Dynamic modulation of spike timing-dependent calcium influx during corticostriatal upstates.

The striatum of the basal ganglia demonstrates distinctive upstate and downstate membrane potential oscillations during slow-wave sleep and under anesthetic. The upstates generate calcium transients in the dendrites, and the amplitude of these calcium transients depends strongly on the timing of the action potential (AP) within the upstate. Calcium is essential for synaptic plasticity in the striatum, and these large calcium transients during the upstates may control which synapses undergo plastic changes. To investigate the mechanisms that underlie the relationship between calcium and AP timing, we have developed a realistic biophysical model of a medium spiny neuron (MSN). We have implemented sophisticated calcium dynamics including calcium diffusion, buffering, and pump extrusion, which accurately replicate published data. Using this model, we found that either the slow inactivation of dendritic sodium channels (NaSI) or the calcium inactivation of voltage-gated calcium channels (CDI) can cause high calcium corresponding to early APs and lower calcium corresponding to later APs. We found that only CDI can account for the experimental observation that sensitivity to AP timing is dependent on NMDA receptors. Additional simulations demonstrated a mechanism by which MSNs can dynamically modulate their sensitivity to AP timing and show that sensitivity to specifically timed pre- and postsynaptic pairings (as in spike timing-dependent plasticity protocols) is altered by the timing of the pairing within the upstate. These findings have implications for synaptic plasticity in vivo during sleep when the upstate-downstate pattern is prominent in the striatum.

Functional MRI Shows Altered Deactivation and a Corresponding Decrease in Functional Connectivity of the Default Mode Network in Patients with Gliomas.

BACKGROUND AND PURPOSE: The default mode network normally decreases in activity during externally directed tasks. Although default mode network connectivity is disrupted in numerous brain pathologies, default mode network deactivation has not been studied in patients with brain tumors. We investigated default mode network deactivation with language task-based fMRI by measuring the anticorrelation of a critical default mode network node, the posterior cingulate cortex, in patients with gliomas and controls; furthermore, we examined default mode network functional connectivity in these patients with task-based and resting-state fMRI. MATERIALS AND METHODS: In 10 healthy controls and 30 patients with gliomas, the posterior cingulate cortex was identified on task-based fMRI and was used as an ROI to create connectivity maps from task-based and resting-state fMRI data. We compared the average correlation in each default mode network region between patients and controls for each correlation map and stratified patients by tumor location, hemisphere, and grade. RESULTS: Patients with gliomas (P = .001) and, in particular, patients with tumors near the posterior default mode network (P < .001) showed less posterior cingulate cortex anticorrelation in task-based fMRI than controls. Patients with both left- and right-hemisphere tumors, as well as those with grade IV tumors, showed significantly lower posterior cingulate cortex anticorrelation than controls (P = .02, .03, and <.001, respectively). Functional connectivity in each default mode network region was not significantly different between task-based and resting-state maps. CONCLUSIONS: Task-based fMRI showed impaired deactivation of the default mode network in patients with gliomas. The functional connectivity of the default mode network in both task-based and resting-state fMRI in patients with gliomas using the posterior cingulate cortex identified in task-based fMRI as an ROI for seed-based correlation analysis has strong overlap.