|Ph.D Student||Abu Amneh-Abbasi Dalal|
|Subject||Uyilizing Multi-Scale and Multi-Model Methods to|
Characterize Neural Systems in Health and Disease
|Department||Department of Medicine||Supervisor||Professor Itamar Kahn|
|Full Thesis text|
The mammalian brain is a highly complex network. It consists of billions of cells that communicate at different scales and modalities of organization, to support the vast diversity of our behavior. One of the greatest challenges in neuroscience is to understand how brain function emerges from this multi-scale multi-modal communication. Considerable effort has been devoted to develop technologies for interrogating structural and functional modalities of connectivity, at the scales of individual neurons, small populations, and brain-wide networks. However, limited “dialog” between the micro and macro scales results in limited consideration of the multi-level nature of the brain.
The work in this thesis complements recent research aimed to bridge the gap between microscopic and macroscopic characterization of brain organization. Here, we illustrate the importance of combining multi-scale and multi-modal methods, using functional magnetic resonance imaging (fMRI), diffusion-based MRI and optogenetics, to shed light on novel aspects in intensively-studied research fields. The first project examines how mouse brain networks changes under chronic cuprizone intoxication. Our findings indicate that both decreases and increases in structural and functional measures are present in cortical and subcortical regions. This work is the first to demonstrate the strong and differential impact of cuprizone intoxication on the limbic system. Critically, though this model is widely-used as a demyelination model, our findings indicate that it was accompanied by abnormal dopamine activity in both functional and behavioral measures. Further, structural and functional results revealed a strong correlation of the paraventricular thalamus (PVT) - central amygdala (CEA) pathway with functional abnormalities. To examine its relevance to abnormal behavior, novel object recognition test demonstrated that cuprizone intoxication results in increased novelty seeking behavior, and a strong linear correlation was found between the behavioral data and changes to PVT-CEA pathway. We show, for the first time, the impact of dopaminergic abnormal activity resulting from cuprizone intoxication on whole-brain structural and functional properties, implicating the involvement of a new pathway as a candidate for modulating dopaminergic and limbic functional networks in this model.
In order to understand sensorimotor integration in the whisker system, we sought to develop a new method that facilitates non-invasive and precise motor control of whisking, and allows mapping whole-brain functional responses of the ongoing sensory feedback. In the second project, we develop a new method, ‘opto-whisking fMRI’, that combines the precise cellular control obtained by optogenetics, and the large-scale functional mapping offered by fMRI, to precisely control the motor loops and globally characterize sensory feedback loops. We illustrate its high specificity in inducing cortical-like and brainstem-like innervations of the facial motor nucleus, which led to distinct whisking behaviors and showed differential functional activation of the sensory feedback pathways. Notably, our data indicated for the first time a high structural and functional correspondence between the functional correlates of each type of motor control and anatomical neuronal connections of the corresponding brainstem nuclei that innervate both sensory pathways. Further, the different motor control patterns demonstrated extreme variations in brain regions recruitment, which may imply on the different significance of both motor drives.