Effects of neonatal amygdala or hippocampus lesions on resting brain metabolism in the macaque monkey: A microPET imaging study

Abstract

Longitudinal analysis of animals with neonatal brain lesions enables the evaluation of behavioral changes during multiple stages of development. Interpretation of such changes, however, carries the caveat that permanent neural injury also yields morphological and neurochemical reorganization elsewhere in the brain that may lead either to functional compensation or to exacerbation of behavioral alterations. We have measured the long-term effects of selective neonatal brain damage on resting cerebral glucose metabolism in nonhuman primates. Sixteen rhesus monkeys (Macaca mulatta) received neurotoxic lesions of either the amygdala (n = 8) or hippocampus (n = 8) when they were 2-weeks-old. Four years later, these animals, along with age-and experience-matched sham-operated control animals (n = 8), were studied with high-resolution positron emission tomography (microPET) and 2-deoxy-2[ 18 F]fluoro-D-glucose ([ 18 F]FDG) to detect areas of altered metabolism. The groups were compared using an anatomically-based region of interest analysis. Relative to controls, amygdala-lesioned animals displayed hypometabolism in three frontal lobe regions, as well as in the neostriatum and hippocampus. Hypermetabolism was also evident in the cerebellum of amygdala-lesioned animals. Hippocampal-lesioned animals only showed hypometabolism in the retrosplenial cortex. These results indicate that neonatal amygdala and hippocampus lesions induce very different patterns of long-lasting metabolic changes in distant brain regions. These observations raise the possibility that behavioral alterations in animals with neonatal lesions may be due to the intended damage, to consequent brain reorganization or to a combination of both factors.The study of neurodevelopmental disorders within a clinical setting is inherently complex since each patient's specific behavioral and cognitive deficits stem from a unique interaction between genetic, neurobiological and environmental factors. Longitudinal analysis of animal models provides a complementary approach, since genetic, neurobiological and environmental factors * Corresponding Author: David G. Amaral, Ph.D., The M.I.N.D. Institute, University of California, Davis, 2825 50 th Street, Sacramento, CA 95817,, Email: dgamaral@ucdavis.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuroimage. Author manuscript; available in PMC 2009 January 15. Published in final edited form as:Neuroimage. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript can be selectively manipulated and tightly controlle...

Neonatal amygdala or hippocampus lesions influence responsiveness to objects

“…This behavioral disruption—decreased behavioral inhibition—observed in our young subjects was similar to that observed after similar brain damage imposed later in life. These findings therefore suggest that, despite reorganization of neural networks following damage (Machado, et al, 2008), early damage to regions of the medial temporal lobe, and the amgydala in particular, may have life-long consequences for emotional processing. …”

“…T2-weighted images of coronal sections through the mid portion of the amygdala are illustrated in previous publications (Lavenex, Banta Lavenex, & Amaral, 2007; Bauman et al, 2004a, 2004b), providing substantial reassurance that the ibotenic acid was injected and was focused in the amygdaloid complex or hippocampal formation. Lesion extent was further characterized in T1-weight MRI images when animals were four years of age (Machado, Snyder, Cherry, et al, 2008). The mean percentage of tissue loss for amygdala-lesioned animals was 71.9% (minimum 67.0%, maximum 80.7%) and for hippocampus-lesioned animals was 76.6% (minimum 66.0%, maximum 86.8%) (Machado et al, 2008).…”

“…Lesion extent was further characterized in T1-weight MRI images when animals were four years of age (Machado, Snyder, Cherry, et al, 2008). The mean percentage of tissue loss for amygdala-lesioned animals was 71.9% (minimum 67.0%, maximum 80.7%) and for hippocampus-lesioned animals was 76.6% (minimum 66.0%, maximum 86.8%) (Machado et al, 2008). …”

Dispositional negativity: An integrative psychological and neurobiological perspective.

“…Interestingly, viral vector manipulations that increase metabolic activity in the Ce—the other major component of the central extended amygdala—are associated with elevated metabolic activity in the OFC, increased functional connectivity between the Ce and OFC, and heightened signs of fear and anxiety during prolonged exposure to threat (Kalin et al, in press ). Conversely, Ce lesions are associated with reduced metabolic activity in the OFC (Machado et al, 2008). In other words, perturbations targeting one region (e.g., OFC or Ce damage) propagate to the others (e.g., reduced BST or OFC metabolism) and damage to either the Ce or OFC reduces, but does not abolish, defensive responses to threat.…”

Relationships between Hippocampal Atrophy, White Matter Disruption, and Gray Matter Hypometabolism in Alzheimer's Disease

“…For instance, PCC hypometabolism was observed in nonhuman primates after hippocampal and parahippocampal lesions (Meguro et al, 1999;Machado et al, 2008). In addition, significant positive correlations were reported in patients with AD between hippocampal formation size on the one hand, and either PCC activation during a memory task (Garrido et al, 2002;Remy et al, 2005) or posterior associative cortical areas resting-state metabolism (Meguro et al, 2001).…”