Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal

Abstract

Functional magnetic resonance imaging (fMRI) has allowed the noninvasive study of task-based and resting-state brain dynamics in humans by inferring neural activity from blood-oxygenation-level dependent (BOLD) signal changes. An accurate interpretation of the hemodynamic changes that underlie fMRI signals depends on the understanding of the quantitative relationship between changes in neural activity and changes in cerebral blood flow, oxygenation and volume. While there has been extensive study of neurovascular coupling in anesthetized animal models, anesthesia causes large disruptions of brain metabolism, neural responsiveness and cardiovascular function. Here, we review work showing that neurovascular coupling and brain circuit function in the awake animal are profoundly different from those in the anesthetized state. We argue that the time is right to study neurovascular coupling and brain circuit function in the awake animal to bridge the physiological mechanisms that underlie animal and human neuroimaging signals, and to interpret them in light of underlying neural mechanisms. Lastly, we discuss recent experimental innovations that have enabled the study of neurovascular coupling and brain-wide circuit function in un-anesthetized and behaving animal models.

The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease

“…Whenever feasible, coupling these imaging tools with genetically-encoded activity sensors and cell specific reporters, as well as chemo- and opto-genetic approaches to activate specific neural pathways may provide novel insights into the spatiotemporal relationships linking neural activity and segmental vascular responses. Using conscious animals will eliminate anesthesia as a major confounder and will allow investigators to probe neurovascular coupling beyond the realm of olfactory, somatosensory or visual stimuli and towards complex behaviors in multiple brain regions (Gao et al, 2017). The introduction of more realistic multicellular in vitro models of the NVU, such as the 3-D microfluidics organ-on-chip technology for the BBB (Adriani et al, 2017) and cerebrovascular organoids derived from human induced pluripotent stem cells (IPS) (Appelt-Menzel et al, 2017), provides the opportunity to explore the molecular interactions among NVU cells beyond what can be achieved with conventional co-culture systems.…”

Delineating the Macroscale Areal Organization of the Macaque Cortex In Vivo

“…Previous studies have demonstrated that FC patterns are sculpted more by structural connectivity under deep anesthesia than the awake state (Barttfeld and Uhrig, 2015; Wu et al, 2016). In anesthesia states, when isoflurane levels were varied, the signal fluctuations and connectivity also exhibited distinct profiles at each level within the same animal (Smith et al, 2017; Gao et al, 2017; Peltier et al, 2005; Hutchison et al., 2014). While it is expected that the parcels revealed will in many cases exhibit a gross similarity to traditionally defined neocortical areas, they are not intended to be 1:1.…”

Global brain signal in awake rats

“…To minimize stress and motion during imaging at the awake state, animals were 134 acclimated to the scanning environment for 7 days (see details described in (Dopfel and Zhang 135 2018; Gao et al 2016)). Briefly, rats were briefly anesthetized (5 min) under isoflurane (2-4%) 136 and placed in a body and head restrainer.…”