Distinct Midbrain and Habenula Pathways Are Involved in Processing Aversive Events in Humans

Abstract

Emerging evidence implicates the midbrain dopamine system and its interactions with the lateral habenula in processing aversive information and learning to avoid negative outcomes. We examined neural responses to unexpected, aversive events using methods specialized for imaging the midbrain and habenula in humans. Robust activation to aversive relative to neutral events was observed in the habenula and two regions within the ventral midbrain: one located within the ventral tegmental area (VTA) and the other in the substantia nigra (SN). Aversive processing increased functional connectivity between the VTA and the habenula, putamen, and medial prefrontal cortex, whereas the SN exhibited a different pattern of functional connectivity. Our findings provide evidence for a network comprising the VTA and SN, the habenula, and mesocorticolimbic structures that supports processing aversive events in humans.

Distinct Contributions of Ventromedial and Dorsolateral Subregions of the Human Substantia Nigra to Appetitive and Aversive Learning

“…Although this procedure did not limit ROIs to be localized to the same hemisphere as was found in the overall analysis, we found that ROIs were largely overlapping and all localized to the same hemisphere (data not shown). Similar asymmetries have been reported in previous studies (D 'Ardenne et al, 2013;Hennigan et al, 2015). For each participant, we created 5 bins of consecutive ranges of TD prediction errors, so that each bin contained the same number of trials (14 trials).…”

“…However, no previous study to date has reported direct comparisons between responses during appetitive and aversive conditioning. Hennigan et al (2015) did indeed include a reward-learning condition, but they did not find any response in the midbrain in that condition, perhaps because the aversive and appetitive cues were delivered in an intermixed fashion in that study (as opposed to in separate sessions as done here). With an intermixed paradigm, contrast effects between the cues may have resulted in the aversive cue dominating (see also Kim et al, 2011).…”

“…Nevertheless, some studies have reported activity in SN and/or VTA in response to prediction errors during reward presentation or omission (O'Doherty et al, 2002;Wittmann et al, 2005;D'Ardenne et al, 2008). A recent study has also reported activity in the SN in response to anticipation of aversive outcomes, although it is not known from this experiment whether this region is encoding a prediction error for aversive outcomes per se, or a pure anticipatory value signal (Hennigan et al, 2015).…”

“…Flexible range adaptation has been reported in midbrain dopamine neurons for encoding of RPE signals (Tobler et al, 2005), so it is possible that such an adaptive coding mechanism is present more extensively within the SN. It is worth noting that a previous fMRI study did report BOLD responses in the SN during aversive conditioning (Hennigan et al, 2015), whereas other studies reported a variety of rewardrelated prediction error-related responses in the same structure (Wittmann et al, 2005;D'Ardenne et al, 2013). However, no previous study to date has reported direct comparisons between responses during appetitive and aversive conditioning.…”

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…These phenotypes are not restricted to zebrafish: Lat À/À mice also show alterations in several brain regions including cortex and habenula, a structure that plays a central role in the positive and negative reinforcements of the reward process. [51][52][53] Cd247 À/À mice show brain morphological defects, in particular reduced glutamatergic synaptic activity in the retina 54 and synaptic plasticity in the hippocampus, 41 as well as impaired learning and memory, a T cell-independent mechanism. 44 In zebrafish, ZAP70 is expressed ubiquitously in early development, and highly and specifically in the head from the 16-somite stage, with low expression level throughout the rest of the embryo.…”