Serotonergic modulation of nucleus reuniens in affective and cognitive behaviors

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PROJECT SUMMARY The nucleus reuniens (RE) of the ventral midline thalamus sits as the nonpareil nexus of prefrontal-hippocampal communication. While RE selectively directs its output to cortical limbic targets including the hippocampus (HF) and orbitomedial prefrontal cortex (PFC), RE receives a diverse array of inputs, including a dense supply of serotonergic (5- HT) fibers from the dorsal (DR) and median (MR) raphe nuclei. While DR and MR form two distinct essentially nonoverlapping 5-HT pathways, RE serves as a key site of convergence as MR and DR both distribute heavily to the midline thalamus. While RE's interactions with PFCàHF circuitry have been linked to cognitive behaviors, virtually nothing is known regarding the neuromodulatory role of 5-HT in RE. With the present proposal, we intend to continue our investigation of RE by utilizing pharmacological and chemogenetic approaches in conjunction with behavioral testing to elucidate how 5-HT modulation of RE participates in affective, mnemonic, and executive functioning. We hypothesize that 5-HT influence of RE is essential to flexible behavior and quelling 5-HT input to RE will increase avoidance behavior and impair executive measures, with each of these behaviors recruiting specific raphe pathways. We will utilize a comprehensive battery of validated rat behavioral assays to assess: 1.) anxiety/avoidance behavior using an open field and elevated plus maze paradigm; 2.) spatial working memory and behavioral flexibility using a delayed nonmatch to sample t-maze paradigm; 3.) and attention and behavioral flexibility using an odor tactile attentional set shifting task. First in Aim 1, we will examine how 5-HT availability in RE affects behavior by locally depleting 5-HT using the neurotoxin 5,7- dihydroxytryptamine. In Aim 2a, we will examine the distinct contributions of DR and MR on RE on behavior by using the inhibitory hM4D DREADD receptor to selectively suppress raphe-RE terminals. In Aim 2b, we will use a TPH2-Cre rat model in combination with DREADD technology to selectively inhibit serotoninergic projections from DR or MR to RE. These aims will be the first to outline the specific contributions of 5-HT input to RE on behavior. These results will provide important information on how raphe-thalamic circuitry contributes to emotional and cognitive functioning and importantly how alterations of this system impact this symptomology in depression, anxiety, and other neuropsychiatric disorders.