer. In layer V, 0.5µM of TRH induced a small increase in spike half-width, while 1 and 5µM induced a strong but transient change in spike half-width, and amplitude; after hyperpolarization amplitude was modified at 5µM of TRH. Cortical layers III and VI neurons responded intensely to 0.5µM TRH; layer II neurons response was small. The effect of 1µM TRH on action potential shape in layer V neurons was blocked by G-protein inhibition. Inhibition of the activity of the TRH-degrading enzyme pyroglutamyl peptidase II (PPII) reproduced the effect of TRH, with enhanced spike half-width. Many cortical PPII mRNA+ cells were VGLUT1 mRNA+, and some GAD mRNA+. These data show that TRH regulates action potential shape in pyramidal cortical neurons, and are consistent with the hypothesis that PPII controls its action in this region. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. Serotonin modulation of cortical neurons and networks.

    PubMed

    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.

  1. 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

  2. Fractional differentiation by neocortical pyramidal neurons

    PubMed Central

    Lundstrom, Brian Nils; Higgs, Matthew H; Spain, William J; Fairhall, Adrienne L

    2008-01-01

    Neural systems adapt to changes in stimulus statistics. However, it is not known how stimuli with complex temporal dynamics drive the dynamics of adaptation and the resulting firing rate. For single neurons, it has often been assumed that adaptation has a single time scale. Here, we show that single rat neocortical pyramidal neurons adapt with a time scale that depends on the time scale of changes in stimulus statistics. This multiple time scale adaptation is consistent with fractional order differentiation, such that the neuron’s firing rate is a fractional derivative of slowly varying stimulus parameters. Biophysically, even though neuronal fractional differentiation effectively yields adaptation with many time scales, we find that its implementation requires only a few, properly balanced known adaptive mechanisms. Fractional differentiation provides single neurons with a fundamental and general computation that can contribute to efficient information processing, stimulus anticipation, and frequency independent phase shifts of oscillatory neuronal firing. PMID:18931665

  3. 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. © The Author 2016. Published by Oxford University Press.

  4. 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

  5. Sturge-Weber Syndrome Is Associated with Cortical Dysplasia ILAE Type IIIc and Excessive Hypertrophic Pyramidal Neurons in Brain Resections for Intractable Epilepsy.

    PubMed

    Wang, Dan-Dan; Blümcke, Ingmar; Coras, Roland; Zhou, Wen-Jing; Lu, De-Hong; Gui, Qiu-Ping; Hu, Jing-Xia; Zuo, Huan-Cong; Chen, Shi-Yun; Piao, Yue-Shan

    2015-05-01

    Sturge-Weber syndrome (SWS) is a rare syndrome characterized by capillary-venous malformations involving skin and brain. Many patients with SWS also suffer from drug-resistant epilepsy. We retrospectively studied a series of six SWS patients with epilepsy and extensive neurosurgical resections. At time of surgery, the patients' age ranged from 11 to 35 years (with a mean of 20.2 years). All surgical specimens were well preserved, which allowed a systematic microscopical inspection utilizing the 2011 ILAE classification for focal cortical dysplasia (FCD). Neuropathology revealed dysmorphic-like neurons with hypertrophic cell bodies reminiscent to those described for FCD type IIa in all cases. However, gross architectural abnormalities of neocortical layering typical for FCD type IIa were missing, and we propose to classify this pattern as FCD ILAE type IIIc. In addition, our patients with earliest seizure onset also showed polymicrogyria (PMG; n = 4). The ictal onset zones were identified in all patients by subdural electrodes, and these areas always showed histopathological evidence for FCD type IIIc. Four out of five patients had favorable seizure control after surgery with a mean follow-up period of 1.7 years. We concluded from our study that FCD type IIIc and PMG are frequently associated findings in SWS. FCD type IIIc may play a major epileptogenic role in SWS and complete resection of the associated FCD should be considered a prognostic key factor to achieve seizure control. © 2014 International Society of Neuropathology.

  6. Electrotonic Coupling between Pyramidal Neurons in the Neocortex

    PubMed Central

    Wang, Yun; Barakat, Amey; Zhou, Hongwei

    2010-01-01

    Electrotonic couplings (i.e., electrical synapses or gap junctions) are fundamental to neuronal synchronization, and thus essential for many physiological functions and pathological disorders. Interneuron electrical synapses have been studied intensively. Although studies on electrotonic couplings between pyramidal cells (PCs) are emerging, particularly in the hippocampus, evidence is still rare in the neocortex. The electrotonic coupling of PCs in the neocortex is therefore largely unknown in terms of electrophysiological, anatomical and synaptological properties. Using multiple patch-clamp recording with differential interference contrast infrared videomicroscopy (IR-DIC) visualization, histochemical staining, and 3D-computer reconstruction, electrotonic coupling was recorded between close PCs, mainly in the medial prefrontal cortex as well as in the visual cortical regions of ferrets and rats. Compared with interneuron gap junctions, these electrotonic couplings were characterized by several special features. The recording probability of an electrotonic coupling between PCs is extremely low; but the junctional conductance is notably high, permitting the direct transmission of action potentials (APs) and even tonic firing between coupled neurons. AP firing is therefore perfectly synchronized between coupled PCs; Postjunctional APs and spikelets alternate following slight changes of membrane potentials; Postjunctional spikelets, especially at high frequencies, are summated and ultimately reach AP-threshold to fire. These properties of pyramidal electrotonic couplings largely fill the needs, as predicted by simulation studies, for the synchronization of a neuronal assembly. It is therefore suggested that the electrotonic coupling of PCs plays a unique role in the generation of neuronal synchronization in the neocortex. PMID:20436674

  7. Sensory deprivation differentially impacts the dendritic development of pyramidal versus non-pyramidal neurons in layer 6 of mouse barrel cortex.

    PubMed

    Chen, Chia-Chien; Tam, Danny; Brumberg, Joshua C

    2012-04-01

    Early postnatal sensory experience can have profound impacts on the structure and function of cortical circuits affecting behavior. Using the mouse whisker-to-barrel system we chronically deprived animals of normal sensory experience by bilaterally trimming their whiskers every other day from birth for the first postnatal month. Brain tissue was then processed for Golgi staining and neurons in layer 6 of barrel cortex were reconstructed in three dimensions. Dendritic and somatic parameters were compared between sensory-deprived and normal sensory experience groups. Results demonstrated that layer 6 non-pyramidal neurons in the chronically deprived group showed an expansion of their dendritic arbors. The pyramidal cells responded to sensory deprivation with increased somatic size and basilar dendritic arborization but overall decreased apical dendritic parameters. In sum, sensory deprivation impacted on the neuronal architecture of pyramidal and non-pyramidal neurons in layer 6, which may provide a substrate for observed physiological and behavioral changes resulting from whisker trimming.

  8. Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model.

    PubMed

    Antón-Fernández, Alejandro; Merchán-Rubira, Jesús; Avila, Jesús; Hernández, Félix; DeFelipe, Javier; Muñoz, Alberto

    2017-01-01

    The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer's disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology.

  9. Phospho-Tau Accumulation and Structural Alterations of the Golgi Apparatus of Cortical Pyramidal Neurons in the P301S Tauopathy Mouse Model

    PubMed Central

    Antón-Fernández, Alejandro; Merchán-Rubira, Jesús; Avila, Jesús; Hernández, Félix; DeFelipe, Javier; Muñoz, Alberto

    2017-01-01

    The Golgi apparatus (GA) is a highly dynamic organelle involved in the processing and sorting of cellular proteins. In Alzheimer’s disease (AD), it has been shown to decrease in size and become fragmented in neocortical and hippocampal neuronal subpopulations. This fragmentation and decrease in size of the GA in AD has been related to the accumulation of hyperphosphorylated tau. However, the involvement of other pathological factors associated with the course of the disease, such as the extracellular accumulation of amyloid-β (Aβ) aggregates, cannot be ruled out, since both pathologies are present in AD patients. Here we use the P301S tauopathy mouse model to examine possible alterations of the GA in neurons that overexpress human tau (P301S mutated gene) in neocortical and hippocampal neurons, using double immunofluorescence techniques and confocal microscopy. Quantitative analysis revealed that neurofibrillary tangle (NFT)-bearing neurons had important morphological alterations and reductions in the surface area and volume of the GA compared with NFT-free neurons. Since in this mouse model there are no Aβ aggregates typical of AD, the present findings support the idea that the progressive accumulation of phospho-tau is associated with structural alterations of the GA, and that these changes may occur in the absence of Aβ pathology. PMID:28922155

  10. Misexpression of ptf1a in cortical pyramidal cells in vivo promotes an inhibitory peptidergic identity.

    PubMed

    Russ, Jeffrey B; Borromeo, Mark D; Kollipara, Rahul K; Bommareddy, Praveen K; Johnson, Jane E; Kaltschmidt, Julia A

    2015-04-15

    The intracellular transcriptional milieu wields considerable influence over the induction of neuronal identity. The transcription factor Ptf1a has been proposed to act as an identity "switch" between developmentally related precursors in the spinal cord (Glasgow et al., 2005; Huang et al., 2008), retina (Fujitani et al., 2006; Dullin et al., 2007; Nakhai et al., 2007; Lelièvre et al., 2011), and cerebellum (Hoshino et al., 2005; Pascual et al., 2007; Yamada et al., 2014), where it promotes an inhibitory over an excitatory neuronal identity. In this study, we investigate the potency of Ptf1a to cell autonomously confer a specific neuronal identity outside of its endogenous environment, using mouse in utero electroporation and a conditional genetic strategy to misexpress Ptf1a exclusively in developing cortical pyramidal cells. Transcriptome profiling of Ptf1a-misexpressing cells using RNA-seq reveals that Ptf1a significantly alters pyramidal cell gene expression, upregulating numerous Ptf1a-dependent inhibitory interneuron markers and ultimately generating a gene expression profile that resembles the transcriptomes of both Ptf1a-expressing spinal interneurons and endogenous cortical interneurons. Using RNA-seq and in situ hybridization analyses, we also show that Ptf1a induces expression of the peptidergic neurotransmitter nociceptin, while minimally affecting the expression of genes linked to other neurotransmitter systems. Moreover, Ptf1a alters neuronal morphology, inducing the radial redistribution and branching of neurites in cortical pyramidal cells. Thus Ptf1a is sufficient, even in a dramatically different neuronal precursor, to cell autonomously promote characteristics of an inhibitory peptidergic identity, providing the first example of a single transcription factor that can direct an inhibitory peptidergic fate.

  11. 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

  12. Synaptic connections between layer 4 spiny neurone-layer 2/3 pyramidal cell pairs in juvenile rat barrel cortex: physiology and anatomy of interlaminar signalling within a cortical column.

    PubMed

    Feldmeyer, Dirk; Lübke, Joachim; Silver, R Angus; Sakmann, Bert

    2002-02-01

    Whole-cell voltage recordings were obtained from 64 synaptically coupled excitatory layer 4 (L4) spiny neurones and L2/3 pyramidal cells in acute slices of the somatosensory cortex ('barrel' cortex) of 17- to 23-days-old rats. Single action potentials (APs) in the L4 spiny neurone evoked single unitary EPSPs in the L2/3 pyramidal cell with a peak amplitude of 0.7 +/- 0.6 mV. The average latency was 2.1 +/- 0.6 ms, the rise time was 0.8 +/- 0.3 ms and the decay time constant was 12.7 +/- 3.5 ms. The percentage of failures of an AP in a L4 spiny neurone to evoke a unitary EPSP in the L2/3 pyramidal cell was 4.9 +/- 8.8 % and the coefficient of variation (c.v.) of the unitary EPSP amplitude was 0.27 +/- 0.13. Both c.v. and percentage of failures decreased with increased average EPSP amplitude. Postsynaptic glutamate receptors (GluRs) in L2/3 pyramidal cells were of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) and the non-NMDAR type. At -60 mV in the presence of extracellular Mg2+ (1 mM), 29 +/- 15 % of the EPSP voltage-time integral was blocked by NMDAR antagonists. In 0 Mg2+, the NMDAR/AMPAR ratio of the EPSC was 0.50 +/- 0.29, about half the value obtained for L4 spiny neurone connections. Burst stimulation of L4 spiny neurones showed that EPSPs in L2/3 pyramidal cells depressed over a wide range of frequencies (1-100 s(-1) ). However, at higher frequencies (30 s(-1)) EPSP summation overcame synaptic depression so that the summed EPSP was larger than the first EPSP amplitude in the train. The number of putative synaptic contacts established by the axonal collaterals of the L4 projection neurone with the target neurone in layer 2/3 varied between 4 and 5, with an average of 4.5 +/- 0.5 (n = 13 pairs). Synapses were established on basal dendrites of the pyramidal cell. Their mean geometric distance from the pyramidal cell soma was 67 +/- 34 microm (range, 16-196 microm). The results suggest that each connected L4 spiny neurone produces a weak but reliable EPSP in

  13. 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

  14. BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses.

    PubMed

    Rutherford, L C; Nelson, S B; Turrigiano, G G

    1998-09-01

    Recently, we have identified a novel form of synaptic plasticity that acts to stabilize neocortical firing rates by scaling the quantal amplitude of AMPA-mediated synaptic inputs up or down as a function of neuronal activity. Here, we show that the effects of activity blockade on quantal amplitude are mediated through the neurotrophin brain-derived neurotrophic factor (BDNF). Exogenous BDNF prevented, and a TrkB-IgG fusion protein reproduced, the effects of activity blockade on pyramidal quantal amplitude. BDNF had opposite effects on pyramidal neuron and interneuron quantal amplitudes and modified the ratio of pyramidal neuron to interneuron firing rates. These data demonstrate a novel role for BDNF in the homeostatic regulation of excitatory synaptic strengths and in the maintenance of the balance of cortical excitation and inhibition.

  15. 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

  16. Dendritic potassium channels in hippocampal pyramidal neurons

    PubMed Central

    Johnston, Daniel; Hoffman, Dax A; Magee, Jeffrey C; Poolos, Nicholas P; Watanabe, Shigeo; Colbert, Costa M; Migliore, Michele

    2000-01-01

    Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back-propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non-uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium-dependent potassium current on action potential repolarization is progressively reduced in the first 150 μm of the apical dendrites, so that action potentials recorded farther than 200 μm from the soma have no fast after-hyperpolarization and are wider than those in the soma. The peak amplitude of back-propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A-type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long-term potentiation induced by pairing EPSPs and back-propagating action potentials. PMID:10811726

  17. Dendritic potassium channels in hippocampal pyramidal neurons.

    PubMed

    Johnston, D; Hoffman, D A; Magee, J C; Poolos, N P; Watanabe, S; Colbert, C M; Migliore, M

    2000-05-15

    Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back-propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non-uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium-dependent potassium current on action potential repolarization is progressively reduced in the first 150 micrometer of the apical dendrites, so that action potentials recorded farther than 200 micrometer from the soma have no fast after-hyperpolarization and are wider than those in the soma. The peak amplitude of back-propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A-type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long-term potentiation induced by pairing EPSPs and back-propagating action potentials.

  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. Dense and overlapping innervation of pyramidal neurons by neocortical chandelier cells

    PubMed Central

    Inan, Melis; Blázquez-Llorca, Lidia; Merchán-Perez, Angel; Anderson, Stewart A.; DeFelipe, Javier; Yuste, Rafael

    2013-01-01

    Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and thus could have an important role controlling the activity of cortical circuits. To understand their connectivity we labeled upper layers chandelier cells (ChCs) from mouse neocortex with a genetic strategy and studied how their axons contact local populations of pyramidal neurons, using immunohistochemical detection of axon initial segments. We studied ChCs located in the border of layers 1 and 2 from primary somatosensory cortex and find that practically all ChC axon terminals contact axon initial segments with an average of 3–5 boutons per cartridge. By measuring the number of putative synapses in initial segments we estimate that each pyramidal neuron is innervated, on average, by at least 4 ChCs. Additionally, each individual ChC contacts 35–50% of pyramidal neurons within its axonal arbor, with pockets of high innervation density. Finally, we find that ChC axons seems to have a conserved innervation pattern at different postnatal ages (P18–90), with only relatively small lateral expansions of their arbor and increases in the total number of their cartridges during the developmental period analyzed. We conclude that ChCs innervate neighboring pyramidal neurons in a dense and overlapping manner, an innervation pattern which could enable ChCs exert a widespread influence on their local circuits. PMID:23365230

  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

    2014-08-01

    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.

  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. Loss of MeCP2 From Forebrain Excitatory Neurons Leads to Cortical Hyperexcitation and Seizures

    PubMed Central

    Zhang, Wen; Peterson, Matthew; Beyer, Barbara; Frankel, Wayne N.

    2014-01-01

    Mutations of MECP2 cause Rett syndrome (RTT), a neurodevelopmental disorder leading to loss of motor and cognitive functions, impaired social interactions, and seizure at young ages. Defects of neuronal circuit development and function are thought to be responsible for the symptoms of RTT. The majority of RTT patients show recurrent seizures, indicating that neuronal hyperexcitation is a common feature of RTT. However, mechanisms underlying hyperexcitation in RTT are poorly understood. Here we show that deletion of Mecp2 from cortical excitatory neurons but not forebrain inhibitory neurons in the mouse leads to spontaneous seizures. Selective deletion of Mecp2 from excitatory but not inhibitory neurons in the forebrain reduces GABAergic transmission in layer 5 pyramidal neurons in the prefrontal and somatosensory cortices. Loss of MeCP2 from cortical excitatory neurons reduces the number of GABAergic synapses in the cortex, and enhances the excitability of layer 5 pyramidal neurons. Using single-cell deletion of Mecp2 in layer 2/3 pyramidal neurons, we show that GABAergic transmission is reduced in neurons without MeCP2, but is normal in neighboring neurons with MeCP2. Together, these results suggest that MeCP2 in cortical excitatory neurons plays a critical role in the regulation of GABAergic transmission and cortical excitability. PMID:24523563

  3. Non-associative Potentiation of Perisomatic Inhibition Alters the Temporal Coding of Neocortical Layer 5 Pyramidal Neurons

    PubMed Central

    Lourenço, Joana; Pacioni, Simone; Rebola, Nelson; van Woerden, Geeske M.; Marinelli, Silvia; DiGregorio, David; Bacci, Alberto

    2014-01-01

    In the neocortex, the coexistence of temporally locked excitation and inhibition governs complex network activity underlying cognitive functions, and is believed to be altered in several brain diseases. Here we show that this equilibrium can be unlocked by increased activity of layer 5 pyramidal neurons of the mouse neocortex. Somatic depolarization or short bursts of action potentials of layer 5 pyramidal neurons induced a selective long-term potentiation of GABAergic synapses (LTPi) without affecting glutamatergic inputs. Remarkably, LTPi was selective for perisomatic inhibition from parvalbumin basket cells, leaving dendritic inhibition intact. It relied on retrograde signaling of nitric oxide, which persistently altered presynaptic GABA release and diffused to inhibitory synapses impinging on adjacent pyramidal neurons. LTPi reduced the time window of synaptic summation and increased the temporal precision of spike generation. Thus, increases in single cortical pyramidal neuron activity can induce an interneuron-selective GABAergic plasticity effectively altering the computation of temporally coded information. PMID:25003184

  4. Target-specific M1 inputs to infragranular S1 pyramidal neurons.

    PubMed

    Kinnischtzke, Amanda K; Fanselow, Erika E; Simons, Daniel J

    2016-09-01

    The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237-2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures. Copyright © 2016 the American Physiological Society.

  5. 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

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

    PubMed

    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

    2015-08-01

    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.

  7. Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi.

    PubMed

    Rice, Ann C; Keeney, Paula M; Algarzae, Norah K; Ladd, Amy C; Thomas, Ravindar R; Bennett, James P

    2014-01-01

    Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD.

  8. Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex

    PubMed Central

    Chen, Jie-Guang; Rašin, Mladen-Roko; Kwan, Kenneth Y.; Šestan, Nenad

    2005-01-01

    Pyramidal neurons of the cerebral cortex display marked layer- and subtype-specific differences in their axonal projections and dendritic morphologies. Here we show that transcription factor Zfp312 is selectively expressed by layer V and VI subcortical projection pyramidal neurons and their progenitor cells. Knocking down Zfp312 with small interfering RNAs dramatically reduced the number of subcortical axonal projections from deep-layer pyramidal neurons and altered their dendritic morphology. In contrast, misexpression of Zfp312 in cortically projecting pyramidal neurons of layers II and III induced the expression of Tbr1, a transcription factor enriched in deep-layer neurons, and the formation of ectopic subcortical axonal projections. Thus, our results indicate that transcription factor Zfp312 plays a critical role in layer- and neuronal subtype-specific patterning of cortical axonal projections and dendritic morphologies. PMID:16314561

  9. Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons.

    PubMed

    Xiao, Dongsheng; Vanni, Matthieu P; Mitelut, Catalin C; Chan, Allen W; LeDue, Jeffrey M; Xie, Yicheng; Chen, Andrew Cn; Swindale, Nicholas V; Murphy, Timothy H

    2017-02-04

    Understanding the basis of brain function requires knowledge of cortical operations over wide-spatial scales, but also within the context of single neurons. In vivo, wide-field GCaMP imaging and sub-cortical/cortical cellular electrophysiology were used in mice to investigate relationships between spontaneous single neuron spiking and mesoscopic cortical activity. We make use of a rich set of cortical activity motifs that are present in spontaneous activity in anesthetized and awake animals. A mesoscale spike-triggered averaging procedure allowed the identification of motifs that are preferentially linked to individual spiking neurons by employing genetically targeted indicators of neuronal activity. Thalamic neurons predicted and reported specific cycles of wide-scale cortical inhibition/excitation. In contrast, spike-triggered maps derived from single cortical neurons yielded spatio-temporal maps expected for regional cortical consensus function. This approach can define network relationships between any point source of neuronal spiking and mesoscale cortical maps.

  10. Morphology and ontogeny of rat perirhinal cortical neurons.

    PubMed

    Furtak, Sharon Christine; Moyer, James Russell; Brown, Thomas Huntington

    2007-12-10

    Golgi-impregnated neurons from rat perirhinal cortex (PR) were classified into one of 15 distinct morphological categories (N = 6,891). The frequency of neurons in each cell class was determined as a function of the layer of PR and the age of the animal, which ranged from postnatal day 0 (P0) to young adulthood (P45). The developmental appearance of Golgi-impregnated neurons conformed to the expected "inside-out" pattern of development, meaning that cells populated in deep before superficial layers of PR. The relative frequencies of different cell types changed during the first 2 weeks of postnatal development. The largest cells, which were pyramidal and spiny multipolar neurons, appeared earliest. Aspiny stellate neurons were the last to appear. The total number of Golgi-impregnated neurons peaked at P10-12, corresponding to the time of eye-opening. This early increase in the number of impregnated neurons parallels observations in other cortical areas. The relative frequency of the 15 cell types remained constant between P14 to P45. The proportion of pyramidal neurons in PR ( approximately 50%) was much smaller than is typical of neocortex ( approximately 70%). A correspondingly larger proportion of PR neurons were nonpyramidal cells that are less common in neocortex. The relative frequency distribution of cell types creates an overall impression of considerable morphological diversity, which is arguably related to the particular manner in which this periallocortical brain region processes and stores information.

  11. 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.

  12. Physiology of Layer 5 Pyramidal Neurons in Mouse Primary Visual Cortex: Coincidence Detection through Bursting

    PubMed Central

    Shai, Adam S.; Anastassiou, Costas A.; Larkum, Matthew E.; Koch, Christof

    2015-01-01

    L5 pyramidal neurons are the only neocortical cell type with dendrites reaching all six layers of cortex, casting them as one of the main integrators in the cortical column. What is the nature and mode of computation performed in mouse primary visual cortex (V1) given the physiology of L5 pyramidal neurons? First, we experimentally establish active properties of the dendrites of L5 pyramidal neurons of mouse V1 using patch-clamp recordings. Using a detailed multi-compartmental model, we show this physiological setup to be well suited for coincidence detection between basal and apical tuft inputs by controlling the frequency of spike output. We further show how direct inhibition of calcium channels in the dendrites modulates such coincidence detection. To establish the singe-cell computation that this biophysics supports, we show that the combination of frequency-modulation of somatic output by tuft input and (simulated) calcium-channel blockage functionally acts as a composite sigmoidal function. Finally, we explore how this computation provides a mechanism whereby dendritic spiking contributes to orientation tuning in pyramidal neurons. PMID:25768881

  13. 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

  14. Locus coeruleus stimulation recruits a broad cortical neuronal network and increases cortical perfusion.

    PubMed

    Toussay, Xavier; Basu, Kaustuv; Lacoste, Baptiste; Hamel, Edith

    2013-02-20

    The locus coeruleus (LC), the main source of brain noradrenalin (NA), modulates cortical activity, cerebral blood flow (CBF), glucose metabolism, and blood-brain barrier permeability. However, the role of the LC-NA system in the regulation of cortical CBF has remained elusive. This rat study shows that similar proportions (∼20%) of cortical pyramidal cells and GABA interneurons are contacted by LC-NA afferents on their cell soma or proximal dendrites. LC stimulation induced ipsilateral activation (c-Fos upregulation) of pyramidal cells and of a larger proportion (>36%) of interneurons that colocalize parvalbumin, somatostatin, or nitric oxide synthase compared with pyramidal cells expressing cyclooxygenase-2 (22%, p < 0.05) or vasoactive intestinal polypeptide-containing interneurons (16%, p < 0.01). Concurrently, LC stimulation elicited larger ipsilateral compared with contralateral increases in cortical CBF (52 vs 31%, p < 0.01). These CBF responses were almost abolished (-70%, p < 0.001) by cortical NA denervation with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride] and were significantly reduced by α- and β-adrenoceptor antagonists (-40%, p < 0.001 and -30%, p < 0.05, respectively). Blockade of glutamatergic or GABAergic neurotransmission with NMDA or GABA(A) receptor antagonists potently reduced the LC-induced hyperemic response (-56%, p < 0.001 or -47%, p < 0.05). Moreover, inhibition of astroglial metabolism (-35%, p < 0.01), vasoactive epoxyeicosatrienoic acids (EETs; -60%, p < 0.001) synthesis, large-conductance, calcium-operated (BK, -52%, p < 0.05), and inward-rectifier (Kir, -40%, p < 0.05) K+ channels primarily impaired the hyperemic response. The data demonstrate that LC stimulation recruits a broad network of cortical excitatory and inhibitory neurons resulting in increased cortical activity and that K+ fluxes and EET signaling mediate a large part of the hemodynamic response.

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    PubMed Central

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

    2014-01-01

    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  20. 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.

  1. Reduced density of dendritic spines in pyramidal neurons of rats exposed to alcohol during early postnatal life.

    PubMed

    De Giorgio, Andrea; Granato, Alberto

    2015-04-01

    Dendritic spines are the main postsynaptic sites of excitatory connections of neocortical pyramidal neurons. Alterations of spine shape, number, and density can be observed in different mental diseases, including those caused by developmental alcohol exposure. Pyramidal neurons of layer 2/3 are the most abundant cells of the neocortex and represent the main source of associative cortico-cortical connections. These neurons are essential for higher functions mediated by the cortex such as feature selection and perceptual grouping. Furthermore, their connections have been shown to be altered in experimental models of fetal alcohol spectrum disorders. Here, we used a Golgi-like tracing method to study the spine density of layer 2/3 associative pyramidal neurons in the somatosensory cortex of adult rats exposed to alcohol during the first postnatal week. The main result of the present study is represented by the decreased spine density in the apical dendrite of alcohol-treated rats, as compared to controls. As to the basal dendritic tree, there were no significant differences between the experimental and the control group. A decreased density of dendritic spines in the apical dendrite may impair the excitatory input onto pyramidal neurons, thus resulting in a widespread alteration of the cortical information flow.

  2. 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.

  3. Postnatal Development of Synaptic Structure Proteins in Pyramidal Neuron Axon Initial Segments in Monkey Prefrontal Cortex

    PubMed Central

    Cruz, Dianne A.; Lovallo, Emily M.; Stockton, Steven; Rasband, Matthew; Lewis, David A.

    2009-01-01

    In the primate prefrontal cortex (PFC), the functional maturation of the synaptic connections of certain classes of GABA neurons is very complex. For example, the levels of both pre- and post-synaptic proteins that regulate GABA neurotransmission from the chandelier class of cortical interneurons to the axon initial segment (AIS) of pyramidal neurons undergo marked changes during both the perinatal period and adolescence in the monkey PFC. In order to understand the potential molecular mechanisms associated with these developmental refinements, we quantified the relative densities, laminar distributions, and lengths of pyramidal neuron AIS immunoreactive for ankyrin-G, ßIV spectrin, or gephyrin, three proteins involved in regulating synapse structure and receptor localization, in the PFC of rhesus monkeys ranging in age from birth through adulthood. Ankyrin-G- and ßIV spectrin-labeled AIS declined in density and length during the first six months postnatal, but then remained stable through adolescence and into adulthood. In contrast, the density of gephyrin-labeled AIS was stable until approximately 15 months of age and then markedly declined during adolescence. Thus, molecular determinants of the structural features that define GABA inputs to pyramidal neuron AIS in monkey PFC undergo distinct developmental trajectories with different types of changes occurring during the perinatal period and adolescence. In concert with previous data, these findings reveal a two-phase developmental process of GABAergic synaptic stability and GABA neurotransmission at chandelier cell inputs to pyramidal neurons that likely contributes to the protracted maturation of behaviors mediated by primate PFC circuitry. PMID:19330819

  4. 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

    2015-03-04

    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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. Glutamatergic Nonpyramidal Neurons From Neocortical Layer VI and Their Comparison With Pyramidal and Spiny Stellate Neurons

    PubMed Central

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L.; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-01-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription–polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity. PMID:19052106

  6. Glutamatergic nonpyramidal neurons from neocortical layer VI and their comparison with pyramidal and spiny stellate neurons.

    PubMed

    Andjelic, Sofija; Gallopin, Thierry; Cauli, Bruno; Hill, Elisa L; Roux, Lisa; Badr, Sammy; Hu, Emilie; Tamás, Gábor; Lambolez, Bertrand

    2009-02-01

    The deeper part of neocortical layer VI is dominated by nonpyramidal neurons, which lack a prominent vertically ascending dendrite and predominantly establish corticocortical connections. These neurons were studied in rat neocortical slices using patch-clamp, single-cell reverse transcription-polymerase chain reaction, and biocytin labeling. The majority of these neurons expressed the vesicular glutamate transporter but not glutamic acid decarboxylase, suggesting that a high proportion of layer VI nonpyramidal neurons are glutamatergic. Indeed, they exhibited numerous dendritic spines and established asymmetrical synapses. Our sample of glutamatergic nonpyramidal neurons displayed a wide variety of somatodendritic morphologies and a subset of these cells expressed the Nurr1 mRNA, a marker for ipsilateral, but not commissural corticocortical projection neurons in layer VI. Comparison with spiny stellate and pyramidal neurons from other layers showed that glutamatergic neurons consistently exhibited a low occurrence of GABAergic interneuron markers and regular spiking firing patterns. Analysis of electrophysiological diversity using unsupervised clustering disclosed three groups of cells. Layer V pyramidal neurons were segregated into a first group, whereas a second group consisted of a subpopulation of layer VI neurons exhibiting tonic firing. A third heterogeneous cluster comprised spiny stellate, layer II/III pyramidal, and layer VI neurons exhibiting adaptive firing. The segregation of layer VI neurons in two different clusters did not correlate either with their somatodendritic morphologies or with Nurr1 expression. Our results suggest that electrophysiological similarities between neocortical glutamatergic neurons extend beyond layer positioning, somatodendritic morphology, and projection specificity.

  7. A Sodium-Pump-Mediated Afterhyperpolarization in Pyramidal Neurons

    PubMed Central

    Dasari, Sameera; Onoue, Keita; Stephens, Emily K.; Hasse, J. Michael; Avesar, Daniel

    2013-01-01

    The sodium-potassium ATPase (i.e., the “sodium pump”) plays a central role in maintaining ionic homeostasis in all cells. Although the sodium pump is intrinsically electrogenic and responsive to dynamic changes in intracellular sodium concentration, its role in regulating neuronal excitability remains unclear. Here we describe a physiological role for the sodium pump in regulating the excitability of mouse neocortical layer 5 and hippocampal CA1 pyramidal neurons. Trains of action potentials produced long-lasting (∼20 s) afterhyperpolarizations (AHPs) that were insensitive to blockade of voltage-gated calcium channels or chelation of intracellular calcium, but were blocked by tetrodotoxin, ouabain, or the removal of extracellular potassium. Correspondingly, the AHP time course was similar to the decay of activity-induced increases in intracellular sodium, whereas intracellular calcium decayed at much faster rates. To determine whether physiological patterns of activity engage the sodium pump, we replayed in vitro a place-specific burst of 15 action potentials recorded originally in vivo in a CA1 “place cell” as the animal traversed the associated place field. In both layer 5 and CA1 pyramidal neurons, this “place cell train” generated small, long-lasting AHPs capable of reducing neuronal excitability for many seconds. Place-cell-train-induced AHPs were blocked by ouabain or removal of extracellular potassium, but not by intracellular calcium chelation. Finally, we found calcium contributions to the AHP to be temperature dependent: prominent at room temperature, but largely absent at 35°C. Our results demonstrate a previously unappreciated role for the sodium-potassium ATPase in regulating the excitability of neocortical and hippocampal pyramidal neurons. PMID:23926257

  8. A sodium-pump-mediated afterhyperpolarization in pyramidal neurons.

    PubMed

    Gulledge, Allan T; Dasari, Sameera; Onoue, Keita; Stephens, Emily K; Hasse, J Michael; Avesar, Daniel

    2013-08-07

    The sodium-potassium ATPase (i.e., the "sodium pump") plays a central role in maintaining ionic homeostasis in all cells. Although the sodium pump is intrinsically electrogenic and responsive to dynamic changes in intracellular sodium concentration, its role in regulating neuronal excitability remains unclear. Here we describe a physiological role for the sodium pump in regulating the excitability of mouse neocortical layer 5 and hippocampal CA1 pyramidal neurons. Trains of action potentials produced long-lasting (∼20 s) afterhyperpolarizations (AHPs) that were insensitive to blockade of voltage-gated calcium channels or chelation of intracellular calcium, but were blocked by tetrodotoxin, ouabain, or the removal of extracellular potassium. Correspondingly, the AHP time course was similar to the decay of activity-induced increases in intracellular sodium, whereas intracellular calcium decayed at much faster rates. To determine whether physiological patterns of activity engage the sodium pump, we replayed in vitro a place-specific burst of 15 action potentials recorded originally in vivo in a CA1 "place cell" as the animal traversed the associated place field. In both layer 5 and CA1 pyramidal neurons, this "place cell train" generated small, long-lasting AHPs capable of reducing neuronal excitability for many seconds. Place-cell-train-induced AHPs were blocked by ouabain or removal of extracellular potassium, but not by intracellular calcium chelation. Finally, we found calcium contributions to the AHP to be temperature dependent: prominent at room temperature, but largely absent at 35°C. Our results demonstrate a previously unappreciated role for the sodium-potassium ATPase in regulating the excitability of neocortical and hippocampal pyramidal neurons.

  9. Mapping cortical mesoscopic networks of single spiking cortical or sub-cortical neurons

    PubMed Central

    Xiao, Dongsheng; Vanni, Matthieu P; Mitelut, Catalin C; Chan, Allen W; LeDue, Jeffrey M; Xie, Yicheng; Chen, Andrew CN; Swindale, Nicholas V; Murphy, Timothy H

    2017-01-01

    Understanding the basis of brain function requires knowledge of cortical operations over wide-spatial scales, but also within the context of single neurons. In vivo, wide-field GCaMP imaging and sub-cortical/cortical cellular electrophysiology were used in mice to investigate relationships between spontaneous single neuron spiking and mesoscopic cortical activity. We make use of a rich set of cortical activity motifs that are present in spontaneous activity in anesthetized and awake animals. A mesoscale spike-triggered averaging procedure allowed the identification of motifs that are preferentially linked to individual spiking neurons by employing genetically targeted indicators of neuronal activity. Thalamic neurons predicted and reported specific cycles of wide-scale cortical inhibition/excitation. In contrast, spike-triggered maps derived from single cortical neurons yielded spatio-temporal maps expected for regional cortical consensus function. This approach can define network relationships between any point source of neuronal spiking and mesoscale cortical maps. DOI: http://dx.doi.org/10.7554/eLife.19976.001 PMID:28160463

  10. Molecular identity of axonal sodium channels in human cortical pyramidal cells

    PubMed Central

    Tian, Cuiping; Wang, Kaiyan; Ke, Wei; Guo, Hui; Shu, Yousheng

    2014-01-01

    Studies in rodents revealed that selective accumulation of Na+ channel subtypes at the axon initial segment (AIS) determines action potential (AP) initiation and backpropagation in cortical pyramidal cells (PCs); however, in human cortex, the molecular identity of Na+ channels distributed at PC axons, including the AIS and the nodes of Ranvier, remains unclear. We performed immunostaining experiments in human cortical tissues removed surgically to cure brain diseases. We found strong immunosignals of Na+ channels and two channel subtypes, NaV1.2 and NaV1.6, at the AIS of human cortical PCs. Although both channel subtypes were expressed along the entire AIS, the peak immunosignals of NaV1.2 and NaV1.6 were found at proximal and distal AIS regions, respectively. Surprisingly, in addition to the presence of NaV1.6 at the nodes of Ranvier, NaV1.2 was also found in a subpopulation of nodes in the adult human cortex, different from the absence of NaV1.2 in myelinated axons in rodents. NaV1.1 immunosignals were not detected at either the AIS or the nodes of Ranvier of PCs; however, they were expressed at interneuron axons with different distribution patterns. Further experiments revealed that parvalbumin-positive GABAergic axon cartridges selectively innervated distal AIS regions with relatively high immunosignals of NaV1.6 but not the proximal NaV1.2-enriched compartments, suggesting an important role of axo-axonic cells in regulating AP initiation in human PCs. Together, our results show that both NaV1.2 and NaV1.6 (but not NaV1.1) channel subtypes are expressed at the AIS and the nodes of Ranvier in adult human cortical PCs, suggesting that these channel subtypes control neuronal excitability and signal conduction in PC axons. PMID:25294986

  11. Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy.

    PubMed

    Child, Nicholas D; Benarroch, Eduardo E

    2014-03-18

    Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.

  12. Three Types of Cortical Layer 5 Neurons That Differ in Brain-wide Connectivity and Function.

    PubMed

    Kim, Euiseok J; Juavinett, Ashley L; Kyubwa, Espoir M; Jacobs, Matthew W; Callaway, Edward M

    2015-12-16

    Cortical layer 5 (L5) pyramidal neurons integrate inputs from many sources and distribute outputs to cortical and subcortical structures. Previous studies demonstrate two L5 pyramid types: cortico-cortical (CC) and cortico-subcortical (CS). We characterize connectivity and function of these cell types in mouse primary visual cortex and reveal a new subtype. Unlike previously described L5 CC and CS neurons, this new subtype does not project to striatum [cortico-cortical, non-striatal (CC-NS)] and has distinct morphology, physiology, and visual responses. Monosynaptic rabies tracing reveals that CC neurons preferentially receive input from higher visual areas, while CS neurons receive more input from structures implicated in top-down modulation of brain states. CS neurons are also more direction-selective and prefer faster stimuli than CC neurons. These differences suggest distinct roles as specialized output channels, with CS neurons integrating information and generating responses more relevant to movement control and CC neurons being more important in visual perception.

  13. 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.

  14. Extrasynaptic Glutamate Receptor Activation as Cellular Bases for Dynamic Range Compression in Pyramidal Neurons

    PubMed Central

    Oikonomou, Katerina D.; Short, Shaina M.; Rich, Matthew T.; Antic, Srdjan D.

    2012-01-01

    Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate, for a brief period of time. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly non-linear dendritic spikes (plateau potentials) are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of “loud sounds” (i.e., strong glutamatergic inputs) and amplify “quiet sounds” (i.e., glutamatergic inputs that barely cross the dendritic threshold for local spike initiation). Our data also explain why consecutive cortical UP

  15. 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.

  16. 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

  17. The Dendrites of CA2 and CA1 Pyramidal Neurons Differentially Regulate Information Flow in the Cortico-Hippocampal Circuit.

    PubMed

    Srinivas, Kalyan V; Buss, Eric W; Sun, Qian; Santoro, Bina; Takahashi, Hiroto; Nicholson, Daniel A; Siegelbaum, Steven A

    2017-03-22

    The impact of a given neuronal pathway depends on the number of synapses it makes with its postsynaptic target, the strength of each individual synapse, and the integrative properties of the postsynaptic dendrites. Here we explore the cellular and synaptic mechanisms responsible for the differential excitatory drive from the entorhinal cortical pathway onto mouse CA2 compared with CA1 pyramidal neurons (PNs). Although both types of neurons receive direct input from entorhinal cortex onto their distal dendrites, these inputs produce a 5- to 6-fold larger EPSP at the soma of CA2 compared with CA1 PNs, which is sufficient to drive action potential output from CA2 but not CA1. Experimental and computational approaches reveal that dendritic propagation is more efficient in CA2 than CA1 as a result of differences in dendritic morphology and dendritic expression of the hyperpolarization-activated cation current (Ih). Furthermore, there are three times as many cortical inputs onto CA2 compared with CA1 PN distal dendrites. Using a computational model, we demonstrate that the differences in dendritic properties of CA2 compared with CA1 PNs are necessary to enable the CA2 PNs to generate their characteristically large EPSPs in response to their cortical inputs; in contrast, CA1 dendritic properties limit the size of the EPSPs they generate, even to a similar number of cortical inputs. Thus, the matching of dendritic integrative properties with the density of innervation is crucial for the differential processing of information from the direct cortical inputs by CA2 compared with CA1 PNs.SIGNIFICANCE STATEMENT Recent discoveries have shown that the long-neglected hippocampal CA2 region has distinct synaptic properties and plays a prominent role in social memory and schizophrenia. This study addresses the puzzling finding that the direct entorhinal cortical inputs to hippocampus, which target the very distal pyramidal neuron dendrites, provide an unusually strong excitatory

  18. Alterations of neocortical pyramidal neurons: turning points in the genesis of mental retardation.

    PubMed

    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.

  19. 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

  20. Intracortical Microstimulation (ICMS) Activates Motor Cortex Layer 5 Pyramidal Neurons Mainly Transsynaptically.

    PubMed

    Hussin, Ahmed T; Boychuk, Jeffery A; Brown, Andrew R; Pittman, Quentin J; Teskey, G Campbell

    2015-01-01

    Intracortical microstimulation (ICMS) is a technique used for a number of purposes including the derivation of cortical movement representations (motor maps). Its application can activate the output layer 5 of motor cortex and can result in the elicitation of body movements depending upon the stimulus parameters used. The extent to which pyramidal tract projection neurons of the motor cortex are activated transsynaptically or directly by ICMS remains an open question. Given this uncertainty in the mode of activation, we used a preparation that combined patch clamp whole-cell recordings from single layer 5 pyramidal neurons and extracellular ICMS in slices of motor cortex as well as a standard in vivo mapping technique to ask how ICMS activated motor cortex pyramidal neurons. We measured changes in synaptic spike threshold and spiking rate to ICMS in vitro and movement threshold in vivo in the presence or absence of specific pharmacological blockers of glutamatergic (AMPA, NMDA and Kainate) receptors and GABAA receptors. With major excitatory and inhibitory synaptic transmission blocked (with DNQX, APV and bicuculline methiodide), we observed a significant increase in the ICMS current intensity required to elicit a movement in vivo as well as to the first spike and an 85% reduction in spiking responses in vitro. Subsets of neurons were still responsive after the synaptic block, especially at higher current intensities, suggesting a modest direct activation. Taken together our data indicate a mainly synaptic mode of activation to ICMS in layer 5 of rat motor cortex. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Anterior cingulate pyramidal neurons display altered dendritic branching in depressed suicides.

    PubMed

    Hercher, Christa; Canetti, Lilian; Turecki, Gustavo; Mechawar, Naguib

    2010-04-01

    It is hypothesized that mood disorders are accompanied by altered wiring and plasticity in key limbic brain regions such as the anterior cingulate cortex (ACC). To test this hypothesis at the cellular level, we analyzed basilar dendritic arborizations extended by layer VI pyramidal neurons in silver-impregnated postmortem ACC samples from well-characterized depressed suicide subjects (n=12) and matched sudden-death controls (n=7). One cm(3) tissue blocks were stained using a Golgi preparation, cut on a microtome, and mounted on slides. Basilar dendritic arbors from 195 neurons were reconstructed, and the number, length, and diameter of branches were determined at each branch order. The size and number of spines borne by these branches were also assessed. Third-order branches were significantly reduced in number (24% fewer; p=0.00262) in depressed suicides compared to controls. The size and average length of these branches, as well as their number of spines/length were unaltered. On average, for each pyramidal neuron analyzed in depressed subjects, the fewer third-order branches resulted in a significant reduction in branch length (28% shorter; p=0.00976) at this branch order. These results provide the first evidence of altered cortical dendritic branching in mood disorders. Given that proximal dendritic branches grow during perinatal development, and that they are generally less plastic at maturity than distal segments, we speculate that these differences in dendritic branching may reflect a biological predisposition to depression and suicide.

  2. Intrinsic Oscillations of Neocortex Generated by Layer 5 Pyramidal Neurons

    NASA Astrophysics Data System (ADS)

    Silva, Laurie R.; Amitai, Yael; Connors, Barry W.

    1991-01-01

    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.

  3. The excitation and depression of mammalian cortical neurones by amino acids

    PubMed Central

    Crawford, J. M.; Curtis, D. R.

    1964-01-01

    Amino acids related to L-glutamic and γ-amino-n-butyric acid have been administered electrophoretically, and by pressure ejection, into the extraneuronal environment of single neurones in the pericruciate cortex of cats anaesthetized with allobarbitone or allobarbitone-urethane. Acidic amino acids related to glutamic acid, particularly N-methyl-D-aspartic acid, excited cortical neurones. Neutral amino acids related to γ-amino-n-butyric acid, particularly 3-amino-1-propanesulphonic acid, depressed cortical neurones. Some of the depressants blocked the antidromic invasion of Betz cells by pyramidal volleys. There are no essential differences between the sensitivities of cortical and spinal neurones towards locally administered amino acids. A transmitter function of such amino acids within the mammalian central nervous system is considered unlikely. PMID:14228133

  4. Dendritic Properties Control Energy Efficiency of Action Potentials in Cortical Pyramidal Cells.

    PubMed

    Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin

    2017-01-01

    Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na(+) entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na(+) entry efficiency of somatic AP. Activating inward Ca(2+) current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca(2+)-activated outward K(+) current in dendrites, however, decreases Na(+) entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na(+) influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption.

  5. Dendritic Properties Control Energy Efficiency of Action Potentials in Cortical Pyramidal Cells

    PubMed Central

    Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin

    2017-01-01

    Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na+ entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na+ entry efficiency of somatic AP. Activating inward Ca2+ current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca2+-activated outward K+ current in dendrites, however, decreases Na+ entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na+ influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption. PMID:28919852

  6. Syngap1 haploinsufficiency damages a postnatal critical period of pyramidal cell structural maturation linked to cortical circuit assembly

    PubMed Central

    Aceti, Massimiliano; Creson, Thomas K.; Vaissiere, Thomas; Rojas, Camilo; Huang, Wen-Chin; Wang, Ya-Xian; Petralia, Ronald S.; Page, Damon T.; Miller, Courtney A.; Rumbaugh, Gavin

    2014-01-01

    Background Genetic haploinsufficiency of Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability (ID), epilepsy, schizophrenia (SCZ), and autism spectrum (ASD) disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathological developmental processes common among distinct brain disorders. Methods A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine damage, cortical circuit assembly and the window for genetic rescue in order to understand how damaging mutations disrupt key substrates of mouse brain development. Results Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis, and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults. Conclusions Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathological process in developmental brain disorders. PMID:25444158

  7. Action potential initiation in a two-compartment model of pyramidal neuron mediated by dendritic Ca(2+) spike.

    PubMed

    Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin

    2017-04-03

    Dendritic Ca(2+) spike endows cortical pyramidal cell with powerful ability of synaptic integration, which is critical for neuronal computation. Here we propose a two-compartment conductance-based model to investigate how the Ca(2+) activity of apical dendrite participates in the action potential (AP) initiation to affect the firing properties of pyramidal neurons. We have shown that the apical input with sufficient intensity triggers a dendritic Ca(2+) spike, which significantly boosts dendritic inputs as it propagates to soma. Such event instantaneously shifts the limit cycle attractor of the neuron and results in a burst of APs, which makes its firing rate reach a plateau steady-state level. Delivering current to two chambers simultaneously increases the level of neuronal excitability and decreases the threshold of input-output relation. Here the back-propagating APs facilitate the initiation of dendritic Ca(2+) spike and evoke BAC firing. These findings indicate that the proposed model is capable of reproducing in vitro experimental observations. By determining spike initiating dynamics, we have provided a fundamental link between dendritic Ca(2+) spike and output APs, which could contribute to mechanically interpreting how dendritic Ca(2+) activity participates in the simple computations of pyramidal neuron.

  8. Action potential initiation in a two-compartment model of pyramidal neuron mediated by dendritic Ca2+ spike

    PubMed Central

    Yi, Guosheng; Wang, Jiang; Wei, Xile; Deng, Bin

    2017-01-01

    Dendritic Ca2+ spike endows cortical pyramidal cell with powerful ability of synaptic integration, which is critical for neuronal computation. Here we propose a two-compartment conductance-based model to investigate how the Ca2+ activity of apical dendrite participates in the action potential (AP) initiation to affect the firing properties of pyramidal neurons. We have shown that the apical input with sufficient intensity triggers a dendritic Ca2+ spike, which significantly boosts dendritic inputs as it propagates to soma. Such event instantaneously shifts the limit cycle attractor of the neuron and results in a burst of APs, which makes its firing rate reach a plateau steady-state level. Delivering current to two chambers simultaneously increases the level of neuronal excitability and decreases the threshold of input-output relation. Here the back-propagating APs facilitate the initiation of dendritic Ca2+ spike and evoke BAC firing. These findings indicate that the proposed model is capable of reproducing in vitro experimental observations. By determining spike initiating dynamics, we have provided a fundamental link between dendritic Ca2+ spike and output APs, which could contribute to mechanically interpreting how dendritic Ca2+ activity participates in the simple computations of pyramidal neuron. PMID:28367964

  9. Selective adaptation in networks of cortical neurons.

    PubMed

    Eytan, Danny; Brenner, Naama; Marom, Shimon

    2003-10-15

    A key property of neural systems is their ability to adapt selectively to stimuli with different features. Using multisite electrical recordings from networks of cortical neurons developing ex vivo, we show that neurons adapt selectively to different stimuli invading the network. We focus on selective adaptation to frequent and rare stimuli; networks were stimulated at two sites with two different stimulus frequencies. When both stimuli were presented within the same period, neurons in the network attenuated their responsiveness to the more frequent input, whereas their responsiveness to the rarely delivered stimuli showed a marked average increase. The amplification of the response to rare stimuli required the presence of the other, more frequent stimulation source. By contrast, the decreased response to the frequent stimuli occurred regardless of the presence of the rare stimuli. Analysis of the response of single units suggests that both of these effects are caused by changes in synaptic transmission. By using synaptic blockers, we find that the increased responsiveness to the rarely stimulated site depends specifically on fast GABAergic transmission. Thus, excitatory synaptic depression, the inhibitory sub-network, and their balance play an active role in generating selective gain control. The observation that selective adaptation arises naturally in a network of cortical neurons developing ex vivo indicates that this is an inherent feature of spontaneously organizing cortical networks.

  10. The efferent projections of neurons in the white matter of different cortical areas of the adult rat.

    PubMed

    Meyer, G; Gonzalez-Hernandez, T; Galindo-Mireles, D; Castañeyra-Perdomo, A; Ferres-Torres, R

    1991-01-01

    Injection of Fast Blue into different cortical areas (frontal, parietal, anterior and posterior cingulate cortex) revealed that neurons in the white matter (interstitial neurons) give rise to association fibers which project mostly to the gray matter of the overlying cytoarchitectonic area, but which may extend also over different cytoarchitectonic areas. The rostrocaudal extent of the projecting axons was up to 1 mm in the frontal and parietal cortex, and up to 3.5 mm in the cingulate cortex. Concurrent processing for dihydronicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry showed that 70% of cortically projecting interstitial neurons were NADPH-d-positive. An analysis of neuronal morphology suggests that the FasT-Blue-labeled, NADPH-d-negative neurons may represent displaced pyramidal neurons of layer VIb; the Fast-Blue-labeled and NADPH-d-positive neurons have bipolar or multipolar dendritic trees, constituting a population of nonpyramidal interstitial neurons that project into the cortical gray matter.

  11. 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.

  12. Quantitative analysis of basal dendritic tree of layer III pyramidal neurons in different areas of adult human frontal cortex.

    PubMed

    Zeba, Martina; Jovanov-Milosević, Natasa; Petanjek, Zdravko

    2008-01-01

    Large long projecting (cortico-cortical) layer IIIc pyramidal neurons were recently disclosed to be in the basis of cognitive processing in primates. Therefore, we quantitatively examined the basal dendritic morphology of these neurons by using rapid Golgi and Golgi Cox impregnation methods among three distinct Brodmann areas (BA) of an adult human frontal cortex: the primary motor BA4 and the associative magnopyramidal BA9 from left hemisphere and the Broca's speech BA45 from both hemispheres. There was no statistically significant difference in basal dendritic length or complexity, as dendritic spine number or their density between analyzed BA's. In addition, we analyzed each of these BA's immunocytochemically for distribution of SMI-32, a marker of largest long distance projecting neurons. Within layer IIIc, the highest density of SMI-32 immunopositive pyramidal neurons was observed in associative BA9, while in primary BA4 they were sparse. Taken together, these data suggest that an increase in the complexity of cortico-cortical network within human frontal areas of different functional order may be principally based on the increase in density of large, SMI-32 immunopositive layer IIIc neurons, rather than by further increase in complexity of their dendritic tree and synaptic network.

  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. High-Degree Neurons Feed Cortical Computations.

    PubMed

    Timme, Nicholas M; Ito, Shinya; Myroshnychenko, Maxym; Nigam, Sunny; Shimono, Masanori; Yeh, Fang-Chin; Hottowy, Pawel; Litke, Alan M; Beggs, John M

    2016-05-01

    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

  15. 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

  16. Motor effects of cortical stimulation after chronic lesion of medullary pyramid in the dog.

    PubMed

    Górska, T; Woolsey, C N; Wetzel, A

    1980-01-01

    In dogs with unilateral pyramidal lesions the motor cortex on both hemispheres was stimulated under Nembutal anesthesia to study the effects of pyramidotomy upon cortically induced movements. Pyramidal lesions resulted in an almost complete abolition of foretoes flexions and marked reduction of wrist ventriflexions. Other movements were not noticeably affected, except for their increased thresholds. The increase in the thresholds of movements elicited from the affected hemispheres diminished as a function of the length of postoperative survival period, so that 6 mo after pyramidotomy the thresholds on the operated side approximated the values obtained on the normal hemispheres.

  17. Effects of 15 Hz square wave magnetic fields on the voltage-gated sodium and potassium channels in prefrontal cortex pyramidal neurons.

    PubMed

    Zheng, Yu; Dou, Jun-Rong; Gao, Yang; Dong, Lei; Li, Gang

    2017-04-01

    Although magnetic fields have significant effects on neurons, little is known about the mechanisms behind their effects. The present study aimed to measure the effects of magnetic fields on ion channels in cortical pyramidal neurons. Cortical pyramidal neurons of Kunming mice were isolated and then subjected to 15 Hz, 1 mT square wave (duty ratio 50%) magnetic fields stimulation. Sodium currents (INa), transient potassium currents (IA) and delayed rectifier potassium currents (IK) were recorded by whole-cell patch clamp method. We found that magnetic field exposure depressed channel current densities, and altered the activation kinetics of sodium and potassium channels. The inactivation properties of INa and IA were also altered. Magnetic field exposure alters ion channel function in neurons. It is likely that the structures of sodium and potassium channels were influenced by the applied field. Sialic acid, which is an important component of the channels, could be the molecule responsible for the reported results.

  18. Loss of sensory input increases the intrinsic excitability of layer 5 pyramidal neurons in rat barrel cortex.

    PubMed

    Breton, Jean-Didier; Stuart, Greg J

    2009-11-01

    Development of the cortical map is experience dependent, with different critical periods in different cortical layers. Previous work in rodent barrel cortex indicates that sensory deprivation leads to changes in synaptic transmission and plasticity in layer 2/3 and 4. Here, we studied the impact of sensory deprivation on the intrinsic properties of layer 5 pyramidal neurons located in rat barrel cortex using simultaneous somatic and dendritic recording. Sensory deprivation was achieved by clipping all the whiskers on one side of the snout. Loss of sensory input did not change somatic active and resting membrane properties, and did not influence dendritic action potential (AP) backpropagation. In contrast, sensory deprivation led to an increase in the percentage of layer 5 pyramidal neurons showing burst firing. This was associated with a reduction in the threshold for generation of dendritic calcium spikes during high-frequency AP trains. Cell-attached recordings were used to assess changes in the properties and expression of dendritic HCN channels. These experiments indicated that sensory deprivation caused a decrease in HCN channel density in distal regions of the apical dendrite. To assess the contribution of HCN down-regulation on the observed increase in dendritic excitability following sensory deprivation, we investigated the impact of blocking HCN channels. Block of HCN channels removed differences in dendritic calcium electrogenesis between control and deprived neurons. In conclusion, these observations indicate that sensory loss leads to increased dendritic excitability of cortical layer 5 pyramidal neurons. Furthermore, they suggest that increased dendritic calcium electrogenesis following sensory deprivation is mediated in part via down-regulation of dendritic HCN channels.

  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. 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. Copyright © 2016 the American Physiological Society.

  1. Population model of hippocampal pyramidal neurons, linking a refractory density approach to conductance-based neurons

    NASA Astrophysics Data System (ADS)

    Chizhov, Anton V.; Graham, Lyle J.

    2007-01-01

    We propose a macroscopic approach toward realistic simulations of the population activity of hippocampal pyramidal neurons, based on the known refractory density equation with a different hazard function and on a different single-neuron threshold model. The threshold model is a conductance-based model taking into account adaptation-providing currents, which is reduced by omitting the fast sodium current and instead using an explicit threshold criterion for action potential events. Compared to the full pyramidal neuron model, the threshold model well approximates spike-time moments, postspike refractory states, and postsynaptic current integration. The dynamics of a neural population continuum are described by a set of one-dimensional partial differential equations in terms of the distributions of the refractory density (where the refractory state is defined by the time elapsed since the last action potential), the membrane potential, and the gating variables of the voltage-dependent channels, across the entire population. As the source term in the density equation, the probability density of firing, or hazard function, is derived from the Fokker-Planck (FP) equation, assuming that a single neuron is governed by a deterministic average-across-population input and a noise term. A self-similar solution of the FP equation in the subthreshold regime is obtained. Responses of the ensemble to stimulation by a current step and oscillating current are simulated and compared with individual neuron simulations. An example of interictal-like activity of a population of all-to-all connected excitatory neurons is presented.

  2. Secreted factors from ventral telencephalon induce the differentiation of GABAergic neurons in cortical cultures.

    PubMed

    Trinh, H-h; Reid, J; Shin, E; Liapi, A; Parnavelas, J G; Nadarajah, B

    2006-12-01

    It is widely believed that the pyramidal cells and interneurons of the cerebral cortex are distinct in their origin, lineage and genetic make up. In view of these findings, the current thesis is that the phenotype determination of cortical neurons is primarily directed by genetic mechanisms. Using in vitro assays, the present study demonstrates that secreted factors from ganglionic eminence (GE) of the ventral telencephalon have the potency to induce the differentiation of a subset of cortical neurons towards gamma-aminobutyric acid (GABA)ergic lineage. Characterization of cortical cultures that were exposed to medium derived from GE illustrated a significant increase in the number of GABA-, calretinin- and calbindin-positive neurons. Calcium imaging together with pharmacological studies showed that the application of exogenous medium significantly elevated the intracellular calcium transients in cortical neurons through the activation of ionotropic glutamate receptors. The increase in GABA+ neurons appeared to be associated with the elevated calcium activity; treatment with blockers specific for glutamate receptors abolished both the synchronized transients and reduced the differentiation of GABAergic neurons. Such studies demonstrate that although intrinsic mechanisms determine the fate of cortical interneurons, extrinsic factors have the potency to influence their neurochemical differentiation and contribute towards their molecular diversity.

  3. Properties of persistent postnatal cortical subplate neurons.

    PubMed

    Torres-Reveron, Juan; Friedlander, Michael J

    2007-09-12

    Subplate (SP) neurons are important for the proper development of thalamocortical innervation. They are necessary for formation of ocular dominance and orientation columns in visual cortex. During the perinatal period, many SP neurons die. The surviving cohort forms interstitial cells in the white matter (WM) and a band of horizontally oriented cells below layer VI (layer VIb, layer VII, or subplate cells). Although the function of embryonic SP neurons has been well established, the functional roles of WM and postnatal SP cells are not known. We used a combination of anatomical, immunohistochemical, and electrophysiological techniques to explore the dendritic morphology, neurotransmitter phenotype, intrinsic electrophysiological, and synaptic input properties of these surviving cells in the rat visual cortex. The density of SP and WM cells significantly decreases during the first month of life. Both populations express neuronal markers and have extensive dendritic arborizations within the SP, WM, and to the overlying visual cortex. Some intrinsic electrophysiological properties of SP and WM cells are similar: each generates high-frequency slowly adapting trains of action potentials in response to a sustained depolarization. However, SP cells exhibit greater frequency-dependent action potential broadening than WM neurons. Both cell types receive predominantly AMPA/kainate receptor-mediated excitatory synaptic input that undergoes paired-pulse facilitation as well as NMDA receptor and GABAergic input. Synaptic inputs to these cells can also undergo long-term synaptic plasticity. Thus, surviving SP and WM cells are functional electrogenic neurons integrated within the postnatal visual cortical circuit.

  4. 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

  5. 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

  6. 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

    2016-06-07

    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.

  7. 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.

  8. Genistein Partly Eases Aging and Estropause-Induced Primary Cortical Neuronal Changes in Rats

    PubMed Central

    Wang, Tsyr-Jiuan; Chen, Jeng-Rung; Wang, Wen-Jay; Wang, Yueh-Jan; Tseng, Guo-Fang

    2014-01-01

    Gonadal hormones can modulate brain morphology and behavior. Recent studies have shown that hypogonadism could result in cortical function deficits. To this end, hormone therapy has been used to ease associated symptoms but the risk may outweigh the benefits. Here we explored whether genistein, a phytoestrogen, is effective in restoring the cognitive and central neuronal changes in late middle age and surgically estropause female rats. Both animal groups showed poorer spatial learning than young adults. The dendritic arbors and spines of the somatosensory cortical and CA1 hippocampal pyramidal neurons were revealed with intracellular dye injection and analyzed. The results showed that dendritic spines on these neurons were significantly decreased. Remarkably, genistein treatment rescued spatial learning deficits and restored the spine density on all neurons in the surgically estropause young females. In late middle age females, genistein was as effective as estradiol in restoring spines; however, the recovery was less thorough than on young OHE rats. Neither genistein nor estradiol rectified the shortened dendritic arbors of the aging cortical pyramidal neurons suggesting that dendritic arbors and spines are differently modulated. Thus, genistein could work at central level to restore excitatory connectivity and appears to be potent alternative to estradiol for easing aging and menopausal syndromes. PMID:24587060

  9. Genistein partly eases aging and estropause-induced primary cortical neuronal changes in rats.

    PubMed

    Wang, Tsyr-Jiuan; Chen, Jeng-Rung; Wang, Wen-Jay; Wang, Yueh-Jan; Tseng, Guo-Fang

    2014-01-01

    Gonadal hormones can modulate brain morphology and behavior. Recent studies have shown that hypogonadism could result in cortical function deficits. To this end, hormone therapy has been used to ease associated symptoms but the risk may outweigh the benefits. Here we explored whether genistein, a phytoestrogen, is effective in restoring the cognitive and central neuronal changes in late middle age and surgically estropause female rats. Both animal groups showed poorer spatial learning than young adults. The dendritic arbors and spines of the somatosensory cortical and CA1 hippocampal pyramidal neurons were revealed with intracellular dye injection and analyzed. The results showed that dendritic spines on these neurons were significantly decreased. Remarkably, genistein treatment rescued spatial learning deficits and restored the spine density on all neurons in the surgically estropause young females. In late middle age females, genistein was as effective as estradiol in restoring spines; however, the recovery was less thorough than on young OHE rats. Neither genistein nor estradiol rectified the shortened dendritic arbors of the aging cortical pyramidal neurons suggesting that dendritic arbors and spines are differently modulated. Thus, genistein could work at central level to restore excitatory connectivity and appears to be potent alternative to estradiol for easing aging and menopausal syndromes.

  10. Enhanced Ras activity in pyramidal neurons induces cellular hypertrophy and changes in afferent and intrinsic connectivity in synRas mice.

    PubMed

    Gärtner, Ulrich; Alpár, Alán; Seeger, Gudrun; Heumann, Rolf; Arendt, Thomas

    2004-05-01

    Neurotrophic actions are critically controlled and transmitted to cellular responses by the small G protein Ras which is therefore essential for normal functioning and plasticity of the nervous system. The present study summarises findings of recent studies on morphological changes in the neocortex of synRas mice expressing Val12-Ha-Ras in vivo under the control of the rat synapsin I promoter. In the here reported model (introduced by Heumann et al. [J. Cell Biol. 151 (2000) 1537]), transgenic Val12-Ha-Ras expression is confined to the pyramidal cell population and starts postnatally at a time, when neurons are postmitotic and their developmental maturation has been basically completed. Expression of Val12-Ha-Ras results in a significant enlargement of pyramidal neurons. Size, complexity and spine density of dendritic trees are increased, which leads, finally, to cortical expansion. However, the main morphological design principles of 'transgenic' pyramidal cells remain preserved. In addition to somato-dendritic changes, expression of Val12-Ha-Ras in pyramidal cells induces augmented axon calibres and upregulates the establishment of efferent boutons. Despite the enlargement of cortical size, the overall density of terminals representing intra- or interhemispheric, specific and non-specific afferents is unchanged or even higher in transgenic mice suggesting a significant increase in the total afferent input to the neocortex. Although interneurons do not express the transgene and are therefore excluded from direct, intrinsic Val12-Ha-Ras effects, they respond with morphological adaptations to structural changes. Thus, dendritic arbours of interneurons are extended to follow the cortical expansion and basket cells establish a denser inhibitory innervation of 'transgenic' pyramidal cells perikarya. It is concluded that expression of Val12-Ha-Ras in pyramidal neurons results in remodelling of neocortical structuring which strongly implicates a crucial involvement of

  11. Structural reorganization of pyramidal neurons in the medial prefrontal cortex of alcohol dependent rats is associated with altered glial plasticity.

    PubMed

    Kim, Airee; Zamora-Martinez, Eva R; Edwards, Scott; Mandyam, Chitra D

    2015-01-01

    In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the activity of pyramidal neurons and decreases the number of glial progenitors in the medial prefrontal cortex (mPFC). Adult male Wistar rats were exposed to CIE and were injected with mitotic markers to label and phenotype proliferating cells to test the hypothesis that CIE produces concurrent alterations in the structure of pyramidal neurons and the cell cycle kinetics and developmental stages of glial progenitors in the mPFC. Medial prefrontal cortical tissue was processed for Golgi-Cox staining, immunohistochemistry and Western blotting analysis. CIE increased dendritic arborization and spine densities within basal and apical dendrites of pyramidal neurons via aberrant reorganization of actin cytoskeleton-associated molecules. CIE concomitantly increased the expression of total NR2B subunits without affecting phosphorylation of NR2B at Tyr-1472 or levels of PSD-95. CIE reduced the length of S-phase of the cell cycle of glial progenitors and reduced proliferation and differentiation of progenitors into bHLH transcription factor Olig2-expressing premyelinating oligodendrocyte progenitor cells (OPCs). CIE also produced a corresponding hyperphosphorylation of Olig2, and reduced expression of myelin basic protein. Our findings demonstrate that CIE-induced alterations in OPCs and myelin-related proteins are associated with profound alterations in the structure of pyramidal neurons. In sum, our results not only provide evidence that alcohol dependence leads to pathological changes in the mPFC, which may in part define a cellular basis for cognitive impairments associated with alcoholism, but also show dependence-associated morphological changes in the PFC at the single neuron level.

  12. Structural reorganization of pyramidal neurons in the medial prefrontal cortex of alcohol dependent rats is associated with altered glial plasticity

    PubMed Central

    Kim, Airee; Zamora-Martinez, Eva R.; Edwards, Scott; Mandyam, Chitra D.

    2014-01-01

    In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the activity of pyramidal neurons and decreases the number of glial progenitors in the medial prefrontal cortex (mPFC). Adult male Wistar rats were exposed to CIE and were injected with mitotic markers to label and phenotype proliferating cells to test the hypothesis that CIE produces concurrent alterations in the structure of pyramidal neurons and the cell cycle kinetics and developmental stages of glial progenitors in the mPFC. Medial prefrontal cortical tissue was processed for Golgi-Cox staining, immunohistochemistry and Western blotting analysis. CIE increased dendritic arborization and spine densities within basal and apical dendrites of pyramidal neurons via aberrant reorganization of actin cytoskeleton-associated molecules. CIE concomitantly increased expression of total NR2B subunits without affecting phosphorylation of NR2B at Tyr-1472 or levels of PSD-95. CIE reduced the length of S phase of the cell cycle of glial progenitors and reduced proliferation and differentiation of progenitors into bHLH transcription factor Olig2-expressing premyelinating oligodendrocyte progenitor cells (OPCs). CIE also produced a corresponding hyperphosphorylation of Olig2, and reduced expression of myelin basic protein. Our findings demonstrate that CIE-induced alterations in OPCs and myelin-related proteins are associated with profound alterations in the structure of pyramidal neurons. In sum, our results not only provide evidence that alcohol dependence leads to pathological changes in the mPFC, which may in part define a cellular basis for cognitive impairments associated with alcoholism, but also show dependence-associated morphological changes in the PFC at the single neuron level. PMID:24667898

  13. A consensus layer V pyramidal neuron can sustain interpulse-interval coding

    PubMed Central

    Singh, Chandan; Levy, William B.

    2017-01-01

    In terms of a single neuron’s long-distance communication, interpulse intervals (IPIs) are an attractive alternative to rate and binary codes. As a proxy for an IPI, a neuron’s time-to-spike can be found in the biophysical and experimental intracellular literature. Using the current, consensus layer V pyramidal neuron, the present study examines the feasibility of IPI-coding and examines the noise sources that limit the information rate of such an encoding. In descending order of importance, the noise sources are (i) synaptic variability, (ii) sodium channel shot-noise, followed by (iii) thermal noise. The biophysical simulations allow the calculation of mutual information, which is about 3.0 bits/spike. More importantly, while, by any conventional definition, the biophysical model is highly nonlinear, the underlying function that relates input intensity to the defined output variable is linear. When one assumes the perspective of a neuron coding via first hitting-time, this result justifies a pervasive and simplifying assumption of computational modelers—that a class of cortical neurons can be treated as linearly additive, computational devices. PMID:28704450

  14. Chattering Cells: Superficial Pyramidal Neurons Contributing to the Generation of Synchronous Oscillations in the Visual Cortex

    NASA Astrophysics Data System (ADS)

    Gray, Charles M.; McCormick, David A.

    1996-10-01

    In response to visual stimulation, a subset of neurons in the striate and prestriate cortex displays synchronous rhythmic firing in the gamma frequency band (20 to 70 hertz). This finding has raised two fundamental questions: What is the functional significance of synchronous gamma-band activity and how is it generated? This report addresses the second of these two questions. By means of intracellular recording and staining of single cells in the cat striate cortex in vivo, a biophysically distinct class of pyramidal neuron termed "chattering cells" is described. These neurons are located in the superficial layers of the cortex, intrinsically generate 20- to 70-hertz repetitive burst firing in response to suprathreshold depolarizing current injection, and exhibit pronounced oscillations in membrane potential during visual stimulation that are largely absent during periods of spontaneous activity. These properties suggest that chattering cells may make a substantial intracortical contribution to the generation of synchronous cortical oscillations and thus participate in the recruitment of large populations of cells into synchronously firing assemblies.

  15. Tonic current through GABAA receptors and hyperpolarization-activated cyclic nucleotide-gated channels modulate resonance properties of rat subicular pyramidal neurons.

    PubMed

    Sah, Nirnath; Sikdar, Sujit K

    2014-07-01

    The subiculum, considered to be the output structure of the hippocampus, modulates information flow from the hippocampus to various cortical and sub-cortical areas such as the nucleus accumbens, lateral septal region, thalamus, nucleus gelatinosus, medial nucleus and mammillary nuclei. Tonic inhibitory current plays an important role in neuronal physiology and pathophysiology by modulating the electrophysiological properties of neurons. While the alterations of various electrical properties due to tonic inhibition have been studied in neurons from different regions, its influence on intrinsic subthreshold resonance in pyramidal excitatory neurons expressing hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is not known. Using pharmacological agents, we show the involvement of α5βγ GABAA receptors in the picrotoxin-sensitive tonic current in subicular pyramidal neurons. We further investigated the contribution of tonic conductance in regulating subthreshold electrophysiological properties using current clamp and dynamic clamp experiments. We demonstrate that tonic GABAergic inhibition can actively modulate subthreshold properties, including resonance due to HCN channels, which can potentially alter the response dynamics of subicular pyramidal neurons in an oscillating neuronal network.

  16. 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

  17. Subchronic vortioxetine treatment -but not escitalopram- enhances pyramidal neuron activity in the rat prefrontal cortex.

    PubMed

    Riga, Maurizio S; Teruel-Martí, Vicent; Sánchez, Connie; Celada, Pau; Artigas, Francesc

    2017-02-01

    Vortioxetine (VOR) is a multimodal antidepressant drug. VOR is a 5-HT3-R, 5-HT7-R and 5-HT1D-R antagonist, 5-HT1B-R partial agonist, 5-HT1A-R agonist, and serotonin transporter (SERT) inhibitor. VOR shows pro-cognitive activity in animal models and beneficial effects on cognitive dysfunction in major depressive patients. Here we compared the effects of 14-day treatments with VOR and escitalopram (ESC, selective serotonin reuptake inhibitor) on neuronal activity in the medial prefrontal cortex (mPFC). Ten groups of rats (5 standard, 5 depleted of 5-HT with p-chlorophenylalanine -pCPA-, used as model of cognitive impairment) were fed with control food or with two doses of VOR-containing food. Four groups were implanted with minipumps delivering vehicle or ESC 10 mg/kg·day s.c. The two VOR doses enable occupation by VOR of SERT+5-HT3-R and all targets, respectively, and correspond to SERT occupancies in patients treated with 5 and 20 VOR mg/day, respectively. Putative pyramidal neurons (n = 985) were recorded extracellularly in the mPFC of anesthetized rats. Sub-chronic VOR administration (but not ESC) significantly increased neuronal discharge in standard and 5-HT-depleted conditions, with a greater effect of the low VOR dose in standard rats. VOR increased neuronal discharge in infralimbic (IL) and prelimbic (PrL) cortices. Hence, oral VOR doses evoking SERT occupancies similar to those in treated patients increase mPFC neuronal discharge. The effect in 5-HT-depleted rats cannot be explained by an antagonist action of VOR at 5-HT3-R and suggests a non-canonical interaction of VOR with 5-HT3-R. These effects may underlie the superior pro-cognitive efficacy of VOR compared with SSRIs in animal models.

  18. 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

  19. The Angelman syndrome protein Ube3a is required for polarized dendrite morphogenesis in pyramidal neurons.

    PubMed

    Miao, Sheng; Chen, Renchao; Ye, Jiahao; Tan, Guo-He; Li, Shuai; Zhang, Jing; Jiang, Yong-hui; Xiong, Zhi-Qi

    2013-01-02

    Pyramidal neurons have a highly polarized dendritic morphology, characterized by one long apical dendrite and multiple short basal dendrites. They function as the primary excitatory cells of the mammalian prefrontal cortex and the corticospinal tract. However, the molecular mechanisms underlying the development of polarized dendrite morphology in pyramidal neurons remain poorly understood. Here, we report that the Angelman syndrome (AS) protein ubiquitin-protein ligase E3A (Ube3a) plays an important role in specifying the polarization of pyramidal neuron dendritic arbors in mice. shRNA-mediated downregulation of Ube3a selectively inhibited apical dendrite outgrowth and resulted in impaired dendrite polarity, which could be rescued by coexpressing mouse Ube3a isoform 2, but not isoform 1 or 3. Ube3a knockdown also disrupted the polarized distribution of the Golgi apparatus, a well established cellular mechanism for asymmetric dendritic growth in pyramidal neurons. Furthermore, downregulation of Ube3a completely blocked Reelin-induced rapid deployment of Golgi into dendrite. Consistently, we also observed selective inhibition of apical dendrite outgrowth in pyramidal neurons in a mouse model of AS. Overall, these results show that Ube3a is required for the specification of the apical dendrites and dendrite polarization in pyramidal neurons, and suggest a novel pathological mechanism for AS.

  20. In vivo multiphoton nanosurgery on cortical neurons.

    PubMed

    Sacconi, Leonardo; O'Connor, Rodney P; Jasaitis, Audrius; Masi, Alessio; Buffelli, Mario; Pavone, Francesco S

    2007-01-01

    Two-photon microscopy has been used to perform high spatial resolution imaging of spine plasticity in the intact neocortex of living mice. Multiphoton absorption has also been used as a tool for the selective disruption of cellular structures in living cells and simple organisms. In this work, we exploit the spatial localization of multiphoton excitation to perform selective lesions on the neuronal processes of cortical neurons in living mice expressing fluorescent proteins. Neurons are irradiated with a focused, controlled dose of femtosecond laser energy delivered through cranial optical windows. The morphological consequences are then characterized with time lapse 3-D two-photon imaging over a period of minutes to days after the procedure. This methodology is applied to dissect single dendrites with submicrometric precision without causing any visible collateral damage to the surrounding neuronal structures. The spatial precision of this method is demonstrated by ablating individual dendritic spines, while sparing the adjacent spines and the structural integrity of the dendrite. The combination of multiphoton nanosurgery and in vivo imaging in mammals represents a promising tool for neurobiology and neuropharmacology research.

  1. Different Ca2+ source for slow AHP in completely adapting and repetitive firing pyramidal neurons.

    PubMed

    Pineda, J C; Galarraga, E; Foehring, R C

    1999-06-23

    Intracellular recordings in an in vitro neocortical slice preparation from immature rats were used to investigate the Ca2 source for slow afterhyperpolarization (sAHP) generation in pyramidal neurons that exhibit complete spike frequency adaptation (CA neurons). In pyramidal neurons that maintain repetitive firing for long periods of time (RF neurons), N-, P- and Q-type Ca2+ channels supply Ca2+ for sAHP generation. In CA neurons, the sAHP was reduced by only 50% by the combination of antagonists for these Ca2+ channel types and L-type channels. Ryanodine and dantrolene, blockers of Ca2(+)-induced Ca2+ release, reduced the sAHP by approximately 45% in CA neurons, but caused no reduction of the sAHP in RF neurons. Dantrolene application caused CA neurons to fire throughout a 1s suprathreshold current injection (as do RF neurons).

  2. Increased Synaptic Excitation and Abnormal Dendritic Structure of Prefrontal Cortex Layer V Pyramidal Neurons following Prolonged Binge-Like Consumption of Ethanol

    PubMed Central

    Klenowski, Paul M.; Fogarty, Matthew J.; Shariff, Masroor; Belmer, Arnauld

    2016-01-01

    Abstract Long-term alcohol use causes a multitude of neurochemical changes in cortical regions that facilitate the transition to dependence. Therefore, we used a model of long-term, binge-like ethanol consumption in rats to determine the effects on morphology and synaptic physiology of medial prefrontal cortex (mPFC) layer V pyramidal neurons. Following 10 weeks of ethanol consumption, we recorded synaptic currents from mPFC neurons and used neurobiotin filling to analyze their morphology. We then compared these data to measurements obtained from age-matched, water-drinking control rats. We found that long-term ethanol consumption caused a significant increase in total dendrite arbor length of mPFC layer V pyramidal neurons. Dendritic restructuring was primarily observed in basal dendrite arbors, with mPFC neurons from animals engaged in long-term ethanol drinking having significantly larger and more complex basal arbors compared with controls. These changes were accompanied by significantly increased total spine densities and spontaneous postsynaptic excitatory current frequency, suggesting that long-term binge-like ethanol consumption enhances basal excitatory synaptic transmission in mPFC layer V pyramidal neurons. Our results provide insights into the morphological and functional changes in mPFC layer V pyramidal neuronal physiology following prolonged exposure to ethanol and support changes in mPFC activity during the development of alcohol dependence. PMID:28032119

  3. 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

  4. 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

  5. Somatostatin immunohistochemistry of hippocampal slices with lucifer yellow-stained pyramidal neurons responding to somatostatin.

    PubMed

    Joëls, M; Madamba, S G; Moore, S D; Morrison, J H; Siggins, G R

    1990-04-24

    We have combined electrophysiology and immunohistochemistry to study the somatostatin (SS) innervation of neurons in the rat hippocampal slice. After recording the intracellular response of a pyramidal CA1 neuron in vitro to SS, Lucifer Yellow was injected into the cell and the slice fixed and processed for immunohistochemical localization of SS in the vicinity of the recorded neuron. Most pyramidal neurons (70%) responded to SS with a hyperpolarization associated with marked slowing of spontaneous discharge and reduced input resistance. SS-containing elements either crossed, ran parallel or seemingly terminated on the Lucifer Yellow-filled SS-responsive cell. These occurrences of close proximity of apparent pre- and postsynaptic elements were observed in all layers of the CA1 region and may represent synaptic terminations of SS elements on a pyramidal neuron that are likely to elicit membrane hyperpolarizations.

  6. Comparison of dendritic fields of layer III pyramidal neurons in striate and extrastriate visual areas of the marmoset: a Lucifer yellow intracellular injection.

    PubMed

    Elston, G N; Rosa, M G; Calford, M B

    1996-01-01

    Basal dendritic field areas of layer III pyramidal neurons were compared between the first (V1), second (V2), dorsolateral (DL) and fundus of the superior temporal (FST) areas in marmoset monkey visual cortex. These areas correspond to early stages of visual processing (V1, V2) and to areas specialized for the analysis of shape (DL) and motion (FST). Neurons in fixed tangential cortical slices (250 microns) were injected with Lucifer Yellow and immunohistochemically processed for a diaminobenzidine reaction product. Dendritic field areas were calculated for layer III pyramidal cells whose complete basal projection was judged to be within the section (n = 189). Borders between different visual areas were established based on cytochrome oxidase immunohistochemistry and myelin patterns in the experimental hemisphere, and electrophysiological recordings in the contralateral hemisphere. Pyramidal neurons in V1 had a mean basal dendritic field area of 1.84 x 10(4) microns2 (SEM = 2.04 x 10(3) microns2; n = 21). Layer III pyramidal cells in V2 had a mean basal dendritic field 1.26 times larger (mean = 2.32 x 10(4) +/- 1.78 x 10(3) microns2; n = 42) than that of V1 neurons. The mean dendritic field area of layer III pyramidal cells in DL (n = 76) was 1.5 times larger than that in V1 (mean = 2.75 x 10(4) +/- 1.59 x 10(3) microns2), and that in FST (n = 50) was 2.3 times larger (mean = 4.26 x 10(4) +/- 2.79 x 10(3) microns2). Our results show that there is a correlation between tangential dendritic field area of basal dendrites of layer III pyramidal neurons and modality of visual processing. The increase in basal dendritic field area of layer III pyramidal cells may allow more extensive sampling of inputs as required by higher-order processing of visual information.

  7. Early establishment of multiple release site connectivity between interneurons and pyramidal neurons in the developing hippocampus.

    PubMed

    Groc, Laurent; Gustafsson, Bengt; Hanse, Eric

    2003-05-01

    The strength of the synaptic transmission between two neurons critically depends on the number of release sites connecting the neurons. Here we examine the development of connectivity between gamma-aminobutyric acid (GABA)ergic interneurons and CA1 pyramidal neurons in the hippocampus. GABAergic postsynaptic currents (PSCs) were recorded in whole-cell voltage-clamped CA1 pyramidal neurons. By comparing spontaneous and miniature (action potential-independent) GABAergic PSCs, we found that multiple release site connectivity is established already at the first postnatal day and that the degree of connectivity remains unaltered into adulthood. During the same time there is a dramatic increase in the number of GABAergic synapses on each pyramidal neuron as indicated by the increase in frequency of miniature GABAergic PSCs. These results indicate that during development a given interneuron contacts an increasing number of target pyramidal neurons but with the same multiple release site connectivity. It has been shown previously that the connectivity between CA3 and CA1 pyramidal neurons is initially restricted to one release site, and develops gradually. The present result thus suggests different mechanisms to govern the maturation of excitatory and inhibitory synaptic transmissions.

  8. 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

  9. PERK regulates Gq protein-coupled intracellular Ca(2+) dynamics in primary cortical neurons.

    PubMed

    Zhu, Siying; McGrath, Barbara C; Bai, Yuting; Tang, Xin; Cavener, Douglas R

    2016-10-01

    PERK (EIF2AK3) is an ER-resident eIF2α kinase required for behavioral flexibility and metabotropic glutamate receptor-dependent long-term depression via its translational control. Motivated by the recent discoveries that PERK regulates Ca(2+) dynamics in insulin-secreting β-cells underlying glucose-stimulated insulin secretion, and modulates Ca(2+) signals-dependent working memory, we explored the role of PERK in regulating Gq protein-coupled Ca(2+) dynamics in pyramidal neurons. We found that acute PERK inhibition by the use of a highly specific PERK inhibitor reduced the intracellular Ca(2+) rise stimulated by the activation of acetylcholine, metabotropic glutamate and bradykinin-2 receptors in primary cortical neurons. More specifically, acute PERK inhibition increased IP3 receptor mediated ER Ca(2+) release, but decreased receptor-operated extracellular Ca(2+) influx. Impaired Gq protein-coupled intracellular Ca(2+) rise was also observed in genetic Perk knockout neurons. Taken together, our findings reveal a novel role of PERK in neurons, which is eIF2α-independent, and suggest that the impaired working memory in forebrain-specific Perk knockout mice may stem from altered Gq protein-coupled intracellular Ca(2+) dynamics in cortical pyramidal neurons.

  10. Visual Receptive Field Heterogeneity and Functional Connectivity of Adjacent Neurons in Primate Frontoparietal Association Cortices.

    PubMed

    Viswanathan, Pooja; Nieder, Andreas

    2017-09-13

    The basic organization principles of the primary visual cortex (V1) are commonly assumed to also hold in the association cortex such that neurons within a cortical column share functional connectivity patterns and represent the same region of the visual field. We mapped the visual receptive fields (RFs) of neurons recorded at the same electrode in the ventral intraparietal area (VIP) and the lateral prefrontal cortex (PFC) of rhesus monkeys. We report that the spatial characteristics of visual RFs between adjacent neurons differed considerably, with increasing heterogeneity from VIP to PFC. In addition to RF incongruences, we found differential functional connectivity between putative inhibitory interneurons and pyramidal cells in PFC and VIP. These findings suggest that local RF topography vanishes with hierarchical distance from visual cortical input and argue for increasingly modified functional microcircuits in noncanonical association cortices that contrast V1.SIGNIFICANCE STATEMENT Our visual field is thought to be represented faithfully by the early visual brain areas; all the information from a certain region of the visual field is conveyed to neurons situated close together within a functionally defined cortical column. We examined this principle in the association areas, PFC, and ventral intraparietal area of rhesus monkeys and found that adjacent neurons represent markedly different areas of the visual field. This is the first demonstration of such noncanonical organization of these brain areas. Copyright © 2017 the authors 0270-6474/17/378919-10$15.00/0.

  11. Cooperative nonlinearities in auditory cortical neurons.

    PubMed

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

    2008-06-26

    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 nonmonotonic. 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.

  12. Silent synapses persist into adulthood in layer 2/3 pyramidal neurons of visual cortex in dark-reared mice.

    PubMed

    Funahashi, Rie; Maruyama, Takuro; Yoshimura, Yumiko; Komatsu, Yukio

    2013-04-01

    Immature excitatory synapses often have NMDA receptors but not AMPA receptors in central neurons, including visual cortical pyramidal neurons. These synapses, called silent synapses, are converted to functional synapses with AMPA receptors by NMDA receptor activation during early development. It is likely that this process underlies the activity-dependent refinement of neuronal circuits and brain functions. In the present study, we investigated postnatal development of excitatory synapses, focusing on the role of visual inputs in the conversion of silent to functional synapses in mouse visual cortex. We analyzed presumably unitary excitatory postsynaptic currents (EPSCs) between a pair of layer 2/3 pyramidal neurons, using minimal stimulation with a patch pipette attached to the soma of one of the pair. The proportion of silent synapses was estimated by the difference in the failure rate between AMPA- and NMDA-EPSCs. In normal development, silent synapses were present abundantly before eye opening, decreased considerably by the critical period of ocular dominance plasticity, and almost absent in adulthood. This decline in silent synapses was prevented by dark rearing. The amplitude of presumably unitary AMPA-EPSCs increased with age, but this increase was suppressed by dark rearing. The quantal amplitude of AMPA-EPSCs and paired-pulse ratio of NMDA-EPSCs both remained unchanged during development, independent of visual experience. These results indicate that visual inputs are required for the conversion of silent to functional synapses and this conversion largely contributes to developmental increases in the amplitude of presumably unitary AMPA-EPSCs.

  13. 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.

  14. 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

  15. In vivo dual intra- and extracellular recordings suggest bidirectional coupling between CA1 pyramidal neurons.

    PubMed

    Chorev, Edith; Brecht, Michael

    2012-09-01

    Spikelets, small spikelike membrane potential deflections, are prominent in the activity of hippocampal pyramidal neurons in vivo. The origin of spikelets is still a source of much controversy. Somatically recorded spikelets have been postulated to originate from dendritic spikes, ectopic spikes, or spikes in an electrically coupled neuron. To differentiate between the different proposed mechanisms we used a dual recording approach in which we simultaneously recorded the intracellular activity of one CA1 pyramidal neuron and the extracellular activity in its vicinity, thus monitoring extracellularly the activity of both the intracellularly recorded cell as well as other units in its surroundings. Spikelets were observed in a quarter of our recordings (n = 36). In eight of these nine recordings a second extracellular unit fired in correlation with spikelet occurrences. This observation is consistent with the idea that the spikelets reflect action potentials of electrically coupled nearby neurons. The extracellular spikes of these secondary units preceded the onset of spikelets. While the intracellular spikelet amplitude was voltage dependent, the simultaneously recorded extracellular unit remained unchanged. Spikelets often triggered action potentials in neurons, resulting in a characteristic 1- to 2-ms delay between spikelet onset and firing. Here we show that this relationship is bidirectional, with spikes being triggered by and also triggering spikelets. Secondary units, coupled to pyramidal neurons, showed discharge patterns similar to the recorded pyramidal neuron. These findings suggest that spikelets reflect spikes in an electrically coupled neighboring neuron, most likely of pyramidal cell type. Such coupling might contribute to the synchronization of pyramidal neurons with millisecond precision.

  16. Modulation of NMDA and AMPA-mediated synaptic transmission by CB1 receptors in frontal cortical pyramidal cells.

    PubMed

    Li, Qiang; Yan, Haidun; Wilson, Wilkie A; Swartzwelder, H Scott

    2010-06-25

    Although the endogenous cannabinoid system modulates a variety of physiological and pharmacological processes, the specific role of cannabinoid CB1 receptors in the modulation of glutamatergic neurotransmission and neural plasticity is not well understood. Using whole-cell patch clamp recording techniques, evoked or spontaneous excitatory postsynaptic currents (eEPSCs or sEPSCs) were recorded from visualized, layer II/III pyramidal cells in frontal cortical slices from rat brain. Bath application of the CB1 receptor agonist, WIN 55212-2 (WIN), reduced the amplitude of NMDA receptor-mediated EPSCs in a concentration-dependent manner. When co-applied with the specific CB1 antagonists, AM251 or AM281, WIN did not suppress NMDA receptor-mediated EPSCs. WIN also reduced the amplitude of evoked AMPA receptor-mediated EPSCs, an effect that was also reversed by AM251. Both the frequency and amplitude of spontaneous AMPA receptor-mediated EPSCs were significantly reduced by WIN. In contrast, WIN reduced the frequency, but not the amplitude of miniature EPSCs, suggesting that the suppression of glutamatergic activity by CB1 receptors in the frontal neocortex is mediated by a presynaptic mechanism. Taken together, these data indicate a critical role for endocannabinoid signaling in the regulation of excitatory synaptic transmission in frontal neocortex, and suggest a possible neuronal mechanism whereby THC regulates cortical function.

  17. Thrombin modulates persistent sodium current in CA1 pyramidal neurons of young and adult rat hippocampus.

    PubMed

    Lunko, O O; Isaev, D S; Krishtal, O O; Isaeva, E V

    2015-01-01

    Serine protease thrombin, a key factor of blood coagulation, participates in many neuronal processes important for normal brain functioning and during pathological conditions involving abnormal neuronal synchronization, neurodegeneration and inflammation. Our previous study on CA3 pyramidal neurons showed that application ofthrombin through the activation of specific protease-activated receptor 1 (PAR1) produces a significant hyperpolarizing shift of the activation of the TTX-sensitive persistent voltage-gated Na+ current (I(Nap)) thereby affecting membrane potential and seizure threshold at the network level. It was shown that PAR1 is also expressed in CA1 area of hippocampus and can be implicated in neuronal damage in this area after status epilepticus. The aim of the present study was to evaluate the effect of thrombin on I(NaP) in CA1 pyramidal neurons from adult and young rats. Using whole cell patch-clamp technique we demonstrate that thrombin application results in the hyperpolarization shift of I(NaP) activation as well as increase in the I(NaP) amplitude in both age groups. We have found that I(NaP) in pyramidal neurons of hippocampal CA 1 region is more vulnerable to the thrombin action than I(NaP) in pyramidal neurons of hippocampal CA3 region. We have also found that the immature hippocampus is more sensitive to thrombin action which emphasizes the contribution of thrombin-dependent pathway to the regulation of neuronal activity in immature brain.

  18. Temporal synchrony and gamma to theta power conversion in the dendrites of CA1 pyramidal neurons

    PubMed Central

    Vaidya, Sachin P.; Johnston, Daniel

    2014-01-01

    Timing is a crucial aspect of synaptic integration. For pyramidal neurons that integrate thousands of synaptic inputs spread across hundreds of microns, it is thus a challenge to maintain the timing of incoming inputs at the axo-somatic integration site. Here we show that pyramidal neurons in the rodent hippocampus use a gradient of inductance in the form of HCN channels as an active mechanism to counteract location-dependent temporal differences of dendritic inputs at the soma. Using simultaneous multi-site whole cell recordings complemented by computational modeling, we find that this intrinsic biophysical mechanism produces temporal synchrony of rhythmic inputs in the theta and gamma frequency ranges across wide regions of the dendritic tree. While gamma and theta oscillations are known to synchronize activity across space in neuronal networks, our results identify a novel mechanism by which this synchrony extends to activity within single pyramidal neurons with complex dendritic arbors. PMID:24185428

  19. Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons.

    PubMed

    Pasquereau, Benjamin; Turner, Robert S

    2011-06-01

    Dysfunction of primary motor cortex (M1) is thought to contribute to the pathophysiology of parkinsonism. What specific aspects of M1 function are abnormal remains uncertain, however. Moreover, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those questions were addressed by studying the resting activity of intratelencephalic-type corticostriatal neurons (CSNs) and distant-projecting lamina 5b pyramidal-tract type neurons (PTNs) in the macaque M1 before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Contrary to previous reports, the general population of M1 neurons (i.e., PTNs, CSNs, and unidentified neurons) showed reduced baseline firing rates following MPTP, attributable largely to a marked decrease in PTN firing rates. CSN firing rates were unmodified. Although burstiness and firing patterns remained constant in M1 neurons as a whole and CSNs in particular, PTNs became more bursty post-MPTP and less likely to fire in a regular-spiking pattern. Rhythmic spiking (found in PTNs predominantly) occurred at beta frequencies (14-32 Hz) more frequently following MPTP. These results indicate that MPTP intoxication induced distinct modifications in the activity of different M1 neuronal subtypes. The particular susceptibility of PTNs suggests that PTN dysfunction may be an important contributor to the pathophysiology of parkinsonian motor signs.

  20. Desynchronization of the Rat Cortical Network and Excitation of White Matter Neurons by Neurotensin.

    PubMed

    Case, Lovisa; Lyons, David J; Broberger, Christian

    2017-04-01

    Cortical network activity correlates with vigilance state: Deep sleep is characterized by slow, synchronized oscillations, whereas desynchronized, stochastic discharge is typical of the waking state. Neuropeptides, such as orexin and substance P but also neurotensin (NT), promote arousal. Relatively little is known about if NT can directly affect the cortical network, and if so, through which mechanisms and cellular targets. Here, we addressed these issues using rat in vitro cortex preparations. Following NT application specifically to deeper layers, slow oscillation activity was attenuated with a significant reduction in UP state frequency. The cortical response to thalamic stimulation exhibited enhanced temporal precision in the presence of NT, consistent with the transition in vivo from sleep to wakefulness. These changes were associated with a relative shift toward inhibition in the excitation/inhibition balance. Whole-cell recordings from layer 6 revealed presynaptically driven NT-induced inhibition of pyramidal neurons and excitation of fast-spiking interneurons. Deeper in the cortex, neurons within the white matter (WM) were strongly depolarized by NT application. The colocalization of NT and tyrosine hydroxylase immunoreactivities in deep layer fibers throughout the cortical mantle indicates mediation via dopaminergic systems. These data suggest a cortical mechanism for NT-induced wakefulness and support a role for WM neurons in state control. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. De novo expression of the neurokinin 1 receptor in spinal lamina I pyramidal neurons in polyarthritis.

    PubMed

    Almarestani, L; Waters, S M; Krause, J E; Bennett, G J; Ribeiro-da-Silva, A

    2009-05-20

    Spinal lamina I (LI) neurons play a major role in the transmission and integration of pain-related information that is relayed to higher centers. Alterations in the excitability of these neurons influence chronic pain development, and expression of the neurokinin 1 receptor (NK-1r) is thought to play a major role in such changes. Novel expression of NK-1r may underlie hyperexcitability in new populations of LI neurons. LI projection neurons can be classified morphologically into fusiform, pyramidal, and multipolar cells, differing in their functional properties, with the pyramidal type being nonnociceptive. In agreement with this, we have shown that spinoparabrachial pyramidal neurons seldom express NK-1r, in contrast with the other two cell types. In this study we investigated in the rat the long-term changes in NK-1r expression by spinoparabrachial LI neurons following the unilateral injection in the hindpaw plantar surface of complete Freund's adjuvant (CFA). Cholera toxin subunit B (CTb) was injected unilaterally into the parabrachial nucleus. Our results revealed that, ipsilaterally, pyramidal neurons were seldom immunoreactive for NK-1r both in saline-injected and in CFA-injected rats, up to 10 days post-CFA. However, a considerable number of pyramidal cells were immunoreactive for NK-1r at 15, 21, and 30 days post-CFA. Our data raise the possibility -- which needs to be confirmed by electrophysiology -- that most LI projection neurons of the pyramidal type are likely nonnociceptive in naive animals but might become nociceptive following the development of arthritis.

  2. 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

  3. Decreased pyramidal neuron size in Brodmann areas 44 and 45 in patients with autism.

    PubMed

    Jacot-Descombes, Sarah; Uppal, Neha; Wicinski, Bridget; Santos, Micaela; Schmeidler, James; Giannakopoulos, Panteleimon; Heinsen, Helmut; Heinsein, Helmut; Schmitz, Christoph; Hof, Patrick R

    2012-07-01

    Autism is a neurodevelopmental disorder characterized by deficits in social interaction and social communication, as well as by the presence of repetitive and stereotyped behaviors and interests. Brodmann areas 44 and 45 in the inferior frontal cortex, which are involved in language processing, imitation function, and sociality processing networks, have been implicated in this complex disorder. Using a stereologic approach, this study aims to explore the presence of neuropathological differences in areas 44 and 45 in patients with autism compared to age- and hemisphere-matched controls. Based on previous evidence in the fusiform gyrus, we expected to find a decrease in the number and size of pyramidal neurons as well as an increase in volume of layers III, V, and VI in patients with autism. We observed significantly smaller pyramidal neurons in patients with autism compared to controls, although there was no difference in pyramidal neuron numbers or layer volumes. The reduced pyramidal neuron size suggests that a certain degree of dysfunction of areas 44 and 45 plays a role in the pathology of autism. Our results also support previous studies that have shown specific cellular neuropathology in autism with regionally specific reduction in neuron size, and provide further evidence for the possible involvement of the mirror neuron system, as well as impairment of neuronal networks relevant to communication and social behaviors, in this disorder.

  4. Kv2 channels regulate firing rate in pyramidal neurons from rat sensorimotor cortex

    PubMed Central

    Guan, Dongxu; Armstrong, William E; Foehring, Robert C

    2013-01-01

    The largest outward potassium current in the soma of neocortical pyramidal neurons is due to channels containing Kv2.1 α subunits. These channels have been implicated in cellular responses to seizures and ischaemia, mechanisms for intrinsic plasticity and cell death, and responsiveness to anaesthetic agents. Despite their abundance, knowledge of the function of these delayed rectifier channels has been limited by the lack of specific pharmacological agents. To test for functional roles of Kv2 channels in pyramidal cells from somatosensory or motor cortex of rats (layers 2/3 or 5), we transfected cortical neurons with DNA for a Kv2.1 pore mutant (Kv2.1W365C/Y380T: Kv2.1 DN) in an organotypic culture model to manipulate channel expression. Slices were obtained from rats at postnatal days (P7-P14) and maintained in organotypic culture. We used biolistic methods to transfect neurons with gold ‘bullets’ coated with DNA for the Kv2.1 DN and green fluorescent protein (GFP), GFP alone, or wild type (WT) Kv2.1 plus GFP. Cells that fluoresced green, contained a bullet and responded to positive or negative pressure from the recording pipette were considered to be transfected cells. In each slice, we recorded from a transfected cell and a control non-transfected cell from the same layer and area. Whole-cell voltage-clamp recordings obtained after 3–7 days in culture showed that cells transfected with the Kv2.1 DN had a significant reduction in outward current (∼45% decrease in the total current density measured 200 ms after onset of a voltage step from –78 to –2 mV). Transfection with GFP alone did not affect current amplitude and overexpression of the Kv2.1 WT resulted in greatly increased currents. Current-clamp experiments were used to assess the functional consequences of manipulation of Kv2.1 expression. The results suggest roles for Kv2 channels in controlling membrane potential during the interspike interval (ISI), firing rate, spike frequency adaptation

  5. Local connections of excitatory neurons in motor-associated cortical areas of the rat

    PubMed Central

    Kaneko, Takeshi

    2013-01-01

    In spite of recent progress in brain sciences, the local circuit of the cerebral neocortex, including motor areas, still remains elusive. Morphological works on excitatory cortical circuitry from thalamocortical (TC) afferents to corticospinal neurons (CSNs) in motor-associated areas are reviewed here. First, TC axons of motor thalamic nuclei have been re-examined by the single-neuron labeling method. There are middle layer (ML)-targeting and layer (L) 1-preferring TC axon types in motor-associated areas, being analogous to core and matrix types, respectively, of Jones (1998) in sensory areas. However, the arborization of core-like motor TC axons spreads widely and disregards the columnar structure that is the basis of information processing in sensory areas, suggesting that motor areas adopt a different information-processing framework such as area-wide laminar organization. Second, L5 CSNs receive local excitatory inputs not only from L2/3 pyramidal neurons but also from ML spiny neurons, the latter directly processing cerebellar information of core-like TC neurons (TCNs). In contrast, basal ganglia information is targeted to apical dendrites of L2/3 and L5 pyramidal neurons through matrix TCNs. Third, L6 corticothalamic neurons (CTNs) are most densely innervated by ML spiny neurons located just above CTNs. Since CTNs receive only weak connections from L2/3 and L5 pyramidal neurons, the TC recurrent circuit composed of TCNs, ML spiny neurons and CTNs appears relatively independent of the results of processing in L2/3 and L5. It is proposed that two circuits sharing the same TC projection and ML neurons are embedded in the neocortex: one includes L2/3 and L5 neurons, processes afferent information in a feedforward way and sends the processed information to other cortical areas and subcortical regions; and the other circuit participates in a dynamical system of the TC recurrent circuit and may serve as the basis of autonomous activity of the neocortex. PMID

  6. 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.

  7. Perineuronal Nets Suppress Plasticity of Excitatory Synapses on CA2 Pyramidal Neurons

    PubMed Central

    Carstens, Kelly E.; Phillips, Mary L.; Pozzo-Miller, Lucas; Weinberg, Richard J.

    2016-01-01

    Long-term potentiation of excitatory synapses on pyramidal neurons in the stratum radiatum rarely occurs in hippocampal area CA2. Here, we present evidence that perineuronal nets (PNNs), a specialized extracellular matrix typically localized around inhibitory neurons, also surround mouse CA2 pyramidal neurons and envelop their excitatory synapses. CA2 pyramidal neurons express mRNA transcripts for the major PNN component aggrecan, identifying these neurons as a novel source for PNNs in the hippocampus. We also found that disruption of PNNs allows synaptic potentiation of normally plasticity-resistant excitatory CA2 synapses; thus, PNNs play a role in restricting synaptic plasticity in area CA2. Finally, we found that postnatal development of PNNs on CA2 pyramidal neurons is modified by early-life enrichment, suggesting that the development of circuits containing CA2 excitatory synapses are sensitive to manipulations of the rearing environment. SIGNIFICANCE STATEMENT Perineuronal nets (PNNs) are thought to play a major role in restricting synaptic plasticity during postnatal development, and are altered in several models of neurodevelopmental disorders, such as schizophrenia and Rett syndrome. Although PNNs have been predominantly studied in association with inhibitory neurons throughout the brain, we describe a dense expression of PNNs around excitatory pyramidal neurons in hippocampal area CA2. We also provide insight into a previously unrecognized role for PNNs in restricting plasticity at excitatory synapses and raise the possibility of an early critical period of hippocampal plasticity that may ultimately reveal a key mechanism underlying learning and memory impairments of PNN-associated neurodevelopmental disorders. PMID:27277807

  8. Chemical interactions with pyramidal neurons in layer 5 of the cerebral cortex: control of pain and anxiety.

    PubMed

    Adams, J D

    2009-01-01

    Pyramidal neurons in layer 5 of the cerebral cortex are involved in learning and memory and have complex connections with other neurons through a very large array of dendrites. These dendrites can switch between long term depression and long term potentiation depending on global summation of various inputs. The plasticity of the input into pyramidal neurons makes the neuronal output variable. Many interneurons in the cerebral cortex and distant neurons in other brain regions are involved in providing input to pyramidal neurons. All of these neurons and interneurons have neurotransmitters that act through receptors to provide input to pyramidal neurons. Serotonin is one of the important neurotransmitters involved with pyramidal neurons and has been implicated in psychosis, psychedelic states and what are called sacred dreams. This review will discuss the various chemicals and receptors that are important with pyramidal neurons including opioids, nicotine, scopolamine, psilocybin, LSD, mescaline, ergot alkaloids, salvinorin A, ergine and other compounds that interact with opioid, nicotinic, muscarinic and serotonergic receptors. The natural compounds provide clues to structure activity relationships with the receptors. It has been postulated that each receptor in the body has a natural agonist and antagonist, in addition to the normal neurotransmitters. It is common for natural antagonists and agonists to be peptides. Various possible peptide structures will be proposed for natural antagonists and agonists at each receptor. Natural antagonists and agonists may provide new ways to explore the functions of pyramidal neurons in normal health and pain management.

  9. K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.

    PubMed

    Hoffman, D A; Magee, J C; Colbert, C M; Johnston, D

    1997-06-26

    Pyramidal neurons receive tens of thousands of synaptic inputs on their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. Surprisingly, there turns out to be a very high density of transient A-type potassium ion channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent initiation of an action potential in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce excitatory synaptic events. The channels act to prevent large, rapid dendritic depolarizations, thereby regulating orthograde and retrograde propagation of dendritic potentials.

  10. Burst generation in rat pyramidal neurones by regenerative potentials elicited in a restricted part of the basilar dendritic tree

    PubMed Central

    Milojkovic, Bogdan A; Radojicic, Mihailo S; Goldman-Rakic, Patricia S; Antic, Srdjan D

    2004-01-01

    The common preconception about central nervous system neurones is that thousands of small postsynaptic potentials sum across the entire dendritic tree to generate substantial firing rates, previously observed in in vivo experiments. We present evidence that local inputs confined to a single basal dendrite can profoundly influence the neuronal output of layer V pyramidal neurones in the rat prefrontal cortical slices. In our experiments, brief glutamatergic stimulation delivered in a restricted part of the basilar dendritic tree invariably produced sustained plateau depolarizations of the cell body, accompanied by bursts of action potentials. Because of their small diameters, basolateral dendrites are not routinely accessible for glass electrode measurements, and very little is known about their electrical properties and their role in information processing. Voltage-sensitive dye recordings were used to follow membrane potential transients in distal segments of basal branches during sub- and suprathreshold glutamate and synaptic stimulations. Recordings were obtained simultaneously from multiple dendrites and multiple points along individual dendrites, thus showing in a direct way how regenerative potentials initiate at the postsynaptic site and propagate decrementally toward the cell body. The glutamate-evoked dendritic plateau depolarizations described here are likely to occur in conjunction with strong excitatory drive during so-called ‘UP states’, previously observed in in vivo recordings from mammalian cortices. PMID:15155788

  11. Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury

    PubMed Central

    2009-01-01

    The anterior cingulate cortex (ACC) is important for cognitive and sensory functions including memory and chronic pain. Glutamatergic excitatory synaptic transmission undergo long-term potentiation in ACC pyramidal cells after peripheral injury. Less information is available for the possible long-term changes in neuronal action potentials or intrinsic properties. In the present study, we characterized cingulate pyramidal cells in the layer II/III of the ACC in adult mice. We then examined possible long-term changes in intrinsic properties of the ACC pyramidal cells after peripheral nerve injury. In the control mice, we found that there are three major types of pyramidal cells according to their action potential firing pattern: (i) regular spiking (RS) cells (24.7%), intrinsic bursting (IB) cells (30.9%), and intermediate (IM) cells (44.4%). In a state of neuropathic pain, the population distribution (RS: 21.3%; IB: 31.2%; IM: 47.5%) and the single action potential properties of these three groups were indistinguishable from those in control mice. However, for repetitive action potentials, IM cells from neuropathic pain animals showed higher initial firing frequency with no change for the properties of RS and IB neurons from neuropathic pain mice. The present results provide the first evidence that, in addition to synaptic potentiation reported previously, peripheral nerve injury produces long-term plastic changes in the action potentials of cingulate pyramidal neurons in a cell type-specific manner. PMID:20015370

  12. Repeated administration of a synthetic cannabinoid receptor agonist differentially affects cortical and accumbal neuronal morphology in adolescent and adult rats

    PubMed Central

    Carvalho, A. F.; Reyes, B. A. S.; Ramalhosa, F.; Sousa, N.

    2014-01-01

    Recent studies demonstrate a differential trajectory for cannabinoid receptor expression in cortical and sub-cortical brain areas across postnatal development. In the present study, we sought to investigate whether chronic systemic exposure to a synthetic cannabinoid receptor agonist causes morphological changes in the structure of dendrites and dendritic spines in adolescent and adult pyramidal neurons in the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) in the nucleus accumbens (Acb). Following systemic administration of WIN 55,212-2 in adolescent (PN 37–40) and adult (P55–60) male rats, the neuronal architecture of pyramidal neurons and MSN was assessed using Golgi–Cox staining. While no structural changes were observed in WIN 55,212-2-treated adolescent subjects compared to control, exposure to WIN 55,212-2 significantly increased dendritic length, spine density and the number of dendritic branches in pyramidal neurons in the mPFC of adult subjects when compared to control and adolescent subjects. In the Acb, WIN 55,212-2 exposure significantly decreased dendritic length and number of branches in adult rat subjects while no changes were observed in the adolescent groups. In contrast, spine density was significantly decreased in both the adult and adolescent groups in the Acb. To determine whether regional developmental morphological changes translated into behavioral differences, WIN 55,212-2-induced aversion was evaluated in both groups using a conditioned place preference paradigm. In adult rats, WIN 55,212-2 administration readily induced conditioned place aversion as previously described. In contrast, adolescent rats did not exhibit aversion following WIN 55,212-2 exposure in the behavioral paradigm. The present results show that synthetic cannabinoid administration differentially impacts cortical and sub-cortical neuronal morphology in adult compared to adolescent subjects. Such differences may underlie the disparate development

  13. Antibiotic Supplements Affect Electrophysiological Properties and Excitability of Rat Hippocampal Pyramidal Neurons in Primary Culture

    PubMed Central

    Bahrami, Farideh; Janahmadi, Mahyar

    2013-01-01

    Introduction: Antibiotic supplements are regularly used in neuronal culture media to control contamination; however, they can interfere with the neuronal excitability and affect electrophysiological properties. Therefore, in this study, the effect of penicillin/streptomycin supplements on the spontaneous electrophysiological activity of hippocampal pyramidal neurons was examined. Methods: Electrophysiological whole-cell patch-clamp recordings from rat hippocampal pyramidal cells in primary culture were performed to investigate the effects of antibiotic supplements on the intrinsic excitability of cultured cells. Results: The present findings indicated that presence of antibiotic supplements (penicillin/streptomycin) in the culture medium altered the intrinsic electrical activity of hippocampal pyramidal neurons in primary culture. These alterations included: 1) depolarized resting membrane potential; 2) a significant enhancement in the after-hyperpolarization amplitude; 3) a significant increase in the area under the action potential and in the decay and rise time of the action potential; 4) a significant broadening of action potential and 5) a significant reduction in the firing frequency. Conclusion: These findings suggest that addition of antibiotic supplements to culture media influences the neuronal excitability and alters the electrophysiological properties of cultured neurons, possibly through changing the ionic conductance underlying neuronal excitability. PMID:23567852

  14. 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

  15. 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

  16. 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.

  17. 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

  18. Voltage-gated ion channels in dendrites of hippocampal pyramidal neurons.

    PubMed

    Chen, Xixi; Johnston, Daniel

    2006-12-01

    The properties and distribution of voltage-gated ion channels contribute to electrical signaling in neuronal dendrites. The apical dendrites of CA1 pyramidal neurons in hippocampus express a wide variety of sodium, calcium, potassium, and other voltage-gated channels. In this report, we provide some new evidence for the role of the delayed-rectifier K(+) channel in shaping the dendritic action potential at different membrane potentials.

  19. Spike Phase Locking in CA1 Pyramidal Neurons depends on Background Conductance and Firing Rate

    PubMed Central

    Broiche, Tilman; Malerba, Paola; Dorval, Alan D.; Borisyuk, Alla; Fernandez, Fernando R.; White, John A.

    2012-01-01

    Oscillatory activity in neuronal networks correlates with different behavioral states throughout the nervous system, and the frequency-response characteristics of individual neurons are believed to be critical for network oscillations. Recent in vivo studies suggest that neurons experience periods of high membrane conductance, and that action potentials are often driven by membrane-potential fluctuations in the living animal. To investigate the frequency-response characteristics of CA1 pyramidal neurons in the presence of high conductance and voltage fluctuations, we performed dynamic-clamp experiments in rat hippocampal brain slices. We drove neurons with noisy stimuli that included a sinusoidal component ranging, in different trials, from 0.1 to 500 Hz. In subsequent data analysis, we determined action potential phase-locking profiles with respect to background conductance, average firing rate, and frequency of the sinusoidal component. We found that background conductance and firing rate qualitatively change the phase-locking profiles of CA1 pyramidal neurons vs. frequency. In particular, higher average spiking rates promoted band-pass profiles, and the high-conductance state promoted phase-locking at frequencies well above what would be predicted from changes in the membrane time constant. Mechanistically, spike-rate adaptation and frequency resonance in the spike-generating mechanism are implicated in shaping the different phase-locking profiles. Our results demonstrate that CA1 pyramidal cells can actively change their synchronization properties in response to global changes in activity associated with different behavioral states. PMID:23055508

  20. 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

  1. Conditioning of cortical neurons in cats with antidromic activation as the unconditioned stimulus.

    PubMed

    O'Brien, J H; Wilder, M B; Stevens, C D

    1977-08-01

    Single-cell activity was recorded from the postcruciate cortex of acutely prepared cats during a differential classical conditioning procedure. The conditioned stimuli (CS) were hind paw stimuli, and the unconditioned stimulus (US) was pyramidal tract stimulation that produced an antidromic response in the recorded cortical neuron. A control group was also examined in which the pyramidal stimulus was set below the threshold to produce an antidromic response. Clear differential conditioning was found for the experimental group, with antidromic activation of the neuron as the US. There was no evidence of differential conditioning in the control group without antidromic activation. Any activation of orthodromic pathways should have been the same in the control and experimental groups. The absence of conditioning in the control group demonstrated that orthodromic pathways were not contributing to the differential conditioning observed in the experimental group. This indicates that it was activation of the neuron produced by antidromic firing which was important for conditioning. All the evidence suggests that the site of learning was in the cortex. It is concluded that the the role of the US in conditioning may be simply to activate the neuron at an appropriate interval following the CS.

  2. Hyaluronan synthesis by developing cortical neurons in vitro

    PubMed Central

    Fowke, Tania M.; Karunasinghe, Rashika N.; Bai, Ji-Zhong; Jordan, Shawn; Gunn, Alistair J.; Dean, Justin M.

    2017-01-01

    Hyaluronan is a linear glycosaminoglycan that forms the backbone of perineuronal nets around neurons in the cerebral cortex. However, it remains controversial whether neurons are capable of independent hyaluronan synthesis. Herein, we examined the expression of hyaluronan and hyaluronan synthases (HASs) throughout cortical neuron development in vitro. Enriched cultures of cortical neurons were established from E16 rats. Neurons were collected at days in vitro (DIV) 0 (4 h), 1, 3, 7, 14, and 21 for qPCR or immunocytochemistry. In the relative absence of glia, neurons exhibited HAS1–3 mRNA at all time-points. By immunocytochemistry, puncta of HAS2–3 protein and hyaluronan were located on neuronal cell bodies, neurites, and lamellipodia/growth cones from as early as 4 h in culture. As neurons matured, hyaluronan was also detected on dendrites, filopodia, and axons, and around synapses. Percentages of hyaluronan-positive neurons increased with culture time to ~93% by DIV21, while only half of neurons at DIV21 expressed the perineuronal net marker Wisteria floribunda agglutinin. These data clearly demonstrate that neurons in vitro can independently synthesise hyaluronan throughout all maturational stages, and that hyaluronan production is not limited to neurons expressing perineuronal nets. The specific structural localisation of hyaluronan suggests potential roles in neuronal development and function. PMID:28287145

  3. Accelerated dendritic development of rat cortical pyramidal cells and interneurons after biolistic transfection with BDNF and NT4/5.

    PubMed

    Wirth, Marcus J; Brun, Annika; Grabert, Jochen; Patz, Silke; Wahle, Petra

    2003-12-01

    Neurotrophins are candidate molecules for regulating dendritogenesis. We report here on dendritic growth of rat visual cortex pyramidal and interneurons overexpressing 'brain-derived neurotrophic factor' BDNF and 'neurotrophin 4/5' NT4/5. Neurons in organotypic cultures were transfected with plasmids encoding either 'enhanced green fluorescent protein' EGFP, BDNF/EGFP or NT4/5/EGFP either at the day of birth with analysis at 5 days in vitro, or at 5 days in vitro with analysis at 10 days in vitro. In pyramidal neurons, both TrkB ligands increased dendritic length and number of segments without affecting maximum branch order and number of primary dendrites. In the early time window, only infragranular neurons were responsive. Neurons in layers II/III became responsive to NT4/5, but not BDNF, during the later time window. BDNF and NT4/5 transfectants at 10 days in vitro had still significantly shorter dendrites than adult pyramidal neurons, suggesting a massive growth spurt after 10 days in vitro. However, segment numbers were already in the range of adult neurons. Although this suggested a role for BDNF, long-term activity-deprived, and thus BDNF-deprived, pyramidal cells developed a dendritic complexity not different from neurons in active cultures except for higher spine densities on neurons of layers II/III and VI. Neutralization of endogenous NT4/5 causes shorter and less branched dendrites at 10 days in vitro suggesting an essential role for NT4/5. Neutralization of BDNF had no effect. Transfected multipolar interneurons became identifiable during the second time window. Both TrkB ligands significantly increased number of segments and branch order towards the adult state with little effects on dendritic length. The results suggested that early in development BDNF and NT4/5 probably accelerate dendritogenesis in an autocrine fashion. In particular, branch formation was advanced towards the adult pattern in pyramidal cells and interneurons.

  4. Experimentally guided modelling of dendritic excitability in rat neocortical pyramidal neurones

    PubMed Central

    Keren, Naomi; Bar-Yehuda, Dan; Korngreen, Alon

    2009-01-01

    Constructing physiologically relevant compartmental models of neurones is critical for understanding neuronal activity and function. We recently suggested that measurements from multiple locations along the soma, dendrites and axon are necessary as a data set when using a genetic optimization algorithm to constrain the parameters of a compartmental model of an entire neurone. However, recordings from L5 pyramidal neurones can routinely be performed simultaneously from only two locations. Now we show that a data set recorded from the soma and apical dendrite combined with a parameter peeling procedure is sufficient to constrain a compartmental model for the apical dendrite of L5 pyramidal neurones. The peeling procedure was tested on several compartmental models showing that it avoids local minima in parameter space. Based on the requirements of this analysis procedure, we designed and performed simultaneous whole-cell recordings from the soma and apical dendrite of rat L5 pyramidal neurones. The data set obtained from these recordings allowed constraining a simplified compartmental model for the apical dendrite of L5 pyramidal neurones containing four voltage-gated conductances. In agreement with experimental findings, the optimized model predicts that the conductance density gradients of voltage-gated K+ conductances taper rapidly proximal to the soma, while the density gradient of the voltage-gated Na+ conductance tapers slowly along the apical dendrite. The model reproduced the back-propagation of the action potential and the modulation of the resting membrane potential along the apical dendrite. Furthermore, the optimized model provided a mechanistic explanation for the back-propagation of the action potential into the apical dendrite and the generation of dendritic Na+ spikes. PMID:19171651

  5. Expression of 5-HT2A receptors in prefrontal cortex pyramidal neurons projecting to nucleus accumbens. Potential relevance for atypical antipsychotic action.

    PubMed

    Mocci, Giuseppe; Jiménez-Sánchez, Laura; Adell, Albert; Cortés, Roser; Artigas, Francesc

    2014-04-01

    The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotic drugs modulate information processing in cortico-limbic circuits via dopamine D2 receptor blockade in nucleus accumbens (NAc) whereas atypical antipsychotic drugs preferentially target cortical serotonin (5-HT) receptors. The brain networks involved in the therapeutic action of atypical drugs are not fully understood. Previous work indicated that medial PFC (mPFC) pyramidal neurons projecting to ventral tegmental area express 5-HT2A receptors suggesting that atypical antipsychotic drugs modulate dopaminergic activity distally, via 5-HT2A receptor (5-HT2A-R) blockade in PFC. Since the mPFC also projects heavily to NAc, we examined whether NAc-projecting pyramidal neurons also express 5-HT2A-R. Using a combination of retrograde tracing experiments and in situ hybridization we report that a substantial proportion of mPFC-NAc pyramidal neurons in rat brain express 5-HT2A-R mRNA in a layer- and area-specific manner (up to 68% in layer V of contralateral cingulate). The functional relevance of 5-HT2A-R to modulate mPFC-NAc projections was examined in dual-probe microdialysis experiments. The application of the preferential 5-HT2A-R agonist DOI into mPFC enhanced glutamate release locally (+66 ± 18%) and in NAc (+74 ± 12%) indicating that cortical 5-HT2A-R activation augments glutamatergic transmission in NAc. Since NAc integrates glutamatergic and dopaminergic inputs, blockade of 5-HT2A-R by atypical drugs may reduce cortical excitatory inputs onto GABAergic neurons of NAc, adding to dopamine D2 receptor blockade. Together with previous observations, the present results suggest that atypical antipsychotic drugs may control the activity of the mesolimbic pathway at cell body and terminal level.

  6. 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.

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

    PubMed

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

    2016-04-07

    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.

  8. 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.

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

    PubMed Central

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

    2009-01-01

    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. PMID:19491244

  10. Layer 4 pyramidal neurons exhibit robust dendritic spine plasticity in vivo after input deprivation.

    PubMed

    Miquelajauregui, Amaya; Kribakaran, Sahana; Mostany, Ricardo; Badaloni, Aurora; Consalez, G Giacomo; Portera-Cailliau, Carlos

    2015-05-06

    Pyramidal neurons in layers 2/3 and 5 of primary somatosensory cortex (S1) exhibit somewhat modest synaptic plasticity after whisker input deprivation. Whether neurons involved at earlier steps of sensory processing show more or less plasticity has not yet been examined. Here, we used longitudinal in vivo two-photon microscopy to investigate dendritic spine dynamics in apical tufts of GFP-expressing layer 4 (L4) pyramidal neurons of the vibrissal (barrel) S1 after unilateral whisker trimming. First, we characterize the molecular, anatomical, and electrophysiological properties of identified L4 neurons in Ebf2-Cre transgenic mice. Next, we show that input deprivation results in a substantial (∼50%) increase in the rate of dendritic spine loss, acutely (4-8 d) after whisker trimming. This robust synaptic plasticity in L4 suggests that primary thalamic recipient pyramidal neurons in S1 may be particularly sensitive to changes in sensory experience. Ebf2-Cre mice thus provide a useful tool for future assessment of initial steps of sensory processing in S1.

  11. 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.

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

    PubMed

    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; Brown, Ritchie E; McCarley, Robert W

    2015-03-17

    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.

  13. Active Percolation Analysis of Pyramidal Neurons of Somatosensory Cortex:

    NASA Astrophysics Data System (ADS)

    Costa, Luciano Da Fontoura; Barbosa, Marconi Soares; Schierwagen, Andreas; Alpár, Alán; Gärtner, Ulrich; Arendt, Thomas

    This article describes the investigation of morphological variations among two sets of neuronal cells, namely a control group of wild type mouse cells and a group of cells of a transgenic line. Special attention is given to singular points in the neuronal structure, namely the branching points and extremities of the dendritic processes. The characterization of the spatial distribution of such points is obtained by using a recently reported morphological technique based on forced percolation and window-size compensation, which is particularly suited to the analysis of scattered points, presenting several coexisting densities. Different dispersions were identified in our statistical analysis, suggesting that the transgenic line of neurons is characterized by a more pronounced morphological variation. A classification scheme based on a canonical discriminant function was also considered in order to identify the morphological differences.

  14. Grid-layout and theta-modulation of layer 2 pyramidal neurons in medial entorhinal cortex.

    PubMed

    Ray, Saikat; Naumann, Robert; Burgalossi, Andrea; Tang, Qiusong; Schmidt, Helene; Brecht, Michael

    2014-02-21

    Little is known about how microcircuits are organized in layer 2 of the medial entorhinal cortex. We visualized principal cell microcircuits and determined cellular theta-rhythmicity in freely moving rats. Non-dentate-projecting, calbindin-positive pyramidal cells bundled dendrites together and formed patches arranged in a hexagonal grid aligned to layer 1 axons, parasubiculum, and cholinergic inputs. Calbindin-negative, dentate-gyrus-projecting stellate cells were distributed across layer 2 but avoided centers of calbindin-positive patches. Cholinergic drive sustained theta-rhythmicity, which was twofold stronger in pyramidal than in stellate neurons. Theta-rhythmicity was cell-type-specific but not distributed as expected from cell-intrinsic properties. Layer 2 divides into a weakly theta-locked stellate cell lattice and spatiotemporally highly organized pyramidal grid. It needs to be assessed how these two distinct principal cell networks contribute to grid cell activity.

  15. Axonal shearing in mature cortical neurons induces attempted regeneration and the reestablishment of neurite polarity.

    PubMed

    Blizzard, Catherine A; King, Anna E; Haas, Matilda A; O'Toole, David A; Vickers, James C; Dickson, Tracey C

    2009-12-01

    While functional recovery after injury is limited, it has become evident that the mature central nervous system does retain some ability to regenerate. This study investigated the intrinsic capacity of relatively mature cortical neurons (21 days in vitro) to respond to axonal loss. Neurons, growing as clusters on poly-L-lysine, were completely sheared of axons through chemical and mechanical disruption and transferred to either an intact astrocyte monolayer or a substrate of poly-L-lysine. Injured neurons exhibited a regenerative sprouting response that was independent of neuronal cell division or neural progenitors, as demonstrated by negative bromodeoxyuridine (BrdU) and the neuronal precursor intermediate filament nestin, labeling. At 24 h after injury, neurons had extended appropriately polarized neurites, demonstrated by compartmentalized microtubule-associated proteins MAP2 and tau immunolabeling. Newly sprouting axons were tipped by growth cones; however, growth cones on the tips of sprouting axons (mean area, 26.32 +/- 2.20 microm) were significantly (p<0.05) smaller than their developmental counterparts (mean area, 48.64 +/- 5.9 microm), independent of substrate. Furthermore, live imaging indicated that regenerating neurons exhibited distinct axonal dynamics, with a significant (p<0.05) reduction (70%) in pausing, considered vital for interstitial branching and pathfinding, relative to developmental growth cones. This study indicates that mature cultured cortical pyramidal and interneurons have the intrinsic potential to survive, extend processes, and reestablish neurite polarity following significant physical damage. These results may aid in defining the cellular basis of neuronal structural plasticity and defining the role of astrocyte reactivity in the response to trauma.

  16. In vivo multi-photon nanosurgery on cortical neurons: focusing on network organization

    NASA Astrophysics Data System (ADS)

    Sacconi, L.; O'Connor, R. P.; Jasaitis, A.; Masi, A.; Buffelli, M.; Pavone, F. S.

    2008-02-01

    Two-photon microscopy has been used to perform high spatial resolution imaging of spine plasticity in the intact neocortex of living mice. Multi-photon absorption has also been used as a tool for the selective disruption of cellular structures in living cells and simple organisms. In this work we exploit the spatial localization of multi-photon excitation to perform selective lesions on the neuronal processes of cortical neurons in living mice expressing fluorescent proteins. This methodology was applied to dissect single dendrites with sub-micrometric precision without causing any visible collateral damage to the surrounding neuronal structures. The spatial precision of this method was demonstrated by ablating individual dendritic spines, while sparing the adjacent spines and the structural integrity of the dendrite. The morphological consequences were then characterized with time lapse 3D two-photon imaging over a period of minutes to days after the procedure. Here we present the results of our systematic study of the morphological response of cortical pyramidal neurons to nanosurgical perturbations. Dendritic branches were followed after transecting distal segments, whilst the plasticity and remodeling of individual dendritic spines on a given branch was also followed after removing of a subset of spines.

  17. Transient Enhancement of Inhibitory Synaptic Transmission in Hippocampal CA1 Pyramidal Neurons after Cerebral Ischemia

    PubMed Central

    Liang, Rui; Pang, Zhi-Ping; Deng, Ping; Xu, Zao C.

    2009-01-01

    Pyramidal neurons in hippocampal CA1 regions are highly sensitive to cerebral ischemia. Alterations of excitatory and inhibitory synaptic transmission may contribute to the ischemia-induced neuronal degeneration. However, little is known about the changes of GABAergic synaptic transmission in the hippocampus following reperfusion. We examined the GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal neurons 12 hours and 24 hours after transient forebrain ischemia. The amplitudes of evoked IPSCs (eIPSCs) were increased significantly 12 hours after ischemia and returned to control levels 24 hours following reperfusion. The potentiation of eIPSCs was accompanied by an increase of miniature IPSCs (mIPSCs) amplitude, and an enhanced response to exogenous application of GABA, indicating the involvement of postsynaptic mechanisms. Furthermore, there was no obvious change of the paired-pulse ratio (PPR) of eIPSCs and the frequency of mIPSCs, suggesting that the potentiation of eIPSCs might not be due to the increased presynaptic release. Blockade of adenosine A1 receptors led to a decrease of eIPSCs amplitude in post-ischemic neurons but not in control neurons, without affecting the frequency of mIPSCs and the PPR of eIPSCs. Thus, tonic activation of adenosine A1 receptors might, at least in part, contribute to the enhancement of inhibitory synaptic transmission in CA1 neurons after forebrain ischemia. The transient enhancement of inhibitory neurotransmission might temporarily protect CA1 pyramidal neurons, and delay the process of neuronal death after cerebral ischemia. PMID:19258028

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

    PubMed Central

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

    2007-01-01

    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 ∼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 ∼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. PMID:17379638

  19. A distinct class of slow (~0.2-2 Hz) intrinsically bursting layer 5 pyramidal neurons determines UP/DOWN state dynamics in the neocortex.

    PubMed

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

    2015-04-08

    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 Ca(2+) 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.

  20. Thalamocortical input onto layer 5 pyramidal neurons measured using quantitative large-scale array tomography

    PubMed Central

    Rah, Jong-Cheol; Bas, Erhan; Colonell, Jennifer; Mishchenko, Yuriy; Karsh, Bill; Fetter, Richard D.; Myers, Eugene W.; Chklovskii, Dmitri B.; Svoboda, Karel; Harris, Timothy D.; Isaac, John T. R.

    2013-01-01

    The subcellular locations of synapses on pyramidal neurons strongly influences dendritic integration and synaptic plasticity. Despite this, there is little quantitative data on spatial distributions of specific types of synaptic input. Here we use array tomography (AT), a high-resolution optical microscopy method, to examine thalamocortical (TC) input onto layer 5 pyramidal neurons. We first verified the ability of AT to identify synapses using parallel electron microscopic analysis of TC synapses in layer 4. We then use large-scale array tomography (LSAT) to measure TC synapse distribution on L5 pyramidal neurons in a 1.00 × 0.83 × 0.21 mm3 volume of mouse somatosensory cortex. We found that TC synapses primarily target basal dendrites in layer 5, but also make a considerable input to proximal apical dendrites in L4, consistent with previous work. Our analysis further suggests that TC inputs are biased toward certain branches and, within branches, synapses show significant clustering with an excess of TC synapse nearest neighbors within 5–15 μm compared to a random distribution. Thus, we show that AT is a sensitive and quantitative method to map specific types of synaptic input on the dendrites of entire neurons. We anticipate that this technique will be of wide utility for mapping functionally-relevant anatomical connectivity in neural circuits. PMID:24273494

  1. Layer-specific optogenetic activation of pyramidal neurons causes beta–gamma entrainment of neonatal networks

    PubMed Central

    Bitzenhofer, Sebastian H; Ahlbeck, Joachim; Wolff, Amy; Wiegert, J. Simon; Gee, Christine E.; Oertner, Thomas G.; Hanganu-Opatz, Ileana L.

    2017-01-01

    Coordinated activity patterns in the developing brain may contribute to the wiring of neuronal circuits underlying future behavioural requirements. However, causal evidence for this hypothesis has been difficult to obtain owing to the absence of tools for selective manipulation of oscillations during early development. We established a protocol that combines optogenetics with electrophysiological recordings from neonatal mice in vivo to elucidate the substrate of early network oscillations in the prefrontal cortex. We show that light-induced activation of layer II/III pyramidal neurons that are transfected by in utero electroporation with a high-efficiency channelrhodopsin drives frequency-specific spiking and boosts network oscillations within beta–gamma frequency range. By contrast, activation of layer V/VI pyramidal neurons causes nonspecific network activation. Thus, entrainment of neonatal prefrontal networks in fast rhythms relies on the activation of layer II/III pyramidal neurons. This approach used here may be useful for further interrogation of developing circuits, and their behavioural readout. PMID:28216627

  2. Active Summation of Excitatory Postsynaptic Potentials in Hippocampal CA3 Pyramidal Neurons

    NASA Astrophysics Data System (ADS)

    Urban, Nathaniel N.; Barrionuevo, German

    1998-09-01

    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.

  3. Stereological study of pyramidal neurons in the human superior temporal gyrus from childhood to adulthood

    PubMed Central

    Barger, Nicole; Sheley, Matthew F.; Schumann, Cynthia M.

    2014-01-01

    The association cortex of the superior temporal gyrus (STG) is implicated in complex social and linguistic functions. As such, reliable methods for quantifying cellular variation in this region could greatly benefit researchers interested in addressing the cellular correlates of typical and atypical function associated with these critical cognitive abilities. To facilitate this task, we first present a general set of cytoarchitectonic criteria targeted specifically toward stereological analyses of thick, Nissl stained sections for the homotypical cortex of the STG, referred to, here, as BA22/TA. Secondly, we use the optical fractionator to estimate pyramidal neuron number and the nucleator for pyramidal somal and nuclear volume to investigate the influence of age and sex on these parameters and to set a typically developing baseline for future comparisons. In 11 typically developing cases aged 4-48 years, the most distinguishing features of BA22/TA were the presence of distinct granular layers, a prominent, jagged layer IIIc, and a distinctly staining VIa. The average number of neurons was 91 ± 15 million, volume of pyramidal soma, 1,512 μm3, and nuclear volume, 348 μm3. We found no correlation with age and neuron number. In contrast, pyramidal somal and nuclear volume were both negatively correlated and linearly associated with age in regression analyses. We found no significant sex differences. Overall, the data support the idea that postnatal neuron numbers are relatively stable through development but also suggest that neuronal volume may be subject to important developmental variation. Both measures are critical variables in the study of developmental neuropathology. PMID:25556320

  4. Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder

    PubMed Central

    Arion, Dominique; Corradi, John P.; Tang, Shaowu; Datta, Dibyadeep; Boothe, Franklyn; He, Aiqing; Cacace, Angela M.; Zaczek, Robert; Albright, Charles F.; Tseng, George; Lewis, David A.

    2014-01-01

    Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3, and to a lesser extent in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression specifically in DLPFC layer 3 or 5 pyramidal cells would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by qPCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly down-regulated in the patient group (p values for MT-related and UPS-related pathways were <10−7 and <10−5 respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell-specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects, were not present or present to a lesser degree in the schizoaffective disorder subjects

  5. Reduced Synaptic Vesicle Recycling during Hypoxia in Cultured Cortical Neurons

    PubMed Central

    Fedorovich, Sergei; Hofmeijer, Jeannette; van Putten, Michel J. A. M.; le Feber, Joost

    2017-01-01

    Improvement of neuronal recovery in the ischemic penumbra, an area around the core of a brain infarct with some remaining perfusion, has a large potential for the development of therapy against acute ischemic stroke. However, mechanisms that lead to either recovery or secondary damage in the penumbra largely remain unclear. Recent studies in cultured networks of cortical neurons showed that failure of synaptic transmission (referred to as synaptic failure) is a critical factor in the penumbral area, but the mechanisms that lead to synaptic failure are still under investigation. Here we used a Styryl dye, FM1-43, to quantify endocytosis and exocytosis in cultures of rat cortical neurons under normoxic and hypoxic conditions. Hypoxia in cultured cortical networks rapidly depressed endocytosis and, to a lesser extent, exocytosis. These findings support electrophysiological findings that synaptic failure occurs quickly after the induction of hypoxia, and confirms that the failing processes are at least in part presynaptic. PMID:28261063

  6. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus.

    PubMed

    Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel

    2012-11-15

    The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; 7 mV) and higher input resistance (R(in); 46 M measured from RMP) observed in VHC neurones. These differences in RMP and R(in) were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic R(in) of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability.

  7. Intrinsic excitability of CA1 pyramidal neurones from the rat dorsal and ventral hippocampus

    PubMed Central

    Dougherty, Kelly A; Islam, Tasnim; Johnston, Daniel

    2012-01-01

    The hippocampus has a central role in learning and memory. Although once considered a relatively homogenous structure along the longitudinal axis, it has become clear that the rodent hippocampus can be anatomically and functionally divided into a dorsal component generally associated with spatial navigation, and a ventral component primarily associated with non-spatial functions that involve an emotional component. The ventral hippocampus (VHC) is also more sensitive to epileptogenic stimuli than the dorsal hippocampus (DHC), and seizures tend to originate in the VHC before spreading to other brain regions. Although synaptic and biochemical differences in DHC and VHC have been investigated, the intrinsic excitability of individual neurones from the DHC and VHC has received surprisingly little attention. In this study, we have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurones from the DHC and the VHC using the whole-cell current-clamp method. Our results demonstrate that somatic current injections of equal magnitude elicit significantly more action potentials in VHC neurones than DHC neurones, and that this difference stems from the more depolarized resting membrane potential (RMP; Δ7 mV) and higher input resistance (Rin; Δ46 MΩ measured from RMP) observed in VHC neurones. These differences in RMP and Rin were also observed in dendritic whole-cell current-clamp recordings. Furthermore, morphological reconstructions of individual neurones revealed significant differences in the dendritic branching pattern between DHC and VHC neurones that could, in principle, contribute to the lower somatic Rin of DHC neurones. Together, our results highlight significant differences in the intrinsic electrophysiological properties of CA1 pyramidal neurones across the longitudinal hippocampal axis, and suggest that VHC neurones are intrinsically more excitable than DHC neurones. This difference is likely to predispose the VHC to hyperexcitability

  8. Unique features of action potential initiation in cortical neurons.

    PubMed

    Naundorf, Björn; Wolf, Fred; Volgushev, Maxim

    2006-04-20

    Neurons process and encode information by generating sequences of action potentials. For all spiking neurons, the encoding of single-neuron computations into sequences of spikes is biophysically determined by the cell's action-potential-generating mechanism. It has recently been discovered that apparently minor modifications of this mechanism can qualitatively change the nature of neuronal encoding. Here we quantitatively analyse the dynamics of action potential initiation in cortical neurons in vivo, in vitro and in computational models. Unexpectedly, key features of the initiation dynamics of cortical neuron action potentials--their rapid initiation and variable onset potential--are outside the range of behaviours described by the classical Hodgkin-Huxley theory. We propose a new model based on the cooperative activation of sodium channels that reproduces the observed dynamics of action potential initiation. This new model predicts that Hodgkin-Huxley-type dynamics of action potential initiation can be induced by artificially decreasing the effective density of sodium channels. In vitro experiments confirm this prediction, supporting the hypothesis that cooperative sodium channel activation underlies the dynamics of action potential initiation in cortical neurons.

  9. 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.

  10. 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

  11. Morphology of Pyramidal Neurons in the Rat Prefrontal Cortex: Lateralized Dendritic Remodeling by Chronic Stress

    PubMed Central

    Perez-Cruz, Claudia; Müller-Keuker, Jeanine I. H.; Heilbronner, Urs; Fuchs, Eberhard; Flügge, Gabriele

    2007-01-01

    The prefrontal cortex (PFC) plays an important role in the stress response. We filled pyramidal neurons in PFC layer III with neurobiotin and analyzed dendrites in rats submitted to chronic restraint stress and in controls. In the right prelimbic cortex (PL) of controls, apical and distal dendrites were longer than in the left PL. Stress reduced the total length of apical dendrites in right PL and abolished the hemispheric difference. In right infralimbic cortex (IL) of controls, proximal apical dendrites were longer than in left IL, and stress eliminated this hemispheric difference. No hemispheric difference was detected in anterior cingulate cortex (ACx) of controls, but stress reduced apical dendritic length in left ACx. These data demonstrate interhemispheric differences in the morphology of pyramidal neurons in PL and IL of control rats and selective effects of stress on the right hemisphere. In contrast, stress reduced dendritic length in the left ACx. PMID:18253468

  12. Cortical neurons gradually attain a post-mitotic state

    PubMed Central

    Anda, Froylan Calderon de; Madabhushi, Ram; Rei, Damien; Meng, Jia; Gräff, Johannes; Durak, Omer; Meletis, Konstantinos; Richter, Melanie; Schwanke, Birgit; Mungenast, Alison; Tsai, Li-Huei

    2016-01-01

    Once generated, neurons are thought to permanently exit the cell cycle and become irreversibly differentiated. However, neither the precise point at which this post-mitotic state is attained nor the extent of its irreversibility is clearly defined. Here we report that newly born neurons from the upper layers of the mouse cortex, despite initiating axon and dendrite elongation, continue to drive gene expression from the neural progenitor tubulin α1 promoter (Tα1p). These observations suggest an ambiguous post-mitotic neuronal state. Whole transcriptome analysis of sorted upper cortical neurons further revealed that neurons continue to express genes related to cell cycle progression long after mitotic exit until at least post-natal day 3 (P3). These genes are however down-regulated thereafter, associated with a concomitant up-regulation of tumor suppressors at P5. Interestingly, newly born neurons located in the cortical plate (CP) at embryonic day 18-19 (E18-E19) and P3 challenged with calcium influx are found in S/G2/M phases of the cell cycle, and still able to undergo division at E18-E19 but not at P3. At P5 however, calcium influx becomes neurotoxic and leads instead to neuronal loss. Our data delineate an unexpected flexibility of cell cycle control in early born neurons, and describe how neurons transit to a post-mitotic state. PMID:27325298

  13. Cortical neurons gradually attain a post-mitotic state.

    PubMed

    Anda, Froylan Calderon de; Madabhushi, Ram; Rei, Damien; Meng, Jia; Gräff, Johannes; Durak, Omer; Meletis, Konstantinos; Richter, Melanie; Schwanke, Birgit; Mungenast, Alison; Tsai, Li-Huei

    2016-09-01

    Once generated, neurons are thought to permanently exit the cell cycle and become irreversibly differentiated. However, neither the precise point at which this post-mitotic state is attained nor the extent of its irreversibility is clearly defined. Here we report that newly born neurons from the upper layers of the mouse cortex, despite initiating axon and dendrite elongation, continue to drive gene expression from the neural progenitor tubulin α1 promoter (Tα1p). These observations suggest an ambiguous post-mitotic neuronal state. Whole transcriptome analysis of sorted upper cortical neurons further revealed that neurons continue to express genes related to cell cycle progression long after mitotic exit until at least post-natal day 3 (P3). These genes are however down-regulated thereafter, associated with a concomitant up-regulation of tumor suppressors at P5. Interestingly, newly born neurons located in the cortical plate (CP) at embryonic day 18-19 (E18-E19) and P3 challenged with calcium influx are found in S/G2/M phases of the cell cycle, and still able to undergo division at E18-E19 but not at P3. At P5 however, calcium influx becomes neurotoxic and leads instead to neuronal loss. Our data delineate an unexpected flexibility of cell cycle control in early born neurons, and describe how neurons transit to a post-mitotic state.

  14. Neurodevelopmental Role for VGLUT2 in Pyramidal Neuron Plasticity, Dendritic Refinement, and in Spatial Learning

    PubMed Central

    He, Hongbo; Mahnke, Amanda H.; Doyle, Sukhjeevan; Fan, Ni; Wang, Chih-Chieh; Hall, Benjamin J.; Tang, Ya-Ping; Inglis, Fiona M.; Chen, Chu; Erickson, Jeffrey D.

    2012-01-01

    The level and integrity of glutamate transmission during critical periods of postnatal development plays an important role in the refinement of pyramidal neuron dendritic arbor, synaptic plasticity, and cognition. Presently, it is not clear how excitatory transmission via the two predominant isoforms of the vesicular glutamate transporter (VGLUT1 and VGLUT2) participate in this process. To assess a neurodevelopmental role for VGLUT2 in pyramidal neuron maturation we have generated recombinant VGLUT2 knockout mice and inactivated VGLUT2 throughout development using Emx1-Cre+/+ knockin mice. We show that VGLUT2-deficiency in cortico-limbic circuits results in reduced evoked glutamate transmission, release probability, and LTD at hippocampal CA3-CA1 synapses during a formative developmental period (postnatal days 11–14). In adults, we find a marked reduction in the amount of dendritic arbor across the span of the dendritic tree of CA1 pyramidal neurons, reduced LTP and levels of synaptic markers spinophilin and VGLUT1. Loss of dendritic arbor is accompanied by corresponding reductions in the number of dendritic spines, suggesting widespread alterations in synaptic connectivity. Conditional VGLUT2 knockout mice exhibit increased open-field exploratory activity, yet impaired spatial learning and memory; endophenotypes similar to NMDA receptor knockdown mice. Remarkably, the impairment in learning can be partially restored selectively increasing NMDA-receptor mediated glutamate transmission in adult mice by prolonged treatment with D-serine and a D-amino acid oxidase inhibitor. Our data indicate that VGLUT2 expression is pivotal to the proper development of mature pyramidal neuronal architecture and plasticity, and that such glutamatergic deficiency leads to cognitive malfunction as observed in several neurodevelopmental psychiatric disorders. PMID:23136427

  15. Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning.

    PubMed

    He, Hongbo; Mahnke, Amanda H; Doyle, Sukhjeevan; Fan, Ni; Wang, Chih-Chieh; Hall, Benjamin J; Tang, Ya-Ping; Inglis, Fiona M; Chen, Chu; Erickson, Jeffrey D

    2012-11-07

    The level and integrity of glutamate transmission during critical periods of postnatal development plays an important role in the refinement of pyramidal neuron dendritic arbor, synaptic plasticity, and cognition. Presently, it is not clear how excitatory transmission via the two predominant isoforms of the vesicular glutamate transporter (VGLUT1 and VGLUT2) participate in this process. To assess a neurodevelopmental role for VGLUT2 in pyramidal neuron maturation, we generated recombinant VGLUT2 knock-out mice and inactivated VGLUT2 throughout development using Emx1-Cre(+/+) knock-in mice. We show that VGLUT2 deficiency in corticolimbic circuits results in reduced evoked glutamate transmission, release probability, and LTD at hippocampal CA3-CA1 synapses during a formative developmental period (postnatal days 11-14). In adults, we find a marked reduction in the amount of dendritic arbor across the span of the dendritic tree of CA1 pyramidal neurons and reduced long-term potentiation and levels of synaptic markers spinophilin and VGLUT1. Loss of dendritic arbor is accompanied by corresponding reductions in the number of dendritic spines, suggesting widespread alterations in synaptic connectivity. Conditional VGLUT2 knock-out mice exhibit increased open-field exploratory activity yet impaired spatial learning and memory, endophenotypes similar to those of NMDA receptor knock-down mice. Remarkably, the impairment in learning can be partially restored by selectively increasing NMDA receptor-mediated glutamate transmission in adult mice by prolonged treatment with d-serine and a d-amino acid oxidase inhibitor. Our data indicate that VGLUT2 expression is pivotal to the proper development of mature pyramidal neuronal architecture and plasticity, and that such glutamatergic deficiency leads to cognitive malfunction as observed in several neurodevelopmental psychiatric disorders.

  16. Distribution and Function of HCN Channels in the Apical Dendritic Tuft of Neocortical Pyramidal Neurons

    PubMed Central

    Harnett, Mark T.; Magee, Jeffrey C.

    2015-01-01

    The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensemble HCN channel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamic-clamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons. PMID:25609619

  17. Clarithromycin increases neuronal excitability in CA3 pyramidal neurons through a reduction in GABAergic signaling.

    PubMed

    Bichler, Edyta K; Elder, Courtney C; García, Paul S

    2017-01-01

    Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. J Psychopharmacol 28: 697-702, 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch-clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose dependent; doses of 30 and 300 μM clarithromycin significantly increased the firing frequency and membrane potential compared with controls (P = 0.003, P < 0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABAA receptor activation. Clarithromycin at 30 μM significantly reduced (P = 0.001) the amplitude of spontaneous miniature inhibitory GABAergic currents and at 300 μM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 μM clarithromycin enhanced burst frequency twofold compared with controls (P = 0.0006). Taken together, these results suggest that blocking GABAergic signaling with clarithromycin increases cellular excitability and potentially serves as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders.

  18. 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.

  19. Electrical Interactions Between Mammalian Cortical Neurons

    DTIC Science & Technology

    1988-09-28

    nuclei. Kynurenic acid and Dtf-glutamylglycine (broad-spectrum EAA antagonists) reduced EPSPs in supraoptic neurons, while N-methyl-D-aspartate (NMDA...antagonists had relatively little effect on EPSPs . Other studies showed that kynurenic acid had dose-dependent effects on EPSPs of at least two types of...The primary method has been to examine the effects of EAA antagonists on EPSPs of hypothalamic neurons. Finally, another objective is to ascertain

  20. 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.

  1. Differential organization of cortical inputs to striatal projection neurons of the matrix compartment in rats

    PubMed Central

    Deng, Yunping; Lanciego, Jose; Goff, Lydia Kerkerian-Le; Coulon, Patrice; Salin, Pascal; Kachidian, Philippe; Lei, Wanlong; Del Mar, Nobel; Reiner, Anton

    2015-01-01

    In prior studies, we described the differential organization of corticostriatal and thalamostriatal inputs to the spines of direct pathway (dSPNs) and indirect pathway striatal projection neurons (iSPNs) of the matrix compartment. In the present electron microscopic (EM) analysis, we have refined understanding of the relative amounts of cortical axospinous vs. axodendritic input to the two types of SPNs. Of note, we found that individual dSPNs receive about twice as many axospinous synaptic terminals from IT-type (intratelencephalically projecting) cortical neurons as they do from PT-type (pyramidal tract projecting) cortical neurons. We also found that PT-type axospinous synaptic terminals were about 1.5 times as common on individual iSPNs as IT-type axospinous synaptic terminals. Overall, a higher percentage of IT-type terminals contacted dSPN than iSPN spines, while a higher percentage of PT-type terminals contacted iSPN than dSPN spines. Notably, IT-type axospinous synaptic terminals were significantly larger on iSPN spines than on dSPN spines. By contrast to axospinous input, the axodendritic PT-type input to dSPNs was more substantial than that to iSPNs, and the axodendritic IT-type input appeared to be meager and comparable for both SPN types. The prominent axodendritic PT-type input to dSPNs may accentuate their PT-type responsiveness, and the large size of axospinous IT-type terminals on iSPNs may accentuate their IT-type responsiveness. Using transneuronal labeling with rabies virus to selectively label the cortical neurons with direct input to the dSPNs projecting to the substantia nigra pars reticulata, we found that the input predominantly arose from neurons in the upper layers of motor cortices, in which IT-type perikarya predominate. The differential cortical input to SPNs is likely to play key roles in motor control and motor learning. PMID:25926776

  2. 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.

  3. 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.

  4. 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.

  5. Visual experience without lines: effect on developing cortical neurons.

    PubMed

    Pettigrew, J D; Freeman, R D

    1973-11-09

    Kittens were reared in a planetarium-like visual environment that lacked straight line contours. Cortical neurons were subsequently highly sensitive to spots of light but not to straight lines, in marked contrast to those from a normal cat. If linear contour processing is an innate function it appears to be subject to substantial modification by early visual experience.

  6. 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.

  7. Long-term adrenalectomy causes loss of dentate gyrus and pyramidal neurons in the adult hippocampus.

    PubMed

    Sapolsky, R M; Stein-Behrens, B A; Armanini, M P

    1991-11-01

    A growing literature suggests that the hippocampus can be damaged by glucocorticoids, the adrenal steroids secreted during stress. Thus, considerable interest was generated by recent reports that prolonged elimination of glucocorticoids by adrenalectomy (ADX) damages hippocampal dentate gyrus neurons. To date, this phenomenon has only been observed in rats of peripubertal age or younger; moreover, reports differ considerably as to the magnitude of the damage induced. Therefore, we examined this issue in rats ADXd at 5 months of age. Three months later, there was a significant 26% loss of dentate neurons in a subset of rats. In agreement with these previous reports, this subset had attenuated weight gain and electrolyte imbalances, suggestive of complete removal of the adrenals and accessory adrenal tissue. As a novel observation, we also observed significant (19%) loss of CA4 pyramidal neurons. Thus, both severe under- or overexposure to glucocorticoids can be deleterious to a number of hippocampal neuron types.

  8. Intracellular activities related to in vitro hippocampal sharp waves are altered in CA3 pyramidal neurons of aged mice.

    PubMed

    Moradi-Chameh, H; Peng, J; Wu, C; Zhang, L

    2014-09-26

    Pyramidal neurons in the hippocampal CA3 area interconnect intensively via recurrent axonal collaterals, and such CA3-to-CA3 recurrent circuitry plays important roles in the generation of hippocampal network activities. In particular, the CA3 circuitry is able to generate spontaneous sharp waves (SPWs) when examined in vitro. These in vitro SPWs are thought to result from the network activity of GABAergic inhibitory interneurons as SPW-correlating intracellular activities are featured with strong IPSPs in pyramidal neurons and EPSPs or spikes in GABAergic interneurons. In view of accumulating evidence indicating a decrease in subgroups of hippocampal GABAergic interneurons in aged animals, we test the hypothesis that the intracellular activities related to in vitro SPWs are altered in CA3 pyramidal neurons of aged mice. Hippocampal slices were prepared from adult and aged C57 black mice (ages 3-6 and 24-28months respectively). Population and single-cell activities were examined via extracellular and whole-cell patch-clamp recordings. CA3 SPW frequencies were not significantly different between the slices of adult and aged mice but SPW-correlating intracellular activities featured weaker IPSC components in aged CA3 pyramidal neurons compared to adult neurons. It was unlikely that this latter phenomenon was due to general impairments of GABAergic synapses in the aged CA3 circuitry as evoked IPSC responses and pharmacologically isolated IPSCs were observed in aged CA3 pyramidal neurons. In addition, aged CA3 pyramidal neurons displayed more positive resting potentials and had a higher propensity of burst firing than adult neurons. We postulate that alterations of GABAergic network activity may explain the reduced IPCS contributions to in vitro SPWs in aged CA3 pyramidal neurons. Overall, our present observations are supportive of the notion that excitability of hippocampal CA3 circuitry is increased in aged mice.

  9. Coincident Generation of Pyramidal Neurons and Protoplasmic Astrocytes in Neocortical Columns

    PubMed Central

    Magavi, Sanjay; Friedmann, Drew; Banks, Garrett; Stolfi, Alberto

    2012-01-01

    Astrocytes, one of the most common cell types in the brain, are essential for processes ranging from neural development through potassium homeostasis to synaptic plasticity. Surprisingly, the developmental origins of astrocytes in the neocortex are still controversial. To investigate the patterns of astrocyte development in the neocortex we examined cortical development in a transgenic mouse in which a random, sparse subset of neural progenitors undergoes CRE/lox recombination, permanently labeling their progeny. We demonstrate that neural progenitors in neocortex generate discrete columnar structures that contain both projection neurons and protoplasmic astrocytes. Ninety-five percent of developmental cortical columns labeled in our system contained both astrocytes and neurons. The astrocyte to neuron ratio of labeled cells in a developmental column was 1:7.4, similar to the overall ratio of 1:8.4 across the entire gray matter of the neocortex, indicating that column-associated astrocytes account for the majority of protoplasmic astrocytes in neocortex. Most of the labeled columns contained multiple clusters of several astrocytes. Dividing cells were found at the base of neuronal columns at the beginning of gliogenesis, and later within the cortical layers, suggesting a mechanism by which astrocytes could be distributed within a column. These data indicate that radial glia are the source of both neurons and astrocytes in the neocortex, and that these two cell types are generated in a spatially restricted manner during cortical development. PMID:22492032

  10. 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

  11. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington’s Disease

    PubMed Central

    Spampanato, Jay; Gu, Xiaofeng; Yang, X. William; Mody, Istvan

    2008-01-01

    Huntington’s disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in huntingtin. A newly developed BAC transgenic mouse model (BACHD) reproduces phenotypic features of HD including predominantly neuropil associated protein aggregation and progressive motor dysfunction with selective neurodegeneration. 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 PV 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

  12. Patterned activity in stratum lacunosum moleculare inhibits CA1 pyramidal neuron firing.

    PubMed

    Dvorak-Carbone, H; Schuman, E M

    1999-12-01

    CA1 pyramidal cells are the primary output neurons of the hippocampus, carrying information about the result of hippocampal network processing to the subiculum and entorhinal cortex (EC) and thence out to the rest of the brain. The primary excitatory drive to the CA1 pyramidal cells comes via the Schaffer collateral (SC) projection from area CA3. There is also a direct projection from EC to stratum lacunosum-moleculare (SLM) of CA1, an input well positioned to modulate information flow through the hippocampus. High-frequency stimulation in SLM evokes an inhibition sufficiently strong to prevent CA1 pyramidal cells from spiking in response to SC input, a phenomenon we refer to as spike-blocking. We characterized the spike-blocking efficacy of burst stimulation (10 stimuli at 100 Hz) in SLM and found that it is greatest at approximately 300-600 ms after the burst, consistent with the time course of the slow GABA(B) signaling pathway. Spike-blocking efficacy increases in potency with the number of SLM stimuli in a burst, but also decreases with repeated presentations of SLM bursts. Spike-blocking was eliminated in the presence of GABA(B) antagonists. We have identified a candidate population of interneurons in SLM and distal stratum radiatum (SR) that may mediate this spike-blocking effect. We conclude that the output of CA1 pyramidal cells, and hence the hippocampus, is modulated in an input pattern-dependent manner by activation of the direct pathway from EC.

  13. Spatial Stream Segregation by Auditory Cortical Neurons

    PubMed Central

    Bremen, Peter

    2013-01-01

    In a complex auditory scene, a “cocktail party” for example, listeners can disentangle multiple competing sequences of sounds. A recent psychophysical study in our laboratory demonstrated a robust spatial component of stream segregation showing ∼8° acuity. Here, we recorded single- and multiple-neuron responses from the primary auditory cortex of anesthetized cats while presenting interleaved sound sequences that human listeners would experience as segregated streams. Sequences of broadband sounds alternated between pairs of locations. Neurons synchronized preferentially to sounds from one or the other location, thereby segregating competing sound sequences. Neurons favoring one source location or the other tended to aggregate within the cortex, suggestive of modular organization. The spatial acuity of stream segregation was as narrow as ∼10°, markedly sharper than the broad spatial tuning for single sources that is well known in the literature. Spatial sensitivity was sharpest among neurons having high characteristic frequencies. Neural stream segregation was predicted well by a parameter-free model that incorporated single-source spatial sensitivity and a measured forward-suppression term. We found that the forward suppression was not due to post discharge adaptation in the cortex and, therefore, must have arisen in the subcortical pathway or at the level of thalamocortical synapses. A linear-classifier analysis of single-neuron responses to rhythmic stimuli like those used in our psychophysical study yielded thresholds overlapping those of human listeners. Overall, the results indicate that the ascending auditory system does the work of segregating auditory streams, bringing them to discrete modules in the cortex for selection by top-down processes. PMID:23825404

  14. 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

  15. Tunable Neuromimetic Integrated System for Emulating Cortical Neuron Models

    PubMed Central

    Grassia, Filippo; Buhry, Laure; Lévi, Timothée; Tomas, Jean; Destexhe, Alain; Saïghi, Sylvain

    2011-01-01

    Nowadays, many software solutions are currently available for simulating neuron models. Less conventional than software-based systems, hardware-based solutions generally combine digital and analog forms of computation. In previous work, we designed several neuromimetic chips, including the Galway chip that we used for this paper. These silicon neurons are based on the Hodgkin–Huxley formalism and they are optimized for reproducing a large variety of neuron behaviors thanks to tunable parameters. Due to process variation and device mismatch in analog chips, we use a full-custom fitting method in voltage-clamp mode to tune our neuromimetic integrated circuits. By comparing them with experimental electrophysiological data of these cells, we show that the circuits can reproduce the main firing features of cortical cell types. In this paper, we present the experimental measurements of our system which mimic the four most prominent biological cells: fast spiking, regular spiking, intrinsically bursting, and low-threshold spiking neurons into analog neuromimetic integrated circuit dedicated to cortical neuron simulations. This hardware and software platform will allow to improve the hybrid technique, also called “dynamic-clamp,” that consists of connecting artificial and biological neurons to study the function of neuronal circuits. PMID:22163213

  16. Alteration in dendritic morphology of pyramidal neurons from the prefrontal cortex of rats with renovascular hypertension.

    PubMed

    Vega, Elenia; Gómez-Villalobos, Maria de Jésus; Flores, Gonzalo

    2004-09-17

    We have studied, in the rat, the dendritic morphological changes of the pyramidal neurons of the medial part of the prefrontal cortex induced by the chronic effect of high blood pressure. Renovascular hypertension was induced using a silver clip on the renal artery by surgery. The morphology of the pyramidal neurons from the medial part of the prefrontal cortex was investigated in these animals. The blood pressure was measured to confirm the increase in the arterial blood pressure. After 16 weeks of increase in the arterial blood pressure, the animals were sacrificed by overdoses of sodium pentobarbital and perfused intracardially with a 0.9% saline solution. The brains were removed, processed by the Golgi-Cox stain method and analyzed by the Sholl method. The dendritic morphology clearly showed that the hypertensive animals had an increase (32%) in the dendritic length of the pyramidal cells with a decrease (50%) in the density of dendritic spines when compared with sham animals. The branch-order analysis showed that the animals with hypertension exhibit more dendritic arborization at the level of the first to fourth branch order. This result suggests that renovascular hypertension may in part affect the dendritic morphology in this limbic structure, which may implicate cognitive impairment in hypertensive patients.

  17. Synaptic and intrinsic homeostatic mechanisms cooperate to increase L2/3 pyramidal neuron excitability during a late phase of critical period plasticity.

    PubMed

    Lambo, Mary E; Turrigiano, Gina G

    2013-05-15

    Visual deprivation profoundly affects visual cortical response properties, but the activity-dependent plasticity mechanisms that underlie these changes are poorly understood. Monocular deprivation (MD) induces ocular dominance (OD) shifts through biphasic changes in cortical excitability, first decreasing responsiveness to the deprived eye, and then slowly increasing responsiveness to both the deprived and spared eyes. It has been suggested that this slow gain of responsiveness is due to homeostatic synaptic scaling, but this prediction has not been tested directly. Here we show that, in rat monocular and binocular primary visual cortex (V1m and V1b), postsynaptic strength onto layer 2/3 (L2/3) pyramidal neurons is modulated in a biphasic manner by MD, first undergoing a net decrease after 1 and 2 d MD, increasing back to baseline after 3 d, and finally undergoing a net potentiation between 3 and 6 d. The time course and direction of these synaptic changes match well the known changes in visual responsiveness during OD plasticity. Viral-mediated delivery of the GluA2 C-tail in vivo blocked these synaptic changes, indicating that, like synaptic scaling in vitro, AMPA receptor trafficking via the GluA2 C-tail is required for the delayed increase in postsynaptic strength. Finally, we also observed a delayed increase in the intrinsic excitability of L2/3 pyramidal neurons following prolonged MD. These data indicate that synaptic and intrinsic homeostatic mechanisms cooperate to increase excitability of L2/3 pyramidal neurons following prolonged MD, and suggest that these homeostatic mechanisms contribute to the delayed gain of visual responsiveness during OD plasticity.

  18. Fluoxetine (Prozac) and Serotonin Act on Excitatory Synaptic Transmission to Suppress Single Layer 2/3 Pyramidal Neuron-Triggered Cell Assemblies in the Human Prefrontal Cortex

    PubMed Central

    Komlósi, Gergely; Molnár, Gábor; Rózsa, Márton; Oláh, Szabolcs; Barzó, Pál

    2012-01-01

    Selective serotonin reuptake inhibitors are the most widely prescribed drugs targeting the CNS with acute and chronic effects in cognitive, emotional and behavioral processes. This suggests that microcircuits of the human cerebral cortex are powerfully modulated by selective serotonin reuptake inhibitors, however, direct measurements of serotonergic regulation on human synaptic interactions are missing. Using multiple whole-cell patch-clamp recordings from neurons in acute cortical slices derived from nonpathological human samples of the prefrontal cortex, we show that neuronal assemblies triggered by single action potentials of individual neurons in the human cortex are suppressed by therapeutic doses of fluoxetine (Prozac). This effect is boosted and can be mimicked by physiological concentrations of serotonin through 5HT-2A and 5HT-1A receptors. Monosynaptic excitatory connections from pyramidal cells to interneurons were suppressed by application of serotonin leaving the monosynaptic output of GABAergic cells unaffected. Changes in failure rate, in paired-pulse ratio, and in the coefficient of variation of the amplitude of EPSPs suggest a presynaptic action of serotonin. In conclusion, activation of neuronal assemblies, which were suggested as building blocks of high order cognitive processes, are effectively downregulated by the acute action of selective serotonin reuptake inhibitors or serotonin at the site of pyramidal output in human microcircuits. PMID:23152619

  19. 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

  20. 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

  1. Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice.

    PubMed

    van Brederode, J F; Rho, J M; Cerne, R; Tempel, B L; Spain, W J

    2001-01-01

    Mice lacking the potassium channel subunit KCNA1 exhibit a severe epileptic phenotype beginning at an early postnatal age. The precise cellular physiological substrates for these seizures are unclear, as is the site of origin. Since KCNA1 mRNA in normal mice is expressed in the neocortex, we asked whether neurons in the neocortex of three to four week-old Kcna1-null mutants exhibit evidence of hyperexcitability. Layer V pyramidal neurons were directly visualized in brain slices with infrared differential-interference contrast microscopy and evaluated with cellular electrophysiological techniques. There were no significant differences in intrinsic membrane properties and action potential shape between Kcna1-null and wild-type mice, consistent with previous findings in hippocampal slice recordings. However, the frequency of spontaneous post-synaptic currents was significantly higher in Kcna1-null compared to wild-type mice. The frequency of spontaneous inhibitory post-synaptic currents and miniature (action-potential-independent) inhibitory post-synaptic currents was also significantly higher in Kcna1-null compared to wild-type mice. However, the frequency of spontaneous and miniature excitatory post-synaptic currents was not different in these two groups of animals. Comparison of the amplitude and kinetics of miniature inhibitory and excitatory post-synaptic currents revealed differences in amplitude, rise time and half-width between Kcna1-null and wild-type mice. Our data indicate that the inhibitory drive onto layer V pyramidal neurons is increased in Kcna1 knockout mice, either directly through an increased spontaneous release of GABA from presynaptic terminals contacting layer V pyramidal neurons, or an enhanced excitatory synaptic input to inhibitory interneurons.

  2. Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways.

    PubMed

    Taylor, Ruth D T; Madsen, Marita Grønning; Krause, Michael; Sampedro-Castañeda, Marisol; Stocker, Martin; Pedarzani, Paola

    2014-01-01

    The slow afterhyperpolarizing current (sIAHP ) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP , resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sIAHP, underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons.

  3. Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors

    PubMed Central

    Graves, Austin R; Moore, Shannon J; Bloss, Erik B; Mensh, Brett D; Kath, William L; Spruston, Nelson

    2012-01-01

    Summary Relating the function of neuronal cell types to information processing and behavior is a central goal of neuroscience. In the hippocampus, pyramidal cells in CA1 and the subiculum process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information, which they transmit throughout the brain. Do these cells constitute a single class, or are there multiple cell types with specialized functions? Using unbiased cluster analysis, we show that there are two morphologically and electrophysiologically distinct principal cell types that carry hippocampal output. We show further that these two cell types are inversely modulated by the synergistic action of glutamate and acetylcholine acting on metabotropic receptors that are central to hippocampal function. Combined with prior connectivity studies, our results support a model of hippocampal processing in which the two pyramidal cell types are predominantly segregated into two parallel pathways that process distinct modalities of information. PMID:23177962

  4. 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.

  5. 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

  6. 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.

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

    PubMed Central

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

    2009-01-01

    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. PMID:19717463

  8. Signal transfer within a cultured asymmetric cortical neuron circuit

    NASA Astrophysics Data System (ADS)

    Isomura, Takuya; Shimba, Kenta; Takayama, Yuzo; Takeuchi, Akimasa; Kotani, Kiyoshi; Jimbo, Yasuhiko

    2015-12-01

    Objective. Simplified neuronal circuits are required for investigating information representation in nervous systems and for validating theoretical neural network models. Here, we developed patterned neuronal circuits using micro fabricated devices, comprising a micro-well array bonded to a microelectrode-array substrate. Approach. The micro-well array consisted of micrometre-scale wells connected by tunnels, all contained within a silicone slab called a micro-chamber. The design of the micro-chamber confined somata to the wells and allowed axons to grow through the tunnels bidirectionally but with a designed, unidirectional bias. We guided axons into the point of the arrow structure where one of the two tunnel entrances is located, making that the preferred direction. Main results. When rat cortical neurons were cultured in the wells, their axons grew through the tunnels and connected to neurons in adjoining wells. Unidirectional burst transfers and other asymmetric signal-propagation phenomena were observed via the substrate-embedded electrodes. Seventy-nine percent of burst transfers were in the forward direction. We also observed rapid propagation of activity from sites of local electrical stimulation, and significant effects of inhibitory synapse blockade on bursting activity. Significance. These results suggest that this simple, substrate-controlled neuronal circuit can be applied to develop in vitro models of the function of cortical microcircuits or deep neural networks, better to elucidate the laws governing the dynamics of neuronal networks.

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

    PubMed

    Landsman, Alexandra S; Schwartz, Ira B

    2007-07-05

    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.

  10. 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

  11. Membrane Potential Dynamics of CA1 Pyramidal Neurons During Hippocampal Ripples in Awake Mice

    PubMed Central

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

    2016-01-01

    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 time scale, 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. PMID:26889811

  12. Regulation of GABAergic Inputs to CA1 Pyramidal Neurons by Nicotinic Receptors and Kynurenic Acid

    PubMed Central

    Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Pereira, Edna F. R.

    2012-01-01

    Impaired α7 nicotinic acetylcholine receptor (nAChR) function and GABAergic transmission in the hippocampus and elevated brain levels of kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway, are key features of schizophrenia. KYNA acts as a noncompetitive antagonist with respect to agonists at both α7 nAChRs and N-methyl-d-aspartate receptors. Here, we tested the hypothesis that in hippocampal slices tonically active α7 nAChRs control GABAergic transmission to CA1 pyramidal neurons and are sensitive to inhibition by rising levels of KYNA. The α7 nAChR-selective antagonist α-bungarotoxin (α-BGT; 100 nM) and methyllycaconitine (MLA; 10 nM), an antagonist at α7 and other nAChRs, reduced by 51.3 ± 1.3 and 65.2 ± 1.5%, respectively, the frequency of GABAergic postsynaptic currents (PSCs) recorded from CA1 pyramidal neurons. MLA had no effect on miniature GABAergic PSCs. Thus, GABAergic synaptic activity in CA1 pyramidal neurons is maintained, in part, by tonically active α7 nAChRs located on the preterminal region of axons and/or the somatodendritic region of interneurons that synapse onto the neurons under study. l-Kynurenine (20 or 200 μM) or KYNA (20–200 μM) suppressed concentration-dependently the frequency of GABAergic PSCs; the inhibitory effect of 20 μM l-kynurenine had an onset time of approximately 35 min and could not be detected in the presence of 100 nM α-BGT. These results suggest that KYNA levels generated from 20 μM kynurenine inhibit tonically active α7 nAChR-dependent GABAergic transmission to the pyramidal neurons. Disruption of nAChR-dependent GABAergic transmission by mildly elevated levels of KYNA can be an important determinant of the cognitive deficits presented by patients with schizophrenia. PMID:22344459

  13. Direct control of paralysed muscles by cortical neurons.

    PubMed

    Moritz, Chet T; Perlmutter, Steve I; Fetz, Eberhard E

    2008-12-04

    A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury by artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralysed limbs. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms, and paralysed muscles have been activated by functional electrical stimulation. Here we show that Macaca nemestrina monkeys can directly control stimulation of muscles using the activity of neurons in the motor cortex, thereby restoring goal-directed movements to a transiently paralysed arm. Moreover, neurons could control functional stimulation equally well regardless of any previous association to movement, a finding that considerably expands the source of control signals for brain-machine interfaces. Monkeys learned to use these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralysed limbs.

  14. Direct control of paralyzed muscles by cortical neurons

    PubMed Central

    Moritz, Chet T.; Perlmutter, Steve I.; Fetz, Eberhard E.

    2011-01-01

    A potential treatment for paralysis resulting from spinal cord injury is to route control signals from the brain around the injury via artificial connections. Such signals could then control electrical stimulation of muscles, thereby restoring volitional movement to paralyzed limbs1–3. In previously separate experiments, activity of motor cortex neurons related to actual or imagined movements has been used to control computer cursors and robotic arms4–10, and paralyzed muscles have been activated by functional electrical stimulation (FES)11–13. Here we show that monkeys can directly control stimulation of muscles using the activity of neurons in motor cortex, thereby restoring goal-directed movements to a transiently paralyzed arm. Moreover, neurons could control functional stimulation equally well regardless of any prior association to movement, a finding that significantly expands the source of control signals for brain-machine interfaces. Monkeys learned to utilize these artificial connections from cortical cells to muscles to generate bidirectional wrist torques, and controlled multiple neuron-muscle pairs simultaneously. Such direct transforms from cortical activity to muscle stimulation could be implemented by autonomous electronic circuitry, creating a relatively natural neuroprosthesis. These results are the first demonstration that direct artificial connections between cortical cells and muscles can compensate for interrupted physiological pathways and restore volitional control of movement to paralyzed limbs. PMID:18923392

  15. Phosphorylation of CRMP2 is involved in proper bifurcation of the apical dendrite of hippocampal CA1 pyramidal neurons.

    PubMed

    Niisato, Emi; Nagai, Jun; Yamashita, Naoya; Nakamura, Fumio; Goshima, Yoshio; Ohshima, Toshio

    2013-02-01

    The neural circuit in the hippocampus is important for higher brain functions. Dendrites of CA1 pyramidal neurons mainly receive input from the axons of CA3 pyramidal neurons in this neural circuit. A CA1 pyramidal neuron has a single apical dendrite and multiple basal dendrites. In wild-type mice, most of CA1 pyramidal neurons extend a single trunk, or alternatively, the apical dendrite bifurcates into two daughter trunks at the stratum radiatum layer. We previously reported the proximal bifurcation phenotype in Sema3A-/-, p35-/-, and CRMP4-/- mice. Cdk5/p35 phosphorylates CRMP2 at Ser522, and inhibition of this phosphorylation suppressed Sema3A-induced growth cone collapse. In this study, we analyzed the bifurcation points of the apical dendrites of hippocampal CA1 pyramidal neurons in CRMP2KI/KI mice in which the Cdk5/p35-phosphorylation site Ser522 was mutated into an Ala residue. The proximal bifurcation phenotype was not observed in CRMP2KI/KI mice; however, severe proximal bifurcation of apical dendrites was found in CRMP2KI/KI;CRMP4-/- mice. Cultured hippocampal neurons from CRMP2KI/KI and CRMP2KI/KI;CRMP4-/- embryos showed an increased number of dendritic branching points compared to those from wild-type embryos. Sema3A increased the number of branching points and the total length of dendrites in wild-type hippocampal neurons, but these effects of Sema3A for dendrites were not observed in CRMP2KI/KI and CRMP2KI/KI;CRMP4-/-hippocampal neurons. Binding of CRMP2 to tubulin increased in both CRMP2KI/KI and CRMP2KI/KI:CRMP4-/- brain lysates. These results suggest that CRMP2 and CRMP4 synergistically regulate dendritic development, and CRMP2 phosphorylation is critical for proper bifurcation of apical dendrite of CA1 pyramidal neurons.

  16. Inferring pathological states in cortical neuron microcircuits.

    PubMed

    Rydzewski, Jakub; Nowak, Wieslaw; Nicosia, Giuseppe

    2015-12-07

    The brain activity is to a large extent determined by states of neural cortex microcircuits. Unfortunately, accuracy of results from neural circuits׳ mathematical models is often biased by the presence of uncertainties in underlying experimental data. Moreover, due to problems with uncertainties identification in a multidimensional parameters space, it is almost impossible to classify states of the neural cortex, which correspond to a particular set of the parameters. Here, we develop a complete methodology for determining uncertainties and the novel protocol for classifying all states in any neuroinformatic model. Further, we test this protocol on the mathematical, nonlinear model of such a microcircuit developed by Giugliano et al. (2008) and applied in the experimental data analysis of Huntington׳s disease. Up to now, the link between parameter domains in the mathematical model of Huntington׳s disease and the pathological states in cortical microcircuits has remained unclear. In this paper we precisely identify all the uncertainties, the most crucial input parameters and domains that drive the system into an unhealthy state. The scheme proposed here is general and can be easily applied to other mathematical models of biological phenomena. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Temporal synchrony and gamma-to-theta power conversion in the dendrites of CA1 pyramidal neurons.

    PubMed

    Vaidya, Sachin P; Johnston, Daniel

    2013-12-01

    Timing is a crucial aspect of synaptic integration. For pyramidal neurons that integrate thousands of synaptic inputs spread across hundreds of microns, it is thus a challenge to maintain the timing of incoming inputs at the axo-somatic integration site. Here we show that pyramidal neurons in the rodent hippocampus use a gradient of inductance in the form of hyperpolarization-activated cation-nonselective (HCN) channels as an active mechanism to counteract location-dependent temporal differences of dendritic inputs at the soma. Using simultaneous multi-site whole-cell recordings complemented by computational modeling, we find that this intrinsic biophysical mechanism produces temporal synchrony of rhythmic inputs in the theta and gamma frequency ranges across wide regions of the dendritic tree. While gamma and theta oscillations are known to synchronize activity across space in neuronal networks, our results identify a new mechanism by which this synchrony extends to activity within single pyramidal neurons with complex dendritic arbors.

  18. 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. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  19. Ammonia inhibits long-term potentiation via neurosteroid synthesis in hippocampal pyramidal neurons.

    PubMed

    Izumi, Y; Svrakic, N; O'Dell, K; Zorumski, C F

    2013-03-13

    Neurosteroids are a class of endogenous steroids synthesized in the brain that are believed to be involved in the pathogenesis of neuropsychiatric disorders and memory impairment. Ammonia impairs long-term potentiation (LTP), a synaptic model of learning, in the hippocampus, a brain region involved in memory acquisition. Although mechanisms underlying ammonia-mediated LTP inhibition are not fully understood, we previously found that the activation of N-methyl-d-aspartate receptors (NMDARs) is important. Based on this, we hypothesize that metabolic stressors, including hyperammonemia, promote untimely NMDAR activation and result in neural adaptations that include the synthesis of allopregnanolone (alloP) and other GABA-potentiating neurosteroids that dampen neuronal activity and impair LTP and memory formation. Using an antibody against 5α-reduced neurosteroids, we found that 100 μM ammonia acutely enhanced neurosteroid immunostaining in pyramidal neurons in the CA1 region of rat hippocampal slices. The enhanced staining was blocked by finasteride, a selective inhibitor of 5α-reductase, a key enzyme required for alloP synthesis. Finasteride also overcame LTP inhibition by 100 μM ammonia, as did picrotoxin, an inhibitor of GABA-A receptors. These results indicate that GABA-enhancing neurosteroids, synthesized locally within pyramidal neurons, contribute significantly to ammonia-mediated synaptic dysfunction. These results suggest that the manipulation of neurosteroid synthesis could provide a strategy to improve cognitive function in individuals with hyperammonemia.

  20. A method for high fidelity optogenetic control of individual pyramidal neurons in vivo.

    PubMed

    Nakamura, Shinya; Baratta, Michael V; Cooper, Donald C

    2013-09-02

    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.

  1. Characterization of postsynaptic calcium signals in the pyramidal neurons of anterior cingulate cortex.

    PubMed

    Li, Xu-Hui; Song, Qian; Chen, Tao; Zhuo, Min

    2017-01-01

    Calcium signaling is critical for synaptic transmission and plasticity. N-methyl-D-aspartic acid (NMDA) receptors play a key role in synaptic potentiation in the anterior cingulate cortex. Most previous studies of calcium signaling focus on hippocampal neurons, little is known about the activity-induced calcium signals in the anterior cingulate cortex. In the present study, we show that NMDA receptor-mediated postsynaptic calcium signals induced by different synaptic stimulation in anterior cingulate cortex pyramidal neurons. Single and multi-action potentials evoked significant suprathreshold Ca(2+) increases in somas and spines. Both NMDA receptors and voltage-gated calcium channels contributed to this increase. Postsynaptic Ca(2+)signals were induced by puff-application of glutamate, and a NMDA receptor antagonist AP5 blocked these signals in both somas and spines. Finally, long-term potentiation inducing protocols triggered postsynaptic Ca(2+) influx, and these influx were NMDA receptor dependent. Our results provide the first study of calcium signals in the anterior cingulate cortex and demonstrate that NMDA receptors play important roles in postsynaptic calcium signals in anterior cingulate cortex pyramidal neurons.

  2. Characterization of postsynaptic calcium signals in the pyramidal neurons of anterior cingulate cortex

    PubMed Central

    Li, Xu-Hui; Song, Qian; Chen, Tao

    2017-01-01

    Calcium signaling is critical for synaptic transmission and plasticity. N-methyl-D-aspartic acid (NMDA) receptors play a key role in synaptic potentiation in the anterior cingulate cortex. Most previous studies of calcium signaling focus on hippocampal neurons, little is known about the activity-induced calcium signals in the anterior cingulate cortex. In the present study, we show that NMDA receptor-mediated postsynaptic calcium signals induced by different synaptic stimulation in anterior cingulate cortex pyramidal neurons. Single and multi-action potentials evoked significant suprathreshold Ca2+ increases in somas and spines. Both NMDA receptors and voltage-gated calcium channels contributed to this increase. Postsynaptic Ca2+signals were induced by puff-application of glutamate, and a NMDA receptor antagonist AP5 blocked these signals in both somas and spines. Finally, long-term potentiation inducing protocols triggered postsynaptic Ca2+ influx, and these influx were NMDA receptor dependent. Our results provide the first study of calcium signals in the anterior cingulate cortex and demonstrate that NMDA receptors play important roles in postsynaptic calcium signals in anterior cingulate cortex pyramidal neurons. PMID:28726541

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. Action potential modulation in CA1 pyramidal neuron axons facilitates OLM interneuron activation in recurrent inhibitory microcircuits of rat hippocampus.

    PubMed

    Kim, Sooyun

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron-O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron-interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits.

  10. 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

  11. High- and low-conductance NMDA receptors are present in layer 4 spiny stellate and layer 2/3 pyramidal neurons of mouse barrel cortex.

    PubMed

    Scheppach, Christian

    2016-12-01

    N-Methyl-D-aspartate (NMDA) receptors are ion channels activated by the neurotransmitter glutamate in the mammalian brain and are important in synaptic function and plasticity, but are also found in extrasynaptic locations and influence neuronal excitability. There are different NMDA receptor subtypes which differ in their single-channel conductance. Recently, synaptic plasticity has been studied in the mouse barrel cortex, the primary sensory cortex for input from the animal's whiskers. Pharmacological data imply the presence of low-conductance NMDA receptors in spiny stellate neurons of cortical layer 4, but of high-conductance NMDA receptors in pyramidal neurons of layer 2/3. Here, to obtain complementary electrophysiological information on the functional NMDA receptors expressed in layer 4 and layer 2/3 neurons, single NMDA receptor currents were recorded with the patch-clamp method. Both cell types were found to contain high-conductance as well as low-conductance NMDA receptors. The results are consistent with the reported pharmacological data on synaptic plasticity, and with previous claims of a prominent role of low-conductance NMDA receptors in layer 4 spiny stellate neurons, including broad integration, amplification and distribution of excitation within the barrel in response to whisker stimulation, as well as modulation of excitability by ambient glutamate. However, layer 4 cells also expressed high-conductance NMDA receptors. The presence of low-conductance NMDA receptors in layer 2/3 pyramidal neurons suggests that some of these functions may be shared with layer 4 spiny stellate neurons.

  12. Otx1 promotes basal dendritic growth and regulates intrinsic electrophysiological and synaptic properties of layer V pyramidal neurons in mouse motor cortex.

    PubMed

    Zhang, Y-F; Liu, L-X; Cao, H-T; Ou, L; Qu, J; Wang, Y; Chen, J-G

    2015-01-29

    The transcription factor Otx1 is specifically expressed in layer V pyramidal cells (L5PCs) in the cerebral cortex. Otx1 null mutant mice have a defect in the developmental axon pruning of L5PCs and show epileptic seizures. However, the role of Otx1 in electrophysiology, morphology and synaptology of the cortical neurons has not been fully investigated. This study examines the influences of Otx1 on neuronal properties of L5PCs by loss- and gain-of-function approaches. Mice with an Otx1-null mutation had decreased structural measurements of basal dendrites in L5PCs. In contrast, the size of basal dendrites was increased in the Otx1-over-expressed pyramidal cells (PCs) in L2/3 where the gene normally does not express. PCs showed burst and non-burst firing patterns of action potentials. The proportion of burst firing neurons was reduced in the Otx1 mutant but increased in the neurons over-expressing Otx1. Although the burst firing population decreased, the proportion of those bursting neurons with a low threshold increased in the Otx1 mutant mice. Moreover, excitatory facilitating synaptic connections formed between L5PCs were predominant in the Otx1 mutant mice, which greatly contrasted with the predominant depressing synaptic connections in the controls. Taken together, it suggests an enhanced activity of neuronal network in the cortex of Otx1 mutant mice. These data indicate that the Otx1 expression is essential for the normal development of dendritic morphology, intrinsic electrophysiology and synaptic dynamics of L5PCs. This study provides new insights into molecular mechanisms underlying the spatial and temporal regulation of neuronal and synaptic properties of L5PCs, and improves our understanding on the generation of epileptic seizures. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  13. Extrasynaptic αβ subunit GABAA receptors on rat hippocampal pyramidal neurons

    PubMed Central

    Mortensen, Martin; Smart, Trevor G

    2006-01-01

    Extrasynaptic GABAA receptors that are tonically activated by ambient GABA are important for controlling neuronal excitability. In hippocampal pyramidal neurons, the subunit composition of these extrasynaptic receptors may include α5βγ and/or α4βδ subunits. Our present studies reveal that a component of the tonic current in the hippocampus is highly sensitive to inhibition by Zn2+. This component is probably not mediated by either α5βγ or α4βδ receptors, but might be explained by the presence of αβ isoforms. Using patch-clamp recording from pyramidal neurons, a small tonic current measured in the absence of exogenous GABA exhibited both high and low sensitivity to Zn2+ inhibition (IC50 values, 1.89 and 223 μm, respectively). Using low nanomolar and micromolar GABA concentrations to replicate tonic currents, we identified two components that are mediated by benzodiazepine-sensitive and -insensitive receptors. The latter indicated that extrasynaptic GABAA receptors exist that are devoid of γ2 subunits. To distinguish whether the benzodiazepine-insensitive receptors were αβ or αβδ isoforms, we used single-channel recording. Expressing recombinant α1β3γ2, α5β3γ2, α4β3δ and α1β3 receptors in human embryonic kidney (HEK) or mouse fibroblast (Ltk) cells, revealed similar openings with high main conductances (∼25–28 pS) for γ2 or δ subunit-containing receptors whereas αβ receptors were characterized by a lower main conductance state (∼11 pS). Recording from pyramidal cell somata revealed a similar range of channel conductances, indicative of a mixture of GABAA receptors in the extrasynaptic membrane. The lowest conductance state (∼11 pS) was the most sensitive to Zn2+ inhibition in accord with the presence of αβ receptors. This receptor type is estimated to account for up to 10% of all extrasynaptic GABAA receptors on hippocampal pyramidal neurons. PMID:17023503

  14. 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.

  15. Potentiated necrosis of cultured cortical neurons by neurotrophins.

    PubMed

    Koh, J Y; Gwag, B J; Lobner, D; Choi, D W

    1995-04-28

    The effects of neurotrophins on several forms of neuronal degeneration in murine cortical cell cultures were examined. Consistent with other studies, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 all attenuated the apoptotic death induced by serum deprivation or exposure to the calcium channel antagonist nimodipine. Unexpectedly, however, 24-hour pretreatment with these same neurotrophins markedly potentiated the necrotic death induced by exposure to oxygen-glucose deprivation or N-methyl-D-aspartate. Thus, certain neurotrophins may have opposing effects on different types of death in the same neurons.

  16. Role of GABAA inhibition in modulation of pyramidal tract neuron activity during postural corrections

    PubMed Central

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

    2007-01-01

    In a previous study we demonstrated that the activity of pyramidal tract neurons (PTNs) of the motor cortex is modulated in relation to postural corrections evoked by periodical tilts of the animal. The modulation included an increase in activity in one phase of the tilt cycle and a decrease in the other phase. It is known that the motor cortex contains a large population of inhibitory GABAergic neurons. How do these neurons participate in periodic modulation of PTNs? The goal of this study was to investigate the role of GABAA inhibitory neurons of the motor cortex in the modulation of postural-related PTN activity. Using extracellular electrodes with attached micropipettes, we recorded the activity of PTNs in cats maintaining balance on a tilting platform both before and after iontophoretic application of the GABAA receptor antagonists gabazine or bicuculline. The tilt-related activity of 93% of PTNs was affected by GABAA receptor antagonists. In 88% of cells, peak activity increased by 75 ± 50% (mean ± SD). In contrast, the trough activity changed by a much smaller value and almost as many neurons showed a decrease as showed an increase. In 73% of the neurons, the phase position of the peak activity did not change or changed by no more than 0.1 of a cycle. We conclude that the GABAergic system of the motor cortex reduces the posture-related responses of PTNs but has little role in determining their response timing. PMID:17425574

  17. 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.

  18. 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

  19. Optogenetic stimulation of GABA neurons can decrease local neuronal activity while increasing cortical blood flow

    PubMed Central

    Anenberg, Eitan; Chan, Allen W; Xie, Yicheng; LeDue, Jeffrey M; Murphy, Timothy H

    2015-01-01

    We investigated the link between direct activation of inhibitory neurons, local neuronal activity, and hemodynamics. Direct optogenetic cortical stimulation in the sensorimotor cortex of transgenic mice expressing Channelrhodopsin-2 in GABAergic neurons (VGAT-ChR2) greatly attenuated spontaneous cortical spikes, but was sufficient to increase blood flow as measured with laser speckle contrast imaging. To determine whether the observed optogenetically evoked gamma aminobutyric acid (GABA)-neuron hemodynamic responses were dependent on ionotropic glutamatergic or GABAergic synaptic mechanisms, we paired optogenetic stimulation with application of antagonists to the cortex. Incubation of glutamatergic antagonists directly on the cortex (NBQX and MK-801) blocked cortical sensory evoked responses (as measured with electroencephalography and intrinsic optical signal imaging), but did not significantly attenuate optogenetically evoked hemodynamic responses. Significant light-evoked hemodynamic responses were still present after the addition of picrotoxin (GABA-A receptor antagonist) in the presence of the glutamatergic synaptic blockade. This activation of cortical inhibitory interneurons can mediate large changes in blood flow in a manner that is by and large not dependent on ionotropic glutamatergic or GABAergic synaptic transmission. This supports the hypothesis that activation of inhibitory neurons can increase local cerebral blood flow in a manner that is not entirely dependent on levels of net ongoing neuronal activity. PMID:26082013

  20. Cortical neuronal mechanisms of sleep homeostasis.

    PubMed

    Vyazovskiy, Vladyslav V

    2013-01-01

    The longer we are awake, the deeper is our subsequent sleep. On the other hand, the shorter and more fragmented is our sleep, the more difficult it is for us to maintain wakefulness and stable cognitive performance the next day. This relationship between wakefulness and subsequent sleep becomes especially apparent after sleep deprivation or during chronic sleep restriction, which is experienced by millions of people in our society, as well as in multiple neurological, respiratory and other chronic diseases. Invariably, poor sleep leads to fatigue, sleepiness, marked cognitive deficits and impaired mood. The crucial question is what happens to the brain after a period of being awake or asleep, and where in the brain and why do these changes occur. This review summarizes information about neurophysiological substrates of sleep homeostatic processes at the cellular and network levels. It is suggested that sensory, behavioral and cognitive deficits after sleep deprivation resulting from the imbalance between local and global neuronal interactions can be reversed only by physiological sleep.

  1. Early postnatal stress suppresses the developmental trajectory of hippocampal pyramidal neurons: the role of CRHR1.

    PubMed

    Liu, Rui; Yang, Xiao-Dun; Liao, Xue-Mei; Xie, Xiao-Meng; Su, Yun-Ai; Li, Ji-Tao; Wang, Xiao-Dong; Si, Tian-Mei

    2016-12-01

    Adverse experiences early in life hamper the development and maturation of the hippocampus, but how early-life stress perturbs the developmental trajectory of the hippocampus across various life stages and the underlying molecular mechanisms remain to be investigated. In this study, we stressed male mice from postnatal day 2 (P2) to P9, and examined the potential role of CRHR1 in postnatal stress-induced structural remodeling of hippocampal CA3 pyramidal neurons directly after stress (P9), in mid-adolescence (P35) and in adulthood (P90). We found that early-life stress exposure significantly reduced apical dendritic arborization and spine density in CA3 neurons on P9 and P90. Moreover, postnatally stressed neurons underwent increased pruning of spines, especially thin spines, between P35 and P90. These stress-induced immediate and long-term structural abnormalities could be abolished by daily systemic administration of the CRHR1 antagonist antalarmin (20 µg/g of body weight) during stress exposure. However, such treatment strategy failed to attenuate the deleterious stress effects in mid-adolescence on P35. We then extended antalarmin treatment until the end of the second postnatal week, and found that prolonged blockade of CRHR1 could prevent the mid-term impact of early postnatal stress on structural remodeling of CA3 neurons. Our study characterized the influences of early-life stress on the developmental trajectory of hippocampal pyramidal neurons, and highlighted the critical role of CRHR1 in modulating these negative outcomes evoked by early-life stress.

  2. Mechanisms and consequences of action potential burst firing in rat neocortical pyramidal neurons

    PubMed Central

    Williams, Stephen R; Stuart, Greg J

    1999-01-01

    Electrophysiological recordings and pharmacological manipulations were used to investigate the mechanisms underlying the generation of action potential burst firing and its postsynaptic consequences in visually identified rat layer 5 pyramidal neurons in vitro.Based upon repetitive firing properties and subthreshold membrane characteristics, layer 5 pyramidal neurons were separated into three classes: regular firing and weak and strong intrinsically burst firing.High frequency (330 ± 10 Hz) action potential burst firing was abolished or greatly weakened by the removal of Ca2+ (n = 5) from, or by the addition of the Ca2+ channel antagonist Ni2+ (250–500 μm; n = 8) to, the perfusion medium.The blockade of apical dendritic sodium channels by the local dendritic application of TTX (100 nm; n = 5) abolished or greatly weakened action potential burst firing, as did the local apical dendritic application of Ni2+ (1 mm; n = 5).Apical dendritic depolarisation resulted in low frequency (157 ± 26 Hz; n = 6) action potential burst firing in regular firing neurons, as classified by somatic current injection. The intensity of action potential burst discharges in intrinsically burst firing neurons was facilitated by dendritic depolarisation (n = 11).Action potential amplitude decreased throughout a burst when recorded somatically, suggesting that later action potentials may fail to propagate axonally. Axonal recordings demonstrated that each action potential in a burst is axonally initiated and that no decrement in action potential amplitude is apparent in the axon > 30 μm from the soma.Paired recordings (n = 16) from synaptically coupled neurons indicated that each action potential in a burst could cause transmitter release. EPSPs or EPSCs evoked by a presynaptic burst of action potentials showed use-dependent synaptic depression.A postsynaptic, TTX-sensitive voltage-dependent amplification process ensured that later EPSPs in a burst were amplified when generated from

  3. Attenuation of Responses to Self-Generated Sounds in Auditory Cortical Neurons.

    PubMed

    Rummell, Brian P; Klee, Jan L; Sigurdsson, Torfi

    2016-11-23

    Many of the sounds that we perceive are caused by our own actions, for example when speaking or moving, and must be distinguished from sounds caused by external events. Studies using macroscopic measurements of brain activity in human subjects have consistently shown that responses to self-generated sounds are attenuated in amplitude. However, the underlying manifestation of this phenomenon at the cellular level is not well understood. To address this, we recorded the activity of neurons in the auditory cortex of mice in response to sounds generated by their own behavior. We found that the responses of auditory cortical neurons to these self-generated sounds were consistently attenuated, compared with the same sounds generated independently of the animals' behavior. This effect was observed in both putative pyramidal neurons and in interneurons and was stronger in lower layers of auditory cortex. Downstream of the auditory cortex, we found that responses of hippocampal neurons to self-generated sounds were almost entirely suppressed. Responses to self-generated optogenetic stimulation of auditory thalamocortical terminals were also attenuated, suggesting a cortical contribution to this effect. Further analyses revealed that the attenuation of self-generated sounds was not simply due to the nonspecific effects of movement or behavioral state on auditory responsiveness. However, the strength of attenuation depended on the degree to which self-generated sounds were expected to occur, in a cell-type-specific manner. Together, these results reveal the cellular basis underlying attenuated responses to self-generated sounds and suggest that predictive processes contribute to this effect.

  4. Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery.

    PubMed

    Tornero, Daniel; Wattananit, Somsak; Grønning Madsen, Marita; Koch, Philipp; Wood, James; Tatarishvili, Jemal; Mine, Yutaka; Ge, Ruimin; Monni, Emanuela; Devaraju, Karthikeyan; Hevner, Robert F; Brüstle, Oliver; Lindvall, Olle; Kokaia, Zaal

    2013-12-01

    Stem cell-based approaches to restore function after stroke through replacement of dead neurons require the generation of specific neuronal subtypes. Loss of neurons in the cerebral cortex is a major cause of stroke-induced neurological deficits in adult humans. Reprogramming of adult human somatic cells to induced pluripotent stem cells is a novel approach to produce patient-specific cells for autologous transplantation. Whether such cells can be converted to functional cortical neurons that survive and give rise to behavioural recovery after transplantation in the stroke-injured cerebral cortex is not known. We have generated progenitors in vitro, expressing specific cortical markers and giving rise to functional neurons, from long-term self-renewing neuroepithelial-like stem cells, produced from adult human fibroblast-derived induced pluripotent stem cells. At 2 months after transplantation into the stroke-damaged rat cortex, the cortically fated cells showed less proliferation and more efficient conversion to mature neurons with morphological and immunohistochemical characteristics of a cortical phenotype and higher axonal projection density as compared with non-fated cells. Pyramidal morphology and localization of the cells expressing the cortex-specific marker TBR1 in a certain layered pattern provided further evidence supporting the cortical phenotype of the fated, grafted cells, and electrophysiological recordings demonstrated their functionality. Both fated and non-fated cell-transplanted groups showed bilateral recovery of the impaired function in the stepping test compared with vehicle-injected animals. The behavioural improvement at this early time point was most likely not due to neuronal replacement and reconstruction of circuitry. At 5 months after stroke in immunocompromised rats, there was no tumour formation and the grafted cells exhibited electrophysiological properties of mature neurons with evidence of integration in host circuitry. Our

  5. Intermediate Progenitor Cohorts Differentially Generate Cortical Layers and Require Tbr2 for Timely Acquisition of Neuronal Subtype Identity.

    PubMed

    Mihalas, Anca B; Elsen, Gina E; Bedogni, Francesco; Daza, Ray A M; Ramos-Laguna, Kevyn A; Arnold, Sebastian J; Hevner, Robert F

    2016-06-28

    Intermediate progenitors (IPs) amplify the production of pyramidal neurons, but their role in selective genesis of cortical layers or neuronal subtypes remains unclear. Using genetic lineage tracing in mice, we find that IPs destined to produce upper cortical layers first appear early in corticogenesis, by embryonic day 11.5. During later corticogenesis, IP laminar fates are progressively limited to upper layers. We examined the role of Tbr2, an IP-specific transcription factor, in laminar fate regulation using Tbr2 conditional mutant mice. Upon Tbr2 inactivation, fewer neurons were produced by immediate differentiation and laminar fates were shifted upward. Genesis of subventricular mitoses was, however, not reduced in the context of a Tbr2-null cortex. Instead, neuronal and laminar differentiation were disrupted and delayed. Our findings indicate that upper-layer genesis depends on IPs from many stages of corticogenesis and that Tbr2 regulates the tempo of laminar fate implementation for all cortical layers. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  6. Cortical neuronal activity does not regulate sleep homeostasis.

    PubMed

    Qiu, M-H; Chen, M C; Lu, J

    2015-06-25

    The neural substrate of sleep homeostasis is unclear, but both cortical and subcortical structures are thought to be involved in sleep regulation. To test whether prior neuronal activity in the cortex or in subcortical regions drives sleep rebound, we systemically administered atropine (100mg/kg) to rats, producing a dissociated state with slow-wave cortical electroencephalogram (EEG) but waking behavior (e.g. locomotion). Atropine injections during the light period produced 6h of slow-wave cortical EEG but also subcortical arousal. Afterward, rats showed a significant increase in non-rapid eye movement (NREM) sleep, compared to the same period on a baseline day. Consistent with the behavioral and cortical EEG state produced by systemic atropine, c-Fos expression was low in the cortex but high in multiple subcortical arousal systems. These data suggest that subcortical arousal and behavior are sufficient to drive sleep homeostasis, while a sleep-like pattern of cortical activity is not sufficient to satisfy sleep homeostasis.

  7. Entorhinal cortical innervation of parvalbumin-containing neurons (Basket and Chandelier cells) in the rat Ammon's horn.

    PubMed

    Kiss, J; Buzsaki, G; Morrow, J S; Glantz, S B; Leranth, C

    1996-01-01

    Physiological data suggest that in the CA1-CA3 hippocampal areas of rats, entorhinal cortical efferents directly influence the activity of interneurons, in addition to pyramidal cells. To verify this hypothesis, the following experiments were performed: 1) light microscopic double-immunostaining for parvalbumin and the anterograde tracer Phaseolus vulgaris-leucoagglutinin injected into the entorhinal cortex; 2) light and electron microscopic analysis of cleaved spectrin-immunostained (i.e., degenerating axons and boutons) hippocampal sections following entorhinal cortex lesion; and 3) an electron microscopic study of parvalbumin-immunostained hippocampal sections after entorhinal cortex lesion. The results demonstrate that in the stratum lacunosum-moleculare of the CA1 and CA3 regions, entorhinal cortical axons form asymmetric synaptic contacts on parvalbumin-containing dendritic shafts. In the stratum lacunosum-moleculare, parvalbumin-immunoreactive dendrites represent processes of GABAergic, inhibitory basket and chandelier cells; these interneurons innervate the perisomatic area and axon initial segments of pyramidal cells, respectively. A feed-forward activation of these neurons by the entorhinal input may explain the strong, short-latency inhibition of pyramidal cells.

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

    PubMed

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

    2016-10-25

    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.

  9. Protein Kinase C Regulates Ionic Conductance in Hippocampal Pyramidal Neurons: Electrophysiological Effects of Phorbol Esters

    NASA Astrophysics Data System (ADS)

    Baraban, Jay M.; Snyder, Solomon H.; Alger, Bradley E.

    1985-04-01

    The vertebrate central nervous system contains very high concentrations of protein kinase C, a calcium-and phospholipid-stimulated phosphorylating enzyme. Phorbol esters, compounds with inflammatory and tumor-promoting properties, bind to and activate this enzyme. To clarify the role of protein kinase C in neuronal function, we have localized phorbol ester receptors in the rat hippocampus by autoradiography and examined the electrophysiological effects of phorbol esters on hippocampal pyramidal neurons in vitro. Phorbol esters blocked a calcium-dependent potassium conductance. In addition, phorbol esters blocked the late hyperpolarization elicited by synaptic stimulation even though other synaptic potentials were not affected. The potencies of several phorbol esters in exerting these actions paralleled their affinities for protein kinase C, suggesting that protein kinase C regulates membrane ionic conductance.

  10. Normalization of Ca2+ signals by small oblique dendrites of CA1 pyramidal neurons.

    PubMed

    Frick, Andreas; Magee, Jeffrey; Koester, Helmut J; Migliore, Michele; Johnston, Daniel

    2003-04-15

    Oblique dendrites of CA1 pyramidal neurons predominate in stratum radiatum and receive approximately 80% of the synaptic input from Schaffer collaterals. Despite this fact, most of our understanding of dendritic signal processing in these neurons comes from studies of the main apical dendrite. Using a combination of Ca2+ imaging and whole-cell recording techniques in rat hippocampal slices, we found that the properties of the oblique dendrites differ markedly from those of the main dendrites. These different properties tend to equalize the Ca2+ rise from single action potentials as they backpropagate into the oblique dendrites from the main trunk. Evidence suggests that this normalization of Ca2+ signals results from a higher density of a transient, A-type K+ current [I(K(A))] in the oblique versus the main dendrites. The higher density of I(K(A)) may have important implications for our understanding of synaptic integration and plasticity in these structures.

  11. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites.

    PubMed

    Poolos, Nicholas P; Migliore, Michele; Johnston, Daniel

    2002-08-01

    The dendrites of pyramidal neurons have markedly different electrical properties from those of the soma, owing to the non-uniform distribution of voltage-gated ion channels in dendrites. It is thus possible that drugs acting on ion channels might preferentially alter dendritic, but not somatic, excitability. Using dendritic and somatic whole-cell and cell-attached recordings in rat hippocampal slices, we found that the anticonvulsant lamotrigine selectively reduced action potential firing from dendritic depolarization, while minimally affecting firing at the soma. This regional and input-specific effect resulted from an increase in the hyperpolarization-activated cation current (I(h)), a voltage-gated current present predominantly in dendrites. These results demonstrate that neuronal excitability can be altered by drugs acting selectively on dendrites, and suggest an important role for I(h) in controlling dendritic excitability and epileptogenesis.

  12. Glia-derived ATP inversely regulates excitability of pyramidal and CCK-positive neurons

    PubMed Central

    Tan, Zhibing; Liu, Yu; Xi, Wang; Lou, Hui-fang; Zhu, Liya; Guo, Zhifei; Mei, Lin; Duan, Shumin

    2017-01-01

    Astrocyte responds to neuronal activity with calcium waves and modulates synaptic transmission through the release of gliotransmitters. However, little is known about the direct effect of gliotransmitters on the excitability of neuronal networks beyond synapses. Here we show that selective stimulation of astrocytes expressing channelrhodopsin-2 in the CA1 area specifically increases the firing frequency of CCK-positive but not parvalbumin-positive interneurons and decreases the firing rate of pyramidal neurons, phenomena mimicked by exogenously applied ATP. Further evidences indicate that ATP-induced increase and decrease of excitability are caused, respectively, by P2Y1 receptor-mediated inhibition of a two-pore domain potassium channel and A1 receptor-mediated opening of a G-protein-coupled inwardly rectifying potassium channel. Moreover, the activation of ChR2-expressing astrocytes reduces the power of kainate-induced hippocampal ex vivo gamma oscillation. Thus, through distinct receptor subtypes coupled with different K+ channels, astrocyte-derived ATP differentially modulates the excitability of different types of neurons and efficiently controls the activity of neuronal network. PMID:28128211

  13. Dynamic Expression Patterns of Progenitor and Pyramidal Neuron Layer Markers in the Developing Human Hippocampus.

    PubMed

    Cipriani, Sara; Nardelli, Jeannette; Verney, Catherine; Delezoide, Anne-Lise; Guimiot, Fabien; Gressens, Pierre; Adle-Biassette, Homa

    2016-03-01

    The molecular mechanisms underlying the formation of hippocampus are unknown in humans. To improve our knowledge of molecules that potentially regulate pyramidal neurogenesis and layering in various hippocampal fields, we investigated the expression of progenitor markers and cell fate molecules from gestational week (GW) 9 to GW 20. At GW 9, the progenitor cell compartment of the hippocampal formation mainly consisted of PAX6(+) cells in the ventricular zone. Between GW 9 and 11, a second germinal area, the subventricular zone (SVZ), was formed, as shown by TBR2 labeling. Postmitotic markers (TBR1, CTIP2, SATB2, and CUX1) might reflect the inside-out layering of the plate from GW 11 onwards. TBR1(+) neurons appeared in the deep plate, whereas CTIP2(+), SATB2(+), and CUX1(+) neurons occupied the upper layers. From GW 16, differences in layer segregation were observed between the ammonic and subicular plates. Moreover, an ammonic-to-subicular maturation gradient was observed in germinal/postmitotic areas. Taken together, these findings demonstrate for the first time the presence of an SVZ in the hippocampus of human fetuses and laminar differences in transcription factor expression in the pyramidal layer of the human ammonic and subicular plate, and provide new information to further investigate the connectivity of the hippocampal formation.

  14. Action Potential Modulation in CA1 Pyramidal Neuron Axons Facilitates OLM Interneuron Activation in Recurrent Inhibitory Microcircuits of Rat Hippocampus

    PubMed Central

    Kim, Sooyun

    2014-01-01

    Oriens-lacunosum moleculare (O-LM) interneurons in the CA1 region of the hippocampus play a key role in feedback inhibition and in the control of network activity. However, how these cells are efficiently activated in the network remains unclear. To address this question, I performed recordings from CA1 pyramidal neuron axons, the presynaptic fibers that provide feedback innervation of these interneurons. Two forms of axonal action potential (AP) modulation were identified. First, repetitive stimulation resulted in activity-dependent AP broadening. Broadening showed fast onset, with marked changes in AP shape following a single AP. Second, tonic depolarization in CA1 pyramidal neuron somata induced AP broadening in the axon, and depolarization-induced broadening summated with activity-dependent broadening. Outside-out patch recordings from CA1 pyramidal neuron axons revealed a high density of α-dendrotoxin (α-DTX)-sensitive, inactivating K+ channels, suggesting that K+ channel inactivation mechanistically contributes to AP broadening. To examine the functional consequences of axonal AP modulation for synaptic transmission, I performed paired recordings between synaptically connected CA1 pyramidal neurons and O-LM interneurons. CA1 pyramidal neuron–O-LM interneuron excitatory postsynaptic currents (EPSCs) showed facilitation during both repetitive stimulation and tonic depolarization of the presynaptic neuron. Both effects were mimicked and occluded by α-DTX, suggesting that they were mediated by K+ channel inactivation. Therefore, axonal AP modulation can greatly facilitate the activation of O-LM interneurons. In conclusion, modulation of AP shape in CA1 pyramidal neuron axons substantially enhances the efficacy of principal neuron–interneuron synapses, promoting the activation of O-LM interneurons in recurrent inhibitory microcircuits. PMID:25409299

  15. Sonic Hedgehog Promotes Neurite Outgrowth of Primary Cortical Neurons Through Up-Regulating BDNF Expression.

    PubMed

    He, Weiliang; Cui, Lili; Zhang, Cong; Zhang, Xiangjian; He, Junna; Xie, Yanzhao

    2016-04-01

    Sonic hedgehog (Shh), a secreted glycoprotein factor, can activate the Shh pathway, which has been implicated in neuronal polarization involving neurite outgrowth. However, little evidence is available about the effect of Shh on neurite outgrowth in primary cortical neurons and its potential mechanism. Here, we revealed that Shh increased neurite outgrowth in primary cortical neurons, while the Shh pathway inhibitor (cyclopamine, CPM) partially suppressed Shh-induced neurite outgrowth. Similar results were found for the expressions of Shh and Patched genes in Shh-induced primary cortical neurons. Moreover, Shh increased the levels of brain-derived neurotrophic factor (BDNF) not only in lysates and in culture medium but also in the longest neurites of primary cortical neurons, which was partially blocked by CPM. In addition, blocking of BDNF action suppressed Shh-mediated neurite elongation in primary cortical neurons. In conclusion, these findings suggest that Shh promotes neurite outgrowth in primary cortical neurons at least partially through modulating BDNF expression.

  16. Short-term memory in networks of dissociated cortical neurons.

    PubMed

    Dranias, Mark R; Ju, Han; Rajaram, Ezhilarasan; VanDongen, Antonius M J

    2013-01-30

    Short-term memory refers to the ability to store small amounts of stimulus-specific information for a short period of time. It is supported by both fading and hidden memory processes. Fading memory relies on recurrent activity patterns in a neuronal network, whereas hidden memory is encoded using synaptic mechanisms, such as facilitation, which persist even when neurons fall silent. We have used a novel computational and optogenetic approach to investigate whether these same memory processes hypothesized to support pattern recognition and short-term memory in vivo, exist in vitro. Electrophysiological activity was recorded from primary cultures of dissociated rat cortical neurons plated on multielectrode arrays. Cultures were transfected with ChannelRhodopsin-2 and optically stimulated using random dot stimuli. The pattern of neuronal activity resulting from this stimulation was analyzed using classification algorithms that enabled the identification of stimulus-specific memories. Fading memories for different stimuli, encoded in ongoing neural activity, persisted and could be distinguished from each other for as long as 1 s after stimulation was terminated. Hidden memories were detected by altered responses of neurons to additional stimulation, and this effect persisted longer than 1 s. Interestingly, network bursts seem to eliminate hidden memories. These results are similar to those that have been reported from similar experiments in vivo and demonstrate that mechanisms of information processing and short-term memory can be studied using cultured neuronal networks, thereby setting the stage for therapeutic applications using this platform.

  17. Mutual information and redundancy in spontaneous communication between cortical neurons.

    PubMed

    Szczepanski, J; Arnold, M; Wajnryb, E; Amigó, J M; Sanchez-Vives, M V

    2011-03-01

    An important question in neural information processing is how neurons cooperate to transmit information. To study this question, we resort to the concept of redundancy in the information transmitted by a group of neurons and, at the same time, we introduce a novel concept for measuring cooperation between pairs of neurons called relative mutual information (RMI). Specifically, we studied these two parameters for spike trains generated by neighboring neurons from the primary visual cortex in the awake, freely moving rat. The spike trains studied here were spontaneously generated in the cortical network, in the absence of visual stimulation. Under these conditions, our analysis revealed that while the value of RMI oscillated slightly around an average value, the redundancy exhibited a behavior characterized by a higher variability. We conjecture that this combination of approximately constant RMI and greater variable redundancy makes information transmission more resistant to noise disturbances. Furthermore, the redundancy values suggest that neurons can cooperate in a flexible way during information transmission. This mostly occurs via a leading neuron with higher transmission rate or, less frequently, through the information rate of the whole group being higher than the sum of the individual information rates-in other words in a synergetic manner. The proposed method applies not only to the stationary, but also to locally stationary neural signals.

  18. Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects

    PubMed Central

    Chu, Hong-Yuan; Gu, Qinhua; Jin, Guo-Zhang; Hu, Guo-Yuan; Zhen, Xuechu

    2010-01-01

    Although the potent anti-parkinsonian action of the atypical D1-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D1 receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present study, the actions of SKF83959 on neuronal membrane potential and neuronal excitability were investigated in CA1 pyramidal neurons of rat hippocampal slices. SKF83959 (10–100 µM) caused a concentration-dependent depolarization, associated with a reduction of input resistance in CA1 pyramidal neurons. The depolarization was blocked neither by antagonists for D1, D2, 5-HT2A/2C receptors and α1-adrenoceptor, nor by intracellular dialysis of GDP-β-S. However, the specific HCN channel blocker ZD7288 (10 µM) antagonized both the depolarization and reduction of input resistance caused by SKF83959. In voltage-clamp experiments, SKF83959 (10–100 µM) caused a concentration-dependent increase of Ih current in CA1 pyramidal neurons, which was independent of D1 receptor activation. Moreover, SKF83959 (50 µM) caused a 6 mV positive shift in the activation curve of Ih and significantly accelerated the activation of Ih current. In addition, SKF83959 also reduced the neuronal excitability of CA1 pyramidal neurons, which was manifested by the decrease in the number and amplitude of action potentials evoked by depolarizing currents, and by the increase of firing threshold and rhoebase current. The above results suggest that SKF83959 increased Ih current through a D1 receptor-independent mechanism, which led to the depolarization of hippocampal CA1 pyramidal neurons. These findings provide a novel mechanism for the drug's neuroprotective effects, which may contributes to its therapeutic benefits in Parkinson's disease. PMID:20957037

  19. Cytosolic phospholipase A(2) alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment.

    PubMed

    Shen, Ying; Kishimoto, Koji; Linden, David J; Sapirstein, Adam

    2007-04-03

    The arachidonic acid-generating enzyme cytosolic phospholipase A(2) alpha (cPLA(2)alpha) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA(2)alpha toxicity have yet to be determined. Here, we used a model system exposing mouse hippocampal slices to NMDA as an excitotoxic injury, in combination with simultaneous patch-clamp recording and confocal Ca(2+) imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA(2)alpha null CA1 neurons. Bath application of NMDA evoked a slow inward current in voltage-clamped neurons (composed of both NMDA receptor-mediated and other conductances) that was smaller in cPLA(2)alpha null than in WT slices. This was not due to down-regulation of NMDA receptor function because NMDA receptor-mediated currents were equivalent in each genotype following brief photolysis of caged glutamate. Current-clamp recordings were made during and following NMDA exposure by eliciting a single action potential with a brief current injection. After NMDA exposure, WT CA1 neurons developed a spike-evoked plateau potential and an increased spike-evoked dendritic Ca(2+) transient. These effects were absent in CA1 neurons from cPLA(2)alpha null mice and WT neurons treated with a cPLA(2)alpha inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca(2+) enhancement in WT and cPLA(2)alpha null slices. NMDA application in WT and arachidonate applied to cPLA(2)alpha null cells occluded the effects of apamin/paxilline. These results indicate that cPLA(2)alpha activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.

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

    PubMed Central

    Ashhad, Sufyan

    2016-01-01

    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

  1. 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.

  2. Dense Neuron Clustering Explains Connectivity Statistics in Cortical Microcircuits

    PubMed Central

    Klinshov, Vladimir V.; Teramae, Jun-nosuke; Nekorkin, Vladimir I.; Fukai, Tomoki

    2014-01-01

    Local cortical circuits appear highly non-random, but the underlying connectivity rule remains elusive. Here, we analyze experimental data observed in layer 5 of rat neocortex and suggest a model for connectivity from which emerge essential observed non-random features of both wiring and weighting. These features include lognormal distributions of synaptic connection strength, anatomical clustering, and strong correlations between clustering and connection strength. Our model predicts that cortical microcircuits contain large groups of densely connected neurons which we call clusters. We show that such a cluster contains about one fifth of all excitatory neurons of a circuit which are very densely connected with stronger than average synapses. We demonstrate that such clustering plays an important role in the network dynamics, namely, it creates bistable neural spiking in small cortical circuits. Furthermore, introducing local clustering in large-scale networks leads to the emergence of various patterns of persistent local activity in an ongoing network activity. Thus, our results may bridge a gap between anatomical structure and persistent activity observed during working memory and other cognitive processes. PMID:24732632

  3. Pyramidal neurons of granular prefrontal cortex of the galago: complexity in evolution of the psychic cell in primates.

    PubMed

    Elston, Guy N; Elston, Alejandra; Casagrande, Vivien; Kaas, Jon H

    2005-07-01

    Typically, cognitive abilities of humans have been attributed to their greatly expanded cortical mantle, granular prefrontal cortex (gPFC) in particular. Recently we have demonstrated systematic differences in microstructure of gPFC in different species. Specifically, pyramidal cells in adult human gPFC are considerably more spinous than those in the gPFC of the macaque monkey, which are more spinous than those in the gPFC of marmoset and owl monkeys. As most cortical dendritic spines receive at least one excitatory input, pyramidal cells in these different species putatively receive different numbers of inputs. These differences in the gPFC pyramidal cell phenotype may be of fundamental importance in determining the functional characteristics of prefrontal circuitry and hence the cognitive styles of the different species. However, it remains unknown as to why the gPFC pyramidal cell phenotype differs between species. Differences could be attributed to, among other things, brain size, relative size of gPFC, or the lineage to which the species belong. Here we investigated pyramidal cells in the dorsolateral gPFC of the prosimian galago to extend the basis for comparison. We found these cells to be less spinous than those in human, macaque, and marmoset. Copyright (c) 2005 Wiley-Liss, Inc.

  4. Resveratrol attenuates early pyramidal neuron excitability impairment and death in acute rat hippocampal slices caused by oxygen-glucose deprivation

    PubMed Central

    Zhang, Huaqiu; Schools, Gary P.; Lei, Ting; Wang, Wei; Kimelberg, Harold; Zhou, Min

    2008-01-01

    Accumulating evidence indicates that the polyphenol resveratrol (trans-3, 5, 4′-trihydroxystibene, RVT) potently protects against cerebral ischemia neuronal damage due to its oxygen free radicals scavenging and antioxidant properties. However, it is unknown whether RVT can attenuate ischemia-induced early impairment of neuronal excitability. To address this question, we simulated ischemic conditions by applying oxygen-glucose deprivation (OGD) to acute rat hippocampal slices and examined the effect of RVT on OGD-induced pyramidal neuron excitability impairment using whole-cell patch clamp recording. 100 μM RVT largely inhibited the 15 min OGD-induced progressive membrane potential (Vm) depolarization and the reduction in evoked action potential frequency and amplitude in pyramidal neurons. In the parallel neuronal viability study using TO-PRO-3 iodide staining, 20 min OGD induced irreversible CA1 pyramidal neuronal death which was significantly reduced by 100 μM RVT. No similar effects were found with PQQ treatment, an antioxidant also showing potent neuroprotection in the rat rMCAO ischemia model. This suggests that antioxidant action per se, is unlikely accounting for the observed early effects of RVT. RVT also markedly reduced the frequency and amplitude of AMPA mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons, which is also an early consequence of OGD. RVT effects on neuronal excitability were inhibited by the large conductance potassium channel (BK channel) inhibitor paxilline. Together, these studies demonstrate that RVT attenuates OGD induced neuronal impairment occurring early in the simulated ischemia slice model by enhancing the activation of BK channel and reducing the OGD-enhanced AMPA/NMDA receptor mediated neuronal EPSCs. PMID:18495119

  5. Low-calcium field burst discharges of CA1 pyramidal neurones in rat hippocampal slices.

    PubMed Central

    Haas, H L; Jefferys, J G

    1984-01-01

    Incubation of rat hippocampal slices in solutions containing low Ca2+ and increased Mg2+ rapidly blocked synaptic responses and increased spontaneous firing of all the principal neurones. More remarkably, a rhythmic and synchronous bursting discharge developed, which was restricted to the CA1 population of pyramidal neurones. These 'field bursts' or 'spreading excitation' were rapidly abolished by restoring the Ca2+ to 2 mM, by increasing the Mg2+ to 6 mM or by decreasing K+ from 6 to 3 mM. The CA1 pyramidal cells depolarized after the change to the low-Ca2+ solution by about 10-20 mV. Individual field bursts were associated with a further depolarization of 10-12 mV surmounted by a burst of action potentials at about 20/s. This transient depolarization shift, recorded extracellularly as a negative field, could be attributed to the increase of [K+]o during the bursts, reaching 9-10 mM as measured by ion-sensitive electrodes. The bursts were followed by a hyperpolarization, seen extracellularly as a small soma-positive field, which was attributed to an electrogenic pump and/or a Ca2+-activated K+ conductance. Stimulation of the tightly packed pyramidal cell axons in the alveus elicited a train of population spikes, instead of the single spike normally seen, and could trigger a full field burst. Recordings of the alvear tract volley suggested that the repeated spikes arose within the pyramidal cells. Multiple recordings from CA1 revealed that field bursts usually, but by no means always, started near the caudal (subicular) end of the area. They spread through the cell layer at 0.04-0.12 m/s. The most rapid propagation was seen when the bursts had an abrupt onset; slower propagation (1-10 mm/s) occurred when the bursts started gradually, which generally was the case near the sites of burst initiation and termination. Usually the action potentials within each burst were synchronized into population spikes which spread across CA1 at 0.04-0.15 m/s. The site of initiation

  6. Anatomical and Electrophysiological Comparison of CA1 Pyramidal Neurons of the Rat and Mouse

    PubMed Central

    Routh, Brandy N.; Johnston, Daniel; Harris, Kristen

    2009-01-01

    The study of learning and memory at the single-neuron level has relied on the use of many animal models, most notably rodents. Although many physiological and anatomical studies have been carried out in rats, the advent of genetically engineered mice has necessitated the comparison of new results in mice to established results from rats. Here we compare fundamental physiological and morphological properties and create three-dimensional compartmental models of identified hippocampal CA1 pyramidal neurons of one strain of rat, Sprague–Dawley, and two strains of mice, C57BL/6 and 129/SvEv. We report several differences in neuronal physiology and anatomy among the three animal groups, the most notable being that neurons of the 129/SvEv mice, but not the C57BL/6 mice, have higher input resistance, lower dendritic surface area, and smaller spines than those of rats. A surprising species-specific difference in membrane resonance indicates that both mouse strains have lower levels of the hyperpolarization-activated nonspecific cation current Ih. Simulations suggest that differences in Ih kinetics rather than maximal conductance account for the lower resonance. Our findings indicate that comparisons of data obtained across strains or species will need to account for these and potentially other physiological and anatomical differences. PMID:19675296

  7. Cellular and Network Contributions to Excitability of Layer 5 Neocortical Pyramidal Neurons in the Rat

    PubMed Central

    Bar-Yehuda, Dan; Korngreen, Alon

    2007-01-01

    There is a considerable gap between investigating the dynamics of single neurons and the computational aspects of neural networks. A growing number of studies have attempted to overcome this gap using the excitation in brain slices elicited by various chemical manipulations of the bath solution. However, there has been no quantitative study on the effects of these manipulations on the cellular and network factors controlling excitability. Using the whole-cell configuration of the patch-clamp technique we recorded the membrane potential from the soma of layer 5 pyramidal neurons in acute brain slices from the somatosensory cortex of young rats at 22°C and 35°C. Using blockers of synaptic transmission, we show distinct changes in cellular properties following modification of the ionic composition of the artificial cerebrospinal fluid (ACSF). Thus both cellular and network changes may contribute to the observed effects of slice excitation solutions on the physiology of single neurons. Furthermore, our data suggest that the difference in the ionic composition of current standard ACSF from that of CSF measured in vivo cause ACSF to depress network activity in acute brain slices. This may affect outcomes of experiments investigating biophysical and physiological properties of neurons in such preparations. Our results strongly advocate the necessity of redesigning experiments routinely carried out in the quiescent acute brain slice preparation. PMID:18030343

  8. Anatomical and electrophysiological comparison of CA1 pyramidal neurons of the rat and mouse.

    PubMed

    Routh, Brandy N; Johnston, Daniel; Harris, Kristen; Chitwood, Raymond A

    2009-10-01

    The study of learning and memory at the single-neuron level has relied on the use of many animal models, most notably rodents. Although many physiological and anatomical studies have been carried out in rats, the advent of genetically engineered mice has necessitated the comparison of new results in mice to established results from rats. Here we compare fundamental physiological and morphological properties and create three-dimensional compartmental models of identified hippocampal CA1 pyramidal neurons of one strain of rat, Sprague-Dawley, and two strains of mice, C57BL/6 and 129/SvEv. We report several differences in neuronal physiology and anatomy among the three animal groups, the most notable being that neurons of the 129/SvEv mice, but not the C57BL/6 mice, have higher input resistance, lower dendritic surface area, and smaller spines than those of rats. A surprising species-specific difference in membrane resonance indicates that both mouse strains have lower levels of the hyperpolarization-activated nonspecific cation current I(h). Simulations suggest that differences in I(h) kinetics rather than maximal conductance account for the lower resonance. Our findings indicate that comparisons of data obtained across strains or species will need to account for these and potentially other physiological and anatomical differences.

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

    PubMed

    Jadi, Monika P; Behabadi, Bardia F; Poleg-Polsky, Alon; Schiller, Jackie; Mel, Bartlett W

    2014-05-01

    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.

  10. Local Control of Postinhibitory Rebound Spiking in CA1 Pyramidal Neuron Dendrites

    PubMed Central

    Ascoli, Giorgio A.; Gasparini, Sonia; Medinilla, Virginia; Migliore, Michele

    2012-01-01

    Postinhibitory rebound spiking is characteristic of several neuron types and brain regions, where it sustains spontaneous activity and central pattern generation. However, rebound spikes are rarely observed in the principal cells of the hippocampus under physiological conditions. We report that CA1 pyramidal neurons support rebound spikes mediated by hyperpolarization-activated inward current (Ih), and normally masked by A-type potassium channels (KA). In both experiments and computational models, KA blockage or reduction consistently resulted in a somatic action potential upon release from hyperpolarizing injections in the soma or main apical dendrite. Rebound spiking was systematically abolished by the additional blockage or reduction of Ih. Since the density of both KA and Ih increases in these cells with the distance from the soma, such “latent” mechanism may be most effective in the distal dendrites, which are targeted by a variety of GABAergic interneurons. Detailed computer simulations, validated against the experimental data, demonstrate that rebound spiking can result from activation of distal inhibitory synapses. In particular, partial KA reduction confined to one or few branches of the apical tuft may be sufficient to elicit a local spike following a train of synaptic inhibition. Moreover, the spatial extent and amount of KA reduction determines whether the dendritic spike propagates to the soma. These data suggest that the plastic regulation of KA can provide a dynamic switch to unmask postinhibitory spiking in CA1 pyramidal neurons. This newly discovered local modulation of postinhibitory spiking further increases the signal processing power of the CA1 synaptic microcircuitry. PMID:20445069

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

    PubMed

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

    2008-06-02

    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

  12. Impact of network activity on the integrative properties of neocortical pyramidal neurons in vivo.

    PubMed

    Destexhe, A; Paré, D

    1999-04-01

    During wakefulness, neocortical neurons are subjected to an intense synaptic bombardment. To assess the consequences of this background activity for the integrative properties of pyramidal neurons, we constrained biophysical models with in vivo intracellular data obtained in anesthetized cats during periods of intense network activity similar to that observed in the waking state. In pyramidal cells of the parietal cortex (area 5-7), synaptic activity was responsible for an approximately fivefold decrease in input resistance (Rin), a more depolarized membrane potential (Vm), and a marked increase in the amplitude of Vm fluctuations, as determined by comparing the same cells before and after microperfusion of tetrodotoxin (TTX). The model was constrained by measurements of Rin, by the average value and standard deviation of the Vm measured from epochs of intense synaptic activity recorded with KAc or KCl-filled pipettes as well as the values measured in the same cells after TTX. To reproduce all experimental results, the simulated synaptic activity had to be of relatively high frequency (1-5 Hz) at excitatory and inhibitory synapses. In addition, synaptic inputs had to be significantly correlated (correlation coefficient approximately 0.1) to reproduce the amplitude of Vm fluctuations recorded experimentally. The presence of voltage-dependent K+ currents, estimated from current-voltage relations after TTX, affected these parameters by <10%. The model predicts that the conductance due to synaptic activity is 7-30 times larger than the somatic leak conductance to be consistent with the approximately fivefold change in Rin. The impact of this massive increase in conductance on dendritic attenuation was investigated for passive neurons and neurons with voltage-dependent Na+/K+ currents in soma and dendrites. In passive neurons, correlated synaptic bombardment had a major influence on dendritic attenuation. The electrotonic attenuation of simulated synaptic inputs was

  13. Neurotoxicity of heroin-cocaine combinations in rat cortical neurons.

    PubMed

    Cunha-Oliveira, Teresa; Rego, A Cristina; Garrido, Jorge; Borges, Fernanda; Macedo, Tice; Oliveira, Catarina R

    2010-09-30

    Cocaine and heroin are frequently co-abused by humans, in a combination known as speedball. Recently, chemical interactions between heroin (Her) or its metabolite morphine (Mor) and cocaine (Coc) were described, resulting in the formation of strong adducts. In this work, we evaluated whether combinations of Coc and Her affect the neurotoxicity of these drugs, using rat cortical neurons incubated with Coc, Her, Her followed by Coc (Her+Coc) and Her plus Coc (Her:Coc, 1:1). Neurons exposed to Her, Her+Coc and Her:Coc exhibited a decrease in cell viability, which was more pronounced in neurons exposed to Her and Her+Coc, in comparison with neurons exposed to the mixture (Her:Coc). Cells exposed to the mixture showed increased intracellular calcium and mitochondrial dysfunction, as determined by a decrease in intracellular ATP levels and in mitochondrial membrane potential, displaying both apoptotic and necrotic characteristics. Conversely, a major increase in cytochrome c release, caspase 3-dependent apoptosis, and decreased metabolic neuronal viability were observed upon sequential exposure to Her and Coc. The data show that drug combinations potentiate cortical neurotoxicity and that the mode of co-exposure changes cellular death pathways activated by the drugs, strongly suggesting that chemical interactions occurring in Her:Coc, such as adduct formation, shift cell death mechanisms towards necrosis. Since impairment of the prefrontal cortex is involved in the loss of impulse control observed in drug addicts, the data presented here may contribute to explain the increase in treatment failure observed in speedball abusers.

  14. Human Temporal Cortical Single Neuron Activity during Language: A Review

    PubMed Central

    Ojemann, George A.

    2013-01-01

    Findings from recordings of human temporal cortical single neuron activity during several measures of language, including object naming and word reading are reviewed and related to changes in activity in the same neurons during recent verbal memory and verbal associative learning measures, in studies conducted during awake neurosurgery for the treatment of epilepsy. The proportion of neurons changing activity with language tasks was similar in either hemisphere. Dominant hemisphere activity was characterized by relative inhibition, some of which occurred during overt speech, possibly to block perception of one’s own voice. However, the majority seems to represent a dynamic network becoming active with verbal memory encoding and especially verbal learning, but inhibited during performance of overlearned language tasks. Individual neurons are involved in different networks for different aspects of language, including naming or reading and naming in different languages. The majority of the changes in activity were tonic sustained shifts in firing. Patterned phasic activity for specific language items was very infrequently recorded. Human single neuron recordings provide a unique perspective on the biologic substrate for language, for these findings are in contrast to many of the findings from other techniques for investigating this. PMID:24961418

  15. 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

  16. 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

  17. 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. Copyright © 2015 the American Physiological Society.

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

    PubMed Central

    Yamada-Hanff, Jason

    2015-01-01

    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. PMID:26289465

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

    PubMed

    Cheriyan, John; Kaushik, Mahesh K; Ferreira, Ashley N; Sheets, Patrick L

    2016-01-01

    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.

  20. Leading role of thalamic over cortical neurons during postinhibitory rebound excitation

    PubMed Central

    Grenier, F.; Timofeev, I.; Steriade, M.

    1998-01-01

    The postinhibitory rebound excitation is an intrinsic property of thalamic and cortical neurons that is implicated in a variety of normal and abnormal operations of neuronal networks, such as slow or fast brain rhythms during different states of vigilance as well as seizures. We used dual simultaneous intracellular recordings of thalamocortical neurons from the ventrolateral nucleus and neurons from the motor cortex, together with thalamic and cortical field potentials, to investigate the temporal relations between thalamic and cortical events during the rebound excitation that follows prolonged periods of stimulus-induced inhibition. Invariably, the rebound spike-bursts in thalamocortical cells occurred before the rebound depolarization in cortical neurons and preceded the peak of the depth-negative, rebound field potential in cortical areas. Also, the inhibitory-rebound sequences were more pronounced and prolonged in cortical neurons when elicited by thalamic stimuli, compared with cortical stimuli. The role of thalamocortical loops in the rebound excitation of cortical neurons was shown further by the absence of rebound activity in isolated cortical slabs. However, whereas thalamocortical neurons remained hyperpolarized after rebound excitation, because of the prolonged spike-bursts in inhibitory thalamic reticular neurons, the rebound depolarization in cortical neurons was prolonged, suggesting the role of intracortical excitatory circuits in this sustained activity. The role of intrathalamic events in triggering rebound cortical activity should be taken into consideration when analyzing information processes at the cortical level; at each step, corticothalamic volleys can set into action thalamic inhibitory neurons, leading to rebound spike-bursts that are transferred back to the cortex, thus modifying cortical activities. PMID:9811903

  1. [Collective behavior of cortical neurons upon long-term reinforcement].

    PubMed

    Zhadin, M N

    1995-01-01

    The differential equation describing behaviour of a large ensemble of cortical cells under the extended action of positive or negative reinforcement is derived. The equation is based on the concept that the reinforcement changes synaptic effectiveness in the learning process and a sign of this change depends on an average pulse frequency of a presynaptic neuron and a reinforcement sign. This equation turns out to be identical to the equation which was derived by us earlier based on the ideas that the reinforcement influences on a threshold of neuronal excitation. The comparison of the equation solution with our experimental data lends support for the solution and enables to believe that the serotoninergic system of the brain is a terminal link of the positive reinforcement system and that the noradrenalinergic one is a terminal link of the negative reinforcement.

  2. Pharmacology of postsynaptic metabotropic glutamate receptors in rat hippocampal CA1 pyramidal neurones.

    PubMed

    Davies, C H; Clarke, V R; Jane, D E; Collingridge, G L

    1995-09-01

    1. Activation of metabotropic glutamate receptors (mGluRs) in hippocampal CA1 pyramidal neurones leads to a depolarization, an increase in input resistance and a reduction in spike frequency adaptation (or accommodation). At least eight subtypes of mGluR have been identified which have been divided into three groups based on their biochemical, structural and pharmacological properties. It is unclear to which group the mGluRs which mediate these excitatory effects in hippocampal CA1 pyramidal neurones belong. We have attempted to address this question by using intracellular recording to test the effects of a range of mGluR agonists and antagonists, that exhibit different profiles of subtype specificity, on the excitability of CA1 pyramidal neurones in rat hippocampal slices. 2. (2S, 1'S,2'S)-2-(2'-carboxycyclopropyl)glycine (L-CCG1) caused a reduction in spike frequency adaptation and a depolarization (1-10 mV) associated with an increase in input resistance (10-30%) at concentrations (> or = 50 microM) that have been shown to activate mGluRs in groups I, II and III. Similar effects were observed with concentrations (50-100 microM) of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) and (1S,3S)-ACPD that exhibit little or no activity at group III mGluRs but which activate groups I and II mGluRs. 3. Inhibition of the release of endogenous neurotransmitters through activation of GABAB receptors, by use of 200 microM (+/-)-baclofen, did not alter the effects of (1S,3R)-ACPD (50-100 microM), (1S,3S)-ACPD (100 microM) or L-CCG1 (100 microM). This suggests that mGluR agonists directly activate CA1 pyramidal neurones. 4. Like these broad spectrum mGluR agonists, the racemic mixture ((SR)-) or resolved (S)-isomer of the selective group I mGluR agonist 3,5-dihydroxyphenylglycine ((SR)-DHPG (50-100 microM) or (S)-DHPG (20-50 microM)) caused a reduction in spike frequency adaptation concomitant with postsynaptic depolarization and an increase in input

  3. 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

  4. Evidence that dendritic mitochondria negatively regulate dendritic branching in pyramidal neurons in the neocortex.

    PubMed

    Kimura, Toshiya; Murakami, Fujio

    2014-05-14

    The precise branching patterns of dendritic arbors have a profound impact on information processing in individual neurons and the brain. These patterns are established by positive and negative regulation of the dendritic branching. Although the mechanisms for positive regulation have been extensively investigated, little is known about those for negative regulation. Here, we present evidence that mitochondria located in developing dendrites are involved in the negative regulation of dendritic branching. We visualized mitochondria in pyramidal neurons of the mouse neocortex during dendritic morphogenesis using in utero electroporation of a mitochondria-targeted fluorescent construct. We altered the mitochondrial distribution in vivo by overexpressing Mfn1, a mitochondrial shaping protein, or the Miro-binding domain of TRAK2 (TRAK2-MBD), a truncated form of a motor-adaptor protein. We found that dendritic mitochondria were preferentially targeted to the proximal portion of dendrites only during dendritic morphogenesis. Overexpression of Mfn1 or TRAK2-MBD depleted mitochondria from the dendrites, an effect that was accompanied by increased branching of the proximal portion of the dendrites. This dendritic abnormality cannot be accounted for by changes in the distribution of membrane trafficking organelles since the overexpression of Mfn1 did not alter the distributions of the endoplasmic reticulum, Golgi, or endosomes. Additionally, neither did these constructs impair neuronal viability or mitochondrial function. Therefore, our results suggest that dendritic mitochondria play a critical role in the establishment of the precise branching pattern of dendritic arbors by negatively affecting dendritic branching.

  5. 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

    2008-07-07

    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.

  6. 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…

  7. 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…

  8. Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia.

    PubMed

    Datta, Dibyadeep; Arion, Dominique; Corradi, John P; Lewis, David A

    2015-12-01

    Cognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the cell division cycle 42 (CDC42)-CDC42 effector protein (CDC42EP) signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia. We examined the integrity of the CDC42-p21-activated serine/threonine protein kinases (PAK)-LIM domain-containing serine/threonine protein kinases (LIMK) signaling pathway in schizophrenia in a layer-specific and cell type-specific fashion in DLPFC deep layer 3. Using laser microdissection, samples of DLPFC deep layer 3 were collected from 56 matched pairs of subjects with schizophrenia and comparison subjects, and levels of CDC42-PAK-LIMK pathway messenger RNAs were measured by quantitative polymerase chain reaction. These same transcripts also were quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from monkeys exposed to antipsychotics. Relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA, and PAK3 messenger RNA levels were significantly upregulated in subjects with schizophrenia in laminar and cellular samples. In contrast, CDC42 and PAK1 messenger RNA levels were significantly downregulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other comorbid factors. Findings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia. Copyright © 2015 Society of Biological Psychiatry

  9. Altered expression of CDC42 signaling pathway components in cortical layer 3 pyramidal cells in schizophrenia

    PubMed Central

    Datta, Dibyadeep; Arion, Dominique; Corradi, John P.; Lewis, David A.

    2015-01-01

    Background Cognitive dysfunction in schizophrenia is associated with a lower density of dendritic spines on deep layer 3 pyramidal cells in the dorsolateral prefrontal cortex (DLPFC). These alterations appear to reflect dysregulation of the actin cytoskeleton required for spine formation and maintenance. Consistent with this idea, altered expression of genes in the CDC42 (cell division cycle 42)-CDC42 effector protein signaling pathway, a key organizer of the actin cytoskeleton, was previously reported in DLPFC gray matter from subjects with schizophrenia. Here, we examined the integrity in schizophrenia of the CDC42-PAK-LIMK signaling pathway in a layer- and cell type-specific fashion in DLPFC deep layer 3. Methods Using laser microdissection, we collected samples of DLPFC deep layer 3 from 56 matched pairs of schizophrenia and comparison subjects and measured levels of CDC42-PAK-LIMK pathway mRNAs by qPCR. These same transcripts were also quantified by microarray in samples of individually microdissected deep layer 3 pyramidal cells from a subset of the same subjects and from antipsychotic-exposed monkeys. Results Relative to comparison subjects, CDC42EP4, LIMK1, LIMK2, ARHGDIA and PAK3 mRNA levels were significantly up-regulated in schizophrenia subjects in both laminar and cellular samples. In contrast, CDC42 and PAK1 mRNA levels were significantly down-regulated specifically in deep layer 3 pyramidal cells. These differences were not attributable to psychotropic medications or other co-morbid factors. Conclusions Findings from the present and prior studies converge on synergistic alterations in CDC42 signaling pathway that could destabilize actin dynamics and produce spine deficits preferentially in deep layer 3 pyramidal cells in schizophrenia. PMID:25981171

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

    PubMed

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

    2016-04-01

    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. 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). 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. 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. © 2016 Associated Professional Sleep Societies, LLC.

  11. Axon guidance of rat cortical neurons by microcontact printed gradients.

    PubMed

    Fricke, Rita; Zentis, Peter D; Rajappa, Lionel T; Hofmann, Boris; Banzet, Marko; Offenhäusser, Andreas; Meffert, Simone H

    2011-03-01

    Substrate-bound gradients expressed in numerous spatio-temporal patterns play a crucial role during the development of complex neural circuits. A deeper understanding of the axon guidance mechanism is provided by studying the effect of a defined substrate-bound cue on a confined neural network. In this study, we constructed a discontinuous substrate-bound gradient to control neuronal cell position, the path of neurite growth, and axon directionality. A variety of gradient patterns, with slight changes in slope, width, and length were designed and fabricated by microcontact printing using laminin/poly-l-lysine (PLL) or PLL alone. The gradients were tested for neurite growth and their impact on axon guidance of embryonic rat cortical neurons. The neurite length was determined and the axon was evaluated by Tau-1 immunostaining. We found that the microgradients of laminin/PLL and PLL directed neurons' adhesion, differentially controlled the neurite growth, and guided up to 84% of the axons. The effect of the protein micropattern on axon guidance and neurite growth depended on the protein and geometric parameters used. Our approach proved to be very successful in guiding axons of single multipolar neurons with very high efficiency. It could thereby be useful to engineer defined neural networks for analyzing signal processing of functional circuits, as well as to unravel fundamental questions of the axon guidance mechanism.

  12. 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

  13. Order-Based Representation in Random Networks of Cortical Neurons

    PubMed Central

    Kermany, Einat; Lyakhov, Vladimir; Zrenner, Christoph; Marom, Shimon

    2008-01-01

    The wide range of time scales involved in neural excitability and synaptic transmission might lead to ongoing change in the temporal structure of responses to recurring stimulus presentations on a trial-to-trial basis. This is probably the most severe biophysical constraint on putative time-based primitives of stimulus representation in neuronal networks. Here we show that in spontaneously developing large-scale random networks of cortical neurons in vitro the order in which neurons are recruited following each stimulus is a naturally emerging representation primitive that is invariant to significant temporal changes in spike times. With a relatively small number of randomly sampled neurons, the information about stimulus position is fully retrievable from the recruitment order. The effective connectivity that makes order-based representation invariant to time warping is characterized by the existence of stations through which activity is required to pass in order to propagate further into the network. This study uncovers a simple invariant in a noisy biological network in vitro; its applicability under in vivo constraints remains to be seen. PMID:19023409

  14. Imbalance between excitation and inhibition among synaptic connections of CA3 pyramidal neurons in cultured hippocampal slices.

    PubMed

    Cruz-Martín, Alberto; Schweizer, Felix E

    2008-03-01

    A fundamental property of small neuronal ensembles is their ability to be selectively activated by distinct stimuli. One cellular mechanism by which neurons achieve this input selectivity is by modulating the temporal dynamics of excitation and inhibition. We explored the interplay of excitation and inhibition in synapses between pyramidal neurons of cornu ammonis field 3 of the hippocampal formation (CA3) in cultured rat hippocampal slices, where activation of a single excitatory cell can readily recruit local interneurons. Simultaneous whole-cell recordings from pairs of CA3 pyramidal neurons revealed that the strength of connections was neither uniform nor balanced. Rather, stimulation of presynaptic neurons elicited distinct combinations of excitatory postsynaptic current-inhibitory postsynaptic current (EPSC-IPSC) amplitudes in the postsynaptic neurons. EPSC-IPSC sequences with small EPSCs had large IPSCs and sequences that contained large EPSCs had small IPSCs. In addition to differences in the amplitudes of the responses, the kinetics of the EPSCs were also different, creating distinct temporal dynamics of excitation and inhibition. Weaker EPSCs had significantly slower kinetics and were efficiently occluded by IPSCs, thereby further limiting their contribution to depolarizing the postsynaptic membrane. Our data suggest that hippocampal pyramidal cells may use an imbalance between excitation and inhibition as a filter to enhance selectivity toward preferential excitatory connections.

  15. Different patterns of motor activity induce differential plastic changes in pyramidal neurons in the motor cortex of rats: A Golgi study.

    PubMed

    Vázquez-Hernández, Nallely; González-Tapia, Diana C; Martínez-Torres, Nestor I; González-Tapia, David; González-Burgos, Ignacio

    2017-09-14

    Rehabilitation is a process which favors recovery after brain damage involving motor systems, and neural plasticity is the only real resource the brain has for inducing neurobiological events in order to bring about re-adaptation. Rats were placed on a treadmill and made to walk, in different groups, at different velocities and with varying degrees of inclination. Plastic changes in the spines of the apical and basal dendrites of fifth-layer pyramidal neurons in the motor cortices of the rats were detected after study with the Golgi method. Numbers of dendritic spines increased in the three experimental groups, and thin, mushroom, stubby, wide, and branched spines increased or decreased in proportion depending on the motor demands made of each group. Along with the numerical increase of spines, the present findings provide evidence that dendritic spines' geometrical plasticity is involved in the differential performance of motor activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Heterogeneous firing responses predict diverse couplings to presynaptic activity in mice layer V pyramidal neurons

    PubMed Central

    2017-01-01

    In this study, we present a theoretical framework combining experimental characterizations and analytical calculus to capture the firing rate input-output properties of single neurons in the fluctuation-driven regime. Our framework consists of a two-step procedure to treat independently how the dendritic input translates into somatic fluctuation variables, and how the latter determine action potential firing. We use this framework to investigate the functional impact of the heterogeneity in firing responses found experimentally in young mice layer V pyramidal cells. We first design and calibrate in vitro a simplified morphological model of layer V pyramidal neurons with a dendritic tree following Rall's branching rule. Then, we propose an analytical derivation for the membrane potential fluctuations at the soma as a function of the properties of the synaptic input in dendrites. This mathematical description allows us to easily emulate various forms of synaptic input: either balanced, unbalanced, synchronized, purely proximal or purely distal synaptic activity. We find that those different forms of dendritic input activity lead to various impact on the somatic membrane potential fluctuations properties, thus raising the possibility that individual neurons will differentially couple to specific forms of activity as a result of their different firing response. We indeed found such a heterogeneous coupling between synaptic input and firing response for all types of presynaptic activity. This heterogeneity can be explained by different levels of cellular excitability in the case of the balanced, unbalanced, synchronized and purely distal activity. A notable exception appears for proximal dendritic inputs: increasing the input level can either promote firing response in some cells, or suppress it in some other cells whatever their individual excitability. This behavior can be explained by different sensitivities to the speed of the fluctuations, which was previously

  17. Attentional modulation of firing rate varies with burstiness across putative pyramidal neurons in macaque visual area V4.

    PubMed

    Anderson, Emily B; Mitchell, Jude F; Reynolds, John H

    2011-07-27

    One of the most well established forms of attentional modulation is an increase in firing rate when attention is directed into the receptive field of a neuron. The degree of rate modulation, however, can vary considerably across individual neurons, especially among broad spiking neurons (putative pyramids). We asked whether this heterogeneity might be correlated with a neuronal response property that is used in intracellular recording studies to distinguish among distinct neuronal classes: the burstiness of the neuronal spike train. We first characterized the burst spiking behavior of visual area V4 neurons and found that this varies considerably across the population, but we did not find evidence for distinct classes of burst behavior. Burstiness did, however, vary more widely across the class of neurons that shows the greatest heterogeneity in attentional modulation, and within that class, burstiness helped account for differences in attentional modulation. Among these broad spiking neurons, rate modulation was primarily restricted to bursty neurons, which as a group showed a highly significant increase in firing rate with attention. Furthermore, every bursty broad spiking neuron whose firing rate was significantly modulated by attention exhibited an increase in firing rate. In contrast, non-bursty broad spiking neurons exhibited no net attentional modulation, and, although some individual neurons did show significant rate modulation, these were divided among neurons showing increases and decreases. These findings show that macaque area V4 shows a range of bursting behavior and that the heterogeneity of attentional modulation can be explained, in part, by variation in burstiness.

  18. 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

  19. Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma.

    PubMed

    Takahashi, D Koji; Gu, Feng; Parada, Isabel; Vyas, Shri; Prince, David A

    2016-07-01

    Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation ("undercut" or "UC") leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3days post UC injury (Graber and Prince 1999, 2004; Li et al. 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments.

  20. Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment

    PubMed Central

    Counts, Scott E.; Alldred, Melissa J.; Che, Shaoli; Ginsberg, Stephen D.; Mufson, Elliott J.

    2014-01-01

    Clinical neuropathologic studies suggest that the selective vulnerability of hippocampal CA1 pyramidal projection neurons plays a key role in the onset of cognitive impairment during the early phases of Alzheimer’s disease (AD). Disruption of this neuronal population likely affects hippocampal pre- and postsynaptic efficacy underlying episodic memory circuits. Therefore, identifying perturbations in the expression of synaptic gene products within CA1 neurons prior to frank AD is crucial for the development of disease modifying therapies. Here we used custom-designed microarrays to examine progressive alterations in synaptic gene expression within CA1 neurons in cases harvested from the Rush Religious Orders Study who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI, a putative prodromal AD stage), or mild/moderate AD. Quantitative analysis revealed that 21 out of 28 different transcripts encoding regulators of synaptic function were significantly downregulated (1.4 to 1.8 fold) in CA1 neurons in MCI and AD compared to NCI, whereas synaptic transcript levels were not significantly different between MCI and AD. The downregulated transcripts encoded regulators of presynaptic vesicle trafficking, including synaptophysin and synaptogyrin, regulators of vesicle docking and fusion/release, such as synaptotagmin and syntaxin 1, and regulators of glutamatergic postsynaptic function, including PSD-95 and synaptopodin. Clinical pathologic correlation analysis revealed that downregulation of these synaptic markers was strongly associated with poorer antemortem cognitive status and postmortem AD pathological criteria such as Braak stage, NIA-Reagan, and CERAD diagnosis. In contrast to the widespread loss of synaptic gene expression observed in CA1 neurons in MCI, transcripts encoding β-amyloid precursor protein (APP), APP family members, and regulators of APP metabolism were not differentially regulated in CA1 neurons across the

  1. Engineering cortical neuron polarity with nanomagnets on a chip.

    PubMed

    Kunze, Anja; Tseng, Peter; Godzich, Chanya; Murray, Coleman; Caputo, Anna; Schweizer, Felix E; Di Carlo, Dino

    2015-01-01

    Intra- and extracellular signaling play critical roles in cell polarity, ultimately leading to the development of functional cell-cell connections, tissues, and organs. In the brain, pathologically oriented neurons are often the cause for disordered circuits, severely impacting motor function, perception, and memory. Aside from control through gene expression and signaling pathways, it is known that nervous system development can be manipulated by mechanical stimuli (e.g., outgrowth of axons through externally applied forces). The inverse is true as well: intracellular molecular signals can be converted into forces to yield axonal outgrowth. The complete role played by mechanical signals in mediating single-cell polarity, however, remains currently unclear. Here we employ highly parallelized nanomagnets on a chip to exert local mechanical stimuli on cortical neurons, independently of the amount of superparamagnetic nanoparticles taken up by the cells. The chip-based approach was utilized to quantify the effect of nanoparticle-mediated forces on the intracellular cytoskeleton as visualized by the distribution of the microtubule-associated protein tau. While single cortical neurons prefer to assemble tau proteins following poly-L-lysine surface cues, an optimal force range of 4.5-70 pN by the nanomagnets initiated a tau distribution opposed to the pattern cue. In larger cell clusters (groups comprising six or more cells), nanoparticle-mediated forces induced tau repositioning in an observed range of 190-270 pN, and initiation of magnetic field-directed cell displacement was observed at forces above 300 pN. Our findings lay the groundwork for high-resolution mechanical encoding of neural networks in vitro, mechanically driven cell polarization in brain tissues, and neurotherapeutic approaches using functionalized superparamagnetic nanoparticles to potentially restore disordered neural circuits.

  2. Intracellular lucifer yellow staining and electron microscopy of neurones in slices of fixed epitumourous human cortical tissue.

    PubMed

    Buhl, E H; Schlote, W

    1987-01-01

    To examine the complete morphology and ultrastructure of lipofuscin-containing human pyramidal cells, epitumourous biopsy tissue was lightly fixed in paraformaldehyde. Cortical slice preparations were immersed in an injection chamber which was transferred to a fixed stage microscope. Electrodes were filled with an aqueous solution of the fluorescent dye Lucifer Yellow and attached to a micromanipulator. Epifluorescence illumination was used to visualize and guide the tip of the Lucifer pipette towards lipofuscin-containing, autofluorescent pyramidal cell somata. After impaling, the neuron was intracellularly stained by iontophoretic injection of Lucifer Yellow. Subsequent graphical reconstructions of injected pyramidal cells revealed complete filling of their dendritic arborizations. Comparison with published Golgi-material prepared for light microscopy revealed no patho-morphological changes in the tissue. Eventually, dye-filled cells were photooxidized in the presence of diaminobenzidine, which resulted in the formation of a homogeneously brown reaction product. Bleached cells were then osmicated and embedded in plastic. Electron microscopy revealed fine electron-opaque label distributed throughout the karyo- and cytoplasm and there were no apparent gross ultrastructural changes. Cytological details, such as organelles and membranes were not obscured by the reaction product. Due to its autofluorescence, the pigment part of the lipofuscin also underwent photoconversion, resulting in a highly enhanced electron-dense matrix. Due to its high selectivity and relative methodological simplicity, the approach presented is considered to be a promising alternative to the gold-toning modification of the Golgi-electron microscope technique.

  3. Active cortical innervation protects striatal neurons from slow degeneration in culture.

    PubMed

    Fishbein, Ianai; Segal, Menahem

    2011-03-01

    Spiny striatal GABAergic neurons receive most of their excitatory input from the neocortex. In culture, striatal neurons form inhibitory connections, but the lack of intrinsic excitatory afferents prevents the development of spontaneous network activity. Addition of cortical neurons to the striatal culture provides the necessary excitatory input to the striatal neurons, and in the presence of these neurons, striatal cultures do express spontaneous network activity. We have confirmed that cortical neurons provide excitatory drive to striatal neurons in culture using paired recording from cortical and striatal neurons. In the presence of tetrodotoxin (TTX), which blocks action potential discharges, the connections between cortical and striatal neurons are still formed, and in fact synaptic currents generated between them when TTX is removed are far larger than in control, undrugged cultures. Interestingly, the continuous presence of TTX in the co-culture caused striatal cell death. These observations indicate that the mere presence of cortical neurons is not sufficient to preserve striatal neurons in culture, but their synchronous activity, triggered by cortical excitatory synapses, is critical for the maintenance of viability of striatal neurons. These results have important implications for understanding the role of activity in neurodegenerative diseases of the striatum.

  4. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurones in the developing rat neocortex.

    PubMed Central

    Markram, H; Lübke, J; Frotscher, M; Roth, A; Sakmann, B

    1997-01-01

    1. Dual voltage recordings were made from pairs of adjacent, synaptically connected thick tufted layer 5 pyramidal neurones in brain slices of young rat (14-16 days) somatosensory cortex to examine the physiological properties of unitary EPSPs. Pre- and postsynaptic neurones were filled with biocytin and examined in the light and electron microscope to quantify the morphology of axonal and dendritic arbors and the number and location of synaptic contacts on the target neurone. 2. In 138 synaptic connections between pairs of pyramidal neurones 96 (70%) were unidirectional and 42 (30%) were bidirectional. The probability of finding a synaptic connection in dual recordings was 0.1. Unitary EPSPs evoked by a single presynaptic action potential (AP) had a mean peak amplitude ranging from 0.15 to 5.5 mV in different connections with a mean of 1.3 +/- 1.1 mV, a latency of 1.7 +/- 0.9 ms, a 20-80% rise time of 2.9 +/- 2.3 ms and a decay time constant of 40 +/- 18 ms at 32-24 degrees C and -60 +/- 2 mV membrane potential. 3. Peak amplitudes of unitary EPSPs fluctuated randomly from trial to trial. The coefficient of variation (c.v.) of the unitary EPSP amplitudes ranged from 0.13 to 2.8 in different synaptic connections (mean, 0.52; median, 0.41). The percentage of failures of single APs to evoke a unitary EPSP ranged from 0 to 73% (mean, 14%; median, 7%). Both c.v. and percentage of failures decreased with increasing mean EPSP amplitude. 4. Postsynaptic glutamate receptors which mediate unitary EPSPs at -60 mV were predominantly of the L-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor type. Receptors of the N-methyl-D-aspartate (NMDA) type contributed only a small fraction (< 20%) to the voltage-time integral of the unitary EPSP at -60 mV, but their contribution increased at more positive membrane potentials. 5. Branching patterns of dendrites and axon collaterals of forty-five synaptically connected neurones, when examined in the light microscope

  5. 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

  6. Cytokine immunoreactivity in cortical and subcortical neurons in periventricular leukomalacia: are cytokines implicated in neuronal dysfunction in cerebral palsy?

    PubMed

    Kadhim, Hazim; Tabarki, Brahim; De Prez, Carine; Sébire, Guillaume

    2003-03-01

    The major neuropathological substrate associated with cerebral palsy (CP) is a form of white matter (WM) injury known as periventricular leukomalacia (PVL). Proinflammatory cytokines were recently shown to be implicated in PVL pathogenesis. Many PVL patients develop cortical and deep gray neuronal dysfunctions such as epilepsy, cognitive deficits and extrapyramidal disorders. The precise nature of the relationship between the WM lesion and the subsequent neuronal disorders is unclear. Cytokines were shown to exert neurotoxicity in experimental models. This raises the need to investigate a possible noxious effect by cytokines on neuronal cortical development. In situ immunohistochemical methods were applied on 22 brains from infants both with PVL (study group) and without PVL (control group) to detect any immunoreactivity for cytokines (TNF-alpha, IL-1beta, IL-6) in cortical and gray matter neurons. While cortical and other neuronal structures in PVL brains did not display noticeable pathological anomalies, strong cytokine immunoreactivity was detected in many neurons in the neocortex, hippocampus, basal ganglia and thalamus. There were, however, regional differences in cytokine labeling. In addition, there was more TNF-alpha staining than IL-1beta; IL-6 was negative. In contrast, neuronal cytokine labeling in the "control" brains was negligible. In conclusion, we report and characterize, for the first time, the in situ immunoreactivity for proinflammatory cytokines in cortical and deep gray neurons in PVL. These findings might provide insights into the neuro-anatomical correlate for the intellectual deficits and the other cortical and deep gray neuronal dysfunctions associated with PVL.

  7. Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease

    PubMed Central

    Ramezani, Matin; Darbandi, Niloufar; Khodagholi, Fariba; Hashemi, Azam

    2016-01-01

    There is currently no treatment for effectively slowing the progression of Alzheimer's disease, so early prevention is very important. Numerous studies have shown that flavonoids can improve memory impairment. The present study investigated the effects of myricetin, a member of the flavonoids, on intracerebroventricular streptozotocin induced neuronal loss and memory impairment in rat models of Alzheimer's disease. Myricetin at 5 or 10 mg/kg was intraperitoneally injected into rats over 21 days. Control rats were treated with 10 mL/kg saline. Behavioral test (the shuttle box test) was performed on day 22 to examine learning and memory in rats. Immediately after that, hematoxylin-eosin staining was performed to observe the morphological change in hippocampal CA3 pyramidal neurons. Myricetin greatly increased the number of hippocampal CA3 pyramidal neurons and improved learning and memory impairments in rats with Alzheimer's disease. These findings suggest that myricetin is beneficial for treatment of Alzheimer's disease. PMID:28197195

  8. A slow excitatory postsynaptic current mediated by a novel metabotropic glutamate receptor in CA1 pyramidal neurons.

    PubMed

    Sheng, Nengyin; Yang, Jing; Silm, Katlin; Edwards, Robert H; Nicoll, Roger A

    2017-03-15

    Slow excitatory postsynaptic currents (EPSCs) mediated by metabotropic glutamate receptors (mGlu receptors) have been reported in several neuronal subtypes, but their presence in hippocampal pyramidal neurons remains elusive. Here we find that in CA1 pyramidal neurons a slow EPSC is induced by repetitive stimulation while ionotropic glutamate receptors and glutamate-uptake are blocked whereas it is absent in the VGLUT1 knockout mouse in which presynaptic glutamate is lost, suggesting the slow EPSC is mediated by glutamate activating mGlu receptors. However, it is not inhibited by known mGlu receptor antagonists. These findings suggest that this slow EPSC is mediated by a novel mGlu receptor, and that it may be involved in neurological diseases associated with abnormal high-concentration of extracellular glutamate. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

  9. Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways

    PubMed Central

    Taylor, Ruth DT; Madsen, Marita Grønning; Krause, Michael; Sampedro-Castañeda, Marisol; Stocker, Martin; Pedarzani, Paola

    2014-01-01

    The slow afterhyperpolarizing current (sIAHP) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP, resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sIAHP, underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc. PMID:23996525

  10. Gene expression levels assessed by CA1 pyramidal neuron and regional hippocampal dissections in Alzheimer’s disease

    PubMed Central

    Ginsberg, Stephen D.; Alldred, Melissa J.; Che, Shaoli

    2011-01-01

    To evaluate molecular signatures of an individual cell type in comparison to the associated region relevant towards understanding the pathogenesis of Alzheimer’s disease (AD), CA1 pyramidal neurons and the surrounding hippocampal formation were microaspirated via laser capture microdissection (LCM) from neuropathologically confirmed AD and age-matched control (CTR) subjects as well as from wild type mouse brain using single population RNA amplification methodology coupled with custom-designed microarray analysis with real-time quantitative polymerase-chain reaction (qPCR) validation. CA1 pyramidal neurons predominantly displayed downregulation of classes of transcripts related to synaptic transmission in AD versus CTR. Regional hippocampal dissections displayed downregulation of several overlapping genes found in the CA1 neuronal population related to neuronal expression, as well as upregulation of select transcripts indicative of admixed cell types including glial-associated markers and immediate-early and cell death genes. Gene level distributions observed in CA1 neurons and regional hippocampal dissections in wild type mice paralleled expression mosaics seen in postmortem human tissue. Microarray analysis was validated in qPCR studies using human postmortem brain tissue and CA1 sector and regional hippocampal dissections obtained from a mouse model of AD/Down syndrome (Ts65Dn mice) and normal disomic (2N) littermates. Classes of transcripts that have a greater percentage of the overall hybridization signal intensity within single neurons tended to be genes related to neuronal communication. The converse was also found, as classes of transcripts such as glial-associated markers were under represented in CA1 pyramidal neuron expression profiles relative to regional hippocampal dissections. These observations highlight a dilution effect that is likely to occur in conventional regional microarray and qPCR studies. Thus, single population studies of specific

  11. Resurgent Na+ current in pyramidal neurones of rat perirhinal cortex: axonal location of channels and contribution to depolarizing drive during repetitive firing

    PubMed Central

    Castelli, Loretta; Biella, Gerardo; Toselli, Mauro; Magistretti, Jacopo

    2007-01-01

    The perirhinal cortex (PRC) is a supra-modal cortical area that collects and integrates information originating from uni- and multi-modal neocortical regions and directed to the hippocampus. The mechanisms that underlie the specific excitable properties of the different PRC neuronal types are still largely unknown, and their elucidation may be important in understanding the integrative functions of PRC. In this study we investigated the expression and properties of resurgent Na+ current (INaR) in pyramidal neurones of rat PRC area 35 (layer II). Patch-clamp experiments in acute PRC slices were first carried out. A measurable INaR was expressed by a large majority of neurones (31 out of 35 cells). INaR appeared as an inward, slowly decaying current elicited upon step repolarization after depolarizations sufficient to induce nearly complete inactivation of the transient Na+ current (INaT). INaR had a peak amplitude of ∼2.5% that of INaT, and showed the typical biophysical properties also observed in other neuronal types (i.e. cerebellar Purkinje and granule cells), including a bell-shaped current–voltage relationship with a peak at approximately −40 mV, and a characteristic acceleration of activation and decay speed at potentials negative to −45 mV. Current-clamp experiments were then carried out in which repetitive action-potential discharge at various frequencies was induced with depolarizing current injection. The voltage signals thus obtained were then used as command waveforms for voltage-clamp recordings. These experiments showed that a Na+ current identifiable as INaR activates in the early interspike phase even at relatively high firing frequencies (20 Hz), thereby contributing to the depolarizing drive and possibly enhancing repetitive discharge. In acutely dissociated area 35 layer II neurones, as well as in nucleated patches from the same neurones, INaR was never observed, despite the presence of typical INaTs. Since in both preparations neuronal

  12. Factors mediating powerful voltage attenuation along CA1 pyramidal neuron dendrites

    PubMed Central

    Golding, Nace L; Mickus, Timothy J; Katz, Yael; Kath, William L; Spruston, Nelson

    2005-01-01

    We performed simultaneous patch-electrode recordings from the soma and apical dendrite of CA1 pyramidal neurons in hippocampal slices, in order to determine the degree of voltage attenuation along CA1 dendrites. Fifty per cent attenuation of steady-state somatic voltage changes occurred at a distance of 238 μm from the soma in control and 409 μm after blocking the hyperpolarization-activated (H) conductance. The morphology of three neurons was reconstructed and used to generate computer models, which were adjusted to fit the somatic and dendritic voltage responses. These models identify several factors contributing to the voltage attenuation along CA1 dendrites, including high axial cytoplasmic resistivity, low membrane resistivity, and large H conductance. In most cells the resting membrane conductances, including the H conductances, were larger in the dendrites than the soma. Simulations suggest that synaptic potentials attenuate enormously as they propagate from the dendrite to the soma, with greater than 100-fold attenuation for synapses on many small, distal dendrites. A prediction of this powerful EPSP attenuation is that distal synaptic inputs are likely only to be effective in the presence of conductance scaling, dendritic excitability, or both. PMID:16002454

  13. 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

  14. 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. © The Author(s) 2014.

  15. 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

  16. Modifications of excitatory and inhibitory transmission in rat hippocampal pyramidal neurons by acute lithium treatment.

    PubMed

    Wakita, Masahito; Nagami, Hideaki; Takase, Yuko; Nakanishi, Ryoji; Kotani, Naoki; Akaike, Norio

    2015-08-01

    The acute effects of high-dose Li(+) treatment on glutamatergic and GABAergic transmissions were studied in the "synaptic bouton" preparation of isolated rat hippocampal pyramidal neurons by using focal electrical stimulation. Both action potential-dependent glutamatergic excitatory and GABAergic inhibitory postsynaptic currents (eEPSC and eIPSC, respectively) were dose-dependently inhibited in the external media containing 30-150 mM Li(+), but the sensitivity for Li(+) was greater tendency for eEPSCs than for eIPSCs. When the effects of Li(+) on glutamate or GABAA receptor-mediated whole-cell responses (IGlu and IGABA) elicited by an exogenous application of glutamate or GABA were examined in the postsynaptic soma membrane of CA3 neurons, Li(+) slightly inhibited both IGlu and IGABA at the 150 mM Li(+) concentration. Present results suggest that acute treatment with high concentrations of Li(+) acts preferentially on presynaptic terminals, and that the Li(+)-induced inhibition may be greater for excitatory than for inhibitory transmission.

  17. 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.

  18. Electrophysiological Properties of CA1 Pyramidal Neurons along the Longitudinal Axis of the Mouse Hippocampus

    PubMed Central

    Milior, Giampaolo; Castro, Maria Amalia Di; Sciarria, Livio Pepe’; Garofalo, Stefano; Branchi, Igor; Ragozzino, Davide; Limatola, Cristina; Maggi, Laura

    2016-01-01

    Evidence for different physiological properties along the hippocampal longitudinal axis is emerging. Here, we examined the electrophysiological features of neurons at different dorso-ventral sites of the mouse CA1 hippocampal region. Cell position was defined with respect to longitudinal coordinates of each slice. We measured variations in neuronal excitability, subthreshold membrane properties and neurotransmitter responses along the longitudinal axis. We found that (i) pyramidal cells of the dorsal hippocampus (DH) were less excitable than those of the ventral hippocampus (VH). Resting Membrane Potential (RMP) was more hyperpolarized and somatic Input Resistance (Ri) was lower in DH compared to VH. (ii) The Paired-pulse ratio (PPR) of focally induced synaptic responses was systematically reduced from the DH to the VH; (iii) Long-term-potentiation was most pronounced in the DH and fell gradually in the intermediate hippocampus and in the VH; (iv) the frequency of miniature GABAergic events was higher in the VH than in the DH; (v) the PPR of evoked inhibitory post-synaptic current (IPSC) was higher in the DH than in the VH. These findings indicate an increased probability of both GABA and glutamate release and a reduced plasticity in the ventral compared to more dorsal regions of the hippocampus. PMID:27922053

  19. Factors determining the efficacy of distal excitatory synapses in rat hippocampal CA1 pyramidal neurones

    PubMed Central

    Andreasen, Mogens; Lambert, John D C

    1998-01-01

    A new preparation of the in vitro rat hippocampal slice has been developed in which the synaptic input to the distal apical dendrites of CA1 pyramidal neurones is isolated. This has been used to investigate the properties of distally evoked synaptic potentials.Distal paired-pulse stimulation (0.1 Hz) evoked a dendritic response consisting of a pair of EPSPs, which showed facilitation. The first EPSP had a rise time (10–90 %) of 2.2 ± 0.05 ms and a half-width of 9.1 ± 0.13 ms. The EPSPs were greatly reduced by CNQX (10 μm) and the remaining component could be enhanced in Mg2+-free Ringer solution and blocked by AP5 (50 μm). In 70 % of the dendrites, the EPSPs were followed by a prolonged after-hyperpolarizarion (AHP) which could be blocked by a selective and potent GABAB antagonist, CGP 55845A (2 μm). These results indicate that the EPSPs are primarily mediated by non-NMDA receptors with a small contribution from NMDA receptors, whereas the AHP is a GABAB receptor-mediated slow IPSP.With intrasomatic recordings, the rise time of proximally generated EPSPs (3.4 ± 0.1 ms) was half that of distally generated EPSPs (6.7 ± 0.5 ms), whereas the half-widths were similar (19.6 ± 0.8 ms and 23.8 ± 1 ms, respectively). These results indicate that propagation through the proximal apical dendrites slows the time-to-peak of distally generated EPSPs.Distal stimulation evoked spikes in 60 % of pyramidal neurones. At threshold, the distally evoked spike always appeared on the decaying phase of the dendritic EPSP, indicating that the spike is initiated at some distance proximal to the dendritic recording site. Furthermore, distally and proximally generated threshold spikes had a similar voltage dependency. These results therefore suggest that distally generated threshold spikes are primarily initiated at the initial segment.At threshold, spikes generated by stimulation of distal synapses arose from the decaying phase of the dendritic EPSPs with a latency determined by the

  20. Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones

    PubMed Central

    Corlew, Rebekah; Bosma, Martha M; Moody, William J

    2004-01-01

    Spontaneous [Ca2+]i transients were measured in the mouse neocortex from embryonic day 16 (E16) to postnatal day 6 (P6). On the day of birth (P0), cortical neurones generated widespread, highly synchronous [Ca2+]i transients over large areas. On average, 52% of neurones participated in these transients, and in 20% of slices, an average of 80% participated. These transients were blocked by TTX and nifedipine, indicating that they resulted from Ca2+ influx during electrical activity, and occurred at a mean frequency of 0.91 min−1. The occurrence of this activity was highly centred at P0: at E16 and P2 an average of only 15% and 24% of neurones, respectively, participated in synchronous transients, and they occurred at much lower frequencies at both E16 and P2 than at P0. The overall frequency of [Ca2+]i transients in individual cells did not change between E16 and P2, just the degree of their synchronicity. The onset of this spontaneous, synchronous activity correlated with a large increase in Na+ current density that occurred just before P0, and its cessation with a large decrease in resting resistance that occurred just after P2. This widespread, synchronous activity may serve a variety of functions in the neonatal nervous system. PMID:15297578

  1. 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.

  2. Prenatal morphine exposure reduces pyramidal neurons in CA1, CA2 and CA3 subfields of mice hippocampus

    PubMed Central

    Ghafari, Soraya; Golalipour, Mohammad Jafar

    2014-01-01

    Objective(s): This study was carried out to evaluate the effect of maternal morphine exposure during gestational and lactation period on pyramidal neurons of hippocampus in 18 and 32 day mice offspring. Materials and Methods: Thirty female mice were randomly allocated into cases and controls. In case group, animals received morphine sulfate 10 mg/kg.body weight intraperitoneally during 7 days before mating, gestational period (GD 0-21), 18 and 32 days after delivery in the experimental groups. The control animals received an equivalent volume of normal saline. Cerebrum of six offsprings in each group was removed and stained with cresyl violet and a monoclonal antibody NeuN for immunohistochemical detection of surviving pyramidal neurons. Quantitative computer-assisted morphometric study was done on hippocampus. Results: The number of pyramidal neurons in CA1, CA2 and CA3 in treated groups was significantly reduced in postnatal day 18 and 32 (P18, P32) compared to control groups (P<0.05). The mean thickness of the stratum pyramidal layer was decreased in the treated groups in comparison with controls (P<0.05), whereas the mean thickness of the stratum oriens, stratum radiatum and stratum lacunosum-moleculare in CA1 field and stratum oriens, stratum lucidum, stratum radiatum and stratum lacunosum-moleculare in CA3 were significantly increased in morphine treated group in comparison with controls (P<0.05). Conclusion: Morphine administration before and during pregnancy and during lactation period causes pyramidal neurons loss in 18 and 32 days old infant mice. PMID:24847417

  3. Neuronal cell sheet of cortical motor neuron phenotype derived from human iPS cells.

    PubMed

    Suzuki, Noboru; Arimitsu, Nagisa; Shimizu, Jun; Takai, Kenji; Hirotsu, Chieko; Takada, Erika; Ueda, Yuji; Wakisaka, Sueshige; Fujiwara, Naruyoshi; Suzuki, Tomoko

    2017-03-17

    Transplantation of stem cells which differentiate into more mature neural cells brings about functional improvement in pre-clinical studies of stroke. Previous transplant approaches in diseased brain have utilized injection of the cells in a cell suspension. In addition, neural stem cells were preferentially used as graft. However, these cells had no specific relationship to the damaged tissue of stroke patients and brain injury. The injection of cells in a suspension destroyed the cell-cell interactions that are suggested to be important for promoting functional integrity as cortical motor neurons.

    In order to obtain suitable cell types for grafting patients with stroke and brain damage, we have modified a protocol for differentiating human iPS cells to cells phenotypically related to cortical motor neurons. Moreover, we applied cell sheet technology to neural cell transplantation due to the idea in which keeping cell-cell communications was regarded as important for the repair of host brain architecture.

    Accordingly, we developed neuronal cell sheets being positive for FEZ family zinc finger 2 (Fezf2), COUP-TF-interacting protein 2 (CTIP2), insulin-like growth factor-binding protein 4 (Igfbp4), cysteine-rich motor neuron 1 protein precursor (CRIM1) and forkhead box p2 (Foxp2). These markers are associated with cortical motoneuron which is appropriate for the transplant location in the lesions. The sheets allowed preservation of cell-cell interactions shown by synapsin1 staining after transplantation to damaged mouse brain. The sheet transplantation brought about structural restoration partly and improvement of motor functions in hemiplegic mice.

    Collectively, the cell sheets were transplanted to damaged motor cortex in a way of a novel neuronal cell sheet that maintained cell-cell interactions and improved motor functions of the hemiplegic model mice. The motoneuron cell sheets are possibly applicable for stroke patients and patients with

  4. 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

  5. Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons.

    PubMed

    Edelmann, Elke; Cepeda-Prado, Efrain; Leßmann, Volkmar

    2017-01-01

    Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo. Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the

  6. 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

  7. 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.

  8. 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

  9. 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

  10. Early neurone loss in Alzheimer's disease: cortical or subcortical?

    PubMed

    Arendt, Thomas; Brückner, Martina K; Morawski, Markus; Jäger, Carsten; Gertz, Hermann-Josef

    2015-02-10

    Alzheimer's disease (AD) is a degenerative disorder where the distribution of pathology throughout the brain is not random but follows a predictive pattern used for pathological staging. While the involvement of defined functional systems is fairly well established for more advanced stages, the initial sites of degeneration are still ill defined. The prevailing concept suggests an origin within the transentorhinal and entorhinal cortex (EC) from where pathology spreads to other areas. Still, this concept has been challenged recently suggesting a potential origin of degeneration in nonthalamic subcortical nuclei giving rise to cortical innervation such as locus coeruleus (LC) and nucleus basalis of Meynert (NbM). To contribute to the identification of the early site of degeneration, here, we address the question whether cortical or subcortical degeneration occurs more early and develops more quickly during progression of AD. To this end, we stereologically assessed neurone counts in the NbM, LC and EC layer-II in the same AD patients ranging from preclinical stages to severe dementia. In all three areas, neurone loss becomes detectable already at preclinical stages and is clearly manifest at prodromal AD/MCI. At more advanced AD, cell loss is most pronounced in the NbM > LC > layer-II EC. During early AD, however, the extent of cell loss is fairly balanced between all three areas without clear indications for a preference of one area. We can thus not rule out that there is more than one way of spreading from its site of origin or that degeneration even occurs independently at several sites in parallel.

  11. 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. © 2016 Wiley Periodicals, Inc.

  12. Neuronal branching patterns and the economy of cortical wiring.

    PubMed

    Mitchison, G

    1991-08-22

    Keeping the volume of connections in the cortex as low as possible may be an important evolutionary constraint on the design of the brain. Much as an engineer tries to arrange the components of a computer in such a way as to give efficient wiring, so the brain may have evolved a layout of neuronal types which gives an economical use of axonal 'wiring'. One key difference between computer and brain is that connections in the brain take the form of elaborate branching structures. It is argued here that certain features of cortical mapping, such as the stripes and patches seen within cortical areas, may be adaptations which allow efficient wiring by such structures. Some simple calculations are given to support this, using as models for axonal arbors certain branching patterns which give a low volume of wiring. In particular, it is shown that a pattern of stripes can give economical wiring when axon diameters follow a law dp = dp1 + dp2 with p greater than 4, where d1 and d2 are the diameters of the daughter branches and d that of the parent.

  13. Repeated cocaine weakens GABAB-Girk signaling in Layer 5/6 pyramidal neurons in the prelimbic cortex

    PubMed Central

    Hearing, Matthew; Kotecki, Lydia; de Velasco, Ezequiel Marron Fernandez; Fajardo-Serrano, Ana; Luján, Rafael; Wickman, Kevin

    2013-01-01

    Summary Repeated cocaine exposure triggers adaptations in Layer 5/6 glutamatergic neurons in the medial prefrontal cortex (mPFC) that promote behavioral sensitization and drug-seeking behavior. While suppression of metabotropic inhibitory signaling has been implicated in these behaviors, underlying mechanisms are unknown. Here, we show that Girk/KIR3 channels mediate most of the GABAB receptor (GABABR)-dependent inhibition of Layer 5/6 pyramidal neurons in the mPFC and that repeated cocaine suppresses this pathway. This adaptation was selective for GABABR-dependent Girk signaling in Layer 5/6 pyramidal neurons of the prelimbic cortex (PrLC) and involved a D1/5 dopamine receptor- and phosphorylation-dependent internalization of GABABR and Girk channels. Persistent suppression of Girk signaling in Layer 5/6 of the dorsal mPFC enhanced cocaine-induced locomotor activity and occluded behavioral sensitization. Thus, the cocaine-induced suppression of GABABR-Girk signaling in Layer 5/6 pyramidal neurons of the prelimbic cortex appears to represent an early adaptation critical for promoting addiction-related behavior. PMID:24094109

  14. 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

  15. 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

  16. Foxp1 in forebrain pyramidal neurons controls gene expression required for spatial learning and synaptic plasticity.

    PubMed

    Araujo, Daniel J; Toriumi, Kazuya; Escamilla, Christine O; Kulkarni, Ashwinikumar; Anderson, Ashley G; Harper, Matthew; Usui, Noriyoshi; Ellegood, Jacob; Lerch, Jason P; Birnbaum, Shari G; Tucker, Haley O; Powell, Craig M; Konopka, Genevieve

    2017-10-04

    Genetic perturbations of the transcription factor Forkhead Box P1 (FOXP1) are causative for severe forms of autism spectrum disorder that are often comorbid with intellectual disability. Recent work has begun to reveal an important role for FoxP1 in brain development, but the brain-region-specific contributions of Foxp1 to autism and intellectual disability phenotypes have yet to be fully determined. Here, we describe Foxp1 conditional knockout (Foxp1(cKO) ) male and female mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1(cKO) mice exhibit behavioral phenotypes that are of potential relevance to autism spectrum disorder including hyperactivity, increased anxiety, communication impairments, and decreased sociability. In addition, Foxp1(cKO) mice have gross deficits in learning and memory tasks of relevance to intellectual disability. Using a genome-wide approach, we identified differentially expressed genes in the hippocampus of Foxp1(cKO) mice associated with synaptic function and development. Furthermore, using magnetic resonance imaging, we uncovered a significant reduction in the volumes of both the entire hippocampus as well as individual hippocampal subfields of Foxp1(cKO) mice. Finally, we observed reduced maintenance of long-term potentiation in area CA1 of the hippocampus in these mutant mice. Together, these data suggest that proper expression of Foxp1 in the pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors reminiscent of those seen in autism and intellectual disability. In particular, Foxp1 regulation of gene expression appears to be crucial for normal hippocampal development, CA1 plasticity, and spatial learning.SIGNIFICANCE STATEMENTLoss-of-function mutations in the transcription factor FOXP1 lead to autism spectrum disorder and intellectual disability. Understanding the potential brain

  17. Clotrimazole analogues: effective blockers of the slow afterhyperpolarization in cultured rat hippocampal pyramidal neurones

    PubMed Central

    Shah, M M; Miscony, Z; Javadzadeh-Tabatabaie, M; Ganellin, C R; Haylett, D G

    2001-01-01

    The pharmacology of the slow afterhyperpolarization (sAHP) was studied in cultured rat hippocampal pyramidal neurones. Clotrimazole, its in vivo metabolite, 2-chlorophenyl-bisphenyl-methanol (CBM) and the novel analogues, UCL 1880 and UCL 2027, inhibited the sIAHP with similar IC50s (1 – 2 μM). Clotrimazole and CBM also inhibited the high voltage-activated (HVA) Ca2+ current in pyramidal neurones with IC50s of 4.7 μM and 2.2 μM respectively. UCL 1880 was a less effective Ca2+ channel blocker, reducing the HVA Ca2+ current by 50% at 10 μM. At concentrations up to 10 μM, UCL 2027 had no effect on the Ca2+ current, indicating that its effects on the sIAHP were independent of Ca2+ channel block. Clotrimazole also inhibited both the outward holding current (IC50=2.8 μM) present at a potential of −50 mV and the apamin-sensitive medium AHP (mAHP; IC50≈amp;10 μM). The other clotrimazole analogues tested had smaller effects on these two currents. The present work also shows that 100 nM UCL 1848, an inhibitor of apamin-sensitive conductances, abolishes the mAHP. Currents were recorded from HEK293 cells transfected with hSK1 and rSK2. The SK currents were very sensitive to inhibition by UCL 1848 but were not significantly reduced by the sIAHP inhibitor, UCL 2027 (10 μM). 10 μM UCL 1880 reduced the hSK1 current by 40%. UCL 2027 appears to be the first relatively selective blocker of the sAHP to be described. Furthermore, the ability of UCL 2027 to block the sAHP with minimal effect on SK1 channel activity questions the role of this channel in the sAHP. PMID:11181430

  18. Properties of GABA-mediated synaptic potentials induced by zinc in adult rat hippocampal pyramidal neurones.

    PubMed Central

    Xie, X; Smart, T G

    1993-01-01

    1. Intracellular recording techniques were used to study the actions of the transition ion, zinc, on CA1 and CA3 pyramidal neurones in adult rat hippocampal slices. 2. Zinc (300 microM) hyperpolarized pyramidal neurones, increased the membrane excitability and also induced periodic, spontaneous giant depolarizing potentials associated with a conductance increase mechanism. 3. The occurrence of spontaneous giant depolarizations was dependent on the zinc concentration (10 microM-1 mM) with an apparent dissociation constant of 98 microM. The frequency of zinc-induced depolarizations was unaffected by the membrane potential from -50 to -100 mV. 4. Stimulation of the Schaffer collaterals or mossy fibre pathways evoked an excitatory and inhibitory synaptic potential complex. In the presence of zinc, nerve fibre stimulation evoked, in an all-or-none fashion, a giant depolarizing potential with an increased membrane conductance. Both spontaneous and evoked depolarizations were inhibited by 1 microM tetrodotoxin. 5. Evoked giant depolarizations were labile with too frequent stimulation resulting in a failure of generation. A minimum time of 140 s was required between stimuli to ensure successive giant depolarizations. 6. Spontaneous and evoked zinc-induced depolarizing potentials were inhibited by bicuculline (10 microM) or picrotoxin (40 microM) and enhanced by pentobarbitone (100 microM) or flurazepam (10 microM), suggesting that these potentials are mediated by activation of gamma-aminobutyric acidA (GABAA) receptors. 7. Ionophoretic application of GABA produced biphasic responses at -60 mV membrane potential. The reversal potentials for the depolarizing and hyperpolarizing GABA responses were -56 +/- 5 and -66 +/- 8 mV respectively. The giant depolarizations induced by zinc reversed at -57 +/- 4 mV. This suggests a dendritic location for the generation of these potentials. 8. Excitatory amino acid antagonists, 2-amino-5-phosphonovalerate (APV, 40 microM) or 6-cyano-7

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

    PubMed

    Lecrux, C; Hamel, E

    2016-10-05

    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'.

  20. Morphological aberrations in therapy-resistant partial epilepsy (TRPE). Confocal laser scanning and 3D reconstructions of Lucifer Yellow injected atypical pyramidal neurons in epileptic human cortex.

    PubMed

    Belichenko, P; Sourander, P; Dahlström, A

    1994-01-01

    Epileptic temporal and parietal cortices, removed from 6 patients with therapy-resistant (intractable) partial epilepsy (TRPE) during neurosurgery, were studied. Neurons (40-50 in each slice) in laminae I-VI and white matter were injected with Lucifer Yellow (LY). Samples were examined in a confocal laser scanning microscope (BioRad [Richmond, CA] MRC 600), and individual cells were scanned at 0.1-2 microns incremental levels. 2D maximal linear projection was used for overview. Frames (50-60) of scanned neurons were transformed into 3D volumes, using VoxelView software on a Silicone Graphics workstation, and rotated. All samples contained pyramidal neurons with duplicated apical dendrites, additional basal dendrites, or were misplaced in a horizontal position in the white matter. Rarely were such cells observed in normal cases. The relation between the observations and the disease is discussed. The attempt to simultaneously apply immunofluorescence was successful concerning synaptic vesicle antigens. This approach will be used for a detailed study of the synaptology of this disease.

  1. 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.

  2. Neurodegenerative, with expression ATF-2 by p38 in cortical neurons.

    PubMed

    Hosseini, M; Ostad, N; Parivar, K; Ghahremani, M H

    2010-03-01

    DNA damage, as an important initiator of neuronal cell death, has been implicated in numerous neurodegenerative conditions. We previously delineated several pathways that control embryonic cortical neuronal cell death evoked by the DNA-damaging agent, camptothecin. The topisomerase-1 inhibitor, camptothecin, has been shown to induce cortical neuronal cell death in a reproducible and synchronistic manner. Primary embryonic neuronal cell culture cortical neurons were prepared. In the study, the survival % of neurons in camptothecin P38 group, after 6 hours (85%), 24 hours (64%) and 48 hours (50%), compared to camptothecin ATF-2 and P38 group after 4 hours (97 and 95%), have been significantly lower, and the expression % of neurons in camptothecin P38 group , after 6 hours (20%), 24 hours (40%) and 48 hours (55%), compared to camptothecin ATF-2 and P38 group after 4 hours (5 and 3%) have been significant lower (p<0.05). The expression % of neurons in camptothecin P38 group, after 24 hours (40%), compared to camptothecin ATF-2 group after 24hours (30%), have been significant lower (p<0.05). This study revealed that camptothecin induces P38 expression and P38 in embryonic cortical neurons to determine the importance of the P38 pathway in neuronal death following DNA damage, and P38 is induce phosphorylation of ATF-2 in embryonic cortical neurons following DNA damage.

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

    PubMed

    Anderson, B; Harvey, T

    1996-06-07

    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.

  4. Age-related dysfunctions of the autophagy lysosomal pathway in hippocampal pyramidal neurons under proteasome stress.

    PubMed

    Gavilán, Elena; Pintado, Cristina; Gavilan, Maria P; Daza, Paula; Sánchez-Aguayo, Inmaculada; Castaño, Angélica; Ruano, Diego

    2015-05-01

    Autophagy plays a key role in the maintenance of cellular homeostasis, and autophagy deregulation gives rise to severe disorders. Many of the signaling pathways regulating autophagy under stress conditions are still poorly understood. Using a model of proteasome stress in rat hippocampus, we have characterized the functional crosstalk between the ubiquitin proteasome system and the autophagy-lysosome pathway, identifying also age-related modifications in the crosstalk between both proteolytic systems. Under proteasome inhibition, both autophagy activation and resolution were efficiently induced in young but not in aged rats, leading to restoration of protein homeostasis only in young pyramidal neurons. Importantly, proteasome stress inhibited glycogen synthase kinase-3β in young but activated in aged rats. This age-related difference could be because of a dysfunction in the signaling pathway of the insulin growth factor-1 under stress situations. Present data highlight the potential role of glycogen synthase kinase-3β in the coordination of both proteolytic systems under stress situation, representing a key molecular target to sort out this deleterious effect. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. The kinetics of multibranch integration on the dendritic arbor of CA1 pyramidal neurons

    PubMed Central

    Yang, Sunggu; Emiliani, Valentina; Tang, Cha-Min

    2014-01-01

    The process by which synaptic inputs separated in time and space are integrated by the dendritic arbor to produce a sequence of action potentials is among the most fundamental signal transformations that takes place within the central nervous system. Some aspects of this complex process, such as integration at the level of individual dendritic branches, have been extensively studied. But other aspects, such as how inputs from multiple branches are combined, and the kinetics of that integration have not been systematically examined. Using a 3D digital holographic photolysis technique to overcome the challenges posed by the complexities of the 3D anatomy of the dendritic arbor of CA1 pyramidal neurons for conventional photolysis, we show that integration on a single dendrite is fundamentally different from that on multiple dendrites. Multibranch integration occurring at oblique and basal dendrites allows somatic action potential firing of the cell to faithfully follow the driving stimuli over a significantly wider frequency range than what is possible with single branch integration. However, multibranch integration requires greater input strength to drive the somatic action potentials. This tradeoff between sensitivity and temporal precision may explain the puzzling report of the predominance of multibranch, rather than single branch, integration from in vivo recordings during presentation of visual stimuli. PMID:24860429

  6. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites.

    PubMed

    Frick, Andreas; Magee, Jeffrey; Johnston, Daniel

    2004-02-01

    The propagation and integration of signals in the dendrites of pyramidal neurons is regulated, in part, by the distribution and biophysical properties of voltage-gated ion channels. It is thus possible that any modification of these channels in a specific part of the dendritic tree might locally alter these signaling processes. Using dendritic and somatic whole-cell recordings, combined with calcium imaging in rat hippocampal slices, we found that the induction of long-term potentiation (LTP) was accompanied by a local increase in dendritic excitability that was dependent on the activation of NMDA receptors. These changes favored the back-propagation of action potentials into this dendritic region with a subsequent boost in the Ca(2+) influx. Dendritic cell-attached patch recordings revealed a hyperpolarized shift in the inactivation curve of transient, A-type K(+) currents that can account for the enhanced excitability. These results suggest an important mechanism associated with LTP for shaping signal processing and controlling dendritic function.

  7. Valproic acid inhibits TTX-resistant sodium currents in prefrontal cortex pyramidal neurons.

    PubMed

    Szulczyk, Bartlomiej; Nurowska, Ewa

    2017-09-16

    Valproic acid is frequently prescribed and used to treat epilepsy, bipolar disorder and other conditions. However, the mechanism of action of valproic acid has not been fully elucidated. The aim of this study was to assess the influence of valproic acid (200 μM) on TTX-resistant sodium currents in mPFC pyramidal neurons. Valproic acid inhibited the maximal amplitude and did not change the activation parameters of TTX-resistant sodium currents. Moreover, valproic acid (2 μM and 200 μM) shifted the TTX-resistant sodium channel inactivation curve towards hyperpolarisation. In the presence of valproic acid, TTX-resistant sodium currents recovered from inactivation more slowly. Valproic acid did not influence the use-dependent blockade of TTX-resistant sodium currents. This study suggests that a potential new mechanism of the antiepileptic action of valproic acid is, among others, inhibition of TTX-resistant sodium currents. Copyright © 2017 Elsevier Inc. All rights reserved.

  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. TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia

    PubMed Central

    Ye, M; Yang, W; Ainscough, J F; Hu, X-P; Li, X; Sedo, A; Zhang, X-H; Zhang, X; Chen, Z; Li, X-M; Beech, D J; Sivaprasadarao, A; Luo, J-H; Jiang, L-H

    2014-01-01

    Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn2+ level ([Zn2+]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia–reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn2+]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn2+]c but abolished the cytosolic Zn2+ accumulation during reperfusion as well as ROS-elicited increases in the [Zn2+]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn2+]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury. PMID:25429618

  10. Back-Propagation of Physiological Action Potential Output in Dendrites of Slender-Tufted L5A Pyramidal Neurons

    PubMed Central

    Grewe, Benjamin F.; Bonnan, Audrey; Frick, Andreas

    2009-01-01

    Pyramidal neurons of layer 5A are a major neocortical output type and clearly distinguished from layer 5B pyramidal neurons with respect to morphology, in vivo firing patterns, and connectivity; yet knowledge of their dendritic properties is scant. We used a combination of whole-cell recordings and Ca2+ imaging techniques in vitro to explore the specific dendritic signaling role of physiological action potential patterns recorded in vivo in layer 5A pyramidal neurons of the whisker-related ‘barrel cortex’. Our data provide evidence that the temporal structure of physiological action potential patterns is crucial for an effective invasion of the main apical dendrites up to the major branch point. Both the critical frequency enabling action potential trains to invade efficiently and the dendritic calcium profile changed during postnatal development. In contrast to the main apical dendrite, the more passive properties of the short basal and apical tuft dendrites prevented an efficient back-propagation. Various Ca2+ channel types contributed to the enhanced calcium signals during high-frequency firing activity, whereas A-type K+ and BKCa channels strongly suppressed it. Our data support models in which the interaction of synaptic input with action potential output is a function of the timing, rate and pattern of action potentials, and dendritic location. PMID:20508744

  11. Kv4 Accessory Protein DPPX (DPP6) is a Critical Regulator of Membrane Excitability in Hippocampal CA1 Pyramidal Neurons

    PubMed Central

    Kim, Jinhyun; Nadal, Marcela S.; Clemens, Ann M.; Baron, Matthew; Jung, Sung-Cherl; Misumi, Yoshio; Rudy, Bernardo; Hoffman, Dax A.

    2008-01-01

    A-type K+ currents have unique kinetic and voltage-dependent p