Functional connectivity MRI tracks memory networks after maze learning in rodents☆
Introduction
A defining characteristic of the brain is its remarkable plasticity to undergo learning-induced functional and morphological remodeling throughout the lifespan of the organism. Current understanding of the neural mechanisms of learning and memory largely relies on invasive methods from electrophysiology, lesions, pharmacological modulation to genetic manipulation. Less invasive imaging could provide an understanding of the brain network at a system level. For example, markers of metabolic activity have been applied in mapping learning-induced plasticity in the brain, such as, 14C-2-deoxyglucose autoradiography of cerebral glucose metabolism (Bontempi et al., 1999, Kennedy et al., 1975, Sif et al., 1991), cytochrome oxidase activity (Conejo et al., 2010, Fidalgo et al., 2011), and c-fos (He et al., 2002). However, the invasiveness of these techniques prohibits longitudinal studies and the detection of dynamics in cognitive processes.
With the advent of MRI, structural and functional changes after learning have been detected in humans using structural imaging (Maguire et al., 1997), diffusion imaging (Schlegel et al., 2012), task functional MRI (fMRI) (Borst and Anderson, 2012) and, recently, resting-state fMRI (rsMRI) (Taubert et al., 2011). Similar approaches have been applied in animal models. For instance, morphological alterations in gray matter volume and diffusion anisotropy were demonstrated in rodents after Morris water maze learning (Blumenfeld-Katzir et al., 2011, Lerch et al., 2011). However, due to the tiny structural difference, high-resolution ex vivo imaging was typically required. Plasticity in brain function could also be detected by fMRI using sensory stimulation to observe cortical plasticity after peripheral nerve amputation (Pelled et al., 2009, Pelled et al., 2007, Weng et al., 2011), or direct hippocampal stimulation to inspect long-term potentiation (LTP) (Canals et al., 2009). However, the lack of suitable task and the use of anesthesia during structural and functional MRI limit its application in cognitive studies in animals, especially rodent models.
RsMRI, which detects the spontaneous, synchronous oscillations across the brain without a task, provides a potential means to investigate learning-induced network change. Strengthened synchronous activity, also known as functional connectivity, has been reported after motor or visual perceptual learning in human (Albert et al., 2009, Lewis et al., 2009, Vahdat et al., 2011). Although others and we have recently demonstrated rsMRI in rodents (Nasrallah et al., 2012, Nasrallah et al., 2014, Pawela et al., 2008), an intriguing question is whether the plasticity in synchronous activity induced after a cognitive task will be preserved so that it can then be subsequently imaged in the sedated rodent. We hypothesized that the ongoing change in neural synchrony can be detected in vivo in sedated rats. Indeed, after training in the Morris water maze (MWM), we observed large-scale plasticity in functional networks using rsMRI.
Section snippets
Experimental design
All experiments were compliant with the National Advisory Committee for Laboratory Animal Research guidelines and approved by the Institutional Care and Use Committee (Biomedical Sciences Institutes, Singapore). A total of 45 male adult Wistar rats (350–400 g) were subdivided into five groups: naive control (n = 10), 5-day trained (n = 9), 5-day swim control (n = 8), 1-day trained (n = 9) and 1-day swim control (n = 9). MRI was performed 1 and 7 days after the last day of MWM training.
Behavior
The trained rats
Behavior
The rats showed a decrease in latency times in the 1st trial on each successive day of the MWM training (Fig. 1A). Since day 3, the latency time decreased significantly to less than 10s (p < 0.05). To evaluate the influence of sedative on memory, probe tests were conducted on day 2 and 8 after training in 3 sets of rats (supplementary method). With medetomidine infusion on both day 1 and 7, no difference in the latency was seen compared to that injected with saline (7.54 ± 0.58 vs 7.12 ± 0.31 s,
Discussion
Intensive learning has been found to alter functional connectivity in the resting human brain (Langer et al., 2013, Lewis et al., 2009, Mackey et al., 2013, Urner et al., 2013, Yoo et al., 2013). While direct stimulation of hippocampal pathways can be used to map learning induced plasticity in rodents (Canals et al., 2009), it is difficult to image the activity under the performance of a cognitive task. Here we demonstrated that large-scale plasticity can also be detected in sedated rodent
Acknowledgments
We like to thank the Singapore Research Centre of GlaxoSmithKline R&D China for the access of the water maze facility. We appreciate Prof K.C. Liang of National Taiwan University, Taiwan on the design of behavior training. The work was supported by the Intramural Research program of the Singapore Bioimaging Consortium, Biomedical Sciences Institutes, Agency for Science, Technology and Research (A*STAR), Singapore.
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Footnote: part of the results have been presented in the joint meeting of the 19th Annual Meeting of the International Society for Magnetic Resonance in Medicine, Montreal, Canada, 2011.