Nonequilibrium calcium dynamics regulate the autonomous firing pattern of rat striatal cholinergic interneurons.

Striatal cholinergic interneurons discharge rhythmically in two patterns associated with different afterhyperpolarization timescales, each dictated by a different calcium-dependent potassium current. Single spiking depends on a medium-duration afterhyperpolarization (mAHP) generated by rapid SK currents that are associated with N-type calcium channels. Periodic bursting is driven by a delayed and slowly decaying afterhyperpolarization (sAHP) current associated with L-type channels. Using calcium imaging we show that the calcium transients underlying these currents exhibit two corresponding timescales throughout the somatodendritic tree. This result is not consistent with spatial compartmentalization of calcium entering through the two calcium channels and acting on the two potassium currents, or with differences in channel gating kinetics of the calcium dependent potassium currents. Instead, we show that nonequilibrium dynamics of calcium redistribution among cytoplasmic binding sites with different calcium binding kinetics can give rise to multiple timescales within the same cytoplasmic volume. The resulting independence of mAHP and sAHP currents allows cytoplasmic calcium to control two different and incompatible firing patterns (single spiking or bursting and pausing), depending on whether calcium influx is pulsatile or sustained. During irregular firing, calcium entry at both timescales can be detected, suggesting that an interaction between the medium and slow calcium-dependent afterhyperpolarizations may underlie this firing pattern.

An intrinsic neuronal oscillator underlies dopaminergic neuron bursting.

Dopaminergic neurons of the ventral midbrain fire high-frequency bursts when animals are presented with unexpected rewards, or stimuli that predict reward. To identify the afferents that can initiate bursting and establish therapeutic strategies for diseases affected by altered bursting, a mechanistic understanding of bursting is essential. Our results show that bursting is initiated by a specific interaction between the voltage sensitivity of NMDA receptors and voltage-gated ion channels that results in the activation of an intrinsic, action potential-independent, high-frequency membrane potential oscillation. We further show that the NMDA receptor is uniquely suited for this because of the rapid kinetics and voltage dependence imparted to it by Mg(2+) ion block and unblock. This mechanism explains the discrete nature of bursting in dopaminergic cells and demonstrates how synaptic signals may be reshaped by local intrinsic properties of a neuron before influencing action potential generation.

Subthalamic and striatal neurons concurrently process motor, limbic, and associative information in rats performing an operant task.

Although the subthalamic nucleus (STN) is commonly assumed to be a relay for striatal (STR) output, anatomical evidence suggests the two structures are connected in parallel, raising the possibility that parallel STN and STR firing patterns mediate behavioral processes. The STR is known to play a role in associative and limbic processes, and although behavioral studies suggest that the STN may do so as well, evaluation of this hypothesis is complicated by a lack of pertinent STN physiological data. We recorded concurrent STN and STR firing patterns in rats learning an operant nose-poke task. Both structures responded in similar proportions to task events including instructive cues, discriminative nose-pokes, and sucrose reinforcement. Neuronal responses to reinforcement comprised phasic excitations preceding reinforcement and inhibitions afterward; the inhibition was attenuated when reinforcement was absent. Reinforcement responses occurred more frequently during later training sessions in which discriminative action was required, suggesting that responses were context-dependent. Nose-pokes were typically preceded by excitations; there also was a nonsignificant trend toward inhibition encoding correct nose-pokes. Sustained changes in firing rate coinciding with specific task events suggested that both nuclei were encoding behavioral sequences; this is the first report of such behavior in the STN. Our findings also reveal complex STN responses to reinforcement. Thus both STN and STR neurons show concurrent involvement in motor, limbic, and associative processes.