22 Using Light to Unveil Depression: The Role of Optogenetics.

IntroductionMajor depressive disorder (MDD) is a highly prevalent and often debilitating condition with a vast impact on modern societies worldwide. Although it interferes significantly with functioning, MDD is frequently unresponsive to conventional treatment approaches and pharmacotherapy failure has been reported in approximately one third of patients. Current knowledge of the exact underlying disease mechanisms is insufficient, and may thus largely contribute to such therapeutic limitations. Optogenetics, a novel study field employing the expression of genetically-encodable light-sensitive proteins in specific cell types, circumvents the limitations of other forms of neuromodulation and enables temporally precise, bidirectional control of cellular activity in well-defined neuronal populations. This strategy has been used successfully to dissect neural pathways and circuitries involved in complex mental diseases such as MDD.

METHODS: A systematic literature search was conducted using the terms "Optogenetics", "Depression" and "Major depressive disorder" on the databases MEDLINE, LILACS, SciELO, Pubmed and BIREME. Inclusion criteria were adopted: articles published in the English language from 1971 (description of bacteriorhodopsin as a light-activated regulator of transmembrane ion flow) to 2017 and articles based on experimental studies were selected.

RESULTS: By using highly validated animal models based on the exposure of phenotypically susceptible rodents to different forms of chronic stress, researchers have been able to reproduce the hallmark symptoms of Depression as well as the histopathological abnormalities found in human brain specimens post-mortem. Several brain regions and neuron populations involved in MDD have been identified by use of a variety of molecular resources including viral vectors, genetically engineered animals, multiple promoters and bacterial opsins. Important areas of dysfunction underlying depression including the medial prefrontal cortex, the ventral tegmental area, the nucleus accumbens, the hippocampus and the basolateral amygdala have been investigated by using optogenetic neuromodulation, yielding new insights into the pathological processes underlying MDD. Researchers have been able to pinpoint affected circuitries and employ time-precise light modulation to successfully revert symptoms of MDD, restoring normal function. It is important to highlight that although promising, studies using optogenetics are controversial, largely due to the variable set tools, models and tests employed in research.

CONCLUSION: Light modulation using optogenetics has greatly aided to establish accurate models to unveil the neurobiological basis of Depression. Further research will continue to help build more complete pathophysiological constructs and pave the way for new treatment strategies.