Analyzing brain-wide bases of neuroplastic change using new imaging tools - The mammalian brain is constantly being shaped by input from the body and external world. The brain's plasticity involves changes in gene expression, protein synthesis and activity, synaptic function, and neuronal growth and death. Understanding how these processes are influenced by stimuli, and how they in turn mold profiles of neural activity and behavior, requires an ability to map the dynamics of molecular and cellular-level changes as they occur throughout the life of an individual. We recently developed an imaging method that enables bioluminescent reporter proteins to be monitored throughout the living brain using hemodynamic magnetic resonance imaging (MRI). Our method, called BLUsH, provides noninvasive readouts of reporter expression at submillimeter resolution in individual animals over time intervals ranging from minutes to days, or longer. In initial studies, we have shown that BLUsH can be used to delineate viral tracing patterns and expression of activity-dependent immediate early genes (IEGs) in vivo. These and related approaches permit longitudinal studies of brain- behavior associations that were previously extremely difficult to study. In this project, we will apply BLUsH to address several paradigmatic questions about brain-wide plasticity: (1) What are the spatiotemporal relationships between neural activity and plasticity gene induction? (2) How are experience-dependent changes in the physical structure of the brain driven by molecular and cellular processes? (3) How does repeated exposure to a stimulus or behavior affect characteristics of plasticity phenomena throughout the brain? (4) What features of neuroplasticity are predictive of individual behavioral variability? We will approach these questions through three specific aims: In Aim 1, we will apply BLUsH IEG imaging and conventional functional MRI (fMRI) in animal models of opioid use disorder to measure relationships between neural activity and plasticity gene induction. We will test hypotheses about variation of these processes over experience and among brain regions and individual animals, in experiments that we expect to reflect broadly on the use and interpretation of IEG mapping in neuroscience. In Aim 2, we will evaluate the contribution of neurogenesis and astrocytic remodeling to neuroanatomical change in a mouse model of voluntary exercise. We will assess whether molecular and cellular markers of neuroplasticity predict individual behavioral performance and test hypotheses about involvement of specific brain structures. In Aim 3, we will improve characteristics of the BLUsH system itself, aiming to enable applications of BLUsH in nontransgenic animals and using multiplexed reporters. The new strategies will be validated in the experimental paradigms of Aim 1, and will ultimately enable applications of BLUsH to studies of plasticity and other phenomena in diverse animal models.
