Decision letter: Dismantling the Papez circuit for memory in rats

The hippocampus is a seahorse-shaped structure in the brain and its role in memory has been recognized since the 1950s. However, much less is known about two small structures called the mammillary bodies that are found near the hippocampus. These bodies are part of the limbic system—a network of brain regions that also includes the hippocampus and the amygdala—and this system is known to be involved in the regulation of emotion and the formation of long-term memories. In 1937, James Papez injected rabies virus into the hippocampus and, by tracing its movement through the brain, identified a distinct circuit within the limbic system. This circuit, which is today known as Papez’ circuit, consists of projections from the hippocampal formation to the mammillary bodies, and from the mammillary bodies on to another region called the anterior thalamus. From here, projections form a loop via several other regions back to the hippocampus. It is widely thought that the mammillary bodies are required for memory formation due to their role in relaying projections from the hippocampus. However, the mammillary bodies also receive projections from other regions, including Gudden's ventral tegmental nucleus, and it is possible that these could contribute to the role of the mammillary bodies in memory. To distinguish between these possibilities, Seralynne Vann compared the performance of three groups of lesioned rats in tests of spatial short-term memory. The first group had lesions of the hippocampal inputs to the mammillary bodies; the second had lesions of the ventral tegmental inputs to the mammillary bodies; and the third group had lesions of the mammillary body outputs to the thalamus. Vann found that the third group was impaired in the memory tasks, consistent with the idea that outputs sent from the mammillary bodies to the thalamus are required for memory formation. Surprisingly, however, blocking signals sent from the hippocampal formation to the mammillary bodies had little impact on the formation of memories, whereas blocking inputs from Gudden's ventral tegmental nucleus led to significant impairments in memory. By revealing that limbic midbrain inputs to the mammillary bodies have an essential role in the formation of memories, these new results challenge dogma in the field, and highlight the importance of looking beyond the hippocampus when considering memory.