Alteration of one sensory system can have striking effects on the processing and organization of the remaining senses, a phenomenon known as cross-modal plasticity. The goal of this thesis was to understand the circuit basis of this form of plasticity. I established the mouse as a model system for studying cross-modal plasticity by comparing population activity in visual cortex between animals reared in complete darkness from birth (DR) to those housed in a normal light/dark environment (LR). I found that secondary visual cortex (V2L) responds much more strongly to auditory stimuli in DR than LR. I provide evidence that there is a sensitive period for cross-modal responses that ends in early adulthood. I also show that exposure to light later in life reduces V2L auditory activity to LR levels. I recorded single units to show that there is a higher percentage of auditory responsive neurons in DR V2L. In collaboration with Lia Min in Michela Fagiolini’s laboratory, we discovered that this was associated with an increase in the number of projections from auditory thalamus and auditory cortex. We also provide evidence that V2L is multimodal from birth and becomes less so with visual experience. I examined several molecular pathways that are affected by dark-rearing to see if they are involved in cross-modal plasticity. I found that Nogo receptor (NgR), Lynx1, and Icam5 signaling all play a fundamental role in controlling the duration of plasticity. I also show that the hyperconnectivity in NgR -/- and DR mice leads to an increase in multisensory enhancement. In primary visual cortex, cross-modal influences were much weaker. Similar to V2L, the distribution of cell types was affected by NgR signaling. I also found that both the range of cross-modal influence and its sign (excitatory or inhibitory) is dependent on visual experience. Finally, I show that NgR signaling and the maturation of inhibitory circuits affect these two properties. Together, these results provide evidence of the molecular mechanisms underlying cross-modal plasticity. We believe that this will further our knowledge of how to improve rehabilitation strategies after loss of a sensory system.

Our ability to learn relies on the potential of neuronal networks to change through experience. The primary visual cortex (V1) has become a popular system for studying how experience shapes cortical neuronal networks. Experience-dependent plasticity in V1 has been extensively studied in young animals, revealing that experiences in early postnatal life substantially shape neuronal activity in the developing cortex. In contrast, less is known about how experiences modify the representation of visual stimuli in the adult brain. In addition, adult experience-dependent plasticity remains largely unexplored in neurodevelopmental disorders. To address this issue, we established a two-photon calcium imaging set-up, suitable for chronic imaging of neuronal activity in awake-behaving mice. We implemented protocols for the reliable expression of genetically encoded calcium indicators (GCaMP6), for the implantation of a chronic cranial window and for the analysis of chronic calcium imaging data. This approach enables us to monitor the activity of hundreds of neurons across days, and up to 4-5 weeks. We used this technique to determine whether the daily exposure to high-contrast gratings would induce experience-dependent changes in V1 neuronal activity. We monitored the activity of putative excitatory neurons and of three non-overlapping populations of inhibitory interneurons in layer 2/3 of adult mice freely running on a cylindrical treadmill. We compared the results obtained from mice that were exposed daily to either a high-contrast grating or to a grey screen and characterized their neuronal response properties. Our results did not reveal significant differences in neuronal properties between these two groups, suggesting a lack of stimulus-specific plasticity in our experimental conditions. However, we did observe and characterize, in both groups, a wide range of activity changes in individual cells over time. We finally applied the same method to investigate impairments in experience-dependent plasticity in a mouse model of intellectual disability (ID), caused by synaptic GTPase-activating protein (SynGAP) haploinsufficiency. SynGAP haploinsufficiency is a common de novo genetic cause of non-syndromic ID and is considered a Type1 risk for autism spectrum disorders. While the impact of Syngap gene mutations has been thoroughly studied at the molecular and cellular levels, neuronal network deficits in vivo remain largely unexplored. In this study, we compared in vivo neuronal activity before and after monocular deprivation in adult mutant mice and littermate controls. These results revealed differences in baseline network activity between both experimental groups. These impairments in cortical neuronal network activity may underlie sensory and cognitive deficits in patients with Syngap gene mutations.