2002 Special issue Neuromodulation, theta rhythm and rat spatial navigation Michael E. Hasselmo * , Jonathan Hay, Maxim Ilyn, Anatoli Gorchetchnikov Department of Psychology, Program in Neuroscience, Center for BioDynamics, Boston University, 64 Cummington Street, Boston, MA 02215, USA Received 31 October 2001; accepted 25 April 2002 Abstract Cholinergic and GABAergic innervation of the hippocampus plays an important role in human memory function and rat spatial navigation. Drugs which block acetylcholine receptors or enhance GABA receptor activation cause striking impairments in the encoding of new information. Lesions of the cholinergic innervation of the hippocampus reduce the amplitude of hippocampal theta rhythm and cause impairments in spatial navigation tasks, including the Morris water maze, eight-arm radial maze, spatial reversal and delayed alternation. Here, we review previous work on the role of cholinergic modulation in memory function, and we present a new model of the hippocampus and entorhinal cortex describing the interaction of these regions for goal-directed spatial navigation in behavioral tasks. These mechanisms require separate functional phases for: (1) encoding of pathways without interference from retrieval, and (2) retrieval of pathways for guiding selection of the next movement. We present analysis exploring how phasic changes in physiological variables during hippocampal theta rhythm could provide these different phases and enhance spatial navigation function. q 2002 Elsevier Science Ltd. All rights reserved. Keywords: Entorhinal cortex; GABAergic innervation; Hippocampal theta rhythm 1. Acetylcholine and GABA modulation in the hippocampus The hippocampus receives extensive cholinergic and GABAergic innervation from the medial septum, which appears important for the role of the hippocampus in human memory function and rat spatial navigation. In humans, blockade of muscarinic acetylcholine receptors by drugs such as scopolamine strongly impairs the encoding of new information but not the retrieval of previously encoded information in verbal memory tasks (Ghoneim & Mewaldt, 1975; Hasselmo, 1995 for review). Similarly, enhancement of GABA receptor responses by benzodiazepine drugs also causes significant encoding impairments in humans (Ghoneim & Mewaldt, 1975). In rats, the muscarinic receptor blocker atropine impairs the encoding of platform location in the Morris water maze (Sutherland, Whishaw, & Regehr, 1982). Acetylcholine levels in the hippocampus are highest when a rat is actively exploring the environment, and lower when the rat sits quietly or performs behaviors such as eating or grooming (Marrosu et al., 1995), as summarized in Fig. 1A. The higher levels of acetylcholine are correlated with theta rhythm oscillations (3 – 12 Hz) in the hippocampal EEG. 1.1. Acetylcholine may enhance encoding dynamics Modeling suggests that acetylcholine could set appro- priate dynamics for encoding of new information within the hippocampal formation (Hasselmo & Bower, 1993; Has- selmo & Schnell, 1994; Hasselmo & Wyble, 1997). That previous work focused on longer periods of encoding versus retrieval, whereas later sections of this article focus on more rapid transitions between encoding and retrieval dynamics within each cycle of the theta rhythm. Acetylcholine causes physiological effects appropriate for encoding of new information. Activation of muscarinic acetylcholine receptors enhances the rate of synaptic modification at excitatory feedback connections in the cortex, as seen in experiments showing cholinergic enhancement of long-term potentiation (Hasselmo & Barkai, 1995; Huerta & Lisman, 1993; Patil, Linster, Lubenov, & Hasselmo, 1998). At the same time as it enhances long-term potentiation (LTP), acetylcholine suppresses excitatory synaptic transmission at feedback synapses (Hasselmo & Bower, 1993; Hasselmo & Schnell, 1994), while leaving excitatory feedforward synapses relatively unaffected. Thus, feedback synapses have weak 0893-6080/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved. PII: S0893-6080(02)00057-6 Neural Networks 15 (2002) 689–707 www.elsevier.com/locate/neunet * Corresponding author. Tel.: þ 1-617-353-1397; fax: þ1-617-353-1424. E-mail addresses: hasselmo@bu.edu (M.E. Hasselmo)