Forebrain dopamine neurons project down to a brainstem region controlling locomotion

Abstract

The contribution of dopamine (DA) to locomotor control is traditionally attributed to ascending dopaminergic projections from the substantia nigra pars compacta and the ventral tegmental area to the basal ganglia, which in turn project down to the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion in vertebrates. However, a dopaminergic innervation of the pedunculopontine nucleus, considered part of the MLR, was recently identified in the monkey. The origin and role of this dopaminergic input are unknown. We addressed these questions in a basal vertebrate, the lamprey. Here we report a functional descending dopaminergic pathway from the posterior tuberculum (PT; homologous to the substantia nigra pars compacta and/or ventral tegmental area of mammals) to the MLR. By using triple labeling, we found that dopaminergic cells from the PT not only project an ascending pathway to the striatum, but send a descending projection to the MLR. In an isolated brain preparation, PT stimulation elicited excitatory synaptic inputs into patch-clamped MLR cells, accompanied by activity in reticulospinal cells. By using voltammetry coupled with electrophysiological recordings, we demonstrate that PT stimulation evoked DA release in the MLR, together with the activation of reticulospinal cells. In a semi-intact preparation, stimulation of the PT elicited reticulospinal activity together with locomotor movements. Microinjections of a D1 antagonist in the MLR decreased the locomotor output elicited by PT stimulation, whereas injection of DA had an opposite effect. It appears that this descending dopaminergic pathway has a modulatory role on MLR cells that are known to receive glutamatergic projections and promotes locomotor output.motor system | Parkinson disease D opamine (DA) neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) modulate motor behaviors, including locomotion, through ascending projections to the basal ganglia, the output of which projects to the mesencephalic locomotor region (MLR) (1-3), a brainstem region known to control locomotion in all vertebrate species tested to date (reviewed in ref. 4). DA is known to control the excitability of striatal cells, and a dysfunction of the ascending DA pathway to the striatum is considered to be the main cause for the motor deficits in Parkinson disease (1). However, there have been hints of descending DA projections that would be in position to directly modulate the MLR and hence locomotor activity. In monkeys, DA terminals of unknown origin were observed in the pedunculopontine nucleus (PPN) (5), considered part of the MLR (reviewed in ref. 4). In addition, there is an axonal projection from the SNc to the PPN in rats, but the transmitter system is unknown (6).We examined the DA system in a basal vertebrate, the lamprey, and found a previously unknown descending DA pathway from the posterior tuberculum (PT) to the MLR, which comprises the PPN and the laterodorsal tegmental nucleus (LDT) in lampreys (ref. 7; reviewed...

A descending dopamine pathway conserved from basal vertebrates to mammals

“…We are thus confident that DA release in the MLR of rats is also evoked by the recruitment of dopaminergic cell bodies in the SNc and RRF, even though only electrical stimulation was used. Importantly, we found that the time-scale of DA release in the MLR was highly correlated with the activation of brainstem locomotor networks, as previously reported in lampreys (22).…”

“…Electrical stimulation not only activates cell bodies but also axons of passage. In some experiments in salamanders, we used chemical stimulation to circumvent the effect of activating en passant fibers, and the results were the same, as previously reported with similar control experiments in lampreys (22). We are thus confident that DA release in the MLR of rats is also evoked by the recruitment of dopaminergic cell bodies in the SNc and RRF, even though only electrical stimulation was used.…”

“…the dopaminergic innervation of the MLR. In lampreys, the diencephalic DA neurons projecting to the spinal cord, which may correspond to the A11 group, are periventricular cells of the mammillary area (41) and are distinct from those projecting to the MLR and striatum (22). In rats, we did not find cells labeled in A11 following tracer or virus injection in the MLR.…”

“…However, we cannot exclude the possibility that such neurons exist in very rare cases. In lampreys, neurons projecting to both the striatum and the MLR were very rare (22). In contrast, in rats, one remarkable aspect of our findings is that the vast majority of the DA neurons that project to the striatum also project to the MLR, implying a simultaneous ascending and descending modulation of the entire locomotor command circuitry from cortex to brainstem.…”

“…In lampreys, only a few meso-diencephalic DA neurons send ascending projections to the striatum (9,22); the majority of DA neurons send a direct descending projection to the MLR (22,23), where DA is released and increases locomotor output through D1 receptors (22). These results demonstrate that the descending dopaminergic pathway to the MLR is an important modulator of locomotor output, but it remains to be determined whether this pathway is conserved in higher vertebrates.…”