Understanding how values of different options that lead to choice are represented in the brain is a basic scientific question with far reaching implications. I recently showed that by the mere-association of a cue and a button press we could influence preferences of snack food items up to two months following a single training session lasting less than an hour. This novel behavioural change manipulation cannot be explained by any of the current learning theories, as external reinforcement was not used in the process, nor was the context of the decision changed. Current choice theories focus on goal directed behaviours where the value of the outcome guides choice, versus habit-based behaviours where an action is repeated up to the point that the value of the outcome no longer guides choice. However, in this novel task training via the involvement of low-level visual, auditory and motor mechanisms influenced high-level choice behaviour. Thus, the far-reaching goal of this project is to study the mechanism, by which low-level sensory, perceptual and motor neural processes underlie value representation and change in the human brain even in the absence of external reinforcement. I will use behavioural, eye-gaze and functional MRI experiments to test how low-level features influence the neural representation of value. I will then test how they interact with the known striatal representation of reinforced behavioural change, which has been the main focus of research thus far. Finally, I will address the basic question of dynamic neural plasticity and if neural signatures during training predict long term success of sustained behavioural change. This research aims at a paradigmatic shift in the field of learning and decision-making, leading to the development of novel interventions with potential societal impact of helping those suffering from health-injuring behaviours such as addictions, eating or mood disorders, all in need of a long lasting behavioural change.

Understanding how the adaptive immune system works is of monumental scientific importance. It is remarkable, then, that despite the sophisticated modeling technologies available today, there are no human-relevant in vitro platforms mimicking the adaptive immune system in a physiological environment. Rather, state-of-the art models involve animals or in vitro systems that capture isolated elements of the immune response (e.g., activation by tumor cells). The challenge in developing immunized in vitro models is that adaptive immune cells cannot be co-cultured with non-autologous tissue, as they become activated and destroy it. We propose a groundbreaking paradigm that tackles this challenge, while advancing the greater ideal of personalized medicine. The approach builds on my expertise with the Organ-on-a-Chip: a microfluidic platform comprising human tissue that closely mimics organ functionality. I will create a novel platform integrating six vascularized Organ-Chips, all originating from iPSCs derived from a specific individual, which have been differentiated into specific tissue types. This fully isogenic platform will accommodate the donor’s adaptive immune cells: Because they originate from the same source, they will not be activated. Indeed, preliminary results support this hypothesis. The resultant system, Immune-Me-on-a-Chip, will constitute a first-of-its kind personalized-immunized-human platform for studying human physiology and biological threats. I will use the system to explore fundamental biological questions: (i) understanding how different isogenic and non-isogenic tissues interact with the immune system, e.g., in organ transplantation; and (ii) identifying how pathogens (antibiotic-resistant E. coli), as well as antibiotic treatment, affect human physiology and the immune response. This research will revolutionize the study of human physiology in general and of immunity in particular, and will open the door to a new era of personalized medicine.

In the movie the ‘Truman Show’, Truman Burbank is astonished when discovering that he spent his entire life in a TV show. Monitoring a human’s life is unethical, but many sociologists secretly dream about running such an experiment. Behavior-Island will allow to continuously monitor and manipulate a large population of bats from birth to adulthood. Behavior-Island will be established on Mauritius - the home of P. niger, which is a very interesting bat-model that: (a) lives for decades relying on long-term memory; (b) roosts in large colonies and is highly social; (c) exhibits immense spatio-temporal memory; and (d) is large enough to carry many sensors allowing to track its pups from day one. Even with current state-of-the-art technologies, studying animal behavior in the wild is highly limited because: (1) it is extremely difficult to monitor the same individual over long periods while also monitoring its environment and (2) it is almost impossible to monitor a substantial part of a population and thus we know little about social interactions. We will overcome these limitations by using a new reverse-GPS system (ATLAS) allowing simultaneous tracking of 1000 bats. Notably, because the bats never leave the island, we will monitor individuals from birth to adulthood. ATLAS also provides locations in real-time, allowing to manipulate specific individuals in the wild and to examine their response. We have already tracked bats with a preliminary ATLAS system on Mauritius. Combined with an arsenal of additional technologies, ATLAS will allow studying fundamental aspects of behavior in the wild, for the first time, including: Navigation and its ontogeny; Long-term spatio-temporal memory, Decision making and Sociality. We will examine how experience and personality interact to shape behavior, and we will monitor an entire colony, documenting behavior in the population level. Because, P. niger is endangered and threatened, our work will also contribute to its protection

Most bacterial pathogens are lysogens, namely carry DNA of active phages within their genome, referred to as prophages. While these prophages have the potential to turn under stress into infective viruses which kill their host bacterium in a matter of minutes, it is unclear how pathogens manage to survive this internal threat under the stresses imposed by their invasion into mammalian cells. In the proposed project, we will study the hypothesis that a complex bacteria-phage cooperative adaptation supports virulence during mammalian infection while preventing inadvertent killing by phages. Several years ago, we uncovered a novel pathogen-phage interaction, in which an infective prophage promotes the virulence of its host, the bacterial pathogen Listeria monocytogenes (Lm), via adaptive behaviour. More recently, we discovered that the prophage, though fully infective, is non-autonomous- completely dependent on regulatory factors derived from inactive prophage remnants that reside in the Lm chromosome. These findings lead us to propose that the intimate cross-regulatory interactions between all phage elements within the genome (infective and remnant), are crucial in promoting bacteria-phage patho-adaptive behaviours in the mammalian niche and thereby bacterial virulence. In the proposed project, we will investigate specific cross-regulatory and cooperative mechanisms of all the phage elements, study the domestication of phage remnant-derived regulatory factors, and examine the hypothesis that they collectively form an auxiliary phage-control system that tempers infective phages. Finally, we will examine the premise that the mammalian niche drives the evolution of temperate phages into patho-adaptive phages, and that phages that lack this adaptation may kill host pathogens during infection. This work is expected to provide novel insights into bacteria-phage coexistence in mammalian environments and to facilitate the development of innovative phage therapy strategies.