Stamatakis AM, Stuber GD. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat Neurosci 15: 1105-1107

University of North Carolina Neurobiology Curriculum, UNC Neuroscience Center, UNC at Chapel Hill, Chapel Hill, North Carolina, USA.
Nature Neuroscience (Impact Factor: 16.1). 06/2012; 15(8):1105-7. DOI: 10.1038/nn.3145
Source: PubMed


Lateral habenula (LHb) projections to the ventral midbrain, including the rostromedial tegmental nucleus (RMTg), convey negative reward-related information, but the behavioral ramifications of selective activation of this pathway remain unexplored. We found that exposure to aversive stimuli in mice increased LHb excitatory drive onto RMTg neurons. Furthermore, optogenetic activation of this pathway promoted active, passive and conditioned behavioral avoidance. Thus, activity of LHb efferents to the midbrain is aversive but can also serve to negatively reinforce behavioral responding.


Available from: Alice Stamatakis, Aug 07, 2014
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    • "bs_bs_banner Stamatakis and Stuber 2012 "
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    ABSTRACT: There has been increasing interest in the lateral habenula (LHb) given its potent regulatory role in many aversion-related behaviors. Interestingly, ethanol can be rewarding as well as aversive; we therefore investigated whether ethanol exposure alters pacemaker firing or glutamate receptor signaling in LHb neurons in vitro and also whether LHb activity in vivo might contribute to the acquisition of conditioned place aversion to ethanol. Surprisingly, in epithalamic slices, low doses of ethanol (1.4 mM) strongly accelerated LHb neuron firing (by ~60%), and ethanol's effects were much reduced by blocking glutamate receptors. Ethanol increased presynaptic glutamate release, and about half of this effect was mediated by dopamine subtype 1 receptors (D1Rs) and cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. In agreement with these findings, c-Fos immunoreactivity in LHb regions was enhanced after a single administration of a low dose of ethanol (0.25 g/kg i.p.). Importantly, the same dose of ethanol in vivo also produced strong conditioned place aversion, and this was prevented by inhibiting D1Rs or neuronal activity within the LHb. By contrast, a higher dose (2 g/kg) led to ethanol conditioned place preference, which was enhanced by inhibiting neuronal activity or D1Rs within the LHb and suppressed by infusing aminomethylphosphonic acid or the D1R agonist SKF38393 within the LHb. Our in vitro and in vivo observations show, for the first time, that ethanol increases LHb excitation, mediated by D1R and glutamate receptors, and may underlie a LHb aversive signal that contributes to ethanol-related aversion. © 2015 Society for the Study of Addiction.
    Addiction Biology 08/2015; DOI:10.1111/adb.12298 · 5.36 Impact Factor
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    • "We next determined the in vivo optofluidic capabilities of these devices. Real-time place preference has become a common tool for neuroscientists to assess the behavioral valence of photostimulated neural circuits or cell bodies in a freely moving animal (Jennings et al., 2013; Kim et al., 2013a; Siuda et al., 2015; Stamatakis and Stuber, 2012; Stamatakis et al., 2013; Tan et al., 2012). In related behavioral models, phasic optogenetic activation of VTA dopaminergic (VTA-DA) neurons is rewarding (Kim et al., 2012, 2013b; Tsai et al., 2009; Witten et al., 2011). "
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    ABSTRACT: In vivo pharmacology and optogenetics hold tremendous promise for dissection of neural circuits, cellular signaling, and manipulating neurophysiological systems in awake, behaving animals. Existing neural interface technologies, such as metal cannulas connected to external drug supplies for pharmacological infusions and tethered fiber optics for optogenetics, are not ideal for minimally invasive, untethered studies on freely behaving animals. Here, we introduce wireless optofluidic neural probes that combine ultrathin, soft microfluidic drug delivery with cellular-scale inorganic light-emitting diode (μ-ILED) arrays. These probes are orders of magnitude smaller than cannulas and allow wireless, programmed spatiotemporal control of fluid delivery and photostimulation. We demonstrate these devices in freely moving animals to modify gene expression, deliver peptide ligands, and provide concurrent photostimulation with antagonist drug delivery to manipulate mesoaccumbens reward-related behavior. The minimally invasive operation of these probes forecasts utility in other organ systems and species, with potential for broad application in biomedical science, engineering, and medicine. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 07/2015; 162(3). DOI:10.1016/j.cell.2015.06.058 · 32.24 Impact Factor
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    • "The LHb is likely to be essential for survival through the promotion of learning and subsequent activities that lead to avoidance of stimuli associated with negative consequences . For instance , optogenetic activation of the LHb promotes active and passive avoidance behavior in mice ( Stamatakis and Stuber , 2012 ) , while bilateral lesion of the LHb reduces escape and avoidance latencies in rats ( Pobbe and Zangrossi , 2010 ) . In addition , under stressful conditions ( i . "
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    ABSTRACT: Abstract Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems, and is the first preventable cause of death worldwide. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here, we show that acute nicotine induces anxiogenic effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.), as measured by the hole-board apparatus and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the lateral habenula (LHb) induced hyperlocomotion and, strikingly, reversed the nicotine-induced anxiety obtained at 1 mg/kg to an anxiolytic-like effect, as shown by T-pattern analysis. We suggest that the LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulation of monoaminergic nuclei.
    Frontiers in Cellular Neuroscience 06/2015; 9. DOI:10.3389/fncel.2015.00197 · 4.29 Impact Factor
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