Presented by Li-xia Gao 2010.07.18

1. Presented by Li-xia Gao 2010.07.18

2. Neural circuits of the basal ganglia are critical for motor planning and action selection Two parallel basal ganglia pathways Direct pathway (dopamine D1) Indirect pathway (dopamine D2) medium spiny neurons (MSNs)

3. The direct and indirect pathway has been proposed exert opposing influences on motor function activation of the direct pathway facilitates movement activation of the indirect pathway inhibits movement However, this model has never been tested, the specific function of these circuits in behaving animals remains unknown.

4. Methods Schematic of Cre-dependent AAV vector expressing ChR2–YFP under control of the EF-1a promoter. Viral expression of DIO-ChR2–YFP in BAC transgenic mice The recombinant AAV1 virus was injected to the dorsomedial striatum in BAC D1-Cre and D2-Cre transgenic mice. DIO constructs encoding ChR2–YFP restricted expression to Cre-positive cells.

5. Striatum GPi SNr Striatum GPe 1. Selective viral-mediated ChR2 expression in striatal direct- or-indirect-pathway medium spiny projection neurons (MSNs).

6. To investigate whether ChR2–YFP was expressed in striatal interneurons, they immunostained each line for choline acetyltransferase, parvalbumin and neuropeptide Y, which are markers of cholinergic, fast-spiking and low-threshold-spiking interneurons, respectively ChR2–YFP-expressing neurons do not co-express the interneuronal markers parvalbumin (PV) and choline acetyltransferase (ChAT)

7. 2. ChR2-mediated excitation of direct- and indirect-pathway MSNs in vivo drives activity in basal ganglia circuitry D2-ChR2-positiveMSNs were more excitable than D1-ChR2-positiveMSNs, this result was consistent with previous reports, it provide further evidence that these subpopulations were selectively labelled by ChR2–YFP Illumination elicited large light-evoked currents in voltage clamp and robust spiking in current clamp, indicating that ChR2 was functional in these neurons.

8. Striatum GPi SNr Striatum GPe STN SNr 3. They tested ChR2 function in vivo in the Str/SNr of anaesthetized D1-ChR2 and D2-ChR2 mice

9. After verifying the expression pattern of ChR2 in the direct or indirect pathways, and confirming their ability to drive direct- and indirect-pathway basal ganglia circuits in vivo, they examined the behavioural effects of activating basal ganglia circuits in awake mice. A parkinsonian state is distinguished by increased freezing, bradykinesia and decreased locomotor initiations

10. 4. In vivo activation of direct or indirect pathways reveals pathway specific regulation of motor function

12. Parkinsonian motor deficits are proposed to result from an overactive indirect pathway and an underactive direct pathway. Surgical treatments for Parkinson’s disease are focused on reducing activity in the indirect pathway, through lesions or deep-brain stimulation. Whetherincreasing direct-pathway activity in Parkinson’s disease models canameliorate parkinsonian motor symptoms is still unknown

15. Summary Their findings establish a critical role for basal ganglia circuitry in the bidirectional regulation of motor behaviour and indicate that modulation of direct-pathway circuitry may represent an effective therapeutic strategy for ameliorating parkinsonian motor deficits.

16. Thank you for your attention! Thank you for your attention!