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In mammals, the selective transformation of transient experience into stored memory occurs in the hippocampus, which develops representations of specific events in the context in which they occur. In this talk, I will focus on the development of hippocampal circuits and the self-organized dynamics embedded in them since the latter critically support the role of the hippocampus in memory. I will discuss evidence that adult hippocampal cells and circuits are remarkably sculpted by development, as early as embryonic neurogenesis. We argue that these primary developmental programs provide a scaffold onto which later experience of the external world can be grafted. Next, I will present data on the emergence of recurrent connectivity and self-organized dynamics in hippocampal circuits and outline the critical turn points and discontinuities in that developmental journey.

Our research team runs several related projects studying the cellular and molecular mechanisms involved in the development of axonal connections in the brain. In particular, our aim is to uncover the principles underlying thalamocortical axonal wiring, maintenance and ultimately the rewiring of connections, through an integrated and innovative experimental programme. The development of the thalamocortical wiring requires a precise topographical sorting of its connections. Each thalamic nucleus receives specific sensory information from the environment and projects topographically to its corresponding cortical. A second level of organization is achieved within each area, where thalamocortical connections display an intra-areal topographical organization, allowing the generation of accurate spatial representations within each cortical area. Therefore, the level of organization and specificity of the thalamocortical projections is much more complex than other projection systems in the CNS. The central hypothesis of our laboratory is that thalamocortical input influences and maintains the functional architecture of the sensory cortices. We also believe that rewiring and plasticity events can be triggered by activity-dependent mechanisms in the thalamus. Three major questions are been focused in the laboratory: i) the role of spontaneous patterns of activity in thalamocortical wiring and cortical development, ii) the role of the thalamus and its connectivity in the neuroplastic cortical changes following sensory deprivation, and iii) reprogramming thalamic cells for sensory circuit restoration. Within these projects we are using several experimental programmes, these include: optical imaging, manipulation of gene expression in vivo, cell and molecular biology, biochemistry, cell culture, sensory deprivation paradigms and electrophysiology. The results derived from our investigations will contribute to our understating of how reprogramming of cortical wiring takes place following brain damage and how cortical structure is maintained.

The concerted production of the correct number and diversity of neurons and glia by neural stem cells is essential for intricate neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. We recently performed a clonal analysis by exploiting the genetic MADM (Mosaic Analysis with Double Markers) technology and discovered a high degree of non-stochasticity and thus deterministic mode of RGP behaviour. However, the cellular and molecular mechanisms controlling RGP lineage progression remain unknown. To this end we use quantitative MADM-based genetic paradigms at single cell resolution to define the cell-autonomous functions of signaling pathways controlling cortical neuron/glia genesis and postnatal stem cell behaviour in health and disease. Here I will outline our current understanding of the mechanistic framework instructing neural stem cell lineage progression and discuss new data about the role of genomic imprinting – an epigenetic phenomenon - in cortical development.

The human brain, in particular the cerebral cortex, has undergone rapid expansion and increased complexity during recent evolution. One striking feature of human corticogenesis is that it is highly protracted in time, from prenatal stages of neurogenesis (taking months instead of days in the mouse), to postnatal stages of neuronal maturation and circuit formation (taking years instead of weeks in the mouse). This prolonged development is thought to contribute in an important fashion to increased cortical size, but also enhanced circuit complexity and plasticity. Here we will discuss how the species-specific temporal patterning of corticogenesis is largely intrinsic to cortical progenitors and neurons, and involves human-specific genes and cell properties that underlie human brain evolution, as well as our selective sensitivity to certain brain diseases.