Stephan Lammel

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

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.

Unique Properties of Mesoprefrontal Neurons within a Dual Mesocorticolimbic Dopamine System

The mesocorticolimbic dopamine system is essential for cognitive and emotive brain functions and is thus an important target in major brain diseases like schizophrenia, drug addiction, and attention deficit hyperactivity disorder. However, the cellular basis for the diversity in behavioral functions and associated dopamine-release pattern within the mesocorticolimbic system has remained unclear. Here, we report the identification of a type of dopaminergic neuron within the mesocorticolimbic dopamine system with unconventional fast-firing properties and small DAT/TH mRNA expression ratios that selectively projects to prefrontal cortex and nucleus accumbens core and medial shell as well as to basolateral amygdala. In contrast, well-described conventional slow-firing dopamine midbrain neurons only project to the lateral shell of the nucleus accumbens and the dorsolateral striatum. Among this dual dopamine midbrain system defined in this study by converging anatomical, electrophysiological, and molecular properties, mesoprefrontal dopaminergic neurons are unique, as only they do not possess functional somatodendritic Girk2-coupled dopamine D2 autoreceptors.

Diversity of transgenic mouse models for selective targeting of midbrain dopamine neurons.

Ventral tegmental area (VTA) dopamine (DA) neurons have been implicated in reward, aversion, salience, cognition, and several neuropsychiatric disorders. Optogenetic approaches involving transgenic Cre-driver mouse lines provide powerful tools for dissecting DA-specific functions. However, the emerging complexity of VTA circuits requires Cre-driver mouse lines that restrict transgene expression to a precisely defined cell population. Because of recent work reporting that VTA DA neurons projecting to the lateral habenula release GABA, but not DA, we performed an extensive anatomical, molecular, and functional characterization of prominent DA transgenic mouse driver lines. We find that transgenes under control of the tyrosine hydroxylase, but not the dopamine transporter, promoter exhibit dramatic non-DA cell-specific expression patterns within and around VTA nuclei. Our results demonstrate how Cre expression in unintentionally targeted cells in transgenic mouse lines can confound the interpretation of supposedly cell-type-specific experiments. This Matters Arising paper is in response to Stamatakis et al. (2013), published in Neuron. See also the Matters Arising Response paper by Stuber et al. (2015), published concurrently with this Matters Arising in Neuron.

New Insights into the Specificity and Plasticity of Reward and Aversion Encoding in the Mesolimbic System

The mesocorticolimbic system, consisting, at its core, of the ventral tegmental area, the nucleus accumbens, and medial prefrontal cortex, has historically been investigated primarily for its role in positively motivated behaviors and reinforcement learning, and its dysfunction in addiction, schizophrenia, depression, and other mood disorders. Recently, researchers have undertaken a more comprehensive analysis of this system, including its role in not only reward but also punishment, as well as in both positive and negative reinforcement. This focus has been facilitated by new anatomical, physiological, and behavioral approaches to delineate functional circuits underlying behaviors and to determine how this system flexibly encodes and responds to positive and negative states and events, beyond simple associative learning. This review is a summary of topics covered in a mini-symposium at the 2013 Society for Neuroscience annual meeting.

Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

See Borgkvist et al. (doi:10.1093/brain/awu150) for a scientific commentary on this article. D2 autoreceptors and L-type calcium channels are both implicated in Parkinson’s disease, but how they interact is unclear. Dragicevic et al. reveal that L-type calcium channels can modulate D2-autoreceptor responses via the neuronal calcium sensor NCS-1. This dopamine-dependent signalling network is altered in Parkinson’s disease and could represent a therapeutic target.

Progress in understanding mood disorders: optogenetic dissection of neural circuits

Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression‐like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit‐targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression‐related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders.

Nucleus Accumbens Subnuclei Regulate Motivated Behavior via Direct Inhibition and Disinhibition of VTA Dopamine Subpopulations

Mesolimbic dopamine (DA) neurons play a central role in motivation and reward processing. Although the activity of these mesolimbic DA neurons is controlled by afferent inputs, little is known about the circuits in which they are embedded. Using retrograde tracing, electrophysiology, optogenetics, and behavioral assays, we identify principles of afferent-specific control in the mesolimbic DA system. Neurons in the medial shell subdivision of the nucleus accumbens (NAc) exert direct inhibitory control over two separate populations of mesolimbic DA neurons by activating different GABA receptor subtypes. In contrast, NAc lateral shell neurons mainly synapse onto ventral tegmental area (VTA) GABA neurons, resulting in disinhibition of DA neurons that project back to the NAc lateral shell. Lastly, we establish a critical role for NAc subregion-specific input to the VTA underlying motivated behavior. Collectively, our results suggest a distinction in the incorporation of inhibitory inputs between different subtypes of mesolimbic DA neurons.

Viral vector strategies for investigating midbrain dopamine circuits underlying motivated behaviors

ABSTRACT Midbrain dopamine (DA) neurons have received significant attention in brain research because of their central role in reward processing and their dysfunction in neuropsychiatric disorders such as Parkinsons disease, drug addiction, depression and schizophrenia. Until recently, it has been thought that DA neurons form a homogeneous population whose primary function is the computation of reward prediction errors. However, through the implementation of viral vector strategies, an unexpected complexity and diversity has been revealed at the anatomical, molecular and functional level. In this review, we discuss recent viral vector approaches that have been leveraged to dissect how different circuits involving distinct DA neuron subpopulations may contribute to the role of DA in reward‐ and aversion‐related behaviors. We focus on studies that have used cell type‐ and projection‐specific optogenetic manipulations, discuss the strengths and limitations of each approach, and critically examine emergent organizational principles that have led to a reclassification of midbrain DA neurons. HIGHLIGHTSViral vector strategies for studying heterogeneity in the dopamine systemRole of dopamine neurons in reward and aversionReclassification of dopamine neurons based on connectivity

Illuminating the Opponent Process: Cocaine Effects on Habenulomesencephalic Circuitry

Drugs of abuse have profound effects on neural circuits that control emotional and motivational states. Most abused drugs promote dopaminergic signaling in pathways that originate in the ventral tegmental area (VTA), and these effects contribute to drug reward and reinforcement. As the initial