RESUMEN
A commonly observed neural correlate of working memory is firing that persists after the triggering stimulus disappears. Substantial effort has been devoted to understanding the many potential mechanisms that may underlie memory-associated persistent activity. These rely either on the intrinsic properties of individual neurons or on the connectivity within neural circuits to maintain the persistent activity. Nevertheless, it remains unclear which mechanisms are at play in the many brain areas involved in working memory. Herein, we first summarize the palette of different mechanisms that can generate persistent activity. We then discuss recent work that asks which mechanisms underlie persistent activity in different brain areas. Finally, we discuss future studies that might tackle this question further. Our goal is to bridge between the communities of researchers who study either single-neuron biophysical, or neural circuit, mechanisms that can generate the persistent activity that underlies working memory.
Asunto(s)
Potenciales de Acción/fisiología , Corteza Cerebral/fisiología , Memoria a Corto Plazo/fisiología , Modelos Neurológicos , Red Nerviosa/fisiología , Animales , Neuronas/fisiología , Transmisión Sináptica/fisiologíaRESUMEN
Many neurons exhibit regular firing that is limited to the duration and intensity of depolarizing stimuli. However, some neurons exhibit all-or-nothing plateau potentials that, once elicited, can lead to prolonged activity that is independent of stimulus intensity or duration. To better understand this diversity of information processing, we compared the voltage-gated and Ca2+-gated currents of three identified neurons from hermaphroditic Aplysia californica Two of these neurons, B51 and B64, generated plateau potentials and a third neuron, B8, exhibited regular firing and was incapable of generating a plateau potential. With the exception of the Ca2+-gated potassium current (I KCa), all three neuron types expressed a similar array of outward and inward currents, but with distinct voltage-dependent properties for each neuron type. Inhibiting voltage-gated Ca2+ channels with Ni+ prolonged the plateau potential, indicating I KCa is important for plateau potential termination. In contrast, inhibiting persistent Na+ (I NaP) blocked plateau potentials, empirically and in simulations. Surprisingly, the properties and level of expression of I NaP were similar in all three neurons, indicating that the presence of I NaP does not distinguish between regular-firing neurons and neurons capable of generating plateau potentials. Rather, the key distinguishing factor is the relationship between I NaP and outward currents such as the delayed outward current (I D), and I KCa We then demonstrated a technique for predicting complex physiological properties such as plateau duration, plateau amplitude, and action potential duration as a function of parameter values, by fitting a curve in parameter space and projecting the curve beyond the tested values.SIGNIFICANCE STATEMENT Plateau potentials are intrinsic properties of neurons that are important for information processing in a wide variety of nervous systems. We examined three identified neurons in Aplysia californica with different propensities to generate a plateau potential. No single conductance was found to distinguish plateau generating neurons. Instead, plateau generation depended on the ratio between persistent Na+ current (I NaP), which favored plateaus, and outward currents such as I KCa, which facilitated plateau termination. Computational models revealed a relationship between the individual currents that predicted the features of simulated plateau potentials. These results provide a more solid understanding of the conductances that mediate plateau generation.
Asunto(s)
Calcio , Neuronas , Calcio/metabolismo , Neuronas/fisiología , Potenciales de Acción/fisiologíaRESUMEN
Striatal spiny projection neurons (SPNs) receive convergent excitatory synaptic inputs from the cortex and thalamus. Activation of spatially clustered and temporally synchronized excitatory inputs at the distal dendrites could trigger plateau potentials in SPNs. Such supralinear synaptic integration is crucial for dendritic computation. However, how plateau potentials interact with subsequent excitatory and inhibitory synaptic inputs remains unknown. By combining computational simulation, two-photon imaging, optogenetics, and dual-color uncaging of glutamate and GABA, we demonstrate that plateau potentials can broaden the spatiotemporal window for integrating excitatory inputs and promote spiking. The temporal window of spiking can be delicately controlled by GABAergic inhibition in a cell-type-specific manner. This subtle inhibitory control of plateau potential depends on the location and kinetics of the GABAergic inputs and is achieved by the balance between relief and reestablishment of NMDA receptor Mg2+ block. These findings represent a mechanism for controlling spatiotemporal synaptic integration in SPNs.
Asunto(s)
Dendritas/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Neuronas/fisiología , Animales , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Dendritas/metabolismo , Femenino , Ácido Glutámico/metabolismo , Masculino , Ratones , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiología , Transmisión Sináptica/fisiología , Tálamo/metabolismo , Tálamo/fisiología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
We here reconsider current theories of neural ensembles in the context of recent discoveries about neuronal dendritic physiology. The key physiological observation is that the dendritic plateau potential produces sustained depolarization of the cell body (amplitude 10-20 mV, duration 200-500 ms). Our central hypothesis is that synaptically-evoked dendritic plateau potentials lead to a prepared state of a neuron that favors spike generation. The plateau both depolarizes the cell toward spike threshold, and provides faster response to inputs through a shortened membrane time constant. As a result, the speed of synaptic-to-action potential (AP) transfer is faster during the plateau phase. Our hypothesis relates the changes from "resting" to "depolarized" neuronal state to changes in ensemble dynamics and in network information flow. The plateau provides the Prepared state (sustained depolarization of the cell body) with a time window of 200-500 ms. During this time, a neuron can tune into ongoing network activity and synchronize spiking with other neurons to provide a coordinated Active state (robust firing of somatic APs), which would permit "binding" of signals through coordination of neural activity across a population. The transient Active ensemble of neurons is embedded in the longer-lasting Prepared ensemble of neurons. We hypothesize that "embedded ensemble encoding" may be an important organizing principle in networks of neurons.
Asunto(s)
Dendritas/fisiología , Potenciales de la Membrana/fisiología , Modelos Neurológicos , Neuronas/fisiología , Percepción/fisiología , Animales , Sincronización Cortical , Ácido Glutámico/fisiología , Humanos , Vías Nerviosas/fisiologíaRESUMEN
The primary literature, as an adjunct to textbooks, lectures, problem sets, and laboratories, has become integral to most undergraduate neuroscience courses by extending learning to topics outside the scope of introductory textbooks, providing insight into experimental methods and design, and offering a platform for critical thinking, independent learning, and student presentations. While introductory and intermediate textbooks cover "Hodgkin-Huxley" (H-H) Na and K channels thoroughly, the characteristics of diverse calcium, chloride, and other sodium and potassium channels, and especially the resulting emergent cellular properties and their functional consequences, receive far less coverage. The specific aim of this report is to identify, summarize, and pedagogically evaluate six articles that describe the biophysical channel properties, resulting cellular emergent properties, and potential functions of two types of somato-dendritic calcium channels: type T- and L- type channels. The three-tier vertical organization (channel, emergence, function) across multiple channels (T-, L-type) will help students connect information across parallel and hierarchical levels of analysis.
RESUMEN
Dendritic NMDA spike/plateau potentials, first discovered in cortical pyramidal neurons, provide supralinear integration of synaptic inputs on thin and distal dendrites, thereby increasing the impact of these inputs on the soma. The more specific functional role of these potentials has been difficult to clarify, partly due to the complex circuitry of cortical neurons. Thalamocortical (TC) neurons in the dorsal lateral geniculate nucleus participate in simpler circuits. They receive their primary afferent input from retina and send their output to visual cortex. Cortex, in turn, regulates this output through massive feedback to distal dendrites of the TC neurons. The TC neurons can operate in two modes related to behavioral states: burst mode prevailing during sleep, when T-type calcium bursts largely disrupt the transfer of signals from retina to cortex, and tonic mode, which provides reliable transfer of retinal signals to cortex during wakefulness. We studied dendritic potentials in TC neurons with combined two-photon calcium imaging and whole-cell recording of responses to local dendritic glutamate iontophoresis in acute brain slices from mice. We found that NMDA spike/plateaus can be elicited locally at distal dendrites of TC neurons. We suggest that these dendritic potentials have important functions in the cortical regulation of thalamocortical transmission. NMDA spike/plateaus can induce shifts in the functional mode from burst to tonic by blockade of T-type calcium conductances. Moreover, in tonic mode, they can facilitate the transfer of retinal signals to cortex by depolarization of TC neurons.
Asunto(s)
Potenciales de Acción/fisiología , Corteza Cerebral/fisiología , Dendritas/fisiología , Neuronas/fisiología , Tálamo/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Corteza Cerebral/efectos de los fármacos , Dendritas/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Femenino , Ácido Glutámico/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Piperazinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tálamo/efectos de los fármacosRESUMEN
Motivated behaviors such as feeding depend on the functional properties of decision neurons to provide the flexibility required for behavioral adaptation. Here, we analyzed the ionic basis of the endogenous membrane properties of an identified decision neuron (B63) that drive radula biting cycles underlying food-seeking behavior in Aplysia. Each spontaneous bite cycle arises from the irregular triggering of a plateau-like potential and resultant bursting by rhythmic subthreshold oscillations in B63's membrane potential. In isolated buccal ganglion preparations, and after synaptic isolation, the expression of B63's plateau potentials persisted after removal of extracellular calcium, but was completely suppressed in a tetrodotoxin (TTX)- containing bath solution, thereby indicating the contribution of a transmembrane Na+ influx. Potassium outward efflux through tetraethylammonium (TEA)- and calcium-sensitive channels was found to contribute to each plateau's active termination. This intrinsic plateauing capability, in contrast to B63's membrane potential oscillation, was blocked by the calcium-activated non-specific cationic current (ICAN) blocker flufenamic acid (FFA). Conversely, the SERCA blocker cyclopianozic acid (CPA), which abolished the neuron's oscillation, did not prevent the expression of experimentally evoked plateau potentials. These results therefore indicate that the dynamic properties of the decision neuron B63 rely on two distinct mechanisms involving different sub-populations of ionic conductances.
Asunto(s)
Aplysia , Calcio , Animales , Aplysia/fisiología , Sodio , Neuronas/fisiología , Potenciales de la Membrana/fisiología , Potenciales de Acción/fisiologíaRESUMEN
Investigations into seizure initiation, in recent years, have focused almost entirely upon alterations of interneuronal function, chloride homeostasis, and extracellular potassium levels. In contrast, little attention has been directed toward a possible role of dendritic plateau potentials in the actual ictogenic transition, despite a substantial literature dating back 40 years regarding its importance generally in epilepsy. Here, we argue that an increase in dendritic excitability, coordinated across the population of pyramidal cells, is a key stage in ictogenesis.
RESUMEN
To successfully perform goal-directed navigation, animals must know where they are and what they are doing-e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this "where/what" code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on available cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.
Asunto(s)
Región CA1 Hipocampal , Plasticidad Neuronal , Animales , Región CA1 Hipocampal/fisiología , Hipocampo/fisiología , Aprendizaje , Ratones , Plasticidad Neuronal/fisiología , Células Piramidales/fisiologíaRESUMEN
Oriens-lacunosum moleculare (OLM) cells are hippocampal inhibitory interneurons that are implicated in the regulation of information flow in the CA1 circuit, inhibiting cortical inputs to distal pyramidal cell dendrites, whilst disinhibiting CA3 inputs to pyramidal cells. OLM cells express metabotropic cholinergic (mAChR) and glutamatergic (mGluR) receptors, so modulation of these cells via these receptors may contribute to switching between functional modes of the hippocampus. Using a transgenic mouse line to identify OLM cells, we found that both mAChR and mGluR activation caused the cells to exhibit long-lasting depolarizing plateau potentials following evoked spike trains. Both mAChR- and mGluR-induced plateau potentials were eliminated by blocking transient receptor potential (TRP) channels, and were dependent on intracellular calcium concentration and calcium entry. Pharmacological tests indicated that Group I mGluRs are responsible for the glutamatergic induction of plateaus. There was also a pronounced synergy between the cholinergic and glutamatergic modulation, plateau potentials being generated by agonists applied together at concentrations too low to elicit any change when applied individually. This synergy could enable OLM cells to function as coincidence detectors of different neuromodulatory systems, leading to their enhanced and prolonged activation and a functional change in information flow within the hippocampus.
RESUMEN
The recent electrophysiological characterization of TH-expressing GABAergic interneurons (THINs) in the neostriatum revealed an unexpected degree of diversity of interneurons in this brain area (Ibáñez-Sandoval et al., 2010, Unal et al., 2011, 2015). Despite being relatively few in number, THINs may play a significant role in transmitting and distributing extra- and intrastriatal neuromodulatory signals in the striatal circuitry. Here we investigated the dopaminergic and cholinergic regulation of THINs in vitro. We found that the dominant effect of dopamine was a dramatic enhancement of the ability of THINs to generate long-lasting depolarizing plateau potentials (PPs). Interestingly, the same effect could also be elicited by amphetamine-induced release of endogenous dopamine suggesting that THINs may exhibit similar responses to changes in extracellular dopamine concentration in vivo. The enhancement of PPs in THINs is perhaps the most pronounced effect of dopamine on the intrinsic excitability of neostriatal neurons described to date. Further, we demonstrate that all subtypes of THINSs tested also express nicotinic cholinergic receptors. All THIS responded, albeit differentially, with depolarization, PPs and spiking to brief application of nicotinic agonists. Powerful modulation of the nonlinear integrative properties of THINs by dopamine and the direct depolarization of these neurons by acetylcholine may play important roles in mediating the effects of these neuromodulators in the neostriatum with potentially important implications for understanding the mechanisms of neuropsychiatric disorders affecting the basal ganglia.
Asunto(s)
Acetilcolina/metabolismo , Dopamina/metabolismo , Interneuronas/fisiología , Neostriado/fisiología , Tirosina 3-Monooxigenasa/metabolismo , Animales , Estimulación Eléctrica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Interneuronas/citología , Interneuronas/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones Transgénicos , Neostriado/citología , Neostriado/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5/agonistas , Receptores de Dopamina D5/metabolismo , Receptores Nicotínicos/metabolismo , Técnicas de Cultivo de Tejidos , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Thin basal dendrites can strongly influence neuronal output via generation of dendritic spikes. It was recently postulated that glial processes actively support dendritic spikes by either ceasing glutamate uptake or by actively releasing glutamate and adenosine triphosphate (ATP). We used calcium imaging to study the role of NR2C/D-containing N-methyl-d-aspartate (NMDA) receptors and adenosine A1 receptors in the generation of dendritic NMDA spikes and plateau potentials in basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. We found that NR2C/D glutamate receptor subunits contribute to the amplitude of synaptically evoked NMDA spikes. Dendritic calcium signals associated with glutamate-evoked dendritic plateau potentials were significantly shortened upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D receptors prolong the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, adenosine A1 receptors act to abbreviate dendritic and somatic signals via the activation of dendritic K(+) current. This current is characterized as a slow-activating outward-rectifying voltage- and adenosine-gated current, insensitive to 4-aminopyridine but sensitive to TEA. Our data support the hypothesis that the release of glutamate and ATP from neurons or glia contribute to initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials.
Asunto(s)
Dendritas/metabolismo , Ácido Glutámico/metabolismo , N-Metilaspartato/metabolismo , Corteza Prefrontal/citología , Células Piramidales/metabolismo , Receptor de Adenosina A1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Potenciales Sinápticos/fisiología , Animales , Dendritas/fisiología , Compuestos de Diazonio , Ratones , Piperidinas , Corteza Prefrontal/fisiología , PiridinasRESUMEN
Intrinsic neurons within the mushroom body of the insect brain, called Kenyon cells, play an important role in olfactory associative learning. In this study, we examined the ionic mechanisms mediating the intrinsic excitability of Kenyon cells in the cricket Gryllus bimaculatus. A perforated whole-cell clamp study using ß-escin indicated the existence of several inward and outward currents. Three types of inward currents (INaf, INaP, and ICa) were identified. The transient sodium current (INaf) activated at -40 mV, peaked at -26 mV, and half-inactivated at -46.7 mV. The persistent sodium current (INaP) activated at -51 mV, peaked at -23 mV, and half-inactivated at -30.7 mV. Tetrodotoxin (TTX; 1 µM) completely blocked both INaf and INaP, but 10nM TTX blocked INaf more potently than INaP. Cd(2+) (50 µM) potently blocked INaP with little effect on INaf. Riluzole (>20 µM) nonselectively blocked both INaP and INaf. The voltage-dependent calcium current (ICa) activated at -30 mV, peaked at -11.3 mV, and half-inactivated at -34 mV. The Ca(2+) channel blocker verapamil (100 µM) blocked ICa in a use-dependent manner. Cell-attached patch-clamp recordings showed the presence of a large-conductance Ca(2+)-activated K(+) (BK) channel, and the activity of this channel was decreased by removing the extracellular Ca(2+) or adding verapamil or nifedipine, and increased by adding the Ca(2+) agonist Bay K8644, indicating that Ca(2+) entry via the L-type Ca(2+) channel regulates BK channel activity. Under the current-clamp condition, membrane depolarization generated membrane oscillations in the presence of 10nM TTX or 100 µM riluzole in the bath solution. These membrane oscillations disappeared with 1 µM TTX, 50 µM Cd(2+), replacement of external Na(+) with choline, and blockage of Na(+)-activated K(+) current (IKNa) with 50 µM quinidine, indicating that membrane oscillations are primarily mediated by INaP in cooperation with IKNa. The plateau potentials observed either in Ca(2+)-free medium or in the presence of verapamil were eliminated by blocking INaP with 50 µM Cd(2+). Taken together, these results indicate that INaP and IKNa participate in the generation of membrane oscillations and that INaP additionally participates in the generation of plateau potentials and initiation of spontaneous action potentials. ICa, through L-type Ca(2+) channels, was also found to play a role in the rapid membrane repolarization of action potentials by functional coupling with BK channels.