Dopamine Enhances Item Novelty Detection via Hippocampal and Associative Recall via Left Lateral Prefrontal Cortex Mechanisms

Abstract

The involvement of fronto-striatal circuits in item and associative memory retrieval as well as in the stabilization of memories by retrieval practice suggests that both retrieval and re-encoding of stored memories might rely on dopaminergic mechanisms in humans. We tested these hypotheses in a placebo-controlled pharmacological fMRI study using 2 mg of the D2 antagonist haloperidol administered acutely before a cued associative recall task of previously encoded picture-word pairs in 53 healthy humans of both sexes. The cued associative recall was moreover repeated 3 d later outside the scanner without pharmacological intervention. Dopaminergic modulation significantly improved associative recall performance and recognition accuracy of verbal items. Moreover, we observed a significant dopamine effect on re-encoding in terms of increased specificity of associative memories from the first to the second cued associative recall. Better association memory under haloperidol was linked with higher activity in the left lateral prefrontal cortex and right parietal cortex, suggesting that dopamine facilitates associative retrieval through increased recruitment of frontoparietal monitoring processes. In contrast, improved recognition of verbal items under haloperidol was reflected by enhanced novelty detection in the hippocampus and increased activity in saliency networks. Together, these results show distinct but concomitant positive effects of dopamine on associative recall and item recognition and suggest that the specificity of associative recall through re-encoding mechanisms is likewise augmented by dopamine.SIGNIFICANCE STATEMENT Although the neurotransmitter dopamine has been linked with learning and memory for a long time, dopaminergic effects on item recognition in humans were demonstrated only recently. The involvement of fronto-striatal monitoring processes in association retrieval suggests that associative memory might be particularly affected by dopamine. Moreover, fronto-striatal dopaminergic signals have been hypothesized to determine the updating and re-encoding of previously retrieved memories. We here demonstrate clear facilitative effects of dopamine on associative recall and item recognition mediated by prefrontal and hippocampal mechanisms respectively. Additionally, effects on re-encoding were reflected by increased specificity of associative memories. These results augment our understanding of dopaminergic processes in episodic memory retrieval and offer new perspectives on memory impairments in dopamine-related disorders and their treatment.

Keywords: associative memory; episodic memory; fMRI; haloperidol; memory retrieval; re-encoding.

Figure 1.

Cued associative recall task. A, Encoding: memorization of 160 picture–word pairs before drug administration outside of the fMRI scanner with intermittent active baseline. B, Retrieval I: combined association retrieval and word item recognition for 160 old and 120 new words in the fMRI scanner under haloperidol/placebo. C, Retrieval II: self-paced combined association retrieval and word item recognition for 160 old and 120 new words measured behaviorally 3 d after drug administration. ? Indicates word remembered as old but association forgotten; X indicates new word without association.

Figure 2.

Behavioral effects in the haloperidol group (dark gray) and the placebo group (light gray) at Retrieval I (RI) under acute medication and at Retrieval II (RII). A, Item memory: frequencies of hit and CR responses (left), memory discrimination d′ (middle), and response bias c (right). B, Associative memory for item hits: CAM overall (associative hits − associative FAs). C, Re-encoding effects on associative memory specificity: specific (left) and general (right) CAM. D, Scatter plot showing the significant positive relationship between item memory and association memory performance per group at Retrieval I (triangle/circle markers). *p < 0.05, **p < 0.01; ‡ significant group × time × specificity interaction at p < 0.05. Error bars denote SEM.

Figure 3.

Main fMRI effects of retrieval across groups. A, Item memory: retrieval success (left) and item novelty detection (right). B, Associative memory: association retrieval success (left) and reinstatement of face and scene associations (right). All activation maps are thresholded at p < 0.05 (FWE-corrected at cluster-level using a cluster forming threshold at voxel level of p < 0.001).

Figure 4.

Main effect of haloperidol on fMRI activity. A, Haloperidol effect across all trials on brain activity compared with placebo. Note that increased activity in the right dorsal striatum was also present but its extent and height did not pass the FWE-corrected threshold of p < 0.05. The inverse contrast (placebo > haloperidol) revealed no significant activity. All activation maps are thresholded at p < 0.05 (FWE-corrected at cluster-level using a cluster-forming threshold at voxel level of p < 0.001). B, Scatter plot showing the individual striatal activity across all trials in the current associative memory recall task and in the previous recognition memory task (Clos et al., 2019) in the haloperidol (dark gray) and the placebo groups (light gray).

Figure 5.

Effects of haloperidol on fMRI activity in memory retrieval. A, Item memory: higher activity for factual new items under haloperidol compared with placebo (haloperidol [(item CR + item FA) > (item hits + item misses)] > placebo [(item CR + item FA) > (item hits + item misses)]). Right, Beta plot shows hippocampal activity across all item trials for the haloperidol group (dark gray) and the placebo group (light gray). B, Association memory: higher activity for association retrieval success under haloperidol compared with placebo [haloperidol (associative hits > associative misses) > placebo (associative hits > associative misses)]. Right, Beta plot shows differential prefrontal activity for associative hits > associative misses between the haloperidol group (dark gray) and the placebo group (light gray). Note that we plotted the differential activity rather than individual betas because of the many regressors in the model. C, Increased coupling from the left lateral PFC to the right striatum for item hits > item misses for haloperidol compared with placebo. Right, Beta plot shows differential prefrontal–striatal coupling parameter for item hits > item misses between the haloperidol group (dark gray) and the placebo group (light gray). The inverse contrasts (placebo > haloperidol) revealed no significant activity. All activation maps are thresholded at p < 0.05 (warm colors: FWE-corrected at cluster-level using a cluster forming threshold at voxel level of p < 0.001; cold colors: small volume FWE-corrected using anatomical masks).