Light up your life: optogenetics for depression?

In the last year, several new studies have shown the po tential of optogenetic stimulation to rapidly modify depressionand anxiety-related behaviours in animal models. Optogenetic technology, as described in a previous editorial, gives a whole new meaning to “light therapy” that is potentially more effective and rapid and has fewer adverse effects than classic light therapy or pharmacological approaches to treat mental illness. Unlike classic light therapy, which involves a generalized effect of photic stimulation of the visual system to medi ate its effects, optogenetics involves the activation by light of engineered light-sensitive ion channel proteins expressed in cells of interest. These light-sensitive channels respond to different colors: channelrhodopsin is activated by blue light and depolarizes to activate neurons, while halorhodopsin is activated by yellow light and hyperpolarizes, inhibiting neuronal activity. Viruses have been generated that can express the light-sensitive channel directly or that express the Cre recombinase to trigger its expression in transgenic animals. For in vivo studies the virus is injected into the brain region of interest, and the channel is activated by light fibres implanted at the region of interest in live behaving animals. Recent studies using optogenetic approaches in mice suggest that stimulation by either laseror LED light at wavelengths to activate channelrhodopsin expressed in transgenically targeted dopamine neurons in the ventral tegmental area (VTA) can mediate an im mediate effect in 2 models of depression. Importantly, the pattern of stimulation was critical, with phasic but not tonic light stimulation mediating the effect. Interestingly, in the social defeat model phasic stimulation resulted in increased susceptibility to depression-like behaviour, while inhibition of the same neurons conferred resilience. By contrast, in a chronic mild stress model of depression, phas ic stimulation conferred resistance and inhibition induced depression-like behaviour in forced swim, tail suspension and sucrose preference tests. Why these results of stimulating or inhibiting VTA dopamine neurons are opposite is unclear, but it could relate to differences between the models: social defeat is an acute high-stress treatment that induces social isolation and anhedonia-like behaviour and may model posttraumatic stress disorder. Chronic mild stress subjects mice to a repeated low level of inescapable stress that is more akin to depression in humans. Phasic activation of the VTA, while considered a reward pathway, is more accurately a salience monitor for both positive and negative events. Its activation is induced by social defeat, and optogenetic activation triggers the negative salience behavioural response. While in chronic mild stress, phasic VTA activation may trigger motivated behaviour, counteracting the demotivating effects of this paradigm. Several studies have shown the importance of regionand cell-specific activation of channelrhodopsin in triggering anxiety-like behaviours. Perhaps most strikingly, by viral injection of channelrhodopsin in the basolateral amygdala and stimu lation of the central amygdala using bevelled light fibres, it was possible to selectively stimulate basolateral projections in the central amygdala to elicit anxiolytic behavioural effects. Kheirbek and colleagues used a nonviral transgenic approach to show that activation of ventral hippocampal granule cells elicits antianxiety responses in open field or elevated plus maze tests, while activation of the dorsal hippocampus enhances context-dependent fear memory. Interestingly these studies found that either dorsal hippocampus inhibition or stimulation prevented contextdependent fear memory, consistent with an ablation of the memory by block or noise due to excess cells activated, respectively. In yet another example of cell specificity, Liu and colleagues specifically labelled cells participating in the fear response using a transgenic mouse containing the eventinducible c-Fos promoter to express the doxycyclineinducible tTA protein and then injected into the hippocampus a viral construct with a tTA response element driving expression of channelrhodpsin. When placed in a conditioned fear environment and treated with doxycycline, only the few fear-activated hippocampal neurons expressed the ChR2; subsequently, light activation of these cells was sufficient to induce the fear response under innocuous conditions.