Dorsal tegmental dopamine neurons gate associative learning of fear

Abstract

Functional neuroanatomy of Pavlovian fear has identified neuronal circuits and synapses associating conditioned stimuli with aversive events. Hebbian plasticity within these networks requires additional reinforcement to store particularly salient experiences into long-term memory. Here we have identified a circuit that reciprocally connects the ventral periaqueductal gray and dorsal raphe region with the central amygdala and that gates fear learning. We found that ventral periaqueductal gray and dorsal raphe dopaminergic (vPdRD) neurons encode a positive prediction error in response to unpredicted shocks and may reshape intra-amygdala connectivity via a dopamine-dependent form of long-term potentiation. Negative feedback from the central amygdala to vPdRD neurons might limit reinforcement to events that have not been predicted. These findings add a new module to the midbrain dopaminergic circuit architecture underlying associative reinforcement learning and identify vPdRD neurons as a critical component of Pavlovian fear conditioning. We propose that dysregulation of vPdRD neuronal activity may contribute to fear-related psychiatric disorders.

The ventrolateral periaqueductal grey updates fear via positive prediction error

“…These results are consistent with the theoretical framework of our behavioural task requiring the use of prediction errors; by preventing +PEs on uncertainty‐shock trials but leaving intact negative prediction errors on uncertainty‐omission trials, eNpHR rats could only utilize neural signals to decrease fear to uncertainty, which matches the resultant behavioural reduction in fear. Our findings complement and extend previous studies demonstrating +PE correlates in the vlPAG (Groessl et al., ; Johansen et al., ; Roy et al., ) and critical roles for the vlPAG in predictive learning (Cole & McNally, ; McNally & Cole, ). Our results are also consistent with a neural circuit framework positing that the critical comparison of expected and actual foot shock takes place in the vlPAG (McNally, Johansen, & Blair, ).…”

“…So while it is possible, albeit unlikely, that vlPAG +PE correlates would not be found in females, vlPAG foot shock activity at the time of +PE is critical to fear updating in both sexes. Previous experiments related to aversive prediction error signalling using rodents have been conducted using only males (Assareh et al., ; Cole & McNally, ; Groessl et al., ; Johansen et al., ; McNally & Cole, ; Ozawa et al., ), and one study in humans used both males and females but did not consider sex as a factor in their analyses (Roy et al., ). Sex differences in baseline behaviour (i.e., nose poke rate and absolute fear levels) in the optogenetics results are consistent with previous findings in the same behavioural task (Walker et al., ).…”

Neural mechanisms of social homeostasis

“…Monitoring fluorescent calcium activity in vivo revealed that these neurons are active in response to social stimuli, and this activity is heightened following acute isolation . However, these neurons are also responsive to other salient stimuli, including palatable food and unexpected foot shock, and show greater activity during wakefulness compared with sleep, suggesting an arousal‐promoting function . This diversity of sensitivities is consistent with the notion that neural circuits regulating social homeostasis may promote attention to a variety of salient stimuli, in an effort to scan the environment for potential threats or opportunities for social engagement.…”

“…Another component of the midbrain dopamine system—the DRN dopamine neurons—also exhibits acute isolation‐induced adaptations. These dopamine neurons were historically considered a caudal extension of the VTA, but accumulating evidence has revealed distinct downstream projections and functional roles . In adult male mice, 24‐h social isolation potentiated glutamatergic synapses onto DRN dopamine neurons, and also heightened their activity in vivo in response to a novel mouse .…”

“…The DRN dopamine neurons lie directly upstream of several regions, most notably the BNST and CeA . While the explicit role of dopamine in these regions in social behavior remains to be determined, dopamine receptor signaling can modulate synaptic transmission and activity in both the BNST and CeA . Specifically, in the dorsolateral BNST blunting of long‐term potentiation (LTP) is evident after 24 h of social isolation in male mice .…”