Leveraging large-scale brain networks in rats to understand neurological and psychiatric disorders in humans

The brain is organized into spatially distributed and functionally specific networks. The default-mode network (DMN) and salience network (SN) in humans have been shown to support a variety of cognitive and affective functions and have been implicated in multiple neurological and psychiatric disorders [1, 2]. As rodents are widely used as preclinical models of human diseases, identification of their brain networks analogous to those of humans would enhance mechanistic, causative understanding of their functions in health and disease.

We have shown, using resting-state functional MRI, that rats possess a DMN that is anatomically similar to the DMNs of nonhuman primates and humans [3]. As shown in Fig. 1A, the identified DMN of rats includes orbital cortex, prelimbic cortex, cingulate cortex, auditory/temporal association cortex, posterior parietal cortex, retrosplenial cortex and hippocampus, which closely resemble the regions of DMN in humans. We further demonstrated that the rat DMN exhibits a modular structure, like that in human DMN, with subcomponents supporting distinct functions [4]. As an example of leveraging the rat DMN to understand various functions of this brain network, we conducted experiments in a rat model of cognitive aging. Relative to both young rats and aged rats with preserved memory, the aged rats with memory deficits displayed disrupted functional connectivity with the retrosplenial/posterior cingulate cortex, a key component of the DMN. These alterations in functional connectivity were coupled with variability in memory function during aging. The data supports the notion that adaptive plasticity in the aged brain contributes to successful cognitive aging [5].

Fig. 1: The default mode network and salience network across species.

A Comparison of the default mode network (DMN) in rats, rhesus monkeys, and humans identified from resting-state functional MRI (adapted with permission from Lu et al. in Proceeding of National Academy of Sciences, copyright 2012 National Academy of Sciences). The rat DMN (left) includes: 1, orbital cortex; 2, prelimbic cortex (PrL); 3, cingulate cortex (CG1, CG2); 4, auditory/temporal association cortex (Au1, AuD, AuV, TeA); 5, posterior parietal cortex; 6, retrosplenial cortex; and 7, hippocampus (CA1). The monkey DMN (center) includes: 2/3, dorsal medial prefrontal cortex (mPFC); 4/5, lateral temporoparietal cortex; 6, posterior cingulate/precuneus cortex; and 7, posterior parahippocampal cortex. The human DMN (right) includes: 1, orbitofrontal cortex (OFC); 2/3, mPFC/anterior cingulate cortex (ACC); 4, lateral temporal cortex; 5, inferior parietal lobe; 6, posterior cingulate/retrosplenial cortex; and 7, hippocampus/parahippocampal cortex. B Comparison of the salience network (SN) in rats, marmoset monkeys, and humans identified from resting-state functional MRI (adapted from Tsai et al. in Biological Psychiatry 2020 with permission from Springer Nature). The rat SN (left) includes: 1/2, ventral/lateral orbital cortex (VO/LO); 3/4, PrL/infralimbic cortex (IL); 5/6, dorsal/ventral agranular insular cortex (AID/AIV); and 7/8, CG1/CG2. The marmoset SN (center) includes: 1, mPFC; 2, ACC; 3, OFC; 4, gustatory cortex; and 5, anterior insula (AI). The human SN (right) includes: 1, ACC; 2, AI; and 3, striatum.

More recently, we identified a SN in rats, using functional MRI and neural tracing data [6]. The anatomical profile of the identified rat SN is analogous to that of nonhuman primates and humans, including primarily the anterior insula and anterior cingulate cortex (Fig. 1B). Leveraging the rat SN, we assessed the response of this network to conditioned cues in rats with a history of heroin self-administration. Our data demonstrated that the rat SN responds to conditioned cues and increases functional connectivity to the DMN during conditioned heroin withdrawal [6].

A crucial element in the success of our functional MRI experiment was the introduction of a new anesthetic regimen [1]. This regimen combined a low dose of dexmedetomidine (an α2 agonist) with the gaseous anesthetic isoflurane, which has now become the preferred anesthesia method in rodent functional MRI. The identification of rat DMN and SN, together with a demonstration of their functional relevance, provides a novel platform to interrogate function and dysfunction of these brain networks. Complementary to clinical studies that are often limited to cross-sectional investigations, preclinical models permit longitudinal studies combined with invasive manipulations. The DMN and SN in rat brains may be used to understand their roles (both cellular and systemic) across the entire trajectory of a brain disorder including predisposing risks, initial onset, full manifestation, and treatment outcome.