The hippocampal-medial prefrontal circuit has been shown to serve a critical role in decision making and goal directed actions. While the hippocampus (HF) exerts a direct influence on the medial prefrontal cortex (mPFC), there are no direct return projections from the mPFC to the HF. The nucleus reuniens (RE) of the midline thalamus is strongly reciprocally connected with the HF and mPFC and represents the major link between these structures. We investigated the role of RE in functions associated with the hippocampus and the mPFC -- or their interactions. Using two different inactivation techniques (pharmacological and chemogenetic), we sought to further define the role of RE in spatial working memory (SWM) and behavioral flexibility using a modified delayed non-match to sample (DNMS) working memory task. We found that the reversible inactivation of RE with muscimol critically impaired SWM performance, abolished well-established spatial strategies and produced a profound inability to correct non-rewarded, incorrect choices on the T-maze (perseverative responding). We observed similar impairments in SWM following the chemogenetic (DREADDs) inactivation of RE or selective RE projections to the ventral HF. In addition, we showed that the inhibition of RE terminals to the dorsal or ventral HF altered task related behaviors by increasing or decreasing the time to initiate the task or reach the reward, respectively. Finally, we examined discharge properties of RE cells across sleep-wake states in behaving rats. We found that the majority of RE cells discharge at high rates of activity in waking and REM and at significantly reduced rates in SWS, with a subpopulation firing rhythmically in bursts during SWS. We identified five distinct subtypes of RE cells that discharged differently across vigilant states; those firing at highest rates in waking (W1, W2), in REM sleep (R1, R2) and SWS (S1). Given the differential patterns of activity of these cells, we proposed they may serve distinct functions in waking – and possibly in SWS/REM sleep. In sum, our findings indicate that RE is critically involved in mnemonic and executive functions and the heterogeneous activity of these cells support a role for RE in arousal/attention, spatial working memory and cognition. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection