Thalamic Hubness as a Predictor of Thalamocortical Connectivity Following Locus Coeruleus Activation
Poster No:
1809
Submission Type:
Abstract Submission
Authors:
LiMing Hsu1, Patricia Jensen2, Yen-Yu Shih1
Institutions:
1University of North Carolina at Chapel Hill, Chapel Hill, NC, 2NIEHS/NIH, RTP, NC
First Author:
Co-Author(s):
Introduction:
The medial prefrontal cortex (mPFC) is robustly manipulated by the locus coeruleus noradrenergic neurons (LC-NE) and integrates a variety of inputs from limbic thalamus that give rise to goal-directed behaviors (i.e., cognitive and executive functions)(1–3). To address how thalamus regulates the LC-NE-induced functional connectivity changes, we employed an intersectional chemogenetic approach4 to modulate LC-NE activity in the mouse brain and examined functional connectivity (FC) and hubness scores using functional magnetic resonance imaging (fMRI). We found that LC-NE neuronal activity driven by chemogenetic stimulation most robustly decreased FC between prelimbic cortex (PrL) and mediodorsal thalamus (MD), and that this observed FC decreases were causally manipulated by baseline hubness of paraventricular thalamic nucleus (PVT). This work suggests a critical role of PVTs thalamus functional integration in regulating the subsequent LC-induced FC changes, which may help explain the individual difference in LC-related behaviors.
Methods:
This study utilized transgenic mice with hM3Dq-DREADD receptors selectively expressed in Dbh+ NE neurons, targeting NE neuronal subpopulations in the LC(4). The experiment involved three groups: LC-NE (n=9), Hoxb1-NE (n=8), and control mice (n=12). Each group was anesthetized and underwent fMRI both before and after chemogenetic stimulation with Clozapine-N-Oxide (CNO). The experimental design incorporated a 10-minute baseline and a subsequent post-CNO segment 20-30 minutes after administration. MRI data acquisition was conducted using a Bruker BioSpec 9.4-Tesla system. The preprocessing of the fMRI data followed protocols established in our previous study(1,2). All animal procedures were approved from the Institutional Animal Care and Use Committee of the University of North Carolina at Chapel Hill.
Results:
Modularity analysis5 of the mPFC during resting state fMRI identified four functional modules: infralimbic cortex (IL), prelimbic cortex (PrL), anterior cingulate cortex (ACC), and posterior cingulate cortex (PCC) (Fig. 1a and 1b). Following CNO injection, the En1 group exhibited a significant FC reduction between the PrL module and mediodorsal MD, with the most notable effect observed at 30 minutes post-injection (Fig. 1c and 1d). Additionally, the LC-NE group also showed a notable decreasing trend in FC over time (Fig. 1e). Correspondingly, the enhanced green fluorescent protein (EGFP) tracer injections into MD and LH were in line with the peak FC changes identified by ANOVA, with projections to the PrL (Fig. 1f)(6).
To discern the thalamic region influencing mPFC-MD circuit changes, we assessed the thalamus's degree of centrality (DC)7 at Baseline, identifying the PVT as a hub linked to PrL-MD FC changes (Fig. 2a). Linear mixed-effects (LME) models further confirmed a causal relationship between baseline DC and subsequent FC changes at multiple time points post-CNO (Fig. 2b). Force-directed graphs showed individual thalamic connectivity at Baseline, highlighting the highest, median, and lowest of mean DC in PVT (Fig. 2c). The global efficiency of PVT at Baseline was significantly correlated with PrL-MD FC changes at Post-30 (Fig. 2d) and showed higher global efficiency than other thalamic regions, confirming its hub status (Fig. 2e). These findings suggest that high DC in PVT is associated with its functional integration in the thalamus and contributes to the LC-NE induced decline in PrL-MD FC.
To discern the thalamic region influencing mPFC-MD circuit changes, we assessed the thalamus's degree of centrality (DC)7 at Baseline, identifying the PVT as a hub linked to PrL-MD FC changes (Fig. 2a). Linear mixed-effects (LME) models further confirmed a causal relationship between baseline DC and subsequent FC changes at multiple time points post-CNO (Fig. 2b). Force-directed graphs showed individual thalamic connectivity at Baseline, highlighting the highest, median, and lowest of mean DC in PVT (Fig. 2c). The global efficiency of PVT at Baseline was significantly correlated with PrL-MD FC changes at Post-30 (Fig. 2d) and showed higher global efficiency than other thalamic regions, confirming its hub status (Fig. 2e). These findings suggest that high DC in PVT is associated with its functional integration in the thalamus and contributes to the LC-NE induced decline in PrL-MD FC.
Conclusions:
The study elucidates the neuromodulatory role of the LC-NE system in thalamocortical connectivity, highlighting the predictive value of thalamic hubness, particularly of PVT, in LC-NE induced changes(8). This research provides insights into the mechanisms underlying LC-NE modulation of cognitive functions, with potential implications for understanding disorders involving mPFC and LC-NE system dysfunctions (9,10).
Brain Stimulation:
Non-Invasive Stimulation Methods Other 2
Higher Cognitive Functions:
Higher Cognitive Functions Other
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural)
fMRI Connectivity and Network Modeling 1
Physiology, Metabolism and Neurotransmission :
Neurophysiology of Imaging Signals
Keywords:
Other - Locus Coeruleus; Medial Prefrontal Cortex; Thalamocortical Connectivity; Chemogenetic Stimulation; Functional MRI; Neurology
1|2Indicates the priority used for review
Provide references using author date format
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