Functional-Magnetic Resonance Imaging (fMRI) has transformed our understanding of brain function due to its ability to noninvasively tag ‘active’ brain regions. Nevertheless, fMRI only detects neural activity indirectly, by relying on slow hemodynamic couplings whose relationships with underlying neural activity are not fully known. We have recently pioneered two unique MR approaches: Non-Uniform Oscillating-Gradient Spin-Echo (NOGSE) MRI and Relaxation Enhanced MR Spectroscopy (RE MRS). NOGSE-MRI is an exquisite microstructural probe, sensing cell sizes (l) with an unprecedented l^6 sensitivity (compared to l^2 in conventional approaches); RE MRS is a new spectral technique capable of recording metabolic signals with extraordinary fidelity at ultrahigh fields. This proposal aims to harness these novel concepts for mapping neural activity directly, without relying on hemodynamics. The specific objectives of this proposal are: (1) Mapping neural activity via sensing cell swellings upon activity (μfMRI): we hypothesize that NOGSE can robustly sense subtle changes in cellular microstructure upon neural firings and hence convey neural activity directly. (2) Probing the nature of elicited activity via detection of neurotransmitter release: we posit that RE MRS is sufficiently sensitive to robustly detect changes in Glutamate and GABA signals upon activation. (3) Network mapping in optogenetically-stimulated, behaving mice: we propose to couple our novel approaches with optogenetics to resolve neural correlates of behavior in awake, behaving mice. Simulations for μfMRI predict >4% signal changes upon subtle cell swellings; further, our in vivo RE MRS experiments have detected metabolites with SNR>50 in only 6 seconds. Hence, these two complementary –and importantly, hemodynamics-independent– approaches will represent a true paradigm shift: from indirect detection of neurovasculature couplings towards direct and noninvasive mapping of neural activity in vivo.

Whether and how adult brains retain the ability to adapt their function and structure, especially in the context of learning, injury or restorative treatment is a fundamental question in neuroscience. In particular, understanding how neurons rewire or adapt during plasticity has been limited to (i) local electrophysiological measurements that lack the ability to report on brainwide aspects of plasticity, (ii) terminal experiments preventing longitudinal exploration in the same animal, or (iii) brainwide functional imaging with little insight into the underlying neural activity. Therefore, despite the scientific and clinical relevance of deciphering the neural substrate of neuroplasticity, a mechanistic, brain-wide study bridging the multiple spatiotemporal scales required for understanding neuroplasticity, is still lacking. We here propose to combine cutting edge functional Magnetic Resonance Imaging with calcium recordings in an animal model of visual pathway plasticity. First, we will use this exceptional multi-modal system to investigate the neurovascular coupling during visual stimulation and at-rest. Second, we will apply advanced computational neural models to characterize the functional organization of receptive fields and underlying circuitry across the rodent visual pathway and cortical layers. Third, we aim to map the time-course of functional reorganization and restructuring of neural circuitry following damage to the visual system. To do so, we will induce localized monocular retinal lesions and quantify changes in cortical organization and micro-circuitry resulting from the damage under differential visual experience (dark/ light exposure). This project will provide the first mechanistic description of adaptive circuitry processes and retinotopic (re)organization of the entire visual pathway associated with experience-dependent plasticity. Clinically, this is critical to assess the optimal timing for visual restorative and rehabilitation treatments.

Maintenance of tissue health requires a variety of cellular and molecular networks. The immune system comprises panoplies of cell subsets that can sense endogenous and exogenous factors to ensure efficient surveillance and defense. Similarly, the nervous system harbors distinct neuronal populations that sense and respond to ever-changing stimuli. Interestingly, discrete neuronal and immune cells in the intestine were shown to share anatomical confinements and influence each other’s function, forming neuronal immune cell units that act as rheostats of gut physiology. Nevertheless, whether brain-derived signals control enteric immune functions and intestinal homeostasis remains elusive. Importantly, neurological dysfunction induced by stroke correlates with severe intestinal problems in humans; including infections, inflammation and colon-rectal cancer. We propose to investigate how Central Nervous System (CNS) signals control intestinal immune homeostasis and how alteration of brain-derived signals induce gastrointestinal disease. We will explore how intestinal homeostasis and immune-mediated diseases are regulated in the context of stroke, which is a major Public Health concern. To achieve this, we propose to employ genetic, cellular and molecular approaches to decipher how brain signals and pathways specifically shape gastro-intestinal immune homeostasis and what is their relevance in intestinal inflammation and cancer. To this end, stroke and gastro-intestinal disease models, together with powerful tractable, chemogenetic technology, will be employed. Astonishing preliminary data revealed that stroke severely disrupts intestinal lymphocyte homeostasis, promoting their exodus from the gut to other organs. We foresee this project as groundbreaking, establishing the link between altered brain signals and intestinal physiology, shedding light into the intricate relationships between the CNS and the gastrointestinal immune system in the context of stroke, and beyond.