Ascending neuromodulation associated with cognitive functions, such as arousal, attention, learning, memory,
decision making, evaluation of reward, are active in any conscious human subject participating in a Blood
Oxygenation Level Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) study. And yet, our
understanding of how these systems affect the BOLD signal remains rudimentary. In fact, our current
knowledge of neurovascular and neurometaboic mechanisms that underlie the BOLD signal has been derived
almost exclusively from studies in anesthetized animals where the state of neuromodulation was uncertain.
Recently, we have developed optical reporters for dopamine (DA), norepinephrine (NE), and acetylcholine
(ACh) applicable for high-resolution imaging of brain function in awake behaving mice. In the proposed project,
we will combine these reporters with an integrated suite of the BRAIN Initiative tools, developed by us
and others, to investigate the microscopic makeup of “brain states” and their reflection in
macroscopic BOLD fMRI signals. These tools (except fMRI) are only applicable to model organisms.
Therefore, all experiments will be performed in awake behaving mice.
Our Central Hypothesis is that ascending projections from one or more neuromodulatory systems
contribute critically to generation of spontaneous (“resting-state”) hemodynamic fluctuations as well
as task-induced hemodynamic responses. To test this hypothesis, we will investigate the relationship
between neuronal, vascular and metabolic activity as a function of (i) intrinsic brain states (Aims 1-2), and (ii)
exposure to cocaine – a common drug of abuse that acts by affecting neuromodulation (Aim 3). Brain states
will be operationally defined based on the readout of DA, NE, and ACh reporters referenced to
electrophysiological/imaging measures of local cortical dynamics. These studies will be performed in the
context of resting-state hemodynamic fluctuations as well as task-induced hemodynamic responses in the
primary somatosensory and frontal cortices.
The proposed project will (i) provide a stronger physiological foundation for resting-state and task-induced fMRI
in healthy individuals; (ii) place the relationship between the state of neuromodulation and energy expenditure
(cerebral metabolic rate of O2, CMRO2) on a quantitative footing; and (iii) examine the effects of cocaine on
neuronal and hemodynamic brain activity. This study will also generate further hypotheses about the ways in
which substance exposure may affect fMRI readouts.