Title: Novel Approaches for Selective, Interspecies Targeting of Midbrain Dopamine Neurons

In-Person Location: 46-3310

On Zoom: https://mit.zoom.us/j/96227757953

Abstract:

Dopamine (DA) is a crucial neuromodulator that enables voluntary movement, motivated behavior, reward processing, and cognitive function. Unsurprisingly, from Parkinson’s disease to addiction, the loss or dysfunction of DA neurons pervades the clinical landscape. In Chapter 1, this thesis comprehensively reviews the literature on DA neurons and the current state of in vivo research methods for targeting them. To provide a cross-species platform for selective DA neuron access across research and clinical applications, without requiring genetically engineered animals or combinatorial systems, this thesis performed single-nucleus multiomics (RNA-seq/ATAC-seq) of the ventral midbrain to develop and benchmark DA enhancer–AAVs (Chapter 2). We further demonstrate applications of DA-enhancer-AAVs for (i) retrograde targeting of projection-defined DA populations in marmoset, (ii) fiber-photometric recording of divergent DA-axonal dynamics in striatal subregions, and (iii) optogenetic VTA-DA self-stimulation in mice (Chapter 3). Our results establish a resource for cross-species DA targeting and two practical guidelines: backbone context critically shapes enhancer performance, and antibody-amplified readouts rigorously assess specificity. Finally, Chapter 4 of this thesis describes a method for spatially targeted stimulation of DA neurons using a novel implantable piezoelectric ultrasound stimulator (ImPULS) developed in the Dagdeviren Lab.