Modulations in neural circuit dynamics and microstructures can translate to functional enhancements (e.g., upon plasticity), or, conversely, to severe functional deficits (e.g., upon neurodegeneration). We are interested in identifying and investigating the links between such longitudinal functional modulations, their underlying micro-architectural modifications, and the ensuing behavioral responses in vivo. To this end, we harness ultrahigh field Magnetic Resonance Imaging (MRI) coupled to specificity-endowing modalities such as optogenetics and optical microscopy. These offer the opportunity of eliciting activity in circuits of interest, and concomitantly monitoring the ensuing activity in 3D. We further develop and apply novel methodologies based on nonBOLD mechanisms, which can potentially provide much insight into the nature of the activity, as well as probe rather fast dynamics. Microstructures are unraveled via MR methodologies tailored to probe cellular-scale size distributions (in white matter) as well as highly heterogeneous morphologies (in gray matter). These measurements are performed in vivo using state of the art 9.4T and 16.4T scanners, in both anesthetized and behaving rodents, as well as in animal models of neurodegeneration and plasticity. Our long term goals are to understand the mechanisms by which modifications in the tissue’s microstructure transcend globally and modulate function and behavior, and to explore the potential of these as early disease biomarkers.
Our long term goals are to understand the mechanisms by which modifications in the tissue’s microstructure transcend globally and modulate function and behavior
To find the “missing link” between behaviour and changes on the molecular, or cellular level, the Neuroplasticity and Neural Activity lab develops pioneering functional magnetic resonance imaging (fMRI) techniques. fMRI is a non-invasive, powerful tool for studying various neuroscience and biomedical questions. Current fMRI methods work by performing indirect measures of neural activity by following changes in blood volume and oxygenation level that accompanies it. However, changes in blood flow, in addition to being an indirect measure, occur over a timescale of seconds, while neural activity occurs within a fraction of a single second. This difference in timescale points out an obvious limitation of current fMRI techniques – they are too slow to resolve many important processes in the brain. To address these issues, the team’s first steps, for which they have received support for from the European Research Council, have been focused on developing novel techniques that harness the power of MRI to perform direct measurements of neural activity on a much faster timescale. For instance, the team will use ultrahigh magnetic fields to image the dynamics of neurotransmitters in the brain. These various measurements will be performed in vivo using state of the art 9.4T and 16.4T scanners, in both anesthetised and behaving rodents.
Different tracks in the rodent spinal cord were mapped using a robust newly developed method for quantifying the axon density, by using ultrahigh field MRI, making possible the contrasting of different tracks
Deciphering distributed neural circuits via advanced fMRI coupled with optogenetics
Complex behaviors ultimately arise from neural activity in widespread, distributed systems in the brain. We are interested in deciphering such networks in awake behaving rodents via optogenetics and advanced ultrafast fMRI. To achieve this goal, we are currently developing optogenetics- and MRI-compatible behavioral paradigms for awake rodents, as well as advanced ultrafast MRI acquisition strategies that will enable the resolution of relatively fast dynamics. The long term goals include the identification of distributed circuits and the investigation of their causal dynamics.
Functional MRI via non-BOLD mechanisms
The success of functional-MRI (fMRI) stems from its ability to portray active brain regions upon prescribing a specific task. However, fMRI relies on the Blood-Oxygenation-Level-Dependent (BOLD) mechanism, which is a surrogate marker for neural activity via neurovasculature couplings. A major goal of the Lab will therefore be to harness MRI’s versatility – especially at the ultrahigh fields – towards capturing signatures for neural activity more directly. Specifically, we are interested in detecting cellular swellings upon activation, as well as neurotransmitter releases in the activated regions. Both phenomena can be considered epitomes of neural activity, and their direct detection is expected to provide much insight into the nature of the ensuing activity. We are investigating these phenomena – as well as BOLD neurophysiology – via MRI coupled to orthogonal modalities such as optical microscopy and optogenetics, in numerous settings from organotypic cultures (where hemodynamics are absent) to in vivo rodents.
Microstructural determinants of functional modulations leading to behavioral changes in healthy and diseased CNS
Modulations in brain function (e.g., enhancements arising from plasticity or aberrations arising from neurodegeneration) are intimately correlated with underlying micro-architectural modifications in the neural tissues. We are interested in studying the links between the two, in vivo, in a longitudinal fashion in animal models of plasticity on the one hand and neurodegeneration on the other hand. We investigate functional modulations (such as neural network reorganizations) using optogenetics as the specific source of stimulation, and BOLD- and nonBOLD-fMRI as the functional readouts. We augment this functional information with advanced in vivo MRI methodologies that are selectively designed to probe even subtle changes in microstructures arising from plasticity or, conversely, neurodegenerative processes. We target microstructural changes in white matter, where we study variations in axonal size distributions (that govern the conduction velocity) as well as in gray matter, where we study changes in randomly oriented tissue components. We further aim to investigate the diagnostic potential arising from the identification of structural changes preceding functional/behavioral modifications.
MSCA-IF 753100: Neuronal MRI: Harnessing chemical exchange between N-Acetylaspartate and water for functional imaging of neural activity
Functional MRI (fMRI) is currently the leading noninvasive modality to assess brain function in vivo. However, it relies on a surrogate marker for neural activity – the hemodynamic responses following activity – which makes fMRI nonspecific and difficult to interpret. Here, we propose to advance the state-of-the-art by developing and evaluating a methodology we term neuronal fMRI (nMRI) which would enable a direct measurement of neuronal activity and its fast dynamics. Achieving this arduous goal calls for a truly interdisciplinary effort, borrowing concepts from Chemistry (Chemical Exchange Saturation Transfer (CEST) of a neuronal-selective metabolite to impart specificity, restricted diffusion to probe cell sizes), Physics and Engineering (advanced MRI and reconstruction methods). Our general approach consists of a development validation- application design, thus our main objectives are:
1. Harnessing the hitherto unexplored downfield resonance of N-Acetylaspartate (NAA) – a metabolite confined solely to neurons – in CEST MRI experiments, thus imparting specificity towards the neuronal population; combining this specificity enhancement with diffusion MRI sequences that are extraordinarily sensitive to cellular sizes, and hence are able to sense subtle cell-swellings arising upon neuronal firing. This new method, which we term neuronal-MRI (nMRI) will thus report on neuronal swellings, and as such reflect activity directly.
2. Implementing ultra-fast imaging techniques based on data multiplexing and the latest compressed sensing frameworks to nMRI, such that the 50 ms timescale can be reached with full brain coverage. This will allow the measurement of fast neuronal activity dynamics in the brain.
3. Applying nMRI to study the auditory circuit as a model system in-vivo.
In summary, we posit that nMRI – upon successful implementation and rigorous testing – will be highly impactful in many disciplines, and pave the way to study the neuronal population in health and disease.