Response of the Tail of the Ventral Tegmental Area to Aversive Stimuli

Abstract

The GABAergic tail of the ventral tegmental area (tVTA), also named rostromedial tegmental nucleus (RMTg), exerts an inhibitory control on dopamine neurons of the VTA and substantia nigra. The tVTA has been implicated in avoidance behaviors, response to drugs of abuse, reward prediction error, and motor functions. Stimulation of the lateral habenula (LHb) inputs to the tVTA, or of the tVTA itself, induces avoidance behaviors, which suggests a role of the tVTA in processing aversive information. Our aim was to test the impact of aversive stimuli on the molecular recruitment of the tVTA, and the behavioral consequences of tVTA lesions. In rats, we assessed Fos response to lithium chloride (LiCl), β-carboline, naloxone, lipopolysaccharide (LPS), inflammatory pain, neuropathic pain, foot-shock, restraint stress, forced swimming, predator odor, and opiate withdrawal. We also determined the effect of tVTA bilateral ablation on physical signs of opiate withdrawal, and on LPS-and LiCl-induced conditioned taste aversion (CTA). Naloxone-precipitated opiate withdrawal induced Fos in μ-opioid receptor-positive (15%) and -negative (85%) tVTA cells, suggesting the presence of both direct and indirect mechanisms in tVTA recruitment during withdrawal. However, tVTA lesion did not impact physical signs of opiate withdrawal. Fos induction was also present with repeated, but not single, foot-shock delivery. However, such induction was mostly absent with other aversive stimuli. Moreover, tVTA ablation had no impact on CTA. Although stimulation of the tVTA favors avoidance behaviors, present findings suggest that this structure may be important to the response to some, but not all, aversive stimuli.

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

“…The lHb consists of glutamatergic neurons that are activated by aversive or unrewarding predictive cues [63]. Most lHb neurons terminate in the GABAergic tail of the VTA [64] and provide inhibitory control over DAergic cells of the VTA [65]. The existence of a direct synaptic link between the mHb and lHb may be important in promoting behavioral avoidance and controlling emotional behavior, although the functional relevance of this connection has yet to be explored.…”

Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons

“…The contributions of the RMTg to the motivational effects of opioid-withdrawal have not been investigated to our knowledge. While naloxone-precipitated withdrawal induces Fos activation in RMTg neurons, RMTg lesions do not alter the physical signs of opioid withdrawal (Sánchez-Catalán et al, 2017). Future experiments may test the effect of RMTg lesions on the acquisition of conditioned place aversion to an environment paired with opioid withdrawal.…”

The Lateral Habenula Circuitry: Reward Processing and Cognitive Control

“…The LHb is interconnected with forebrain and midbrain areas required for working memory and behavioral flexibility performance (Baker et al, 2015;Quina et al, 2015), often regarded as the ability to switch behaviors when external contingencies change. Refinement of early lesion work and electrophysiological recording in freely behaving rodents suggests the LHb plays a broad role in behavioral flexibility.…”

“…A major input to the LHb arises from the GPi, also called the entopeduncular nucleus in rodents (Rajakumar et al, 1993;Parent et al, 2001;Hong and Hikosaka, 2008). Neurons in the habenula-projecting globus pallidus, hereafter named as GPh, are distinct from the canonical GPi neurons.…”

“…Neurons in the habenula-projecting globus pallidus, hereafter named as GPh, are distinct from the canonical GPi neurons. Whereas the latter population is inhibitory and controls motor function through projections to the brainstem and thalamic motor areas (Graybiel, 2008), the former uses glutamate as a major neurotransmitter (Shabel et al, 2012(Shabel et al, , 2014 and projects exclusively to the LHb (Rajakumar et al, 1993;Parent et al, 2001;Hong and Hikosaka, 2008;Stephenson-Jones et al, 2016). Interestingly, GPh neurons respond to reward and punishment, as well as the expectation of reward and punishment, in a manner similar to that of LHb neurons Hikosaka, 2008, 2013).…”