The adult mammalian brain harbours at least two germinal - or neurogenic - niches in which new neurons are born throughout life. These neurogenic niches comprise the subependymal zone which lines the ventricular system, and the subgranular zone in the hippocampal dentate gyrus. Post-natal hippocampal neurogenesis was in fact first identified experimentally in the 1960s. However perhaps due partly to aforementioned institutionalised belief and partly to a lack of accessible experimental tools, the phenomenon of hippocampal neurogenesis was widely recognised by the scientific community only shortly before the millennium. Consequent study has established that adult hippocampal neurogenesis has been conserved through millions of years of evolution in nearly every mammalian species studied to date. Importantly, post-mortem studies and radioisotope carbon dating techniques suggest that it also occurs in humans. A great deal of this research has focused on understanding the inner workings of the cells that undergo the transformation to become new adult-born neurons. By contrast, relatively little is known about the potential regulatory role of the surrounding extracellular microenvironment. This might be useful to know in light of much evidence that the extracellular matrix is a key regulator of developmental neurogenesis. This thesis describes my study of whether extracellular matrix regulates hippocampal neurogenesis.

No description available.

Changes in the strength of connections between neurons underlie information storage in the mammalian brain. Long-term potentiation (LTP) is a long-lasting form of synaptic plasticity that has been described extensively in the hippocampus, a brain structure that plays a key role in memory formation. The molecular events that realise the persistence of LTP are not well understood, but it is known to require protein synthesis. The aim of this thesis was to investigate synaptic protein expression during the late-phase of hippocampal LTP in freely moving rats. LTP was induced in the perforant path input to the dentate gyrus of Sprague-Dawley rats using high-frequency electrical stimulation paradigms known to produce LTP that persists for many days. To focus on late-occurring events, and complement existing data sets, rats were sacrificed 48 h after LTP induction. A broad survey of synaptic proteins was conducted by two-dimensional gel electrophoresis using postsynaptic density (PSD) fractions. Over 200 protein spots were resolved, from which 163 individual proteins were identified by mass spectrometry. These included cytoskeletal proteins, signalling molecules, molecular chaperones and mitochondrial components, but no transmembrane receptor proteins were detected. Few of the identified proteins were found to undergo significant changes in expression, although proteomic comparison of PSDs prepared from LTP-stimulated and control dentate gyri showed reduced expression of the three component proteins of the mitochondrial voltage-dependent anion channel. While these data complement earlier studies suggesting that the late-phase of LTP is associated with mitochondrial restructuring, they cannot alone explain the persistence of LTP. To directly test whether LTP persistence is associated with increased expression of presynaptic marker proteins, suggesting increased neurotransmitter release; and/or increased postsynaptic receptor expression, implicating an increase in postsynaptic contact area, a targeted approach using Western Blot analysis of dentate gyrus subcellular fractions was undertaken.

Depression is one of the top ten health problems in the world, affecting millions of Canadians. Research indicates that exercise is an effective treatment for depression but it is not clear on exactly how and why it works. Animal studies show that exercise improves the ability of the brain to function. It can even lead to new cell formation in a part of the brain called the hippocampus, which is important for memory processing. This study is investigating whether exercise may also improve hippocampal function in depressed humans. One way exercise may improve brain function is by normalizing levels of the hormone cortisol, and its toxic effects on the hippocampus. Exercise may also normalize levels of biochemical markers called cytokines involved in inflammation, while improving levels of growth factors important to brain cell function. This feasibility study aimed to develop protocols to investigate changes in hippocampal activity while participants are performing memory tests involving association of images and words in a functional magnetic resonance scanner before and after a 12 week exercise program. It also aimed to develop and validate protocols to measure changes in cortisol, cytokines and growth factors which are likely to be affected by exercise. Our preliminary imaging results revealed hippocampal dysregulation in the depressed brain, and biomarker analysis revealed abnormal concentrations of interleukin-6, vascular endothelial growth factor and salivary cortisol when compared to normal healthy controls. However, following the 12-week exercise program a more normalized pattern of hippocampal activation associated with successful memory encoding was observed. Additionally, biomarker concentrations either resembled or were closer to normal healthy values. Over the long term, the project arising from this feasibility study has the potential to provide a tool to improve exercise prescription, to predict exercise responders and to guide development of combined treatment approaches related to biochemical markers in order to optimize depression outcomes for Canadians. / UOIT

The hippocampus, which is a critical brain region for episodic autobiographical memory (AM), is particularly vulnerable to damage following periods of early thyroid hormone (TH) deficiency. Although numerous studies have examined AM performance in adult patients with hippocampal damage, no study has yet examined AM in children exposed to early TH deficiency, such as children with congenital hypothyroidism (CH) and offspring of women who were hypothyroid during pregnancy (HYPO). Given that both animal and human studies have shown that early TH deficiency results in significant hippocampal abnormalities and memory impairments, the purpose of this dissertation was to investigate the effects of early TH deficiency on AM and hippocampal structure and function during childhood. Study I examined AM performance in a large sample of typically developing children and adolescents in order to validate the use of the newly-developed Children’s Autobiographical Interview (CAI). In Study II, the CAI was used to investigate AM performance in children with early TH deficiency (i.e., CH and HYPO groups). Similar to the findings observed in adults with hippocampal damage, CH and HYPO groups both exhibited weaknesses in episodic AM, but not semantic AM, relative to controls. In addition, structural MRI revealed mild bilateral hippocampal volume reductions in HYPO, but not CH, which is consistent with animal models suggesting that early prenatal TH deficiency (i.e., HYPO) may be associated with greater abnormalities in hippocampal structure than postnatal TH deficiency (i.e., CH). Study III investigated children’s AM accuracy performance using a staged event and indicated that children with early TH deficiency had proportionally less accurate recollections of the staged event than controls. Importantly, smaller hippocampal volumes in both CH and HYPO groups predicted lower AM accuracy scores. Finally, in Study IV, functional MRI revealed that children with early TH deficiency exhibited abnormal (i.e., greater bilateral) hippocampal activation during episodic AM retrieval, but not during semantic AM retrieval, relative to controls, which may reflect neural compensation or may be a by-product of the degree of hippocampal damage. Overall, this dissertation provides critical new insight into the long-term effects of early TH deficiency on children’s AM performance and the hippocampus.

A class of hippocampal interneurons in CA1, bordering the lacunosum-moleculare and radiatum hippocampal layers (the LM/R cell), has been shown to exhibit membrane potential oscillations (MPOs) subthreshold to action potential generation. MPOs occur at theta frequency (4-12 Hz) and are of interest because of their putative role in promoting network level theta activity. MPOs arise without synaptic input suggesting that they originate through interactions in the cell’s repertoire of currents. To investigate the generation of MPOs we develop a single compartment model of the cell based on the physiological characterization of its currents. The model includes both deterministic current models and white noise. Our analysis allows for a complete characterization of the cell’s dynamics over the subthreshold range and shows that MPOs arise through the interaction between current dynamics and system noise. We find that MPOs show a particular dependency on the A-type potassium and persistent sodium current magnitudes.

The hippocampus, which is a critical brain region for episodic autobiographical memory (AM), is particularly vulnerable to damage following periods of early thyroid hormone (TH) deficiency. Although numerous studies have examined AM performance in adult patients with hippocampal damage, no study has yet examined AM in children exposed to early TH deficiency, such as children with congenital hypothyroidism (CH) and offspring of women who were hypothyroid during pregnancy (HYPO). Given that both animal and human studies have shown that early TH deficiency results in significant hippocampal abnormalities and memory impairments, the purpose of this dissertation was to investigate the effects of early TH deficiency on AM and hippocampal structure and function during childhood. Study I examined AM performance in a large sample of typically developing children and adolescents in order to validate the use of the newly-developed Children’s Autobiographical Interview (CAI). In Study II, the CAI was used to investigate AM performance in children with early TH deficiency (i.e., CH and HYPO groups). Similar to the findings observed in adults with hippocampal damage, CH and HYPO groups both exhibited weaknesses in episodic AM, but not semantic AM, relative to controls. In addition, structural MRI revealed mild bilateral hippocampal volume reductions in HYPO, but not CH, which is consistent with animal models suggesting that early prenatal TH deficiency (i.e., HYPO) may be associated with greater abnormalities in hippocampal structure than postnatal TH deficiency (i.e., CH). Study III investigated children’s AM accuracy performance using a staged event and indicated that children with early TH deficiency had proportionally less accurate recollections of the staged event than controls. Importantly, smaller hippocampal volumes in both CH and HYPO groups predicted lower AM accuracy scores. Finally, in Study IV, functional MRI revealed that children with early TH deficiency exhibited abnormal (i.e., greater bilateral) hippocampal activation during episodic AM retrieval, but not during semantic AM retrieval, relative to controls, which may reflect neural compensation or may be a by-product of the degree of hippocampal damage. Overall, this dissertation provides critical new insight into the long-term effects of early TH deficiency on children’s AM performance and the hippocampus.

A class of hippocampal interneurons in CA1, bordering the lacunosum-moleculare and radiatum hippocampal layers (the LM/R cell), has been shown to exhibit membrane potential oscillations (MPOs) subthreshold to action potential generation. MPOs occur at theta frequency (4-12 Hz) and are of interest because of their putative role in promoting network level theta activity. MPOs arise without synaptic input suggesting that they originate through interactions in the cell’s repertoire of currents. To investigate the generation of MPOs we develop a single compartment model of the cell based on the physiological characterization of its currents. The model includes both deterministic current models and white noise. Our analysis allows for a complete characterization of the cell’s dynamics over the subthreshold range and shows that MPOs arise through the interaction between current dynamics and system noise. We find that MPOs show a particular dependency on the A-type potassium and persistent sodium current magnitudes.

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Integrative Neuroscience." Includes bibliographical references (p. 124-148).

The hippocampus is an integral brain region for affective disorders. HCN1 protein shows age-dependent increase in expression resulting in an increase in I[subscript h] in the dorsal hippocampal CA1 region. TRIP8b knockout mice lacking functional HCN channels as well as both HCN1 and HCN2 knockout mice have been shown to display antidepressant-like behaviors. The mechanisms or brain regions involved in these alterations in behavior, however, are not clear. We developed a lentiviral shRNA system to examine whether knockdown of HCN1 protein, and therefore h-channels, in the dorsal hippocampal CA1 region is sufficient to produce antidepressant-like effects. We found that silencing of HCN1 gene resulted in physiological changes consistent with a reduction of I[subscript h] and increased cellular excitability of CA1 pyramidal neurons. Rats infused with lentiviral-shRNA-HCN1 in the dorsal hippocampal CA1 region displayed antidepressant- and anxiolytic-like behaviors. Using voltage-sensitive dye imaging, we found that knockdown of HCN1 in the dorsal hippocampal CA1 region led to enhancement of hippocampal activity in large regions of the dorsal hippocampus. Our results demonstrate that changed hippocampal network activity by local manipulation of HCN1 channels in dorsal hippocampus led to anxiolytic- and antidepressant-like behaviors and suggest that HCN1 channels could be a potential target for treatment of anxiety and depression. / text