Exploring Brain Functional Networks Using Multimodal Approaches in Awake Rodents
Restricted (Penn State Only)
- Author:
- Han, Xu
- Graduate Program:
- Molecular, Cellular, and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- April 03, 2023
- Committee Members:
- Melissa Rolls, Major Field Member
Xiaojun Lian, Major Field Member
Xiao Liu, Outside Field Member
Nanyin Zhang, Chair & Dissertation Advisor
Melissa Rolls, Program Head/Chair
Patrick Drew, Outside Unit Member - Keywords:
- rsfMRI
brain network
resting state
RSFC
optogenetics
chemogenetics
neurovascular coupling - Abstract:
- The brain is a highly coordinated network, consisting of a set of interconnected regions. Resting state functional magnetic resonance imaging (rsfMRI) is the predominant method used to investigate functional brain networks. It measures brain-wide resting state functional connectivity (RSFC) by estimating co-fluctuations of spontaneous brain activities between different regions. Despite significant progress, current research on brain network function using rsfMRI largely remains at the correlational and descriptive level. A comprehensive understanding of causal relationships of brain networks and how brain networks mediate behavior remains elusive. To address this issue, this dissertation comprises three studies. In the first study, the feasibility of deriving causality (i.e., directional information) in the brain network was examined by utilizing neural modulation techniques and rsfMRI. The study was carried out on a resting-state rodent model using stabilized step-function opsin (SSFO)-based optogenetics combined with rsfMRI. The impact of a localized increase of excitability on brain-wide RSFC was examined by incorporating Pearson's correlation and partial correlation analyses in a graphical model to derive both directness and directional information in connections that displayed RSFC modulations. The results showed that upon SSFO activation of the dentate gyrus (DG), there were significant changes in connectivity within several brain regions associated with the DG, particularly in the medial prefrontal cortex. Based on a causal inference model, an accuracy rate of 84%-100% was achieved when compared to the directional information obtained from anatomical tracing data. In the second study, the causal impact of inhibiting a central node in the memory network (i.e., the dorsal hippocampus) on both brain-wide RSFC and behavior was investigated by combining chemogenetics, rsfMRI, and behavior tests. The results demonstrated that the suppression of dorsal hippocampus (dHP) activity led to significant alterations in RSFC in an extended hippocampal-related brain network. Importantly, the data suggest that these changes contributed to the impaired performance observed in a memory-related test (i.e., Y-maze). In a separate research line, the development of neurovascular coupling in postnatal mice was investigated. Neurovascular coupling is the mechanism that associates neural activity with subsequent blood flow and forms the foundation of the fMRI signal. However, neurovascular coupling is not mature in neonates, hindering the interpretation of fMRI signals in young animals. In this dissertation, hemodynamic response was measured in awake mice from 10 days postnatal to adulthood (P10-P60). The data showed that the stimulation-evoked BOLD response was lower or even negative in young pups, and the time-to-peak of the BOLD signal in young mice was longer. Collectively, this dissertation established the optogenetic- and chemogenetic-fMRI systems to investigate the relationship between local region activity and RSFC modulation. It provided a way to analyze causal relationships between brain regions and determine network contributions to behavioral changes under neural modulation. It also characterized development-related neurovascular coupling.