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. 2011;6(11):e27839.
doi: 10.1371/journal.pone.0027839. Epub 2011 Nov 18.

Default-mode-like Network Activation in Awake Rodents

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Free PMC article

Default-mode-like Network Activation in Awake Rodents

Jaymin Upadhyay et al. PLoS One. .
Free PMC article

Abstract

During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimer's, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess 'DMN-like' functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = -0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks.

Conflict of interest statement

Competing Interests: Jaymin Upadhyay, Scott J. Baker, Prasant Chandran, Loan Miller, Younglim Lee, Gerard J. Marek, Unal Sakoglu, Chih-Liang Chin, Feng Luo, Gerard B. Fox, and Mark Day are stated as employees of Abbott Laboratories during the time at which this experiment took place and was completed. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Respiratory Rates and Head Displacement During Awake Resting-State fMRI for Days 2-8.
A. Respiratory rates significantly decreased between Day 2 and every other scanning session (Days 4-8) where the lowest respiratory rate was measured at Day 8. Respiratory rates between Day 2 and each of the other scanning days (Days 4, 6 and 8) were statistically compared using a 2-tailed unpaired, t-tests. (Day 4: t10 = 2.42, p = 0.036; Day 6: t12 = 2.52, p = 0.027; Day 8: t12 = 3.64, p = 0.027) The ANOVA test revealed significant between day differences for respiratory rate (F3,22 = 3.99, p = 0.021), but not for head displacement (F3,22 = 0.88, p = 0.47). B. Head displacement was less than the size of the imaging voxel for all scanning sessions, but did not significantly differ between Days 2-8. The displacement is relative to a reference volume (Volume 60 of 120). Respiratory rates and head displacement between Day 2 and each of the other scanning days (Days 4, 6 and 8) were statistically compared using a 2-tailed unpaired, t-tests (Day 4: t10 = 0.58, p = 0.57; Day 6: t12 = 0.39, p = 0.70; Day 8: t12 = 1.55, p = 0.15). Error bars represent s.e.m. Day 2 (N = 7); Day 4 (N = 5); Day 6 (N = 7); Day 8 (N = 7). # p<0.05 and ## p<0.005.
Figure 2
Figure 2. Presence of DMN-like Activity in Awake Rodents.
A. At Day 2, seed region (anterior cingulate cortex) functional connectivity analysis did not yield CNS circuitry indicative of the DMN, but rather circuitry mediating anxiety ( Figure 3 ). CNS circuitry reflective of the DMN emerged at Day 8, when animals were more habituated to the MRI environment. All modeling and estimation of within-group (Day 2 and Day 8) and between-group (Day 2 < Day 8) functional connectivity with the anterior cingulate cortex was performed using mixed-effects analysis. Cluster size correction for all activation maps was also performed. All statistical maps are superimposed upon an in-house, high-resolution rat anatomical template. B. Time courses demonstrate increased coherence between cingulate and retrosplenial cortices at Day 8. C. An increasing trend in functional connectivity between the cinguate cortex and three other DMN structures was observed between Days 2-8. The ANOVA test for the three functional interactions quantified in C. An increasing trend in functional connectivity between the cinguate cortex and three other DMN structures was observed between Days 2-8. The ANOVA test for the three functional interactions quantified in C. were significant for cingulate-retrospenial (F3,22 = 3.69, p = 0.027) and cingulate-parietal (F3,22 = 4.44, p = 0.014) but not for cingulate-CA1 (F3,22 = 2.57, p = 0.080). Two-tailed, t-test were also implemented for specific pairwise comparisons (cingulate-retrosplenial- Day 4: t10 = -1.92, p = 0.084; Day 6: t12 = -2.26, p = 0.043; Day 8: t12 = -2.79, p = 0.016). (cingulate-parietal- Day 4: t10 = -1.96, p = 0.078; Day 6: t12 = -3.09, p = 0.0093; Day 8: t12 = -3.34, p = 0.0059). (cingulate-CA1- Day 4: t10 = -0.51, p = 0.62; Day 6: t12 = -1.13, p = 0.28; Day 8: t12 = -2.23, p = 0.045). All error bars represent s.e.m. Day 2 (N = 7); Day 4 (N = 5); Day 6 (N = 7); Day 8 (N = 7). # p<0.05.
Figure 3
Figure 3. Functional Connectivity in the Anxiety Network in Non-habituated, Awake Rats.
A-B. Functional connectivity amongst the anterior cingulate cortex and brain regions implicated in anxiety was significantly greater during the initial scanning session at Day 2. All statistical maps are superimposed upon an in-house, high-resolution rat anatomical template. B. Functional connectivity at Day 2 and Day 8 is quantified between the cingulate and anteroventral thalamus, and also with the posterior hypothalamic area. The ANOVA test yielded insignificant results for the cingulate-anteroventral thalamus (F3,22 = 2.49, p = 0.087) and cingulate-posterior hypothalamic area (F3,22 = 1.37, p = 0.27) functional interactions. Two-tailed, t-test did reveal significant differences particularly between Day 2 and Day 8 (cingulate-anteroventral thalamus- Day 4: t10 = 1.91, p = 0.09; Day 6: t12 = 1.31, p = 0.22; Day 8: t12 = 2.26, p = 0.043). (cingulate-posterior hypothalamic area- Day 4: t10 = 1.07, p = 0.30; Day 6: t12 = 0.52, p = 0.61; Day 8: t12 = 2.74, p = 0.018). All error bars represent s.e.m. Day 2 (N = 7); Day 4 (N = 5); Day 6 (N = 7); Day 8 (N = 7). # p<0.05 C. A significant inverse correlation was detected between the cingulate-default mode and cingulate-anxiety network structures. One statistical outlier (Z = 3.76) was detected using Grubb's test for outlier detection, and not included in correlation analysis. For N = 26, Z-critical  =  2.84 (p<0.05).
Figure 4
Figure 4. At Day 2, the within group, functional connectivity analysis demonstrated a significant de-coherence between the cingulate and insula cortex as well as the hippocampal formation (dentate gyrus, subiculum) and periaqueductal gray.
Significant de-coherences between the cingulate and components of the task positive network such as the motor cortex were not observed.

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