Mechanisms of action initiation and maintenance

The vertebrate basal ganglia convey sensorimotor, limbic and associative information corresponding to action selection between behavioural modules that are competing for the control of a limited set of motor resources. Focal lesions and birth- or disease-related dysfunction of basal ganglia substructures are associated with movement disorders, such as Parkinsonism, as well as neuropsychiatric disorders including autism spectrum disorder and schizophrenia. To elucidate the neural mechanisms of action selection and decision-making, several in vivo models have been established that rely predominantly on rodents (mouse, rat) and primates (marmoset, macaque, baboon). These animal studies led to insights into the functional anatomy of basal ganglia substructures, their role in adaptive behaviour and their disease-related pathology. In addition, several neural computation models for action selection and decision-making have been developed which allow specific predictions to be tested. However, these predictions are usually tested either in rodent and primate models within a very limited area of basal ganglia activity, or they are applied to imaging studies that are at best correlative and with low cellular/circuit resolution. Thus far, the in vivo mechanisms and neural computations underlying action selection for adaptive behaviour have remained elusive. We recently resolved a highly conserved structural and functional ground pattern organization in the insect central complex (CX) and the vertebrate basal ganglia. We also showed that dysfunction of CX circuitries in Drosophila can result in synaptic and behavioural phenotypes that resemble dysfunction of basal ganglia substructures, including Parkinsonism and frontotemporal dementia with motor neuron disease. Moreover, our preliminary data identify CX circuitries that mediate the selection and maintenance of behavioural actions. These data suggest a deep homology between the basal ganglia and insect CX in action selection, and make the insect CX an ideal platform to study in vivo mechanisms and neural computations underlying action selection in health and disease. Here we propose to establish the fruitfly Drosophila as an in vivo model system to determine action selection mechanisms. Specifically we will test the hypoptheses that (i) CX circuitries mediate action selection; that (ii) reciprocal GABAergic inhibition represents an effective neural mechanism for action selection in vivo; and (iii), that dopaminergic modulation mediates action initiation. We expect that our findings will lead to fundamental insights into the mechanisms of action selection that are important to the health services, the pharmaceutical industry, as well as to veterinaries and animal welfare in general.

Action selection is a central mechanism whereby behavioural repertoires compete for control of a finite set of motor resources. A central brain region involved in action selection are the basal ganglia (BG), their dysfunction being associated with movement and motivation disorders. Previous studies led to insights into the functional anatomy of BG substructures and their role in adaptive behaviour. In addition, neural computation models have been developed which allow specific predictions to be tested. However, these predictions are usually tested either in animal models within a very limited area of BG activity, or they are applied to imaging studies that are at best correlative and with low cellular/circuit resolution. Thus far, the mechanisms underlying action selection for adaptive behaviour have remained elusive. We recently resolved a highly conserved structural and functional ground pattern organization of the insect central complex (CX) and the vertebrate BG. Moreover, our preliminary data identify CX circuitries and neural computations that mediate the selection and maintenance of behavioural actions. Our data suggest a deep homology between the BG and insect CX and make the insect CX an ideal platform to study in vivo mechanisms and neural computations underlying action initiation and maintenance. Here we propose to establish the fruitfly Drosophila as an in vivo model system to investigate action initiation and maintenance. Specifically we will test the hypoptheses that (i) CX circuitries mediate action selection; that (ii) reciprocal GABAergic inhibition represents an effective mechanism for action initiation and maintenance; and (iii), that dopaminergic modulation mediates action initiation. We expect that our findings will lead to fundamental insights into the mechanisms of action selection that are important to the health services, the pharmaceutical industry, as well as to veterinaries and animal welfare in general.

Research towards understanding the mechanisms and neural computations of action selection is highly relevant to the health services, the pharmaceutical industry, as well as to veterinaries and animal welfare in general. Although several in vivo animal models have been established, using predominantly rodents (mouse, rat) and non-human primates (marmoset, macaque, baboon), thus far however, the in vivo mechanisms and neural computations underlying action selection for adaptive behaviour have remained elusive. We recently resolved a highly conserved structural and functional ground pattern organization in the insect central complex (CX) and the vertebrate basal ganglia. We also showed that dysfunction of CX circuitries in Drosophila can result in synaptic and behavioural phenotypes that resemble dysfunction of basal ganglia substructures. With our proposed research we will establish the insect Drosophila and central complex circuitries as a highly relevant alternative to rodents and non-human primates in the study of action selection and decision-making, and their dysfunction in behavioural disorders. We expect to identify highly conserved neural mechanism for action selection. Moreover, we will actively advocate our novel experimental approach by presenting it at relevant scientific meetings to report our results to those engaged in animal research, health services, and the pharmaceutical industry, and by communicating our paradigm and findings to the wider public. Furthermore we will actively engage in public dissemination with radio interviews as we have done previously, and by distributing freely the large collection of tools already in our hands and those that we will generate for this project. In a wider perspective, results gained from our studies in fruitflies will not only reveal conserved mechanisms of action selection, we also expect that our insights will guide research into basal ganglia-related dysfunction, and thus ultimately inform health services and the pharmaceutical industry, as well as veterinaries and animal welfare in general.