The inhibitory influence of the lateral habenula on midbrain dopamine cells: Ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus
ABSTRACT The lateral habenula (LHb) provides an important source of negative reinforcement signals to midbrain dopamine (DA) cells in the substantia nigra and ventral tegmental area (VTA). This profound and consistent inhibitory influence involves a disynaptic connection from glutamate neurons in the LHb to some population of γ-aminobutyric acid (GABA) cells that, in turn, innervates DA neurons. Previous studies demonstrated that the GABA cells intrinsic to the VTA receive insufficient synaptic input from the LHb to serve as the primary source of this intermediate connection. In this investigation, we sought ultrastructural evidence supporting the hypothesis that a newly identified region of the brainstem, the rostromedial mesopontine tegmental nucleus (RMTg), is a more likely candidate for inhibiting midbrain DA cells in response to LHb activation. Electron microscopic examination of rat brain sections containing dual immunoreactivity for an anterograde tracing agent and a phenotypic marker revealed that: 1) more than 55% of the synapses formed by LHb axons in the RMTg were onto GABA-labeled dendrites; 2) more than 80% of the synapses formed by RMTg axons in the VTA contacted dendrites immunoreactive for the DA synthetic enzyme tyrosine hydroxylase; and 3) nearly all RMTg axons formed symmetric synapses and contained postembedding immunoreactivity for GABA. These findings indicate that the newly identified RMTg region is an intermediate structure in a disynaptic pathway that connects the LHb to VTA DA neurons. The results have important implications for understanding mental disorders characterized by a dysregulation of reward circuitry involving LHb and DA cell populations.
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ABSTRACT: Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal Increased anxiety is a prominent withdrawal symptom in abstinent smokers, yet the neu-roanatomical and molecular bases underlying it are unclear. Here we show that withdrawal-induced anxiety increases activity of neurons in the interpeduncular intermediate (IPI), a subregion of the interpeduncular nucleus (IPN). IPI activation during nicotine withdrawal was mediated by increased corticotropin releasing factor (CRF) receptor-1 expression and signalling , which modulated glutamatergic input from the medial habenula (MHb). Pharmacological blockade of IPN CRF1 receptors or optogenetic silencing of MHb input reduced IPI activation and alleviated withdrawal-induced anxiety; whereas IPN CRF infusion in mice increased anxiety. We identified a mesointerpeduncular circuit, consisting of ventral teg-mental area (VTA) dopaminergic neurons projecting to the IPN, as a potential source of CRF. Knockdown of CRF synthesis in the VTA prevented IPI activation and anxiety during nicotine withdrawal. These data indicate that increased CRF receptor signalling within a VTA–IPN–MHb circuit triggers anxiety during nicotine withdrawal.Nature Communications 04/2015; DOI:10.1038/ncomms7770
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ABSTRACT: The lateral habenula (LHb) is involved in reward and aversion and is reciprocally connected with dopamine (DA)-containing brain regions, including the ventral tegmental area (VTA). We used a multidisciplinary approach to examine the properties of DA afferents to the LHb in the rat. We find that >90% of VTA tyrosine hydroxylase (TH) neurons projecting to the LHb lack vesicular monoamine transporter 2 (VMAT2) mRNA, and there is little coexpression of TH and VMAT2 protein in this mesohabenular pathway. Consistent with this, electrical stimulation of LHb did not evoke DA-like signals, assessed with fast-scan cyclic voltammetry. However, electrophysiological currents that were inhibited by L741,742, a DA-D4-receptor antagonist, were observed in LHb neurons when DA uptake or degradation was blocked. To prevent DA activation of D4 receptors, we repeated this experiment in LHb slices from DA-depleted rats. However, this did not disrupt D4 receptor activation initiated by the dopamine transporter inhibitor, GBR12935. As the LHb is also targeted by noradrenergic afferents, we examined whether GBR12935 activation of DA-D4 receptors occurred in slices depleted of norepinephrine (NE). Unlike DA, NE depletion prevented the activation of DA-D4 receptors. Moreover, direct application of NE elicited currents in LHb neurons that were blocked by L741,742, and GBR12935 was found to be a more effective blocker of NE uptake than the NE-selective transport inhibitor nisoxetine. These findings demonstrate that NE is released in the rat LHb under basal conditions and that it activates DA-D4 receptors. Therefore, NE may be an important regulator of LHb function. Copyright © 2015 the authors 0270-6474/15/353460-10$15.00/0.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2015; 35(8):3460-3469. DOI:10.1523/JNEUROSCI.4525-13.2015
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ABSTRACT: Background: The lateral habenula (LHb) is a brain region that has been critically implicated in modulating negative emotional states and responses to aversive stimuli. Exposure to addictive drugs such as cocaine negatively impacts affective states, an effect persisting longer than acute drug effects. However, the mechanisms of this effect are poorly understood. We hypothesized that drugs of abuse, such as cocaine, may contribute to drug-induced negative affective states by altering the firing properties of LHb neurons, thus changing the signaling patterns from the LHb to downstream circuits. Methods: Using whole-cell current-clamp recording of acutely prepared brain slices of rats after various periods of withdrawal from cocaine self-administration, we characterized an important heterogeneous subregion of the LHb based on membrane properties. Results: We found two major relevant neuronal subtypes: burst firing neurons and regular spiking neurons. We also found that LHb regular spiking neurons had higher membrane excitability for at least 7 days following cocaine self-administration, likely due to a greater membrane resistance. Both the increase in LHb excitability and membrane resistance returned to baseline when tested after a more prolonged period of 45 days of withdrawal. Conclusion: This is the first study to look at intrinsic LHb neuron properties following cocaine exposure beyond acute drug effects. These results may help to explain how cocaine and other drugs negatively impact affect states. © The Author 2014. Published by Oxford University Press on behalf of CINP.The International Journal of Neuropsychopharmacology 12/2014; 18(6). DOI:10.1093/ijnp/pyu109