Local inhibition in a model of the indirect pathway globus pallidus network slows and deregularizes background firing, but sharpens and synchronizes responses to striatal input

Olivares, Erick; Higgs, Matthew H.; Wilson, Charles J.

doi:10.1007/s10827-022-00814-y

Cited by 7 publications

(11 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our study is specific to layer 2/3 medial entorhinal cortex because both intrinsic and synaptic parameters of the network were constrained by data from this region [15]. The only other study that has previously attempted to capture the true extent of heterogeneity in the intrinsic properties of the PV+ interneuronal network, carried out in the external segment of the globus pallidus [71], did not address network synchronization. A recent model of the PV+ interneuronal network in the dentate gyrus considered both heterogeneity in the synaptic connectivity, as PLOS COMPUTATIONAL BIOLOGY well as the Poisson excitatory synaptic drive input, and used combinations of five different reconstructed interneurons in networks with 200 interneurons [72]; they found that the dendritic location of heterogeneous excitatory input greatly mitigated its desynchronizing effects, regardless of whether the inhibition was shunting or hyperpolarizing.…”

Section: Caveats On Generalitymentioning

confidence: 99%

Interneuronal network model of theta-nested fast oscillations predicts differential effects of heterogeneity, gap junctions and short term depression for hyperpolarizing versus shunting inhibition

et al. 2022

View full text Add to dashboard Cite

Theta and gamma oscillations in the hippocampus have been hypothesized to play a role in the encoding and retrieval of memories. Recently, it was shown that an intrinsic fast gamma mechanism in medial entorhinal cortex can be recruited by optogenetic stimulation at theta frequencies, which can persist with fast excitatory synaptic transmission blocked, suggesting a contribution of interneuronal network gamma (ING). We calibrated the passive and active properties of a 100-neuron model network to capture the range of passive properties and frequency/current relationships of experimentally recorded PV+ neurons in the medial entorhinal cortex (mEC). The strength and probabilities of chemical and electrical synapses were also calibrated using paired recordings, as were the kinetics and short-term depression (STD) of the chemical synapses. Gap junctions that contribute a noticeable fraction of the input resistance were required for synchrony with hyperpolarizing inhibition; these networks exhibited theta-nested high frequency oscillations similar to the putative ING observed experimentally in the optogenetically-driven PV-ChR2 mice. With STD included in the model, the network desynchronized at frequencies above ~200 Hz, so for sufficiently strong drive, fast oscillations were only observed before the peak of the theta. Because hyperpolarizing synapses provide a synchronizing drive that contributes to robustness in the presence of heterogeneity, synchronization decreases as the hyperpolarizing inhibition becomes weaker. In contrast, networks with shunting inhibition required non-physiological levels of gap junctions to synchronize using conduction delays within the measured range.

show abstract

Section: Caveats On Generalitymentioning

confidence: 99%

Interneuronal network model of theta-nested fast oscillations predicts differential effects of heterogeneity, gap junctions and short term depression for hyperpolarizing versus shunting inhibition

et al. 2022

View full text Add to dashboard Cite

show abstract

“…By obtaining a PRC for current input and an interspike membrane potential trajectory, the responses of the neuron to synaptic conductances can be predicted. PRCs obtained this way have predicted spike responses of several types of pacemaker neurons ( Wilson et al, 2014 ; Higgs and Wilson, 2017 ; Simmons et al, 2018 , 2020 ; Morales et al, 2020 ; Olivares et al, 2022 ) and other neurons that fire rhythmically when depolarized ( Wilson, 2017 ; Higgs and Wilson, 2019 ). A previous study measured PRCs of VTA DA neurons using optogenetic stimuli ( van der Velden et al, 2020 ) but did not investigate the ionic mechanisms that determine the PRC.…”

Section: Introductionmentioning

confidence: 99%

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

Higgs

Jones²,

Wilson³

et al. 2023

eNeuro

Self Cite

View full text Add to dashboard Cite

Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input-output properties of pacemaking neurons can be characterized by the phase resetting curve (PRC), which describes the sensitivity of inter-spike interval (ISI) length to inputs arriving at different phases of the firing cycle. Here we determined PRCs of putative DA neurons in the substantia nigra pars compacta (SNc) in brain slices from male and female mice using gramicidin-perforated current-clamp recordings with electrical noise stimuli applied through the patch pipette. On average, and compared to nearby putative GABA neurons, DA neurons showed a low, nearly constant level of sensitivity across most of the ISI, but individual cells had PRCs showing relatively greater sensitivity at early or late phases. Pharmacological experiments showed that DA neuron PRCs are shaped by small-conductance calcium-activated potassium (SK) and Kv4 channels, which limit input-sensitivity across early and late phases of the ISI. Our results establish the PRC as a tractable experimental measurement of individual DA neuron input-output relationships and identify two of the major ionic conductances that limit perturbations to rhythmic firing. These findings have applications in modeling and for identifying biophysical changes in response to disease or environmental manipulations.SIGNIFICANCE STATEMENTIn substantia nigra pars compacta dopamine neurons, pacemaking mechanisms determine the response to an instantaneous synaptic input according to the phase resetting curve (PRC). Here we measured PRCs of dopamine neurons and determined how they are shaped by small-conductance calcium-activated potassium (SK) and Kv4 channels, which regulate pacemaking rate and regularity. We found that both types of channel limit sensitivity to perturbations in firing. Thus, the currents responsible for slow pacemaking also control spike time responses to synaptic input.

show abstract

“…The resulting matrix of applied charges was subjected to multiple regression analysis to estimate the iPRC values at each bin. The resulting iPRCs were parameterized as in Olivares et al (2022) [47] using an ad hoc function with 7 free parameters that has proven capable of capturing the shape and size of the GPe iPRC. The parameterized iPRC was used to simulate the phase equation (see below) and obtain the iPRC Fourier components.…”

Section: Methodsmentioning

confidence: 99%

“…The resulting iPRCs were parameterized as in Olivares et al (2022) [47] using an ad hoc function with 7 free parameters that has proven capable of capturing the shape and size of the GPe iPRC. The parameterized iPRC was used to simulate the phase equation (see below)…”

Section: Iprc Measurementsmentioning

confidence: 99%

Phase delays between mouse globus pallidus neurons entrained by common oscillatory drive arise from their intrinsic properties, not their coupling

Olivares,

Wilson,

Goldberg

2024

Preprint

Self Cite

View full text Add to dashboard Cite

A hallmark of Parkinson’s disease is the appearance of correlated oscillatory discharge throughout the cortico-basal ganglia (BG) circuits. In the primate globus pallidus (GP), where the discharge of GP neurons is normally uncorrelated, pairs of GP neurons exhibit oscillatory spike correlations with a broad distribution of pairwise phase delays in experimental parkinsonism. The transition to oscillatory correlations is considered an indication of the collapse of the normally segregated information channels traversing the BG, and the large phase delays are thought to reflect pathological changes in synaptic connectivity in the BG. Here we study the structure and phase delays of correlations measured from independent neurons in the mouse external GP (GPe) subjected to an identical 1-100 Hz sinusoidal drive. We find that spectral modes of a GPe neuron’s empirical instantaneous phase response curve (iPRC), elucidate at what phases of the oscillatory drive the GPe neuron locks when it is entrained, and the distribution of phases at which it fires when it is not. We show, mathematically, that the spike cross-intensity function (CIF) is the cross-correlation function of the spike phase distributions of a neuronal pair. Moreover, the distribution of GPe CIF phase delays arises from the diversity of iPRCs, and is broadened when the neurons become entrained. Modeling GPe networks with realistic intranuclear connectivity demonstrates that the connectivity decorrelates GPe neurons without affecting CIF phase delays. Thus, common oscillatory drive gives rise to GPe correlations whose diverse structure and pairwise phase delays reflect their intrinsic properties as captured by their iPRCs.Author’s summaryThe external globus pallidus (GPe) is a hub in the basal ganglia, whose neurons impose a barrage of inhibitory synaptic currents on neurons of the subthalamic nucleus, substantia nigra and internal globus pallidus. GPe neurons normally fire independently, but in experimental parkinsonism, they become correlated in the frequency range associated with the pathological rhythms seen in human Parkinson’s disease, raising the possibility that they may be generators of the pathological oscillation. We drove individual pallidal neurons with an oscillatory input over a wide range of frequencies. Cross-correlations of these neurons reproduced many of the features seen in parkinsonism, suggesting that their correlated oscillations might derive from a shared input rather than internal interconnections.

show abstract

Local inhibition in a model of the indirect pathway globus pallidus network slows and deregularizes background firing, but sharpens and synchronizes responses to striatal input

Cited by 7 publications

References 63 publications

Interneuronal network model of theta-nested fast oscillations predicts differential effects of heterogeneity, gap junctions and short term depression for hyperpolarizing versus shunting inhibition

Interneuronal network model of theta-nested fast oscillations predicts differential effects of heterogeneity, gap junctions and short term depression for hyperpolarizing versus shunting inhibition

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

Phase delays between mouse globus pallidus neurons entrained by common oscillatory drive arise from their intrinsic properties, not their coupling

Contact Info

Product

Resources

About