The hippocampus and non-hippocampal long-term memory systems each have the capacity to learn and express contextual fear memory. How these systems interact during learning and remembering revolves around hippocampal mediated interference, where the hippocampus dominates for both the acquisition and expression of long-term memory. Hippocampal interference during learning can be overcome by modifying learning parameters such that learning is distributed across multiple independent sessions. The standard view of the role of the hippocampus in long-term memory retrieval is that it is temporally limited, where recently acquired memory is dependent on hippocampal function though as a memory ages, dependency is transferred to other memory systems by a process called systems consolidation. Distributed training demonstrates that learning parameters create a memory that is resistant to hippocampal damage. We find little evidence to support temporally based systems consolidation, and present data that supports the view that if the hippocampus is initially involved in learning a memory, it will always be necessary for accurate retrieval of that memory. A critical assessment of the rat literature revealed that initial memory strength, and/or lesion techniques might be responsible for the few studies that report temporally graded retrograde amnesia using contextual fear conditioning. Our experiments designed to directly test these possibilities resulted in flat gradients, providing further evidence that the hippocampus plays a permanent role in long-term memory retrieval. We propose and assess alternatives to the standard model and conclude that a dual store model is most parsimonious within the presented experiments and related literature. Interactions of the hippocampus and non-hippocampal systems take place at the time of learning and remembering, and are persistent over time. / xvi, 161 leaves : ill. (some col.) ; 29 cm

Long-term adrenalectomy (ADX) results in a specific loss of dentate gyrus granule cells in the hippocampus of adult rats, occurring over a period of weeks to months. This loss of granule cells results in cognitive deficits in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition are similar to those experienced by patient populations suffering from a variety of pathological conditions. Here we present an animal model by which we use ADX to produce a loss of granule cells within the hippocampus of rats. We also provide experimental evidence for a treatment strategy by which the lost granule cells may be replaced, with the goal of functional recovery in mind. / xii, 191 leaves : ill. (chiefly col.) ; 28 cm

Adrenalectomy (ADX) has been shown to cause selective degeneration of granule cells in the dentate gyrus (DG). This occurs due to the reduction of corticosterone (CORT) and behavioural deficits are associated with the loss of these neurons. Dentate lesions and cell loss associated with ADX have been shown to effect behaviour in a number of spatial tasks. In contras, it has been shown granule cell loss does not affect the specificity of place cells in CA3 and CA1. We used the ADX model to examine the role of DG granule cells plays in representing space using immediate early gene (IEG) activation in the principal hippocampal subfields after exploration of novel environments. Rats were allowed to free explore multiple novel environments and then the mRNA for the IEG Homer 1a (H1a) was used as a marker of neural activity. After degeneration of approximately half of the DG granule cells we found a significant increase in number of active cells in the DG, CA3 and CA1 in ADX animals. The results indicate a reduction in granule cells causes a dramatic increase in the proportion of remaining DG granule cells in response to exploration. The change in DG activation disrupts the representations in CA3 and CA1 and thereby affects behaviour. / vii, 60 leaves : ill. (some col.) ; 29 cm

Sutherland, Sparks and Lehmann (2010) proposed a new theory of memory consolidation, termed Distributed Reinstatement Theory (DRT), where the hippocampus (HPC) is needed for initial encoding but some types of memories are established in non-HPC systems through post-learning HPC activity. An evaluation of the current methodology of temporary inactivation was conducted experimentally. By permanently implanting two bilateral guide cannulae in the HPC and infusing ropivacaine cellular activity could be reduced by 97%. Rats were trained in a context-fear paradigm. Six learning episodes distributed across three days made the memory resistant to HPC inactivation while three episodes did not. Blocking post-learning HPC activity following three of six training sessions failed to reduce the rat’s memory of the fearful context. These results fail to support DRT and indicate that one or more memory systems outside the HPC can acquire context memory without HPC post-event activity. / x, 85 leaves : ill. ; 29 cm

This study sought to determine whether the DG, CA3, and CA1 regions contain uniformly excitable populations and test the hypothesis that rapid addition of new, more excitable, granule cells in prepubescence results in a low activation probability (P1) in the DG. The immediate-early gene Homer1a was used as a neural activity marker to quantify activation in juvenile (P28) and adult (~5 mo) rats during track running. The main finding was that P1 in juveniles was substantially lower not only the DG, but also CA3 and CA1. The P1 for a DG granule cell was close to 0 in juveniles, versus 0.58 in adults. The low P1 in juveniles indicates that sparse, but non-overlapping, subpopulations participate in encoding events. Since sparse, orthogonal coding enhances a network’s ability to decorrelate input patterns (Marr, 1971; McNaughton & Morris, 1987), the findings suggest that juveniles likely possess greatly enhanced pattern separation ability. / ix, 51 leaves : ill. ; 29 cm

Indiana University-Purdue University Indianapolis (IUPUI) / Posttraumatic epilepsy, the development of temporal lobe epilepsy (TLE) following traumatic brain injury, accounts for 20% of symptomatic epilepsy. Reorganization of mossy fibers within the hippocampus is a common pathological finding of TLE. Normal mossy fibers project into the CA3 region of the hippocampus where they form synapses with pyramidal cells. During TLE, mossy fibers are observed to innervate the inner molecular layer where they synapse onto the dendrites of other dentate granule cells, leading to the formation of recurrent excitatory circuits. To date, the molecular mechanisms contributing to mossy fiber sprouting are relatively unknown. Recent focus has centered on the involvement of tropomycin-related kinase receptor B (TrkB), which culminates in glycogen synthase kinase 3β (GSK3β) inactivation. As the neurite outgrowth promoting collapsin response mediator protein 2 (CRMP2) is rendered inactive by GSK3β phosphorylation, events leading to inactivation of GSK3β should therefore increase CRMP2 activity. To determine the involvement of CRMP2 in mossy fiber sprouting, I developed a novel tool ((S)-LCM) for selectively targeting the ability of CRMP2 to enhance tubulin polymerization. Using (S)-LCM, it was demonstrated that increased neurite outgrowth following GSK3β inactivation is CRMP2 dependent. Importantly, TBI led to a decrease in GSK3β-phosphorylated CRMP2 within 24 hours which was secondary to the inactivation of GSK3β. The loss of GSK3β-phosphorylated CRMP2 was maintained even at 4 weeks post-injury, despite the transience of GSK3β-inactivation. Based on previous work, it was hypothesized that activity-dependent mechanisms may be responsible for the sustained loss of CRMP2 phosphorylation. Activity-dependent regulation of GSK3β-phosphorylated CRMP2 levels was observed that was attributed to a loss of priming by cyclin dependent kinase 5 (CDK5), which is required for subsequent phosphorylation by GSK3β. It was confirmed that the loss of GSK3β-phosphorylated CRMP2 at 4 weeks post-injury was likely due to decreased phosphorylation by CDK5. As TBI resulted in a sustained increase in CRMP2 activity, I attempted to prevent mossy fiber sprouting by targeting CRMP2 in vivo following TBI. While (S)-LCM treatment dramatically reduced mossy fiber sprouting following TBI, it did not differ significantly from vehicle-treated animals. Therefore, the necessity of CRMP2 in mossy fiber sprouting following TBI remains unknown.

Indiana University-Purdue University Indianapolis (IUPUI) / Methamphetamine (MA) is a widely abused psychostimulant that has been shown to evoke an array of neurobiological abnormalities and cognitive deficits in humans and in rodent models (Marshall & O'Dell, 2012). Alterations in cognitive function after repeated drug use may lead to impaired decision-making, a lack of behavioral control, and ultimately the inability to abstain from drug use. Human studies have shown that alterations in neurobiology resulting from prolonged MA use may lead to a number of cognitive deficits, including impairments in executive function, learning, memory, and impulsivity. These impairments, specifically those that engage the prefrontal cortex (PFC) or hippocampus (HC), may persist or recover based on the duration of abstinence. In rodents, repeated intermittent injections of MA yield protracted changes in neurobiology and behavior, which have been shown to effectively model a number of the biological and cognitive abnormalities observed in addiction. In order to assess the temporal evolution of impaired cognitive function throughout abstinence, sensitization was first induced in rats (7 x 5.0 mg/kg MA over 14 days). MA-treated rats initially exhibited a robust increase in locomotion that transitioned to stereotypy as the induction phase progressed. Then, the effects of MA sensitization on social interaction (SI), temporal order recognition (TOR) and novel object recognition (NOR) was assessed at one-day and 30-days post induction. No differences were observed in SI in either group or after a single injection of MA. However, an acute injection of 5.0 mg/kg of MA 30-minutes prior to testing dramatically reduced SI time. Impairments in TOR and NOR were observed in MA-treated rats after one day of abstinence, and impairments in TOR, but not NOR, were observed on day 30 of abstinence. No differences in TOR and NOR after a single injection of MA or saline were observed. These data establish that after 30 days of abstinence from a sensitizing regimen of MA, the ability to recall the temporal sequence that two stimuli were encountered was impaired and that was not attributable to impaired novelty detection. These data also suggest that at least some of the neurocognitive abnormalities caused by chronic MA administration may normalize after prolonged abstinence, since the ability to detect novelty recovered after 30 days of abstinence. These data provide compelling support that, since MA-sensitization caused temporal deficits in memory, PFC and HC function may be differentially impaired throughout the time course of abstinence.