Contemporary cellular models of learning and memory are articulated around the idea that synapses undergo activity-dependent weight changes. However, conventional forms of Hebbian plasticity do not adequately address certain features inherent to behavioral learning. First, associative learning driven by delayed behavioral outcomes introduces a temporal credit assignment problem, whereby one must remember which action corresponds to which outcome. Yet, current models of associative synaptic plasticity, such as spike-timing-dependent plasticity, require near coincident activation of pre- and postsynaptic neurons (i.e., within ~ 10 ms), a time delay that is orders of magnitude smaller than that required for behavioral associations. For individual neurons to associate two cues, a biological mechanism capable of potentiating synaptic weights must be able to bind events that are separated in time. Theoretical work has suggested that a synaptic eligibility trace, a time-limited process that momentarily renders synapses eligible for weight updates via delayed instructive signals, can solve this problem. However, no material substrate of eligibility traces has been identified in the brain. Second, under certain conditions, neurons need to swiftly update their weights to reflect rapid learning. Current plasticity experiments require the repetition of multiple pairings to induce long-term synaptic plasticity. In this thesis, I addressed these problems using a combination of whole-cell recordings, two-photon uncaging, calcium imaging, and mechanistic modeling. I uncovered a form of synaptic plasticity known as behavioral timescale synaptic plasticity (BTSP) in layer 5 pyramidal neurons in the prefrontal cortex of mice. BTSP induced synaptic potentiation by pairing temporally separated pre- and postsynaptic events (0.5 s - 1 s), regardless of their order. The temporal window for BTSP induction offers a line of solution to the temporal credit assignment problem by highlighting the presence of a synaptic mechanism that expands the time for the induction of activity-dependent long-term synaptic plasticity, spanning hundreds of milliseconds. We further found that BTSP can be induced following a single pairing, enabling rapid weight updates required for one-shot learning. Using two-photon calcium imaging in apical oblique dendrites, I discovered a novel short-term and associative plasticity of calcium dynamics (STAPCD) that exhibited temporal characteristics mirroring the induction rules of BTSP. I identified a core set of molecular components crucial for both STAPCD and BTSP and developed a computational simulation that models the calcium dynamics as a latent memory trace of neural activity (i.e., eligibility traces). Together, we find that calcium handling by the endoplasmic reticulum enables synaptic weight updates upon receipt of delayed instructive signals, obeys rules of burst-dependent one-shot learning, and thus provides a mechanism that satisfies the requirements anticipated of eligibility traces. Collectively, these findings offer a neural mechanism for the binding of cellular events occurring in single shot and separated by behaviorally relevant temporal delays to induce potentiation at synapses, providing a cellular model of associative learning.

No description available.

Experimentelle Modelle und aktuelle Studien legen nahe, dass epileptische Anfälle mit Störungen des adrenergen Systems im Gehirns einhergehen. Noradrenalin, welches an beta-adrenerge Rezeptoren bindet, ist für hippokampale Plastizität sowie für das hippokampale Lernen und Gedächtnis von großer Bedeutung. Die vorliegende Arbeit untersucht epilepsieinduzierte Veränderungen der noradrenergen Steuerung von hippokampalen Ausgangssignalen. Gezielt werden die funktionellen Konsequenzen synaptischer Plastizität, hervorgerufen durch beta-adrenerge Rezeptoraktivierung an CA1-Subiculum Synapsen, für die neuronale Signaltransduktion zwischen Hippocampus und parahippokampal Regionen in einem Tiermodell für Epilepsie untersucht. Wir kombinieren elektrophysiologische Methoden (Single-Cell- und Multi-Elektroden-Array Ableitungen) um zu zeigen, dass die Aktivierung von beta-adrenergen Rezeptoren eine zellspezifische Form der Langzeit-Potenzierung in subiculären Pyramidenzellen induziert und eine Verstärkung der Konnektivität zwischen Subiculum und Presubiculum, beziehungsweise Subiculum und entorhinalen Cortex nach sich zieht. Bei Tieren, die mit dem Parasympathomimetikum Pilocarpin behandelten wurden, ist die beta-adrenerge Modulation zwischen dem Hippocampus und verschiedenen parahippokampal Zielstrukturen beeinträchtigt. Die gestörte polysynaptische Transmission zwischen CA1, dem Subiculum und parahippokampalen Zielstrukturen resultiert in einer Abnahme der Langzeit-Potenzierung im Presubiculum, wohingegen die Transmission zum medialen EC intakt bleibt. Diese Beeinträchtigung der beta-Adrenorezeptor abhängigen Modulation der Informationsübertragung vom Hippocampus zu seine Zielstrukturen können zu hippocampalen Defiziten, wie Gedächtnis- und Stimmungsstörungen beitragen, die häufig bei Patienten mit Temporallappen-Epilepsie beobachtet werden. / Experimental models and previous studies suggest that seizures are accompanied by disturbances in the beta-adrenergic (beta-AR) system of the brain. Norepinephrine acting via beta-ARs plays a major role in hippocampal plasticity and hippocampus-dependent learning and memory. To elucidate seizure-associated alterations in the norepinephrine-dependent encoding of hippocampal output, the present study investigates the functional consequences of the beta-AR mediated synaptic plasticity at CA1-subiculum synapses for the transduction of hippocampal output to the parahippocampal region in an animal model of epilepsy. Using combined electrophysiological (single-cell and multi-electrode array recordings) approaches, we show that activation of beta-AR induces a cell-specific form of long-term potentiation in subicular pyramidal cells that may allow a strengthening of target-specific connectivity to the presubiculum and entorhinal cortex (EC). In pilocarpine-treated animals, the beta-AR-mediated modulation of functional connectivity between the hippocampus and distinct parahippocampal target str uctures is disturbed. The attenuated long-term potentiation is associated with a disturbed polysynaptic transmission from the CA1, via the subiculum to the presubiculum, but with a preserved transmission to the medial EC. The impairment in the beta-AR-dependent modulation of information transfer from the hippocampus to its target structures may contribute to hippocampus-dependent deficits like memory impairments and mood disorders which are often observed in patients with temporal lobe epilepsy.

Pang Petti. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Conceptual design is a series of complex cognitive processing tasks and research seeking to further understand design cognition will benefit by considering literature from the field of psychology. This thesis presents two research projects, which sought to understand and mitigate design biases in conceptual design through the application of theories from biological and cognitive psychology. The first of these puts forward a novel model of design creativity based on connectionist theory and a neurological phenomenon known as long-term potentiation. This model is applied to provide new insights into design fixation and develop interventions to assist designers overcome fixation. The second project seeks to establish that cognitive heuristics and biases predictably influence design cognition. Two studies are discussed that examined the role of confirmation bias in design. The first establishes that confirmation bias is present during concept generation; the second demonstrates that decision matrices can mitigate confirmation bias in concept evaluation.

Conceptual design is a series of complex cognitive processing tasks and research seeking to further understand design cognition will benefit by considering literature from the field of psychology. This thesis presents two research projects, which sought to understand and mitigate design biases in conceptual design through the application of theories from biological and cognitive psychology. The first of these puts forward a novel model of design creativity based on connectionist theory and a neurological phenomenon known as long-term potentiation. This model is applied to provide new insights into design fixation and develop interventions to assist designers overcome fixation. The second project seeks to establish that cognitive heuristics and biases predictably influence design cognition. Two studies are discussed that examined the role of confirmation bias in design. The first establishes that confirmation bias is present during concept generation; the second demonstrates that decision matrices can mitigate confirmation bias in concept evaluation.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 67-80).

Οι ιπποκάμπιες συνάψεις επιδεικνύουν σημαντική ικανότητα για μακρόχρονη πλαστικότητα, η οποία θεωρείται ότι είναι η βάση της μνήμης και της μάθησης. Υπάρχουν ολοένα και αυξανόμενες αποδείξεις ότι αυτή η ικανότητα διαφέρει κατά μήκος του ιπποκάμπου, με τις συνάψεις της CA1 περιοχής του κοιλιακού ιπποκάμπου να επιδεικνύουν σημαντικά μικρότερη ικανότητα για μακρόχρονη ενίσχυση (LTP) σε σύγκριση με τις αντίστοιχες συνάψεις του ραχιαίου ιπποκάμπου, όταν ενεργοποιούνται με υψηλόσυχνο ερεθισμό. Στην παρούσα εργασία, δείχνουμε ότι μία μικρή συχνότητα ερεθισμού, των 10 Hz, επάγει μακρόχρονη ενίσχυση πιο αξιόπιστα στην περιοχή CA1 του ραχιαίου απ' ό,τι του κοιλιακού ιπποκάμπου. Προτείνουμε ότι η δραστηριότητα που επάγεται από του υποδοχείς α5GABAA παίζει έναν σημαντικό ρόλο στην ρύθμιση του κατωφλίου επαγωγής του LTP ειδικά στις συνάψεις της περιοχής CA1 του κοιλιακού ιπποκάμπου. Αυτό το γεγονός μπορεί να έχει σημαντικές συνέπειες για την λειτουργική εξειδίκευση κατά μήκος του ιπποκάμπου. / The hippocampal synapses display conspicuous ability for long-term plasticity which is thought to underlie learning and memory. Growing evidence shows that this ability differs along the long axis of the hippocampus, with the ventral CA1 hippocampal synapses displaying remarkably lower ability for long-term potentiation(LTP) compared with their dorsal counterpart when activated with high-frequency stimulation. Here, we show that low frequency, 10Hz stimulation induced LTP more reliably in DH than in VH CA1 field. Blockade of alpha5 subunit-containing GABAA receptors eliminated the difference between DH and VH. We propose that α5GABAA receptor-mediated activity plays a crucial role in regulating the threshold for induction of LTP especially at the ventral CA1 hippocampal synapses. This might have important implications for the functional specialization along the hippocampus.

Recent evidence indicates that the mature neocortex retains a higher degree of plasticity than traditionally assumed. Up- and down-regulation of synaptic strength, long-term potentiation (LTP) and long-term depression (LTD), is thought to be the primary mechanism mediating experience-dependent plasticity of cortical networks. The present thesis investigate factors that regulate adult cortical plasticity, focusing on the role of neuromodulators, recent sensory experience, and different anatomical divisions of the cortex in influencing synaptic strength. First, I investigated the role of the neuromodulator histamine in gating plasticity in the primary visual cortex (V1) of urethane anesthetized adult rats. Histamine applied locally in V1 produced an enhancement of LTP elicited by theta burst stimulation (TBS) of dorsal lateral geniculate nucleus (dLGN) and allowed a sub-threshold TBS to produce stable LTP. Second, the impact of visual deprivation on LTP in V1 was assessed. Animals that received 2 and 5 hr dark exposure showed greater potentiation of field potentials when stimulated though retinal light flashes or weak TBS of the dLGN, which failed to induce LTP in control animals kept in continuous light. Third, I performed a detailed characterization of LTP induced by different TBS protocols, recording in either the monocular or binocular segment of both V1 hemispheres (i.e., ipsi- and contralateral to the stimulated dLGN). Stronger, NMDA receptor-independent LTP was found in the contralateral V1. Interestingly, weak TBS induced LTD that was NMDA receptor-dependent in the ipsilateral V1. Furthermore, a lower LTP induction threshold was observed in the binocular than the monocular segment of ipsilateral V1. Lastly, I investigated cholinergic modulation of sensory-induced activity in the barrel cortex. Basal forebrain stimulation enhanced multi-unit activity elicited by whisker deflection, an effect that was more pronounced for weaker response driven by a secondary whisker than principal whisker deflection. This thesis demonstrates that neocortical plasticity consists of multiple forms of synaptic modification. Adult cortical plasticity is greatly influenced by preceding activity of the synapse by various neuromodulator systems, and by anatomical subdivisions within primary sensory cortex fields. Together, these mechanisms may facilitate the detection, amplification, and storage of inputs to primary sensory fields of the neocortex. / Thesis (Ph.D, Psychology) -- Queen's University, 2010-04-29 14:02:30.742

Many molecules and the complex interactions between them underlie plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but very little is known about its function during plasticity induction in the cerebellum. The aim of this thesis is to contribute to a better understanding of the molecular mechanisms that regulate the induction of synaptic plasticity in cerebellar Purkinje cells (PCs). The focus of the thesis is to investigate the role of CaMKII isoforms in the bidirectional modulation of plasticity induction at parallel fibre (PF)-PC synapses. For this investigation, computational models that represent the CaMKII activation and the signalling network that mediates plasticity induction at these synapses were constructed. The model of CaMKII activation by calcium-calmodulin developed by Dupont et al (2003) replicates the experiments by De Koninck and Schulman (1998). Both theoretical and experimental studies have argued that the phosphorylation and activation of CaMKII depends on the frequency of calcium oscillations. Using a simplified version of the Dupont model, it was demonstrated that the CaMKII phosphorylation is mostly determined by the average calcium-calmodulin concentration, and therefore depends only indirectly on the actual frequency of calcium oscillations. I have shown that a pulsed application of calcium-calmodulin is, in fact, not required at all. These findings strongly indicate that the activation of CaMKII depends on the average calcium-calmodulin concentration and not on the oscillation frequency per se as asserted in those studies. This thesis also presents the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. The results of computer simulations of a simple mathematical model suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors determines whether LTD or LTP occurs in cerebellar PCs. This model replicates the experimental observations by Van Woerden et al (2009) that indicate that CaMKII controls the direction of plasticity at PF-PC synapses. My computer simulations support Van Woerden et al’s original suggestion that filamentous actin binding can enable CaMKII to regulate bidirectional plasticity at these synapses. The computational models of intracellular signalling constructed in this thesis advance the understanding of the mechanisms of synaptic plasticity induction in the cerebellum. These simple models are significant tools for future research by the scientific community.