Despite decades of research, the neural mechanisms of working memory, the ability to hold information over a temporal delay to guide goal-directed behavior, remain poorly understood. Although oscillatory synchrony between the hippocampus (HC) and the prefrontal cortex (PFC) is known to increase in situations of high working memory demand, the mechanisms and circuitry supporting HC-PFC interactions during working memory is unknown. The midline thalamic nucleus reuniens (RE) is reciprocally connected to both the HC and the PFC and has been shown to be critical for working memory tasks. Therefore, the guiding hypothesis of the current proposal is that HC-PFC oscillatory synchrony is regulated by the RE. If this hypothesis is true, when working memory demand is high, RE should drive HC-PFC oscillatory synchrony, giving rise to relatively higher HC-PFC theta coherence and stronger PFC phase-locking to the hippocampal theta rhythm. Similarly, suppression of RE activity should yield reduced HC-PFC oscillatory synchrony and lead to working memory impairments. We have shown that hippocampal neurons exhibit different patterns of spatial coding in response to manipulation of working memory demand. New published data from our lab demonstrate that RE inactivation selectively impairs a working memory task, leaving a very similar, but non-working memory, task unchanged. Additional preliminary data show that HC-PFC oscillatory synchrony is also modulated by working memory demand. The proposed studies will use a combination of electrophysiological methods, bidirectional optogenetic manipulation of neuronal excitation, and behavior to address the following questions (1) Does RE inactivation reduce hippocampal-PFC synchrony and concomitantly impair working memory? (2) Does RE activation increase HC-PFC synchrony and concomitantly improve working memory? (3) Does RE show increased oscillatory synchrony with the HC and PFC during working memory task performance? If funded, the proposed work will have a significant impact on memory research and on the field of neuroscience by advancing the basic understanding of the circuit-level interactions between the HC, RE and PFC. More broadly, the proposal will advance the understanding of the neural mechanisms underlying working memory by uncovering the mechanisms underlying HC-PFC oscillatory synchrony. Moreover, by pioneering RE recordings during memory-guided behavior, we will not only characterize RE behavioral correlates for the first time, but also identify the role of the RE in regulating functinal interactions between the HC and the PFC. Finally, we will be the first to use optogenetic methods to manipulate the activity of the RE and measure the effects on memory-guided behavior as well as on HC-PFC synchrony. Although optogenetic methods are becoming more widely used, the studies proposed here will advance the use of this state-of-the-art technique as a tool for understanding circuits and mechanisms underlying higher cognitive functions.
Neuropsychiatric disorders such as schizophrenia, major depressive disorder and generalized anxiety disorder share the common problem of impairments in working memory, the ability to actively maintain and flexibly update goal or task-relevant information. These impairments are likely due to structural and functional changes in the hippocampus and the prefrontal cortex, which result in dysfunctional hippocampal- prefrontal interactions. The proposed work will lead to a better understanding of the relationship between working memory and hippocampal-prefrontal interactions and could lead to the development of therapeutic approaches that improve working memory by finding ways to enhance hippocampal-prefrontal communication.