Individual animals differ in traits and preferences. These differences shape their interactions, their prospects for survival, their susceptibility to diseases but also their response to drugs or treatments modulating neural circuits. While there are some evidences that neurogenesis or neuromodulation play a role in the process of individuation, both circuit and molecular-level understandings of this phenomenon are lacking. Determining the neuronal substrate of our individuality and how it is shaped during adulthood is a major frontier in neurosciences and the focus of this proposal. It aims at deciphering neural circuits involved in individuation and to question whether long-range connectivity in the adult brain is stable or subject to structural modifications depending on individual performance. To disentangle the social, environmental or stochastic causes of the individuation process, we use two complementary behavioural assays. These aims discriminate mice based on individual behaviour and to study the mechanisms responsible for these differences at a circuit and molecular levels. The first of these assays will take advantage of our recently developed system “Souris-City” (SC), a large environment where animals live together and perform self-initiated cognitive tests in isolation. This system tracks social and cognitive activities over very long periods of time at the resolution of individual mice, enabling the assessment of individual traits and strategies. On the other hand, we will use nest building behaviour as a complementary scalable assay. Mice build nests naturally in a laboratory setting and the time they invest on this task varies from mouse to mouse. Because of the quantitative outcome, ease of implementation and non-obligatory nature of the task, nesting is an ideal model to study how brain circuits integrate many cues to freely engage in a complex task, but also how neuronal plasticity can introduce individual variations in the engagement in this behaviour. Overall three complementary goals will be addressed. - We will characterize neural networks associated with these two specific behaviours and seek to identify the substrates differentiating the brains of two individuals at the level of the long-range connectivity in the key circuits controlling these behaviours. - We will explore the idea that adult plasticity can be a source of behavioural variability leading to individuation. We will combine next-generation whole brain imaging methods with RNA-sequencing of the neurons involved in variable behaviours. This will shed a light on whether variations in the transcriptome of these neurons point to molecular changes affecting their excitability, synaptic transmission or structural connectivity. - Finally, in the “Souris-City” we will build a predictive model of nicotine addiction based on the interface of precise, automated behaviour recordings, whole brain activity mapping and axonal tracing of key circuits involved in nicotine response. This will determine which individual differences in neural structures could underlie different susceptibilities to nicotine. Our work program spans technological development, automated behavioural analyses, electrophysiology, projection mapping and activity-dependent transcriptome analysis in mouse. Each member of this consortium brings unique complementary areas of technical expertise as well as converging theoretical interests to generate data that support a Systems Biology approach to understanding the mechanisms of individuation. This approach challenges the classical view that brain circuits are rigids after the closing of the developmental embryonic and post-natal critical windows, and puts forward alternative ways mouse models for neuropsychiatric disorders are phenotyped and facilitate screening for novel treatment strategies.