This is a collaborative international project with the laboratory of Anthony Holtmaat (University of Geneva, Switzerland), funded by the Weave cross-European initiative. The project is at the interface of the expertise of the De Wit lab (molecular mechanisms of synaptic connectivity) and of the Holtmaat lab (synaptic integration of sensory input and context in cortical circuits). The project will unravel molecular mechanisms of synaptic specificity in cortical and thalamocortical circuits. Our recent work has shown that higher-order thalamocortical inputs and cortical inputs to pyramidal neurons in the somatosensory cortex display striking differences in their synaptic properties, even when intermingled on the same cortical dendrite. This project will explore the molecular mechanisms that mediate this specificity and test how these regulate structure and function of higher-order thalamocortical inputs in cortical circuits. The applicant will use a broad array of technologies including super-resolution imaging, CRISPR/Cas9 gene editing, viral vectors, conditional knockout mice, optogenetics, and in vivo imaging.

In highly volatile environments, performing actions that address current needs and desires is an ongoing challenge for living organisms. For example, the predictive value of environmental signals needs to be updated when predicted and actual outcomes differ. Furthermore, organisms also need to gain control over the environment through actions that are expected to produce specific outcomes. The data to be presented will show that these processes are highly reliant on thalamocortical circuits wherein thalamic nuclei make a critical contribution to adaptive decision-making, challenging the view that the thalamus only acts as a relay station for the cortical stage. Over the past few years, our work has highlighted the specific contribution of multiple thalamic nuclei in the ability to update the predictive link between events or the causal link between actions and their outcomes via the combination of targeted thalamic interventions (lesion, chemogenetics, disconnections) with behavioral procedures rooted in experimental psychology. We argue that several features of thalamocortical architecture are consistent with a prominent role for thalamic nuclei in shaping mental representations.