The effects of ethanol on the brain are far reaching. However, the effect of ethanol on synaptic plasticity has not yet been fully explored. Although it has been established that ethanol inhibits long-term potentiation (LTP) in the CA1 of the hippocampus, before our study, it was unclear whether long-term depression (LTD) was attenuated or enhanced by ethanol. We found that different concentrations of ethanol attenuated LTD in the CA1 (CA1-LTD) at younger ages. At more mature ages, CA1-LTD was completely blocked by ethanol. In contrast to this, LTD in the dentate gyrus (DG-LTD) was not significantly affected by ethanol concentrations up to 100 mM at any age group tested. These results suggest there are mechanistic differences in LTD induction in the DG and CA1, using the same induction protocol and that CA1-LTD is ethanol sensitive but DG-LTD is not.

Research on the neural and cognitive basis of spatial navigation over the last 30 years has been largely guided by cognitive map theory and many of the studies have used a standardized procedure in a single task, the Morris Water Maze (MWM). Although this theory proposes that acquisition of place knowledge should be very rapid, little evidence has been provided to support this point. The present study investigates the possibility that a new procedure for measuring place knowledge in the MWM will show that place learning is faster than previously shown. In a virtual MWM with a fixed goal location, participants were given pairs of standard learning trials plus new explicit probe trials in which they were directed to go to where they found the goal on the immediately preceding trial. The distance between their estimate and the actual location was measured as “Place Error”. Results indicated that Place Errors were surprisingly small after just one learning trial and were equivalent for females and males. These findings provide new evidence for the fast learning proposed by cognitive map theory and demonstrate the value of this new method for measuring place learning. / Graduate

Reliving the past requires the integration of multi-modal sensory details into a coherent mental impression of the initial event. In most people, memory for life episodes, or Autobiographical Memory (AM), is rich in sensory-perceptual elements that provide the vivid impression of travelling back in time. Abundant evidence indicates that the hippocampus plays a central role in AM recollection, but much research is still needed to determine which AM attributes engage the hippocampus at retrieval. My work assessed the relationship between hippocampal function and the perceptual richness of memory episodes. I designed a paradigm that captured the complexity of AM, and that manipulated perceptual richness while controlling for other AM confounds, such as recency, rehearsal, personal relevance, and “story” content. Participants studied and recalled perceptually enriched and impoverished laboratory events (film clips and written narratives, respectively) matched for the complexity of their storyline. An AM condition was also included for comparison. I tested healthy individuals and participants with unilateral medial temporal lobe epilepsy (mTLE), a clinical population with well documented hippocampal damage, on this paradigm. Perceptual richness was greatly reduced in people with mTLE, an effect that was most salient in the perceptually enriched conditions (AM and film clips). In a functional MRI version of this paradigm conducted on healthy individuals, I identified neural regions sensitive to the perceptual richness of AM and laboratory events, which included the anterior portion of the right hippocampus and other regions known to play a role in imagery and visual processing. In patients with right-lateralized mTLE, activation in these brain regions was markedly reduced in all memory conditions, which was consistent with the reduced perceptual richness I observed behaviourally. I reveal a clear relationship between hippocampal function and the perceptual richness of episodic memory, suggesting that the hippocampus plays a central role among brain regions that support the integration of multi-modal details into enriched memory experiences. My findings also advance our knowledge of how pathology and the nature of memory representation affect the neural correlates of episodic memory.

Two amnesic patients with MTL damage that included the hippocampus and perirhinal cortex were tested along controls on a series of “oddity” discrimination tasks, in which they had to select an odd item from a visual array. Participants’ eye moments were monitored while they performed these tasks. Three types of stimuli were used: greebles, scenes, and faces. Results revealed that patients were impaired on tasks that required them to discriminate between items that shared features in common and tasks that required processing items from different viewpoints. An analysis of their eye movements revealed that their impaired performance was linked with decreased viewing times of target items compared to controls, when discriminating between greebles and scenes; their poor performance on the faces task could not be explained by the same token.

The underlying mechanism of morphine tolerance remains unclear. EphB2 regulates synaptic efficiency with respect to learning and memory. Previously, we demonstrated that loss of EphB2 significantly accelerates the rate of morphine tolerance and alters behavioural responses to morphine following tolerance. However, EphB2 null mice exhibit no significant alteration in their metabolism of morphine compared to littermate controls, or altered mu opioid receptor expression levels within the spinal cord or brain compared to littermate controls. Therefore, we investigated whether loss of EphB2 alters learned responsiveness to morphine through modification of hippocampal function. Interestingly, results indicate that electrolytic lesions of the dorsal hippocampus of wild-type mice display similar behavioural responses seen in EphB2 null mice compared to sham operated controls. These findings suggest that loss of EphB2 function within the hippocampus is a critical feature in mediating morphine-dependent tolerance, and suggests a novel role for EphB2 receptor signaling in opiate-dependent learning.

Reliving the past requires the integration of multi-modal sensory details into a coherent mental impression of the initial event. In most people, memory for life episodes, or Autobiographical Memory (AM), is rich in sensory-perceptual elements that provide the vivid impression of travelling back in time. Abundant evidence indicates that the hippocampus plays a central role in AM recollection, but much research is still needed to determine which AM attributes engage the hippocampus at retrieval. My work assessed the relationship between hippocampal function and the perceptual richness of memory episodes. I designed a paradigm that captured the complexity of AM, and that manipulated perceptual richness while controlling for other AM confounds, such as recency, rehearsal, personal relevance, and “story” content. Participants studied and recalled perceptually enriched and impoverished laboratory events (film clips and written narratives, respectively) matched for the complexity of their storyline. An AM condition was also included for comparison. I tested healthy individuals and participants with unilateral medial temporal lobe epilepsy (mTLE), a clinical population with well documented hippocampal damage, on this paradigm. Perceptual richness was greatly reduced in people with mTLE, an effect that was most salient in the perceptually enriched conditions (AM and film clips). In a functional MRI version of this paradigm conducted on healthy individuals, I identified neural regions sensitive to the perceptual richness of AM and laboratory events, which included the anterior portion of the right hippocampus and other regions known to play a role in imagery and visual processing. In patients with right-lateralized mTLE, activation in these brain regions was markedly reduced in all memory conditions, which was consistent with the reduced perceptual richness I observed behaviourally. I reveal a clear relationship between hippocampal function and the perceptual richness of episodic memory, suggesting that the hippocampus plays a central role among brain regions that support the integration of multi-modal details into enriched memory experiences. My findings also advance our knowledge of how pathology and the nature of memory representation affect the neural correlates of episodic memory.

Two amnesic patients with MTL damage that included the hippocampus and perirhinal cortex were tested along controls on a series of “oddity” discrimination tasks, in which they had to select an odd item from a visual array. Participants’ eye moments were monitored while they performed these tasks. Three types of stimuli were used: greebles, scenes, and faces. Results revealed that patients were impaired on tasks that required them to discriminate between items that shared features in common and tasks that required processing items from different viewpoints. An analysis of their eye movements revealed that their impaired performance was linked with decreased viewing times of target items compared to controls, when discriminating between greebles and scenes; their poor performance on the faces task could not be explained by the same token.

The underlying mechanism of morphine tolerance remains unclear. EphB2 regulates synaptic efficiency with respect to learning and memory. Previously, we demonstrated that loss of EphB2 significantly accelerates the rate of morphine tolerance and alters behavioural responses to morphine following tolerance. However, EphB2 null mice exhibit no significant alteration in their metabolism of morphine compared to littermate controls, or altered mu opioid receptor expression levels within the spinal cord or brain compared to littermate controls. Therefore, we investigated whether loss of EphB2 alters learned responsiveness to morphine through modification of hippocampal function. Interestingly, results indicate that electrolytic lesions of the dorsal hippocampus of wild-type mice display similar behavioural responses seen in EphB2 null mice compared to sham operated controls. These findings suggest that loss of EphB2 function within the hippocampus is a critical feature in mediating morphine-dependent tolerance, and suggests a novel role for EphB2 receptor signaling in opiate-dependent learning.

We conducted experiments to understand the role of Ventral Hippocampus (vHPC) projections to the Nucleus Accumbens (NAc) in exploratory locomotion, and to determine if the reduced vHPC parvalbumin neuron activity can result in behaviors associated with schizophrenia. Through the use of optogenetics, we activated vHPC neurons and vHPC terminals in the NAc. Both manipulations significantly increased locomotor activity in the open field. Selective inhibition of vHPC terminals in the NAc during a test for novel environment exploration significantly reduced preference for novel environments over familiar environments. DREADD-mediated inhibition of activation of vHPC parvalbumin neuron activity did not significantly alter amphetamine-induced locomotion. Overall, these experiments provide support for the role of the vHPC-NAc pathway in mediating exploratory behavior in novel environments, but it remains inconclusive whether dysregulated vHPC activity due to the loss of parvalbumin neurons leads to behaviors associated with schizophrenia.

Tottering and leaner mutant mice carry mutations in the pore-forming subunit (1A) of P/Q-type (CaV 2.1) voltage-gated calcium ion (Ca2+) channels that result in reduced Ca2+ current density. Since Ca2+ influx via voltage-dependent Ca2+ channels regulates important Ca2+-dependent neuronal processes including neurotransmitter release and synaptogenesis, we assessed effects of these mutations on hippocampus volume, neuronal density, neuronal morphology of hippocampal pyramidal cells in adult (six-month-old) mice, and adult neurogenesis in three-week-old and six-month-old mice. Hippocampal volume and neuronal density were assessed using hematoxylin and eosin stained serial sections. Neuronal morphology was assessed using Golgi-Cox staining as well as ultrastructural assessment using transmission electron microscopy. Adult hippocampal neurogenesis was assessed using standard 5-bromo-2’-deoxyuridine (BrdU) labeling with fluorescent immunohistochemistry (IHC) and proliferating cell nuclear antigen (PCNA) with diaminobenzidine IHC. To determine neuron and astrocyte survival, we used fluorescent double labeling for neurons with BrdU-neuronal nuclei IHC or astrocytes using BrdU-glial fibrillary acidic protein, respectively. Fluoro-Jade histochemistry was used to assess numbers of degenerating cells in the dentate gyrus subgranular zone. Decreased hippocampus volume was observed in tottering female mice and increased dentate hilar and CA1 cell density in mutant mice compared to wild type mice. Cell proliferation was increased in the hilus and combined CA3, CA2 and CA1 regions of mutant mice compared to wild type mice. Decreased total dendritic length and decreased number of dendritic intersections was observed in tottering mice compared to wild type mice. The decrease in dendritic arborization of tottering mice occurred at the concentric circles close to the neuronal cell body indicating that basal dendrites of CA1 pyramidal neurons are reduced. Taken together, P/Q-type voltage gated calcium channel mutation has age variable influence on adult hippocampal cell proliferation, and it altered neuronal morphology in terms of dendritic complexity in tottering mice, while the leaner mutation reduced mitochondrial density.