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Review
. 2018 May 18;11(5):dmm031724.
doi: 10.1242/dmm.031724.

A guide to using functional magnetic resonance imaging to study Alzheimer's disease in animal models

Mazen Asaad  1   2 , Jin Hyung Lee  3   4   5   6
Affiliations
Review

A guide to using functional magnetic resonance imaging to study Alzheimer's disease in animal models

Mazen Asaad et al. Dis Model Mech. .

Abstract

Alzheimer's disease is a leading healthcare challenge facing our society today. Functional magnetic resonance imaging (fMRI) of the brain has played an important role in our efforts to understand how Alzheimer's disease alters brain function. Using fMRI in animal models of Alzheimer's disease has the potential to provide us with a more comprehensive understanding of the observations made in human clinical fMRI studies. However, using fMRI in animal models of Alzheimer's disease presents some unique challenges. Here, we highlight some of these challenges and discuss potential solutions for researchers interested in performing fMRI in animal models. First, we briefly summarize our current understanding of Alzheimer's disease from a mechanistic standpoint. We then overview the wide array of animal models available for studying this disease and how to choose the most appropriate model to study, depending on which aspects of the condition researchers seek to investigate. Finally, we discuss the contributions of fMRI to our understanding of Alzheimer's disease and the issues to consider when designing fMRI studies for animal models, such as differences in brain activity based on anesthetic choice and ways to interrogate more specific questions in rodents beyond those that can be addressed in humans. The goal of this article is to provide information on the utility of fMRI, and approaches to consider when using fMRI, for studies of Alzheimer's disease in animal models.

Keywords: Alzheimer's disease; Anesthesia; Mouse models; Resting state; fMRI.

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Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Figures

Fig. 1.
Fig. 1.
Schematic of rodent and human brain regions commonly identified in fMRI studies of AD. (A,B) Locations of brain regions in which fMRI detects changes in AD in rodent (A) and human (B) subjects. Regions are shown overlayed on a sagittal view of the brain. Numbers in brackets in A indicate the number of published studies that found a particular brain region to be affected in animal models of AD by using fMRI; specifically, the cingulate cortex (CC) [4] (Grandjean et al., 2016; Mueggler et al., 2002; Parent et al., 2017; Shah et al., 2016); the entorhinal cortex (EC) [3] (Little et al., 2012; Moreno et al., 2007; Nuriel et al., 2017); the hippocampus (Hipp) [10] (Grandjean et al., 2016; Latif-Hernandez et al., 2017; Little et al., 2012; Moreno et al., 2007; Nuriel et al., 2017; Parent et al., 2017; Shah et al., 2013, 2016; Wiesmann et al., 2016, 2017); the motor cortex (MC) [4] (Grandjean et al., 2014b; Mueggler et al., 2002; Wiesmann et al., 2016, 2017); the prefrontal cortex (PFC) [2] (Latif-Hernandez et al., 2017; Grandjean et al., 2016); the somatosensory cortex (SC) [9] (Grandjean et al., 2014b, 2016; Little et al., 2012; Mueggler et al., 2002, 2003; Sanganahalli et al., 2013; Shah et al., 2013; Wiesmann et al., 2016, 2017); and the visual cortex (VC) [5] (Grandjean et al., 2016; Little et al., 2012; Mueggler et al., 2002; Wiesmann et al., 2016, 2017).
Fig. 2.
Fig. 2.
Regions found to be affected by AD in rodent fMRI studies. (A-C) The highlighted areas, overlayed onto MRI images of normal rodent brains, represent the brain regions that show different activities in fMRI studies of AD (summarized in Table 3). For clarity, the study results are divided into three groups: those that investigated the response to a specific stimulus (A), those that looked at changes within a single specific brain region during the resting state (B), and those that looked at changes in functional connectivity between brain regions during the resting state (C). AC, auditory cortex; CC, cingulate cortex; dHipp, dorsal hippocampus; EC, entorhinal cortex; MC, motor cortex; PC, piriform cortex; PFC, prefrontal cortex; RSC, retrosplenial cortex; SC, somatosensory cortex; Str, striatum; VC, visual cortex; vHipp, ventral hippocampus.
Fig. 3.
Fig. 3.
Schematic of optogenetic fMRI experiments. (A) First, rodents are injected with a viral vector that induces neurons to express opsins, light-responsive membrane-bound proteins that, when expressed, allow light to trigger or inhibit neural firing. The animals are also implanted with an optic fiber that allows light to be delivered to a specific region of the brain. (B) The opsin can be expressed in specific cell types, shown here as different colored neurons. Note that only the green neuron is expressing the opsin, as highlighted by the blue proteins in the membrane of the cell. Cell-type-specific targeting allows researchers to focus on specific cell types, such as cholinergic neurons, a population known to be degenerated in AD, in order to better understand the downstream effects of cholinergic dysfunction. (C) Opsin-expressing neurons are stimulated with light during fMRI in order to visualize the resulting circuit activity throughout the whole brain. (D) Example of ofMRI data from wild-type rats showing the response of hippocampal neurons to optogenetic stimulation. Higher coherence values indicate stronger activation in that region. The location of the optic fiber is indicated by the blue arrowhead.
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