Since the field-defining patient HM, consistent links have been made between a region of the brain called the hippocampus and memories that can be consciously declared - so called declarative memories. Declarative memories fall into two categories (1) episodic memories, memories that are highly detailed and re-experiential, and (2) semantic memories, fact-based memories for personal and public information but that have no sense of re-experiencing. It is believed that the intrinsic anatomy of the hippocampus supports episodic memory but not semantic memory. The hippocampus consists of five regions (cornu Ammonis, CA, 1-3, dentate gyrus, subiculum) with each purported to have a specific role in episodic memory acquisition and retrieval. However, controversy surrounds the temporal extent to which episodic memories rely on the hippocampus for retrieval: current consensus suggests the hippocampus supports these memories for five-10 years post-acquisition, but some suggest that it is required for retrieval across the lifetime. Voltage-gated potassium channel-complex antibody-mediated limbic encephalitis (VGKC-complex LE) is a recently described autoimmune disease that causes chronic hippocampal atrophy and mild amnesia on standardized neuropsychological assessment. Two subfields of the hippocampus - CA1 and CA3 - contain the antigenic targets of the disease but it is unknown if specific atrophy of these subfields underlies the hippocampal damage in humans. Here, the human hippocampal subfield volumes of VGKC-complex LE patients (n = 19, mean age: 64.0±2.55; range: 24-71) were investigated using ultra-high spatial resolution MRI at 7.0-Tesla. Assessment also included standardized neuropsychology to examine the impact of the pathology on hippocampal-dependent and -independent memory performance, as well as attention, language, executive function, and perception Declarative memory assessment measured semantic and episodic memory performance across the lifespan. Manual segmentation detected lesions to just CA3, with no volume loss noted elsewhere in the hippocampus or brain. Patients were impaired on hippocampal-dependent memory domains but not the hippocampal-independent and non-memory domains. Notably, episodic memory assessment revealed episodic amnesia across the lifetime except for their earliest memories. This counters the received convention that the hippocampus has a temporally limited role in episodic retrieval. Conversely, the performance of the VGKC-complex LE patients for semantic memory, including a new test developed herein, was comparable to controls across the lifespan. It was then shown that CA3 volume predicted episodic memory performance across the lifetime. Together, the results suggest that VGKC-complex LE provides a novel model of human hippocampal subfield pathology, with which to explore the roles of hippocampal subfields in episodic memory acquisition and retrieval.

According to Piaget and Bartlett, learning involves both assimilation of new memories into networks of preexisting knowledge and alteration of existing networks to accommodate new information into existing schemas. Recent evidence suggests that the hippocampus integrates related memories into schemas that link representations of separately acquired experiences. In this thesis, I first review models for how memories of individual experiences become consolidated into the structure of world knowledge. Disruption of consolidated memories can occur during related learning, which suggests that consolidation of new information is the reconsolidation of related memories. The accepted role of the hippocampus during memory consolidation and reconsolidation suggests that it is also involved in modifying appropriate schemas during learning. To study schema development, I trained rats to retrieve rewards at different loci on a maze while recording hippocampal calls. About a quarter of cells were active at multiple goal sites, though the ensemble as a whole distinguished goal loci from one another. When new goals were introduced, cells that had been active at old goal locations began firing at the new locations. This initial generalization decreased in the days after learning. Learning also caused changes in firing patterns at well-learned goal locations. These results suggest that learning was supported by modification of an active schema of spatially related reward loci. In another experiment, I extended these findings to explore a schema of object and place associations. Ensemble activity was influenced by a hierarchy of task dimensions which included: experimental context, rat's spatial location, the reward potential and the identity of sampled objects. As rats learned about new objects, the cells that had previously fired for particular object-place conjunctions generalized their firing patterns to new conjunctions that similarly predicted reward. In both experiments, I observed highly structured representations for a set of related experiences. This organization of hippocampal activity counters key assumptions in standard models of hippocampal function that predict relative independence between memory traces. Instead, these findings reveal neural mechanisms for how the hippocampus develops a relational organization of memories that could support novel, inferential judgments between indirectly related events.

The hippocampus is crucial for episodic memory and certain forms of spatial navigation. Firing activity of hippocampal principal neurons contains environmental information, including the presence of specific objects, as well as the animal’s spatial and temporal position relative to environmental and behavioral cues. The organization of these firing correlates may allow the formation of memory traces through the integration of object and event information onto a spatiotemporal framework of cell assemblies. Characterizing how external inputs guide internal dynamics in the hippocampus to enable this process across different experiences is crucial to understanding hippocampal function. A body of literature implicates the medial entorhinal cortex (MEC) in supplying spatial and temporal information to the hippocampus. Here we develop a protocol utilizing bilaterally implanted custom designed triple fiber optic arrays and the red-shifted inhibitory opsin JAWS to transiently inactivate large volumes of MEC in freely behaving rats. This was coupled with extracellular tetrode recording of ensembles in CA1 of the hippocampus during a novel memory task involving temporal, spatial and object related epochs, in order to assess the importance of MEC activity for hippocampal feature selectivity during a rich and familiar experience. We report that inactivation of MEC during a mnemonic temporal delay disrupts the existing temporal firing field sequence in CA1 both during and following the inactivation period. Neurons with firing fields prior to the inactivation on each trial remained relatively stable. The disruption of CA1 temporal firing field sequences was accompanied by a behavioral deficit implicating MEC activity and hippocampal temporal field sequences in effective memory across time. Inactivating MEC during the object or spatial epochs of the task did not significantly alter CA1 object selective or spatial firing fields and behavioral performance remained stable. Our findings suggest that MEC is crucial specifically for temporal field organization and expression during a familiar and rich experience. These results support a role for MEC in guiding hippocampal cell assembly sequences in the absence of salient changing stimuli, which may extend to the navigation of cognitive organization in humans and support memory formation and retrieval.

The hippocampal to medial prefrontal cortex (HPC-mPFC) pathway has a role in mnemonic processing. A key function of the hippocampus (HPC) is to organize contextual memories by how they were experienced, and the prefrontal cortex (PFC) retrieves contextual memories by sorting and suppressing irrelevant memories for the task at hand. Studies have highlighted the HPC-mPFC connection in rodents, however, there is a relative paucity of primate studies. The present study addressed this issue by investigating the connection from the HPC to anterior cingulate cortex (ACC; areas 24a, 25 and 32) of the mPFC in rhesus monkeys (Macaca mulatta). The distribution of hippocampal axons and terminals (boutons) was largest in area 25. Bouton diameter was largest in the deep layers of area 25, suggesting an efficient transmission system from the HPC. The robust projections from the HPC terminated most densely in the superficial layers of area 25. The HPC pathway also innervated some inhibitory neurons, labeled for the calcium binding proteins calbindin or calretinin in the superficial layers of the ACC, whereas axons innervated parvalbumin inhibitory neurons in the deep layers of the ACC. The findings suggest that area 25 may be a fundamental pathway from the HPC for memory processing and can be a focal point in therapeutic interventions in neurological and psychiatric diseases.

A healthy memory is essential to personal identity, completion of everyday tasks, and social acceptance. As factors such as age and illness threaten this key aspect of life, scientific and commercial attention has shifted to software, pharmaceuticals, and medical devices that help stave off inevitable memory decline. There is evidence suggesting that changes in lifestyle similarly work to improve memory. Mindfulness meditation, which is a practice rooted in the spiritual beliefs of Buddhism, has emerged as a promising technique to improve facets of cognition, including memory, as well as to change structures in the brain. Pattern separation is a key process of episodic memory that allows one to keep similar memories distinct. In this study, we evaluate the efficacy of a 4-week mindfulness training program on visual object pattern separation against an active creative writing control intervention and find that mindfulness meditation improves pattern separation and promotes changes in hippocampal brain structures.

OSÓRIO, Frederico Moreira. Estudo populacional do cavalo-marinho HIPPOCAMPUS REIDI GINSBURG, 1933 (TELEOSTEI: SYNGNATHIDAE) em dois estuários cearenses. 2008. 62 f. Dissertação (Mestrado em Ciencias Marinhas Tropicais) - Instituto de Ciências do Mar, Universidade Federal do Ceará, Fortaleza, 2008. / Submitted by Debora Oliveira (deby_borboletinha@hotmail.com) on 2011-12-07T17:53:15Z No. of bitstreams: 1 2008_dis_fmosorio.pdf: 3361733 bytes, checksum: 107c0f8f4e10ff5ec9e9761b74c6466f (MD5) / Approved for entry into archive by Nadsa Cid(nadsa@ufc.br) on 2011-12-07T17:56:46Z (GMT) No. of bitstreams: 1 2008_dis_fmosorio.pdf: 3361733 bytes, checksum: 107c0f8f4e10ff5ec9e9761b74c6466f (MD5) / Made available in DSpace on 2011-12-07T17:56:46Z (GMT). No. of bitstreams: 1 2008_dis_fmosorio.pdf: 3361733 bytes, checksum: 107c0f8f4e10ff5ec9e9761b74c6466f (MD5) Previous issue date: 2008 / Seahorses are bony fishes included in the Hippocampus genus. Many aspects of their biology make them extremely vulnerable to overexploitation. The intense commerce and habitat degradation allied to their biology, contribute to the decline of their populations. Considering the level of threat to these animals around the world and their relevance as a “flagship species”, studies concerning their ecology are extremely important. The purpose of this study was to determine spatial and temporal distribution of the abundance of Hippocampus reidi at the Pacoti and Malcozinhado rivers, registering also other ecological aspects of the species. Transects with an area of 100 m2 were conducted along the riverbanks. Each river was divided into two stations with increasing distances from the sea. The mean density determined was of 0,008 individuals/m2. The Pacoti River showed a significantly higher mean density when compared to the Malcozinhado River (p=0,019). There was no difference between the two stations in the Pacoti River, while in the Malcozinhado an evident difference was noticed. Both rivers showed a decreasing trend in the densities during the study, but the differences were not significant (p=0,33 and p=0,41, for Pacoti and Malcozinhado, respectively). No seazonal variation in abundance was determined. The animals from the Pacoti River were significantly higher than those from the Malcozinhado (p=0,027). Sez ratio was 1:1, and males were higher on average than the females (p=0,013). Black and brown colored seahorses were more abundant than other colors. The roots of Laguncularia racemosa were preferably chosen as anchoring substrata. The present study showed that environmental differences on the estuaries, such as mangrove areas, discharge volume and vulnerability to impacts might cause differences in the abundance of H. reidi. The adequate management of this threatened species depend strongly on a good knowledge of its ecology. / Os cavalos-marinhos são peixes ósseos do gênero Hippocampus. Algumas características deste grupo os tornam bastante vulneráveis a sobreexploração. O intenso comércio e a degradação de seus habitats aliados aos seus aspectos biológicos, contribuem para o declínio de suas populações. Diante da ameaça que estes animais estão sujeitos em todo o mundo e da sua relevância como espécie bandeira, é de fundamental importância estudos a respeito de sua ecologia. O objetivo deste trabalho foi verificar a distribuição espacial e temporal da abundância de Hippocampus reidi nos rios Pacoti e Malcozinhado, além de documentar características ecológicas desta espécie na natureza. Foram realizados transectos com área de 100 m2 ao longo das margens dos dois rios. Cada rio foi dividido em duas estações com distâncias crescentes do mar, estas distâncias eram aproximadamente equivalentes nos dois estuários. A densidade média verificada foi de 0,008 indivíduos/m2. O rio Pacoti apresentou uma densidade média significativamente superior à do rio Malcozinhado (p = 0,019). O Pacoti não apresentou diferença de densidade no gradiente de distância do mar, sendo que o mesmo não ocorreu com o Malcozinhado. Os dois rios apresentaram uma pequena diminuição nas densidades em um intervalo de aproximadamente 3 anos, mas sem diferença significativa (p = 0,33 e p = 0,41, para o Pacoti e Malcozinhado, respectivamente). Foi observado que não há variação sazonal na abundância de cavalos-marinhos. Os indivíduos avistados no rio Pacoti apresentaram altura significativamente superior aos do rio Malcozinhado (p = 0,027). A razão sexual foi de 1:1, onde os machos apresentaram altura média superior à das fêmeas (p = 0,013). Os indivíduos de coloração preta e marrom foram os mais abundantes. As raízes de Laguncularia racemosa foi o substrato de apoio preferido dos animais avistados. Este estudo demonstrou que diferenças ambientais nos estuários como área do manguezal, vazão fluvial e vulnerabilidade a impactos ambientais podem causar diferença na abundância de H. reidi e que o conhecimento de aspectos ecológicos destes animais na natureza é de fundamental importância na elaboração de planos de manejo para esta espécie.

xi, 64 p. : ill. (some col.) / In humans and other mammals the hippocampus is critical for episodic memories, or memories of events that happen in a particular place and at a particular time. When one records from hippocampal pyramidal neurons in awake, behaving rodents, however, the most obvious firing correlate of these neurons is the animal's position within the environment, earning them the name "place cells". Their aggregate activity is thought to provide the animal with a "cognitive map": a map-like neural representation of the external world used to solve spatial problems. Since rats' ability to take shortcuts through novel space was the major evidence leading Edward Tolman to propose the concept of a cognitive map, it follows that place cells should exist for parts of the environment that the animal has not directly-experienced. We therefore compared the relative stability of place cells recorded from rats in observed versus directly explored parts of an environment in response to a pharmacological manipulation that preferentially destabilizes newly-generated place fields. In contrast to the classical cognitive map hypothesis, the formation of stable place fields clearly requires direct experience with a space, suggesting place cells are part of an autobiographical record of events and their spatial context rather than a map-like representation of space automatically calculated from observed environmental geometry. This dissertation includes previously unpublished co-authored material. / Committee in charge: Janis Weeks, Chairperson; Clifford Kentros, Advisor; William Roberts, Member; Terry Takahashi, Member; Edward Vogel, Outside Member

The loss and dysfunction of selected populations of synapses is characteristic of mammalian brain ageing and alterations in these receptive compartments are considered to underpin age-related cognitive decline. Discrete neuro-anatomical regions of the cortical architecture harbour disparate populations of synapses that demonstrate significant heterogeneity with regards to advancing age. Of particular interest is the hippocampus, which is selectively vulnerable during ageing. The hippocampal synaptic architecture exhibits subtle structural and biophysical alterations, which are considered to promote the manifestation of cognitive symptoms in aged patients. This notion of “selective synaptic vulnerability” has been the focal point of a multitude of morphological studies investigating age-related cognitive decline, which have often provided tentative conclusions as to how this phenomenon may be regulated. The molecular correlates bolstering the reported age-dependent morphological and functional shift remain elusive and studies are only now beginning to unravel how discrete organelles, proteins and signalling cascades may hierarchically or synergistically attenuate synaptic function. Until there is considerable comprehension of how functional mediators drive the biochemical substrates regulating age-related cognitive decline, there are limited strategic avenues for the development of efficacious therapeutic interventions that promote successful ageing. To address the phenomenon of selective synaptic vulnerability, we have utilised an unbiased combinatorial approach, including quantitative proteomic analyses coupled with in vivo candidate assessments in lower order animals (Drosophila), to temporally profile regional synapse and synaptic mitochondrial biochemistry during normal healthy ageing. We begin by demonstrating that cortical mitochondria located at the synaptic terminal are morphologically distinct from non-synaptic mitochondria in adult rodents and human patients. Biochemical isolation and purification of discrete mitochondrial subpopulations from control adult rat fore-brain enabled generation of synaptic and non-synaptic mitochondrial molecular fingerprints using quantitative proteomics, which revealed that expression of the mitochondrial proteome is highly dependent on subcellular localisation. We subsequently demonstrate that the molecular differences observed between mitochondrial sub-populations are capable of selectively influencing synaptic morphology in-vivo. Next, we sought to examine how the synaptic mitochondrial proteome was dynamically and temporally regulated throughout ageing to determine whether protein expression changes within the mitochondrial milieu are actively regulating the age-dependent vulnerability of the synaptic compartment. Proteomic profiling of wild-type mouse cortical synaptic and non-synaptic mitochondria across the lifespan revealed significant age-dependent heterogeneity between mitochondrial subpopulations, with aged organelles exhibiting unique protein expression profiles. Recapitulation of aged synaptic mitochondrial protein expression at the Drosophila neuromuscular junction has the propensity to perturb the synaptic architecture, demonstrating that temporal regulation of the mitochondrial proteome may directly modulate the stability of the synapse in vivo. Although we had comprehensively characterised the temporal regulation of rodent cortical mitochondrial subpopulations, providing a number of novel candidates that may be mediating synaptic vulnerability during ageing, we sought to establish whether similar alterations were occurring in the primate brain. Using synaptic isolates from neuroanatomically distinct age-resistant (occipital cortex) and age-vulnerable (hippocampus) regions, we demonstrate that synaptic ageing is brainregion dependent and that discrete populations of synapses significantly differ at a biochemical level in the healthy human and non-human primate brain. Recapitulation of aged hippocampal protein expression with genetic manipulation in vivo revealed numerous novel candidates that have the propensity to significantly modulate multiple morphological parameters at the synapse. Furthermore, we demonstrate that several of these candidates sit downstream of TGFβ1 and activation of the TGFβ1 signalling cascade in hippocampal synaptic populations drives the aberrant expression of selected candidates during ageing. Finally, we show that selective pharmacological inhibition of this pathway rescues synaptic phenotypes in multiple candidate lines. The data affirmed that activation of the TGFβ1 transduction pathway modulates synaptic stability and thus may contribute to the selective vulnerability of hippocampal synapses during ageing.

O enriquecimento ambiental pode ser considerado uma condição que proporciona aumento da estimulação sensorial, cognitiva e motora, que levaria, a curto e longo prazos, a mudanças comportamentais importantes. O objetivo deste trabalho foi avaliar os efeitos da exposição ao enriquecimento ambiental (1) na ansiedade e memória aversiva, ambos no labirinto em cruz elevado, (2) na memória operacional espacial no labirinto aquático de Morris, e (3) na neurogênese hipocampal, em ratos. Os animais foram expostos ao enriquecimento ambiental a partir do desmame (22 dias), onde permaneceram até o último dia de teste (17º mês). Nesse período, foram submetidos ao Labirinto em Cruz Elevado (LCE) no 3º e 15º mês, e ao Labirinto Aquático de Morris (LAM) no 9º e 16º mês. Uma semana antes da exposição ao labirinto aquático, receberam uma injeção intraperitonal de bromodeoxyuridina (BrdU). Vinte e quatro horas e trinta dias após essa injeção grupos independentes de animais foram sacrificados e seus encéfalos processados imunohistoquímicamente para revelar o BrdU. O enriquecimento ambiental produziu um efeito ansiolítico em animais jovens, mas não nos idosos. A memória aversiva de animais jovens e idosos não se alterou. No labirinto aquático, enquanto os animais expostos ao ambiente enriquecido por 9 meses apresentaram uma estratégia mais eficiente de busca em relação aos respectivos controles, os animais expostos ao ambiente enriquecido por 15 meses apresentaram mais flexibilidade para se adaptar as novas situações; no entanto, o enriquecimento ambiental parece não alterar diretamente o desempenho na memória operacional espacial. Em relação a neurogênese hipocampal, o enriquecimento foi capaz de aumentar cerca de 2 vezes o número de novas células; no entanto, a exposição ao labirinto aquático foi capaz de aumentar a taxa de sobrevivência de novos neurônios / Environmental enrichment in laboratory animals is a housing condition that provides enhanced sensorial, motor and social stimulation as compared to maintenance in standard laboratory cages. It has been claimed that this kind of stimulation improves cognition. The aim of this study was to investigate the effects of exposure to environmental enrichment on anxiety and aversive memory in the elevated plus maze, spatial working memory in the Morris\' water maze, and hippocampal neurogenesis. The animals were subjected to environmental enrichment from weaning (22 days) up to the last test (17 months). During this period, they were tested in the 3rd and 15th months of life in the elevated plus maze, and in the 9th and 16th months of life in the Morris\' water maze. A week before exposure to the water maze, the animals received an intraperitoneal injection of BrdU. Twenty-four hours and 30 days after the injection independent groups of animals were sacrificed for performing immunohistochemistry. Exposure to the enriched environment rendered young animals, but not elderly, less anxious. In addition, the aversive memory of both groups remained unchanged along aging. In the Morris\' water maze, animals exposed to the enriched environment showed a more effective searching strategy to find the hidden platform on the first trial than the controls, when tested at 9 months. In addition, the flexibility to deal with novel situations at 15 months was greater for animals exposed to the enriched environment. Even though, exposure to the enriched environment did not alter performance of spatial working memory. Environmental enrichment doubled hippocampal neurogenesis, and the survival of the new neurons was greater when the subjects were exposed to the Morris\' water maze task

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