Striatal dopamine explains novelty-induced behavioral dynamics and individual variability in threat prediction

Abstract

Animals exhibit diverse behavioral responses, such as exploration and avoidance, to novel cues in the environment. However, it remains unclear how dopamine neuron-related novelty responses influence behavior. Here, we characterized dynamics of novelty exploration using multi-point tracking (DeepLabCut) and behavioral segmentation (MoSeq). Novelty elicits a characteristic sequence of behavior, starting with investigatory approach and culminating in object engagement or avoidance. Dopamine in the tail of striatum (TS) suppresses engagement, and dopamine responses were predictive of individual variability in behavior. Behavioral dynamics and individual variability were explained by a novel reinforcement learning (RL) model of threat prediction, in which behavior arises from a novelty-induced initial threat prediction (akin to shaping bonus), and a threat prediction that is learned through dopamine-mediated threat prediction errors. These results uncover an algorithmic similarity between reward- and threat-related dopamine sub-systems.

Behavioral and dopaminergic signatures of resilience

“…While previous work found differences in the intrinsic properties of mesolimbic dopamine (DA) neurons in susceptible and resilient individuals after stress was over; [3][4][5][6][7][8][9][10] the causal links between DA activity during stress, dynamic stress-evoked behavior, and individual differences in susceptibility and resilience are not known. Here, we record behavior and neural activity in DA projections to the nucleus accumbens (NAc, signals reward [11][12][13][14] ) and to the tail striatum (TS, signals threat [15][16][17][18] ) during a multiday chronic social defeat paradigm and discover behavioral and neural signatures of resilience. Using supervised and unsupervised behavioral quantification, we find that resilient and susceptible individuals employ different behavioral strategies during stress.…”

“…In addition, different DA projections in the striatum are known to perform distinct roles 38 . DA projections to the tail of the striatum (TS) are primarily from the lateral substantia nigra and are active in response to threatening [15][16][17][18] or alarming 39 stimuli. DA projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) respond vigorously to rewards such as palatable food [11][12][13][14] and non-aggressive social investigation 40,14 .…”

Dynamical management of potential threats regulated by dopamine and direct- and indirect-pathway neurons in the tail of the striatum

“…What is the relationship between stimulus intensity and threat avoidance? We previously proposed that TS dopamine signals physical salience of a stimulus as an initial estimate of threat level (Akiti et al, 2021), although the idea had not been tested experimentally. To address this, we next examined the relationship between physical salience of a threatening stimulus, TS dopamine activity, and avoidance behaviors (Figure 5A-D).…”

“…In the monster paradigm, we found that mice displayed dynamical threat management with avoidance, prediction, and overcoming of threat manifesting at different stages. We focused on TS, because we previously found that dopamine in TS is important for avoidance of a potential threat including a novel object (Akiti et al, 2021; Menegas et al, 2018). Interestingly, phasic dopamine responses in TS are modulated by various parameters that are known to affect physical salience of external stimuli (Menegas et al, 2018), suggesting that an initial estimate of the threat level is shaped by physical salience conveyed by phasic TS dopamine responses (Akiti et al, 2021).…”

“…Histology was conducted in the same manner as previously reported (Akiti et al, 2021; Menegas et al, 2018). Mice were perfused using 4% paraformaldehyde, then brains were sliced into 100 µm thick coronal sections using a vibratome (Leica, Germany) and stored in PBS.…”