The dentate gyrus (DG) is a sub-region of the hippocampus which is important for memory formation and storage in the brain.  It comprises two major classes of neurons called granule cells (GCs), the local principal cells and the interneurons which receive sensory information from the entorhinal cortex (EC).  The GCs contain glutamate as neurotransmitter and excite the postsynaptic cells whereas the interneurons release GABA and inhibit the target cells.  While the GCs are abundant in number and transmit the processed information to CA3 via mossy fibres (MFs), the interneurons determine when and where the information flows through the principal cell network.  To understand how information is processed in DG, it is paramount to understand the role of interneurons in the network in detail.  Moreover, disruption of this basal transmission set-up forms the basis of many neurological disorders.  For example, reduced inhibition on GCs is implicated in epilepsy.  Treatment/prevention of such diseases also necessitates better understanding of the role of inhibition in DG. While greater degree of knowledge exists on how interneurons inhibit GCs, how they are activated by afferent inputs is not clear.  Hence, the present work is primarily focussed on studying the physiology behind synaptic activation of interneurons by afferent excitatory inputs in DG.  The results obtained might help in studying the causes of pathological conditions of DG in addition to elucidating the circuit mechanisms of information processing.

New neurons are generated throughout adulthood in the dentate gyrus of the hippocampus. The aim of the current study was to address whether differences in the morphological complexity of adult-born granule cells affect their integration into existing dentate gyrus circuitry. To selectively label proliferating cells, we injected a CAG-retrovirus into the dentate gyrus of mice. Either 10, 20, 40, or 80 days following viral infection, mice were injected with pentylenetetrazol (PTZ) to induce hippocampal activation, and expression of the immediate early gene c-fos was used as a marker of activated neurons. We then compared morphological features of neurons across age groups and between Fos+ and Fos- neurons within each age group. We found that dendritic length and branch number increased from 10 to 20 days post infection. Unexpectedly, we also found that dendritic length and branch number decreased from 20 to 40 days post infection, suggesting that the maturation of adult-generated neurons is associated with an active pruning process. Furthermore, we found no significant difference in morphological complexity between Fos+ and Fos- neurons, suggesting that dendritic morphology does not influence integration into dentate gyrus circuitry.

New neurons are generated throughout adulthood in the dentate gyrus of the hippocampus. The aim of the current study was to address whether differences in the morphological complexity of adult-born granule cells affect their integration into existing dentate gyrus circuitry. To selectively label proliferating cells, we injected a CAG-retrovirus into the dentate gyrus of mice. Either 10, 20, 40, or 80 days following viral infection, mice were injected with pentylenetetrazol (PTZ) to induce hippocampal activation, and expression of the immediate early gene c-fos was used as a marker of activated neurons. We then compared morphological features of neurons across age groups and between Fos+ and Fos- neurons within each age group. We found that dendritic length and branch number increased from 10 to 20 days post infection. Unexpectedly, we also found that dendritic length and branch number decreased from 20 to 40 days post infection, suggesting that the maturation of adult-generated neurons is associated with an active pruning process. Furthermore, we found no significant difference in morphological complexity between Fos+ and Fos- neurons, suggesting that dendritic morphology does not influence integration into dentate gyrus circuitry.

Psychiatric illnesses are disorders that affect millions worldwide. Evidence from quantitative and molecular genetics analysis suggests a strong genetic component to these disorders. There is also evidence that embryonic neurodevelopment is a key period in the progression schizophrenia. The aim of the present study was to use post-mortem human hippocampus from subjects of a variety of psychiatric phenotypes to investigate neurodevelopmentally- relevant gene expression in this region of the adult human brain. Particular interest is paid to schizophrenia risk gene DISC1; it has been shown to exhibit linkage and association to schizophrenia and is highly involved in embryonic and post natal neurodevelopmental processes. The results reported in this study indicate that DISC1 binding partners, and genes used to mark neurogenesis, can be found aberrantly expressed in schizophrenia and bipolar disorder, relative to controls. The results also suggest that DISC1 genotype may predict expression patterns of DISC1 binding partners and neurogenesis markers, irrespective of diagnosis. This may provide clues to the timing and nature of abnormal brain development in this illness and aid in development of treatment strategies.

No description available.

Early life stress (ELS) leads to alterations in anatomy and function of the adult hippocampal dentate gyrus (DG), but the mechanisms by which these lasting changes occur have not been fully elucidated. We tested the hypothesis that the immediate decrease in cell proliferation and neurogenesis induced by stress is the key mediator of the negative long-term outcomes of ELS. First, we tested whether inhibition of cell proliferation during early life is sufficient to reproduce the ELS-induced reduction in adult DG neurogenesis. We demonstrate that targeting dividing stem cells for elimination during the first or third postnatal weeks leads to diminished adult neurogenesis and reduction of the stem cell pool. Also, we hypothesized that ELS leads to more persistent effects on DG function than stress later in life because of the stress-induced elimination of specific birth cohorts of DG granule cells (GCs) that have distinct functions. We tested whether different birth cohorts of DG GCs differ in function by assessing behavioral and stress response outcomes of pharmacogenetic elimination or optogenetic activation of adult GCs born during the first or third postnatal week. We demonstrate that dorsal GCs born during the first or third postnatal week may be involved in modulating exploratory and anxiety behavior, but that only third postnatal week born GCs stimulate HPA activity. These results suggest that mature DG GCs may differ in specific functions with birth date determining their functional role. Third, we directly assessed the effect of ELS on DG development to better understand the immediate effects of ELS on the DG and to identify other potential mediators of the long-term effects. We demonstrate that ELS using the limited bedding/nesting paradigm leads to developmental delay of the DG. The work presented in this dissertation contributes to our understanding of the mechanisms by which ELS produces lasting impairments in DG function and also to our knowledge of how DG GC function is specified.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2001. / Bibliography: leaves 71-78.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2003. / Bibliography: leaves 205-228.

Thesis (Ph.D.)--Memorial University of Newfoundland, 2003. / Bibliography: leaves 150-201.

Fluoxetine is a Selective Serotonin Reuptake Inhibitor (SSRI) often prescribed for the treatment of anxiety and depression. Many of its effects are thought to be mediated by the dentate gyrus, but the mechanism by which some patients respond to treatment and some do not remains poorly understood. In this study we have characterized a previously-unknown component of the behavioral response to fluoxetine in the dentate gyrus, using a combination of genomic, behavioral, and imaging techniques. We have found that different components of the opioid system are involved in the treatment efficacy of fluoxetine in the dentate gyrus. Specifically, we have identified a population of anatomically and transcriptionally distinct mature granule cells that are defined by their high levels of proenkephalin expression after fluoxetine treatment. Furthermore, we have shown that the delta opioid receptor is partly mediating some of the behavioral effects of fluoxetine in a neurogenesis-independent manner. These results open an interesting new avenue for research into the involvement of the opioid system in the behavioral response to SSRIs.