Project Summary. Most neuropsychiatric disorders have developmental origins. Such developmental vulnerability is often restricted to sensitive periods, but affected behaviors, modulating factors, and underlying mechanisms are scarcely understood. We have identified an early postnatal 5-HT-sensitive period in mice that affects adult anxiety/depression-related behaviors and cognitive function. Altered adult behaviors are associated with reduced 5-HTergic activity in this mouse model, but it remains unknown if a causal relationship exists. In wildtype mice, it is well established that 5-HT signaling modulates anxiety and depression-related behaviors and cognitive function. But also here, mechanistic insight at the level of 5-HTergic circuitry remains superficial. Hence, in the context of understanding normal brain function as well as developmental vulnerability, we view it as critical to understand the role of 5-HT input into postsynaptic circuits and its relationship with behavior. We furthermore believe that such insight into circuit function is needed to improve diagnosis and treatment strategies for neuropsychiatric disorders. Our proposal focuses on studying 5-HTergic input into the hippocampus. We study the hippocampus, because it receives dense 5-HTergic innervation from raphé nuclei, and it mediates and modulates emotional behaviors and cognitive function. Through optogenetics and in vivo calcium-photometry, we will directly investigate the relationship between 5-HTergic neurotransmission in CA1 and spatial memory and anxiety. We focus on CA1, because it is the converging point and the output region of the direct and indirect pathway within the hippocampus. We study the dorsal and ventral CA1 separately, because of their hypothesized differential role in cognitive and emotional function. Our research will impact the understanding of the pathophysiology in depression/anxiety and cognitive impairment. Importantly our research will likewise impact our understanding of how to treat these same conditions. Our preliminary data suggest that increased 5-HTergic signaling during development leads to reduced 5-HTergic neuronal activity in adulthood, which in turn causes behavioral inhibition/anxiety and cognitive impairment. Conversely, increasing 5-HTergic activity through optogenetic means reverses at least some cognitive impairment. These findings already indicate that the firing rate of 5-HTergic neurons might be a promising biological target for the treatment of anxiety and depression related symptomatology. We already identified the 5-HT receptor within the hippocampus that relays the 5-HTergic signal to the postsynaptic circuitry to improve learning and memory. This receptor might be an interesting molecular target for drug development. Clearly, more research is needed to increase confidence in such ideas. However, we believe these examples provide strong evidence that the novel insight our studies will provide could in fact lead to improved d...