OPTO-REW

Optogenetic investigation of GABAergic interneurons in the limbic system during reward and addiction

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 Obiettivo del progetto (Objective)

'Many psychiatric disorders involve dysfunction of the limbic system that is manifested in a reduced ability to experience pleasure and learning and memory impairment. Dopamine is important in the limbic system, which includes structures such as the nucleus accumbens, ventral tegmental area and prefrontal cortex. Drugs such as opiates and cocaine, but also antidepressant agents, and deep brain stimulation can possibly recruit certain types of interneurons, whose function is to regulate the firing and integration of information in local circuits. Functional study of local inhibitory interneurons of two classes, parvalbumin and somatostatin interneurons, using optogenetics and mouse genetics are the main focus of this proposal. It is of great interest to better understand the function of distinct neuronal classes during reward-related behaviors, and to identify how dopamine neurtransmission in specific neuronal classes regulate behavior. I propose to apply optogenetics to study the functional impact of GABAergic interneurons during reward-related behaviors. Functional studies of the limbic system have previously been limited to pharmacological approaches or lesion studies that provide poor cell-type specificity and low temporal resolution. Expression and control of light-activated channels using genetic methods in mice allows us to dissect the function of each neuronal class during awake behavior with millisecond resolution. The proposed research can provide important information on the function of discrete neuronal classes and their specific receptors, thereby providing the foundation for rational design of novel therapeutics targeting the limbic system.'

Introduzione (Teaser)

An EU-funded research project is endeavouring to identify how dopamine neurotransmission in specific neuronal classes regulates reward-related behaviour. The study will employ optogenetics and mouse genetics with a focus on the local inhibitory interneurons parvalbumin and somatostatin.

Descrizione progetto (Article)

Many psychiatric disorders are characterised by dysfunction of the limbic system, which results in reduced ability to experience pleasure, and in learning and memory impairment. Understanding how diverse neuronal classes are wired and communicate to produce behaviour is necessary for enhanced understanding of neuropsychiatric disorders.

Functional studies of the limbic system have until now been limited to pharmacological approaches or lesion studies. These provide poor cell-type specificity and low temporal resolution. With advances in technology, however, genetic methods can now be used for the expression and control of light-activated channels. Employing this approach in mice will allow researchers to dissect the function of each neuronal class during awakening behaviour, at millisecond resolution.

The 'Optogenetic investigation of GABAergic interneurons in the limbic system during reward and addiction' (OPTO-REW) project is focused on investigating the function of GABAergic interneurons in the limbic system and their role in reward-related behaviours. Taking a multidisciplinary approach to neural circuit dysfunction, the project has outlined two main objectives. The first involves optogenetic manipulation of GABAergic interneurons in the limbic system with a view to studying connectivity during reward and addiction. The second centres on investigation of the role of dopamine and serotonin neurotransmission for GABAergic interneurons of the limbic system based on genetic models.

Using optogenetics and electrophysiology, OPTO-REW researchers have identified the targets of the inhibitory actions of parvalbumin-expressing (PV+) cells. They found that these cells inhibit the major neuronal population but avoid the cholinergic interneurons and somatostatin-expressing (SOM+) interneurons. Relevant findings in this area have been published in the Journal of Neuroscience (January 2013).

Various experimental activities, such as the establishment of behavioural assays based on operant conditioning, have enabled OPTO-REW to activate as well as silence PV+ and SOM+ interneurons of the striatum. Such progress is necessary for investigating their functional role during encoding of reward-associated cues and the learning of new habits.

As project work continues, scientists will further investigate how serotonin and dopamine affect the behaviour of PV+ neurons in response to rewards and drug response. Outcomes of the project's research stand to shed light on the function of discrete neuronal classes and their specific receptors. This will provide a foundation for the rational design of novel therapeutics targeting the limbic system.