Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons

doi:10.1016/J.NEURON.2012.03.017

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Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons

Journal Article•DOI•

Whole-Brain Mapping of Direct Inputs to Midbrain Dopamine Neurons

Mitsuko Watabe-Uchida¹, Lisa Zhu¹, Sachie K. Ogawa¹, Archana Vamanrao¹, Naoshige Uchida¹ - Show less +1 more•Institutions (1)

Harvard University¹

07 Jun 2012-Neuron (Cell Press)-Vol. 74, Iss: 5, pp 858-873

TL;DR: This work comprehensively identified each area's monosynaptic inputs using the rabies virus to show that dopamine neurons in both areas integrate inputs from a more diverse collection of areas than previously thought, including autonomic, motor, and somatosensory areas.

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About: This article is published in Neuron.The article was published on 2012-06-07 and is currently open access. It has received 1051 citations till now. The article focuses on the topics: Medium spiny neuron & Ventral tegmental area.

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Journal Article•DOI•

Input-specific control of reward and aversion in the ventral tegmental area

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Stephan Lammel¹, Byung Kook Lim¹, Chen Ran¹, Kee Wui Huang¹, Michael J. Betley¹, Kay M. Tye², Karl Deisseroth¹, Robert C. Malenka¹ - Show less +4 more•Institutions (2)

Stanford University¹, Picower Institute for Learning and Memory²

08 Nov 2012-Nature

TL;DR: It is established that distinct VTA circuits generate reward and aversion, and thereby provides a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

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Abstract: Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

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1,053 citations

Input-specific control of reward and aversion in the ventral tegmental area

[...]

Stephan Lammel¹, Byung Kook Lim¹, Chen Ran¹, Kee Wui Huang¹, Michael J. Betley¹, Kay M. Tye², Karl Deisseroth¹, Robert C. Malenka¹ - Show less +4 more•Institutions (2)

Stanford University¹, Picower Institute for Learning and Memory²

01 Oct 2012

TL;DR: In this article, the authors show that activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively.

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874 citations

Journal Article•DOI•

Neuronal Reward and Decision Signals: From Theories to Data

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Wolfram Schultz¹•Institutions (1)

University of Cambridge¹

01 Jul 2015-Physiological Reviews

TL;DR: Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts.

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Abstract: Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations. The approach and choice functions involve subjective value, which is objectively assessed by behavioral choices eliciting internal, subjective reward preferences. Utility is the formal mathematical characterization of subjective value and a prime decision variable in economic choice theory. It is coded as utility prediction error by phasic dopamine responses. Utility can incorporate various influences, including risk, delay, effort, and social interaction. Appropriate for formal decision mechanisms, rewards are coded as object value, action value, difference value, and chosen value by specific neurons. Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts. The neuronal reward signals provide guidance for behavior while constraining the free will to act.

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803 citations

Cites background from "Whole-Brain Mapping of Direct Input..."

...Negative dopamine error responses may arise from GABAergic inputs from VTA, substantia nigra pars reticulata, or striatum (625)....
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...The monosynaptic habenula-dopamine projection is weak (625), and electrophysiology reports depression-activation sequence of VTA and nigral dopamine impulse activity following habenula stimulation (95, 250, 344, 566) that likely involves the inhibitory rostromedial reticular nucleus (226, 249)....
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...Dopamine neurons receive main reward information from striatum, amygdala, subthalamic nucleus, pedunculopontine nucleus, rostromedial reticular nucleus, and GABAergic neurons of pars reticulata of substantia nigra (625)....
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...However, dorsal, medial, and orbital prefrontal cortical areas in monkeys provide probably less direct inputs to dopamine neurons than often assumed (625) but could influence them transsynaptically via the striatum....
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Journal Article•DOI•

Ventral tegmental area: cellular heterogeneity, connectivity and behaviour.

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Marisela Morales¹, Elyssa B. Margolis²•Institutions (2)

National Institute on Drug Abuse¹, University of California, San Francisco²

01 Feb 2017-Nature Reviews Neuroscience

TL;DR: Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.

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Abstract: Neurons in the ventral tegmental area (VTA) are highly heterogeneous and project to a range of different brain regions. Morales and Margolis summarize recent efforts to characterise VTA neurons, dissect their circuitry and understand their roles in motivation- and reward-related behaviours. Dopamine-releasing neurons of the ventral tegmental area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.

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745 citations

Journal Article•DOI•

Circuit Architecture of VTA Dopamine Neurons Revealed by Systematic Input-Output Mapping.

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Kevin T. Beier¹, Elizabeth E. Steinberg¹, Katherine E. DeLoach², Stanley Xie², Kazunari Miyamichi², Lindsay A. Schwarz², Xiaojing J. Gao², Eric J. Kremer³, Robert C. Malenka¹, Liqun Luo² - Show less +6 more•Institutions (3)

Stanford University¹, Howard Hughes Medical Institute², University of Montpellier³

30 Jul 2015-Cell

TL;DR: The utility of viral-genetic tracing strategies to elucidate the complex neural substrates that underlie motivated behaviors is highlighted, including a previously unappreciated top-down reinforcing circuit from anterior cortex to lateral nucleus accumbens via VTA-DA neurons.

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736 citations

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References

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Book•

The Mouse Brain in Stereotaxic Coordinates

[...]

George Paxinos

31 Jul 2001

TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.

...read moreread less

Abstract: "The Mouse Brain in Stereotaxic Coordinates" is the most widely used and cited atlas of the mouse brain in print. It provides researchers and students with both accurate stereotaxic coordinates for laboratory use, and detailed delineations and indexing of structures for reference. The accompanying DVD provides drawings of brains structures that can be used as templates for making figures for publication. The 3rd edition is both a major revision and an expansion of previous editions. Delineations and photographs in the horizontal plane of section now complement the coronal and sagittal series, and all the tissue sections are now shown in high resolution digital color photography. The photographs of the sections and the intermediate sections are also provided on the accompanying DVD in high-resolution JP 2000 format. The delineations of structures have been revised, and naming conventions made consistent with Paxinos and Watson's "Rat Brain in Stereotaxic Coordinates, 6th Edition". The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use. This edition is in full color throughout. It includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material. Coronal and sagittal diagrams are completely reworked and updated. Rhombomeric borders are included in sagittal figures, for the first time in mammals. Microscopic plates are scanned with a new method in much higher quality.

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15,681 citations

"Whole-Brain Mapping of Direct Input..." refers background or methods in this paper

...Using custom software, we identified 860 Neuron 74, 858–873, June 7, 2012 ª2012 Elsevier Inc. anatomical areas based on a standard mouse atlas (Franklin and Paxinos, 2008) using fluorescent Nissl staining; the location of each neuron was registered on the anatomical coordinate....
[...]
...(I) Unrolled representation of cortical areas as defined in a standard mouse atlas (Franklin and Paxinos, 2008)....
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...anatomical areas based on a standard mouse atlas (Franklin and Paxinos, 2008) using fluorescent Nissl staining; the location of each neuron was registered on the anatomical coordinate....
[...]
...Scale bar, 1 mm. (C) Schematic of cortical areas at the similar bregma level (2.34 mm) as defined by Franklin and Paxinos (2008)....
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...These bands often did not reflect the boundaries of anatomically identified areas (Franklin and Paxinos, 2008), but the densely labeled regions included various areas in the striatum and pallidum and, more posteriorly, the basal forebrain and hypothalamus (Figures 2–4)....
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Journal Article•DOI•

A Neural Substrate of Prediction and Reward

[...]

Wolfram Schultz¹, Peter Dayan², P R Montague³•Institutions (3)

University of Fribourg¹, Massachusetts Institute of Technology², Baylor College of Medicine³

14 Mar 1997-Science

TL;DR: Findings in this work indicate that dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events can be understood through quantitative theories of adaptive optimizing control.

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Abstract: The capacity to predict future events permits a creature to detect, model, and manipulate the causal structure of its interactions with its environment. Behavioral experiments suggest that learning is driven by changes in the expectations about future salient events such as rewards and punishments. Physiological work has recently complemented these studies by identifying dopaminergic neurons in the primate whose fluctuating output apparently signals changes or errors in the predictions of future salient and rewarding events. Taken together, these findings can be understood through quantitative theories of adaptive optimizing control.

...read moreread less

8,163 citations

"Whole-Brain Mapping of Direct Input..." refers background in this paper

...Electrophysiological studies have shown that dopamine neurons are activated phasically (100–500 ms) by unpredicted reward or sensory cues that predict reward (Bromberg-Martin et al., 858 Neuron 74, 858–873, June 7, 2012 ª2012 Elsevier Inc. 2010; Schultz et al., 1997)....
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...Article...
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Journal Article•DOI•

Dopamine, learning and motivation

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Roy A. Wise¹•Institutions (1)

National Institute on Drug Abuse¹

01 Jun 2004-Nature Reviews Neuroscience

TL;DR: Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.

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Abstract: The hypothesis that dopamine is important for reward has been proposed in a number of forms, each of which has been challenged. Normally, rewarding stimuli such as food, water, lateral hypothalamic brain stimulation and several drugs of abuse become ineffective as rewards in animals given performance-sparing doses of dopamine antagonists. Dopamine release in the nucleus accumbens has been linked to the efficacy of these unconditioned rewards, but dopamine release in a broader range of structures is implicated in the 'stamping-in' of memory that attaches motivational importance to otherwise neutral environmental stimuli.

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3,012 citations

"Whole-Brain Mapping of Direct Input..." refers background in this paper

...Dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) play pivotal roles in various brain functions including motivation, reinforcement learning, and motor control (Cohen et al., 2012; Ikemoto, 2007; Redgrave and Gurney, 2006; Schultz, 2007; Wise, 2004)....
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...Article...
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Journal Article•DOI•

Dopamine in Motivational Control: Rewarding, Aversive, and Alerting

[...]

Ethan S. Bromberg-Martin¹, Masayuki Matsumoto¹, Masayuki Matsumoto², Okihide Hikosaka¹•Institutions (2)

National Institutes of Health¹, Primate Research Institute²

09 Dec 2010-Neuron

TL;DR: It is proposed that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control, and it is hypothesized that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior.

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1,832 citations

"Whole-Brain Mapping of Direct Input..." refers background in this paper

...Previous studies proposed that inputs from the Ce, PB, SC, and the basal forebrain may account for short-latency activations of SNc dopamine neurons (Bromberg-Martin et al., 2010; Coizet et al., 2010; Dommett et al., 2005; Matsumoto and Hikosaka, 2009)....
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...More generally, although the aforementioned findings indicate that dopamine neurons integrate diverse kinds of information, the mechanisms by which the firing of dopamine neurons is regulated in a behavioral context remain largely unknown (Bromberg-Martin et al., 2010; Lee and Tepper, 2009; Sesack and Grace, 2010)....
[...]
...…the aforementioned findings indicate that dopamine neurons integrate diverse kinds of information, the mechanisms by which the firing of dopamine neurons is regulated in a behavioral context remain largely unknown (Bromberg-Martin et al., 2010; Lee and Tepper, 2009; Sesack and Grace, 2010)....
[...]
...Although efforts have been made to identify the sources of such inputs, they remain unidentified (Bromberg-Martin et al., 2010; Coizet et al., 2010; Dommett et al., 2005; Jhou et al., 2009; Matsumoto and Hikosaka, 2007)....
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Journal Article•DOI•

Neurotransmitters and neuromodulators in the basal ganglia

[...]

Ann M. Graybiel¹•Institutions (1)

Massachusetts Institute of Technology¹

01 Jul 1990-Trends in Neurosciences

TL;DR: A new view of the basal ganglia is emerging on the basis of this neurochemical heterogeneity, suggesting that dynamic regulation of transmitter expression may be a key to extrapyramidal function.

...read moreread less

1,550 citations

"Whole-Brain Mapping of Direct Input..." refers background in this paper

...Importantly, dopamineneuron-projecting striatal neurons differ from GABAergicneuron-projecting medium spiny neurons in their morphology and calbindin D-28k expression, suggesting that these neurons are a new class of medium spiny neurons....
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...Red, calbindin D-28k immunostaining; green, EGFP (input neurons); ac, anterior commissure; AcbC, nucleus accumbens core; AcbSh, nucleus accumbens shell; DS, dorsal striatum....
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...(I) Quantification of calbindin D-28k expression levels. p < 10 13, t test (n = 126, 68 neurons)....
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...The DS can be parceled into patch and matrix compartments that may define distinct projection systems (Gerfen, 1992; Graybiel, 1990)....
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...Red, calbindin D-28k immunostaining....
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