Signals through the StriatopallidalIndirectPathway Stop Movements by Phasic Excitation in the Substantia Nigra

Abstract

The striatum and subthalamic nucleus (STN) are the input stations of the basal ganglia and receive excitatory afferents from the cerebral cortex. The basal ganglia control voluntary movements through three parallel pathways mediated by the input stations: the hyperdirect pathway, which conveys direct cortical inputs to the substantia nigra pars reticulata (SNr), the output nucleus, through the STN; the direct pathway, which arises from striatal neurons expressing dopamine D1 receptors and projects to the SNr; and the indirect pathway, which arises from striatal neurons expressing dopamine D2 receptors (D2Rs) and projects indirectly to the SNr by way of the globus pallidus (GP) and STN. Our previous study showed that immunotoxin-mediated cell targeted ablation of D2R-expressing striatal neurons in mice induced motor hyperactivity. To elucidate the mechanism underlying the hyperactivity, here we examined neuronal activity in the GP and SNr. The ablation of D2R-expressing striatal neurons had little effect on spontaneous activity in the GP and SNr, but induced dramatic changes in the cortically evoked triphasic response composed of early excitation, inhibition, and late excitation in the GP and SNr (i.e., reduced inhibition in the GP, and reduced late excitation in the GP and SNr). In contrast, the ablation of striatal cholinergic interneurons, which also express D2Rs, did not show such effects. Therefore, the reduction of the cortically evoked late excitation in the SNr seems to be responsible for hyperactivity. These observations suggest that phasic late excitation in the SNr through the striatopallidal indirect pathway plays a key role in stopping movements.

Robust presynaptic serotonin 5-HT1B receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment

“…This is important because the pause in the high-frequency firing of SNr GABA neurons releases the downstream targets such as the thalamus and brainstem motor nuclei (Basso and Sommer 2011; Hikosaka et al 2000Hikosaka et al , 2014Kaneda et al 2008;Kravitz at al. 2010;Sano et al 2013), and consequently, a reduction in the pause is likely to affect the activity of these downstream nuclei.…”

“…1A) (Haber 2003;Hikosaka 2007) that is important to motor control (Friend and Kravitz 2014) and also to cognition (Simpson et al 2010), emotion (Marchand et al 2012;Révy et al 2014), and learning and habit formation (Graybiel and Smith 2014;Sesack and Grace 2010). A main characteristic of the SNr is that its GABA projection neurons fire autonomous high-frequency spikes that are paused by the massive GABA input from the striatonigral projection (Hikosaka et al 2000(Hikosaka et al , 2014Sano et al 2013;Schultz 1986;Zhou and Lee 2011). Another prominent anatomic feature of the SNr is its dense serotonin (5-HT) innervation, originated in the dorsal raphe ( Fig.…”

Response Inhibition

“…Inactivation of the GPe results in more errors in an antisaccade task while leaving prosaccades intact (Yoshida & Tanaka, 2009). Ablation of D2 receptor-expressing striatal neurons alters cortically evoked responses in the GP and SNr, resulting in hyperactivity (Sano et al, 2013). However, other neurophysiological data are much more complex to accommodate with such a simple conceptual scheme.…”

Striking the Right Balance: Cortical Modulation of the Subthalamic Nucleus-Globus Pallidus Circuit

“…The STN receives monosynaptic cortical excitation, known as the hyperdirect pathway, which has been linked to a rapid, immediate stop signal (Schmidt et al, 2013). The STN also receives indirect cortical information through the GPe, known as the indirect pathway, which is responsible for the suppression or cancellation of motor plans (Sano et al, 2013).…”