Biology subjects

Gaertner, Z.

Publications and source records attributed to Gaertner, Z..

3 recordsLinked to original sources

bioRxiv2024

Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson's disease

Several studies have revealed that midbrain dopamine (DA) neurons, even within a single neuroanatomical area, display heterogeneous properties. In parallel, studies using single cell profiling techniques have begun to cluster DA neurons into subtypes based on their molecular signatures. Recent work has shown that molecularly defined DA subtypes within the substantia nigra (SNc) display distinctive anatomic and functional properties, and differential vulnerability in Parkinsons disease (PD). Based on these provocative results, a granular understanding of these putative subtypes and their alterations in PD models, is imperative. We developed an optimized pipeline for single-nuclear RNA sequencing (snRNA-seq) and generated a high-resolution hierarchically organized map revealing 20 molecularly distinct DA neuron subtypes belonging to three main families. We integrated this data with spatial MERFISH technology to map, with high definition, the location of these subtypes in the mouse midbrain, revealing heterogeneity even within neuroanatomical sub-structures. Finally, we demonstrate that in the preclinical LRRK2G2019S knock-in mouse model of PD, subtype organization and proportions are preserved. Transcriptional alterations occur in many subtypes including those localized to the ventral tier SNc, where differential expression is observed in synaptic pathways, which might account for previously described DA release deficits in this model. Our work provides an advancement of current taxonomic schemes of the mouse midbrain DA neuron subtypes, a high-resolution view of their spatial locations, and their alterations in a prodromal mouse model of PD. Teaser: Using snRNASeq and MERFISH we identified midbrain DA subtypes, mapped their spatial location, and identified alterations in a LRRK2 model

neuroscience↗

bioRxiv2022

Unique functional responses differentially map onto genetic subtypes of dopamine neurons

Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. Here, we establish that three genetic dopamine subtypes within the substantia nigra pars compacta each have a unique set of responses to rewards, aversive stimuli, accelerations and decelerations, and these signaling patterns are highly-correlated between somas and axons within subtypes. Remarkably, reward responses were not detected in one subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.

neuroscience↗

bioRxiv2022

Dopaminergic axons track somatic signaling in behaving mice

Striatal dopamine released from the axons of midbrain dopamine neurons has been linked to a wide range of functions, including movement control and reward-based learning. Recent studies have reported functional signaling differences between axons and somas of dopamine neurons, suggesting that local modulation controls dopamine release and calling into question the classical view of somatic control. However, these experiments are technically challenging, making it difficult to ensure that axonal and somatic recordings come from the same neurons, particularly given the heterogeneity of dopaminergic cell types. Here we used genetic strategies to isolate key dopaminergic neuron subtypes and monitor their axonal and somatic signaling patterns in behaving mice. Contrary to the inferences drawn from previous studies, these experiments revealed a robust correlation between somatic and axonal signaling. Thus, by exploiting a previously unknown connection between genetic and functional diversity in dopamine neurons, we establish that subtypes must be considered to understand the mechanisms of dopamine release in striatum during behavior.

neuroscience↗