Deep brain stimulation-guided optogenetic rescue of parkinsonian symptoms

AbstractDeep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson’s disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.

IntroductionParkinson’s disease results from the neurodegeneration of the nigro-striatal dopaminergic neurons. The main symptomatic treatment for Parkinson’s disease consists in substituting lacking dopamine with levodopa and/or dopaminergic agonists, but after a typical “honeymoon” period with dopaminergic therapy, patients inevitably develop motor complications1. At this stage, deep brain stimulation at high frequency of the subthalamic nucleus (DBS) constitutes to date the most efficient symptomatic treatment2,3. However, due to its surgical invasiveness and strict eligibility criteria, DBS benefits only to a minority of patients (~5–10%). Several hypotheses have been proposed to explain the beneficial effects of DBS4,5,6. Notably, a growing body of evidence points towards a cortical effect of DBS in both parkinsonian rodent models7,8,9,10,11 and patients12,13,14,15,16,17. Here, we reasoned that mimicking the cortical effects of DBS should reproduce its therapeutic benefits, thus paving the way for less invasive approaches.For this purpose, we (i) determined DBS effects on cortical cell-type specific populations using a combination of in vivo electrophysiological and optogenetic approaches, (ii) reproduced these effects using optogenetics in freely-moving parkinsonian mice, and (iii) explored mathematically how DBS and DBS-guided optogenetics could restore cortical information processing capabilities. We showed that DBS normalized pathological hyperactivity of motor cortex pyramidal cells, while concurrently inhibiting parvalbumin (PV)- and activating somatostatin (SST)-expressing GABAergic interneurons. Furthermore, reproducing these effects by direct opto-activation of cortical SST interneurons alleviates motor symptoms in a parkinsonian mouse model. Lastly, our computational model shows that the dampening of the firing activity of pyramidal cells by DBS and DBS-guided optogenetics restores cortical information processing capabilities. Overall, these results establish that cortical SST interneurons constitute a promising target for a less invasive alternative to DBS.ResultsDBS decreases pathological hyperactivity of pyramidal cellsTo understand how DBS affects cortical activity, we first aimed at depicting the electrophysiological signature of Parkinson’s disease at the neuronal level in the primary motor cortex (M1). We performed in vivo single unit juxtacellular recordings of pyramidal neurons in deep layers of M1 in a rat model of Parkinson’s disease (Fig. 1a and Supplementary Fig. 1a) by unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA) in the substantia nigra pars compacta (SNc). In anesthetized 6-OHDA-lesioned rats, we observed an increase in the spontaneous firing rate of M1 pyramidal cells (n = 41) compared to sham animals (n = 36) (p = 0.0014) (Fig. 1b), in line with previous observations10,18. We then explored the effect of DBS (STN stimulation parameters: 2–4 V, 60 μs at 130 Hz during 2 min) on this pathophysiological hyperactivity of M1 pyramidal neurons. In 6-OHDA-lesioned rats, we found that the increased firing activity was diminished by DBS (p = 0.0311, n = 20) back to physiological firing rates (Fig. 1b), with 68% of pyramidal cells inhibited by DBS (Fig. 1c). DBS also decreased M1 neuron firing rate in sham animals (p = 0.0266, n = 19), and the proportion of inhibited neurons, as well as the change in firing rate, were similar in sham and 6-OHDA-lesioned rats (p = 1 and p = 0.7894, respectively) (Supplementary Fig. 1b, c). Overall, DBS diminished the firing rate of pyramidal cells in sham rats and normalized their pathophysiological hyperactivity in parkinsonian rats.Fig. 1: DBS mediates in vivo inhibition M1 pyramidal cells in rats.a In vivo experimental set-up in anesthetized adult rats. b TH immunostaining and representative raster plots (15 s) of M1 neurons activity recorded in sham rats and in 6-OHDA-lesioned rats with or without DBS. Spontaneous activity of cortical neurons (mean ± SEM and individual neurons are represented) was higher in 6-OHDA-lesioned (n = 41 neurons) compared to sham (n = 36) rats (p = 0.0014, t-test); DBS decreased the hyperactivity observed in 6-OHDA-lesioned rats (Off vs DBS: p = 0.0311, DBS vs Post: p = 0.0811, paired t-test, n = 20 neurons). c Heatmap of individual cortical neurons normalized firing rate (top), and averaged time course (bottom), before, during and after DBS (10s bins) in 6-OHDA-lesioned rat: bars correspond to the median of all neurons (mean ± 2×SD of the baseline is indicated) and separate time courses (mean ± SEM) for activated and inhibited neurons are superimposed. Under DBS, 65% of the pyramidal cells were inhibited while 35% were activated (n = 20). All statistical tests are two-tailed. *p 
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