Behavioural effects of chemogenetic dopamine neuron activation

Abstract

Various psychiatric disorders, including schizophrenia, attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder, have been associated with altered dopamine signalling in the brain. However, it remains unclear which specific changes in dopamine activity are related to specific psychiatric symptoms. Recent clinical studies have proposed that aberrant dopamine neuronal activity may play a vital role in the pathophysiology of, amongst others, schizophrenia and ADHD. In this thesis, we have tested the behavioural effects of increased dopamine neuronal activity. To do so, we used the recently developed Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, also called chemogenetics, in TH::Cre transgenic rats. This approach enables us to directly and transiently enhance the excitability of selective populations of dopamine cells. We determined the impact of chemogenetic dopamine neuron activation on behavioural domains that are disturbed in psychiatric disorders, including hyperactivity, motivation and attention. Our findings show that activation of dopamine neurons in the ventral tegmental area (VTA) induced locomotor hyperactivity, increased motivational behaviour, disrupted feeding patterns, and impaired sustained attention. In follow-up experiments we selectively targeted different VTA neuronal pathways, and found that these effects were reproduced by chemogenetic activation of VTA mesolimbic neurons, projecting to ventral striatum. Chemogenetic activation of dopamine neurons in the substantia nigra pars compacta (SNc) yielded a wholly different phenotype, including a modest increase in locomotion, no effect on motivation or feeding, yet pronounced deficits in performance of an attentional task. Dopamine neurons in the SNc project primarily to the dorsal striatum. Our findings show that dopamine neuronal activity in the VTA and SNc are differentially involved in the regulation of psychiatry-related behaviours, including locomotor activity, motivation and attentional processes. We propose that enhanced mesolimbic VTA dopamine neuronal activity promotes behavioural activation, resulting in a hyperactive and distracted phenotype. In contrast, increased SNc dopamine neuron activity seems to disrupt selection of appropriate motor actions, resulting in attentional deficits. These findings have implications for understanding the role of dopamine neuronal activity in psychiatric disorders, and may contribute to the development of novel, target-specific treatments.