KAC Elliott Lecture: Unexpected regulators of striatal dopamine release: insulin, exercise, and GABA

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Margaret E. Rice

Professor, Neuroscience Institute, NYU Langone, New York, USA

Abstract: Dopamine (DA) plays key roles in movement, motivation, mood, and motor learning. These roles are linked – we move because we are motivated to do so. Identifying factors that regulate DA release can provide insight into how DA mediates these effects, as well as how DA dysregulation might contribute to neuropsychiatric disorders, including Parkinson’s disease, depression, and obesity. Primary target regions for DA release are the dorsal striatum (dStr) and the nucleus accumbens (NAc, or ventral striatum). The dStr receives dense innervation from midbrain DA neurons in the substantia nigra pars compacta (SNc) and the NAc receives input primarily from the ventral tegmental area (VTA). In addition to regulation of striatal DA release by patterned activity of DA neurons, DA release is regulated locally and dynamically at the level of DA axons. The most striking local regulator is acetylcholine (ACh) from cholinergic interneurons (ChIs), which can drive DA release via nicotinic ACh receptors (nAChRs) on DA axons. Other unexpected factors alter DA release, as well, including the peripheral hormones insulin and leptin, metabolic states including obesity and exercise, and endogenous GABA, the major inhibitory transmitter discovered by Prof. K.A.C. Elliott. These influencers will be the focus of this lecture. Together with other local factors, these substances and states define the rich, yet nuanced repertoire of DA transmission patterns and consequent regulation of DA-dependent behaviors.

The KAC Elliott Lecture was instituted in honour of Dr. Kenneth Allan Caldwell Elliott who was a neurochemist at the MNI (1944-1968). Dr. Elliott contributed immensely to the understanding of the basic chemical mechanisms of cerebral edema, epilepsy, and brain tumours. Importantly, in 1957, Dr. Elliot and his colleagues identified the role of gamma-aminobutyric acid (GABA), now believed to be the major inhibitory transmitter in the brain.