**Abstract**

Optogenetics has emerged as a revolutionary technology that enables circuit-specific restoration of neuronal function with millisecond temporal resolution. Restoring vision is one of the most promising and forefront applications of optogenetics. This chapter discusses essential components, mechanisms, present challenges, and future prospects of optogenetic retinal prostheses. The theoretical framework and analysis of optogenetic excitation of retinal ganglion neurons are also presented, which are useful in developing a better understanding and guidance for future experiments. It shows that the newly discovered ChRmine opsin provides control at light powers that are two orders of magnitude smaller than that required with experimentally studied opsins that include ChR2, ReaChR, and ChrimsonR, while maintaining single-spike temporal resolution, in retinal ganglion neurons.

**Keywords:** optogenetics, computational optogenetics, retinal prostheses, channelrhodopsin, vision restoration

## **1. Introduction**

Loss of vision due to retinal degenerative diseases, including retinitis pigmentosa (RP) and macular degeneration affects millions of people worldwide [1–3]. The degeneration of light-sensitive rod and cone photoreceptors in the retina breaks the process of converting the light signal into an electrical signal. It thus results in partial vision loss or complete blindness. Earlier studies have confirmed that the remaining retinal tissue retains functionality and connections to the brain without these photoreceptors [4, 5]. Direct electrical stimulation of the remaining retinal neurons enables light sensation and visual perception, which confirms that the remaining retinal neural circuits can transmit information to the brain even in the late stage of retinal degenerative diseases [6–8]. However, applications of electrical prosthetic devices are limited due to their poor spatial resolution and highly invasive nature [4, 9, 10]. Although there are alternative methods for treating blindness, that includes pharmaceuticals, gene therapy, and stem cells, they are limited in certain conditions [11–14].

The emergence of optogenetics has revolutionized neuroscience by providing unprecedented spatiotemporal resolution in bidirectionally controlling neural activity with relatively lower invasiveness [15, 16]. In optogenetics, the gene of a light-sensitive protein is introduced into light-insensitive cells. In response to light, the expressed protein generates either inward or outward current and thus depolarizes or hyperpolarizes the cell [17]. It has contributed to our knowledge of how neural circuits operate and holds tremendous prospects in neural prostheses, particularly in vision restoration [18–23]. As one of the most promising technologies, optogenetics has applications in and beyond neuroscience, including cardiac optogenetics, sensory restoration, all-optical manipulation, and imaging of neural circuits in living animals [24]. More recently, a pioneering human clinical study on optogenetic retinal prostheses has reported successful partial vision recovery in a blind patient [25].

#### **2. Optogenetic strategies for retinal prostheses**

The method of optogenetic retinal prostheses is fundamentally different from electrical prostheses [26]. In optogenetics, injection of genetically encoded opsin viral vector into the surviving retinal neurons imparts light sensitivity to the light-insensitive retinal neurons. Thus, vision can be restored with the help of an optoelectronic device that converts visual scene pixels into appropriate light pulses and delivers them to the targeted cells. The implantation of optoelectronic headsets does not require the same level of invasiveness as their electronic counterpart [18, 26].

As the retina is a layered structure, the signal from photoreceptor cells in the foremost layer undergoes various processing before reaching the inner most layer *i.e.,* retinal ganglion neurons (RGNs). After that, the processed signal is transmitted to higher visual areas in the brain. As optogenetics allows cell-specific opsin expression, in principle, it would be best to transfect as early as possible in the visual pathway taking advantage of internal signal processing in the retinal circuits [26]. Once transfected, the retinal neurons require spatiotemporal patterns of high-intensity light depending on the dynamic range and spatial configuration of the targeted neurons and the kinetics and photosensitivity of light-sensitive proteins [27–29]. The selection of targeted cell type and opsin construct decides the quality of restored vision. Furthermore, the safety of retinal tissue after the expression of opsin into the desired neural population must be ensured [30].

In patients with RP, cone cells are not necessarily completely destroyed. These cells lose their outer segment and survive until very late stages of the condition [31]. Typically, the cone photoreceptor cells hyperpolarize in the presence of light and get depolarized in the dark. Thus, it would be better to use light-driven chloride pumps to perfectly mimic the signal in response to light [32–34]. Optogenetic excitation of the surviving cone cells through genetic expression of these cells with halorhodopsin has restored visual responses in the mouse with RP [35]. However, a major drawback of targeting cone cells is their very few surviving populations. Furthermore, there might be no chance of survival of these cells in late stages of other retinal dystrophies. Thus, the restored vision will be restricted to tunnel vision similar to mid-stage RP [8, 26]. The next best layer to target is the bipolar cells. There are two types of these bipolar cells, *i.e.,* ON and OFF cells, which depolarize and hyperpolarize in response to light. Thus, these cells need to be expressed with excitatory and inhibitory opsins to avoid conflicting responses to visual stimuli, respectively [28, 34].

Alternatively, direct optogenetic excitation of RGNs is possible. RGNs also come in ON and OFF varieties. A key issue with the direct excitation of inner retinal neurons is the absence of normal retinal processing. A possible solution to overcome the issue is to process the visual scene by the computational circuit of retinal encoding before delivering it to inner retinal neurons [36]. In the case of direct excitation of RGNs,

*Recent Advances in Optogenetic Retinal Prostheses DOI: http://dx.doi.org/10.5772/intechopen.109205*

optoelectronic goggles have been used to mimic retinal processing and to modify visual scene intensity and color compatible with the light-sensitive protein expressed in RGNs [26].

To accurately restore vision by direct photostimulation of inner retinal neurons, these neurons are to be driven at their natural frequencies, evoked in response to dynamic visual stimuli [18]. There are at least 16 different types of RGNs having different temporal properties [37]. Recently, monitoring 342 RGNs in the human retina revealed that the maximum neural population fires at ∼50 Hz, in response to full-field contrast steps, but it could reach up to 180 Hz in a few cells [37]. Although opsins with fast turn-off kinetics would allow precise spiking in those neurons, they invariably require high irradiances, as light sensitivity and kinetics are inversely correlated. Furthermore, the intensity threshold to evoke spikes in opsin-expressing retinal neurons should be below a safety threshold to reduce the possibility of photochemical damage in the retina [38]. Also, the opsins should respond to large intensity variations [26].
