PROJECT SUMMARY/ABSTRACT Functional magnetic resonance imaging (fMRI) with blood oxygenation level-dependent (BOLD) contrast indirectly measures neuronal activity by way of their localized hemodynamic responses. BOLD responses typically show sustained increases above their baseline (i.e., positive BOLD responses, PBR), but sometimes show sustained decreases below their baseline (i.e., negative BOLD responses, NBR). While the PBR is well associated with increased neuronal activity, the NBR has been associated with decreased neuronal activity or is thought to have non-neuronal origins, such as “blood stealing”, whereby blood is diverted from lesser active regions to more active regions due to local pressure changes independent of local neuronal activity. Therefore, the physiological origin of the NBR remains elusive. Our long-term goal is to determine how properties of neurovascular coupling change with varying locus coeruleus (LC) activity, and the associated changes in noradrenaline (NA) release, in behaving animals. The overall objective in this application is to determine and characterize the involvement of LC activity in the generation of the NBR in the rodent somatosensory cortex. Our central hypothesis is that modulations of LC activity evoked by sensory stimulation directly alters both vascular tone and neuronal activity, which affect the NBR as well as the PBR. The rationale for this project is that determining how LC activity is involved in fMRI signals in normal physiological conditions will facilitate a deeper understanding of how functional alterations of LC activity in diseased states, such as with schizophrenia and Alzheimer's disease, may contribute to noninvasive fMRI signal changes. The central hypothesis will be tested by pursuing the specific aim to identify the effects of direct LC modulations on the NBR and, specifically, the effect of NA on the NBR. Under this aim, LC-NA activity will be enhanced by electrical stimulation of LC and, in different experiments, suppressed by optogenetic inhibition of LC to evaluate how it modulates the NBR. In addition, NBRs evoked by sensory stimulation in the somatosensory cortex will be suppressed by blocking presynaptic release of NA to evaluate if NA modulates the NBR. The research proposed in this application is innovative because it focuses on the direct and transient modulations of LC activity to test their effects on the NBR and examines the actions of LC on modality-specific brain regions, which is a departure from the status quo. The proposed research is significant because it will integrate the dual vascular and neuronal origins of the NBR by demonstrating a sensory-stimulation driven role of the LC-NA system on neuromodulation and hemodynamic responses. Without such information, the neural interpretation of fMRI maps will likely remain limited, especially inferences from resting-state fMRI studies and hemodynamic responses of different LC-dependent cortical states.

PROJECT NARRATIVE The proposed research is relevant to public health because understanding the underlying physiological mechanisms of the non-invasive functional MRI signal is expected to advance how fMRI maps should be interpreted, which is essential for the proper understanding of human brain function. Thus, the proposed research is relevant to the NIH's mission that seeks fundamental knowledge about the nature and behavior of humans. Such knowledge will enhance health and reduce illness and disability.