Regulation of Dopamine Release and Locomotor Activity by Leptin

About This Grant

Project Summary Brain motor circuitry is influenced by neurohormonal regulators that underlie energy homeostasis through regulation of food intake (satiety) and physical activity. Leptin is a key player in these incompletely understood interactions. We have shown that leptin boosts striatal dopamine release by increasing the excitability of striatal cholinergic interneurons (ChIs) that regulate dopamine release via activation of nicotinic acetylcholine (ACh) receptors on dopamine axons. We also find that leptin directly excites dopamine neurons of the substantia nigra pars compacta (SNc). Moreover, systemic leptin enhances locomotor behavior in open-field testing. Given the role of the nigrostriatal pathway in motor regulation, highlighted by the motor deficits of Parkinson’s disease, which is characterized by loss of SNc dopamine neurons, our findings suggest that nigrostriatal dopamine is the neural substrate for leptin’s motor enhancing effect. Key aspects of this regulatory process are missing, including how leptin activates ChIs and SNc dopamine neurons, and whether motor activation by leptin is mediated at the level of the striatum or SNc, or both. In Aim 1, we will focus on the cellular level by identifying ion channels involved in ChI and SNc DA neuron activity. Experiments will test possible closure of two different K+ channels (Kv1.3 and TASK-3) as the mechanism by which leptin excites these cells using current-clamp recording in ex vivo striatal and midbrain slices. We will also examine the influence of these channels on evoked dopamine release in slices, monitored using fast-scan cyclic voltammetry. In Aim 2, we will move to the circuit level and determine the extent of dopamine and ACh release in dorsolateral striatum in vivo after leptin administration, with dopamine and ACh detection using genetically encoded sensors (GRAB-DA and GRAB-ACh) with fiber photometry. A key experiment will be to determine whether the motor-enhancing effect of leptin is absent in mice lacking ACh synthesis in striatum. Overall, the cellular mechanisms and circuits examined in this project highlight the role of leptin as a novel regulator of motor output, which may have implications for alternative therapies in Parkinson’s disease, while leptin’s DA-enhancing effects may also be relevant for depression and other neuropsychiatric disorders that are linked to dopamine dysregulation.