Subthalamic nucleus exclusively evokes dopamine release in the tail of the striatum

Abstract

A distinct population of dopamine neurons in the substantia nigra pars lateralis (SNL) has a unique projection to the most caudolateral (tail) region of the striatum. Here, using two electrochemical techniques to measure basal dopamine and electrically evoked dopamine release in anesthetized rats, we characterized this pathway, and compared it with the ‘classic’ nigrostriatal pathway from neighboring substantia nigra pars compacta (SNc) dopamine neurons to the dorsolateral striatum. We found that the tail striatum constitutes a distinct dopamine domain compared with the dorsolateral striatum, with consistently lower basal and evoked dopamine, and diverse dopamine release kinetics. Importantly, electrical stimulation of the SNL and SNc evoked dopamine release in entirely separate striatal regions; the tail and dorsolateral striatum, respectively. Furthermore, we showed that stimulation of the subthalamic nucleus (STN) evoked dopamine release exclusively in the tail striatum, likely via the SNL, consistent with previous anatomical evidence of STN afferents to SNL dopamine neurons. Our work identifies the STN as an important modulator of dopamine release in a novel dopamine pathway to the tail striatum, largely independent of the classic nigrostriatal pathway, which necessitates a revision of the basal ganglia circuitry with the STN positioned as a central integrator of striatal information.

Deep learning-based image-analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra.

“…Up to now, only for VTA DA neurons, lower DAT expression was systematically analyzed (Fu et al, 2012;Lammel et al, 2008;Li et al, 2013). On the contrary, for SN DA neurons, DAT is commonly used as marker besides TH (Kim et al, 2015;Palermo & Ceravolo, 2019;Poulin et al, 2020), and for their targeting, for instance, via DAT-Cre transgenic mouse lines, expressing the Cre-recombinase under the DAT-promotor (Lammel et al, 2015;Papathanou et al, 2019;Stuber et al, 2015;Todd et al, 2022). Our results imply that with such approaches, target-gene expression might not be affected in those lateral SN DA neurons that are immuno-negative for DAT protein.…”

“…What is known about the function of lateral SN DA neurons? Vglut2 and CB positive but Aldh1a1 negative lateral SN DA neurons are important for responses to novel cues and salience (Kim et al, 2015;Menegas et al, 2017;Todd et al, 2022). Some lateral SN DA neurons are activated by aversive stimuli or cues that predict aversive stimuli (Matsumoto & Hikosaka, 2009).…”

“…The identification of a DAT negative SN DA neuron population has not only physiological relevance (Bu et al, 2021;Miller et al, 2021;Savchenko et al, 2022), but it has additional implications, as DAT is commonly used as marker for SN DA neurons and for their specific targeting, e.g. to generate DA neuron specific knock out mice, expressing Cre-recombinase under the control of the DAT-promoter (Lammel et al, 2015;Papathanou et al, 2019;Stuber et al, 2015;Todd et al, 2022).…”

Deep learning-based image-analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra

“…What is known about the function of lateral SN DA neurons? Vglut2 and CB positive but Aldh1a1 negative lateral SN DA neurons are important for responses to novel cues and salience (Kim, Ghazizadeh, & Hikosaka, 2015; Menegas, Babayan, Uchida, & Watabe-Uchida, 2017; Todd, Lipski, & Freestone, 2022). Some lateral SN DA neurons are activated by aversive stimuli or cues that predict aversive stimuli (Matsumoto & Hikosaka, 2009).…”

Microglia Mediated Neuroinflammation in Parkinson’s Disease

“…In addition to the SNpc, there is neuronal loss in the cerebral cortex, basal ganglia, thalamus, locus coeruleus, and brain stem, especially the dorsal motor nucleus [ 4 , 5 ]. Different brain regions are affected depending on the stage of PD.…”