Optogenetics in Psychiatry – A Simplified Review

OPTOGENETIC TECHNOLOGY

Optogenetics involves the precise delivery of light with lasers and fibre optics into the brain to activate or inhibit cellular function. [Deisseroth, 2015]

This technique involves two key components:

1. Lasers and fibre optics for light delivery into the nervous system
2. The focal delivery of microbial opsin genes using a viral vector to specific targets in the brain.

The protein family of microbial opsins are fast light-responsive transmembrane conductance proteins that primarily include halorhodopsin and channelrhodopsin. [Zhang F et al., 2007]

These microbial opsin genes have been engineered to allow researchers to regulate various biochemical pathways at any point of interest in the brain. For example, by including genes that encode a proton pump or cation channel, the action potential in these neural projections can be inhibited or stimulated, respectively. [Stuber G et al., 2011], [Tye et al., 2011]

By using different light wavelengths for light activation or light inhibition, the neural projection can be inhibited or stimulated in a specific manner. This is known as optogenetic control, and by monitoring a fluorescent readout using fibre photometry, neural activity can be precisely observed and monitored.

In the below video, Associate Professor of Biological Engineering and Brain and Cognitive Sciences Ed Boyden explains optogenetics and its use in neurological research.

APPLICATION OF OPTOGENETICS AND CIRCUIT MODULATION IN ANXIETY

Anxiety disorders are one of the most common classes of psychiatric conditions. [Kessler R et al., 2005]

Anxiety is characterised as a sustained state of apprehension in the absence of an immediate threat. The amygdala is a critical brain region involved in learning fearful memories, and through this functionality, it is implicated in fear and anxiety.

However, specific brain sub-regions and the precise neural mechanisms that control anxiety are unknown. Initial optogenetic investigations have used freely moving mice in a maze and open-field test assay that allows for the inference of apprehension without the presence of an immediate threat.

In a groundbreaking study, researchers inserted microbial opsin genes into the basolateral amygdala (BLA) terminals in the central nucleus of the amygdala. [Tye et al., 2011]

The aim was to discover whether specific projections could be related to the specific expression of risk-avoidance behaviours.

The researchers showed that temporally precise optogenetic stimulation of neurons had a calming effect, whereas selective optogenetic inhibition of the same projections increased anxiety-related behaviours. Therefore, projections from the BLA terminals to the central nucleus of the amygdala are essential functional elements in how the mammalian brain controls anxiety.

Subsequent optogenetic research has shown that neural projections from the BLA are also associated with respiratory rate changes and aversive subjective sensations—both of which are clinical features of the anxious state. [Kim S et al., 2013]

This study showed that separate anxiety-related features are components of different neural projection pathways that originate from a single coordinating brain region: the bed nucleus of the stria terminalis (BNST)

The BNST has previously been shown to have a complex involvement in fear, anxiety, and the reward response. However, by integrating optogenetics with behavioural assays, the researchers showed that specific sub-regions in the BNST have opposing effects on two distinct features of anxiety: reward and aversion.

Moreover, the BNST projections to the hypothalamus, the ventral tegmental area, and the brainstem were associated with risk-avoidance, positive-valence conditioning, and respiratory rate, respectively. Thus, by using projection targeting of circuit dynamics, this technique has allowed researchers to elicit how relatively complex and specific behaviours are assembled and disassembled.

APPLICATION OF OPTOGENETICS AND CIRCUIT MODULATION IN DEPRESSION

Beck describes hopelessness as an important risk factor for negative outcomes associated with depression.[Beck A et al., 1974], [Brown G et al., 2000]

Hopelessness is also a strong predictor of depression and suicidal behaviour, and individuals with depression generally experience higher hopelessness levels than those without depression. [Chimich and Nekolaichuk, 2004]

Most researchers consider hopelessness to be a maladaptive process controlled by the prefrontal cortex (PFC). Neuroimaging studies have shown that the PFC controls the decision to execute actions. The presence of lesions in this region can result either in impulsivity (a tendency to initiate action) or an amotivational state (a tendency for apathy and reduced activity). [Ridderinkhof K et al., 2004], [Mayberg H et al., 1999]

This phenotypic complexity underscores the basis for maladaptive behaviours such as depression. Under challenging circumstances, the execution of physical action becomes an effort, which requires the brain to decide whether the anticipated outcome is justifiable.

However, inaction to challenging circumstances can become maladaptive, and this is represented as reduced psychomotor activity, hopelessness, and depressed mood.

A study by Warden and colleagues published in Nature in 2012 studied the neural circuitry that translates action and motivation in goal-orientated behaviour. [Warden M et al., 2012]

Optogenetics was used in free-moving rats transitioning between a passive and active response to elucidate the PFC circuitry involved and the neural projections responsible for effortful behavioural responses to challenging situations.

Using the automated forced swim test (FST), a rat’s behaviour would shift to either actively swimming or passively floating. During the automated FST, optogenetic stimulation of the medial PFC projection to the dorsal raphe nucleus caused the rats to display an active response. However, when the medial PFC projection to the lateral habenula was targeted, the opposite occurred, and the rats shifted towards a passive response.

Interestingly, no behavioural responses were observed when cells from the medial PFC to the BLA projection were optogenetically targeted. Thus, this study illustrates the importance of optogenetics and a fibre-optic neural interface to determine the functional distinction of cell types and neural projections associated with specific maladaptive behaviours.

OTHER APPLICATIONS

Optogenetics was successfully used in vivo to demonstrate orexin neurons’ mechanistic and causal contribution to the sleep-to-wake transition. [Adamantidis et al., 2007]

Parvalbumin (PV) neuron-related abnormalities in gamma oscillations have been proposed to account for the altered information processing associated with schizophrenia. Optogenetic stimulation of these neurons enhances cortical circuit performance. [Sohal et al., 2009]

Optogenetic stimulation of the Orbitofrontal cortex – Ventromedial Striatum (OFC-VMS) circuit induced OCD like behaviours in mice, highlighting the OFC-VMS pathway hyperactivity in the pathophysiology of obsessive-compulsive disorder (OCD). [Ahmari et al., 2013]

Step-function opsins (SFO) are used to modulate cellular excitation and inhibition balance (E/I).

This modulation was applied in studying the pathophysiology of autism behaviours. An increase in the E/I balance in the medial prefrontal cortex led to specific behavioural impairments, whereas compensatory elevation of inhibitory cell excitability partially reduced the social deficits from E/I balance elevation.

These results support the causal involvement of an altered E/I balance in the pathophysiology of autistic behaviours. [Shirai et al., 2017]

CLINICAL APPLICATIONS

Microbial opsins are application flexible and can be integrated into any number of target and readout strategies that are bidirectional, reversible, and spatiotemporally precise.

In clinical psychiatry, the insights afforded by the advances in optogenetics research are numerous.

Refine Psychiatric Nosology:

• By linking brain regions with psychiatric symptoms, thus allowing researchers to refine psychiatric nosology.

Improve diagnosis and predict treatment outcomes:

• Optogenetic research has provided specific cells and pathways for developing biomarkers that could be used to improve diagnosis and better predict treatment outcomes.

Development of novel treatments: 

• Finally, optogenetic research also guides research into developing novel treatments based on discovering disease-related circuit pathophysiology, helping target specific circuits and targets.

Optogenetic models have been successfully applied in mice in ophthalmology and neurology. For example, enhancing light sensitivity in mice models of retinitis pigmentosa and ameliorating seizures in neurology.

The application in psychiatry is more challenging as the pathophysiological circuits have not been elucidated. Amongst the best applications of optogenetics in psychiatry has been identifying the optimal stimulation protocol of DBS in ameliorating behavioural sensitisation. Thus optogenetics may help identify optimal stimulation protocols for DBS and TMS in treating a range of psychiatric disorders. [Shirai et al., 2017]

SUMMARY

Optogenetics is a methodological advance that is beginning to reveal the biological principles that underpin complex behavioural phenotypes in psychiatry.

By determining the precise neural circuits and cell types that are causally related to psychiatric disorders,  the hope is that this will translate into developing novel treatment strategies.

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