Abstract
The hypothalamic A11 region has been identified in several species including rats, mice, cats, monkeys, zebrafish, and humans as the primary source of descending dopamine (DA) to the spinal cord. It has been implicated in the control of pain, modulation of the spinal locomotor network, restless leg syndrome, and cataplexy, yet the A11 cell group remains an understudied dopaminergic (DAergic) nucleus within the brain. It is unclear whether A11 neurons in the mouse contain the full complement of enzymes consistent with traditional DA neuronal phenotypes. Given the abundance of mouse genetic models and tools available to interrogate specific neural circuits and behavior, it is critical first to fully understand the phenotype of A11 cells. We provide evidence that, in addition to tyrosine hydroxylase (TH) that synthesizes L-DOPA, neurons within the A11 region of the mouse contain aromatic L-amino acid decarboxylase (AADC), the enzyme that converts L-DOPA to dopamine. Furthermore, we show that the A11 neurons contain vesicular monoamine transporter 2 (VMAT2), which is necessary for packaging DA into vesicles. On the contrary, A11 neurons in the mouse lack the dopamine transporter (DAT). In conclusion, our data suggest that A11 neurons are DAergic. The lack of DAT, and therefore the lack of a DA reuptake mechanism, points to a longer time of action compared to typical DA neurons.
Highlights
Dopaminergic (DAergic) innervation of the spinal cord is thought to originate primarily from a small nucleus of tyrosine hydroxylase (TH) expressing cells in the diencephalon, known as the A11 region [1]
The overall aim of the current work was to examine whether A11 neurons projecting to the spinal cord contained amino acid decarboxylase (AADC), TH, vesicular monoamine transporter 2 (VMAT2) and dopamine reuptake transporters (DAT) consistent with the synthesis and reuptake of DA
We demonstrate that THpositive neurons contain AADC, the enzyme necessary to produce DA, and VMAT2 that is essential for the packaging of DA into vesicles for synaptic release
Summary
Dopaminergic (DAergic) innervation of the spinal cord is thought to originate primarily from a small nucleus of tyrosine hydroxylase (TH) expressing cells in the diencephalon, known as the A11 region [1]. Projections from the A11 region may contribute to locomotion [5,6,7,8], pain control [8,9], migraines [10], and restless leg syndrome [11], yet, this cell population remains understudied in relation to other DAergic areas of the brain These neurons were described to send projections to a wide variety of brain regions, including the dorsal raphe, thalamus, hypothalamus, and cortex [12,13], placing the A11 in an ideal position to potentially provide an alternative motor innervation to locomotor circuits compared to the well-described DAergic substantia nigra pars compacta-striatal network. It remains uncertain in the mouse whether A11 neurons are DAergic or not
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