Elsevier

NeuroImage

Volume 127, 15 February 2016, Pages 196-202
NeuroImage

Functional connectivity MRI tracks memory networks after maze learning in rodents

https://doi.org/10.1016/j.neuroimage.2015.08.013Get rights and content

Highlights

  • Learning induced plasticity can be detected by resting state connectivity in sedated rodent brain.

  • After water maze learning, correlations with hippocampal CA3 increased in septum, thalamus, cingulate cortex, etc.

  • The connectivity then reorganized toward the cortex 7 days after training.

  • Learning enhanced connectivity in the default mode network.

Abstract

Learning and memory employs a series of cognitive processes which require the coordination of multiple areas across the brain. However in vivo imaging of cognitive function has been challenging in rodents. Since these processes involve synchronous firing among different brain loci we explored functional connectivity imaging with resting-state fMRI. After 5-day training on a hidden platform watermaze task, notable signal correlations were seen between the hippocampal CA3 and other structures, including thalamus, septum and cingulate cortex, compared to swim control or naïve animals. The connectivity sustained 7 days after training and was reorganized toward the cortex, consistent with views of memory trace distribution leading to memory consolidation. These data demonstrates that, after a cognitive task, altered functional connectivity can be detected in the subsequently sedated rodent using in vivo imaging. This approach paves the way to understand dynamics of area-dependent distribution processes in animal models of cognition.

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.

References (62)

  • M. Hasselmo et al.

    Hippocampal mechanisms for the context-dependent retrieval of episodes

    Neural Netw.

    (2005)
  • J. He et al.

    A role of Fos expression in the CA3 region of the hippocampus in spatial memory formation in rats

    Neuropsychopharmacology

    (2002)
  • N. Langer et al.

    The effects of working memory training on functional brain network efficiency

    Cortex

    (2013)
  • J. Lerch et al.

    Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning

    NeuroImage

    (2011)
  • Z. Liang et al.

    Anticorrelated resting-state functional connectivity in awake rat brain

    NeuroImage

    (2012)
  • L. Nadel et al.

    Memory consolidation, retrograde amnesia and the hippocampal complex

    Curr. Opin. Neurobiol.

    (1997)
  • F. Nasrallah et al.

    Pharmacological modulation of functional connectivity: alpha-2-adrenergic receptor agonist alters synchrony but not neural activation

    NeuroImage

    (2012)
  • F. Nasrallah et al.

    Detection of functional connectivity in the resting mouse brain

    NeuroImage

    (2014)
  • G. Pelled et al.

    Functional MRI detection of bilateral cortical reorganization in the rodent brain following peripheral nerve deafferentation

    NeuroImage

    (2007)
  • P. Schweinhardt et al.

    A template for spatial normalisation of MR images of the rat brain

    J. Neurosci. Methods

    (2003)
  • J. Sif et al.

    Time-dependent sequential increases in [14C]2-deoxyglucose uptake in subcortical and cortical structures during memory consolidation of an operant training in mice

    Behav. Neural Biol.

    (1991)
  • L. Squire et al.

    The neuroscience of remote memory

    Curr. Opin. Neurobiol.

    (2007)
  • A. Tambini et al.

    Enhanced brain correlations during rest are related to memory for recent experiences

    Neuron

    (2010)
  • M. Taubert et al.

    Long-term effects of motor training on resting-state networks and underlying brain structure

    NeuroImage

    (2011)
  • M. Urner et al.

    Early visual learning induces long-lasting connectivity changes during rest in the human brain

    NeuroImage

    (2013)
  • T. van Groen et al.

    The role of the laterodorsal nucleus of the thalamus in spatial learning and memory in the rat

    Behav. Brain Res.

    (2002)
  • J. Weng et al.

    Mapping plasticity in the forepaw digit barrel subfield of rat brains using functional MRI

    NeuroImage

    (2011)
  • J. Aggleton et al.

    Episodic memory, amnesia, and the hippocampal–anterior thalamic axis

    Behav. Brain Sci.

    (1999)
  • J. Aggleton et al.

    Hippocampal–anterior thalamic pathways for memory: uncovering a network of direct and indirect actions

    Eur. J. Neurosci.

    (2010)
  • G. Berns et al.

    Short- and long-term effects of a novel on connectivity in the brain

    Brain Connect.

    (2013)
  • T. Blumenfeld-Katzir et al.

    Diffusion MRI of structural brain plasticity induced by a learning and memory task

    PLoS ONE

    (2011)
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