The theta rhythm appears in the rat hippocampal EEG during exploration and shows phase locking to stimulus acquisition. Lesions which block theta rhythm impair performance in tasks requiring reversal of prior learning, including reversal in a T-maze where associations between one arm location and food reward need to be extinguished in favor of associations between the opposite arm location and food reward. Here, a hippocampal model shows how theta rhythm could be important for reversal in this

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... ask by providing separate functional phases during each 100-300 msec cycle, consistent with physiological data. In the model, effective encoding of new associations occurs in the phase when synaptic input from entorhinal cortex is strong, and when long-term potentiation (LTP) of excitatory connections arising from hippocampal region CA3 is strong, but when synaptic currents arising from region CA3 input are weak (to prevent interference from prior learned associations). Retrieval of old associations occurs in the phase when entorhinal input is weak and synaptic input from region CA3 is strong, but when depotentiation occurs at synapses from CA3 (to allow extinction of prior learned associations that do not match current input). These phasic changes require that longterm potentiation (LTP) at synapses arising from region CA3 should be strongest at the phase when synaptic transmission at these synapses is weakest. Consistent with these requirements, our recent data shows that synaptic transmission in stratum radiatum is weakest at the positive peak of local theta, which is when previous data shows induction of LTP is strongest in this layer. Introduction. Hasselmo, Bodelón and Wyble 3 Manuscript # 2327 The hippocampal theta rhythm is a large amplitude, 3-10 Hz oscillation that appears prominently in the rat hippocampal EEG during locomotion or attention to environmental stimuli, and decreases during immobility or consummatory behaviors such as eating or grooming (Green and Arduini, 1957; Buzsaki et al., 1983). In this paper, we link the extensive data on physiological changes during theta to the specific requirements of behavioral reversal tasks. Theta rhythm is associated with phasic changes in the magnitude of synaptic currents in different layers of the hippocampus, as shown by current source density analysis of hippocampal region CA1 (Buzsaki et al., 1986; Brankack et al., 1993; Bragin et al., 1995) . As summarized in Figure 1 , at the trough of the theta rhythm recorded at the hippocampal fissure, afferent synaptic input from the entorhinal cortex is strong, synaptic input from region CA3 is weak (Brankack et al., 1993), but long-term potentiation at synapses from region CA3 is strong (Holscher et al., 1997; Wyble et al., 2001) . In contrast, at the peak of the fissure theta rhythm, afferent input from entorhinal cortex is weak, the amount of synaptic input from region CA3 is strong (Brankack et al., 1993), but stimulation of synaptic input from region CA3 induces depotentiation (Holscher et al., 1997). FIGURE 1 ABOUT HERE Role of theta rhythm in behavior. This paper relates these phasic changes in synaptic properties to data showing behavioral effects associated with blockade of theta rhythm. Physiological data suggest that rhythmic input from the medial septum paces theta-frequency oscillations recorded from the hippocampus and entorhinal cortex (Stewart and Fox, 1990; Toth et al., 1997). This regulatory input from the septum enters the hippocampus via the fornix, and Hasselmo, Bodelón and Wyble 4 Manuscript #2327 destruction of this fiber pathway attenuates the theta rhythm (Buzsaki et al., 1983). Numerous studies show that fornix lesions cause strong impairments in reversal of previously learned behavior (Numan, 1978; M'Harzi et al., 1987; Whishaw and Tomie, 1995), including reversal of spatial response in a T-maze. The T-maze task is shown schematically in Figure 2 . During each trial in a T-maze reversal, a rat starts in the stem of the maze and finds food reward when it runs down the stem and into one arm of the maze (e.g. the left arm). After extensive training of this initial association, the food reward is moved to the opposite arm of the maze (e.g. the right arm), and the rat must extinguish the association between left arm and food, and learn the new association between right arm and food. Rats with fornix lesions make more errors after the reversal --continuing to visit the old location (left arm) which is no longer rewarded. FIGURE 2 ABOUT HERE. In the analysis and simulations presented here, we test the hypothesis that phasic changes in the amount of synaptic input and synaptic modification during cycles of the hippocampal theta rhythm could enhance reversal of prior learning. Specifically, these phasic changes allow new afferent input (from entorhinal cortex) to be strong when synaptic modification is strong, to encode new associations between place and food reward, without interference caused by synaptic input (from region CA3) representing retrieval of old associations. Synaptic input from region CA3 is strong on a separate phase when depotentiation at these synapses can allow extinction of old associations. Overview of the model. In the model, we focus on the strengthening and weakening of associations between location (in left or right arm) and food reward (in left or right arm). These Hasselmo, Bodelón and Wyble 5 Manuscript # 2327 associations are encoded by modifying synaptic connections between neurons in region CA3 and region CA1 representing location (place cells) and food reward. The place representations are consistent with evidence of hippocampal neurons showing place selective responses in a variety of spatial environments (McNaughton et al., 1981; Skaggs et al., 1996). The food reward representations are consistent with studies showing unit activity selective for the receipt of reward during behavioral tasks (Wiener et al., 1989; Otto and Eichenbaum, 1992; Hampson and Deadwyler, 1999; Young et al., 1997). Units have been shown to be selective for the receipt of reward at a particular location (Wiener et al., 1989), and reward-dependent responses have been shown in both region CA1 (Otto and Eichenbaum, 1992) and entorhinal cortex (Young et al., 1997). This model assumes place cell representations already exist, and does not focus on their formation or properties, which have been modeled previously (e.g. Kali and Dayan, 2000). Instead, the mathematical analysis focuses on encoding and retrieval of associations between place cell activity in each maze arm and the representation of food reward. The structure and phases in the model are summarized in Figure 1. The analysis presented here suggests that oscillatory changes in magnitude of synaptic transmission, long-term potentiation and post-synaptic depolarization during theta rhythm cause transitions between two functional phases within each theta cycle: 1.) In the encoding phase, entorhinal input is dominant, activating cells in region CA3 and CA1. At this time, excitatory connections arising from region CA3 have decreased transmission, but these same synapses show enhanced long-term potentiation to form associations between sensory events. 2.) In the retrieval phase, entorhinal input is relatively weak, but still brings retrieval cues into the network. At this time, excitatory synapses arising Brankack, J, Stewart, M, Fox, SE (1993). Current source density analysis of the hippocampal theta rhythm: associated sustained potentials and candidate synaptic generators. Brain Research, 615(2): 310-327 Buno W Jr, Velluti JC (1977) Relationships of hippocampal theta cycles with bar pressing during self-stimulation. Physiol Behav 19(5):615-21 Buzsaki, G, Czopf, J, Kondakor, I, Kellenyi, L (1986). Laminar distribution of hippocampal rhythmic slow activity (RSA) in the behaving rat: current-source density analysis, effects of urethane and atropine. Brain Res, 365(1): 125-37 Buzsaki G, Leung LW, Vanderwolf CH. (1983) Cellular bases of hippocampal EEG in the behaving rat. Brain Res. 287(2):139-71. Fox, S. E. (1989). Membrane potential and impedence changes in hippocampal pyramidal cells during theta rhythm. Exp. Brain Res., 77, 283-294. Fox, S. E., Wolfson, S. and Ranck, J. B. J. (1986). Hippocampal theta rhythm and the firing of neurons in walking and urethane anesthetized rats. Exp. Brain Res., 62, 495-508. Frank LM, Brown EN, Wilson M. (2000) Trajectory encoding in the hippocampus and entorhinal cortex. Neuron. 27(1):169-78. Hasselmo, Bodelón and Wyble 27 Manuscript # 2327 Givens B (1996) Stimulus-evoked resetting of the dentate theta rhythm: relation to working memory. Neuroreport 8: 159-163. Golding NL, Spruston N. (1998) Dendritic sodium spikes are variable triggers of axonal action potentials in hippocampal CA1 pyramidal neurons. Neuron. 21(5):1189-200. Gustafsson B, Wigstrom H, Abraham WC, Huang YY (1987) Long-term potentiation in the hippocampus using depolarizing current pulses as the conditioning stimulus to single volley synaptic potentials. J Neurosci. 7(3):774-80 Hampson RE, Jarrard LE, Deadwyler SA (1999) Effects of ibotenate hippocampal and extrahippocampal destruction on delayed-match and -nonmatch-to-sample behavior in rats. J Neurosci. 19(4):1492-507. Hampson RE, Simeral JD, Deadwyler SA (1999) Distribution of spatial and nonspatial information in dorsal hippocampus. Nature 402(6762):610-4 Hasselmo, M.E., Wyble, B.P. and Wallenstein, G.V. (1996) Encoding and retrieval of episodic memories: Role of cholinergic and GABAergic modulation in the hippocampus. Hippocampus, 6(6): 693-708. Holscher, C, Anwyl, R, Rowan, MJ (1997). Stimulation on the positive phase of hippocampal theta rhythm induces long-term potentiation that can Be depotentiated by stimulation on the negative phase in area CA1 in vivo. J Neurosci, 17(16): 6470-6477. Hopfield JJ (1995) Pattern recognition computation using action potential timing for stimulus representation. Nature 376(6535):33-36. Huerta, PT, Lisman, JE (1993). Heightened synaptic plasticity of hippocampal CA1 neurons during a cholinergically induced rhythmic state. Nature, 364: 723-725 Huerta PT, Lisman JE (1995). Bidirectional synaptic plasticity induced by a single burst during cholinergic theta oscillation in CA1 in vitro. Neuron, 15(5): 1053-1063. Hasselmo, Bodelón and Wyble 28 Manuscript #2327 Jensen O, Lisman JE (1996) Novel lists of 7 +/-2 known items can be reliably stored in an oscillatory short-term memory network: interaction with long-term memory. Learn Mem. 3(2-3):257-63. Kali, S., Dayan, P. (2000) The involvement of recurrent connections in area CA3 in establishing the properties of place fields: a model. J. Neurosci. 20(19):7463-7477. Kamondi, A, Acsady, L, Wang, XJ, Buzsaki, G (1998). Theta oscillations in somata and dendrites of hippocampal pyramidal cells in vivo: activity-dependent phase-precession of action potentials. Hippocampus, 8(3): 244-61 Leung, L.-W. S. (1984) Model of gradual phase shift of theta rhythm in the rat. J. Neurophysiol. 52: 1051-1065. Macrides F., Eichenbaum, HB, Forbes, W.B (1982) Temporal relationship between sniffing and the limbic theta rhythm during odor discrimination reversal learning. J. Neurosci. 2: 1705-1717. Markowska AL, Olton DS, Murray EA, Gaffan D (1989) A comparative analysis of the role of fornix and cingulate cortex in memory: rats. Exp Brain Res. 74(1):187-201. M'Harzi, M., Palacios, A., Monmaur P, Willig F, Houcine O and Delacour J. (1987) Effects of selective lesions of fimbria-fornix on learning set in the rat. Physiol. & Behav. 40: 181-188. Murray EA, Davidson M, Gaffan D, Olton DS, Suomi S. (1989) Effects of fornix transection and cingulate cortical ablation on spatial memory in rhesus monkeys. Exp Brain Res. 74(1):173-86 Numan, R., Feloney, M.P., Pham, K.H. and Tieber, L.M. (1995) Effects of medial septal lesions on an operant go/no-go delayed response alternation task in rats. Physiol. Behav. 58: 1263-1271. Hasselmo, Bodelón and Wyble 29 Manuscript # 2327 Numan R, Klis D (1992) Effects of medial septal lesions on an operant delayed go/no-go discrimination in rats. Brain Res. Bull. 29: 643-650. Numan R, Quaranta, JR Jr. (1990) Effects of medial septal lesions on operant delayed alternation in rats. Brain Res. 531: 232-241. O'Keefe, J. and Recce, M.L. (1993) Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3: 317-330. Orr G, Rao G, Stevenson GD, Barnes CA, McNaughton BL (1999) Hippocampal synaptic plasticity is modulated by the theta rhythm in the fascia dentata of freely behaving rats. Soc. Neurosci. Abstr. 25: 2165 (864.14). Otto T, Eichenbaum H (1992) Neuronal activity in the hippocampus during delayed non-match to sample performance in rats: evidence for hippocampal processing in recognition memory. Hippocampus 2(3):323-34. Paulsen O, Moser EI. (1998) A model of hippocampal memory encoding and retrieval: GABAergic control of synaptic plasticity. Trends Neurosci. 21(7):273-8. Pavlides C, Greenstein YJ, Grudman M, Winson J. (1988) Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm. Brain Res. 439(1-2):383-7. Rao, G, Orr, G, Barnes, CA, and McNaughton BL (1998) Theta rhythm modulation of CA1 evoked potential size during locomotion. Soc. Neurosci. Abstr. 24: 933 (367.16). Rudell, A. P. and Fox, S. E. (1984). Hippocampal excitability related to the phase of the theta rhythm in urethanized rats. Brain Res., 294, 350-353 Rudell, A. P., Fox, S. E. and Ranck, J. B. J. (1980). Hippocampal excitability phaselocked to the theta rhythm in walking rats. Exp. Neurol., 68, 87-96.