Reduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats

The changes in firing probability produced by a synaptic input are usually visualized using the poststimulus time histogram (PSTH). It would be useful if postsynaptic firing patterns could be predicted from patterns of afferent synaptic activation, but attempts to predict the PSTH from synaptic potential waveforms using reasoning based on voltage trajectory and spike threshold have not been successful, especially for inhibitory inputs. We measured PSTHs for substantia nigra pars reticulata (SNr) neurons inhibited by optogenetic stimulation of striato-nigral inputs or by matching artificial inhibitory conductances applied by dynamic clamp. The PSTH was predicted by a model based on each SNr cell’s phase-resetting curve (PRC). Optogenetic activation of striato-nigral input or artificial synaptic inhibition produced a PSTH consisting of an initial depression of firing followed by oscillatory increases and decreases repeating at the SNr cell’s baseline firing rate. The phase resetting model produced PSTHs closely resembling the cell data, including the primary pause in firing and the oscillation. Key features of the PSTH, including the onset rate and duration of the initial inhibitory phase, and the subsequent increase in firing probability could be explained from the characteristic shape of the SNr cell’s PRC. The rate of damping of the late oscillation was explained by the influence of asynchronous phase perturbations producing firing rate jitter and wander. Our results demonstrate the utility of phase-resetting models as a general method for predicting firing in spontaneously active neurons and their value in interpretation of the striato-nigral PSTH. NEW & NOTEWORTHY The coupling of patterned presynaptic input to sequences of postsynaptic firing is a Gordian knot, complicated by the multidimensionality of neuronal state and the diversity of potential initial states. Even so, it is fundamental for even the simplest understanding of network dynamics. We show that a simple phase-resetting model constructed from experimental measurements can explain and predict the sequence of spike rate changes following synaptic inhibition of an oscillating basal ganglia output neuron.

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Chronic L-DOPA administration increases the firing rate but does not reverse enhanced slow frequency oscillatory activity and synchronization in substantia nigra pars reticulata neurons from 6-hydroxydopamine-lesioned rats

Neurobiology of Disease ◽

10.1016/j.nbd.2016.02.003 ◽

2016 ◽

Vol 89 ◽

pp. 88-100 ◽

Cited By ~ 17

Author(s):

A. Aristieta ◽

J.A. Ruiz-Ortega ◽

C. Miguelez ◽

T. Morera-Herreras ◽

L. Ugedo

Keyword(s):

Substantia Nigra ◽

Firing Rate ◽

Oscillatory Activity ◽

Substantia Nigra Pars Reticulata ◽

6 Hydroxydopamine ◽

Slow Frequency

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Unitary synaptic connections among substantia nigra pars reticulata neurons

Journal of Neurophysiology ◽

10.1152/jn.00094.2016 ◽

2016 ◽

Vol 115 (6) ◽

pp. 2814-2829 ◽

Cited By ~ 11

Author(s):

Matthew H. Higgs ◽

Charles J. Wilson

Keyword(s):

Substantia Nigra ◽

Firing Rate ◽

Success Probability ◽

Brain Slices ◽

Reversal Potential ◽

Network Activity ◽

Substantia Nigra Pars Reticulata ◽

Direct Measurements ◽

Inhibitory Coupling ◽

Kinetics Of

Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was −64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate.

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

Journal of Neurophysiology ◽

10.1152/jn.00678.2019 ◽

2020 ◽

Vol 123 (2) ◽

pp. 800-814

Author(s):

DeNard V. Simmons ◽

Matthew H. Higgs ◽

Sharmon Lebby ◽

Charles J. Wilson

Keyword(s):

Substantia Nigra ◽

Firing Rate ◽

Globus Pallidus ◽

Substantia Nigra Pars Reticulata ◽

Phase Resetting ◽

Indirect Pathway ◽

Single Action ◽

Phase Models ◽

Phase Resetting Curves

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.

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Discharge Rate of Substantia Nigra Pars Reticulata Neurons Is Reduced In Non-Parkinsonian Monkeys With Apomorphine-Induced Orofacial Dyskinesia

Journal of Neurophysiology ◽

10.1152/jn.01036.2003 ◽

2004 ◽

Vol 92 (4) ◽

pp. 1973-1981 ◽

Cited By ~ 21

Author(s):

Alon Nevet ◽

Genela Morris ◽

Guy Saban ◽

Nina Fainstein ◽

Hagai Bergman

Keyword(s):

Substantia Nigra ◽

Firing Rate ◽

Discharge Rate ◽

Substantial Reduction ◽

Mean Amplitude ◽

Tic Disorders ◽

Substantia Nigra Pars Reticulata ◽

Neuroleptic Drug ◽

Common Symptom ◽

Orofacial Dyskinesia

Involuntary movements (dyskinesia) are a common symptom of dopamine-replacement therapy in parkinsonian patients, neuroleptic drug treatment of mental patients, and tic disorders. Levodopa-induced dyskinesia has been shown to be associated with substantial reduction of firing rate in the internal part of the globus pallidus. This study characterizes the changes that occur in the activity of the substantia nigra pars reticulata (SNr) of non-parkinsonian (normal) monkeys with apomorphine (APO)-induced orofacial dyskinesia. We conducted extracellular recordings of SNr neurons of two monkeys before and after induction of orofacial dyskinesia by systemic administration of APO. Involuntary orofacial movements appeared a few minutes after the injections and lasted 20–40 min. Almost all recorded neurons changed their firing rate after APO injection (96%), and most declined (70%). The mean amplitude of decreases was also larger than that of increases (40 vs. 21% of the control rate). Changes in firing pattern were not significant on average. Pairs of SNr neurons were uncorrelated before APO injection, similar to the normal pallidum. However, unlike the increased correlations in the pallidum that accompany parkinsonism, orofacilal dyskinesia in non-parkinsonian monkeys was not associated with changes in correlation between SNr neurons. We conclude that normal monkeys treated with APO can model orofacial dyskinesia and tic disorders that are a consequence of dopaminergic over-activity. These symptoms appear to be more related to reduced firing rate of SNr neurons and thus to disinhibition of their targets, than to changes in pattern and synchronization.

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