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 GABA A 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 Ca 2ϩ influx through voltage-gated Ca 2ϩ 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 ϳ20% 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.

No abstract

Moyer JT, Wolf JA, Finkel LH. Effects of dopaminergic modulation on the integrative properties of the ventral striatal medium spiny neuron. J Neurophysiol 98: 3731-3748, 2007. First published October 3, 2007 doi:10.1152/jn.00335.2007. Dopaminergic modulation produces a variety of functional changes in the principal cell of the striatum, the medium spiny neuron (MSN). Using a 189-compartment computational model of a ventral striatal MSN, we simulated whole cell D1-and D2-receptor-mediated modulation of both intrinsic (sodium, calcium, and potassium) and synaptic currents (AMPA and NMDA). Dopamine (DA) modulations in the model were based on a review of published experiments in both ventral and dorsal striatum. To objectively assess the net effects of DA modulation, we combined reported individual channel modulations into either D1-or D2-receptor modulation conditions and studied them separately. Contrary to previous suggestions, we found that D1 modulation had no effect on MSN nonlinearity and could not induce bistability. In agreement with previous suggestions, we found that dopaminergic modulation leads to changes in input filtering and neuronal excitability. Importantly, the changes in neuronal excitability agree with the classical model of basal ganglia function. We also found that DA modulation can alter the integration time window of the MSN. Interestingly, the effects of DA modulation of synaptic properties opposed the effects of DA modulation of intrinsic properties, with the synaptic modulations generally dominating the net effect. We interpret this lack of synergy to suggest that the regulation of whole cell integrative properties is not the primary functional purpose of DA. We suggest that D1 modulation might instead primarily regulate calcium influx to dendritic spines through NMDA and L-type calcium channels, by both direct and indirect mechanisms. I N T R O D U C T I O NDysfunction in the dopamine (DA) modulatory system is involved in a number of clinical disorders, including Parkinson's disease, drug addiction, and schizophrenia. One of the major sites of dopaminergic innervation in the brain is the striatum, consisting of the dorsal striatum (which includes the caudate and putamen) and the ventral striatum (which includes the nucleus accumbens core and shell). The principal cell of the striatum is the medium spiny projection neuron (MSN), which constitutes between 85 and 95% of the total cell population, depending on the species and relative location in the striatum (O'Donnell and Grace 1993;Tepper et al. 2004).The effects of DA on the MSN have been extensively studied and depend on the class of receptor expressed by the cell. Most MSNs coexpress two or more species of receptors, although D1 and D2 receptors (D1R and D2R, respectively) are the most prevalent. D2, D3, and D4 receptors are pharmacologically similar, as are D1 and D5 receptors (Vallone et al. 2000). Research to date suggests that striatal MSNs express primarily either D1Rs or D2Rs (Gerfen et al. 1990;Le Moine and Bloch 1996;Maurice e...

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.

SUMMARY Electroencephalography (EEG) - the direct recording of the electrical activity of populations of neurons - is a tremendously important tool for diagnosing, treating, and researching epilepsy. While standard procedures for recording and analyzing human EEG exist and are broadly accepted, no such standards exist 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 International League Against Epilepsy (ILAE)- American Epilepsy Society (AES) Translational Research Task Force (TASK1-Workgroup 5), and is part of a larger effort to harmonize video-electroencephalography interpretation and analysis methods across studies using in vivo and in vitro seizure and epilepsy models.