Conductance-Based Adaptive Exponential Integrate-and-Fire Model.

Spiking behavior and epileptiform oscillations in a discrete model of cortical neural networks

This paper reports further development and applications of a computational model permitting analysis of frequency response characteristics of simulated neurons. The original single‐neuron model, as described by Peddicord and Sampson in 1974, is briefly reviewed here. There follows a thorough description of a new interactive implementation of the model on a PDP‐11/45. The implementation permits high‐speed simulation of large neural networks, and is designed for easy use by investigators with no special knowledge of computers or programming. Experiments with the new system have included the design of improved bandpass filters, pacemaker neurons and networks, and a cerebellar circuit. Simulation results are presented and, in the last case, compared with available physiological data. The paper concludes with a critique of the system, suggestions for further experiments, and a comparison with the simulation system developed by Perkel. Two appendices document the system data structures and show a sample simulation run.

BackgroundThe molecular mechanisms leading to Alzheimer's disease (AD) are poorly known. This is due to the lack of human tissue samples for research representing early changes of AD pathology, raising a need for development of novel human‐based preclinical models for AD. Idiopathic normal pressure hydrocephalus (iNPH) is an neurodegenerative disease characterized by an impaired cerebrospinal fluid (CSF) clearance. iNPH is treated by a shunt surger to drain the excess CSF into the abdominal cavity. During the surgery, 10‐20mm3 Broadman area 8 biopsy can be excised by minimally invasive methods for preclinical studies. Due to the early AD‐related pathology present in a subpopulation of iNPH patients, the brains of these patients offer a unique window to evaluate cellular events taking place during the course of AD pathology progression.MethodWe have set up a pipeline to evaluate, in a layer and cell‐type dependent manner, the intrinsic neuronal operational properties in the iNPH biopsies. Our patch clamp and multi electrode array (MEA) studies show that these biopsies are viable and retain the required microcircuit to study network and synaptic function in human cortex. We have carried out integrative analysis of human neuronal electrophysiology at single neuron and network level followed by subsequent cellular morphological reconstructions to register the primary pathological changes in neuronal functions in correlation with existing AD‐related pathology.ResultThe presence of Aβ deposits induced a decrease in the L1‐induced inhibition and led to hyperexcitability in response to application of NMDA in MEA recordings. Interestingly, the global spine density of supraganular pyramidal neurons was increased in biopsies with AD‐related pathology. Pyramidal neurons in cases with both Aβ and tau exhibited more consistent deficits in the intrinsic neuronal properties with increase in sodium and potassium currents and a strong propensity to bursting under NMDA stimulation.ConclusionThis is the first study to show that the accumulation of Aβ and tau alters synaptic transmission and consolidation of a hyperexcitable supragranular cortical network. The iNPH biopsies provide a unique opportunity to unravel how AD‐related pathology alters neuronal network functionality in humans.

The fasciola cinereum (FC) is a small, conserved hippocampal subregion whose function has remained largely unexplored. Anatomically situated between dorsal CA1 and the third ventricle in rodents, the FC receives diverse cortical and subcortical inputs yet is often omitted from hippocampal circuit models. There remains a fundamental knowledge gap regarding the cell types and intrinsic properties of neurons in FC and whether they are distinct from neighboring hippocampal subregions. Here, we performed ex vivo whole-cell patch-clamp recordings in mouse hippocampal slices to characterize FC neurons. We found that FC cells are functionally distinct from neighboring CA1 pyramidal cells, exhibiting significantly reduced excitability, delayed spike initiation, and enhanced afterhyperpolarization (AHP) currents, consistent with strong potassium conductance. Notably, we identified two electrophysiologically distinguishable FC neuron excitatory cell subtypes, differing in excitability and potassium channel activity. Pharmacological analyses demonstrated that Kv2.1 and Kv7 potassium channels play a key role in shaping the intrinsic properties of FC neurons, underlying their reduced excitability. These findings suggest that the FC is a heterogeneous structure, molecularly and functionally specialized for gating excitability within the hippocampal circuit.

The dorsal and ventral regions of the rat longitudinal hippocampal axis are functionally distinct. That is, each region is associated with different behavioral tasks and disease susceptibilities due to underlying anatomical, and physiological differences. These differences are especially pronounced in area CA1, where significant differences in morphology, synaptic physiology, intrinsic excitability, and gene expression have been reported between CA1 pyramidal neurons from the dorsal (DHC) and ventral hippocampus (VHC). However, despite a significant amount of recent attention, a cogent picture of the intrinsic electrophysiological profile of DHC and VHC neurons has remained elusive, due, in part, to experiments performed on rats at different developmental time points. Moreover, the resulting intrinsic electrophysiological profiles are sufficiently different as to warrant a thorough investigation of the spatial and temporal changes in the intrinsic excitability of CA1 pyramidal neurons across developmental time. Accordingly, in this study, I have characterized the intrinsic electrophysiological properties of CA1 pyramidal neurons from acute hippocampal slices prepared from the DHC and VHC throughout an approximately 3-week developmental period (P14-P37). DHC and VHC neurons exhibited distinct intra-region changes (DHC or VHC) and inter-region differences (DHC versus VHC) in their intrinsic electrophysiological properties, which yielded two developmental timelines: (a) a common developmental timeline describing changes observed in both DHC and VHC neurons, and (b) a differential developmental timeline highlighting unique features observed in DHC neurons. Specifically, DHC neurons exhibited significant inter-region differences in RMP, input resistance, threshold, and spike frequency adaptation relative to VHC neurons, as well as an intra-region change in the rebound slope (a proxy for Ih ). These observations both integrate and reconcile previous work performed with rats at different developmental stages and suggest a distinct developmental trajectory for DHC neurons that might shed light on the normal physiological functions and disease susceptibility of the DHC.

Feasibility of electrical recordings from unconnected vertebrate CNS neurons cultured in a three-dimensional extracellular matrix

Information flow in neocortical circuits is regulated by two key parameters: intrinsic neuronal properties and the short-term activity-dependent plasticity of synaptic transmission. Using multineuronal whole-cell voltage recordings, we characterized the postnatal maturation of the electrophysiological properties and short-term plasticity of excitatory synaptic transmission between pairs of layer 5 (L5) pyramidal neurons (n = 158) in acute slices of rat visual cortex over the first postnatal month. We found that the intrinsic and synaptic properties of L5 pyramidal neurons develop in parallel. Before postnatal day 15 (P15), intrinsic electrophysiological properties were tuned to low-frequency operation, characterized by high apparent input resistance, a long membrane time constant, and prolonged somatic action potentials. Unitary excitatory synaptic potentials were of large amplitude (P11-P15; median, 514 μV), but showed pronounced use-dependent depression during prolonged regular and physiologically relevant presynaptic action potential firing patterns. In contrast, in mature animals we observed a developmental decline of the peak amplitude of unitary EPSPs (P25-P29; median, 175 μV) paralleled by a decrease in apparent input resistance, membrane time constant, and somatic action potential duration. Notably, synaptic signaling of complex action potential firing patterns was also transformed, with P25-P29 connections faithfully signaling action potential trains at frequencies up to 40 Hz (1st to 50th action potential ratio, 0.91 ± 0.12). Postnatal refinement of intrinsic properties and short-term plasticity therefore transforms the capacity of the L5 excitatory neural network of the visual cortex to generate and process patterns of action potential firing and contribute to network activity.

We investigated the effects of repeated early-life seizures induced by flurothyl inhalation on intrinsic membrane properties of hippocampal pyramidal neurons from young rats (postnatal day 15-20). Intracellular recordings of CA1 and CA3 pyramidal neurons from flurothyl-treated and control rats revealed no significant differences in resting membrane potential, input resistance, membrane time constant, and action potential characteristics. In CA1 pyramidal cells from flurothyl-treated rats, the spike frequency adaptation and afterhyperpolarizing potential following a spike train were markedly reduced when compared with controls. In contrast, no significant alterations in the firing properties of CA3 pyramidal neurons were found. It is concluded that neonatal seizures lead to persistent changes in intrinsic membrane properties of CA1 pyramidal neurons. These alterations are consistent with an increase in neuronal excitability and may contribute to the behavioral deficit and epileptogenic predisposition observed in rats that experienced repeated neonatal seizures.

Describes a scalable parallel architecture for real-time, large scale neural network simulations. Currently the SIMD architecture is largely adopted for implementing digital neurocomputers. However, it is not efficient for simulating large scale neural networks in real-time because of its limited scalability and flexibility. The authors investigate, as a solution, a wavefront array processing (WAP) architecture based on asynchronous communications. The authors compare both architectures in scalability, performance, and flexibility for simulating multi-layer perceptrons. The authors also briefly discuss implementing a high performance digital neurocomputer based on the WAP.

Parallel processing is a promising technique for reducing the execution time of a large and complex wireless network simulation. In this article, a parallel processing technique is presented for time-driven simulations of large and complex wireless networks. The technique explicitly considers the physical-layer details of wireless network simulators such as shadowing and co-channel interference. The technique uses multiple processors interconnected with highspeed links. Principles and issues are elaborated, including workload partitioning, synchronization, and database design. Numerical results from two different wireless network simulators employing the technique are presented to demonstrate the performance of the technique. The results indicate that the technique can significantly improve the run-time performance of time-driven simulations of large and complicated wireless networks of different types.

A common theme of diverse neural systems is that circuits that are important for initial acquisition of learning do not necessarily serve as a substrate for the long-term storage of that memory. The neural basis of vocal learning in songbirds provides an example of this phenomenon, since a circuit that is necessary for vocal production during initial stages of vocal development apparently plays no subsequent role in controlling learned vocalizations. This striking functional change suggests the possibility of marked physiological changes in synaptic transmission within this circuit. We therefore examined intrinsic and synaptic properties of neurons in the cortical nucleus IMAN (lateral magnocellular nucleus of the anterior neostriatum), which forms part of this developmentally regulated circuit, in an in vitro preparation of the zebra finch forebrain. Although both functional and morphological characteristics of these neurons change substantially during vocal development, we did not observe widespread, substantive changes in the electrophysiological characteristics of juvenile versus adult IMAN neurons examined in vitro. Overall, both the intrinsic properties and synaptic responses of IMAN neurons were similar in slices from juvenile birds (at ages when lesions of IMAN disrupt vocal production) and in slices from adult birds (when IMAN lesions have no effect on song production). However, one intrinsic property that did vary between juvenile and adult cells was spike duration, which was longer in juvenile cells, suggesting the potential for activation of second-messenger cascades and/or enhanced synaptic transmission onto target cells of IMAN neurons. The pattern of synaptic response observed in both juvenile and adult cells suggests that IMAN projection neurons receive direct excitatory afferent inputs, as well as disynaptic inhibitory inputs from interneurons within IMAN. Activation of inhibitory interneurons rapidly curtails the excitatory response seen in projection neurons. This inhibition was abolished by bicuculline, indicating that the inhibitory interneurons normally exert their postsynaptic response via GABA(A) receptors on projection neurons. The inhibitory response could also be blocked by CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), suggesting that the activation of inhibitory interneurons within IMAN may be governed primarily by AMPA receptors.

Simulation of spiking neural networks — architectures and implementations

Almost all theoretical and experimental studies of the mechanisms underlying learning and memory focus on synaptic efficacy and make the implicit assumption that changes in synaptic efficacy are both necessary and sufficient to account for learning and memory. However, network dynamics depends on the complex interaction between intrinsic membrane properties and synaptic strengths and time courses. Furthermore, neuronal activity itself modifies not only synaptic efficacy but also the intrinsic membrane properties of neurons. This paper presents examples demonstrating that neurons with complex temporal dynamics can provide short-term "memory" mechanisms that rely solely on intrinsic neuronal properties. Additionally, we discuss the potential role that activity may play in long-term modification of intrinsic neuronal properties. While not replacing synaptic plasticity as a powerful learning mechanism, these examples suggest that memory in networks results from an ongoing interplay between changes in synaptic efficacy and intrinsic membrane properties.

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy; however, the mechanisms underlying hyperexcitability in the affected cortical regions remain poorly understood. In this study, we employed a freeze-induced neocortical malformation model in rats to investigate the electrophysiological properties of pyramidal neurons surrounding the microgyrus and to evaluate changes in synaptic transmission. Using whole-cell patch-clamp recordings, we analyzed passive and active membrane properties, synaptic responses, and epileptiform activity in brain slices from rats with FCD and sham-operated controls. Our results revealed that while the intrinsic biophysical properties of neurons remained largely unchanged, the summation of excitatory and inhibitory inputs was significantly enhanced. Notably, the balance of inhibitory and excitatory synaptic currents was shifted toward excitation, making the perilesional cortex more susceptible to seizure generation. In a model of epileptiform activity induced by GABAA receptor blockade and reduced Mg2+ concentration, we observed early ictal activity originating in the microgyrus and spreading to adjacent regions. These findings demonstrate that synaptic perturbations, rather than alterations in intrinsic neuronal properties, are the primary drivers of hyperexcitability in this model. Our study highlights the importance of synaptic dysregulation in FCD-related epilepsy and suggests that targeting synaptic transmission may offer a promising therapeutic strategy for controlling seizures in patients with cortical malformations.

The anterior forebrain pathway (AFP) of the oscine song system is essential for song learning but not song production. Most cells recorded in this serially connected pathway show increased firing in response to song playback, suggesting largely excitatory connections among AFP nuclei. However, the neurons forming a key projection in this pathway, from area X to the medial nucleus of the dorsolateral thalamus (DLM), express glutamic acid decarboxylase in their somata and terminals, suggesting an inhibitory connection. To investigate the firing properties of DLM neurons and the functional influence of area X afferents in DLM, we made whole-cell recordings from DLM neurons in brain slices from adult male zebra finches. Most cells had intrinsic properties closely resembling those of mammalian thalamocortical cells, including a low-threshold Ca(2+) spike and time-dependent, hyperpolarization-activated inward rectification. Activation of afferents from area X evoked a strong, all-or-none IPSP whose amplitude and latency were unchanged by application of glutamate antagonists, consistent with a monosynaptic contact. The IPSP had a reversal potential near -70 mV and was blocked by the GABA(A) receptor antagonist bicuculline methiodide. Post-inhibitory rebound firing occurred in DLM neurons with a delay near 50 msec. Strong inhibition can combine with the intrinsic properties of DLM neurons to allow signaling on disinhibition. Our data are consistent with the hypothesis that the AFP corresponds to the mammalian corticobasal ganglia-thalamocortical loop. The similar functional properties of avian and mammalian thalamic neurons suggest conserved forebrain mechanisms of sensorimotor information processing across vertebrate taxa.