• A Novel Habenulo-Mesencephalic Circuit in Aversive Signaling

      Brown, Paul Leon; Shepard, Paul (2014)
      Midbrain dopamine (DA) neurons are central to reward processes. In general, rewarding stimuli increase, and aversive stimuli decrease, both DA spike firing and terminal release. Stimulation of the lateral habenula (LHb), an area activated by aversive stimuli, or its efferent pathway the fasciculus retroflexus (fr), results in GABAergic inhibition of midbrain DA neurons, suggesting that the LHb encodes negative valence. The source of GABAergic inhibition is uncertain, but a recently described brain area, the mesopontine rostromedial tegmental nucleus (RMTg), is a strong candidate. A series of experiments was designed to elucidate the role of the LHb-RMTg-midbrain DA circuit in the encoding of aversive events. Both low and high intensity foot shocks elevated RMTg cFos, an immediate early gene that reflects cellular activation. Lesions of the fr blocked low intensity foot shock induced cFos elevation, demonstrating that the LHb is necessary for RMTg activation following mild aversive stimuli. To test whether LHb-stimulation induced inhibition of DA neurons occurs via RMTg GABA neurons, two electrophysiological experiments were conducted. In patch clamp recordings in rat parasagittal slices fr stimulation induced excitation in about half of all DA and non-DA neurons. Few neurons showed inhibition and excision of the RMTg had no effect on the DA population response to fr stimulation. In the whole animal, however, RMTg lesions decreased the prevalence of LHb-stimulation induced DA inhibition, giving physiological support for an LHb-RMTg-midbrain DA inhibitory circuit. To test whether changes in activation of the LHb-RMTg circuit alter behavioral sequelae associated with the presentation of aversive stimuli, we monitored the development of learned helplessness following manipulations of this circuit. LHb stimulation concurrent with foot shock during induction increased the prevalence of learned helplessness in rats. Conversely, lesions of the RMTg impeded the development of a helpless phenotype. We found that the LHb-RMTg circuit is activated by aversive events, mediates transient inhibition of DA neurons, and affects the development of depressive phenotypes. These data, which elucidate the role played by the LHb and RMTg in the encoding of aversive stimuli, have implications for future research in the areas of mood disorders and drug abuse.
    • The Role of the Habenula in Reward Processing

      Danna, Carolyn; Elmer, Greg I. (2010)
      Reward processing is a complex task that is arguably the most important motivational force behind decision-making and actions. Rewarding and aversive events are processed by comparing reality with expectations. The result of the comparison, termed temporal difference error, influences the likelihood that the behavior immediately preceding the event will be repeated and alters future expectations of reward. A variety of brain regions are hypothesized to be associated with the computation of this comparison; recent discoveries now include the habenula in this list. The aim of the experiments described in this thesis was to examine of the role of the habenula in reward processing. We hypothesized that the habenula plays a critical role in two core features of reward learning, signaling less than expected outcomes and action selection. To test this, we used a Pavlovian autoshaping procedure that quantifies the acquisition of learned association between predictive stimuli and outcomes as well as the attribution of incentive salience to reward predictive cues using conditioned approach to reward or stimuli, respectively. Dopamine antagonists, lesions of the output tract of the habenula (fasciculus retroflexus (fr)) and discretely time fr stimulation during reward processing were used to parse out the role the habenula plays in reward learning. The dopamine antagonist studies confirmed a role for dopamine in incentive salience attribution. Surprisingly, habenula lesion dramatically increases the incentive motivational salience attributed to a reward predictive cue. Conversely, stimulation had the inverse effect of reducing the salience of the reward predictive cue. These interventions were found to have a less than anticipated impact on behavior following `less than expected outcomes' (cue reversal). Further experimentation revealed that lesion of the Hb also prevented animals from developing discriminated approach to cues predictive of rewards with different outcome probabilities. Overall, the evidence suggests that the Hb is important for scaling relative incentive values of rewarded cues and refines habenula's role to include attribution of relative incentive value. A better understanding of how rewards and cues are evaluated under normal conditions improves our capacity to understand how certain mental disorders are altering motivation and decision making.