A consensus protocol for functional connectivity analysis in the rat brain.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience.

Suppressing Anterior Cingulate Cortex Modulates Default Mode Network and Behavior in Awake Rats.

The default mode network (DMN) is a principal brain network in the mammalian brain. Although the DMN in humans has been extensively studied with respect to network structure, function, and clinical implications, our knowledge of DMN in animals remains limited. In particular, the functional role of DMN nodes, and how DMN organization relates to DMN-relevant behavior are still elusive. Here we investigated the causal relationship of inactivating a pivotal node of DMN (i.e., dorsal anterior cingulate cortex [dACC]) on DMN function, network organization, and behavior by combining chemogenetics, resting-state functional magnetic resonance imaging (rsfMRI) and behavioral tests in awake rodents. We found that suppressing dACC activity profoundly changed the activity and connectivity of DMN, and these changes were associated with altered DMN-related behavior in animals. The chemo-rsfMRI-behavior approach opens an avenue to mechanistically dissecting the relationships between a specific node, brain network function, and behavior. Our data suggest that, like in humans, DMN in rodents is a functional network with coordinated activity that mediates behavior.

An open database of resting-state fMRI in awake rats.

Rodent models are essential to translational research in health and disease. Investigation in rodent brain function and organization at the systems level using resting-state functional magnetic resonance imaging (rsfMRI) has become increasingly popular. Due to this rapid progress, publicly shared rodent rsfMRI databases can be of particular interest and importance to the scientific community, as inspired by human neuroscience and psychiatric research that are substantially facilitated by open human neuroimaging datasets. However, such databases in rats are still rare. In this paper, we share an open rsfMRI database acquired in 90 rats with a well-established awake imaging paradigm that avoids anesthesia interference. Both raw and preprocessed data are made publicly available. Procedures in data preprocessing to remove artefacts induced by the scanner, head motion and non-neural physiological noise are described in details. We also showcase inter-regional functional connectivity and functional networks obtained from the database.

Rodent models of post-traumatic stress disorder: behavioral assessment.

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.

Individual variability in behavior and functional networks predicts vulnerability using an animal model of PTSD.

Only a minority of individuals experiencing trauma subsequently develop post-traumatic stress disorder (PTSD). However, whether differences in vulnerability to PTSD result from a predisposition or trauma exposure remains unclear. A major challenge in differentiating these possibilities is that clinical studies focus on individuals already exposed to trauma without pre-trauma conditions. Here, using the predator scent model of PTSD in rats and a longitudinal design, we measure pre-trauma brain-wide neural circuit functional connectivity, behavioral and corticosterone responses to trauma exposure, and post-trauma anxiety. Freezing during predator scent exposure correlates with functional connectivity in a set of neural circuits, indicating pre-existing circuit function can predispose animals to differential fearful responses to threats. Counterintuitively, rats with lower freezing show more avoidance of the predator scent, a prolonged corticosterone response, and higher anxiety long after exposure. This study provides a framework of pre-existing circuit function that determines threat responses, which might directly relate to PTSD-like behaviors.

Mapping stress networks using functional magnetic resonance imaging in awake animals.

The neurobiology of stress is studied through behavioral neuroscience, endocrinology, neuronal morphology and neurophysiology. There is a shift in focus toward progressive changes throughout stress paradigms and individual susceptibility to stress that requires methods that allow for longitudinal study design and study of individual differences in stress response. Functional magnetic resonance imaging (fMRI), with the advantages of noninvasiveness and a large field of view, can be used for functionally mapping brain-wide regions and circuits critical to the stress response, making it suitable for longitudinal studies and understanding individual variability of short-term and long-term consequences of stress exposure. In addition, fMRI can be applied to both animals and humans, which is highly valuable in translating findings across species and examining whether the physiology and neural circuits involved in the stress response are conserved in mammals. However, compared to human fMRI studies, there are a number of factors that are essential for the success of fMRI studies in animals. This review discussed the use of fMRI in animal studies of stress. It reviewed advantages, challenges and technical considerations of the animal fMRI methodology as well as recent literature of stress studies using fMRI in animals. It also highlighted the development of combining fMRI with other methods and the future potential of fMRI in animal studies of stress. We conclude that animal fMRI studies, with their flexibility, low cost and short time frame compared to human studies, are crucial to advancing our understanding of the neurobiology of stress.