Of the thousands of dividing progenitor cells (PCs) generated daily in the adult brain only a very small proportion survive to become mature neurons through the process of neurogenesis. Identification of the mechanisms that regulate cell death associated with neurogenesis would aid in harnessing the potential therapeutic value of PCs. Apoptosis, or programmed cell death, is suggested to regulate death of PCs in the adult brain as overexpression of B-cell lymphoma 2 (Bcl-2), an anti-apoptotic protein, enhances the survival of new neurons. To directly assess if Bcl-2 is a regulator of apoptosis in PCs, this study examined the outcome of removal of Bcl-2 from the developing PCs in the adult mouse brain. Retroviral mediated gene transfer of Cre into adult floxed Bcl-2 mice eliminated Bcl-2 from developing PCs and resulted in the complete absence of new neurons at 30 days post viral injection. Similarly, Bcl-2 removal through the use of nestin-induced conditional knockout mice resulted in reduced number of mature neurons. The function of Bcl-2 in the PCs was also dependent on Bcl-2-associated X (BAX) protein, as demonstrated by an increase in new neurons formed following viral-mediated removal of Bcl-2 in BAX knockout mice. Together these findings demonstrate that Bcl-2 is an essential regulator of neurogenesis in the adult hippocampus.

Noise-like activity (NLA) refers to spontaneous subthreshold fluctuations in membrane potential. In this thesis, we examine the role that synaptic channel fluctuations play in contributing to NLA by comparing a detailed biophysical model to experimental data from whole-intact hippocampal interneurons. To represent the contribution from synaptic channel fluctuations, we switch the synapses in the model from traditional to Markovian formalisms and demonstrate statistically relevant increases the standard deviation; power-law scaling exponent; and power spectral density in the 5-100 Hz and 1-5 kHz ranges. However, while synaptic channel fluctuations have a definite effect, we found that they were significantly more subtle than the synaptic response to network activity. This indicates that synaptic channel fluctuations do indeed play a significant role in subthreshold noise, but, overall, synaptic NLA is dominated by the synaptic response to presynaptic network activity.

Consolidation of associative memories may depend on communication between the lateral entorhinal cortex (LEC) and hippocampus (HPC) for recently learned memories and the LEC and medial prefrontal cortex (mPFC) for remote memories. To determine whether direct connections between these regions are necessary for the retrieval of a recently or remotely learned memory, rats acquired an associative memory through trace eyeblink conditioning and were tested for memory retention after inactivating the regions of interest with the GABAA agonist, muscimol. Inactivating the LEC-HPC connection did not impair memory retrieval. However, inactivating the LEC-mPFC connection impaired remote, but not recent, memory retrieval. Thus, the LEC and mPFC connection is necessary for the retrieval of a remotely, but not recently learned associative memory. Increased reliance on the entorhinal-prefrontal connection indicates the strengthening of functional connectivity between the two regions, which may be a biological correlate for the proposed reorganization during systems consolidation.

Consolidation of associative memories may depend on communication between the lateral entorhinal cortex (LEC) and hippocampus (HPC) for recently learned memories and the LEC and medial prefrontal cortex (mPFC) for remote memories. To determine whether direct connections between these regions are necessary for the retrieval of a recently or remotely learned memory, rats acquired an associative memory through trace eyeblink conditioning and were tested for memory retention after inactivating the regions of interest with the GABAA agonist, muscimol. Inactivating the LEC-HPC connection did not impair memory retrieval. However, inactivating the LEC-mPFC connection impaired remote, but not recent, memory retrieval. Thus, the LEC and mPFC connection is necessary for the retrieval of a remotely, but not recently learned associative memory. Increased reliance on the entorhinal-prefrontal connection indicates the strengthening of functional connectivity between the two regions, which may be a biological correlate for the proposed reorganization during systems consolidation.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.

Behavioral deficits caused by fetal-alcohol are well expressed in juvenile subjects but usually ameliorate with maturation. It suggests some kind of postnatal regeneration. The aim of the present study was to examine the potential correlation between behavioral recovery and the postnatal hippocampal development in the fetal-alcohol rats. This study included behavioral tests applied to juvenile and adult subjects, unbiased stereology to investigate changes in neuron numbers and hippocampal volumes, the postnatal tracing and analysis of the hippocampal principal neuron&rsquo / s morphology, investigation of age-dependent changes in the distribution of doublecortin-expressing neurons, and evaluation of synaptic development by assessing age-dependent changes in the regional immunoreactivity/expression of synaptophysin and PSD95. Rats have been exposed to ethanol throughout 7-21 gestation days with daily ethanol dose of 6g/kg delivered by intragastric intubation to the pregnant dams. The morphological characteristics were examined on postnatal days P1, P10, P30, P60, in hippocampal CA1, CA3, and DG subregions, in fetal-alcohol and control rats. Both, stereological and doublecortin-immunoreactivity data pointed towards a possibility of limited neurogenesis taking place during a protracted postnatal period not only in the germinal zones (SGZ and SVZ) but also in the hippocampal CA regions. Ethanol effect on postnatal hippocampal development was limited to marginally lower number of granular cells in DG on P30. It correlated with poorer cognitive performance in the fetal-alcohol group. The treatment effect on the morphology of hippocampal neurons was observed mainly in CA region at P1 and seemed to be attributed more to the intubation stress than the ethanol itself.

Noise-like activity (NLA) refers to spontaneous subthreshold fluctuations in membrane potential. In this thesis, we examine the role that synaptic channel fluctuations play in contributing to NLA by comparing a detailed biophysical model to experimental data from whole-intact hippocampal interneurons. To represent the contribution from synaptic channel fluctuations, we switch the synapses in the model from traditional to Markovian formalisms and demonstrate statistically relevant increases the standard deviation; power-law scaling exponent; and power spectral density in the 5-100 Hz and 1-5 kHz ranges. However, while synaptic channel fluctuations have a definite effect, we found that they were significantly more subtle than the synaptic response to network activity. This indicates that synaptic channel fluctuations do indeed play a significant role in subthreshold noise, but, overall, synaptic NLA is dominated by the synaptic response to presynaptic network activity.

Extensive evidence suggests that glucose has both positive and negative effects on memory and these effects likely involve an influence on the brain. For instance, direct infusions of glucose into the septum (MS) or hippocampus can enhance or impair memory. The present set of experiments attempted to determine the different conditions that dissociate the memory-enhancing and -impairing effects of glucose in rats. Specifically, these experiments examined the effects of glucose in spontaneous alternation, a measure of spatial working memory and shock avoidance, an index of emontional long-term memory. The results showed that the memory-impairing effects of MS infusions of glucose are not concentration-dependent. These data also indicated that the memory-impairing effects of MS glucose elevations are specific to gamma-aminobutyric acid GABA receptor activation but do not depend on increases in MS GABA synthesis or release. Importantly, we showed that the memory-impairing interaction between MS glucose and GABA agonists does not generalize to the hippocampus, suggesting the memory-modulating effects of glucose are brain region-dependent. We showed further that these brain region-dependent effects of glucose are not due to difference in basal extracellular glucose levels. Moreover, these findings showed that the memory-enhancing effects of hippocampus glucose override the memory-impairing interaction between MS glucose and GABA. These findings are important because they are the first to show that the memory-modulating effects of glucose are both neurotransmitter- and brain region-dependent. Furthermore, these findings provide preliminary evidence suggesting that the memory-impairing effects of MS glucose may involve compromised hippocampal function. These data also suggest the memory-impairing effects of MS co-infusions of glucose with GABA agonists likely involve an influence on the GABAergic SH projection. Finally, these findings demonstrate the mnemonic and neurochemical consequences of glucose in the MS and hippocampus, two brain regions affected by normal aging, Alzheimer’s disease, and diabetes.

Stress affects virtually all organisms and can result in both physiological and behavioral changes. Conditioned defeat in Syrian hamsters is a model of stress-induced behavioral plasticity that occurs in a social context. In this model, hamsters are defeated by a larger, more aggressive counterpart. Defeated hamsters subsequently fail to defend their own territory and show striking and long-lasting increases in submissive behavior even when paired with a non-threatening counterpart. The present series of experiments seeks to identify the brain regions and molecular mediators that contribute to this behavioral plasticity. One brain region that has been overlooked by our laboratory is the hippocampus. The results of the first study suggested that the ventral, but not dorsal, hippocampus is important for the acquisition of conditioned defeat as temporary inactivation of the ventral hippocampus prior to defeat training significantly reduced submissive and defensive behaviors when hamsters were tested with a non-aggressive intruder. Next, we sought to identify a potential molecular mediator of social stress-induced behavioral plasticity in hamsters identified as winners or losers after a fight. Using in situ hybridization for brain-derived neurotrophic factor (BDNF) mRNA, we showed that winning and losing hamsters exhibited differences in BDNF mRNA in several regions including the basolateral and medial amygdala as well as the dentate gyrus of the dorsal hippocampus and CA1 of the ventral hippocampus. We next showed that neurotrophic activity in the basolateral amygdala is important for the acquisition of conditioned defeat because K252a infused into the basolateral amygdala prior to defeat training by an aggressive counterpart, significantly decreased submissive and defensive behavior during subsequent testing. Finally, existing data suggest that the amygdala and hippocampus interact to modulate the formation of emotional memories. To test the hypothesis that the basolateral amygdala and ventral hippocampus interact to mediate the behavioral plasticity observed in conditioned defeat, we simultaneously inactivated these regions either contralaterally or ipsilaterally prior to social defeat. Our results suggest that BLA and VHPC interact to mediate the acquisition of conditioned defeat, however, the nature of this interaction remains to be determined.

Fructose consumption has increased exponentially during the past four decades. The physiological effects of a high fructose diet include obesity and insulin resistance. In animal models, the effects of a high fructose diet on fat distribution are inconclusive in that some studies find increases in body mass and lipids while others find no effect. Recent findings indicate that a high fructose diet causes hippocampal insulin resistance in hamsters, raising the possibility that the diet causes impairments in cognition. The following experiments tested the hypotheses that a high fructose diet alters fat distribution rather than total body mass and impairs hippocampal-dependent memory. Results indicated that the high fructose diet did not affect fat distribution, but did increase plasma triacylglycerides. Interestingly, the diet also impaired spatial reference memory in the Morris water maze, and this effect was correlated with plasma triacylglycerides. These results indicate that a high fructose diet impairs brain function.