Note:

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 88-105).

Historically, there have been two lines of research on mammalian hippocampus. The first one is concerned with the role of hippocampus in formations of new memories and owes its origin to the seminal study by Brenda Milner and William Scoville of a single memory disorder patient, widely known as H.M. The second line of research views the hippocampus as the brain area concerned with orienting and navigating in space. It started with John O’Keefe’s discovery of place cells, pyramidal neurons in the CA3 area of hippocampus, that fire when the animal enters a particular place in its environment. I argue that both lines of discoveries seem to be consistent with a more general view of hippocampus as a brain area strongly involved in the integration of sensory, and possibly internal, information. The first part of the thesis presents an investigation of the effect of limited connectivity constraint on the model network in the framework of pattern classification. It is shown that feed-forward neural classifiers with numerous long range connections can be replaced by networks with sparse feed-forward connectivity and local recurrent connectivity without sacrificing the classification performance. The limited connectivity constraint is relevant for most biological networks, and especially for the hippocampus. The second part describes a decoding analysis from the calcium signal recorded in mouse dentate gyrus. The animal’s position can be decoded with approximately 10cm accuracy and the neural representation of position in the dentate gyrus have close to maximal dimensionality. The analysis also suggests that cells with single firing field and cells with multiple firing fields contribute approximately equal amount of information to the decoder.

The hippocampus is traditionally thought to transmit contextual information to limbic structures where it acquires valence. Using freely moving calcium imaging and optogenetics, we show that while the dorsal CA1 subregion of the hippocampus is enriched in place cells, ventral CA1 (vCA1) is enriched in anxiety cells that are both activated by anxiogenic environments and required for avoidance behavior. Imaging cells defined by their projection target revealed that anxiety cells were enriched in the vCA1 population projecting to the lateral hypothalamic area (LHA), but not to the basal amygdala (BA). Consistent with this selectivity, optogenetic activation of vCA1 terminals in LHA, but not BA increased anxiety and avoidance, while activation of terminals in BA, but not LHA impaired contextual fear memory. Thus, the hippocampus encodes not only neutral but also valence-related contextual information, and the vCA1-LHA pathway is a direct route by which the hippocampus can influence innate anxiety behavior.

No description available.

Changes in the strength of connections between neurons underlie information storage in the mammalian brain. Long-term potentiation (LTP) is a long-lasting form of synaptic plasticity that has been described extensively in the hippocampus, a brain structure that plays a key role in memory formation. The molecular events that realise the persistence of LTP are not well understood, but it is known to require protein synthesis. The aim of this thesis was to investigate synaptic protein expression during the late-phase of hippocampal LTP in freely moving rats. LTP was induced in the perforant path input to the dentate gyrus of Sprague-Dawley rats using high-frequency electrical stimulation paradigms known to produce LTP that persists for many days. To focus on late-occurring events, and complement existing data sets, rats were sacrificed 48 h after LTP induction. A broad survey of synaptic proteins was conducted by two-dimensional gel electrophoresis using postsynaptic density (PSD) fractions. Over 200 protein spots were resolved, from which 163 individual proteins were identified by mass spectrometry. These included cytoskeletal proteins, signalling molecules, molecular chaperones and mitochondrial components, but no transmembrane receptor proteins were detected. Few of the identified proteins were found to undergo significant changes in expression, although proteomic comparison of PSDs prepared from LTP-stimulated and control dentate gyri showed reduced expression of the three component proteins of the mitochondrial voltage-dependent anion channel. While these data complement earlier studies suggesting that the late-phase of LTP is associated with mitochondrial restructuring, they cannot alone explain the persistence of LTP. To directly test whether LTP persistence is associated with increased expression of presynaptic marker proteins, suggesting increased neurotransmitter release; and/or increased postsynaptic receptor expression, implicating an increase in postsynaptic contact area, a targeted approach using Western Blot analysis of dentate gyrus subcellular fractions was undertaken.

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Integrative Neuroscience." Includes bibliographical references (p. 124-148).

published_or_final_version / Biochemistry / Master / Master of Philosophy

Levels of retinoic acid (RA), the active metabolite of vitamin A, are tightly regulated throughout vertebrate CNS development by RA synthesising and catabolising enzymes. However, increasing evidence suggests that similar regulatory mechanisms exist in the adult brain to maintain RA at the optimum level. The hippocampus is one of very few regions where neurons continue to be born. Furthermore, the hippocampus is one of the regions in which RA regulates function. RA is synthesised in the region of the hippocampus by the enzyme, retinaldehyde dehydrogenase 2 (RALDH2), expressed in the adjacent meninges. CYP26B1 has been previously shown to be present by in situ hybridisation in the CA4/3 region between the two blades of the dentate gyrus. We hypothesised that a gradient was set up between the source and sink of RA in the adult hippocampus. To test this, we disrupted the balance using exogenous RA and using inhibitors to its catabolising enzymes. A reporter mouse was used to detect RA signalling and significantly more lacZ expression was detected in the infrapyramidal blade (closest to the meninges) compared to the suprapyramidal blade. Furthermore, administration of RA equalised lacZ expression between the two blades. RA is a potent differentiation agent; however, its effects on cell proliferation are less clear. In order to examine the direct effects RA on cell proliferation, an organotypic hippocampal slice culture technique was optimised and it was found that RA inhibits cell proliferation specifically in the dentate gyrus in a dose dependent manner. Taken together, this thesis provides insight for the first time into a parallel regulatory mechanism in the adult hippocampus to the embryo where RA is tightly regulated by its synthesising and catabolising enzymes and this mechanism is involved in the regulation of cell proliferation in the adult dentate gyrus.

No description available.