VTA and Anterior Hippocampus Target Dissociable Neocortical Networks for Post-Novelty Enhancements

Abstract

The detection of novelty indicates changes in the environment and the need to update existing representations. In response to novelty, interactions across the VTA-hippocampal circuit support experience-dependent plasticity in the hippocampus. While theories have broadly suggested plasticity-related changes are also instantiated in the cortex, research has also shown evidence for functional heterogeneity in cortical networks. It therefore remains unclear how the hippocampal-VTA circuit engages cortical networks, and whether novelty targets specific cortical regions or diffuse, large-scale cortical networks. To adjudicate the role of the VTA and hippocampus in cortical network plasticity, we used fMRI to compare resting-state functional coupling before and following exposure to novel scene images in human subjects of both sexes. Functional coupling between right anterior hippocampus and VTA was enhanced following novelty exposure. However, we also found evidence for a double dissociation, with anterior hippocampus and VTA showing distinct patterns of post-novelty functional coupling enhancements, targeting task-relevant regions versus large-scale networks, respectively. Further, significant correlations between these networks and the novelty-related plasticity in the anterior hippocampal-VTA functional network suggest that the central hippocampal-VTA network may facilitate the interactions with the cortex. These findings support an extended model of novelty-induced plasticity, in which novelty elicits plasticity-related changes in both local and global cortical networks.SIGNIFICANCE STATEMENT Novelty detection is critical for adaptive behavior, signaling the need to update existing representations. By engaging the bidirectional hippocampal-VTA circuit, novelty has been shown to induce plasticity-related changes in the hippocampus. However, it remains an open question how novelty targets such plasticity-related changes in cortical networks. We show that anterior hippocampus and VTA target cortical networks at different spatial scales, with respective enhancements in post-novelty functional coupling with a task-relevant cortical region and a large-scale memory network. The results presented here support an extended model of novelty-related plasticity, in which engaging the anterior hippocampal-VTA circuit through novelty exposure propagates cortical plasticity through hippocampal and VTA functional pathways at distinct scales, targeting specific or diffuse cortical networks.

Keywords: VTA; cortex; fMRI; functional coupling; hippocampus; novelty.

Figure 1.

Experiment design. In the first phase of the experiment, participants were familiarized with scene images during a continuous recognition task. In the scanner, participants first underwent a baseline resting-state scan (pre-novelty rest), followed by the novelty-exposure phase, in which novel scene images were presented intermixed with the familiar images while participants completed a target detection task. Immediately following this task, participants completed a second, post-novelty, resting-state scan.

Figure 2.

Changes in resting-state functional coupling between right hippocampus and VTA. a, Right anterior hippocampal-VTA functional coupling is significantly greater during the post-task rest scan (dark blue) compared with the pre-task baseline (light blue), whereas posterior hippocampal-VTA functional coupling did not significantly change following novelty exposure. Error bars indicate SEM. b, The change in right anterior hippocampal-VTA functional coupling (post-task minus pre-task) marginally correlates with univariate activation in right anterior hippocampus during novel task trials, but not familiar or target trials during the task. All plots: Black dots represent individual participants. Gray ribbon represents 95% CIs.

Figure 3.

Dissociation in novelty-related plasticity in functional coupling of anterior hippocampus and VTA with cortical network targets. a, Comparing changes in anterior hippocampal (left) and VTA (right) functional coupling with the task-relevant PhC region following novelty exposure yielded a significant Seed × Session interaction effect, driven by a significant post-task enhancement only for anterior hippocampal-PhC functional coupling, with no significant change in VTA-PhC functional coupling between the pre- and post-task scans. Error bars indicate SEM. b, In contrast, VTA-PMAT functional coupling showed a post-novelty enhancement compared with pre-task baseline, but there was no significant change in anterior hippocampal-PMAT functional coupling, driving the significant Seed × Session interaction effect.

Figure 4.

Change in functional coupling between VTA and AT and PM cortical networks. VTA showed significant post-task enhancements in functional coupling with the regions of the AT network (left). While only marginally significant, VTA-PM functional coupling showed a similar pattern (right), suggesting that the VTA targets a relatively diffuse set of memory-related regions for plasticity-related changes. Error bars indicate SEM.

Figure 5.

Pairwise change in functional coupling between PMAT regions with VTA and anterior hippocampus. a, Visualizing the change in functional coupling following novelty exposure (post-/pre-task) between VTA and all regions included in the PMAT networks illustrates the widespread nature of these effects. The majority of regions show positive difference scores, indicating greater post-task functional coupling with VTA compared with the pre-task measure. b, In contrast, in the bottom two graphs, the visualization of the post-/pre-task change in functional coupling between anterior hippocampus with all regions included in the PMAT networks shows a variable pattern of effects. Unlike with VTA, only a few regions show positive values, confirming that anterior hippocampus does not seem to target widespread regions for novelty-related functional coupling enhancements. These graphs were used only for visualization purposes, and no statistical tests were calculated on these values.

Figure 6.

Relationship between anterior hippocampal-VTA functional coupling and coupling changes in cortical networks. a, The change in right anterior hippocampal-VTA functional coupling (post- minus pre-task) positively correlates with the changes in functional coupling between both right anterior hippocampal-PhC (left) and VTA-PMAT networks (right), suggesting that the extent of novelty-related enhancements in the central anterior hippocampal-VTA circuit is related to the changes between anterior hippocampus and VTA and their respective cortical target networks. b, In contrast, the change in anterior hippocampal-VTA functional coupling did not significantly correlate with the change in either anterior hippocampal-PMAT functional coupling (left) or VTA-PhC functional coupling (right). These networks did not show experience-dependent coupling enhancements, suggesting that these results may be in line with the scale of cortical networks targeted by the anterior hippocampus and VTA. All plots: Black dots represent individual participants. Gray ribbon represents 95% CIs.

Figure 7.

Univariate activation in ROIs. BOLD signal was differentially modulated during novel, familiar, and target trials depending on the ROI. In right anterior hippocampus, PhC, and PMAT regions, univariate activation during novel and familiar trials was significantly greater than target trials. However, univariate activation in VTA was greater during target trials than novel or familiar trials. Only PhC showed significantly greater univariate activation during novel trials than familiar trials, consistent with the sensitivity of this region to novelty. Error bars indicate SEM.

Figure 8.

Schematic model illustrating plasticity-related network changes resulting from novelty exposure. In this model integrating the current results with prior literature, the anterior hippocampus and VTA form a bidirectional circuit (top row) in which the hippocampus responds to novelty in the environment and activates the VTA to release dopamine, in turn enhancing hippocampal LTP. Engaging the VTA-hippocampal circuit also facilitates plasticity-dependent changes in cortical networks, with each region influencing the cortex at distinct scales: anterior hippocampus targets task-relevant sensory regions (bottom left) while VTA targets large-scale memory networks (bottom right). Plasticity-related changes in these local and global networks may contribute to the diverse behavioral outcomes evoked by novelty exposure, including specific memory reactivation and information processing across diffuse regions, respectively. Together, this expanded model illustrates how novelty influences neural networks, shedding light on the differential contributions of the anterior hippocampus and VTA in propagating cortical network plasticity.