Neuroanatomical changes in a mouse model of early life neglect - PubMed (original) (raw)

Neuroanatomical changes in a mouse model of early life neglect

Alvaro Duque et al. Brain Struct Funct. 2012 Apr.

Abstract

Using a novel mouse model of early life neglect and abuse (ENA) based on maternal separation with early weaning, George et al. (BMC Neurosci 11:123, 2010) demonstrated behavioral abnormalities in adult mice, and Bordner et al. (Front Psychiatry 2(18):1-18, 2011) described concomitant changes in mRNA and protein expression. Using the same model, here we report neuroanatomical changes that include smaller brain size and abnormal inter-hemispheric asymmetry, decreases in cortical thickness, abnormalities in subcortical structures, and white matter disorganization and atrophy most severely affecting the left hemisphere. Because of the similarities between the neuroanatomical changes observed in our mouse model and those described in human survivors of ENA, this novel animal model is potentially useful for studies of human ENA too costly or cumbersome to be carried out in primates. Moreover, our current knowledge of the mouse genome makes this model particularly suited for targeted anatomical, molecular, and pharmacological experimentation not yet possible in other species.

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Figures

Fig. 1

Hemispheric asymmetry and gross structural changes. Structural and myelination differences can be observed throughout the rostrocaudal extent in coronal sections between the two hemispheres of MSEW animals. a–d Differences in hemispheric size, denoted in a with a dorsal red line contour of the RH whose mirror image does not match the LH. In every case, at least dorsally, the LH is smaller than the RH at both rostral and caudal levels and in nissl (not shown), golgi (a, b), and myelin (c, d)-stained material. a, b Illustrate, in sections from different animals, differences in cortical thickness most strikingly clear in the dorsal LH (#1). The dotted white lines in b illustrate the general dorsal cortical areas where measurements were taken to compare cortical thickness between the two hemispheres. c–f Illustrate, in Black Gold II myelin-stained material, both structural changes and myelin deficits in the MSEW animals as compared with controls. Some abnormalities observed are: (#2) a very marked difference in the mediolateral extent of the hippocampus between LH and RH of MSEW animals; (#3) a very salient deficit in the thickness, at this rostrocaudal level, of the cc as well as the amount of myelinated septofimbrial fibers of MSEW as compared with control; (#4) very poor amount of myelinated fibers in the internal capsule and stria terminalis in the LH of the MSEW as compared with its RH counterpart or to the corresponding controls; and similarly, (#5) a thinner stria medullaris and absent fornix or fornix not detected with myelin staining. Other differences included widespread disorganization of myelin fibers and decreased content in areas such as those surrounding the basolateral amygdala (#6) and the anterior commissure (not shown). In controls, hemisphere size and the sizes and positions of different structures always appear symmetrical and all myelin fibers and other structures appear present. The inter-hemispheric differences in size of different structures in the MSEW case cannot be accounted for by inter-hemispheric difference in the rostroventral axis, i.e., it is not the case that one hemisphere is at a substantially more caudal level than the other. Brain sections from control cases always appeared more symmetrical than those from MSEW cases at all rostro-caudal levels and in both medio-lateral as well as dorso-ventral directions

Fig. 2

Alterations in white matter tracks. Myelination defects are not limited to one hemisphere but are more salient in the LH and at both rostral and caudal levels. a The LH ac of a MSEW animal appears shrunk or incomplete in its robustness. Demyelinated and apparently degenerating fibers make the periphery of the fiber bundle appear empty. The extent of demyelination was very clear in 7 of 12 MSEW cases examined and in none of the controls (b, also 12 cases examined). Similarly, there are clear differences in myelination between the LH and the RH of a MSEW case at a more caudal level. These differences are obvious in both myelin (c) and in cresyl violet nissl (d) staining (adjacent sections). In d, black arrowheads indicate the presence of lemniscal fibers in the RH and white arrowheads indicate the absence of the corresponding bundle in the LH. Series of sections were followed in this particular case and the same observation was made in several other MSEW cases (5 out of 12 cases examined). This was not observed in any of the control cases (0 of 12 cases examined). Also noticeable in c, d is the difference in hippocampal size between RH and LH. e, f Magnetic resonance (spin-echo) anatomical images from a single MSEW animal show clear differences in size between LH and RH. In the rostral image (e) the dashed line helps distinguish the difference. At the caudal level the difference in size is so obvious the dashed line is unnecessary (there is also a small notch of the LH ventrolateral pole). In an individual case like this it is not possible to ascertain internal morphological details. In g, h averaged FA maps indicate that, in general, the DTI imaging results agree with the histological results. Here g shows asymmetry in the LH ac, which appears smaller, of MSEW mice (n = 5), than the corresponding ac in control mice (n = 5). At a more caudal level h shows higher density of fibers in the RH (black arrowheads) than in LH (white arrowheads) of MSEW mice (n = 5). The FA scale was contracted between 0 and 0.36 (instead of 0 and 1) to allow better visualization of differences between the MSEW and control cases. Additional gross changes are visualized in Fig. 4. Note that histology and imaging were done in different groups of animals

Fig. 3

Hemispheric and hippocampal perimeters and cortical and corpus callosum thickness are affected in MSEW mice. a Example of LH versus RH perimeters in one pair of animals (1 control, 1 MSEW). To facilitate viewing the hemispheres are color coded and not all perimeters are shown. Differences in size between LH and RH in the MSEW case are obvious and also easy to see in reference to controls when perimeters are superimposed. b The average LH perimeter of MSEW animals is significantly smaller than its RH counterpart and any hemisphere of controls. This difference is statistically significant. c The LH of the MSEW animals is approximately 6% smaller than its RH counterpart or any hemisphere of controls. d When cortical thickness is compared between LH and RH of controls, the difference is on average only 1.1 ± 1.6% while the same comparison in MSEW animals indicates a mean difference of 10. 3 ± 2.2%. The difference in the means between control and MSEW is statistically significant. e When the size of the hippocampus in the LH is compared with the size of the corresponding RH hippocampus in the same section, the mean difference in mediolateral (3.4 ± 1.4%), dorsoventral (2.8 ± 1.4%) or whole perimeter (3.2 ± 1.5%) is less than 5% for every parameter measured. On the other hand, because in all MSEW cases the LH hippocampus is substantially smaller than the RH hippocampus, the same comparisons indicate substantial differences: 26.8 ± 2.4% for the ML extent, 9.5 ± 3.2% for the DV extent, and 22.8 ± 2.7% for perimeter. Comparison of differences between controls and MSEW cases reached statistical significance for the ML extent and perimeter. f Since the corpus callosum thickness was taken at the midline between the hemispheres, sections, matched at rostrocaudal levels, between control and MSEW cases were compared. The corpus callosum thickness was made 100% in every control section. The decrease in the thickness of the corpus callosum for MSEW cases was calculated to be on average 14.6 ± 3.4%. All mean values are given ±SEM, as indicated also by the error bars. **p < 0.05

Fig. 4

Diffusion tensor imaging (DTI) indicates reduced FA in MSEW mice. Averaged FA maps for MSEW (n = 5) and control mice (n = 5) for five contiguous slices, where each slice was 100-μm thick and spaced apart by 200 μm. In all regions identified by the black arrowheads the FA values were lower in MSEW cases. These regions include, among others, middle and deeper cortical layers, external capsule, thalamus, basaloteral amygdala, and an apparent disconnection between corpus callosum and cingulum. Differences in hemispheric size between MSEW and control cannot be discerned here because unsmoothed FA maps were warped to a common coordinate space. The FA scale was contracted between 0 and 0.36 (instead of 0 and 1) to allow better visualization of differences

Fig. 5

Olig2 is altered in different regions of MSEW mice. The density of Olig2-positive cells per mm3 was statistically significantly higher in the PFC and genu of the cc of the LH as compared with it RH counterpart and to the average of both hemispheres in controls. There was little difference in the Olig2 density between hemispheres of control animals, or these hemispheres and the RH of MSEW animals. In the motor cortex the density of Olig2-positive cells was lower in the LH as compared with the RH, and in the PFC the RH of MSEW had lower density than the average in controls but these differences did not reach statistical significance

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Neuroanatomical changes in a mouse model of early life neglect - PubMed (original) (raw)