Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor

Abstract

Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders. Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these neurons. The injections led to the appearance of episodic rest tremor, accompanied by coherent oscillations in neuronal activity, which was reversed following corticostriatal inhibition. These results suggest that the balance between corticostriatal excitation and feedforward FSI inhibition is crucial for maintaining the striatal decorrelation process, and that its breakdown leads to the formation of oscillations resulting in rest tremor typical of multiple basal ganglia disorders.

Top-down alteration of functional connectivity within the sensorimotor network in focal dystonia

“…2 Similarly, animal studies have shown that reduced putaminal feedforward inhibition produces paroxysmal dystonia in the dt sz mutant hamster, 37 while selective inhibition of fast-spiking interneurons in rodents leads to dyskinesia, dystonia, and episodic tremor. 38,39 The manifested symptom variability was attributed to the differences between species and experimental and analytic protocols. Based on its symptomatology, frequency, and harmonics, an argument was made that selective inhibition of feedforward projections from fast-spiking interneurons leads to tremor rather than other types of movement disorders.…”

“…Based on its symptomatology, frequency, and harmonics, an argument was made that selective inhibition of feedforward projections from fast-spiking interneurons leads to tremor rather than other types of movement disorders. 39 Characteristic to tremor, abnormal firing patterns of putaminal and pallidal neurons were temporarily and spatially correlated, becoming oscillatory and coherent with large-amplitude tremor. 39 Notably, selective reduction of the excitatory corticostriatal input resulted in the disappearance of tremor and the reversal of temporal and spatial correlatory activity.…”

Dopaminergic modulation of striatal function and Parkinson’s disease

“…choice execution) but not others (cue or reward). The causal role of FSI was first probed by pharmacological blockade: striatal local infusion of IEM-1460, which silences the FSI population, causes dyskinesia and tremor in mice (Gittis et al 2011;Oran and Bar-Gad 2018), consistent with the role of FSI in tuning SPN activity and suppressing undesired movements. In more recent years, use of genetic tools has allowed selective, bidirectional manipulation of FSI activity to see the consequence on behavioral tasks.…”

Disinhibition of the Nucleus Accumbens Leads to Macro-Scale Hyperactivity Consisting of Micro-Scale Behavioral Segments Encoded by Striatal Activity

“…In four animals, additional recording electrodes were placed in the dorsolateral striatum (AP: 0.5, ML: 4.0, DV: 3.5-5.5). All the surgical procedures were described in detail in previous studies by our group (Bronfeld et al, 2013;Yael et al, 2013;Israelashvili and Bar-Gad, 2015;Oran and Bar-Gad, 2018).…”

“…In this study we use disinhibition to deconstruct the behavioral elements controlled by the NAc core on multiple timescales and identify the underlying neurophysiological mechanism encoding these elements. The relation between behavior and striatal activity has been explored during in the dorsolateral striatum during normal behavior (Klaus et al, 2017;Markowitz et al, 2018) and disinhibition (Bronfeld et al, 2011;Israelashvili and Bar-Gad, 2015;Oran and Bar-Gad, 2018) but is lacking for the ventral striatum during either states. This neuronal-behavioral relationship may serve as a basis for establishing the unique role of the NAc in the control of movement in normal and hyperkinetic conditions.…”