Optogenetic Inhibition

Parkinson disease (PD) is one of the most common neurologic disorders. and it affects approximately 1% of individuals older than 60 years old. Parkinson’s disease is a condition that progresses slowly by treatment. In addition, loss of pigmented dopaminergic neurons of the substantianigra pars compacta and the presence of Lewy bodies and Lewyneurites are the two major neuropathologic findings in Parkinson disease (Hauser, 2016).

In the past twenty years, many drugs have been developed to treat the disease. Although the cause of Parkinson's disease is still unknown, scientists have been developing methods of treatment and therapy. The idea is to replace dopamine in the brain, which is accomplished, to some extent, with the administration of L-Dopa. In conjunction with other drugs, L- Dopa "inhibits the enzymes that break down L-dopa in the liver, thus making a greater part of it available to the brain" (5). This treatment is very successful, but it only hinders the disease for a time and it is by no means a cure. That leaves us with stem-cells and the role they play in treatment of Parkinson's disease.

Parkinson’s disease is a “neurodegenerative disorder of the basal nuclei due to insufficient secretion of the neurotransmitter dopamine” (Marieb & Hoehn, 2013, p. G-17). The cause of Parkinson’s disease is unknown, but many factors play a role in the development of Parkinson’s disease. One factor that has been found in an individual who has Parkinson’s disease causes over activity of targeted dopamine-deprived basal nuclei. This over activity is caused by the breakdown of neurons that release dopamine in the substantia nigra (Marieb & Hoehn, 2013). Another factor that is present in a person who has Parkinson’s disease, is the presence of lewy bodies in the brain stem ("What is lbd?," 2014). Lewy bodies are unusual

The major component shared by both Parkinson’s disease and dementia is the functioning of neurons, with a then understandable association. Dementia is caused by neuron demise or diminished capacity of communication with other cells, while Parkinson’s disease, neurons in the basal ganglia experience deterioration that disrupts the normal neurotransmitter dopamine balance where neurons waste and die. With this shared neuron deterioration, the prevalence of dementia associated with Parkinson’s disease is clearly understood. One-third of all patients with Parkinson’s disease will display dementia (LeMone, Burke, & Bauldoff, 2011) with indicators identical to Alzheimer’s form of dementia.

“Genetic engineering and drug development can cure and therapies of Parkinson’s disease and Alzheimer’s disease, so embryonic stem cells in not the only way to treat patients” (McLean 3). People witness the development of cancer treatments with the enhancement of more effective drugs. Also, nanotechnology allows scientists to deliver drugs only to the cancerous cells, so that the nearby healthy cells remain unaffected. Genetic engineering provides prospect in curing Parkinson’s disease which causes loss of body control. “Scientists develop Parkinson’s disease in laboratory mice to and genetically engineer their nerve cells to make them become light sensitive. When these nerve cells are exposed to light, then nerve impulses travel along them and the mice are again able to move their bodies” (McLean 4). People speculate that this discovery can be used to cure Parkinson’s in humans. Critics of embryonic stem cell research believe that people don’t need to pursuing embryonic stem cell research will be negated by promising advances in drug development and genetic

In Parkinson's Disease and Huntington's disease the nigra-striatum neural communication assemblage is severely hampered. PD results from a depletion in the amount of dopamine produced by the brain. At the onset of the disease, dopamine-secreting cells of the substania nigra, either because of genetic factors or environmental toxins, experience mass cell death. Thus, the nigra cells are unable to form synapses through which they secrete and relay dopamine to the striatum in a neural circuit within the basal ganglia (18).

There are two specific sites inside the brain have been most commonly targeted for deep-brain stimulation in Parkinson's disease are the subthalamic nucleus and the internal segment of the globus pallidus (Okun 2012). Both are nuclei in the basal ganglia, where a majority of degenerative change in Parkinson's disease occurs (Okun 2012). There are many adverse effects from having deep brain stimulators implanted; the two that stand out are infection and intracranial hemorrhage. These are a major problem as they can be the reason why deep brain stimulators are removed. While deep brain stimulators can be very helpful, the safeness and outcome are not set in stone and one should be careful considering it for

Microfluidic chips allow for the manipulation, at small quantities of neuronal cells. Further, these chips allow for precise temporal and spatial control. This model is one that can be useful in the framework of neurodegeneration. Deleglise et al (2013) fabricated a 3 chamber microfluidic chip. The chambers held one of: coritical neuron soma and dendrites, cortical axons, or striatal neurons. The chip was designed to replicate an oriented neuronal connection from the coritcal to the striatal cells. Through the use of a chemically induced axotomy, by adding fluid to the central chamber (housing the cortical axon), showed that their chip could be used to simulate a lesion in the neuronal network. An emphasis was placed on the protection of synapses, and event that in axotomy studies, traumatic injury and in many neurodegenerative disorders precedes the loss of neuronal cell soma and axons. They then showed that zVAD-fmk, a caspase inhibitor and resveratrol did not show synaptic protection, while NAD+ and Y27632, a Rho Kinase inhibitor showed significant synaptic protection, despite the mechanism not being clear. Pointing at potential therapeutic targets for neurodegeneration. This can also be further looked at from the functionality of the chip - it is a useful tool in the evaluation of drugs in the axotomy model they presented.

Over 70% of patients experience momentous improvements in motor control and function and 72-85% of patients with essential tremor experience symptom improvement ("Deep Brain Stimulation," 2016). After 12-month follow-up, according to the Unified Parkinson’s Disease Rating Scale (UPDRS), 45% of patients saw improvement in activities of daily living without medication and dopamine supplementation was discontinued in 50% of patients (Benabid, 2003). Both of these outcomes were sustained over a period of 5 years (Benabid, 2003). In this same study, patients saw immediate symptom improvement when DBS stimulation was turned on, even after a 90% return of symptoms when the stimulation was switched off during a two-hour period (Benabid, 2003). In a comparison trial between DBS and Best Medical Therapy, patients who received DBS demonstrated improved working memory ability at baseline and reported a better quality of life in 7 of 8 Parkinson Disease Questionnaire subscales (Weaver,

Parkinson’s disease is affected by the degeneration of dopaminergic neurons which is responsible to produce dopamine. Dopaminergic neurons have their cell bodies in substantia nigra pars compacta (SNpc) in basal ganglia (O’Sullivan and Schmitz, 2007). Basal ganglia are a collection of interconnected gray matter nuclear masses deep within the brain”. These gray matter masses are caudate, putamen, globus pallidus, subthalamic nucleus and the substantia nigra. Basal ganglia receive its input through striatum (O’Sullivan and Schmitz, 2007).

In this paper AAV6 is again used to infuse channelrhodopsin-2 into mouse tissue. However, this experiment injects it into muscle cells, which allows the ion channel to be expressed only in the neurons that activate the injected muscle. This results in activation of a given muscle in response to light. Instead of transdermal exposure, this experiment uses an implanted fiber optic cuff to wrap around the nerve and emit the light necessary for optogenetic nerve activation. The experimenters were then able to activate the muscle in a freely moving mouse using light, with high temporal sensitive (although other rhodopsins hold the potential for even higher temporal sensitivity). The implantation had limited effect on the natural gait of mice, and neural activation was measured with electrophysiology

Although essentially a broad term, the principal technology in optogenetics incorporates two key functions: light-responsive, control tools that can convey a function in the cell and customizable elements for delivering light to cells of interest; personalizing the control tools for use in the cell of interest; and acquiring analyzable data (Boyden, et. al., 2005). Optogenetically controlled systems had their beginnings in neuroscience, where the need to control a certain type of cell without altering others in the brain was the ultimate goal. This was the underlying concern with classic techniques used to obtain neuronal data; electrical stimulation could not be used for the targeting of individual cells, and the use of drugs to alter neuronal functioning is a slow, imprecise method that is potentially toxic to the cells. Fortunately, optical manipulation of neural activity was accomplished through a microbial opsin gene, a light-sensitive protein that allowed the neurons to react to specific wavelengths of light (Boyden, et. al., 2005). This “light-switching” was capable of being tested in freely motile organisms with no harm inflicted to the organism. Success with this particular group of proteins directed the research of optogenetics to the engineering of several variable

There are many advantages and disadvantages of using optogenetics. Some of the benefits of using optogenetics include being able to apply the technique to numerous levels of brain function such as neurons, synapses, local circuits and even behaviour to obtain a visual record and manipulate activity. By targeting the probe or light source to specific cellular compartments or areas of interests, specificity is achieved and researchers are able to establish links when optogenetics is implemented at different levels of the nervous system. Moreover, both the spatial resolution and temporal resolution is very precise with a millisecond scale as opsins are able to rapidly cause changes in targeted neurons by either activating or inhibiting them. Lastly,

Attempts to cure or slow down the progression of Parkinson’s disease have largely failed; researchers in this paper maintain this is obviously a direct result of the lack of insight into the pathogenesis of the disease. Parkinson’s disease is the product of the deaths of a number of dopaminergic (dopamine-secreting) neurons in the substantia nigra pars compacta region (SNc) of the brain. But what causes these deaths? In the paper “‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease,” Chen and researchers find that older neurons in the SNc are unusually reliant on calcium channels and that after blocking these channels, the cells are “rejuvenated” and begin acting like their juvenile counterparts; as a

It has been known that PD is a disorder affecting the basal ganglia. The term basal ganglia is generally applied to a collection of nuclei situated deep within the cerebral hemispheres, lying laterally to the thalamus (Gazzeniga, George, and Mangun, 2008). The basal ganglia are important subcortical structures. They are composed of five nuclei: caudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra. These nuclei are not thought of a single anatomical entity; rather, they form a functional unity whose contribution is greatly to motor control. Interestingly, this system does not influence movement through spinal cord pathways, but rather acts as part of a feedback loop to all areas of the cerebral cortex, with primary input into motor areas (Aird, 2000). A number of excitatory and inhibitory neurotransmitters are what control this whole process, and a balance of both is required to ensure that smooth, purposeful movement takes place. In order to understand the pathways of which the basal ganglia take part in, it is essential to know the input and output connections of the basal ganglia. The input