Presented by Li-xia Gao

2010.07.18

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)

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.

Viral expression of DIO-ChR2–YFP in BAC transgenic miceThe 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.

Methods

Schematic of Cre-dependentAAV vector expressing ChR2–YFP under control of the EF-1a promoter.

Striatum GPi SNr Striatum GPe

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

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)

2. ChR2-mediated excitation of direct- and indirect-pathway MSNs in vivo drives activity in basal ganglia circuitry

D2-ChR2-positive MSNs were more excitable than D1-ChR2-positive MSNs, 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.

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

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

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

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.

Whether increasing direct-pathway activity in Parkinson’s disease models can ameliorate parkinsonian motor symptoms is still unknown

Their findings establish a critical role for basal

ganglia circuitry in the bidirectional regulation

of motor behaviour and indicate that modulati

on of direct-pathway circuitry may represent a

n effective therapeutic strategy for amelioratin

g parkinsonian motor deficits.

Summary

Thank you for your attention!