Abstract
In the last decade, optogenetics has revolutionised the neurosciences. The technique, which allows for cell-type specific excitation and inhibition of neurons in the brain of freely moving rodents, has been used to tighten the links of causality between neural activity and behaviour. Optogenetics is also enabling an unprecedented characterisation of circuits and their dysfunction in a number of brain diseases, above all those conditions that are not caused by neurodegeneration. Notable progress has been made in addiction, depression and obsessive-compulsive disorders, as well as other anxiety disorders. By extension, the technique has also been used to propose blueprints for innovative rational treatment of these diseases. The goal is to design manipulations that disrupt pathological circuit function or restore normal activity. This can be achieved by targeting specific projections in order to apply specific stimulation protocols validated by ex-vivo analysis of the mechanisms underlying the dysfunction. In a number of cases, specific forms of pathological synaptic plasticity have been implicated. For example, addictive drugs via strong increase of dopamine trigger a myriad of alterations of glutamate and γ-aminobutyric acid transmission, also called drug-evoked synaptic plasticity. This opens the way to the design of optogenetic reversal protocols, which might restore normal transmission with the hope to abolish the pathological behaviour. Several proof of principle studies for this approach have recently been published. However, for many reasons, optogenetics will not be translatable to human applications in the near future. Here, we argue that an intermediate step is novel deep brain stimulation (DBS) protocols that emulate successful optogenetic approaches in animal models. We provide a roadmap for a translational path to rational, optogenetically inspired DBS protocols to refine existing approaches and expand to novel indications.
Highlights
Optogenetics is enabling an unprecedented characterisation of circuits and their dysfunction in a number of brain diseases, above all those conditions that are not caused by neurodegeneration
Notable progress has been made in addiction, depression and obsessive-compulsive disorders, as well as other anxiety disorders
We argue that an intermediate step is novel deep brain stimulation (DBS) protocols that emulate successful optogenetic approaches in animal models
Summary
Optogenetics has revolutionised the neurosciences. The technique, which allows for cell-type specific excitation and inhibition of neurons in the brain of freely moving rodents, has been used to tighten the links of causality between neural activity and behaviour. Addictive drugs via strong increase of dopamine trigger a myriad of alterations of glutamate and γ-aminobutyric acid transmission, called drug-evoked synaptic plasticity This opens the way to the design of optogenetic reversal protocols, which might restore normal transmission with the hope to abolish the pathological behaviour. The anatomical-clinical correlation can be confirmed with modern imaging techniques This is not possible in schizophrenia, depression, anxiety disorders and addiction, where even latest generation imaging fails to visualise the disease in an individual patient. On the other hand, the function of fear circuits would be overactive and lead to generalisation whereby a normally harmless stimulus triggers an intense fear response These models are supported by much experimental evidence (above all because of advances of optogenetics, see below). The symptoms of many neurological disorders, such as Parkinson’s disease, tremors, dystonia, chorea and Gilles de la Tourette syndrome, are associated with a network alteration related either to local circuit dysfunction or as a remote consequence of neuronal degeneration
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