Spatial memory and navigation relies on estimation of location. This can be achieved through several strategies, including the use of landmarks and by path integration. The latter involves inferring location from direction and distance moved relative to a known start point. The neural mechanisms of path integration are not well understood and implementation of experiments that dissociate path integration from alternative strategies is challenging. The roles of specific cell types are also unknown. Although grid cells in layer 2 of the medial entorhinal cortex (MEC) are theorised to be involved given their periodic and repeating firing fields that form a grid-like map that tiles the environment. Two excitatory cell populations have been identified in layer 2 of the MEC. Clusters of pyramidal cells that project to the CA1 are surrounded by dentate gyrus (DG) projecting stellate cells. Both populations have been shown to exhibit grid-like activity. The extent to which these cell types contribute to path integration or other strategies for solving spatial tasks is unknown. To investigate these issues, I developed a spatial memory task for mice, which uses virtual reality to generate sensitive measures of an animal’s ability to path integrate. In this task mice are trained to locate a reward zone marked with a visual cue within a virtual linear track. Use of path integration strategies can be tested in trials in which the reward zone is unmarked. In this task mice can locate the reward zone using either a local beaconing cue or path integration strategies. To assess whether self-motion derived motor information or visual feedback is used for path integration, I manipulated the translation between physical and virtual movement, putting optic and motor feedback in conflict. These manipulations suggest that mice use motor information to locate the reward zone on path integration trials. To test roles of stellate cells in the task I injected adeno-associated virus expressing the light chain of tetanus toxin, conditionally on the presence of Cre, into the MEC of mice expressing Cre specifically in stellate cells. This abolishes synaptic output from stellate cells therefore preventing them from influencing downstream neurons. I find mice with dorsal expression of the tetanus toxin virus in layer 2 stellate cells are unable to locate the reward zone using a local beaconing cue or path integration strategies. In contrast, mice with expression of green fluorescent protein (GFP) were able to locate the reward zone using both strategies. Locating the reward zone using path integration strategies first requires animal’s to learn the reward zone location, as denoted in trials with a beacon cue. To distinguish the role of stellate cells in learning versus execution of the tasks, I temporally modified the activity of stellate cells after mice had learnt to locate the reward zone using both strategies. Temporal control was achieved by use of cre-dependent adeno-associated viruses expressing mutant human muscarinic 4 receptor (hM4). When activated by clozapine - N - oxide (CNO), this receptor opens G-protein inwardly rectifying potassium (GIRK) channels and attenuates neuronal firing. Using this method, the activity of stellate cells can be temporally controlled during task execution and potentially distinguish their involvement in learning and execution of spatial memory tasks. No effect on behavioural performance was seen under these conditions. This may indicate stellate cells are required for learning but not execution of spatial memory tasks that require the use of local beaconing cues or path integration.

Temporal regularity and metrical organisation are important factors in beat and metre perception. The current thesis aims to investigate neural correlates of beat and metre perception in healthy non-musician volunteers, using functional magnetic resonance imaging (fMRI). In particular, the thesis focuses on determining the role of the Inferior Frontal Gyrus (IFG, in particular BA44/45) in beat and metre perception. The IFG has been proposed to be involved in higher order cognitive processes during various temporal sequencing, such as speech, movement, and music. Previous studies have shown that the temporal processing of rhythm activates auditory and sensorimotor areas, but the role of the IFG in rhythm perception has not yet been fully understood. Study 1 investigated beat perception in complex rhythms, in which the addition of volume accents either enhanced or weakened the beat perception, resulting in Unaccented, Beat Accented or Non-Beat Accented rhythms. Participants (N=14; 6 males) listened to rhythm pairs across all three conditions, and judged whether each rhythm pair was the same or different. Results showed that left IFG activation (BA44) was significantly greater during the Non-Beat Accented condition compared to Beat Accented condition, whereas the right IFG activation showed no significant difference between the two conditions. Study 2 investigated metre perception of a series of isochronous sequences, of which metrical organisation was grouped by 2/4 (C2), 3/4 (C3), or 4/4 (C4) using pitch accents, or remained without metrical grouping (or 1/4, C1). The same participants (N=15; 6 males) listened to the stimuli and indicated the perceived metrical grouping level. Results showed that the activation of bilateral IFG parametrically increased from C2 to C3 to C4. Interestingly, the activation was found to be significantly greater in C1 relative to C2, suggesting that involuntary subjective in C1 may increase the brain response. Converging results from both Study 1 and Study 2 demonstrated, firstly, that the bilateral IFG is involved in rhythm perception in addition to the auditory and sensorimotor areas, including primary and secondary auditory areas, supplementary motor areas, premotor areas, insula, and basal ganglia. Secondly, the left IFG (BA44) in particular was significantly modulated by the rhythmic complexity relating to both temporal regularity and metrical organisation, while showing the suppression during the Beat Accented rhythm condition of Study 1 and the binary pattern (C2) of Study 2. This thesis argues that the left IFG (BA44) may have the role the higher order cognitive processing, such as attention and prediction, in the perception of hierarchical structures in metric rhythms.

Conclusion: The results suggest that ASD children have deficits in attentional and inhibitory control. Frontal dysfunction and weak ACC engagement in ASD were supported as the underlying neuronal inefficiency. / Methods: 20 children with high-functioning ASD [Mean Age (SD): 10.75 years old (2.07 years); Mean IQ (SD): 101.4 (16.8)] and age- and IQ-matched normal children (NC) [Mean Age (SD): 9.80 years old (1.88 years); Mean IQ (SD): 110.7(17.8)] were investigated electrophysiologically during performance of a visual Go/NoGo task. An electrophysiological source localization method was employed to further analyze the data. Several different neurospsychological tests were also performed to provide behavioral measures on attention and inhibition. / Objectives: To investigate neurophysiologic abnormalities in frontal and anterior cingulate cortex underlying attentional and inhibitory control in children with Autism Spectrum Disorder (ASD). / Results: ASD children showed a significantly task-related lower frontal theta activity. This effect was associated with a significantly reduced activation of the anterior cingulate cortex (ACC). Both groups also differ significantly regarding the behavioral aspects of attention and inhibition. / Leung, Shuk Yin Connie. / "November 2009." / Adviser: Chan Sue-Yin Agnes. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 65-85). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.

The abuse of methylenedioxymethamphetamine (MDMA) during pregnancy is of concern. MDMA treatment of rats during a period of brain growth analogous to late human gestation leads to neurochemical and behavioral changes. MDMA from postnatal day (P)11–20 in rats produces reductions in serotonin and deficits in spatial and route-based navigation. In this experiment we examined the impact of MDMA from P11 to P20 (20 mg/kg twice daily, 8 h apart) on neuronal architecture. Golgi impregnated sections showed significant changes. In the nucleus accumbens, the dendrites were shorter with fewer spines, whereas in the dentate gyrus the dendritic length was decreased but with more spines, and for the entorhinal cortex, reductions in basilar and apical dendritic lengths in MDMA animals compared with saline animals were seen. The data show that neuronal cytoarchitectural changes are long-lasting following developmental MDMA exposure and are in regions consistent with the learning and memory deficits observed in such animals.

Abnormal connectivity of the intrinsic anticorrelated networks, the task-negative network (TNN) and task-positive network (TPN), is implicated in schizophrenia. Comparisons between schizophrenic patients and their unaffected siblings offer an opportunity to further understand illness susceptibility and pathophysiology. We hypothesized that schizophrenic patients would demonstrate hyperconnectivity in the intrinsic networks and that similar, but less pronounced, hyperconnectivity would be evident in the networks of the unaffected siblings. Resting-state functional magnetic resonance images were obtained from schizophrenic patients (n=25), their unaffected siblings (n=25), and healthy controls (n=25). The posterior cingulate cortex/precuneus (PCC/PCu) and right dorsolateral prefrontal cortex (DLPFC) were used as seed regions to identify the TNN and TPN. Interregional connectivity strengths were analyzed using overlapped intrinsic networks composed of regions common to the intrinsic networks of the three subject groups. In the TNN, schizophrenic patients alone demonstrated hyperconnectivity between the PCC/PCu and left inferior temporal gyrus and between the ventral medial prefrontal cortex and the right lateral parietal cortex. Both schizophrenic patients and their unaffected siblings showed increased connectivity in the TNN between the bilateral inferior temporal gyri. In the TPN, schizophrenic patients showed hyperconnectivity between the left DLPFC and right inferior frontal gyrus relative to unaffected siblings, though this trend only approached statistical significance in comparison to healthy controls. Resting-state hyperconnectivity of the intrinsic networks may underlie the pathophysiology of schizophrenia by disrupting network coordination. Similar, though milder, hyperconnectivity in unaffected siblings of schizophrenic patients may contribute to their cognitive deficits and increased risk to develop schizophrenia.

The dentate gyrus is a region that hosts most of the hippocampal cells in mammals. Nevertheless, its role in spatial memory remains poorly understood, especially in light of the recently-studied phenomenon of adult hippocampal neurogenesis and its possible role in aging and chronic brain disease. We found that chronic over-expression of transforming growth factor beta1 (TGFbeta1), a cytokine involved in neurodegenerative disease, results in several modifications of brain structure, including volumetric changes and persistent astrogliosis. Furthermore, TGFbeta1 over-expression affects the generation of new neurons, leading to an increased number of neurons in the dentate gyrus and deficits in spatial memory acquisition and storage in aged mice. Nonetheless, reducing neurogenesis via pharmacological treatment impairs spatial memory in juvenile mice but not in adult or aged mice. This suggests that the addition of new cells to hippocampal circuitry, and not the increased plasticity of these cells, is the most relevant role of neurogenesis in spatial memory. We tested this idea by modifying proliferation in the dentate gyrus at several ages using multiple techniques and evaluating the incorporation of newborn neurons into hippocampal circuitry. We found that all granule neurons, recently generated or not, have the same probability of being incorporated. Therefore, the number of new neurons participating in memory circuits is proportional to their availability. Our conclusion is that adult-generated cells have the same functional relevance as those generated during development. Together, our data show that the dentate gyrus is important for memory processing and that adult neurogenesis may be relevant to its functionality by optimizing the number of neurons for memory processing. The equilibrium between neurogenesis and optimal dentate gyrus size is disrupted when TGFbeta1 is chronically increased, which occurs in neurodegenerative pathologies, leading to cognitive impairment in aged animals.

Representing a major public health concern, suicide is a leading cause of death worldwide. Generally regarded as a behavior with a multitude of state and trait dependent risk factors (e.g. psychiatric disorders, substance abuse, genetics), explanations as to why certain individuals commit suicide while others do not are complex. Of interest is in studying potential trait dependent variables involved in the neurobiology of suicide, particularly at the cellular level. Knowledge of the cellular integrity may aid in explaining the observed macroscopic alterations and ultimately the behavioral correlates associated with suicidality. Therefore we set out to summarize extant knowledge of the cellular alterations occurring in the brains of major depressive and suicide individuals. Following this, we conducted our own cellular investigation in a region known to be altered in major depression and suicide, a supracallosal area of BA24a. Neuronal and glial cell densities as well as neuronal cell sizes were assessed in upper and lower cortical layers between sudden-death controls and MDD suicide subjects. Secondary analyses were also conducted to examine the effect of alcohol on depressed suicides. Analyses of cell densities and neuronal soma sizes between controls and MDD suicide subjects did not reveal any significant differences. Further analyses showed increased glial cell densities in alcoholic depressed suicides. Future studies are necessary to examine explicit changes in the cellular compositions occurring in alcoholic dependent individuals. Staining techniques aimed at targeting specific subtypes of neurons and glial cells will help determine if these cell populations do in fact have an influential role in suicide and MDD.

Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.

Hippocampal neurogenesis continues throughout life in mammals. These adult-generated dentate granule cells (DGCs) are generally believed to contribute to hippocampal memory processing and are generated at varying rates in response to neuronal network activity. Deep brain stimulation (DBS) allows clinicians to influence brain activity for therapeutic purposes and raises the possibility of targeted modulation of adult hippocampal neurogenesis. It has recently been shown that DBS may ameliorate cognitive decline associated with Alzheimer’s disease (AD), and while underlying mechanisms are unknown, one possibility is activity-dependent regulation of hippocampal neurogenesis. To this end, whether or not adult-generated DGCs can assume functional roles of developmentally-generated neurons, and stimulation-induced enhanced neurogenesis can benefit memory function in the normal and diseased brain, warrant study. First, we examined separate cohorts of developmentally- and adult-generated DGCs in intact mice and demonstrated similar rates of activation during hippocampus-dependent spatial memory processing, suggesting functional equivalence. Second, we examined the neurogenic and cognitive effects of targeted entorhinal cortex (EC) stimulation in mice using parameters analogous to clinical high frequency DBS. Stimulation increased the generation of DGCs. Moreover, stimulation-induced neurons were functionally recruited by hippocampal spatial memory processing in a cell age-dependent fashion that is consistent with DGC maturation. Importantly, stimulation facilitated spatial memory in the same maturation-dependent manner, and not when stimulation-induced promotion of adult neurogenesis was blocked, suggesting a causal relationship. Finally, we are in the process of testing whether similar stimulation facilitates spatial memory in a transgenic (Tg) disease model of AD that exhibits amyloid neuropathology and cognitive impairment. Preliminary results suggest stimulation promotes neurogenesis and rescues impaired spatial memory in Tg animals. When considered in the context of promising clinical results, this body of work suggests stimulation-induced neurogenesis could provide a novel therapeutic modality in settings where functional hippocampal regenerative therapy is desirable.

Females exhibit superior object location memory (OLM) compared to males, but the reasons for this sex difference remains unknown. This thesis investigates the role of the dentate gyrus (DG) in an OLM task in normal rats (Experiment 1) and after bilateral adrenalectomy (ADX; Experiment 2). ADX is known to reduce volume of the DG and impair spatial learning. There was no sex difference for OLM in Experiment 1 but females exhibited superior OLM in Experiment 2. Experiment 2 found a significantly smaller DG due to ADX but this had no effect on behaviour. The male DG was significantly larger than the female DG in both experiments. Behaviour during the OLM task was not a predictor of DG volume, although a larger than average DG was related to poor OLM memory in females Thus, the DG involvement for OLM appears to differ between the sexes. / ix, 72 leaves : ill. ; 29 cm