Biomedical Engineering Reference
In-Depth Information
causes the sleep disorder narcolepsy. Photostimulation on ChR2-expressing
hypocretin neurons increased the probability of sleep/wake transitions
(Adamantidis et al.
2007
) and increased neuronal activity in downstream wake-
promoting nuclei (Carter et al.
2009
). It has also been shown that optogenetic stimu-
lation of the locus coeruleus (LC) produces immediate sleep-to-wake transitions,
whereas optogenetic inhibition causes a decrease in wakefulness (Carter et al.
2010
). In addition, tonic stimulation of the LC led the mice to a cataplexy-like state,
which is a sign of narcolepsy.
8.2.3
Motor Behavior
The selective loss of dopaminergic neurons in the substantia nigra pars compacta
leads to a severe neurodegenerative disorder known as Parkinson's disease, charac-
terized by muscle rigidity and uncoordinated physical movements. Two major out-
put routes from striatal neurons, known as the direct and indirect pathways, are
thought to be related to this disease. The indirect pathway output neurons express a
specifi c dopamine receptor called dopamine receptor type 2 (D2R), a G-protein-
coupled receptor that inhibits adenylate cyclase and thus suppresses calcium signal-
ing. Stimulation of D2R by dopamine leads to suppression of the indirect pathway.
Under normal circumstances, the indirect pathway suppresses the inhibitory output
of the external capsule of globus pallidus (GPe), which is involved in suppressing
the subthalamic nucleus (STN). It is generally thought that losing dopamine results
in increased indirect pathway activity, due to the loss of D2R-mediated suppression
of this pathway. When GPe can no longer function as a major inhibitor of the STN,
the ensuing net increase in STN activity may explain the motor symptoms of
Parkinson's disease. Optogenetics has recently clarifi ed that activation of the indi-
rect pathway indeed mimics the parkinsonian state (Kravitz et al.
2010
). In this
study, the relative contributions of dopamine D1-receptor- and D2-receptor-
expressing neurons in the striatum were investigated by selectively targeting each
type with ChR2. Stimulation of D1-expressing neurons in the striatum reduced par-
kinsonian symptoms in a mouse model of the disease, whereas stimulation of
D2-expressing neurons—which mimics dopamine depletion of indirect pathway—
caused symptoms in wild-type mice.
In addition to deepening our understanding of Parkinson's disease circuitry,
another recent optogenetics study shed light on how one of the traditional treat-
ments for this disease may be relieving the symptoms. A crude technique called
deep-brain electrical stimulation within STN causes a reversal of Parkinson's dis-
ease symptoms. To understand the underlying principles of this phenomenon, opto-
genetic probes were used to systematically stimulate or inhibit a mixture of distinct
circuit elements containing neurons, glia, and fi ber projections in the STN of freely
moving rodent models of Parkinson's disease (Gradinaru et al.
2009
). When the
excitatory afferent axons projecting to the STN—such as those of motor neurons in
