Showing papers by "Jacob Raber published in 2009"

Sex-dependent effects of 56Fe irradiation on contextual fear conditioning in C57BL/6J mice.

Abstract: Effects of irradiation on hippocampal function have been mostly studied in male rodents and relatively little is known about potential effects of irradiation on hippocampal function in female rodents. Moreover, although the long-term effects of clinical radiation on cognitive function have been well established, the effects of other forms of irradiation, such as high charged, high energy radiation (HZE particles) that astronauts encounter during space missions have not been well characterized. In this study we compared the effects of 56Fe irradiation on fear conditioning in C57BL/6J female and male mice. Hippocampus-dependent contextual fear conditioning was impaired in female mice but improved in male mice following 56Fe irradiation. Such impairment was not seen for hippocampus-independent cued fear conditioning. Thus, the effects of 56Fe irradiation on hippocampus-dependent contextual fear conditioning are critically modulated by sex. © 2009 Wiley-Liss, Inc.

Glutathione peroxidase activity modulates recovery in the injured immature brain.

Abstract: Objective Mice subjected to traumatic brain injury at postnatal day 21 show emerging cognitive deficits that coincide with hippocampal neuronal loss. Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain. Methods Wild-type and transgenic (GPxTg) mice overexpressing GPx were subjected to traumatic brain injury or sham surgery at postnatal day 21. Animals were killed acutely (3 or 24 hours after injury) to assess oxidative stress and cell injury in the hippocampus or 4 months after injury after behavioral assessments. Results In the acutely injured brains, a reduction in oxidative stress markers including nitrotyrosine was seen in the injured GPxTg group relative to wild-type control mice. In contrast, cell injury, with marked vulnerability in the dentate gyrus, was apparent despite no differences between genotypes. Magnetic resonance imaging demonstrated an emerging cortical lesion during brain maturation that was also indistinguishable between injured genotypes. Stereological analyses of cortical volumes likewise confirmed no genotypic differences between injured groups. However, behavioral tests beginning 3 months after injury demonstrated improved spatial memory learning in the GPxTg group. Moreover, stereological analysis within hippocampal subregions demonstrated a significantly greater number of neurons within the dentate of the GPx group. Interpretation Our results implicate GPx in recovery of spatial memory after traumatic brain injury. This recovery may be attributed, in part, to a reduction in early oxidative stress and selective, long-term sparing of neurons in the dentate. Ann Neurol 2009;65:540–549

Testosterone and dihydrotestosterone differentially improve cognition in aged female mice

Abstract: Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to 24-mo-old gonadally intact female mice treated for 6 wk with silastic capsules containing either testosterone (T) or dihydrotestosterone (DHT) or empty capsules (placebo). Compared with placebo-treated mice, spatial memory retention in the water maze was enhanced by testosterone treatment, but not DHT treatment. In contrast, DHT treatment improved passive avoidance (PA) retention, while T treatment only did so marginally. These data support that androgen supplementation in old female mice improves cognitive performance differentially depending upon the type of hormone treatment and cognitive task.

Dihydrotestosterone modulates spatial working-memory performance in male mice.

Abstract: Androgens affect cognitive processes in both humans and animals. The effects of androgens may be limited to certain cognitive domains, specifically spatial memory, but this hypothesis remains elusive. Here, we tested castrated and sham-operated mice in various behavioral tasks to ask whether androgens affect multiple or specific cognitive domains in male mice. Castration impaired spatial working memory performance in the delayed matching to place water maze task following a 1-h, but not a 1-min, retention interval, as has been reported for rats. In contrast, castration had no effect on novel object recognition memory, spatial reference memory in the water maze, motor coordination, or passive avoidance memory. Castration increased anxiety-like behavior in the open field test, but not the elevated zero maze. Finally, we assessed the effects of androgen replacement with non-aromatizable dihydrotestosterone on spatial working memory following various retention intervals. Dihydrotestosterone recovered spatial memory performance following a 24-h, but not a 1-h retention interval, and had no effect at other retention intervals. These data support that in male mice androgens specifically affect spatial working memory performance, and that the neurobiological processes underlying spatial memory formation may be differentially affected by androgens.

The impact of ApoE on cognition and behavior

Abstract: Background: It has been demonstrated that APP transgenic mice with engineered disruption of Abca1 (ABCA1ko) have an increased level of amyloid plaques. In addition, Abca1ko mice have decreased levels of soluble ApoA-I and ApoE in brain whereas the level of insoluble apolipoproteins is not changed. In APP mice with global deletion of Abca1 the decrease of ApoE and ApoA-I is accompanied by an increased insoluble Amyloid beta (Ab). Our most recent experiments demonstrate that APP23 mice with one functional Abca1 allele (APP/Abca1þ/ ) have cognitive deficits when compared to APP23 with intact Abca1 (APP/Abca1wt). We have further investigated if Abca1-regulated generation of lipid-rich ApoE, not the decreased levels of ApoE and ApoA-I, is a critical mediator of Ab aggregation and behavioral deficits. Methods: To test this hypothesis we generated APP/PS1DE9 transgenic mice with global deletion of ApoE and ApoA-I genes (APP/ApoA-Iko/ApoEko) and have compared the amyloid deposition and cognitive decline in APP/ApoA-Iko/ ApoEko to those in APP/Abca1-ko and APP/Abca1wt. Results: The results of these experiments show that APP/Abca1-/mice have the highest level of amyloid deposition as well as the most prominent memory deficits. In contrast, APP/ApoA-Iko/ApoEko animals have virtually no amyloid plaques and significantly decreased insoluble Ab, but worse cognitive performance compared to APP/Abca1wt, whose memory deficits were the same as those of APP/ApoEko mice. Most surprisingly the levels of soluble Ab oligomers recognized as Ab*, were indistinguishable in APP/Abca1ko and APP/ApoA-Iko/ApoEko mice. Conclusions: The results from our study demonstrate that Abca1 and brain lipoproteins have a significant, yet not fully understood, impact on Ab aggregation and, even more, the formation of Ab oligomer structures. Considering the regulatory role of ABCA1 on ApoE and ApoA-I lipidation a prerequisite for their normal function related to brain cholesterol and phospholipid metabolism and transport, further studies will undoubtedly improve our understanding of central pathogenic mechanisms in Alzheimer Disease and will substantiate new therapeutic approaches.