Transcript Regulation of parkinsonian motor behaviours by optogenetic control

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.
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.
1. Selective viral-mediated ChR2 expression in striatal director-indirect-pathway medium spiny projection neurons (MSNs).
Striatum
GPi
SNr
Striatum
GPe
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.
3. They tested ChR2 function in vivo in the Str/SNr of anaesthetized
D1-ChR2 and D2-ChR2 mice
Striatum
GPi
SNr
Striatum
GPe
STN
SNr
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
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.
Thank you for
your attention!