Optimization of a goal maintenance task for use in clinical applications.

BACKGROUND: We sought to develop a Dot Pattern Expectancy task (DPX) to assess goal maintenance for use in clinical trials. Altering the standard task created 5 versions of the DPX to compare-a standard version and 4 others. Alterations in the interstimulus interval (ISI) length and the strength of a learned prepotent response distinguished the different tasks. These adjustments were designed to decrease administration time and/or improve reliability of the data. METHODS: We determined participant eligibility in an initial session (the first of 3) using clinical interviewing tools. The initial session also included a demographic assessment and assessments of community functioning and symptom severity. All versions of the DPX were administered, across 3 sessions. Specific deficits on the context processing compared with difficulty control condition were evaluated using mixed-effects logistic regression within a hierarchical linear model. RESULTS: We analyzed the data from 136 control participants and 138 participants with schizophrenia. Relative to a difficulty control condition, patients performed worse than controls on context processing conditions that required goal maintenance. ISI did not predict errors. Stronger prepotency was associated with increased errors in the difficulty control relative to context processing condition for controls, which improved the interpretability of findings for patients. Reliability was acceptable for a version of the task with a 10-minute running time. CONCLUSIONS: The best compromise between task duration and interpretability occurred on a version with a short ISI and a strong prepotency.

Low-voltage activated calcium currents in ganglion cells of the tiger salamander retina: experiment and simulation.

We examined the functional properties of a low-voltage-activated (LVA) calcium current in ganglion cells of the neotenous tiger salamander (Ambystoma tigrinum) retina. Our analysis was based on whole-cell recordings from acutely dissociated ganglion cell bodies identified by retrograde dye injections. Using a continuously perfused cell preparation, the LVA current was isolated with the use of potassium channel blocking agents added to the bathing medium and the pipette solution, while tetrodotoxin was added to the bathing medium to block Na+ channels. Approximately 70% of ganglion cells had an easily identified LVA current. The LVA current activated at membrane potentials more positive than -90 mV, and inactivated rapidly. It was relatively insensitive to nickel (IC50 > 500 microM) and amiloride (IC50 > 750 microM). Voltage- and current-clamp studies allowed us to generate a model of this current using the NEURON simulation program. Studies were also carried out to measure the LVA Ca2+ current in ganglion cells with dendrites to confirm that it had a significant dendritic representation. Physiological mechanisms that may depend on LVA Ca2+ currents are discussed with an emphasis on the role that dendrites play in ganglion cell function.

Evidence for low-voltage-activated (LVA) calcium currents in the dendrites of tiger salamander retinal ganglion cells.

We have evaluated the spatial distribution of low-voltage-activated calcium currents in ganglion cells of the tiger salamander retina. Whole-cell recordings were obtained from ganglion cells in a retinal slice preparation and from acutely dissociated ganglion cells that were identified through retrograde dye injection. In single dissociated cells, we estimated the magnitude (pA) and current density (pA/pF) of LVA currents in ganglion cells, both with and without dendritic processes. Ganglion cells that retained a portion of their dendritic arbor had larger LVA calcium currents and higher LVA current densities than those which lacked processes. When cell capacitance measurements were used to derive the surface area of the soma and dendritic processes, we concluded that a higher LVA current density was present in the dendrites; we estimate that, on average, the current density in the dendrites is approximately five times that of the soma. The presence of a significant density of LVA calcium channels in the dendrites of ganglion cells suggests that they could be involved in a number of cellular functions, including dendritic integration of synaptic currents, impulse generation, and homeostatic functions related to changes in the intradendritic calcium concentration.

Neuroectodermal differentiation from mouse multipotent adult progenitor cells.

We recently showed that a rare cell from murine bone marrow, which we termed multipotent adult progenitor cells (MAPCs), can be expanded for >120 population doublings. Mouse (m)MAPCs differentiate into mesenchymal lineage cells as well as endothelium and endoderm, and, when injected in the blastocyst, mMAPCs contribute to most if not all somatic cell lineages including the different cell types of the brain. Our results, reported herein, demonstrate that mMAPCs can also be induced to differentiate into cells having anatomical and electrophysiological characteristics similar to those of midbrain neurons. Differentiation to a neuronal phenotype was achieved by coculturing mMAPCs with astrocytes, suggesting that neuronal differentiation may require astrocyte-derived factors similar to what is required for the differentiation of embryonic stem cells and neural stem cells to neurons. Differentiation of mMAPCs to neuron-like cells follows similar developmental steps as described for embryonic stem cells and neural stem cells. MAPCs therefore may constitute a source of cells for treatment of central nervous system disorders.