Sensory experiences during development profoundly influence sensory processing in mature animals. Since most of an animal?s sensory experiences are multimodal, the activity of one sensory modality often causes long-term changes in another modality. Such cross-modal plasticity not only leads to compensation for sensory functions in the case of sensory deprivation, but also allows normal individuals to respond properly to sensory stimuli in their unique habitats or situations and contributes to individual?s differences in the perception of multisensory cues. Despite the importance of cross-modal plasticity, the underlying circuit and molecular mechanisms are poorly understood. In the proposed research, a novel form of cross-modal plasticity has been discovered in Drosophila and developed into a system for studying the underlying mechanisms at the behavioral, circuit, synaptic, and molecular levels. This system allows for comparison of cross-modal and modality-specific plasticity in the same sensory system. A genetic screen has identified novel regulators of cross-modal plasticity. The objective of the proposed research is to identify the mechanisms that underlie cross-modal plasticity in the developing somatosensory system of Drosophila larvae, and provide circuit and molecular models for guiding future studies in other species. The central hypothesis is that gentle mechanosensory inputs during development strengthen serotonergic inhibition of the synaptic transmission from nociceptors to multisensory second-order neurons (MSONs), which is achieved through specific genes in the MSONs. This hypothesis will be tested by identifying the circuit (Aim 1) and molecular (Aim 2) mechanisms that underlie cross-modal plasticity. The proposed research is innovative because it proposes the novel concept of distinct mechanisms that underlie cross-modal and modality-specific plasticity and will use a novel system that is amenable to the use of genetic screens to study cross-modal plasticity. This research is significant because it is expected to: 1) elucidate how cross- modal and modality-specific plasticity co-exist in a developing sensory system and demonstrate the role of neuromodulatory interneurons in establishing cross-modal plasticity during development; 2) identify a novel molecular mechanism that underlies cross-modal plasticity, particularly one that distinguishes it from modality-specific plasticity within the same neural circuit; 3) yield a multidisciplinary, state-of-the-art experimental system for identifying the principles that govern the experience--dependent assembly of neural circuits for multisensory integration. Moreover, because a common problem of many neurodevelopmental disorders is dysregulated multisensory integration, the proposed study will offer insights into the pathogenesis of these disorders.