Interactions of Thyroid Hormones and Nerve Growth Factor in Normal Development of the Rat Hippocampus and Basal Forebrain and in Recovery From Early Hypothyroid Retardation

192 p.Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 1999.We propose that decreased neural growth in hypothyroid animals and the robust rate of recovery is mediated by interactions of thyroid hormones with neurotrophins. We have found that hypothyroidism results in decreased hippocampal NGF levels, while up-regulating its receptors: the p75 neurotrophin and p140 trk A receptor. We propose that declining levels hippocampal NGF results in decreased trophic support for basal forebrain cholinergic neurons, leading to a compensatory up-regulation of NGF receptors. Thyroid hormone normalization restores total hippocampal NGF, causing hypertrophic growth responses in both the basal forebrain and hippocampal formation. Our findings present strong evidence for hippocampal plasticity lasting beyond the normal developmental period. This plasticity may be a result of regulatory and compensatory changes in neurotrophins and their receptors.U of I OnlyRestricted to the U of I community idenfinitely during batch ingest of legacy ETD

Lentiviral vector-mediated transduction of neural progenitor cells before implantation into injured spinal cord and brain to detect their migration, deliver neurotrophic factors and repair tissue

Stem cells represent an attractive source for cell replacement therapy in neurological disorders due to their self-renewal and multi-potency. Genetic manipulation of these cells may allow controlled release of therapeutic proteins, suppress immune rejection, or produce essential neurotransmitters. Furthermore, when the expression cassette is incorporated into the host genome ex vivo, this technique also may be used as a method to trace cells following implantation into tissues of interest. We explored the possibility of transducing pluripotent fetal rat cortical neural progenitor cells (NPCs) using lentiviral vectors encoding the green fluorescent protein (GFP) or neurotrophic factors (BDNF, CNTF, D15A, GDNF, MNT and NT-3) prior to implanting these cells into the contused spinal cord or injured brain. In vitro staining of these cells for neural markers (such as nestin, GFAP, Tuj-1 and RIP) after transduction did not reveal any significant difference from non-transduced cells. When they were transduced with a vector encoding CNTF or MNT, however, cells started expressing GFAP in vitro. Following delayed (1 week) implantation into the lesion site of the moderately contused rat spinal cord or the injured brain, transduced cells survived up to 12 weeks post-implantation (the longest time point examined) and most of the NPCs turned into an astrocytic phenotype in the spinal cord, but not in the brain. Nestin and GFP positive cells were detected in the brain, but not in the spinal cord lesion. GFP positive cells in the spinal cord migrated rostrally and caudally from the lesion/implantation site towards uninjured tissue. Novel findings in this study are the longterm expression of a foreign gene in NPCs using lentiviral vectors; this enabled tracking of the cells following implantation. This expression also allowed the observation that NPCs developed differently in the injured spinal cord and brain. Moreover, NPCs could be transduced to overexpress neurotrophic factors. In sum, NPC survival and the long-term transgene expression that allows easy tracking of migrating cells make NPCs promising candidates for implantation into the injured spinal cord or brain and a potentially powerful tool to enhance regeneration when transduced ex vivo to produce therapeutic molecules

Myeloid Sarcoma: A Rare Case of an Orbital Mass Mimicking Orbital Pseudotumor Requiring Neurosurgical Intervention

Objective. A rare case of myeloid sarcoma (MS), previously referred to as granulocytic sarcoma or chloroma, is presented. Representing a unique form of acute myeloid leukemia (AML), MS may rarely occur in adults. Even rarer, MS may occur as the initial presentation of AML. Methods. We report a singular and illustrative case of an orbital pseudotumor mimicking mass in a 65-year-old male as the initial presentation of AML. Results. Neurosurgical intervention was required to establish the definitive diagnosis via right modified orbitofrontozygomatic craniotomy as well as to decompress the optic canal, superior orbital fissure, and orbit. Conclusion. Postoperatively, he reported decreased pain and improvement of his vision. Further examination revealed decreased proptosis and improved extraocular mobility. Pathological findings demonstrated MS. We review the literature and discuss the neurosurgical relevance of MS as the initial presentation of AML

Imipramine Treatment Improves Cognitive Outcome Associated with Enhanced Hippocampal Neurogenesis after Traumatic Brain Injury in Mice

Previous animal and human studies have demonstrated that chronic treatment with several different antidepressants can stimulate neurogenesis, neural remodeling, and synaptic plasticity in the normal hippocampus. Imipramine is a commonly used tricyclic antidepressant (TCA). We employed a controlled cortical impact (CCI) mouse model of traumatic brain injury (TBI) to assess the effect of imipramine on neurogenesis and cognitive and motor function recovery after TBI. Mice were given daily imipramine injections for either 2 or 4 weeks after injury. Bromodeoxyuridine (BrdU) was administered 3–7 days post-brain injury to label the cells that proliferated as a result of the injury. We assessed the effects of imipramine on post-traumatic motor function using a beam-walk test and an assessment of cognitive function: the novel object recognition test (NOR). Histological analyses were performed at 2 and 4 weeks after CCI. Brain-injured mice treated with imipramine showed significantly improved cognitive function compared to a saline-treated group (p<0.001). However, there was no significant difference in motor function recovery between imipramine-treated and saline-treated mice. Histological examination revealed increased preservation of proliferation of Ki-67- and BrdU-positive cells in the hippocampal dentate gyrus (DG) at 2 and 4 weeks after TBI. Immunofluorescence double-labeling with BrdU and neuron-specific markers at 4 weeks after injury showed that most progenitors became neurons in the DG and astrocytes in the hilus. Notably, treatment with imipramine increased preservation of the total number of newly-generated neurons. Our findings provide direct evidence that imipramine treatment contributes to cognitive improvement after TBI, perhaps by enhanced hippocampal neurogenesis