Jason T. Moyer

NMDA/AMPA Ratio Impacts State Transitions and Entrainment to Oscillations in a Computational Model of the Nucleus Accumbens Medium Spiny Projection Neuron

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an “up” state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of “up” and “down” state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be ∼20% of the “up” state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.

Homeostatic Synapse-Driven Membrane Plasticity in Nucleus Accumbens Neurons

Stable brain function relies on homeostatic maintenance of the functional output of individual neurons. In general, neurons function by converting synaptic input to output as action potential firing. To determine homeostatic mechanisms that balance this input–output/synapse–membrane interaction, we focused on nucleus accumbens (NAc) neurons and demonstrated a novel form of synapse-to-membrane homeostatic regulation, homeostatic synapse-driven membrane plasticity (hSMP). Through hSMP, NAc neurons adjusted their membrane excitability to functionally compensate for basal shifts in excitatory synaptic input. Furthermore, hSMP was triggered by synaptic NMDA receptors (NMDARs) and expressed by the modification of SK-type Ca2+-activated potassium channels. Moreover, hSMP in NAc neurons was abolished in rats during a short- (2 d) or long- (21 d) term withdrawal from repeated intraperitoneal injections of cocaine (15 mg/kg/d, 5 d). These results suggest that hSMP is a novel form of synapse-to-membrane homeostatic plasticity and dysregulation of hSMP may contribute to cocaine-induced cellular alterations in the NAc.

Exposure to Cocaine Dynamically Regulates the Intrinsic Membrane Excitability of Nucleus Accumbens Neurons

Drug-induced malfunction of nucleus accumbens (NAc) neurons underlies a key pathophysiology of drug addiction. Drug-induced changes in intrinsic membrane excitability of NAc neurons are thought to be critical for producing behavioral alterations. Previous studies demonstrate that, after short-term (2 d) or long-term (21 d) withdrawal from noncontingent cocaine injection, the intrinsic membrane excitability of NAc shell (NAcSh) neurons is decreased, and decreased membrane excitability of NAcSh neurons increases the acute locomotor response to cocaine. However, animals exhibit distinct cellular and behavioral alterations at different stages of cocaine exposure, suggesting that the decreased membrane excitability of NAc neurons may not be a persistent change. Here, we demonstrate that the membrane excitability of NAcSh neurons is differentially regulated depending on whether cocaine is administered contingently or noncontingently. Specifically, the membrane excitability of NAcSh medium spiny neurons (MSNs) was decreased at 2 d after withdrawal from either 5 d intraperitoneal injections (15 mg/kg) or cocaine self-administration (SA). At 21 d of withdrawal, the membrane excitability of NAcSh MSNs, which remained low in intraperitoneally pretreated rats, returned to a normal level in SA-pretreated rats. Furthermore, after a reexposure to cocaine after long-term withdrawal, the membrane excitability of NAcSh MSNs instantly returned to a normal level in intraperitoneally pretreated rats. Conversely, in SA-pretreated rats, the reexposure elevated the membrane excitability of NAcSh MSMs beyond the normal level. These results suggest that the dynamic alterations in membrane excitability of NAcSh MSNs, together with the dynamic changes in synaptic input, contribute differentially to the behavioral consequences of contingent and noncontingent cocaine administration.

Conventional MRI Is Inadequate to Delineate the Relationship between the Red Nucleus and Subthalamic Nucleus in Parkinson’s Disease

Background: An understanding of the relationships between the anterior commissure-posterior commissure line (AC-PC), the subthalamic nucleus (STN), and red nucleus (RN) is imperative if these structures are to be used for targeting in deep brain stimulation. Currently, these relationships are incompletely understood and difficult to assess using conventional MRI. We examined the location and relationships of the STN and the RN to the AC-PC line and to each other in order to provide a greater understanding of their utility when targeting the STN, and the consistency of these anatomic relationships when examined using conventional MRI. Methods: A total of 52 STN and RN in 26 patients with Parkinson’s disease were evaluated on T2-weighted MR images. The anterior and posterior commissures and the border coordinates of the STN and RN were derived using frame coordinates. The distances from the midcommissural point (mcp) to the centers of the STN and RN, the diameters for each nucleus, and the distances between the nuclei were calculated in the x-, y-, and z-axes. Results: The mean AC-PC length was 26.1 ± 1.3 mm. The distance from the mcp to the center of the STN was 10 ± 0.7 mm in the x-axis, 0.2 ± 0.7 mm in the y-axis, and 3.3 ± 0.9 mm in the z-axis. The distance from the mcp to the center of the RN was 4.7 ± 0.6 mm in the x-axis, –5.9 ± 1.0 mm in the y-axis, and 6.1 ± 1.3 mm in the z-axis. The distance between the STN and RN was 2.3 ± 0.7 mm in the x-axis, 2.1 ± 1.0 mm in the y-axis, and –0.2 ± 1.3 mm in the z-axis. Conclusions: Although recent studies imply that the RN can be used as a relatively consistent marker for the position of the STN, the present data suggest otherwise. These data indicate that a single targeting method may be inadequate given the resolution of conventional MRI, and that it is imperative to use multiple anatomical measurements when targeting the STN for deep brain stimulation in Parkinson’s disease.

High-frequency oscillations (>200 Hz) in the human non-parkinsonian subthalamic nucleus.

The human basal ganglia, and in particular the subthalamic nucleus (STN), can oscillate at surprisingly high frequencies, around 300 Hz [G. Foffani, A. Priori, M. Egidi, P. Rampini, F. Tamma, E. Caputo, K.A. Moxon, S. Cerutti, S. Barbieri, 300-Hz subthalamic oscillations in Parkinsons disease, Brain 126 (2003) 2153-2163]. It has been proposed that these oscillations could contribute to the mechanisms of action of deep brain stimulation (DBS) [G. Foffani, A. Priori, Deep brain stimulation in Parkinsons disease can mimic the 300 Hz subthalamic rhythm, Brain 129 (2006) E59]. However, the physiological role of high-frequency STN oscillations is questionable, because they have been observed only in patients with advanced Parkinsons disease and could therefore be secondary to the dopamine-depleted parkinsonian state. Here, we report high-frequency STN oscillations in the range of the 300-Hz rhythm during intraoperative microrecordings for DBS in an awake patient with focal dystonia as well as in a patient with essential tremor (ET). High-frequency STN oscillations are therefore not exclusively related to parkinsonian pathophysiology, but may represent a broader feature of human STN function.

Lateral and feedforward inhibition suppress asynchronous activity in a large, biophysically-detailed computational model of the striatal network

Striatal medium spiny neurons (MSNs) receive lateral inhibitory projections from other MSNs and feedforward inhibitory projections from fast-spiking, parvalbumin-containing striatal interneurons (FSIs). The functional roles of these connections are unknown, and difficult to study in an experimental preparation. We therefore investigated the functionality of both lateral (MSN-MSN) and feedforward (FSI-MSN) inhibition using a large-scale computational model of the striatal network. The model consists of 2744 MSNs comprised of 189 compartments each and 121 FSIs comprised of 148 compartments each, with dendrites explicitly represented and almost all known ionic currents included and strictly constrained by biological data as appropriate. Our analysis of the model indicates that both lateral inhibition and feedforward inhibition function at the population level to limit non-ensemble MSN spiking while preserving ensemble MSN spiking. Specifically, lateral inhibition enables large ensembles of MSNs firing synchronously to strongly suppress non-ensemble MSNs over a short time-scale (10–30 ms). Feedforward inhibition enables FSIs to strongly inhibit weakly activated, non-ensemble MSNs while moderately inhibiting activated ensemble MSNs. Importantly, FSIs appear to more effectively inhibit MSNs when FSIs fire asynchronously. Both types of inhibition would increase the signal-to-noise ratio of responding MSN ensembles and contribute to the formation and dissolution of MSN ensembles in the striatal network.

Implementation of Dual Simultaneous Microelectrode Recording Systems during Deep Brain Stimulation Surgery for Parkinson's Disease: Technical Note

OBJECTIVE Microelectrode recording during deep brain stimulation surgery improves the likelihood of successful target localization and enables the electrophysiological characterization of human neural structures. Many clinical recording systems do not support the ability to capture research-quality recordings. Established clinical centers already using such equipment may be prevented from acquiring human intracranial data because of the need to completely change recording systems to obtain research-quality recordings. This technical note describes the novel design and implementation of a recording system that significantly improves research capabilities without disrupting the existing clinical setup. METHODS This design introduces a second recording system (including pre-amplifier, differential amplifier, analog-to-digital converter, and computer with analysis software) that divides the microelectrode signal into two independent streams. RESULTS This design preserves the existing intraoperative recording setup, but significantly improves research-level recording, data storage, and analysis capabilities. CONCLUSION We provide the first description of such a system using components that are all commercially available and relatively inexpensive. This approach presents an appealing alternative to the purchase of an entirely new system for surgical teams that already perform intraoperative recordings to assist in stereotactic target localization, yet wish to expand their neurophysiological recording capabilities.

Standards for data acquisition and software-based analysis of in vivo electroencephalography recordings from animals. A TASK1-WG5 report of the AES/ILAE Translational Task Force of the ILAE

Electroencephalography (EEG)—the direct recording of the electrical activity of populations of neurons—is a tremendously important tool for diagnosing, treating, and researching epilepsy. Although standard procedures for recording and analyzing human EEG exist and are broadly accepted, there are no such standards for research in animal models of seizures and epilepsy—recording montages, acquisition systems, and processing algorithms may differ substantially among investigators and laboratories. The lack of standard procedures for acquiring and analyzing EEG from animal models of epilepsy hinders the interpretation of experimental results and reduces the ability of the scientific community to efficiently translate new experimental findings into clinical practice. Accordingly, the intention of this report is twofold: (1) to review current techniques for the collection and software‐based analysis of neural field recordings in animal models of epilepsy, and (2) to offer pertinent standards and reporting guidelines for this research. Specifically, we review current techniques for signal acquisition, signal conditioning, signal processing, data storage, and data sharing, and include applicable recommendations to standardize collection and reporting. We close with a discussion of challenges and future opportunities, and include a supplemental report of currently available acquisition systems and analysis tools. This work represents a collaboration on behalf of the American Epilepsy Society/International League Against Epilepsy (AES/ILAE) Translational Task Force (TASK1‐Workgroup 5), and is part of a larger effort to harmonize video‐EEG interpretation and analysis methods across studies using in vivo and in vitro seizure and epilepsy models.

Stimulation-Induced Dyskinesias Inform Basal Ganglia Models and the Mechanisms of Deep Brain Stimulation

High-frequency (or deep brain) stimulation (HFS) of the subthalamic nucleus (STN) represents an effective treatment for intermediate to late-stage Parkinsons disease (PD). The success of HFS for treatment of PD has accelerated research into its use for a number of other disorders, ranging from

Deep brain stimulation: Anatomical, physiological, and computational mechanisms

INTRODUCTION—THE ALBIN AND DELONG MODELModern understanding of the basal ganglia (BG) dates to the Albin and DeLongmodel, which proposed a functional relationship between the nuclei of the BG[striatum, pallidum, substantia nigra, and subthalamic nucleus (STN)] (1,2). Inthis model, the BG controls the initiation and execution of motor programsthrough the interplay of the direct and indirect projection pathways, both ofwhich originate in the striatum (Fig. 1A). According to the model, activation F1of the direct pathway results in inhibition of pallidal output and consequentdisinhibition of thalamocortical projection neurons. Activation of the indirectpathway results in excitation of the internal segment of the globus pallidus