A well-motivated and common working hypothesis is that learning involves some change in the functional connectivity among nerve cells, probably at their synaptic interconnections. In searching for a likely synaptic candidate for such changes in the mammalian central nervous system (CNS), the phenomenon of associative long-term potentiation (LTP) is an obvious choice, for three reasons: associative LTP is an increased synaptic efficacy that can be induced by brief tetanic stimulation; it lasts hours or longer; and the conditions required for its induction bear a tantalizing similarity to some of the laws of classical conditioning. The fact that associative LTP occurs in the in vitro hippocampus is extremely important because this is the only known mammalian telencephalic preparation that is amenable to many of our most powerful analytical neurophysiological techniques and in which a promising synaptic model for associative memory has been demonstrated. In the present proposal I will use the in vitro hippocampus slice preparation to investigate four key aspects of associative LTP. First, the spatial and temporal rules governing the induction of associative LTP will be elucidated. Second, certain conditions that control the persistence or rate of decay of associative LTP will be analyzed, paying particular attention to possible parallels to the extinction phenomenon seen in classical conditioning studies. Third, the basis of the change responsible for the enhanced synaptic efficacy will be determined. Specifically, I want to know whether the ultimate change is pre- and/or postsynaptic. Fourth, I will provide evidence about the key features underlying the mechanisms responsible for the associativity. In particular, I want to determine which consequences of the associative paradigm are causally instrumental in the induction of the enhancement.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Modified Research Career Development Award (K04)
Project #
5K04NS001196-05
Application #
3074998
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1987-03-01
Project End
1992-02-29
Budget Start
1991-03-01
Budget End
1992-02-29
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Langdon, R B; Johnson, J W; Barrionuevo, G (1993) Asynchrony of mossy fibre inputs and excitatory postsynaptic currents in rat hippocampus. J Physiol 472:157-76
Fleck, M W; Henze, D A; Barrionuevo, G et al. (1993) Aspartate and glutamate mediate excitatory synaptic transmission in area CA1 of the hippocampus. J Neurosci 13:3944-55
Xie, X; Berger, T W; Barrionuevo, G (1992) Isolated NMDA receptor-mediated synaptic responses express both LTP and LTD. J Neurophysiol 67:1009-13
Fleck, M W; Palmer, A M; Barrionuevo, G (1992) Potassium-induced long-term potentiation in rat hippocampal slices. Brain Res 580:100-5
Hirsch, J C; Barrionuevo, G; Crepel, F (1992) Homo- and heterosynaptic changes in efficacy are expressed in prefrontal neurons: an in vitro study in the rat. Synapse 12:82-5
Bradler, J E; Barrionuevo, G; Panchalingam, K et al. (1991) Actions of phosphomonoesters on CA1 hippocampal neurons as revealed by a combined electrophysiological and nuclear magnetic resonance study. Synapse 9:7-13