Showing papers by "Jacob Raber published in 2013"

Spatial navigation impairments among intellectually high-functioning adults with autism spectrum disorder: Exploring relations with theory of mind, episodic memory, and episodic future thinking

Abstract: Research suggests that spatial navigation relies on the same neural network as episodic memory, episodic future thinking, and theory of mind (ToM). Such findings have stimulated theories (e.g., the scene construction and self-projection hypotheses) concerning possible common underlying cognitive capacities. Consistent with such theories, autism spectrum disorder (ASD) is characterized by concurrent impairments in episodic memory, episodic future thinking, and ToM. However, it is currently unclear whether spatial navigation is also impaired. Hence, ASD provides a test case for the scene construction and self-projection theories. The study of spatial navigation in ASD also provides a test of the extreme male brain theory of ASD, which predicts intact or superior navigation (purportedly a systemizing skill) performance among individuals with ASD. Thus, the aim of the current study was to establish whether spatial navigation in ASD is impaired, intact, or superior. Twenty-seven intellectually high-functioning adults with ASD and 28 sex-, age-, and IQ-matched neurotypical comparison adults completed the memory island virtual navigation task. Tests of episodic memory, episodic future thinking, and ToM were also completed. Participants with ASD showed significantly diminished performance on the memory island task, and performance was positively related to ToM and episodic memory, but not episodic future thinking. These results suggest that (contra the extreme male brain theory) individuals with ASD have impaired survey-based navigation skills—that is, difficulties generating cognitive maps of the environment—and adds weight to the idea that scene construction/self-projection are impaired in ASD. The theoretical and clinical implications of these results are discussed.

Early Effects of Whole-Body 56Fe Irradiation on Hippocampal Function in C57BL/6J Mice

Abstract: Relatively little is known about early irradiation effects on hippocampal function in wild-type mice. In this study, the effects of (56)Fe irradiation on hippocampal function were assessed starting 2 weeks after whole-body irradiation. Compared to sham irradiation, radiation impaired novel object recognition in female and male C57BL/6J wild-type mice. There were no effects of irradiation on contextual fear conditioning or spatial memory retention in the water maze. It is possible that oxidative damage might contribute to radiation-induced cognitive changes. Therefore, hippocampal and cortical levels of 3-nitrotyrosine (3NT) and lipid peroxidation, measures of oxidative damage were assessed. There were no effects of irradiation on these measures of oxidative damage. As (56)Fe irradiation can increase reactive oxygen species (ROS) levels, which may contribute to the impairments in novel object recognition, the effects of the antioxidant alpha-lipoic acid (ALA) on cognition following sham irradiation and irradiation were also assessed. ALA did not prevent radiation-induced impairments in novel object recognition and impaired spatial memory retention of sham-irradiated and irradiated mice in the probe trial after the first day of hidden platform training in the water maze. Thus, the novel object recognition test is particularly sensitive to detect early cognitive effects of (56)Fe irradiation through a mechanism unlikely involving ROS or oxidative damage.

Enhanced hippocampus-dependent memory and reduced anxiety in mice over-expressing human catalase in mitochondria.

Abstract: Oxidative stress (OS) and reactive oxygen species (ROS) play a modulatory role in synaptic plasticity and signaling pathways. Mitochondria (MT), a major source of ROS because of their involvement in energy metabolism, are important for brain function. MT-generated ROS are proposed to be responsible for a significant proportion of OS and are associated with developmental abnormalities and aspects of cellular aging. The role of ROS and MT function in cognition of healthy individuals is relatively understudied. In this study, we characterized behavioral and cognitive performance of 5- to 6-month-old mice over-expressing mitochondrial catalase (MCAT). MCAT mice showed enhancements in hippocampus-dependent spatial learning and memory in the water maze and contextual fear conditioning, and reduced measures of anxiety in the elevated zero maze. Catalase activity was elevated in MCAT mice in all brain regions examined. Measures of oxidative stress (glutathione, protein carbonyl content, lipid peroxidation, and 8-hydroxyguanine) did not significantly differ between the groups. The lack of differences in these markers of oxidative stress suggests that the differences observed in this study may be due to altered redox signaling. Catalase over-expression might be sufficient to enhance cognition and reduce measures of anxiety even in the absence of alteration in levels of OS.

Evaluation of a Short-Form of the Berg Card Sorting Test

Abstract: The Psychology Experimental Building Language http://pebl.sourceforge.net/ Berg Card Sorting Test is an open-source neurobehavioral test. Participants (N = 207, ages 6 to 74) completed the Berg Card Sorting Test. Performance on the first 64 trials were isolated and compared to that on the full-length (128 trials) test. Strong correlations between the short and long forms (total errors: r = .87, perseverative response: r = .83, perseverative errors r = .77, categories completed r = .86) support the Berg Card Sorting Test-64 as an abbreviated alternative for the full-length executive function test.

Effects of alpha-lipoic acid on associative and spatial memory of sham-irradiated and 56Fe-irradiated C57BL/6J male mice.

Abstract: Cranial irradiation with 56Fe, a form of space radiation, causes hippocampus-dependent cognitive changes. 56Fe irradiation also increases reactive oxygen species (ROS) levels, which may contribute to these changes. Therefore, we investigated the effects of the antioxidant alpha lipoic acid (ALA) on cognition following sham-irradiation and irradiation. Male mice were irradiated (brain only) with 56Fe (3 Gy) or sham-irradiated at 6–9 months of age. Half of the mice remained fed a regular chow and the other half of the mice were fed a caloric-matched diet containing ALA starting two-weeks prior to irradiation and throughout cognitive testing. Following cognitive testing, levels of 3-nitrotyrosine (3NT), a marker of oxidative protein stress, and levels of microtubule-associated protein (MAP-2), a dendritic protein important for cognition, were assessed using immunohistochemistry and confocal microscopy. ALA prevented radiation-induced impairments in spatial memory retention in the hippocampal and cortical dependent water maze probe trials following reversal learning. However, in sham-irradiated mice, ALA treatment impaired cortical-dependent novel object recognition and amygdala-dependent cued fear conditioning. There was a trend towards lower 3NT levels in irradiated mice receiving a diet containing ALA than irradiated mice receiving a regular diet. In the hippocampal dentate gyrus of mice on regular diet, irradiated mice had higher levels of MAP-2 immunoreactivity than sham-irradiated mice. Thus, ALA might have differential effects on the brain under normal physiological conditions and those involving environmental challenges such as cranial irradiation.

Effects of Radiation Combined Injury on Hippocampal Function are Modulated in Mice Deficient in Chemokine Receptor 2 (CCR2)

Abstract: Chemokines and their receptors play a crucial role in normal brain function as well as in pathological conditions such as injury and disease-associated neuroinflammation. Chemokine receptor-2 (CCR2), which mediates the recruitment of infiltrating and resident microglia to sites of central nervous system (CNS) inflammation, is upregulated by ionizing irradiation and traumatic brain injury. Our objective was to determine if a deficiency in CCR2 and subsequent effects on brain microglia affect neurogenesis and cognitive function after radiation combined injury (RCI). CCR2 knock-out (–/–) and wild-type (WT) mice received 4 Gy of whole body 137Cs irradiation. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohistochemical assessme...

Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal-axis-associated proteins

Abstract: Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or saline from postnatal day (P) 11 to P20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and the area occupied by vasopressin immunoreactivity in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin immunoreactivity in the PVN, or GR immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, the area occupied by GR immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin immunoreactivity no longer differed from saline controls. No effects of MA were found on oxytocin or GR immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin immunoreactivity and short-term effects on GR immunoreactivity.

Non-replication of an association of Apolipoprotein E2 with sinistrality

Abstract: A recent report found that left-handed adolescents were more than three times more likely to have an Apolipoprotein (APOE) ϵ2 allele. This study was unable to replicate this association in young adults (N=166). A meta-analysis of nine other datasets (N=360 to 7559, Power > 0.999) including that of National Alzheimer's Coordinating Center also failed to find an over-representation of ϵ2 among left-handers indicating that this earlier outcome was most likely a statistical artefact.

Related functions of mGlu4 and mGlu8

Abstract: Metabotropic glutamate receptors modulate glutamatergic and GABAergic neurotransmission. Our previous pharmacological data indicate that metabotropic receptor 4 (mGlu4) and metabotropic receptor 8 (mGlu8) might have related and overlapping functions. We explored this by analyzing the behavioral phenotypes of mice deficient in either (mGlu4(-/-) or mGlu8(-/-)) or both receptors (mGlu4/8(-/-)). Our analysis focused on measures of anxiety in the open field and elevated zero maze, sensorimotor function on the rotarod and fear conditioning, as mGlu4 and/or mGlu8 were shown to affect performance in these tests. mGlu8(-/-) mice weighed more than mGlu4/8(-/-) mice. In the open field, mGlu4(-/-) mice showed lower levels of anxiety than mGlu8(-/-) and mGlu4/8(-/-) mice. In the elevated zero maze, mGlu4(-/-) mice showed lower levels of anxiety than wild-type, mGlu8(-/-) and mGlu4/8(-/-) mice. In the open field, but not elevated zero maze, mGlu4(-/-) mice showed lower activity levels than wild-type, mGlu8(-/-) and mGlu4/8(-/-) mice. mGlu4/8(-/-) female mice showed less contextual freezing than wild-type and mGlu4(-/-) female mice and there was a trend toward less freezing in male mGlu4/8(-/-) than wild-type male mice. There were no genotype differences in cued fear conditioning. There were significant negative correlations between body weight and fall latency on the rotarod in wild-type, mGlu8(-/-) and mGlu4/8(-/-), but not mGlu4(-/-), mice. These data suggest related functions of mGlu4 and mGlu8 in behavioral performance.

Paradoxical effects of apolipoprotein E on cognitive function and clinical progression in mice with experimental autoimmune encephalomyelitis.

Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease characterized by sensory, motor, and cognitive impairments. Apolipoprotein E (apoE) plays an important role in cholesterol and lipid metabolism in the brain and in susceptibility to cognitive impairment and pathology following brain injury. Studies in mice with a mild form of experimental autoimmune encephalomyelitis (EAE), an MS animal model, support only protective roles for apoE in MS. We examined behavioral and cognitive changes prior to onset of clinical disease and the onset and progression of a more severe form of EAE in female Apoe(-/-) and C57Bl/6 wild-type mice. Apoe(-/-) mice had a later day of onset, a later day of peak symptoms and disease severity, and a lower cumulative disease index compared to wild type mice. Apoe(-/-) mice also showed decreased CD4+ cell invasion following EAE induction compared to wild type mice, and less spinal cord demyelination at 17 but not 30 days following EAE induction. In contrast, EAE-challenged Apoe(-/-) mice showed reduced exploratory activity, rotorod performance, and impaired contextual fear conditioning compared to wild type animals. These data indicate paradoxical effects of apoE on EAE-induced behavioral and cognitive changes and the onset and progression of clinical disease.

Dose- and ApoE Isoform-Dependent Cognitive Injury after Cranial 56Fe Irradiation in Female Mice

Abstract: Apolipoprotein E (ApoE) plays an important role in lipid metabolism and neuronal repair. In humans, there are three major apoE isoforms: apoE2, apoE3 and apoE4. Compared to apoE3, apoE4 increases the risk to develop Alzheimer's disease, particularly in women, and of developing cognitive impairments after specific environmental challenges. ApoE isoform might also be a determinant of cognitive injury after cranial 56Fe irradiation. To assess this possibility, in this study female apoE2, apoE3 and apoE4 mice were cranially irradiated with 56Fe particles (600 MeV, 0, 1 or 2 Gy) and behaviorally tested 3 months later. Exploratory activity and measures of anxiety were also assessed as they can affect performance on cognitive tests. There were no effects of irradiation on exploratory activity or measures of anxiety in the open field or elevated zero maze. However, there were dose- and apoE isoform-dependent effects of irradiation on novel object recognition and spatial memory retention in the water maze. Compare...

Suppression of the T cell Response and Enhancement of Detrimental Effects of Radiation on the Brain

Abstract: Methods Objectives • Cognitive impairments are common but poorly understood complications of cancer and cancer therapy involving chemotherapy and/or irradiation1. • The temporal lobe, and in particular the hippocampus, seems particularly sensitive to detrimental effects of chemotherapy and radiation on cognition2. • A pro-inflammatory profile in the brain has been associated with behavioral changes and cognitive impairments, including memory impairments and decreased executive function3–5. • Enhanced pro-inflammatory tumor environments are associated with increased survival and tumor regression, while anti-inflammatory tumor environments are correlated with severely limited survival6. • An improved immune environment in the tumor at the time of treatment also increases the efficacy of radiation therapy (Figure 1). • Though immunotherapy enhances the immune response of patients with poor tumor infiltrate profiles, it is unclear how immunotherapy might modulate the effects of radiation on the brain7.