The Effects of Locus Coeruleus Stimulation on Quasi-Periodic Patterns in Rats.
Poster No:
2333
Submission Type:
Abstract Submission
Authors:
Nmachi Anumba1, Michael Kelberman2, Nan Xu1, Wen-Ju Pan1, David Weinshenker2, Shella Keilholz1
Institutions:
1Georgia Tech and Emory University, Atlanta, GA, 2Emory University, Atlanta, GA
First Author:
Co-Author(s):
Introduction:
The Locus Coeruleus (LC), located in the brainstem, is the primary structure that synthesizes and delivers norepinephrine to other parts of the brain [4] and is also involved in arousal, cognition, and attention [2]. Due to its diffuse projections throughout the brain, studying the effects of LC activity on whole-brain spatially evolving activity, such as quasi-periodic patterns (QPPs), is of great interest. QPPs are whole-brain patterns of activation and deactivation between different brain regions that propagate across the brain. Though their origins are unknown, preliminary work suggests that disruptions from baseline LC activity perturb the propagation of QPPs [1]. In this work, we used optogenetic-fMRI to study how optogenetic stimulation of the LC affects QPPs in real time.
Methods:
This study used a cohort of 6-month-old wildtype Fisher 344 rats that were bred in-house. When the rats (n=7) were 2 months old, they were injected intra-LC with a lentivirus containing channelrhodopsin-2 (ChR2) under the expression of the noradrenergic-specific promotor PRSx8. Control animals were injected with a similar virus that contained mCherry instead of ChR2 (n=9). Two weeks before scanning, rats were implanted with an optic ferrule and optogenetic LC stimulation was confirmed using pupillometry [5]. Resting-state fMRI scans were acquired using a 9.4 T Bruker MRI scanner while rats were intubated and maintained under 1.3% isoflurane. All 10-minute fMRI scans were gradient echo EPI with partial Fourier encoding with a factor of 1.4 and acquired with the following parameters: voxel size = 500 um3, matrix size = 70 x 70, slice number = 24, TE = 15 ms, TR = 1250 ms, and phase-locked to every other breath of a 1.6 Hz respiratory rate. Scans were preprocessed using a custom preprocessing pipeline [6]. A baseline scan with no stimulation, a scan at 5 Hz of constant LC stimulation, and a scan at 15 Hz phasic stimulation (3 pulses every 10 seconds) were acquired for each rat. All scans from each group were concatenated and a spatiotemporal pattern-finding algorithm [3] was used to identify QPPs within the datasets.
Results:
The activity of each region within the QPP was acquired and plotted over time (Figure 1). The QPP activity observed in the control rats (top row) showed similar regional activity across the differing levels of stimulation. However, in the LC stimulated rats (bottom row), stimulation at 5 Hz and 15 Hz resulted in distinct differences. Primarily, LC stimulation at both frequencies resulted in a notable increase of contribution from the cingulate cortex, which was not observed in the control rats. Additionally, LC stimulation at 5 Hz appeared to result in a phase shift in the somatosensory, insular, and striatal networks.
Conclusions:
These results indicate that stimulation of the LC at 5 Hz and 15 Hz phasic frequencies had distinct effects on the regions involved in the QPP, specifically the cingulate network. Additionally, in the case of 5 Hz stimulation, the timing of activity of other networks appeared to be affected. This analysis shows that LC stimulation at different frequencies resulted in distinct regional differences within the QPPs.
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 2
Novel Imaging Acquisition Methods:
BOLD fMRI 1
Keywords:
FUNCTIONAL MRI
Noradrenaline
Norpinephrine
1|2Indicates the priority used for review
Provide references using author date format
2. Aston-Jones, G. & Cohen, J. D. (2005) AN INTEGRATIVE THEORY OF LOCUS COERULEUS-NOREPINEPHRINE FUNCTION: Adaptive Gain and Optimal Performance. Annual Review of Neuroscience 28, 403–450.
3. Majeed, W. et al. (2011) Spatiotemporal dynamics of low frequency BOLD fluctuations in rats and humans. NeuroImage 54, 1140–1150.
4. Poe, G. R. et al. (2020) Locus coeruleus: a new look at the blue spot. Nature Review Neuroscience 21, 644–659.
5. Privitera, M. et al. (2020) A complete pupillometry toolbox for real-time monitoring of locus coeruleus activity in rodents. Nature Protocols 15, 2301–2320.
6. Xu, N. et al. (2023) Rodent Whole-Brain fMRI Data Preprocessing Toolbox. Aperture Neuro, 3, 1-3. https://doi.org/10.52294/001c.85075.