Role of the Rostromedial Tegmental Nucleus (Rmtg) in Aversive Processing

Reward learning is increasingly well understood to involve a major role of dopamine (DA) in reward-seeking and reinforcement, but reward-seeking behavior almost always incurs some costs or punishment, which are less well understood, especially in addictive disorders involving a marked failure to inhibit reward-seeking in the face of high costs or punishment. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain DA neurons, has been hypothesized to encode punishment-related signals and inhibit DA responses to them. However, existing studies have only tested RMTg responses to a few aversive stimuli and generalizability of RMTg encoding of aversive stimuli has not been examined. Furthermore, a direct causal relationship between RMTg activation by aversive stimuli, and subsequent DA inhibition has also never been tested in awake-behaving animals. Also, the RMTg receives inputs from many brain regions that are implicated in processing punishment signals, including prelimbic cortex, lateral habenula, and parabrachial nucleus, yet the relative functions between these RMTg afferents are largely unknown. In this dissertation, we demonstrate that the RMTg is activated by a wide range of aversive stimuli of different sensory modalities, drives DA inhibition by these stimuli, and integrates distinct punishment learning signals from distinct afferents (brainstem, cortex, and habenula) driving correspondingly distinct phases of punishment learning (reinforcement, performance, and expectation modulation). In addition, we further find that motivational processing in lateral habenula is greatly dependent on the entopeduncular nucleus