The goal of this study is to find an optimal dose of cytostatic Temozolomide (TMZ) for Long-Evans strain of rats. This dose should reduce neurogeneis while having a minimal pernicious health side-effects. Temozolomide is newly used to suppress neurogenesis but similarly to any other cytostatic has an effect on all dividing cells in an organism. This can affect health of an animal. Contrary to the mice, there was no systematic attempt to establish optimal dose. In our experiment rats were divided into four groups - one control group and three treatment groups which received different doses of temozolomide (10, 25, 40 mg/kg of TMZ). To detect level of neurogenesis cells were labeled by bromodeoxyuridine. During the experiment blood element counts were assessed, sensorimotoric tests were conducted, and weight increment was monitored. The results indicate that dose of 10mg/kg is adequate as it reduces neurogenesis by 64% compared to the control group and does not significantly differ from higher doses. In this group weight increment is comparable with the control group, while in the higher doses of TMZ weight increment is significantly lower. Effect of myelosupression is same for all treatment groups.

The incidence of Alzheimer’s Disease (AD) in the African American (AA) and Hispanic or Latino American populations in the United States (US) is twice as high compared to non-Hispanic White Americans. The study of race-related factors to explain the disparity in the incidence of AD and other health outcomes has been of growing interest. African Americans in the US experience higher discrimination due to race on a daily basis than any other minority group, and race-based discrimination (racism) is a known chronic stressor. It has been shown that in humans and rodents, chronic stress negatively affects hippocampal-dependent memory and reduces hippocampal volume. Pattern separation (PS), the ability to create distinguishable memory traces for similar information and thus avoiding interference to discriminate between similarly patterned visual percepts, is known to rely on the dentate gyrus (DG) hippocampal subfield integrity. Although the detrimental effects of chronic stress have been documented before, the effects of racism-related chronic stress (RRCS) on hippocampal-dependent memory system remain understudied. This pilot/preliminary study tested the hypothesis that higher frequency of experiences of discrimination in AA older adults would correlate with deficits in a behavioral PS task and with DG/CA3 volume. Seven African American older residents from the greater Boston area participated in both the cognitive testing to examine behavioral PS and structural MRI to examine DG/CA3 volume. Contrary to our hypothesis, a Spearman correlation analysis did not demonstrate a significant association between discrimination scores and behavioral PS performance or DG/CA3 volume. However, a significant correlation was found between performance on the behavioral PS task and right DG/CA3 volume. These results are consistent with previous studies on PS. Continued future research on the impact of RRCS on the hippocampal memory system among AA older adults as an important modulating factor in health for this population is needed.

Adult hippocampal neurogenesis, the generation of new neurons in the adult hippocampus, represents the most drastic form of ongoing plasticity in the human brain. When these adult-born neurons are a few weeks old, they have developed enough connections with surrounding hippocampal neurons to evoke meaningful change in network dynamics, but still have different morphological and physiological properties compared to developmentally generated neurons that render them more plastic. As such, and due to their location in the hippocampus, many have theorized that these new neurons play an important role in certain forms of learning memory as well as emotion. This dissertation outlines the first attempt to answer the question “what are new neurons in the hippocampus good for?” using human participants. Aerobic exercise is a lifestyle factor well-established from the animal literature to upregulate neurogenesis, while chronic stress is a known downregulator of neurogenesis. The second chapter of this thesis describes a study in which aerobic capacity and depression inventory scores demonstrated a significant positive correlation and a significant negative correlation with putative neurogenesis-dependent memory, respectively, in separate cohorts of healthy young adults. The third chapter outlines a study that expands on the one presented in the second by elucidating another potential role for neurogenesis in human cognition – remote memory. Finally, Chapter 4 describes a study investigating the utility of neurotrophins measured from peripheral blood as biomarkers for neurogenic activity in humans by examining how changes in their expression following chronic exercise predict changes in putative neurogenesis-dependent memory performance. These studies are the first to explicitly test and provide supporting evidence for the theoretical roles of adult hippocampal neurogenesis in humans. Taken together, these studies provide a strong foundation for how investigators and clinicians can indirectly quantify and test the function of adult-born neurons in the human brain. / Dissertation / Doctor of Philosophy (PhD) / New neurons are generated in the adult hippocampus throughout life. The hippocampus is a structure in the medial temporal lobe important for learning and memory as well as emotion. It is currently unknown what the contributions of newborn neurons are to these processes. This dissertation outlines the first attempt to answer the question “what are new neurons in the hippocampus good for?” using human participants. Aerobic exercise is a lifestyle factor well-known from research in rodents to positively influence the rate of birth of newborn neurons in the hippocampus, while long-term stress reduces the rate of birth. The second chapter of this thesis describes a study in which aerobic fitness and depression inventory scores demonstrated a significant positive correlation and a significant negative correlation with a memory test susceptible to high interference, respectively, in different populations of healthy young adults. The third chapter outlines a study that expands on the one presented in the second chapter by elucidating another potential role for neurogenesis in human cognition – long-term memory. Finally, Chapter 4 describes a study investigating the how measuring various proteins found in circulating blood may help us to understand how exercise influence the rate of birth of new hippocampal neurons in humans. These studies are the first to test and provide supporting evidence for the potential roles of newborn hippocampal neurons in humans. Taken together, these studies provide a strong foundation for how investigators and clinicians can indirectly quantify and test the role of adult-born neurons in the human brain.

While people sleep, the brain replays the same neural firings that resulted from waking activities that day. This results in greater memory strength following a sleeping delay than a waking delay. The current project built upon this fact in a series of three experiments. Experiment 1. Although previous research has demonstrated a benefit of sleep to memory strength, the literature has not established the impact of sleep on memory specificity. Computational models of medial temporal lobe function posit that discrimination and generalization across similar memories are accomplished through processes known as pattern separation and pattern completion, respectively. To discover whether sleep predisposes people toward pattern separation or pattern completion, participants studied pictures of common objects. After a 12-hour delay, during which participants either slept or stayed awake, participants indicated whether “lure” images were exactly the same or merely similar to those they studied. There was better memory discrimination in those who slept, consistent with a bias toward pattern separation following sleep. Experiment 2. In order to discover whether the pattern of memory demonstrated in Experiment 1 would carry over to semantic memories, participants studied textbook material and took a true/false test 12 hours later. There was a shift in the response trends following sleep, such that participants were more likely to mistakenly endorse highly similar false statements as “true” but were also more likely to correctly endorse more dissimilar false statements as “false.” However, we did not detect evidence of an increased bias toward pattern separation or pattern completion following sleep for this material. Our findings appear consistent with the prediction that memory specificity is benefitted by sleep. Experiment 3. Previous research has demonstrated that memories encoded later in the day are consolidated better than memories encoded earlier in the day. However, these studies have not controlled for the differential decay that memories suffer across these two elapsed periods. In this study, we attempted to show the degree of improvement afforded by sleep using a before-sleep comparison group. However, post hoc analyses revealed a significant interaction between the proposed outcomes and whether participants had napped during the day. These preliminary findings may suggest that napping differentially affects the consolidation of information studied before and after napping.

Long-term declarative memory depends on pattern separation, which reduces the degree of overlap between similar representations, to maintain memory specificity, and on pattern completion, which occurs when a degraded cue is used to retrieve a previously stored memory. Previous studies aimed at evaluating the underlying neuronal substrates of these computational processes have used a mnemonic discrimination paradigm and fMRI to focus on the hippocampus, to the exclusion of cortical processing. We aim to investigate the influences extra-hippocampal processes have on pattern separation in the following two studies. Study 1. Computational models of pattern completion suggest it occurs cortically and results in generalized memories whereas pattern separation occurs in the hippocampus and results in memory specificity. It is unknown how the incongruity of these two neuronal processes is resolved. Many studies evaluating the neuronal correlates of pattern separation have used fMRI to evaluate activity in the hippocampus. The sluggish time resolution of fMRI and the restricted spatial focus leave room for considerable differences between pattern completion and pattern separation to go undetected. Here, we use encephalography (EEG) and an event-related potential (ERP) analysis to examine neuronal activity during pattern separation and pattern completion to investigate whether or not cortical processing is employed to resolve the discrepancy between these two neuronal processes. We largely did not observe differences between the ERPs associated with pattern separation and pattern completion. Failure to identify neuronal differences could result from the bulk of neuronal processing differentiating between the two processes occurring deeper in the brain than can be measured by ERPs. Study 2. Extrinsic rewards contingent on memory performance can boost memory and learning. However, the effects of extrinsic rewards on memory specificity, particularly in regards to the process of pattern separation, are not well understood. In this behavioral study, we evaluate how extrinsic rewards affect behavioral performance in a task that taxes pattern separation. Our data show that rewards given for participation at the time of encoding boost mnemonic discrimination between target-lure pairs while rewards given for memory performance at the time of retrieval do not. We hypothesize this is because pattern separation is an encoding dependent process. This boost in discriminability is only seen when the rewarded stimuli are blocked together in separate blocks from the non-rewarded stimuli. When the rewarded and non-rewarded stimuli are interspersed within blocks, discriminability does not significantly differ between the rewarded and non-rewarded trials. Overall, performance was better when rewards were contingent on performance than when rewards independent of performance, although this difference is eliminated when attention during encoding is controlled.

La neurogenèse adulte est cruciale pour certaines fonctions mnésiques dépendantes de l'hippocampe. La mise en évidence d'une altération de la neurogenèse dans le cerveau de souris transgéniques modèles de la maladie d'Alzheimer (MA), en parallèle d'une réduction du contenu mitochondrial de leurs nouveaux neurones ouvre une nouvelle piste de recherche ciblant les mitochondries. Aujourd'hui, l'hypothèse d'un rôle causal des dysfonctionnements mitochondriaux dans l'étiologie des pathologies neurodégénératives est particulièrement pertinente dans la MA. Les mitochondries, " centrales électriques " et régulateurs du métabolisme oxydatif, forment un réseau dynamique qui s'adapte aux différents types et contextes cellulaires, via des événements antagonistes de fusion et de fission de leurs membranes. Les protéines clés ont été identifiées, dont OPA1 qui permet la fusion. Les dysfonctionnements de cette dynamique influent non seulement sur la forme et la distribution des mitochondries dans les neurones, mais affectent aussi leurs principales activités que sont respiration, régulation calcique, production de ROS et apoptose. Dans les neurones, cellules excitables à l'architecture complexe, les dysfonctionnements mitochondriaux ont des conséquences particulièrement cruciales pour la transmission synaptique. Au cours de cette thèse, nous avons étudié parallèlement des souris modèles de la MA, les souris Tg2576 (mutation d'APP) et des souris OPA1+/-, porteuses d'une mutation d'OPA1, modèles de l'Atrophie Optique Dominante. Nous avons observé chez ces deux lignées de souris une altération précoce des performances dans des tests comportementaux mettant en jeu le gyrus denté et les nouveaux neurones (tests de localisation d'objet et de séparation de patron). Nous avons démontré chez les souris Tg2576 et OPA1+/- que ces déficits cognitifs sont associés à des perturbations de la neurogenèse hippocampique adulte.[...] / Adult neurogenesis is crucial for some hippocampus-dependent memory functions. Both the demonstration of an alteration of neurogenesis in the brain of transgenic mouse models of Alzheimer's disease (AD), in parallel with a reduction in the mitochondrial content of their new neurons, open a new research avenue targeting the mitochondria. Today, the hypothesis of a causal role of mitochondrial dysfunctions in the etiology of neurodegenerative pathologies is particularly relevant in AD. Mitochondria, "power plants" and regulators of oxidative metabolism, form a dynamic network that adapts to different cell types and contexts, via antagonistic events of fusion and fission of their membranes. Key proteins have been identified, including OPA1 that allows fusion. Dysfunctions of this dynamics affect not only the shape and distribution of mitochondria in neurons, but also alter their main activities: respiration, calcium regulation, ROS production and apoptosis. In neurons, excitable cells with complex architecture, mitochondrial dysfunctions have particularly crucial consequences for synaptic transmission. In this thesis, we studied in parallel an AD mouse model, the Tg2576 mice (APP mutation) and the OPA1 +/- mice, carrying a mutation of OPA1, a Dominant Optic Atrophy model. In both mouse lines, we observed precocious performance alterations in behavioral tests involving the dentate gyrus and new neurons (object location, pattern separation tests). We demonstrated in Tg2576 and OPA1 +/- mice that these cognitive deficits are associated with disturbances of adult hippocampal neurogenesis. [...]

This report aims to explore if pattern recognition and pattern separation tasks performance degenerate with age. This as there are studies by Brickman et al. (2014) that suggest that these tasks are being performed by the hippocampus in particular, the dentate gyrus part. The tasks used in this report were replicated from a study in which it was assumed that they tested this parts. As both the hippocampus and the dentate gyrus supposedly degenerate with age, the tasks tested this degeneration by looking if the participant’s performance on the tasks changed with age. The performance on the pattern separation task did not change with age while the pattern recognition task did. This preservation of pattern separation might mean that the pattern separation tasks does not measure the dentate gyrus. It might also mean that the hippocampus might not degenerate as previously assumed or that the pattern separation task really test the hippocampus.

This dissertation investigates the mechanisms underlying pattern separation, using rodent models and behavioural tasks that assess the use of representations for similar stimuli. Pattern separation is a theoretical mechanism involving the transformation of inputs into output representations that are less correlated to each other. Because of this orthogonalizing process, similar experiences are stored as discrete non-overlapping representations. Studying pattern separation emphasizes the important but often overlooked fact that successful memory involves more than just remembering events over a period of time, but also differentiating between similar memories. Through a series of experiments this dissertation adds support to the literature that the dentate gyrus (DG) subregion of the hippocampus is important for pattern separation when encoding spatial and contextual inputs. Using the Spontaneous Location Recognition (SLR) task it is shown the brain-derived neurotrophic factor (BDNF) can improve performance by acting via N-methyl-D-aspartate (NMDA) glutamate receptors in the DG and adult-born hippocampal neurons. Manipulating the level of neurogenesis by inhibiting Wnt signalling or by administering acyl-ghrelin systemically is shown to impair and enhance performance on SLR, respectively. Using a novel exposure paradigm in combination with SLR, it is demonstrated for the first time that the relationship between pattern separation and neurogenesis may be reciprocal, such that inhibiting neurogenesis impairs pattern separation, enhancing neurogenesis improves pattern separation, and performing pattern separation enhances the production or survival of adult-born hippocampal neurons. Finally, it is shown that the $TgTau^{P301L}$ mouse model of dementia exhibits spatial and object recognition memory impairments once aged, recapitulating a dementia-like phenotype. Understanding the mechanisms that contribute to effective pattern separation may help elucidate the processes underlying the memory impairment experienced by AD patients. This dissertation concludes with a critical discussion about whether pattern separation can be studied using behavioural paradigms.

The processes of pattern separation and pattern completion are very important in the correct discrimination of similar memories. Much research has been conducted on these processes, but there are some gaps that need to be addressed. First, there is some debate as to whether false alarms to lure items come about because of a failure to accurately encode a memory or a failure to retrieve a memory. Second, much of the research on pattern separation and pattern completion in humans is done with visual stimuli and contributions of stimulus modality to these processes are not well understood as a result.Study 1 consisted of three experiments conducted using a combination of eye tracking and functional magnetic resonance imaging (fMRI) methods. Analyses of eye tracking data in the experiments examined the contribution of fixation counts at encoding and retrieval, as well as target-lure similarity level, to accuracy on lure trials. Task designs were altered across studies to attempt to replicate specific research previously conducted with a specific answer period, as well as generalize the findings to a broader body of research that allows participants to answer while the stimulus is presented. The three experiments showed mixed support for the contribution of fixation counts at encoding and retrieval to the accurate discrimination of similar lures. Target- lure similarity, however, was a robust predictor of accuracy for all three experiments.Prior research examining activity in the hippocampus demonstrates a reduction of fMRI activity to repetitions of a stimulus. Greater activity is also observed in the dentate gyrus/CA3 (DG/CA3) subregions for correct rejections of lure items compared to lure false alarms. There should be a greater reduction in the DG/CA3 as a function of encoding for lure false alarms than for lure correct rejections if memory encoding drives the activity differences between these outcomes. The fMRI data showed a marked reduction of activity in the left hippocampus to repetition trials as a function of encoding trial fixation count. There was no significant difference between activity as a function of encoding fixation count in the DG/CA3 for lure correct rejections and lure false alarms. There was also no difference in activity for the CA1 either. Overall, the results of the eye tracking and fMRI data give support for the contribution of pattern completion to false alarms to lure stimuli rather than poor encoding.Study 2 examined the contribution of sensory modality to accurate discriminations of lure stimuli. A behavioral task was developed to directly compare discrimination of similar lures on visual and auditory stimuli. Participants were significantly more accurate and more confident of their responses when discriminating visual stimuli as compared to discriminating auditory stimuli.

One of the few areas in the brain that still exhibits experience-dependent neuroplasticity in adulthood is found in the medial temporal lobe (MTL) system. Within the MTL, this plasticity has been observed in the hippocampus in both humans and animal models. Rodent model studies focusing on the effect of aerobic exercise have shown a positive increase of neuroplasticity in the dentate gyrus subregion of the hippocampus. Another area in the MTL, the entorhinal cortex (EC), serves as a primary input to the hippocampus, and studies on environmental enrichment have reported greater EC volume in rodents supplied with toys and running wheels. Previous work in our lab working with healthy young adults showed a positive correlation between right EC volume, and aerobic fitness (VO2 max). In this thesis, I examined two aims, first whether aerobic fitness predicts changes in thickness or volume of the MTL as well as performance in an MTL dependent task in healthy young adults. Additionally, whether the brain morphology measures of the MTL can predict performance on the memory task. The second aim looks at the longitudinal effect a 12-week exercise intervention has on thickness or volume in the MTL and performance on an MTL dependent task in the same population. Results indicate that there is a positive baseline correlation between aerobic fitness and thickness of the EC on the left hemisphere but there are no longitudinal changes in morphology after the exercise intervention. These data extend previous work on the effects aerobic exercise has on MTL structure and offer interesting venues to combat neurodegenerative diseases that affect the MTL memory system like Alzheimer’s disease.