A combination of electrophysiological experiments and computational modeling has led to the hypothesis that acetylcholine may set the appropriate dynamics for learning in the cortex, while removal of cholinergic modulation may set the appropriate dynamics for recall. In this application, we propose to test this hypothesis using the techniques of brain slice physiology. Predictions have been generated using simplified representations of cortical structures as systems of differential equations. In these simulations, feedback regulation of cortical cholinergic modulation allows cortical regions to set their own state of learning or recall dependent upon the familiarity of the incoming information. The memory function of the network is evaluated using a performance measure based on normalized dot products. This leads to predictions about the parameters of cholinergic modulation which give the most effective memory function. Biophysical network simulations will be used to further analyze the validity of these predictions. Experimental data about the relative amplitude of cholinergic effects on cortical parameters will be compared with computational predictions. Experimental work will determine the relative amplitude and dose response curves for cholinergic suppression of neuronal adaptation and afterhyperpolarization currents, the cholinergic suppression of inhibitory synaptic transmission, the cholinergic enhancement of synaptic modification, and the cholinergic suppression of synaptic transmission within the hippocampal formation. In addition, the possibility that GABAergic innervation arising from the basal forebrain selectively suppresses synaptic transmission in a manner similar to acetylcholine will be tested experimentally. Understanding the feedback regulation of cortical cholinergic innervation may shed light on the basis for degeneration of this cholinergic innervation in Alzheimer's disease. In addition, this work will increase understanding of the general role of neuromodulators in cortical function, since other neuromodulators influence many of the same physiological parameters. This may suggest new strategies for the use of drugs in the treatment of psychiatric disorders, since many of these drugs have a strong influence on neuromodulatory systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29MH052732-01
Application #
2252608
Study Section
Cognitive Functional Neuroscience Review Committee (CFN)
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Harvard University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Giocomo, Lisa M; Hasselmo, Michael E (2009) Knock-out of HCN1 subunit flattens dorsal-ventral frequency gradient of medial entorhinal neurons in adult mice. J Neurosci 29:7625-30
Koene, Randal A; Hasselmo, Michael E (2008) Reversed and forward buffering of behavioral spike sequences enables retrospective and prospective retrieval in hippocampal regions CA3 and CA1. Neural Netw 21:276-88
Sohal, V S; Hasselmo, M E (2000) A model for experience-dependent changes in the responses of inferotemporal neurons. Network 11:169-90
Wyble, B P; Linster, C; Hasselmo, M E (2000) Size of CA1-evoked synaptic potentials is related to theta rhythm phase in rat hippocampus. J Neurophysiol 83:2138-44
Hasselmo, M E; McClelland, J L (1999) Neural models of memory. Curr Opin Neurobiol 9:184-8
Patil, M M; Hasselmo, M E (1999) Modulation of inhibitory synaptic potentials in the piriform cortex. J Neurophysiol 81:2103-18
Wallenstein, G V; Eichenbaum, H; Hasselmo, M E (1998) The hippocampus as an associator of discontiguous events. Trends Neurosci 21:317-23
Wallenstein, G V; Hasselmo, M E (1997) GABAergic modulation of hippocampal population activity: sequence learning, place field development, and the phase precession effect. J Neurophysiol 78:393-408
Hasselmo, M E; Wyble, B P (1997) Free recall and recognition in a network model of the hippocampus: simulating effects of scopolamine on human memory function. Behav Brain Res 89:1-34
Wallenstein, G V; Hasselmo, M E (1997) Functional transitions between epileptiform-like activity and associative memory in hippocampal region CA3. Brain Res Bull 43:485-93

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