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The Journal of Neuroscience, November 2, 2005, 25(44):10273-10281; doi:10.1523/JNEUROSCI.2386-05.2005

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Behavioral/Systems/Cognitive
Cholinergic Deafferentation of the Entorhinal Cortex in Rats Impairs Encoding of Novel But Not Familiar Stimuli in a Delayed Nonmatch-to-Sample Task

Jill McGaughy, Randal A. Koene, Howard Eichenbaum, and Michael E. Hasselmo

Department of Psychology Center for Memory and Brain, Program in Neuroscience, Boston University, Boston, Massachusetts 02215

Acetylcholine may regulate working memory for novel stimuli by activating intrinsic mechanisms for sustained spiking in entorhinal cortical neurons, which have been demonstrated in slice preparations of the entorhinal cortex. Computational modeling demonstrates that loss of the cholinergic activation of intrinsic mechanisms for sustained activity could selectively impair working memory for novel stimuli, whereas working memory for familiar stimuli could be maintained because of previously modified synapses. Blockade of muscarinic cholinergic receptors and selective cholinergic lesions has been shown to impair encoding in delayed matching tasks. However, previous studies have not compared explicitly the role of cholinergic modulation in working memory for novel versus familiar stimuli. Here, we show that lesions of the cholinergic innervation of the entorhinal cortex selectively impair delayed nonmatch to sample performance for novel odors, whereas delayed nonmatch to sample for familiar odors is spared. This indicates an important role for cholinergic innervation of the entorhinal cortex in working memory for novel stimuli.

Key words: acetylcholine; episodic buffer; sustained activity; computational modeling; working memory; persistent spiking

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Received June 10, 2005; revised September 26, 2005; accepted September 27, 2005.

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