Veränderungen des zentralen serotonergen Systems können mit diversen psychiatrischen Krankheiten wie z. B. Depressionen, Aufmerksamkeitsdefizit/ Hyperaktivitäts-Störung (ADHS), Phobien oder Panik- und Angststörungen assoziiert werden. Die fortlaufende Untersuchung des Neurotransmitters Serotonin (5-HT) und seine Bedeutung für physiologische und verhaltens- bezogene Prozesse ist daher unerlässlich. Tiermodelle, die auf Ausschaltung elementarer oder assoziierter Gene des serotonergen Systems beruhen, sind infolgedessen eine ausgezeichnete Möglichkeit anatomische, (patho)physiolo- gische und verhaltensbezogene Auswirkungen eines fehlgeleiteten serotoner- gen Systems zu untersuchen und zu analysieren. Aufgrund ihrer großen Be- deutung für Lern- und Gedächtnisprozesse steht die Hirnregion des dorsalen Hippocampus im Fokus dieser Dissertation. Die Analyse umfasste jeweils die gesamte Hirnstruktur des Hippocampus bzw. seine Unterregionen, Gyrus dentatus (DG), Cornu Ammonis (CA)1 und CA3. Die Zielsetzung dieser Arbeit war die Untersuchung zellulärer bzw. molekularer Veränderungen von konstitutiven Tryptophanhydroxylase 2 (Tph2) knockout (KO) Mäusen. Durch die Inaktivierung von Tph2 und damit dem geschwindig- keitsbestimmenden Enzym (TPH2) der Serotoninsynthese, wurde im zentralen Nervensystem (ZNS) der KO Mäuse ein Mangel von 5-HT festgestellt. Der dorsale Hippocampus wurde auf zellspezifische Veränderungen nach dem Furchtkonditionierungstest analysiert. Die Reaktion der Neurone in den drei Unterregionen der Hirnstruktur wurde durch Immunofluoreszenzfärbung des „immediate-early“ Genprodukts c-fos bzw. des Calcium-bindenden Proteins Parvalbumin untersucht. Es wurde dabei zum einen die absolute Zellzahl in den Strukturen erfasst und zum anderen die Analyse bezüglich des Volumens vorgenommen. Die Zelldichte von c-Fos wies signifikante Unterschiede zwischen den Gruppen im gesamten dorsalen Hippocampus und bei genauerer Betrachtung in der Unterregion des DG auf. Die Tph2-/- Mäuse zeigten nach dem Furchtkonditionierungstest eine prägnante Erhöhung der aktivierten Zellen. Es scheint, dass 5-HT eine zu starke Aktivierung des dorsalen Hippocampus verhindert um schlechte kontextbezogene Gedächtnisinhalte nicht zu verfesti- gen. Dabei inhibiert 5-HT Zellen im DG und der CA1 Region die nicht zu den Parvalbumin-immunoreaktiven GABAergen Interneuronen gehören. / Although multiple lines of evidence implicate brain serotonin (5-HT) system dysfunction in the pathophysiology of anxiety disorders such as the panic syndrome, the neural processes are not well understood. Here, we investigated the impact of constitutively deficient 5-HT synthesis on fear response-related network function in the hippocampus using tryptophan hydroxylase-2 (Tph2) mutant mice. A double immunostaining of c-Fos and Parvalbumin, a calcium-binding protein expressed in a subpopulation of the GABAergic interneurons of the hippocampus, was established. Tph2-/- mice showed increased c-Fos expression after fear conditioning in the dorsal hippocampus while the number of c-Fos/Parvalbumin-positive cells was not changed. This data support the view that 5-HT is necessary to inhibit neuronal activity within fear acquisition in the dorsal hippocampus possibly excluding Parvalbumin - positive cells.

Thesis (Ph.D.) -- University of Texas at Dallas, 2006. / Includes vita. Includes bibliographical references (leaves 81-94)

No description available.

Thesis (Ph. D.)--Open University.

Thesis (Ph. D.)--University of California, San Diego, 2002. / Vita. Includes bibliographical references.

The normal aging process is accompanied by changes in cognitive function. One of the brain regions known to be an early target of the aging process is the hippocampus, a medial temporal lobe structure that is critically involved in spatial learning and memory function. The formation and maintenance of memory relies on rapid and sustainable synaptic modification, which requires new gene expression. Immediate-early genes are the first genes to be induced following relevant stimuli, and include genes that encode transcription factors, such as c-fos and zif268, and effector proteins that directly influence cellular function, such as Arc (activity-regulated cytoskeletal gene) and Homer1A. Blocking the expression of any one of these genes interferes with memory function, and thus, each of these genes is thought to have a memory enhancing effect. The hypothesis tested here was that aged animals would show a reduction in the expression of memory-promoting immediate-early genes within the hippocampus, and moreover, that these changes in expression would be subregion specific, based on the finding that the dentate gyrus is most vulnerable to the aging process.Potential age-related changes in immediate-early gene expression within the hippocampus was determined under basal conditions and after induction by a simple behavioral task. Of the genes under investigation, only c-fos did not show age-related changes under basal conditions, or following behavioral induction. The remaining genes, Arc, zif268 and Homer1A, each showed subregion specific patterns of change within the hippocampus under basal conditions or following induction (or both). The coordinate expression of immediate-early genes within the hippocampus was also investigated by assessing the extent to which Arc was expressed within the same neurons as c-fos, zif268 or H1a. The coordinate transcription of these genes was not significantly altered in the aged hippocampus, even though changes in the size of Arc and zif268 neural ensembles occurs within the aged denate gyrus.Taken together, these data indicate that age-related reductions in the basal and induced levels of immediate-early genes occur within the hippocampus, and that these changes are subregion specific.

Biophysical simulations of memory must choose which aspects of known neurophysiology and neuroanatomy to model. Relevant aspects were constrained by functional requirements determined for on-line acquisition in context dependent memory, memory that is retrieved by contextual cues. In an on-line task, the protocol of data presentation and the tunes at which encoding or retrieval in memory is needed are not predetermined. A sequence of neuronal spike patterns representing items may be presented only once. Yet, episodic memory of the sequence immediately encodes the temporal context of familiar items, a process known to depend on hippocampal function. For this, interference caused by overlapping spike patterns must be avoided, a requirement that suggested the relevance of coincidental spiking. Overlap in the input to the hippocampus was reduced by recruiting such spikes in a model of encoding in dentate gyrus. Durable encoding is required in the hippocampus, since hippocampal damage can cause retrograde amnesia in context dependent memory that spans years. Long-lasting synaptic changes involved modeling relevant neurophysiology concerning protein production elicited by the spaced reactivation of spike patterns. The likelihood of reactivation was increased by the well-known process of long-term potentiation of synaptic transmission. Such potentiation is elicited when a presynaptic spike precedes a postsynaptic spike within a specific time window repeatedly. The intervals in a sequence of spike patterns must be compressed and the sequence repeated, requirements that were achieved with a model of short-term memory based on persistent spiking. Retrieval may be concurrent with these encoding processes due to effects of different phases of a brain rhythm at theta frequency (3-12 Hz) that modulate transmission and plasticity. A model of short-term memory by Lisman and Idiart (Science 267:1512-15), extended by Jensen et al. (Learning and Memory 3:243

One of the central questions of neuroscience research has been how the cellular and molecular components of the brain give rise to complex behaviours. Three major breakthroughs from the past sixty years have made the study of learning and memory central to our understanding of how the brain works. First, the psychologist Donald Hebb proposed that information storage in the brain could occur through the strengthening of the connections between neurons if the strengthening were restricted to neurons that were co-active (Hebb, 1949). Second, Milner and Scoville (1957) showed that the hippocampus is required for the acquisition of new long-term memories for consciously accessible, or declarative, information. Third, Bliss and Lømo (1973) demonstrated that the synapses between neurons in the dentate gyrus of the hippocampus could indeed be potentiated in an activity-dependent manner. Long-term potentiation (LTP) of the glutamatergic synapses in area CA1, the primary output of the hippocampus, has since become the leading model of synaptic plasticity due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals, and its robust pathway specificity. Using whole-cell recording in hippocampal slices from adult rats, I find that the efficacy of synaptic transmission from CA3 to CA1 can in fact be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, I show that the induction of GABAergic plasticity at feedforward inhibitory inputs in CA1 results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials which is dependent on NMDAR activation and is pathway specific. The sharing of these fundamental properties with classic LTP suggests the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain.

Although once thought to be incapable of regeneration, the adult mammalian brain generates new neurons in two regions: the SVZ of the lateral ventricle and the DG of the hippocampus. While the cell types involved in adult neurogenesis have been broadly characterized, the transcriptional regulation of this process remains poorly understood. Here, we demonstrate that transcription factor Cux2 is important for normal postnatal hippocampal neurogenesis. Cux2neo/neo mutant mice generated fewer Dcx-positive neuroblasts, Tbr2-positive transit amplifers, and Calretinin-positive immature neurons, without affecting gliogenesis. Moreover, we show that Cux2 is principally expressed in Type1/Type2a cells. Using cultured embryonic NPCs we show that Cux2 mutants generate fewer neurons. Indeed, Cux2 plays a pro-neuronal role in both the postnatal hippocampus and in cultured embryonic NPCs. Cux2 may thus serve as an important regulator of the neuronal fate and may be a novel marker for neuronally committed Type 1/2a NPCs in the postnatal DG.

It is assumed that plasticity involving up-and down regulation of synaptic strength (i.e., long-term potentiation, LTP; long-term depression, LTD) mediates learning and memory processes. Typically, high-frequency stimulation (HFS) of afferent fibers results in LTP, while low-frequency stimulation (LFS) elicits LTD. In stark contrast to this “HFS- LTP vs. LFS-LTD” dogma, the present thesis characterizes a novel form of LFS-induced LTP in the septohippocampal system. The first set of experiments show that alternating, single pulse stimulation (1 Hz) of the medial septum (MS) and CA3 hippocampal (H) commissural fibres results in a long-lasting potentiation of field excitatory postsynaptic potentials (fEPSPs) in CA1 of urethane-anesthetised rats (MS-H-LTP). MS-H LTP is long lasting (>5 h), requires a specific inter-stimulus interval of 1 s between MS and CA3 stimulation, saturates with repeated stimulation episodes and depends on NMDA receptor activation. In the third chapter (review) I suggest that LFS protocols may more accurately mimic some oscillatory activity patterns (~ 1Hz) present in hippocampal and neocortical circuits during sleep-related memory consolidation. Moreover, I compare the mechanisms underlying classical, HFS-LTP to those mediating MS-H LTP as well as several other types of LFS-LTP in the hippocampus and amygdala in vitro. Subsequently, I investigated cellular mechanisms of MS-H LTP and their similarity to classical HFS-LTP via drug application at the CA1 recording site and showed that MS-H LTP depends on protein kinase A and protein synthesis. This surprising similarity between mechanisms mediating HFS-LTP and MS-H LTP was further supported by occlusion experiments whereby LFS and HFS, delivered to the same animal, competed for the available synaptic potentiation of CA3-CA1 synapses. The final experiments showed that MS-H LTP is compromised in early aged rats, while similar levels of potentiation are expressed in the juvenile and adult hippocampus. Interestingly, MS-H LTP could not be induced (i.e., was occluded) 3 h after training on the hidden platform version of the Morris water maze, while it was unaltered at 8 and 24 h intervals. This thesis characterizes a novel form of hippocampal plasticity at the cellular, synaptic and behavioural level and suggests that LFS-LTP may mediate processes of sleep-related memory consolidation. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2010-10-04 11:35:21.288