[ARTICLE] Optogenetic Modulation for the Treatment of Traumatic Brain Injury – Full Text

Abstract

Although research involving traumatic brain injury (TBI) has traditionally focused on the acute clinical manifestations, new studies provide evidence for chronic and progressive neurological sequelae associated with TBI, highlighting the risk of persistent, and sometimes life-long, consequences for affected patients. Several treatment modalities to date have demonstrated efficacy in experimental models. However, there is currently no effective treatment to improve neural structure repair and functional recovery of TBI patients. Optogenetics represents a potential molecular tool for neuromodulation and monitoring cellular activity with unprecedented spatial resolution and millisecond temporal precision. In this review, we discuss the conceptual background and preclinical evidence of optogenetics for neuromodulation, and translational applications for TBI treatment are considered.

Introduction

Traumatic brain injury (TBI) is a significant public health issue worldwide and is predicted to be the third largest contributor to the global disease burden by 2020 [1,2]. The multifaceted and heterogeneous pathological aspects of this disease, which occur within days to months postinjury, cause significant neurological sequelae in TBI patients. Current empirical evidence provides new insight into these pathological mechanisms that lead to both focal neurological, as well as cognitive, deficits [3–5].

Recovery following TBI is complex and incompletely understood, yet studies have begun to elucidate important aspects of endogenously activated mechanisms that facilitate the process. Much of this research has been conducted to understand the fundamental concept of plasticity. Although neurogenesis within the mature brain continues, it is limited primarily to the subventricular zone (SVZ) surrounding the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) [6–8]. A distinct subpopulation of cells from these regions migrate through adult white matter and differentiate into neurons in several cortical locations. Recent evidence suggests these cells may be involved in cell repair or renewal mechanisms [9,10].

Exploitation of this endogenous population of stem cells is of particular interest with regard to TBI. Following both diffuse and focal injury, a significant increase in proliferation within the SVZ and DG has been demonstrated in both mouse and rat TBI models alike [11,12]. Importantly, newly generated and injury-induced granular cells are able to integrate into the existing hippocampal circuitry, a phenomenon thought to facilitate innate cognitive recovery following injury [13,14]. A more recent study of human TBI models found proliferation of cells expressing markers of neural stem cells (NSCs) and neural progenitor cells in the perilesion cortex, thus representing an intrinsic effort by the injured brain to repair and regenerate damaged tissue [15].

This observed endogenous plasticity can be further investigated and manipulated using precise electrical modulation. To date, several methods have been explored to induce or accelerate functional and adaptive recovery in TBI patients, including both invasive (eg, electrical cortical stimulation [ECS]) and noninvasive (eg, transcranial magnetic stimulation [TMS], transcranial direct current stimulation, and pharmacologic) methods, each mediating an upregulation in plasticity following TBI [16–20]. However, animal studies and clinical trials involving the use of these interventions are scarce, and such approaches are often cell type indiscriminate, invasive, and render surrounding tissues susceptible to damage [21,22]. Due to a universal understanding that newer therapeutic approaches must circumvent these limitations, recent developments have successfully incorporated precision and cell type specificity into the treatment modality. Optogenetics builds upon previous research through the use of genetically encoded channels and receptors that serve to selectively activate or inhibit neuronal subpopulations with unprecedented spatial resolution and millisecond temporal precision. In this review, we discuss optogenetics as a means to evaluate and modulate neural circuits in the context of recovery following TBI.

Fundamentals of Optogenetics

Optogenetics is a modern advancement incorporating the fields of bioengineering, optics, and genetics for the purpose of modulating and monitoring cellular activity at the level of molecularly defined neuronal classes. This innovation involves the artificial introduction of light-sensitive proteins (eg, opsins) into cell membranes [23,24]. Neuronal plasma membranes themselves are thus made sensitive to light, permitting direct activation and inhibition of specified, targeted neurons within intact neuronal circuits [25]. In addition, optical monitoring of neuronal activity is achieved using genetically encoded sensors that respond to changes in ion concentration (eg, calcium) or membrane voltage. By utilizing tools with the ability to utilize light energy, neuronal imaging can achieve both high spatial and high temporal resolution [26,27].

While previous approaches typically fall short with respect to temporal and spatial accuracy, optogenetics expands the capability for optical imaging and genetic targeting by simultaneously controlling or monitoring either the activity of many neurons within a circuit or certain regions within a single neuron. Single-cell optogenetics is able to map neural circuits with excellent accuracy and zero-spike crosstalk [28]. Expression of certain light-sensitive proteins can also behave as actuators and switch neurons on and off, inducing either depolarizations or hyperpolarizations for varying periods of time with exquisite precision. This capability allows the opsins to probe neural activity at the resolution of single spikes, raising the possibility that this method can one day mimic natural neural code [29]. Since its inception, optogenetic tools have been developed to further map complex neural circuits and target specific neurons to facilitate behavior modulation, which are significant ambitions of current research in the field of neuroscience.[…]

 

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