Journal Articles

  • Progress in understanding mood disorders: optogenetic dissection of neural circuits GENES BRAIN AND BEHAVIOR Lammel, S., Tye, K. M., WARDEN, M. R. 2014; 13 (1): 38-51


    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.

    View details for DOI 10.1111/gbb.12049

    View details for Web of Science ID 000329160500005

    View details for PubMedID 23682971

  • Reward and aversion in a heterogeneous midbrain dopamine system NEUROPHARMACOLOGY Lammel, S., Lim, B. K., Malenka, R. C. 2014; 76: 351-359


    The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

    View details for DOI 10.1016/j.neuropharm.2013.03.019

    View details for Web of Science ID 000330083600016

    View details for PubMedID 23578393

  • New insights into the specificity and plasticity of reward and aversion encoding in the mesolimbic system. journal of neuroscience Volman, S. F., Lammel, S., Margolis, E. B., Kim, Y., Richard, J. M., Roitman, M. F., Lobo, M. K. 2013; 33 (45): 17569-17576


    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.

    View details for DOI 10.1523/JNEUROSCI.3250-13.2013

    View details for PubMedID 24198347

  • Input-specific control of reward and aversion in the ventral tegmental area NATURE Lammel, S., Lim, B. K., Ran, C., Huang, K. W., Betley, M. J., Tye, K. M., Deisseroth, K., Malenka, R. C. 2012; 491 (7423): 212-?


    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 (?-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.

    View details for DOI 10.1038/nature11527

    View details for Web of Science ID 000310774300035

    View details for PubMedID 23064228

  • Projection-Specific Modulation of Dopamine Neuron Synapses by Aversive and Rewarding Stimuli NEURON Lammel, S., Ion, D. I., Roeper, J., Malenka, R. C. 2011; 70 (5): 855-862


    Midbrain dopamine (DA) neurons are not homogeneous but differ in their molecular properties and responses to external stimuli. We examined whether the modulation of excitatory synapses on DA neurons by rewarding or aversive stimuli depends on the brain area to which these DA neurons project. We identified DA neuron subpopulations in slices after injection of "Retrobeads" into single target areas of adult mice and found differences in basal synaptic properties. Administration of cocaine selectively modified excitatory synapses on DA cells projecting to nucleus accumbens (NAc) medial shell while an aversive stimulus selectively modified synapses on DA cells projecting to medial prefrontal cortex. In contrast, synapses on DA neurons projecting to NAc lateral shell were modified by both rewarding and aversive stimuli, which presumably reflects saliency. These results suggest that the mesocorticolimbic DA system may be comprised of three anatomically distinct circuits, each modified by distinct aspects of motivationally relevant stimuli.

    View details for DOI 10.1016/j.neuron.2011.03.025

    View details for Web of Science ID 000291843500007

    View details for PubMedID 21658580

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