PANEPISTHMIO KRHTHS SQOLH JETIKWN KAI TEQNOLOGIKWN EPISTHMWN TMHMA EPISTHMHS UPOLOGISTWN

This modeling study focuses on the investigation of the functional alterations in hippocampus, which underlie the long-term episodic memory decrements during aging. Although aged subjects may have intact memory for individual features of an event, they have a difficulty to perform associations between them. The feature binding deficit probably arises from deficits at the encoding processes that support working memory tasks, i.e., the short-term maintenance or manipulation of information. In CA1 hippocampal pyramidal cells, the successful association of selected features of an event, is signified by repeated postsynaptic bursting activity in θ frequency band (5-12 Hz). In rodents, θ-bursting is commonly observed ’in vivo’ in states of selective attention during exploratory behavior, and reliably induces long-term potentiation (LTP) of stimulated synapses in CA1 cells. In learning-impaired aged animals, however, θ-frequency synaptic stimulation fails to induce LTP. During early aging, the intrinsic, calcium-dependent, membrane mechanisms of pyramidal neurons, are the first to be disrupted, before a significant change in the number of synapses or the dendritic morphology occurs. Moreover, these alterations induce an excitability reduction which has been correlated to the learning impairments in aged subjects. In this work, the effects of these active membrane properties on neuronal excitability, have been investigated ”in silico”. A multi-compartmental model of a hippocampal CA1 pyramidal cell has been built, mainly based on two biophysically detailed compartmental models of the same cell. Main novel features are the simple coupling mechanisms between specific types of Ca-channels and functionally colocalized, Ca-dependent potassium channels. The coupled channels exhibit concurrent activation (or inactivation) by specific voltage waveforms, and the ionic currents through them exhibit the same time course. The competing excitatory and inhibitory feedback loops arising from their coupled activity, enable the fine-tuning of neuronal excitability. Model parameters have been calibrated using physiological data. Computer simulations reproduce the decreased excitability of aged CA1 cells as a result of increased internal calcium accumulation, subsequently larger post-burst slow after-hyperpolarization, and enhanced spike frequency adaptation in the ”aged” cell model. The cell model has been further tested in simulations of a physiological pattern of activity, θ-bursting, using antidromic (non-synaptic) stimulation at θ-frequency. Relevant electrophysiology experiments have revealed a graded increase in postsynaptic spiking in successive bursts, which is thought to depict physiologic temporal integration at the cellular level. This ability of the postsynaptic neuron to integrate over time the effects of recent stimuli, is thought to be a short-term, working memory mechanism which is critical for the association of multiple stimuli (”features” of a memory object). In simulations, θ-frequency antidromic stimulation could induce bursts with a gradually increasing number of spikes only when the slow and medium afterhyperpolarization potassium currents, were sufficiently suppresed, imitating cholinergic-like influence. Moreover, self-sustaining oscillatory firing in the γ frequency band was induced in the ”young”, but not in the ”aged” cell model. It has been suggested that the intrinsic frequency preferences of neurons, enable the selective communication between resonant subsets of cells within a network. When a single cell fires persistently under physiological temporal patterns of stimulation, it could intrinsically drive a specific cellular assembly in synchronous rhythmic activity. Coherent network oscillations in the brain have been correlated with different behavioral and mental states; persistent hippocampal γ oscillations have been implicated in feature binding and short-term memory. Perhaps that, during aging, reduction in excitability impairs CA1 cell’s pacemaking ability, delaying onset of network oscillations, hence inducing memory binding deficits. Supervisor: Stelios Orphanoudakis Professor of Computer Science University of Crete