Cell-type specific investigation of the basal forebrain with fMRI in healthy and Alzheimer's disease mice

The brain is a complex and vastly interconnected structure. Understanding how its different networks interact under physiological and pathological conditions has long been a difficult endeavor. However, technological advancements over the past few decades has led to the advent of optogenetic functional magnetic resonance imaging (ofMRI), through which we are now able to manipulate specific circuits and monitor the functional consequences throughout the entire brain. Thanks to developments in transgenic mouse models, we are able to target such circuits not only with spatial and temporal specificity, but neurochemical as well. The work presented in this dissertation combines these technologies to interrogate the functional roles of different cell types in the basal forebrain. The basal forebrain is a large and diverse brain region in itself, and as such it is implicated in a number of normal physiological processes such as sleep, attention, memory, and motivation. Additionally, it is one of the key regions prone to dysfunction in Alzheimer's disease, the leading cause of dementia today and a problem that has eluded proper understanding since its discovery over 100 years ago. Historically, much of the work examining the connectivity of the basal forebrain has been limited to either the functional relationships of a small number of nodes, or it has tried to identify brain-wide anatomical projection patterns. With ofMRI, this work can be extended further by combining functional connectivity with brain-wide projection mapping. We used ofMRI to examine the brain-wide functional consequences of stimulation of the three major cell types of the basal forebrain: cholinergic, GABAergic, and glutamatergic neurons. We found that all three cell types led to robust but distinct responses throughout cortical and subcortical areas. Cholinergic stimulation was restricted to the brain hemisphere ipsilateral to stimulation, in line with much of what has been found anatomically for basal forebrain inputs and outputs. However, GABAergic and glutamatergic stimulation resulted in bilateral activity implying a key distinction between functional and anatomical projections. We followed up ofMRI with in vivo extracellular electrophysiology in the ventral pallidum, somatosensory cortex, central thalamus, and zona incerta in order to better characterize the downstream consequences of cell-types specific basal forebrain activation. Additionally, we looked at the cholinergic basal forebrain in old mice with and without the APP/PS1 transgene, a model of Alzheimer's disease. In older mice, we found a weakened response to cholinergic basal forebrain stimulation, most notably in the somatosensory cortex where a significant cluster of negative BOLD signal disappeared relative to the young cohort. Interestingly, this cluster of activity was preserved in the APP/PS1 mice. While surprising, this finding is in line with a few recent studies examining brain areas that are particularly resistant to dysfunction in Alzheimer's disease, which includes the somatosensory cortex. More research in this area could open up new avenues for understanding what leads to differences in disease vulnerability that may elucidate the underlying pathological mechanisms as well as future treatment options. Taken together, the work presented here highlights the power of mapping cell-type specific functional circuits with ofMRI and adds a wealth of new information to our understanding of both the basal forebrain and Alzheimer's disease

Keywords: Molecular and Cellular Physiology.
Advisor: Lee Jin Hyung
Südhof Thomas C. 
Gitler Aaron D. 
Madison Daniel V.