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Vive La Difference! Dissecting the Diversity of Midbrain Dopamine Neurons

Beier KT, Steinberg EE, DeLoach KE, et al. Circuit architecture of VTA dopamine neurons revealed by systematic
input-output mapping. Cell 2015;162(3):622-634.
Lerner TN, Shilyansky C, Davidson TJ, et al. Intact-brain analyses reveal distinct information carried by SNc dopamine
subcircuits. Cell 2015;162(3):635-647.

Dopamine neuron dysfunction has been implicated in numerous brain disorders, including addiction, depression, schizophrenia, and Parkinsons disease (PD). In PD, the motor
manifestations are primarily linked to the selective, progressive
loss of dopaminergic (DA) neurons in the ventrolateral tier of
the substantia nigra pars compacta (SNpc). In contrast, the
very similar neurons in the ventral tegmental area (VTA)
undergo a much lesser degree of degeneration.1 Elucidating
the mechanisms underlying the phenomenon of differential DA
vulnerability in PD has proved to be extremely challenging.2
However, an increasing number of recent studies are beginning
to demonstrate that considerable molecular and electrophysiological heterogeneity exists among DA neurons in the midbrain.
For example, a recent viral circuit tracing study showed that
VTA and SNc DA neurons receive different proportions of
inputs from key brain regions.3 So, distinct locations within the
SNc and the VTA could give rise to projections targeting distinct locations within the striatum (ie, dorsomedial or dorsolateral). Moreover, SNc or VTA DA neurons alone could be further
divisible into functionally distinct subsets. Recently, 2 new
studies combining intact-brain circuit interrogation tools,
including CLARITY and CLARITY-optimized light-sheet microscopy (COLM),4 optogenetics, viral tracing (TRIO),5 and fiber
photometry have been used to reveal the diversity of dopamine
neurons in the mammalian brain. Despite sharing dopamine as
their neurotransmitter, these neurons differ in their biophysical
properties, wiring, and activity during behavior, distinctions
only uncovered by constructing input-output maps and that
may underlie functional differences.
By stimulating inputs from the striatum to SNc DA neurons using optogenetic methods, Lerner and collaborators
discovered that dorsolateral striatum inputs to SNc are
stronger than those from the dorsomedial striatum, a finding
that could not have been predicted anatomically but is
nevertheless likely to be crucial in thinking about SNc circuit
function. Anatomically, they also demonstrate that the efferent projections from SNc DA neurons to the dorsomedial
and dorsolateral striatum arise from distinct locations within
the SNc. In addition, afferents to projection-defined SNc DA
neurons differ; in particular, the authors identified new principles of afferent-projection complexity in SNc subcircuits. For
example, the dorsomedial and dorsolateral striatum are preferentially reciprocally connected with the very same DA neurons that project back to these areas. Moreover, the authors

observed strong dorsolateral projections to dorsomedialprojecting DA neurons.

Concurrently, using similar methods, Beier and collaborators
described the input and output connectivity map of VTA DA neurons, revealing previously unknown connections, such as an
anterior cortex-VTA-nucleus accumbens circuit. They found that
VTA DA neurons that project to subdivisions of the ventral striatum (ie, medial or lateral) receive highly biased inputs from different brain regions. This also suggests that these projections
originate from different populations of dopaminergic neurons.
Altogether, these two articles reveal independently operating
nigrostriatal information streams, with implications for understanding the logic of dopaminergic feedback circuits and the
diversity of mammalian neuronal cell types. Together with the differential gene expression and firing patterns, these observations
strongly suggest that DA neuron subpopulations are integrated
into different circuits and serve distinct biological functions. How
these subpopulations are related to PD symptoms remains
unknown. The discovery of key pathways that regulate the differential susceptibility of DA neurons to degeneration holds great
potential for the discovery of novel drug targets and the development of neuroprotective treatment strategies for PD and other
neurodegenerative disorders.
Javier Blesa, PhD
Center for Integrative Neuroscience A.C (HM CINAC) and HM
Hospitales-Hospital Puerta del Sur, Madrid, Spain

References
1.

Brichta L, Greengard P. Molecular determinants of selective

dopaminergic vulnerability in Parkinsons disease: an update.
Front Neuroanat. 2014;8:152.

2.

Blesa J, Lanciego JL, Obeso JA. Editorial: Parkinsons disease: cell

vulnerability and disease progression. Front Neuroanat. 2015;9:125.

3.

Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N.

Whole-brain mapping ofdirect inputs to midbrain dopamine
neurons. Neuron 2012;74(5):858-873.

4.

Chung K, Deisseroth K. CLARITY for mapping the nervous

system. Nat Methods 2013;10(6):508-513.

5.

Schwarz LA, Miyamichi K, Gao XJ, et al. Viral-genetic tracing

of the input-output organization of a central noradrenaline
circuit. Nature 2015;524(7563):88-92.

-----------------------------------------------------------Received: 22 October 2015; Revised: 28 October 2015; Accepted: 29

October 2015
Published online 00 Month 2015 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26487

Movement Disorders, Vol. 00, No. 00, 2015