Indirect pathway control of firing rate and pattern in the substantia nigra pars reticulata

Unitary pallido-nigral synaptic currents were measured using optogenetic stimulation, which activated up to three unitary synaptic inputs to each substantia nigra pars reticulata (SNr) cell. Episodic barrages of synaptic conductances were generated based on in vivo firing patterns of globus pallidus pars externa (GPe) cells and applied to SNr cells using conductance clamp. Barrage inputs were compared to continuous step conductances with the same mean. Barrage inputs and steps both slowed SNr neuron firing and produced disinhibition responses seen in peristimulus histograms. Barrages were less effective than steps at producing inhibition and disinhibition responses. Barrages, but not steps, produced irregular firing during the inhibitory response. Phase models of SNr neurons were constructed from their phase-resetting curves. The phase models reproduced the inhibition and disinhibition responses to the same inputs applied to the neurons. The disinhibition response did not require rebound currents but arose from reset of the cells’ oscillation. The differences in firing rate and irregularity in response to barrage and step inhibition resulted from the high sensitivity of SNr neurons to inhibition at late phases in their intrinsic oscillation. During step inhibition, cells continued rhythmic firing at a reduced rate. During barrages, brief bouts of intense inhibition stalled the cells’ phase evolution late in their cycle, close to firing, and even very brief respites from inhibition rapidly released single action potentials. The SNr cell firing pattern reflected the fine structure of the synaptic barrage from GPe, as well as its onset and offset. NEW & NOTEWORTHY The pallido-nigral pathway connects the striatum to spontaneously active basal ganglia output neurons in the substantia nigra. Each substantia nigra neuron receives powerful inhibitory synaptic connections from a small group of globus pallidus cells and may fire during pauses in pallidal activity. Despite lacking any hyperpolarization-activated rebound currents, they fire quickly to even brief pauses in the pallido-nigral inhibition. The mechanism of their rapid disinhibitory response is explained by features of their phase-resetting curves.

All Phase Resetting Curves Are Bimodal, but Some Are More Bimodal Than Others

Phase resetting curves (PRCs) are phenomenological and quantitative tools that tabulate the transient changes in the firing period of endogenous neural oscillators as a result of external stimuli, for example, presynaptic inputs. A brief current perturbation can produce either a delay (positive phase resetting) or an advance (negative phase resetting) of the subsequent spike, depending on the timing of the stimulus. We showed that any planar neural oscillator has two remarkable points, which we called neutral points, where brief current perturbations produce no phase resetting and where the PRC flips its sign. Since there are only two neutral points, all PRCs of planar neural oscillators are bimodal. The degree of bimodality of a PRC, that is, the ratio between the amplitudes of the delay and advance lobes of a PRC, can be smoothly adjusted when the bifurcation scenario leading to stable oscillatory behavior combines a saddle node of invariant circle (SNIC) and an Andronov-Hopf bifurcation (HB).