Distinct alterations in cerebellar connectivity with substantia nigra and ventral tegmental area in Parkinson's disease.

In Parkinson's disease (PD), neurodegeneration of dopaminergic neurons occurs in the midbrain, specifically targeting the substantia nigra (SN), while leaving the ventral tegmental area (VTA) relatively spared in early phases of the disease. Although the SN and VTA are known to be functionally dissociable in healthy adults, it remains unclear how this dissociation is altered in PD. To examine this issue, we performed a whole-brain analysis to compare functional connectivity in PD to healthy adults using resting-state functional magnetic resonance imaging (rs-fMRI) data compiled from three independent datasets. Our analysis showed that across the sample, the SN had greater connectivity with the precuneus, anterior cingulate gyrus, and areas of the occipital cortex, partially replicating our previous work in healthy young adults. Notably, we also found that, in PD, VTA-right cerebellum connectivity was higher than SN-right cerebellum connectivity, whereas the opposite trend occurred in healthy controls. This double dissociation may reflect a compensatory role of the cerebellum in PD and could provide a potential target for future study and treatment.

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

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.