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.

Although the etiology and expression of psychiatric disorders are complex, mammals show biologically preserved behavioral and neurobiological responses to valent stimuli which underlie the use of rodent models of post-traumatic stress disorder (PTSD). PTSD is a complex phenotype that is difficult to model in rodents because it is diagnosed by patient interview and influenced by both environmental and genetic factors. However, given that PTSD results from traumatic experiences, rodent models can simulate stress induction and disorder development. By manipulating stress type, intensity, duration, and frequency, preclinical models reflect core PTSD phenotypes, measured through various behavioral assays. Paradigms precipitate the disorder by applying physical, social, and psychological stressors individually or in combination. This review discusses the methods used to trigger and evaluate PTSD-like phenotypes. It highlights studies employing each stress model and evaluates their translational efficacies against DSM-5, validity criteria, and criteria proposed by Yehuda and Antelman’s commentary in 1993. This is intended to aid in paradigm selection by informing readers about rodent models, their benefits to the clinical community, challenges associated with the translational models, and opportunities for future work. To inform PTSD model validity and relevance to human psychopathology, we propose that models incorporate behavioral test batteries, individual differences, sex differences, strain and stock differences, early life stress effects, biomarkers, stringent success criteria for drug development, Research Domain Criteria, technological advances, and cross-species comparisons. We conclude that, despite the challenges, animal studies will be pivotal to advances in understanding PTSD and the neurobiology of stress.

Intrinsic connectional architecture of the brain is a crucial element in understanding the governing principle of brain organization. To date, enormous effort has been focused on addressing this issue in humans by combining resting-state functional magnetic resonance imaging (rsfMRI) with other techniques. However, this research area is significantly underexplored in animals, perhaps because of confounding effects of anesthetic agents used in most animal experiments on functional connectivity. To bridge this gap, we have systematically investigated the intrinsic connectional architecture in the rodent brain by using a previously established awake-animal imaging model. First, group independent component analysis was applied to the rsfMRI data to extract elementary functional clusters of the brain. The connectional relationships between these clusters, as evaluated by partial correlation analysis, were then used to construct a graph of whole-brain neural network. This network exhibited the typical features of small-worldness and strong community structures seen in the human brain. Finally, the whole-brain network was segregated into community structures using a graph-based analysis. The results of this work provided a functional atlas of intrinsic connectional architecture of the rat brain at both intraregion and interregion levels. More importantly, the current work revealed that functional networks in rats are organized in a nontrivial manner and conserve fundamental topological properties that are also seen in the human brain. Given the high psychopathological relevance of network organization of the brain, this study demonstrated the feasibility of studying mechanisms and therapies of multiple neurological and psychiatric diseases through translational research.

A majority of ATP in the brain is formed in the mitochondria through oxidative phosphorylation of ADP with the F ₁ F ₀ -ATP (ATPase) enzyme. This ATP production rate plays central roles in brain bioenergetics, function and neurodegeneration. In vivo ³¹ P magnetic resonance spectroscopy combined with magnetization transfer (MT) is the sole approach able to noninvasively determine this ATP metabolic rate via measuring the forward ATPase reaction flux ( F _f,ATPase ). However, previous studies indicate lack of quantitative agreement between F _f,ATPase and oxidative metabolic rate in heart and liver. In contrast, recent work has shown that F _f,ATPase might reflect oxidative phosphorylation rate in resting human brains. We have conducted an animal study, using rats under varied brain activity levels from light anesthesia to isoelectric state, to examine whether the in vivo ³¹ P MT approach is suitable for measuring the oxidative phosphorylation rate and its change associated with varied brain activity. Our results conclude that the measured F _f,ATPase reflects the oxidative phosphorylation rate in resting rat brains, that this flux is tightly correlated to the change of energy demand under varied brain activity levels, and that a significant amount of ATP energy is required for “housekeeping” under the isoelectric state. These findings reveal distinguishable characteristics of ATP metabolism between the brain and heart, and they highlight the importance of in vivo ³¹ P MT approach to potentially provide a unique and powerful neuroimaging modality for noninvasively studying the cerebral ATP metabolic network and its central role in bioenergetics associated with brain function, activation, and diseases.

The neural mechanism of unconsciousness has been a major unsolved question in neuroscience despite its vital role in brain states like coma and anesthesia. The existing literature suggests that neural connections, information integration, and conscious states are closely related. Indeed, alterations in several important neural circuitries and networks during unconscious conditions have been reported. However, how the whole-brain network is topologically reorganized to support different patterns of information transfer during unconscious states remains unknown. Here we directly compared whole-brain neural networks in awake and anesthetized states in rodents. Consistent with our previous report, the awake rat brain was organized in a nontrivial manner and conserved fundamental topological properties in a way similar to the human brain. Strikingly, these topological features were well maintained in the anesthetized brain. Local neural networks in the anesthetized brain were reorganized with altered local network properties. The connectional strength between brain regions was also considerably different between the awake and anesthetized conditions. Interestingly, we found that long-distance connections were not preferentially reduced in the anesthetized condition, arguing against the hypothesis that loss of long-distance connections is characteristic to unconsciousness. These findings collectively show that the integrity of the whole-brain network can be conserved between widely dissimilar physiologic states while local neural networks can flexibly adapt to new conditions. They also illustrate that the governing principles of intrinsic brain organization might represent fundamental characteristics of the healthy brain. With the unique spatial and temporal scales of resting-state fMRI, this study has opened a new avenue for understanding the neural mechanism of (un)consciousness.