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Neuromodulation, Theta Rhythm and Rat Spatial Navigation

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Neural Networks 15 (2002) 689–707 www.elsevier.com/locate/neunet 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 are correlated with theta rhythm oscillations (3–12 Hz) in hippocampus the hippocampal EEG. The hippocampus receives extensive cholinergic and 1.1. Acetylcholine may enhance encoding dynamics GABAergic innervation from the medial septum, which appears important for the role of the hippocampus in human Modeling suggests that acetylcholine could set appro- memory function and rat spatial navigation. In humans, priate dynamics for encoding of new information within the blockade of muscarinic acetylcholine receptors by drugs hippocampal formation (Hasselmo & Bower, 1993; Has- such as scopolamine strongly impairs the encoding of new selmo & Schnell, 1994; Hasselmo & Wyble, 1997). That information but not the retrieval of previously encoded previous work focused on longer periods of encoding versus information in verbal memory tasks (Ghoneim & Mewaldt, retrieval, whereas later sections of this article focus on more 1975; Hasselmo, 1995 for review). Similarly, enhancement rapid transitions between encoding and retrieval dynamics of GABA receptor responses by benzodiazepine drugs also within each cycle of the theta rhythm. causes significant encoding impairments in humans Acetylcholine causes physiological effects appropriate (Ghoneim & Mewaldt, 1975). In rats, the muscarinic for encoding of new information. Activation of muscarinic receptor blocker atropine impairs the encoding of platform acetylcholine receptors enhances the rate of synaptic location in the Morris water maze (Sutherland, Whishaw, & modification at excitatory feedback connections in the Regehr, 1982). Acetylcholine levels in the hippocampus are cortex, as seen in experiments showing cholinergic highest when a rat is actively exploring the environment, enhancement of long-term potentiation (Hasselmo & Barkai, 1995; Huerta & Lisman, 1993; Patil, Linster, and lower when the rat sits quietly or performs behaviors Lubenov, & Hasselmo, 1998). At the same time as it such as eating or grooming (Marrosu et al., 1995), as enhances long-term potentiation (LTP), acetylcholine summarized in Fig. 1A. The higher levels of acetylcholine suppresses excitatory synaptic transmission at feedback synapses (Hasselmo & Bower, 1993; Hasselmo & Schnell, * Corresponding author. Tel.: þ1-617-353-1397; fax: þ1-617-353-1424. 1994), while leaving excitatory feedforward synapses E-mail addresses: [email protected] (M.E. Hasselmo) 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)00057-6 690 M.E. Hasselmo et al. / Neural Networks 15 (2002) 689–707 modeling is consistent with a general role for acetylcholine in setting the learning rate of cortical structures (see Doya, 1999, 2002). The level of cholinergic modulation can be regulated by the match of input with prior learning (Hasselmo & Schnell, 1994) causing effects relevant to the stable maintenance of prior associations (Carpenter & Grossberg, 1993). The regulation of relative strength of feedback connections is consistent with cholinergic regu- lation of top–down versus bottom–up influences on cortical representations (Yu & Dayan, 2002). The role of acetylcholine in preventing interference during encoding has been supported by experimental work. Blockade of muscarinic acetylcholine receptors increases proactive interference from previous learning (DeRosa and Hasselmo, 2000; DeRosa, Hasselmo, & Baxter, 2001), and increases generalization between similar odorants (Linster Fig. 1. (A) Neuromodulatory changes in the hippocampus during move- ment through the environment and during immobility. Microdialysis & Hasselmo, 2001; Linster, Garcia, Hasselmo, Baxter, measurement of acetylcholine levels shows higher ACh during movement 2001). In addition, lesions of the fornix and medial septum, than during immobility (Marrosu et al., 1995). Recording of GABAergic which remove cholinergic innervation of the hippocampus, cells in the hippocampus and medial septum shows rhythmic firing during cause impairments in tasks requiring learning of new movement and less regular firing during immobility (Brazhnik & Fox, responses to replace previously learned responses. 1999; Fox et al., 1986). Both of these changes contribute to the appearance of theta rhythm oscillations in the hippocampal EEG during movement. (B) The theoretical mechanism of theta rhythm generation in the hippocampus. 1.2. Theta rhythm may allow rapid transitions between High levels of acetylcholine depolarize pyramidal cells and interneurons, encoding and retrieval causing them to generate spikes. Rhythmic GABAergic input to GABAergic interneurons in the hippocampus causes rhythmic changes in While it is important to prevent interference during interneuron spiking activity, and rhythmic changes in pyramidal cell activity (Stewart & Fox, 1990). These effects in hippocampus and encoding, it is important to have an ongoing ability to access entorhinal cortex cause rhythmic changes in the strength of excitatory hippocampal representations for retrieval. The relatively synaptic input to region CA1 from region CA3 and entorhinal cortex. slow time course of muscarinic cholinergic effects on synaptic transmission and postsynaptic depolarization suggest that acetylcholine would require several seconds effects in the presence of acetylcholine, but the activation of to change network dynamics (Hasselmo & Fehlau, 2001). feedback synapses in the presence of acetylcholine causes This motivated a search for potential mechanisms LTP which makes them stronger at later times. This allowing faster transitions between encoding and paradoxical combination of effects can be understood in retrieval. Recent work suggests that rapid transitions the context of associative memory models of piriform cortex between encoding and retrieval could be provided by and hippocampus (Hasselmo & Bower, 1993; Hasselmo & theta rhythm oscillations (Hasselmo, Bodelon, & Wyble, Schnell, 1994). Effective associative memory function 2002a), which are induced in the hippocampal formation requires that network activity be clamped to feedforward due to rhythmic input to the hippocampus from both input during encoding, this prevents new associations from cholinergic and GABAergic cells of the medial septum being distorted by the spread of activity across previously (as summarized in Fig. 1B). Here we show how theta modified feedback connections. In contrast, during rhythm oscillations may provide a mechanism by which retrieval, activity must spread more freely across encoding and retrieval dynamics could rapidly alternate feedback synapses. within the hippocampal formation, allowing encoding of Thus, acetylcholine may prevent interference during the new information without interference due to retrieval of strengthening of feedback synapses by selectively suppress- previously encoded information. ing excitatory feedback synapses but not feedforward During movement through the environment, the hippo- synapses (Hasselmo, 1999; Hasselmo & Bower, 1993; campal EEG shows a prominent oscillation in the 6–12 Hz Hasselmo & Schnell, 1994). At the same time, acetylcholine frequency range referred to as theta rhythm (Buzsaki, further enhances the response to feedforward input by Leung, & Vanderwolf, 1983). This theta rhythm activity causing post-synaptic depolarization of neurons (Barkai and appears to be regulated by cholinergic and GABAergic Hasselmo, 1994; Benardo & Prince, 1982), suppression of input from the medial septum (Stewart & Fox, 1990), as neuronal adaptation (Barkai & Hasselmo, 1994)and shown in Fig. 1B. During theta rhythm, acetylcholine suppression of feedback inhibition (Patil & Hasselmo, depolarizes both excitatory and inhibitory neurons in the 1999). Modeling demonstrates that these combined physio- hippocampus, and rhythmic
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