Unraveling the interplay of brain networks by combining neuromodulatory tools and in vivo MRI in rodents

The increasing prevalence of neurological disorders poses an ever-increasing healthcare burden on society. A better understanding of the underlying mechanisms mediating these neurological disorders is indispensable for the identification of new potential therapeutic targets. Various neurological disorders have been associated with disturbances in the interplay of functional brain networks. This thesis focuses on unraveling the relationships between functional brain networks, with particular interest for the default mode-like network and task-positive networks in rodents. We utilized a relatively new multi-modal approach combining chemogenetics and non-invasive functional magnetic resonance imaging (fMRI). This combined approach allows collecting valuable information about the role of specific subsets of cells in brain network function and dysfunction. In the first part of this thesis, we found that chemogenetic manipulation of a specific area, i.e. the anterior cingulate area (ACC), is able to modulate the neural activity and functional connectivity of brain networks. More specifically, silencing of the ACC resulted in altered neural activity and functional connectivity in brain networks including connections with sensory cortex, thalamus, basolateral amygdala and ventral pallidum, areas involved in attention processes, working memory, fear behavior and reward, respectively. In addition, we found that damage to the ACC is associated with decreased functional connectivity in the default mode-like network, the task-positive network and visual system. Interestingly, these affected functional networks demonstrated distinguishable recovery patterns over time. In the second part of this thesis, we focused on the interactions between the default mode-like network and attentional processes. We found that stimulating bottom-up sensory processes (by presenting continuous random flickering light to sedated rats) could decrease the activity and functional connectivity in the default mode-like network, similarly as task-related deactivations. In a next study, we aimed to shed light on the mechanisms involved in the deactivation of the default mode-like network during attentional processes. Our results indicated functional connectivity decreases in the default mode-like network upon chemogenetic stimulation of basal forebrain cholinergic neurons, suggesting a role for the cholinergic system in default mode-like network regulation. Taken together, this thesis provides unique insights on functional and dysfunctional brain networks. Furthermore, this thesis underscores the significance of combining chemogenetics with fMRI for future studies as well as its promise for future neurotherapeutics as it can eliminate the off-target effects of current therapeutics and allows the on-demand control of specified neurons.

Jaar van publicatie:2020

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open