Acute Stress Enhances Associative Learning via Dopamine Signaling in the Ventral Lateral Striatum

Abstract

Acute stress transiently increases vigilance, enhancing the detection of salient stimuli in one's environment. This increased perceptual sensitivity is thought to promote the association of rewarding outcomes with relevant cues. The mesolimbic dopamine system is critical for learning cue-reward associations. Dopamine levels in the ventral striatum are elevated following exposure to stress. Together, this suggests that the mesolimbic dopamine system could mediate the influence of acute stress on cue-reward learning. To address this possibility, we examined how a single stressful experience influenced learning in an appetitive pavlovian conditioning task. Male rats underwent an episode of restraint prior to the first conditioning session. This acute stress treatment augmented conditioned responding in subsequent sessions. Voltammetry recordings of mesolimbic dopamine levels demonstrated that acute stress selectively increased reward-evoked dopamine release in the ventral lateral striatum (VLS), but not in the ventral medial striatum. Antagonizing dopamine receptors in the VLS blocked the stress-induced enhancement of conditioned responding. Collectively, these findings illustrate that stress engages dopamine signaling in the VLS to facilitate appetitive learning.SIGNIFICANCE STATEMENT Acute stress influences learning about aversive and rewarding outcomes. Dopamine neurons are sensitive to stress and critical for reward learning. However, it is unclear whether stress regulates reward learning via dopamine signaling. Using fast-scan cyclic voltammetry as rats underwent pavlovian conditioning, we demonstrate that a single stressful experience increases reward-evoked dopamine release in the ventral lateral striatum. This enhanced dopamine signal accompanies a long-lasting increase in conditioned behavioral responding. These findings highlight that the ventral lateral striatum is a node for mediating the effect of stress on reward processing.

Keywords: dopamine; learning; stress; ventral striatum.

Figure 1.

Voltammetry electrode and cannula placement. A, Histologically verified locations of voltammetry electrodes in control rats (black circles) and stressed rats (magenta circles). The lateral edge of the anterior commissure was used as the boundary of the ventral medial (left) and ventral lateral (right) striatum. B, Histologically verified locations of microinjector tips and approximate infusion area of vehicle (left, blue) and flupenthixol (right, orange) in control rats (above, black border) and stressed rats (below, magenta border).

Figure 2.

A single stress experience enhances subsequent pavlovian conditioning. A, Training paradigm. Animals are stressed once, 20 min prior to the first conditioning session. B, Task structure. C, Elevated conditioned responding to the reward-predictive CS in rats stressed before the first training session. Magenta arrows denote restraint stress/control procedure. D, Latency to head entry. E, Non-CS tray entries. F, Training paradigm with a 2 h delay between the stress/control treatment and the start of conditioning. G, Conditioned responding is not increased when training begins 2 h after the stressor. H, Latency to head entry. I, Non-CS tray entries. J, Training paradigm with stress/control treatment occurring 20 min prior to the sixth conditioning session. K, Conditioned responding is not increased when stress experience occurs after acquisition of the task. L, Latency to head entry. M, Non-CS tray entries. **p < 0.01.

Figure 3.

Acute stress does not alter dopamine signals in the VMS. A, Voltammetry recordings were taken from the VMS (shaded in cyan). B, Representative color plots of voltammetry recordings during session 3 from a single electrode in a control rat (left) and a stressed rat (right). C, Average dopamine signals across electrodes in control rats (left) and stressed rats (right) during the first, third, and fifth training sessions. The blue bar denotes CS presentation and the gray arrow denotes reward delivery. D, Average CS-evoked dopamine release. Magenta arrows denote restraint stress/control procedure. E, Average US-evoked dopamine release.

Figure 4.

Acute stress selectively enhances US-evoked dopamine signals in the VLS. A, Voltammetry recordings were taken from the VLS (shaded in orange). B, Representative color plots of voltammetry recording during session 3 from a single electrode in a control rat (left) and a stressed rat (right). C, Average dopamine responses across electrodes in control rats (left) and stressed rats (right) during the first, third, and fifth training sessions. The blue bar denotes CS presentation, and the gray arrow denotes reward delivery. D, Average CS-evoked dopamine release does not differ between groups. Magenta arrows denote restraint stress/control procedure. E, Average US-evoked dopamine release is enhanced in stressed rats. **p < 0.01.

Figure 5.

Stress-induced elevation of US-evoked VLS dopamine responses precedes the enhancement of conditioned responding. A, Conditioned responding during the first two training sessions, plotted in 10-trial bins. Conditioned responding was not significantly elevated in stressed rats during session 1. A group difference emerged during session 2. B, US-evoked VLS dopamine signals during sessions 1 and 2, plotted in 10-trial bins. The US-evoked dopamine response in stressed rats was elevated in sessions 1 and 2. *p < 0.05, **p < 0.01.

Figure 6.

VLS dopamine signals are required for conditioning in stressed rats. A, Training paradigm. Rats were stressed once, 20 min prior to the first session. Flupenthixol or vehicle was infused to the VLS before each of the first five training sessions. Training continued for five additional sessions without injections. B, Conditioned responding acquisition was not initially impaired by flupenthixol treatment in control rats, but a delayed deficit emerged with additional training. C, Response latency was not altered by flupenthixol treatment in controls. D, Flupenthixol treatment impaired conditioned responding in stressed rats. E, Flupenthixol treatment reversibly increased the latency in stressed rats. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 7.

Stress shifts the timing of behavioral regulation by VLS dopamine transmission. A, Calculation of response vigor. B, Response vigor was not initially impaired by flupenthixol treatment in control rats, but a delayed deficit emerged in subsequent sessions without drug treatment. C, Response vigor in control rats during session 5 (VLS microinjection of vehicle or flupenthixol) and session 6 (no injection), plotted in 10-trial bins. D, Flupenthixol treatment impairs response vigor in stressed rats. E, Response vigor was impaired in sessions 5 and 6 in stressed rats. *p < 0.05, **p < 0.01, ****p < 0.0001.