Step into the world of Valentina Emiliani, a visionary researcher who’s reshaping neuroscience with light. As a leading mind at the Vision Institute in Paris, Emiliani pioneers the fusion of optogenetics and advanced optics, unleashing unprecedented precision in neural circuit manipulation. Discover her journey from Italy to Paris, and how her interdisciplinary approach is unlocking the secrets of the brain. Join us as we explore how Emiliani’s innovative techniques are revolutionising brain research and propelling us into a new era of understanding brain function and behaviour.

Which wall does your research break?

The combination of wavefront shaping and optogenetics, that I pioneered with my lab, breaks the wall of conventional limitations in neural circuit manipulation.
Optogenetics, as a cutting-edge technique, has revolutionized our understanding of the brain by utilizing light-sensitive opsins to precisely control neural activity with cell type specificity. The genetic engineering of these opsins into specific neurons enables researchers to activate or inhibit their function using precisely timed light pulses. To date, optogenetics has provided invaluable insights into the intricate workings of the brain, shedding light on the roles of different neural types in behaviour, cognition, and neurological disorders. Conventional optogenetics uses bulk illumination methods where visible light is used to activate or inhibit a relatively broad area, affecting multiple neurons simultaneously. The consequent lack of precise control over neural activity in space and time limits the study of complex neural circuits and understanding of specific spatiotemporal patterns’ contributions to brain function. The combination of wavefront shaping approaches, such as computer-generated holography, generalized phase contrast, and temporal focusing with two-photon microscopy, that we proposed almost 15 years ago, has shattered these conventional barriers. By sculpting tailored light patterns, researchers can now target and control the activity of individual neurons or specific cell populations within complex circuits with unprecedented spatiotemporal precision.
Despite being a relatively nascent technology, the combination of these approaches has already enabled significant discoveries in neuroscience. To name a few, the single-cell precision of two-photon optogenetics has allowed for the first time the observation of how hub cells orchestrate network bursts in the intact mouse brain. The capability to holographically control selected ensembles of neurons has enabled for the first time in vivo high-throughput connectivity mapping of 100s cells in the mouse cortex. Combining holographic optogenetics with behavioural assays has revealed how the activation of a few cells can bias behavior by triggering the activity of precisely defined ensembles in mice. Sequential projection of multiple holographic patterns at variable time intervals in the mouse olfactory bulb has also provided insights into how perceptual responses in mice depend on both the specific group of cells and the number of cells activated and their relative activation.
As holographic optogenetics continues to evolve, it holds the potential to unlock new frontiers in neuroscience research, providing deeper insights into brain function, and offering promising avenues for advancements in brain research.

What inspired or motivated you to work on your current research or project?

Since a young age, my fascination with optics and microscopy has shaped my academic journey. During my Ph.D. at the European Laboratory for Non-linear Spectroscopy (LENS) in Florence and later during a postdoc at the Max Born Institute, Berlin, I focused on exploring the optical properties of quantum confined systems. Inspired by these experiences, I returned to Italy in 2000 and established the “High resolution microscopy” group at LENS. During that time, discoveries like the green fluorescent proteins opened up new possibilities for fluorescence microscopy in life sciences, inspiring me to investigate the mysteries of living matter using optics. For personal reasons, I moved to Paris shortly after. Taking advantage of this change, I continued my journey towards reorienting my research towards the interface between physics and biology by joining the Jacque Monod Institute. There, I worked on a project that used fluorescence microscopy to track specific proteins at cell adhesion contacts, employing holographic optical tweezers to mimic cell/substrate interactions. As I delved deeper into the world of light and life science, my horizons expanded through attending lectures and conferences, including those at the Imaging and function of the nervous system annual school in Cold Spring Harbor Laboratory. It was during one such school that I discovered the captivating concept of “uncaging” an ingenious approach that allows to control neuronal signals by photo-uncaging “caged” active molecules. Motivated by the potential of holography for shaping neuronal signals, I proposed a research project on holographic uncaging at the European Competition of Young Investigators (EURYI). With the prestigious EURY award, I established my research group, “Wavefront Engineering Microscopy,” at Paris Descartes University in 2006. During the same period, optogenetics emerged as a transformative approach for neuroscience. The impact of my approaches combined with optogenetics to neuronal circuits investigation became then even more evident, giving rise to what I termed ‘circuits optogenetics’ enabling precise control of single and defined cell assemblies within millimetre-cubed volumes with cellular resolution and millisecond temporal precision. Beyond the scientific motivation, another significant driving force behind many of my professional choices has been to support and enable interdisciplinary research, where physicists, biologists, engineers, and biophysicists can work together synergistically in the same group. Pursuing this path has often encountered institutional and cultural barriers, but I firmly believe that it remains an essential and necessary choice to achieve a deeper understanding of the brain’s functioning – an understanding that cannot be limited by disciplinary boundaries.

In what ways does society benefit from your research?

The technique of circuits optogenetics has the potential to significantly impact various aspects of society, from enhancing our understanding of the human brain and its functioning to improving healthcare. Specifically, understanding how neural circuits function and interact using animal models and circuits optogenetics is essential for improving our understanding of the human brain’s complexities and potentially advancing our knowledge of brain-related diseases and disorders. The insights gained from precise optical manipulation of neural circuits can also lead to advancements in medical treatments. For instance, understanding how specific circuits are involved in certain diseases may open up new avenues for targeted therapies and precision medicine for conditions like epilepsy, Parkinson’s disease, and mental health disorders. Progress in understanding and manipulating neural circuits could pave the way for more advanced brain-machine interfaces. These interfaces allow direct communication between the brain and external devices, benefiting individuals with physical disabilities by enabling them to control prosthetics, computers, or other devices using their thoughts. In this framework, circuits optogenetics can guide us in generating activity patterns that closely mimic physiological conditions as much as possible. In the realm of vision restoration, a recent breakthrough has demonstrated partial vision restoration in humans using engineered goggle technology, enabling the projection of elementary patterns into retinal ganglion cells using a light-emitting diode light source projected onto an array of individually switchable micromirrors mounted on the goggles. Achieving high-resolution vision restoration necessitates now more sophisticated approaches capable of converting real scenes into corresponding physiological activity patterns in photoreceptors, retinal ganglion cells or inner retina layers. To this end, simple geometrical transformations can be achieved through the implementation of thin meta-surface optical lenses, offering basic conversion capabilities. For more intricate conversions, sophisticated holographic patterning approaches might become the solution.

Further information

3. Valentina Emiliani – Neurophotonics: reading and writing neuronal activity at the relevant spatiotemporal scales
4. Médaille d’Argent 2021 – Valentina Emiliani, chercheuse en physique
5. Valentina Emiliani – All-optical interrogation of brain circuits –
6. Circuit Optogenetics by the Emiliani Lab;

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