Cerebellar outputs contribute to spontaneous and movement-related activity in the motor cortex of monkeys

Highlights

• M1 neurons that responded to dentate nucleus (DN) stimulations were examined.

• DN stimulations induced facilitation and/or suppression in M1 neurons.

• Population firing rates of responding neurons were higher than those of no-response neurons.

Abstract

Cerebellar outputs originate from the dentate nucleus (DN), project to the primary motor cortex (M1) via the motor thalamus, control M1 activity, and play an essential role in coordinated movements. However, it is unclear when and how the cerebellar outputs contribute to M1 activity. To address this question, we examined the response of M1 neurons to electrical stimulation of the DN and M1 activity during performance of arm-reaching tasks. Based on response patterns to DN stimulation, M1 neurons were classified into facilitation-, suppression-, and no-response-types. During tasks, not only facilitation- and suppression-type M1 neurons, but also no response-type M1 neurons increased or decreased their firing rates in relation to arm reaching movements. However, the firing rates of facilitation- and suppression-type neurons were higher than those of no-response-type neurons during both inter-trial intervals and arm reaching movements. These results imply that cerebellar outputs contribute to both spontaneous and movement-related activity in the M1, which help to maintain muscle tones and execute coordinated movements, although other inputs also contribute to movement-related activity. Pharmacological inactivation of the DN supports this notion, in that DN inactivation reduced both spontaneous firing rates and movement-related activity in the M1.

Introduction

The cerebellum plays an essential role in smooth and accurate limb movements (Holmes, 1917, 1939; Dow and Moruzzi, 1958; Kitazawa, 2002; Manto et al., 2012). Cerebellar impairment results in deficits in limb movements in humans, such as delay in movement initiation (Beppu et al., 1984), slowness of movements (Hore et al., 1991), increased variability of movement trajectory (Brown et al., 1990), and consistent decrease in muscle tone (Holmes, 1917, 1939). In non-human primates, ablation or transient inactivation of the cerebellum shows similar impairments in motor behaviors (Gilman, 1969; Meyer-Lohmann et al., 1977; Goodkin and Thach, 2003; Nashef et al., 2019). However, how cerebellar activity controls normal motor behaviors is unclear.

The main targets of cerebellar outputs are the motor cortices (Sasaki et al., 1976; Dum and Strick, 2003; Hashimoto et al., 2010), especially the primary motor cortex (M1), which plays an essential role in voluntary limb movements (Evarts, 1968; Cheney and Fetz, 1980; Dum and Strick, 1991; Lemon, 2008). Neurons in the cerebellar dentate nucleus (DN), one of the output nuclei of the cerebellum, send prominent di-synaptic excitatory projections to the M1 (Sasaki et al., 1976; Shinoda et al., 1985; Steriade, 1995; Na et al., 1997) through the motor thalamus (Asanuma et al., 1983; Nambu et al., 1991), and this pathway is well established as the cerebello-thalamo-cortical pathway (Allen and Tsukahara, 1974; Horne and Butler, 1995). Electrical stimulation of the cerebello-thalamo-cortical pathway evokes local field potentials in the M1 and causes both facilitation and/or suppression in most M1 neurons with short latencies (Holdefer et al., 2000; Nashef et al., 2018). Thus, the cerebello-thalamo-cortical pathway can immediately and broadly affect motor cortical activity. Furthermore, previous studies showed that firing rate changes of motor cortical neurons in the cerebello-thalamo-cortical pathway are involved in movement initiation (Meyer-Lohmann et al., 1977; Nashef et al., 2018). Taken together, these results suggest that DN outputs to the M1 are involved in the timing control for initiation of movement. However, it remains unclear how cerebellar outputs contribute to the motor cortical activity in other phases of motor tasks, such as inter-trial intervals (ITIs), preparation, and movement periods.

To address this question, we identified M1 neurons involved in the cerebello-thalamo-cortical pathway by recording responses to DN stimulations and neuronal activity while monkeys performed an arm-reaching task, which includes ITIs, preparation, and execution. We found that the firing rate of M1 neurons responding to the DN stimulation was significantly higher than that of the other neurons. These results suggest that cerebellar outputs contribute to M1 activity not only in initiation of movement, but also during ITIs, movement preparation, and execution. Reversible pharmacological inactivation of the DN supports this notion, in that DN inactivation induced a reduction of mean firing rates of M1 neurons during not only ITIs and movement preparation, but also the execution period.