Optogenetics and the dissection of neural circuits underlying depression and substance-use disorders

Introduction to Reward-related Mood Disorders Neuropsychiatric disorders encompass a range of diseases that create a huge burden on society. In the last 60 years, research into the biological basis of these disorders has progressed tremendously because of technological precision in studying cellular neurobiology, advances in the scale of genome-wide studies, refined animal models and the tuned dissection of neural circuits. Of particular interest is the study of the causes, mechanisms and treatments of major depressive disorder (MDD) and pathological substance-use disorders. The serendipitous discovery in the 1950s of tricyclic antidepressants has created a foundation for the generation of receptor- and transporter-based pharmacotherapeutics for MDD and substance-use disorders. Of particular interest in the study of MDD and substance-use disorders are the neurons involved in the emotion- and reward-related midbrain dopaminergic system. This circuit consists of ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC) and the amygdala, regions involved with encoding reward, modulating executive control and associating context and cues (Figure 18.1) (Hyman, 2007; Russo and Nestler, 2013). Neurons in these downstream regions are dopaminoceptive and express either dopamine receptor-1 (D1) neurons or dopamine receptor-2 (D2) neurons. Many pharmacotherapeutics that are used to treat MDD and substance-use disorders, such as monoamine oxidase inhibitors (MAOIs), selective serotonin and norepinephrine reuptake inhibitors and antagonists of opioid receptors, have been found to have robust actions on neural substrates in the dopaminergic reward system (Berton and Nestler, 2006). However, with the success of deep brain stimulation in the treatment of MDD and substance-use disorders (a technique that uses chronically implanted stimulating electrodes to specifically target brain regions in the reward system for electrical stimulation), there is an ever-evolving hypothesis that neuropsychiatric disorders are neural circuit disorders (Lobo et al., 2012; Volkow and Koob, 2015). Thus, the importance of identifying how neural substrates of this circuit are pathologically altered in MDD and substance-use disorders is critical. Optogenetics has granted researchers the unique ability to selectively target genetically distinct cell populations or neural circuits for temporally precise stimulation or inhibition in awake and behaving animal models. This has shed light on the neural circuit mechanisms involved in depression and substance abuse. Optogenetics, in conjunction with validated animal models for neuropsychiatric disorders, has dramatically altered how researchers approach and interpret the study of depression and substance-use disorders.