Light and chemical control of neuronal circuits: possible applications in neurotherapy

Abstract

Millions of people worldwide suffer from diseases that result from a failure of central pathways to regulate behavioral and physiological processes. Advances in genetics and pharmacology have already allowed us to appreciate that rather than this dysregulation being systemic throughout the brain, it is usually rooted in specific subsets of dysfunctional cells within discrete neurological circuits. This article discusses the advent of opto- and chemogenetic tools and how they are providing the means to dissect these circuits with a degree of temporal and spatial sensitivity not previously possible. We also highlight the potential applications for treating disease and the key developments likely to have the greatest impact over the next 5 years.

Keywords::

• arcuate nucleus
• chemogenetics
• circuits
• depression
• DREADD
• metabolism
• neural network
• neuromodulator
• optogenetics
• Parkinson’s disease
• VTA

Acknowledgements

The authors thank W Giardino for his constructive feedback and guidance.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Dysregulated neurological circuits are a major causal factor in not only neurological and psychological disorders, but also other widespread complex illnesses such as obesity.

• Existing therapeutics strategies to treat these widespread conditions, for example, depression and metabolic syndrome, are largely ineffective and often carry unwanted side effects. This can, in many cases, be attributed to a lack of specificity and a degree of compensation and adaptation to chronic agonism/antagonism of neuroendocrine systems.

• Previous approaches to study neural networks have made good use of transgenic and pharmacological approaches to define dependencies and the requirement of specific signaling molecules for eliciting behavioral responses. However, they lack temporal and spatial control and are often subject to the same caveat of adaptation to a chronic manipulation of the system under study.

• Optogenetic approaches allow for the targeted activation/inhibition of specific subsets of molecularly distinct neurons (usually targeted using Cre-expressing lines). This can be performed in free-living animals, while monitoring a specific behavioral outcome (anxiety, feeding and aversion) and with the system under scrutiny functionally identical to that of a wild-type animal, until optical stimulation commences.

• Optogenetic constructs are constantly being improved to allow for periods of neuronal stimulation lasting only while optically stimulated or for several minutes after light stimulation has ceased. The use of designer receptors exclusively activated by designer drugs (which lead to neuronal activation/inhibition following treatment with a synthetic ligand) allows for periods of neuromodulation lasting a number of hours and has expanded the possible range of physiological assays that can be performed while neural circuits are being manipulated.

• These new neuromodulatory tools have already allowed us to dissect complex circuits involved in depression, anxiety and metabolism in far more detail than was possible using the previous available techniques. In addition, they have helped to explain some apparent paradoxes, which arose due to the use of transgenic mice not fully recapitulating the circuit dynamics of the neuronal circuits under investigation.

• There are still many technological hurdles to using opto- and chemogenetic approaches directly to treat human disease, but the technology for light stimulation and receptor dynamics is rapidly developing. In the mean time, current therapies are likely to benefit from better understanding of the brain circuits and neuronal populations they target.

• The next 5 years are likely to see more complex neural circuits being dissected in even greater detail in rodent models and many of these circuits being validated and probed in higher organisms such as primates. It is likely that current neurotherapeutic approaches will undergo dramatic rethinking based on new information about circuit interdependency, dysregulation and compensation in disease.

Notes