It is clear from these results that a beneficial effect is seen in ameliorating pathological motor deficits in a frequency-dependent manner, similar to that of DBS. Optogenetics offers temporal precision and cell-type specific targeting which are necessary parameters in high-frequency stimulation of a selective cell population.

Though DBS is a potent treatment for Parkinson's disease, the actual mechanism through which it can regulate motor deficits is still complex due to the multitude of neural circuitry involved as well as other glial modulators that could play a role.

A positive ion like hydrogen (H+), sodium (Na+), or potassium (K+).

A tube inserted into the body to facilitate the delivery of fluids or materials to a specific region.

The authors used Channelrhodopsin-2 to selectively photostimulate hypocretin-producing neurons in the lateral hypothalamus and showed a frequency-dependent effect on sleep-to-wakefulness transition. This paper supported optogenetics' ability to stimulate cells and elicit a physiological effect.

This paper discusses targeting strategies to selectively express opsins to certain regions or cell types as well as methods to read out expression and activity. Methods include electrophysiology, imaging, and behavior analysis.

By doing a separated-optrode experiment where an optrode was placed over M1 and a recording electrode placed in the STN, the researchers were able to see a frequency-dependent resolution of parkinsonian motor deficits.

Based upon the investigators' results, they can extrapolate how their findings will impact future treatment of Parkinson's disease—not by implementing an optogenetic approach, but by targeting a different area in the pathological neural circuit that could prove more effective.

A paper describing the first use of halorhodopsin—a chloride pump expressed in an archaeon named Natronomonas pharaonis that expressed temporal optical inhibition of neural activity. The investigators were then able to co-express both NpHR and ChR2 in the same cell and optically control its activity.

The authors engineered the NpHR from the F. Zhang et al. paper in 2007 to be better expressed at the cell membrane by inserting a membrane-insertion signal and an endoplasmic reticulum export signal. Both interventions created eNpHR (enhanced NpHR) that improved protein trafficking and membrane expression. This was a necessary modification for the current paper published by the same first author. Temporal precision is a key parameter when dealing with neural firing which can occur at millisecond resolution.

The authors investigated a red-shifted cation-conducting opsin variant from the algae species Volvox carteri that could be stimulated at a wavelength of 595nm. VChR1 can be stimulated by yellow light and offered a third class of microbial opsins.

A group of nuclei located at the base of the forebrain that is responsible for motor control and cognition.

Major component of the basal ganglia that targets the substantia nigra.

Opposite the lesion.

An optrode is a combined optical fiber with a metal electrode that can both stimulate via light and record via a tungsten wire. The tungsten wire was tightly attached to the optical fiber with the electrode tip being slightly deeper to ensure proper recording from light-stimulated neurons.

Though they showed an increase in electrical activity upon blue light ChR2 activation, the high-frequency stimulation did not alter motor symptoms, and the increase in electrical activity does not sufficiently account for high-frequency stimulation's therapeutic effects in Parkinson's disease.

In accordance with high-frequency stimulation's therapeutic effects in Parkinson's disease patients via deep brain stimulation, the authors observed that HFS of the afferent fibers via ChR2 blue light activation reduced STN spiking.

As proof of principle, the authors were able to selectively target projection neurons and express ChR2 using the promoter Thy1. Upon high-frequency stimulation, the hemiparkinsonian rats showed a significant therapeutic decrease in rotation behavior, while low-frequency stimulation exacerbated the motion deficits.

S100β, also known as calcium-binding protein B, is expressed by mature astrocytes. S100β can also be used as a peripheral biomarker of blood-brain barrier permeability.

Adamantidis et al. previously showed that a light power intensity of 1mW/mm2 was necessary to drive the action of microbial opsin currents in hypocretin-producing neurons within the lateral hypothalamus .

A subregion of the midbrain responsible for motor control.

Progressive loss of function of neurons, usually a result of neuron death.

A progressive degenerative disorder primarily impacting motor control that can lead to tremors or stiffness. Pathologically characterized by the loss of dopamine-secreting neurons in two parts of the brain (the substantia nigra pars compacta and basal ganglia), as well as the presence of Lewy bodies—aggregates of a protein called alpha synuclein contained within the neuron.

The first paper describing the algal protein, Channelrhodopsin-2, which was successfully cloned and expressed into mammalian neurons. The authors performed electrophysiological recordings of neurons expressing an opsin and measured the spiking activity.

Nerve fibers arriving in the STN. In the peripheral nervous system, afferent fibers are those that carry signals from the target back to the spinal cord.

Nerve fibers exiting the STN. Directionality in the central nervous system is dependent upon the brain region in question. In the peripheral nervous system, efferents are in relation to the spinal cord—neurons that carry signals out of the spinal cord and to a target.

Real or true.

Here, referring to tissues made up of many different cell types with specific functions.

The brain is a highly interconnected network of neurons that project to distant regions. It is in this network that neurons can connect in very specific patterns to form a "circuit," or a specific path that has been mapped to a specific function.

A long, threadlike projection from a neuron's cell body that conducts impulses from one cell to the next.

GAD67 is an enzyme that catalyzes a reaction converting glutamate to GABA. GABA is one of the major inhibitory neurotransmitters in the nervous system.

A tool designed to control cellular behavior using genetically encoded proteins that are responsive to light.

A therapy option for Parkinson's disease, epilepsy, and depression patients where metal electrodes are inserted into deep brain regions. A stimulator placed near the collarbone then sends an electrical impulse through wires connected to the electrodes targeting neurons in the implanted area.

Also known as the soma; is considered to be the cell body of the neuron.

Glial fibrillary acidic protein (GFAP) is an intermediate filament (cytoskeletal component) protein expressed by glial cells including astrocytes. Glial cells are non-neuronal cells within the central and peripheral nervous systems whose roles include providing support and protection for neurons. When a gene like ChR2 is under the control of a GFAP promoter, only those cells that express the transcription factor for GFAP will express ChR2.

Selectively targeting eNpHR to the excitatory neurons of the STN showed to be insufficient at impacting the rotational behavior in the hemiparkinsonian rats. This alludes to the possibility of another mechanism of action being involved other than strict inhibition of excitatory neurons.

To test whether optogenetics can be used to dissect neural circuits, the authors utilized an established model of induced Parkinson's disease. 6-OHDA is a synthetic neurotoxin that selectively destroys dopaminergic and noradrenergic neurons in the brain. When injected on one side, it can cause side-biased motor deficits. The right medial forebrain bundle is a neural pathway that passes through the hypothalamus and basal forebrain and contains a high number of dopaminergic neurons.

The authors were able to demonstrate the utility of selectively targeting specific excitatory neurons with an inhibitory opsin and then reversibly inhibit and record neural activity.

To accurately target the subthalamic nucleus (STN), the authors used extracellular recordings to determine accurate position within the deep brain structure since the STN has a characteristic firing pattern. Guided by this method, accurate injection of opsin vectors to the region was accomplished.

On the same side as the lesion.

A material with the ability to reflect, refract, and polarize light.

Deep brain region, part of the basal ganglia, composed of glutamatergic neurons and shaped like a lens.

Cells that synthesize and release a compound called dopamine, commonly referred to as a neurotransmitter. Neurotransmitters are released at distant structures of a neuron that come into contact with close or distant cells, called synapses.

Difficult to control or deal with.