Synaptic integration and intrinsic firing properties of basal ganglia neurons

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

Our laboratory focuses on the cellular and subcellular principles of excitability and integration of neurons in the midbrain dopamine system. A major goal of our work is to identify functionally unique subpopulations of midbrain dopamine neurons and to understand how these neurons are controlled by basal ganglia circuits and contribute to behavior. Ultimately, our hope is to correlate the activity of these dopamine subpopulations with their function in motor learning behaviors but also to identify factors that contribute to their selective vulnerability in Parkinson's disease. In past in vivo experiments, a subset of substantia nigra pars compacta (SNc) dopaminergic neurons were shown to exhibit rebound activity at the termination of an aversive stimulus. This rebounding triggers dopamine release that may be involved in avoidance learning. Therefore, we set out to probe local inhibitory inputs circuits that may rebound firing patterns in dopaminergic neurons. To do this, we functionally mapped the inhibitory projections from the striatum (striosome and matrix), and globus pallidus (Pvalb and Lhx6) at subcellular resolution. We found that the striosomal inputs selectively inhibit a subset of SNc dopamine neurons that express the marker, aldehyde dehydrogenase 1A1 (Aldh1a1). Specifically, striosome innervate the ventral SNr dendrites to facilitate rebounding through relief of GABA-B receptors. Therefore, inhibition from striosomes onto SNc dopamine neurons is optimally placed to produce rebound firing. This study was published (Evans et al., Cell Reports 2020). Our lab also contributed to a review of substantia nigra dopamine neurons that express Aldha1a through collaboration with Huaibin Cai (Carmichael et al. Front Neural Circuits 2021). In a separate project, we continue to follow interests in how axonal excitability influences dopamine release. To study this question, we performed direct recordings from the cut ends of dopaminergic neuron that as they innervate the dorsal striatum. In our initial publication on this topic (Kramer et al. eLife 2020), we provided definitive evidence for the existence of GABA-A receptor-mediated conductances. In a current project, we use direct recordings combined with calcium imaging to examine how GABA-A receptors on the dopaminergic axons modulate the speed of action potential propagation throughout the complex branching axon arbor. In a separate project, we are performing a detailed analysis of how transmission from cholinergic interneurons within the dorsal striatum locally control dopamine release through activation of axonal receptors.