Nest -Building Behavior In House Mice (Mus Musculus), A Potential Model Of Obsessive -Compulsive Disorder In Humans

Thesis (Ph.D.) University of Alaska Fairbanks, 2007OCD (obsessive-compulsive disorder) is a chronic and debilitating psychiatric condition characterized by intrusive and persistent thoughts (obsessions) and repetitive behaviors (compulsions) that become ritualistic in an attempt to escape the obsessions. Currently there is a paucity of animal models with robust and spontaneous (non-drug or non-behaviorally induced) compulsive-like behaviors. This study is aimed at validating a novel robust and spontaneous genetic mouse model of OCD. The compulsive-like nest-building behavior in mice selected for high levels of nest-building behavior (BIG) has good face validity, with a behavioral phenotype that resembles hoarding behavior characteristic of OCD. In addition, male and female BIG mice displayed compulsivelike digging behavior relative to mice selected for low levels of nest-building behavior (SMALL), as assessed by the marble-burying test. Both chronic oral fluoxetine and clomipramine treatment reduced compulsive-like nest-building behavior in male BIG mice. Furthermore, chronic oral fluoxetine administration decreased nest-building behavior of BIG mice in a dose-dependent manner, while desipramine, an antidepressant not effective for treating OCD, did not significantly alter this behavior. The administration of fluoxetine did not cause a decrease in general locomotor behavior. These findings suggest that the nest-building phenotype has predictive validity. In addition, chronic oral fluoxetine treatment reduced compulsive-like digging behavior in male and female BIG mice as compared to SMALL mice. Gender effects were also found in treatment response. Clomipramine did not reduce nest-building in female BIG mice in a dose-dependent manner, which is consistent with previous studies. These data are in contrast to previous studies using BIG male mice which had a significant decrease in nest-building behavior with oral clomipramine. These results are consistent with studies on humans, which have found gender differences in the treatment effects of antidepressants. Additional construct validity is implicated by the results of targeted serotonergic lesions of the raphe nuclei in male BIG mice, which reduced repetitive nest-building behavior. More research is necessary to confirm the appropriateness of this model for human OCD; however, this model is promising based on the data that support good face, predictive and construct validity

Long-term cognitive effects of human stem cell transplantation in the irradiated brain

PURPOSE: Radiotherapy remains a primary treatment modality for the majority of central nervous system tumors, but frequently leads to debilitating cognitive dysfunction. Given the absence of satisfactory solutions to this serious problem, we have used human stem cell therapies to ameliorate radiation-induced cognitive impairment. Here, past studies have been extended to determine whether engrafted cells provide even longer-term benefits to cognition. MATERIALS AND METHODS: Athymic nude rats were cranially irradiated (10 Gy) and subjected to intrahippocampal transplantation surgery 2 days later. Human embryonic stem cells (hESC) or human neural stem cells (hNSC) were transplanted, and animals were subjected to cognitive testing on a novel place recognition task 8 months later. RESULTS: Grafting of hNSC was found to provide long lasting cognitive benefits over an 8-month post-irradiation interval. At this protracted time, hNSC grafting improved behavioral performance on a novel place recognition task compared to irradiated animals not receiving stem cells. Engrafted hESC previously shown to be beneficial following a similar task, 1 and 4 months after irradiation, were not found to provide cognitive benefits at 8 months. CONCLUSIONS: Our findings suggest that hNSC transplantation promotes the long-term recovery of the irradiated brain, where intrahippocampal stem cell grafting helps to preserve cognitive function

Assessment of cellular and molecular changes in the rat brain after gamma radiation and radioprotection by anisomycin

The objective of the study was to describe cellular and molecular markers of radioprotection by anisomycin, focusing on the changes in rat brain tissue. Two-month-old Wistar rats were exposed to a 60Co radiation source at a dose of 6 Gy, with or without radioprotection with anisomycin (150 mg/kg) administered subcutaneously 30 min before or 3 or 6 h after irradiation. Survivors were analyzed 30 days after treatment. Astroglial and microglial responses were investigated based on the expression of glial markers assessed with immunohistochemistry, and quantitative changes in brain biomolecules were investigated by Raman microspectroscopy. In addition, blood plasma levels of pro-inflammatory (interleukin 6 and tumor necrosis factor α) and anti-inflammatory (interleukin 10) cytokines were assessed. We found that application of anisomycin either before or after irradiation significantly decreased the expression of the microglial marker Iba-1. We also found an increased intensity of Raman spectral bands related to nucleic acids, as well as an increased level of cytokines when anisomycin was applied after irradiation. This suggests that the radioprotective effects of anisomycin are by decreasing Iba-1 expression and stabilizing genetic material by increasing the level of nucleic acids

Emerging pharmacotherapy for cancer patients with cognitive dysfunction

Advances in the diagnosis and multi-modality treatment of cancer have increased survival rates for many cancer types leading to an increasing load of long-term sequelae of therapy, including that of cognitive dysfunction. The cytotoxic nature of chemotherapeutic agents may also reduce neurogenesis, a key component of the physiology of memory and cognition, with ramifications for the patient's mood and other cognition disorders. Similarly radiotherapy employed as a therapeutic or prophylactic tool in the treatment of primary or metastatic disease may significantly affect cognition. A number of emerging pharmacotherapies are under investigation for the treatment of cognitive dysfunction experienced by cancer patients. Recent data from clinical trials is reviewed involving the stimulants modafinil and methylphenidate, mood stabiliser lithium, anti-Alzheimer's drugs memantine and donepezil, as well as other agents which are currently being explored within dementia, animal, and cell culture models to evaluate their use in treating cognitive dysfunction