The basal ganglia are composed of multiple nuclei, including the striatum, the external globus pallidus (GPe), the subthalamic nucleus (STN), the internal globus pallidus (GPi), the substantia nigra pars reticulata (SNr) and the substantia nigra pars compacta (SNc). The main input nucleus of the basal ganglia is the striatum, in which over 90% of neurons are GABAergic medium spiny neurons (MSNs). The striatum receives excitatory inputs from the cortex and thalamus, and dopaminergic inputs from neurons in the SNc. The basal ganglia are critical for movement initiation and execution. In neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease, loss of dopamine neurons in SNc or GABAergic neurons in striatum causes deficits in motor function. 

The outputs of the basal ganglia are GABAergic neurons in the SNr and GPi, whose tonic activity is believed to suppress movements by inhibiting neurons in thalamocortical and brainstem motor circuits. Striatum MSNs are divided to two classes: the direct pathway MSNs express the D1-type dopamine receptors (D1-MSNs) and project directly to the output nuclei at SNr and GPi; the indirect pathway MSNs express the D2-type dopamine receptors (D2-MSNs) and project indirectly to the output nuclei via the GPe and the STN, which are composed primarily of GABAergic and glutamatergic neurons, respectively. According to the classical rate model, activity in the direct pathway facilitates movement by causing pauses in the activity of basal ganglia output neurons, whereas activity in the indirect pathway inhibits movement by disinhibition of the output neurons of basal ganglia.  

However, recent studies suggest that direct and indirect pathway neurons encode movement information in a manner more complex than the rate model describes. Several questions remain to be addressed: What is the temporally precise relationship between activity in direct and indirect pathway striatal neurons? What is the functional role of direct and indirect pathway striatal activity at sub-second timescale? During movement, how does the activity of direct and indirect pathway striatal neurons influence the responses of neurons in SNr? 

As licking behavior in rodent consists of rhythmic tongue movements at fine timescale and the ventrolateral striatum (VLS) is important for tongue movements, Dr. YAO’s Lab used voluntary licking behavior in head-fixed mice to examine the response patterns of direct and indirect pathway striatal neurons at timescale of a lick cycle as well as a lick bout, and how striatal activities in the two pathways regulate the responses of SNr neurons during licking.  

The researchers found that, at timescale of a lick bout, inactivation of D1-MSNs reduced lick rate, whereas inactivation of D2-MSNs increased lick rate. Using optogenetic tagging, they found that D1- and D2-MSNs were both activated during licking movement, but had different activity during the initiation and execution of lick sequence. At fine timescale, D1- and D2-MSNs displayed different phases of oscillation time-locked to the lick cycle, and the peak response of oscillatory activity in D1-MSNs was around the time of spout contact. Interestingly, transient inactivation of D1-MSNs during tongue protrusion reduced spout contact probability, whereas transiently inactivating D2-MSNs had no effect. The researchers also found that inactivation of D1- and D2-MSNs led to distinct response changes in sub-populations of SNr neurons. In conclusion, the authors have uncovered the distinct roles of D1- and D2-MSNs in regulating movement at both coarse and fine timescales, and that the endogenous activity of D1- and D2-MSNs oppositely regulated the responses of a subset of SNr neurons during movement. 

This work entitled “Direct and indirect pathway neurons in ventrolateral striatum differentially regulate licking movement and nigral responses” was published online in Cell Reports on October 19, 2021. This work was completed by CHEN Zhaorong and ZHANG Zhi-Yu, under the supervision of Dr. YAO Haishan, with help from XIE Taorong and LI Yaping, and with strong support from Dr. XU Xiao-Hong and Dr. ZHANG Wen. This work was supported by grants from National Natural Science Foundation of China, Chinese Academy of Sciences, and Shanghai Municipal Government.   

　　　　Distinct roles of D1- and D2-MSNs in regulating licking movement and nigral responses  

　　Figure legend: A. Behavioral measurement and optogenetic manipulation. B. D1- and D2-MSNs in VLS exhibit different oscillatory phases relative to the lick cycle. C. Transient inactivation of D1-MSNs reduces probability of individual spout-contact. D. D1- and D2-MSNs oppositely regulate the responses of SNr neurons during licking. （Image by CEBSIT）

　　AUTHOR CONTACT 

　　YAO Haishan, Ph.D. 

　　Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. 

　　Email：haishanyao@ion.ac.cn