Large-scale topology and the default mode network in the mouse connectome

Abstract

Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, wholebrain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that largescale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)-a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.connectivity | mouse | resting-state functional MRI | structural connectivity | default mode network U nderstanding the functional architecture of brain systems in both typical and atypical populations has the potential to improve diagnosis, prevention, and treatment of various neurologic and mental illnesses. Human functional neuroimaging, because of its ease of use, noninvasive nature, and wide availability, has significantly advanced this goal. However, because functional brain imaging is an indirect measure of the underlying neuronal dynamics (1), a number of basic questions about the molecular and structural underpinnings of these functional signals needs to be answered before the full clinical promise of the technique can be realized. Insight into these underpinnings would be vastly enhanced by translation to rodent models, where rich methodology for studying high-throughput genetic, histological, and therapeutic conditions in a tightly controlled environment exists. Mouse models, in particular, are likely to contribute significantly to this end.Efforts aimed at using mouse models to enrich findings obtained in humans with noninvasive imaging would benefit greatly from bridge measurements-measurements that can be obtained and compared directly between species, such as resting-...

Chronic psychosocial stress in mice leads to changes in brain functional connectivity and metabolite levels comparable to human depression

“…supplementary, barrel field, and visual, and areas proposed to contribute to the "rodent default-mode network" ("DMN"), namely prefrontal and cingulate cortices (Gozzi and Schwarz, 2016;Sforazzini et al, 2014;Stafford et al, 2014). The present findings were robust and reproducible, as evidenced by the similar and significant CPS effects on network strengths obtained in each run, comprising 12-15 mice per CPS and control group per run, and with similar variances observed in the CPS and control data sets.…”

“…In rats, a recent rs-fMRI study demonstrated that the physical stressor of repeated immobilisation results in increased FC within the "DMN" as well as somatosensory-cortex and visual-cortex networks (Henckens et al, 2015). In mice, rs-fMRI has been applied to demonstrate that structurally connected brain areas also exhibit FC, that brain topology and networks exhibit homology with primate species (Stafford et al, 2014), and that network alterations are sensitive indicators of pathology (Grandjean et al, 2014b). In mice, chronic social stressors combined with behavioural tests have identified changes in emotional, motivational and cognitive states that are relevant to human psychopathologies.…”

Basal forebrain contributes to default mode network regulation

“…Because the DMN is an anatomically and functionally interconnected network (15), the fMRI activations in component areas tend to fluctuate in a coordinated manner even in anesthetized animals. However, some animal work has described a DMN based on awake-state data that is more in line with the studies in humans.…”

Functional connectivity with the retrosplenial cortex predicts cognitive aging in rats

“…30). As a starting point, our initial aim was to determine whether aged rats, like young animals (24,25,(31)(32)(33), display coherent rs-FC in the rodent homolog of the DMN, as defined by placing a seed in a key DMN hub, the retrosplenial/posterior cingulate cortex (RSC/PCC). Second, brain-wide rs-FC examined in this context allowed us to test whether changes in cortical network dynamics are specifically coupled with age-related cognitive decline or instead reflect an obligatory outcome of chronological aging.…”