Light up your life: optogenetics for depression?

In the last year, several new studies have shown the potential of optogenetic stimulation to rapidly modify depression- and anxiety-related behaviours in animal models. Optogenetic technology, as described in a previous editorial,1 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 mediate its effects,2 optogenetics involves the activation by light of engineered light-sensitive ion channel proteins expressed in cells of interest.3 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 laser-or LED light at wavelengths to activate channelrhodopsin expressed in transgenically targeted dopamine neurons in the ventral tegmental area (VTA) can mediate an immediate effect in 2 models of depression.4,5 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.4 By contrast, in a chronic mild stress model of depression, phasic stimulation conferred resistance and inhibition induced depression-like behaviour in forced swim, tail suspension and sucrose preference tests.5 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.6 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.7 Its activation is induced by social defeat, and optogenetic activation triggers the negative salience behavioural response.4 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 region- and cell-specific activation of channelrhodopsin in triggering anxiety-like behaviours. Perhaps most strikingly, by viral injection of channelrhodopsin in the basolateral amygdala and stimulation 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.8 Kheirbek and colleagues9 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 context-dependent 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 colleagues10 specifically labelled cells participating in the fear response using a transgenic mouse containing the event-inducible c-Fos promoter to express the doxycycline-inducible 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. In contrast to the immediate actions of optogenetic stimulation described above, other studies show region-specific effects of chronic stimulation on behaviour. For example, chronic, but not acute, stimulation of 5 min/d over 5–6 days of medial orbitofrontal, but not adjacent prelimbic cortical, glutamate neurons can elicit obsessive–compulsive grooming behaviour in mice.11 On the other hand, activation of adjacent lateral orbitofrontal cortex reduced compulsive grooming in a genetic model of obsessive–compulsive disorder.12 The chronic studies are important because they show that in addition to immediate effects, optogenetic stimulation can be used to modify long-term behaviour and further broaden the ability of light-activated channels to modify behaviour. However, the studies in mice are extremely invasive and involve microinjection of virus into deep brain regions, implantation of light fibres in the brain above the injected brain areas and attachment to laser or LED devices. Is it possible to overcome these obstacles and envisage a clinical use for optogenetics? If the answer is yes, optogenetics might provide an effective new clinical paradigm for treatment of depression that is a more refined version of deep brain stimulation, but the obstacles must be solved.