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. [...]

Considerable research has been carried out to establish a rodent model for the study of human memory, yet functional similarities between the species remain up for debate. The hippocampus, a region deep within the medial temporal lobe of the mammalian CNS, is critical for long-term episodic memory. Projections from the medial entorhinal cortex convey spatial/contextual information, while projections from the lateral entorhinal cortex convey item/object information to the hippocampus. The functional significance of these parallel projections to the rodent hippocampus has been suggested to support spatial processing, while the same projections to the human hippocampus support spatial and non-spatial memory. Discharging in a location-specific manner, hippocampal place cells contribute to spatial memory; however, evidence for neuronal correlates of non-spatial object memory has not been fully defined. The current experiments were designed to address the following questions, while utilizing electrophysiology, functional inactivation during a novel behavioral task, and immunohistochemistry. Is the memory for objects hippocampal-dependent, solely due to the location of the object, or are objects represented within hippocampal activity independent of location? To tease apart spatial and non-spatial processing by the hippocampus, the spatial aspects of 3D objects were enhanced by utilizing movement. A novel discriminatory avoidance task, Knowing Your Enemy, was adapted from an Enemy Avoidance task to test true object memory in mice. Current findings support the notion that object-associations acquisition depends upon a specific context. Retrieval of such object-associations is not context-dependent, yet remains sensitive to temporary inactivation of the CA1 region of the dorsal hippocampus. The avoidance impairments observed following hippocampal inactivation were shown to not be a result of reduced anxiety. Immunohistochemical marker expression suggests that the CA1 region was highly active during object exposures, yet the hippocampal system responded differentially to moving and to stationary objects. Recordings of CA1 neurons yielded non-bursting object-related activity during object exploration, and place cell activity remained unaffected in the presence of moving objects; supporting independent, yet simultaneous processing of spatial and non-spatial information within the hippocampus. Together, the current findings support the notion that the CA1 region of the rodent hippocampus processes object-related information, independent of spatial information. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection

Decision makers flexibly deploy decision-making strategies based on the specific features of the problems they face (Ford, Schmitt, Schechtman, Hults, & Doherty, 1989; Payne, Bettman, & Johnson, 1993). However, research on the neuroscience of decision making has focused on a "policy capture" approach that utilizes static decision problems to study the relationships between input (the problem presented), output (the choices made), and the brain. Since the decision problems are prepackaged, this approach does not provide information about the neural bases of predecisional processes critical for flexible decision making, such as selecting an appropriate decision-making strategy and dynamically acquiring and integrating the information needed to progress toward choice. The aim of the current project is to use the lesion method to explore the neural bases of predecisional processes. The fronto-limbic information acquisition network (FLIAN) is proposed as a neural framework critical for predecisional processes in flexible decision making. According to the FLIAN model, the ventromedial prefrontal cortex (vmPFC) represents the decision problem as currently perceived (i.e., the decision space), which is the basis for selecting a decision strategy via interactions with limbic structures. The vmPFC implements the strategy through the coordination of attribute-based information acquisition induced by the amygdala and relational, option-based acquisition induced by the hippocampus. In Chapter 1, the literature pertinent to FLIAN structures is reviewed, including the neuroanatomical and functional backgrounds of those structures, their roles in decision making, and their potential roles in predecisional processes. Chapter 2 provides a review of the behavioral literature on predecisional processes and outlines the FLIAN model in detail. Chapters 3 and 4 present studies that test, and provide partial support for, the FLIAN model using the lesion method and information board tasks. As predicted, the hippocampus is shown to be critical for relational, option-based information acquisition. The vmPFC is shown to be critical for determining how attributes are weighted in the decision space representation and for organizing predecisional behavior. The amygdala was not found to play its role in attribute-based acquisition, but previous studies do support this function and further research is warranted on the role of the amygdala, as well as the hippocampus and vmPFC, in predecisional processes. Future research should also explore the consequences of abnormal predecisional functioning for social behavior, memory, and emotion processing.

In spite of the many discoveries made in neuroscience, the mechanism by which memories are formed is still unclear. To better understand how some disorders of the brain arise, it is necessary to improve our knowledge of memory formation in the brain. With the aid of a biological experiment, an artificial neural network is developed to provide insight into how information is stored and recalled. In particular, the bi-conditional association of distinct spatial and non-spatial information is examined using computational techniques. The thesis defines three versions of a computational model based on a combination of feedforward and recurrent neural networks and a biologically-inspired spike time dependent plasticity learning rule. The ability of the computational model to store and recall the bi-conditional object-space association task through reward-modulated plastic synapses is numerically investigated. Further, the network's response to variation of certain parameter values is numerically addressed. A parallel algorithm is introduced to reduce the running time necessary to test the robustness of this artificial neural network. The numerical results produced with this algorithm are then analyzed by a statistical approach, and the network's ability for learning is assessed.

2.5 million people sustain a traumatic brain injury (TBI) annually in the United States. Although there is potential for functional recovery following TBI, there is no definitive treatment to improve recovery after TBI. Our lab has shown that TBI enhances an endogenous neurogenic response in the subventricular zone and hippocampus. TBI-induced neural stem cells (NSCs) can integrate into regions such as the hippocampus and olfactory bulb. Although the mechanism behind TBI-enhanced neurogenesis remains unknown, the Notch signaling pathway has been implicated as a regulator in the maintenance and survival of NSCs. This thesis explores the effects of Notch pathway manipulation on functional recovery following TBI. We hypothesize that Notch signaling plays a critical role in recovery after TBI. Activation of this pathway via a Notch agonist (Notch1) will facilitate post-injury recovery while inhibition of this pathway via a Notch antagonist (recombinant Jagged-1 Fc) will deter post-injury recovery. Functional recovery was assessed within 30 days or 60 days post-injury in two different cohorts of animals. The behavior assays conducted in this study included motor, cognitive, and olfactory assessment. In the 30-day phase, Notch pathway manipulation following TBI did not affect functional performance. In the 60-day study, significant group differences were found. While the FPI+Vehicle animals exhibited a functional recovery in Morris water maze, injured animals with Notch inhibition failed to show this cognitive recovery, indicating the involvement of the Notch pathway in cognitive recovery at the chronic stage following TBI. Motor and olfaction were not significantly affected by Notch pathway manipulation.

The stress system is essential for humans and other organisms to survive. However, when stress is prolonged it can have pathological effects on the brain. To experience long-term unemployment is often stressful, for it has been shown to correlate with depression, low self- esteem, learned helplessness and self-destructive behavior. Long-term unemployment also seems to have physiological consequences, for it has been shown to correlate with cortisol dysregulation. The hippocampus is a highly adaptable part of the brain located in the temporal lobe and is long known for its sensitivity to cortisol dysregulation due to stress. The aim of this thesis is to study how long-term unemployment affects physical and psychological well- being, focusing in particular upon finding out whether it affects the hippocampus. The results suggest that that the kind of stress caused by long-term unemployment is similar to the stress affecting the hippocampus. It thus seems to be a reasonably hypothesis that long-term unemployment has a negative influence upon the brain, and the hippocampus in particular.However, there is an additional issue that one needs to take into account. For some studies have shown that people with poor mental health are more likely to be unemployed. If poor mental health is associated with physiological disorders (including a damaged hippocampus), this implies that not only can long-term unemployment (via stress) affect the hippocampus, but a damaged hippocampus (along with other physiological factors) can increase the probability to become unemployed. This means that the relationship between long-term unemployment and a damaged hippocampus need not be a one-way causal relationship.

Semantic memory includes vocabulary and word meanings, conceptual information, and general facts about the world (Tulving, 1972). According to the standard view of semantic memory in cognitive neuroscience, the hippocampus is necessary to first acquire new semantic information (Gabrieli, Cohen, & Corkin, 1988), but these representations are then consolidated in the neocortex and become independent of the hippocampus with time (McClelland, McNaughton, & O'Reilly, 1995). Remote semantic memory is considered independent of the hippocampus, and the hippocampus is not thought to play a critical role in the processing and use of such representations. The current work challenges the notion that previously acquired semantic knowledge, and its use during communication, is independent of the hippocampus. A group of patients with bilateral hippocampal damage and severe impairments in declarative memory were tested. Intact naming and word-definition matching performance in amnesia, has led to the notion that remote semantic memory is intact in patients with hippocampal amnesia. Motivated by perspectives of word learning as a protracted process where additional features and senses of a word are added over time, and by recent discoveries about the time course of hippocampal contributions to on-line relational processing, reconsolidation, and the flexible integration of information, we revisit the notion that remote semantic memory is intact in amnesia. Using measures of semantic richness and vocabulary depth from psycholinguistics and first and second language-learning studies, we examined how much information is associated with previously acquired, highly familiar words in hippocampal amnesic patients. Relative to healthy demographically matched comparison participants and a group of brain-damaged comparison participants, the patients with hippocampal amnesia performed significantly worse on both productive and receptive measures of vocabulary depth and semantic richness. In the healthy brain, semantic memory appears to get richer and deeper with time. Healthy participants of all ages were tested on these measures and strong correlations are seen with age as older healthy adults displayed richer semantic knowledge than the younger adults. The patient data provides a mechanism: hippocampal relational binding supports the deepening and enrichment of knowledge over time. These findings suggest that remote semantic memory is impoverished in patients with hippocampal amnesia and that the hippocampus supports the maintenance and updating of semantic memory beyond its initial acquisition. The use of lexical and semantic knowledge during discourse was also examined. Amnesic patients displayed significantly lower levels of lexical diversity in the speech they produced, and showed a strong trend toward producing language with reduced levels of semantic detail suggesting that patients cannot use their semantic representations as richly during communication. These results add to a growing body of work detailing a role for the hippocampus in language processing more generally. By documenting a role for the hippocampus in maintaining, updating, and using semantic knowledge, this work informs theories of semantic memory and it's neural bases, advances knowledge of the role of the hippocampus in supporting human behavior, and brings more sensitive measures to the neuroscientific study of semantic memory.

Previous research investigating the neural circuitry underlying memory consolidation has primarily focused on single “nodes” in the circuit rather than the neural connections between brain regions, despite the likely importance of these connections in mediating different aspects or forms of memory. This focus has, in part, been due to technical limitations; however the advent of optogenetics has altered our capabilities in this regard, enabling optical control over neural pathways with temporal and spatial precision. The current set of experiments took advantage of optogenetics to control activity in specific pathways connecting brain regions in rats immediately after different kinds of learning. Chapter 2 first established the use of optogenetics to manipulate activity in the basolateral amygdala (BLA), which has been shown to modulate memory consolidation for a variety of types of learning likely through its connections to various downstream regions. Using a one-trial inhibitory avoidance task, a simple and robust fear learning paradigm, we found that both post-training stimulation and inhibition of BLA activity could enhance or impair later retention of the task, respectively. Enhancement was specific to stimulation using trains of 40, but not 20, Hz light pulses. Chapters 3 and 4 examined the projections from the BLA to the ventral hippocampus (VH) and medial entorhinal cortex (mEC) as the BLA’s ability to influence the consolidation for many types of memory is believed to be mediated through discrete projections to distinct brain regions. Indeed, the BLA innervates both structures, and prior studies suggest that the mEC and VH have distinct roles in memory processing related to contextual and nociceptive (footshock) learning, such as those involved in contextual fear conditioning (CFC). Optogenetic stimulation or inhibition of the BLA-VH or BLA-mEC pathway after training on a modified CFC task, in which the nociceptive or emotional stimulus (the footshock) and the context are separated, enabled experimental manipulations to selectively affect the consolidation for learning about one component and not the other. Optogenetic stimulation/inhibition was given to each candidate pathway immediately after the relevant training to determine its role in influencing consolidation for that component of the CFC learning. Chapter 3 results showed that stimulation of the BLA-VH pathway following footshock, but not context, training enhanced retention, an effect that was specific to trains of 40 Hz stimulation. Post-footshock photoinhibition of the same pathway impaired retention for the task. Similar investigations of the BLA-mEC pathway in Chapter 4 produced complementary findings. Post-context, but not footshock, stimulation of the pathway enhanced retention. In this particular case, only trains of 8 Hz stimulation were effective at enhancing retention. These results are the first, to our knowledge, to find that BLA inputs to different structures selectively modulate consolidation for different aspects of learning, thus enhancing our understanding of the neural connections underlying the consolidation of contextual fear conditioning and providing a critical foundation for future research.

Stress has been shown to influence learning and memory in humans and rats (Diamond et al, 1996; Diamond et al, 1999; Krugers et al, 1997; Kirschbaum et al, 1996; Lupien et al, 1997). The hippocampus and is an area of the brain involved in memory function in humans and rats (Kirschbaum et al, 1996; Lupien et al, 1997) and is highly susceptible to stress (Diamond et al, 1990). Research has indicated that a number of stressors such as exposure to a predator (Diamond et al, 1999) can lead to stress effects. Recently efforts have been made to counteract the effects of stress on brain function and related behavioral performance. The antidepressant drug tianeptine has been used in this setting. Little is known about tianeptine's role in blocking stress effects on behavior and memory performance with regard to interactions with stress hormones, such as corticosterone. Here a set of experiments delineates the role of corticosterone and its link to stress effects on memory as well as an investigation into the actions of tianeptine and ADX in the blockade of stress effects on memory. First, I examined the effects of tianeptine on multi-day RAWM working memory training and a novel one-day learning and memory training task. Second, the effects of propranolol, an anti-anxiety medication, were tested with regard to the alleviation of stress effects on memory, allowing for a comparison between two anti-anxiety drugs, tianeptine and propranolol. Third, adrenalectomy (ADX) and the resultant depletion of adrenal hormones were examined in connection with learning and memory in the one-day learning task. Fourth, the effects and interactions of tianeptine and ADX were examined to see if tianeptine can exert its effects in the absence of adrenal hormones. Tianeptine blocked stress-induced memory errors in two different tasks and under ADX conditions. All effects were independent of corticosterone levels. In contrast, propranolol was ineffective in blocking stress-induced memory changes. The current data may prove useful in the development of antidepressant drugs and further the study of the mechanisms by which stress affects memory.

A habênula é uma estrutura epitalâmica diferenciada em dois complexos nucleares, a habênula medial (MHb) e a habênula lateral (LHb). Recentemente, a MHb junto com seu alvo principal, o núcleo interpeduncular (IP), foram identificados como estruturas chaves envolvidas na mediação dos efeitos aversivos da nicotina. Contudo, estruturas intimamente interligadas com o eixo MHb-IP, como o núcleo mediano (MnR), a parte caudal do núcleo dorsal da rafe (DRC), e o núcleo tegmental laterodorsal (LDTg) podem contribuir para os efeitos comportamentais da nicotina. As conexões aferentes e eferentes do IP, até agora, não foram sistematicamente investigadas com traçadores sensíveis. Assim, realizamos injeções de traçadores retrógrados ou anterógrados em diferentes subdivisões do IP, no MnR, ou LDTg e também examinamos a assinatura neuroquímica de algumas das mais proeminentes aferências dessas três estruturas através da combinação de rastreamento retrógrada com métodos de imunofluorescência e hibridização in situ. Além de receber entradas topograficamente organizadas da MHb e também da LHb, observamos que o IP está principalmente interligado de forma recíproca com estruturas da linha média, incluindo o MnR/DRC, o núcleo incerto, o núcleo supramamilar, o septo e o LDTg. As conexões bidirecionais entre o IP e o MnR assim como as entradas do LDTg para o IP provaram de ser principalmente GABAérgicas. Com respeito a uma possível topografia das saídas do IP, todos os subnúcleos do IP deram origem a projeções descendentes, enquanto as suas projeções ascendentes, incluindo projeções focais para o hipocampo ventral, o septo ventrolateral, e a LHb originaram da região dorsocaudal do IP. Nossos resultados indicam que o IP está intimamente associado a uma rede de estruturas da linha média, todos eles considerados moduladores chave da atividade teta do hipocampo. Assim, o IP forma um elo que liga MHb e LHb com esta rede e com o hipocampo. Além disso, as proeminentes interconexões predominantemente GABAérgicas entre IP e MnR, assim como IP e LDTg, suportam um papel chave dessas vias bidirecionais na resposta comportamental à nicotina. / The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR), caudal dorsal raphe nucleus (DRC), and the laterodorsal tegmental nucleus (LDTg), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions, the MnR, or LDTg and additionally examined the transmitter phenotype of some major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques. Besides receiving topographically organized inputs from MHb and also LHb, we found that the main theme of IP connectivity are strong reciprocal interconnections with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and LDTg. The bidirectional connections between IP and MnR and the LDTg inputs to the IP proved to be mostly GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas ascending projections, including focal projections to the ventral hippocampus, ventrolateral septum, and LHb mostly originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures, all of them considered key modulators of hippocampal theta activity. Thus, IP forms a node that links MHb and LHb with this network and the hippocampus. Moreover, the rich predominantly GABAergic interconnections between IP and MnR, as well as IP and LDTg, support a cardinal role of these bidirectional pathways in the behavioral response to nicotine.