Cerebellar Interactions with the Anterior Cingulate and Hippocampus During Associative Learning

The cerebellum has traditionally been viewed as a motor structure, but recent research indicates that it contributes to various aspects of cognition, emotion, and social behavior. These non-motor functions are thought to be generated through interactions with forebrain areas such as the prefrontal cortex, amygdala, and hippocampus; however, there has been surprisingly little research on the mechanisms underlying cerebellum- forebrain interactions. We aim to address this gap in knowledge with a systematic analysis of cerebellum- forebrain interactions during learning in rats. We will examine cerebellum-forebrain interactions using trace conditioning. Trace conditioning requires the anterior cingulate (ACC), dorsal hippocampus (HPC), and cerebellum. Moreover, neurons in the ACC, HPC, and cerebellum show learning-related increases in activity during trace conditioning – these neural signatures of learning are not seen in control conditions such as unpaired training. Thus, trace conditioning is an ideal paradigm for investigating the mechanisms underlying cerebellar interactions with the forebrain. The main goal of the current proposal is to leverage the findings of our previous research toward a more comprehensive analysis of cerebellar interactions with the ACC and HPC during learning. Our general hypothesis is that the cerebellum receives inputs from the HPC and ACC and it then sends feedback to these forebrain areas to facilitate learning. We will use multi-site electrophysiology and optogenetics to test this hypothesis. We have extensive experience with these techniques and preliminary data demonstrate feasibility for the proposed experiments. In Aim 1 we will determine the dynamic nature of interactions among the ACC, HPC, and cerebellum during learning using multiple tetrodes to simultaneously record spike and local field potential (LFP) activity from these areas to examine feedforward and feedback interactions during learning. We hypothesize that the cerebellum has bidirectional interactions with the ACC and HPC throughout learning. In Aim 2 we will examine the role of cerebellar projections to the ACC and HPC during learning. We will use optogenetics to manipulate cerebellar output while simultaneously recording neural activity from the ACC and HPC. We hypothesize that cerebellar output to the ACC and HPC during training trials facilitates trace conditioning. In Aim 3 we will determine the role of post-trial cerebellar activity in learning. We hypothesize that the cerebellum sends feedback to the HPC and ACC after training trials, and that the post-trial cerebellar signal facilitates learning by increasing forebrain neural responses to the training stimulus on subsequent trials. To test this hypothesis, we will manipulate cerebellar output with optogenetics in the post-US period while recording spikes and LFPs in the ACC and HPC during learning. The findings from this fundamental science project will provide a clearer understanding of how the cerebellum communicates with forebrain areas. The results may have implications for developing treatments for cognitive deficits associated with neurological disorders and stroke such as stimulation of cerebellar output to the forebrain. Project Number: 1R01NS140098-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: John Freeman (+1 co-PI) | Institution: UNIVERSITY OF IOWA, IOWA CITY, IA | Award Amount: $540,503 | Activity Code: R01 | Study Section: Biobehavioral Regulation, Learning and Ethology Study Section[BRLE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11374726