102

Brain Research, 529 f19911) 102--10~4 Elsevier

BRES 15895

Role of the medial septum and hippocampal theta rhythm in exploration-related synaptic efficacy changes in rat fascia dentata E.J. Green, B.L. McNaughton and C.A. Barnes Department of Psychology, University of Colorado, Boulder, CO (U.S.A.) (Accepted 27 March 1990) Key words: Dentate gyrus; Exploration; Medial septum; Theta; Synaptic transmission

Animals transferred from their home cages to a different environment exhibited an increase in exploratory behavior which was accompanied by a substantial increase in perforant path-evoked population excitatory postsynaptic potentials and decreases in both the areas and the onset latencies of population spikes. As reported previously, these changes substantially outlasted the exploratory behaviors that induced them. Electrolytic lesions of the medial septum severely attenuated the theta rhythm of the hippocampal EEG, but had no significant effect on the exploration related changes in the synaptic and postsynaptic components of the evoked response. In urethane-anesthetized animals, long trains of hippocampal theta produced by sensory stimulation failed to affect the amplitude of evoked responses. These results show that the information critical for the exploration-related alterations in dentate evoked responses does not originate in or pass through the medial septum, and that the changes are not linked to hippocampal EEG states. INTRODUCTION Previous reports have described a novel type of behaviorally associated alteration in the magnitude of electrically evoked synaptic responses in the fascia dentata 12"26'27. Rats induced to explore their environment exhibit a robust increase in the initial slope of the population excitatory postsynaptic potential (EPSP) and a corresponding decrease in both the area and latency of the evoked population spike (see Fig. 1C). These changes develop gradually, and considerably outlast the exploratory behavior with which they are associated, clearly distinguishing them from the momentary behavioral 'gating' of synaptic transmission in fascia dentata originally described by Winson and colleagues 7'9'33-37. Sharp et al. 27 showed that the evoked synaptic (EPSP) response changes were well described by the time integral of exploratory behavior, less an exponential decay term. For example, animals that have engaged in minimal levels of exploratory behavior generally exhibit a modest increase in the slope of the synaptic response. The same animals exhibit much larger synaptic growth following periods of vigorous exploratory activity. This growth decays only slowly after exploration ceases, with responses returning to baseline levels within 30 min. The decrease in spike discharge returns to pre-exploration levels much more slowly, remaining depressed for hours 12.

While substantial response alterations accompany voluntary environmental exploration, such changes do not consistently occur following locomotion in an enclosed treadmill 12. During such intense locomotion there is, in fact, a transient reduction in EPSP amplitude that recovers immediately upon cessation of the treadmill. As described by Green et al. 12, this transient reduction is proportional to the previous exploration-related increase of EPSP slope rather than to the absolute magnitude of the EPSP. Thus, neither locomotion per se nor the theta rhythm which normally accompanies locomotion is sufficient to account for the exploration-associated synaptic changes. In addition, recent data have provided additional support for the idea that the synaptic changes associated with environmental exploration reflect a genuine increase in the efficacy of perforant path synapses onto granule cells. Exploration-related increases in EPSP slope can be observed at the site of synaptic activation in the stratum moleculare as well as at the major synaptic current source in the stratum granulosum/hilus and are independent of stimulus intensity over a wide range ~2. These data, taken with the experimental evidence for a hippocampal role in spatial learning and memory proc e s s e s 14"16"2°-22'25-28 provide support for the possibility that these alterations may be involved in the initial storage of spatial information. The present report focuses on the possible involve-

Correspondence: E.J. Green. Present address: Department of Psychology, University of Miami, P.O. Box 248185, Coral Gables, FL 33124, U.S.A. 0006-8993/90/$03.50 ~ 1990 Elsevier Science Publishers B.V. (Biomedical Division)

103 m e n t of the medial septal region and the hippocampal E E G state in t h e s e c h a n g e s . T h e m e d i a l s e p t u m exerts a powerful modulatory influence on synaptic transmission t h r o u g h t h e fascia d e n t a t a l'4,5'lz'17-z9,24 a n d is .critically

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i n v o l v e d in t h e e x p r e s s i o n of t h e h i p p o c a m p a l theta r h y t h m 2'6'32. F u r t h e r m o r e , lesions o r reversible inactivation of the s e p t u m disrupt b e h a v i o r a l p e r f o r m a n c e o n tasks which are also d i s r u p t e d b y h i p p o c a m p a l d a m a g e TM 14,18,22,32. T h e f o r e g o i n g i n f o r m a t i o n p r o m p t e d us to e v a l u a t e f u r t h e r the possible roles of the h i p p o c a m p a l

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Seventeen male, Fischer-344 rats (12 rats aged 10-14 months; 5 rats aged 23-25 months) were used in these experiments. Rats were singly housed in clear plastic tubs (43 x 22 × 10 era) and allowed free access to food and water. The colony room was maintained on a 12/12 h light/dark cycle, and all testing was carded out during the light phase of the cycle.

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Fig. 1. A: representative perforant path evoked response recorded from the stratum granulosum. The dotted lines show the approximate points of measurement of the EPSP, and the arrow depicts the onset of the population spike. Spike area was taken as the area between the data curve and the line tangent to the curve. Calibration: 5 mV, 3 ms. B: EEG epochs recorded from an individual animal walking on the treadmill prior to lesioning the medial septum (top trace) and subsequent to the septal lesion (bottom trace). Calibration: 0.4 mV, 1 s. C: alterations in evoked response parameters accompanying exploration. An individual animal was transported from the colony to the experimental room, plugged into the recording equipment, and allowed to adapt overnight in a plastic tub (which served as its home cage). The following day, the experimenter entered the room, collected 20 min of baseline evoked response and EEG data (evoked responses elicited every 10 s), and transferred the animal from its home cage to an open field containing various junk objects. The animal was allowed to explore for 20 rain and was then returned to its home cage. The period of exploration in the open field (denoted by the bar) was associated with an increase in hippocampal theta (top left panel), and a gradual but substantial (>40%) increase in EPSP slope (top right panel). The increase in EPSP slope was apparent during all of the behavioral states observed in the open field, including exploration, grooming and still-alert behavior. Following the period of exploration, EPSP slope declined slowly to baseline levels. Population spike area declined considerably during the period of EPSP slope increases and remained low for the duration of the experiment (bottom left panel). Note the decrease in spike onset latency associated with the increases in EPSP slope, and the gradual, parallel recovery of values for the two measures towards pre-exploration levels (bottom right panel).

Chronic surgical implantation of electrodes for stimulation of the perforant path (PP) and recording of field potentials in the hilus of the fascia dentata (FD) was conducted under sodium pentobarbital anesthesia as described previously12. Ten of the animals received an additional monopolar electrode for stimulation of the medial septum (MS). This was constructed of 114/~m (o.d.) stainless steel wire, insulated with teflon to within 300/~m of the tip. During surgery, the depth of the MS electrode was adjusted to produce maximum facilitation of the porforant path-evoked granule cell population spike, between 5.5 and 6.0 mm below the dural surface it. Nominal stereotaxic coordinates (flat skull) for the electrode placements, with reference to bregma and the midline, were (in mm): PP, 8.1 E 4.4 L; MS, 0.5 A, 0.0 L; FD, 4.0 P, 2.2 L. For acute experiments, the perforant path and fascia dentata electrode placements were as described above, and the animal was maintained under urethane anesthesia (1.5 g/kg). Body temperature was monitored by a rectal probe and maintained at 37 + 1 °C throughout the experiment with a D.C. heating pad. Sensory, rather than electrical stimulation was used to elicit theta in order to preclude direct effects of electrical stimulation on hippocampal pathways. Urethane anesthesia was maintained at a level such that moderate tail pinches could elicit theta reliably with a minimum of spontaneous theta.

Stimulation and recording Constant-current, disphasic stimuli (100 ms/half cycle) were delivered at 0.1 Hz. Stimulus intensity was individually determined for each rat and adjusted to elicit population spikes that were approximately half-maximal at the beginning of the first day's recording session. Evoked field potentials were filtered (half amplitude attenuation) at 1 Hz (high pass) and 3 kHz (low pass), amplified, and sampled by computer at 20 kHz. EEG epochs of 10.24 s (in chronic preparations) or 2.56 s (in acute preparations) were collected from the hilar electrode immediately prior to each evoked field potential, band-pass filtered between 0.1 and 30 Hz, amplified, and sampled by computer at 100 Hz. An FET follower headstage mounted on top of the head plug assembly was used to minimize electrical noise and movement artifact. Evoked potentials and EEG data were stored on magnetic disk and analyzed off-line. Representative response waveforms and hippocampal EEG under various experimental conditions are illustrated in Fig. 1. Population EPSP magnitude was assessed by measuring the amplitude difference between two points (indicated by dotted lines) at fixed latencies from the stimulus artifact, on the rising phase of the waveform (Fig. 1A). The amount of granule cell discharge was estimated by computing the population spike area, taken as the area between the data curve and a line tangent to the curve at two points

104 (Fig. 1A). Spike area is highly correlated with spike height under normal conditions (r > 0.90), but, unlike spike height, is much less influenced by discharge synchrony3. The unique tangent points noted above were defined as the spike onset and offset times. Spike onset latency was taken as the latency between the apparent EPSP onset and the spike onset time noted above. Artifact-free EEG epochs were subjected to fast-Fourier analysis, and the spectral power between 6 and 8 Hz was computed for each epoch. Samples of EEG collected from an animal during sessions of walking on the treadmill prior and subsequent to a septal lesion are shown in Fig. lB. Amplitude and area measures from each recording session were normalized relative to a baseline condition which was taken as the intercept of a linear regression of the first 10 data points collected each day. This intercept value was then used as a divisor for each data point in the recording session. The data were thus expressed as the change in response magnitude, relative to an initial value of 1.0. For example, a response value of 1.4 indicates a response which was 40% greater than the initial baseline value at the beginning of the recording session (see Fig. 1C). Statistical analyses were accomplished using paired t-tests except where noted in the next. RESULTS

Experiment 1: septal lesions and exploration-related alteration in evoked responses Procedure For the recording sessions, each rat was carried in a plastic tub (which served as the home environment in the animal colony) to the recording room, connected to the recording apparatus, and returned to the tub. The elapsed time between initial handling of the tub in the colony r o o m until commencement of recording ranged between 60 and 120 s. Evoked responses were elicited every 10 s. Each animal was carefully monitored throughout each recording session for behavioral and E E G signs of sleep. At the time of each stimulus delivery the animals behavior was categorized as either exploratory or non-exploratory. Exploratory behaviors included walking, sniffing and rearing, which are associated with theta rhythm in the hippocampal E E G of rats s'29-31. Nonexploratory behaviors included grooming and awake immobility. At no time in these experiments did the animals exhibit behavioral or E E G signs of sleep. Following the initial 15 min in the plastic tub, the rat was placed into the treadmill, moving at 9 cm/s. After 2.5 min in the treadmill, animals were returned to the plastic tub for an additional 12.5 rain. Transfers between the tub and the treadmill were accomplished without interruption in data collection. Septal lesions. The prelesion phase of the experiment was conducted for 3 days. Each animal was then anesthetized with methoxyflurane, and septal lesions were made by passing 3 - 4 m A of anodal, constant current through the indwelling septal electrode for 20 s. Following a 5 day recovery period, the animals were tested for an additional 3 days using the same procedures

and environment as in the prelesion sessions. During the last session, the animals were tested under red light conditions in order to facilitate exploration. Following completion of the experiment, each animal was deeply anesthetized with pentobarbital (60 mg/kg) and perfused through the heart with formal-saline. Tissue blocks containing the septal area were cut at 40~tm, and every third section was stained with Cresyl violet. The extent of damage through the entire medial septum and diagonal band region was assessed by two independent observers, using boundaries defined by Paxinos and Watson 23. Prelesion recording sessions. There was no significant age difference in either exploratory behavior, increase in EPSP slope or spike decline in these experiments, in accordance with previous unpublished observations from this laboratory. Therefore, data from the young and old animals were combined. The pattern of exploratory behavior and evoked response alterations observed in these experiments was similar to those described in previous reports 12'27. Animals exhibited the greatest amount of exploration and EPSP slope increase on day 1, and a general decrease in both exploration and EPSP slope increase on days 2 and 3. Data for the first prelesion session (day 1) are illustrated in the left column of Fig. 2. After the initial environmental transfer from the colony room, animals exhibited a substantial amount of exploratory behavior and hippocampal theta, both of which declined gradually over the first 15 min of the session. Transfer from the colony room resulted in a significant change in the initial slope of evoked EPSPs and the area of population spikes. Over the first 15 min, EPSP slopes increased an average of 29.1 + 4.1% (P < 0.01). Over the same period, population spike areas declined to 65 + 7% of their initial values ( e < 0.01). Transfer to the moving treadmill produced a renewed increase in hippocampal theta, and a transient attenuation in EPSP slope which persisted for the 2.5 min period of treadmill activation. This EPSP attenuation was superimposed upon the previous within-session growth in EPSP slope, a result consistent with previous observations 12. In those experiments it was noted that the EPSP slope reduction was related neither to the absolute magnitude of the EPSP slope per se (i.e. before normalization), nor to the intensity of the perforant path stimuli used to evoke the response. Rather, the magnitude of EPSP slope reduction was proportional to the amount of

exploration-related increase in EPSP slope above baseline. Therefore, the phenomenon is not likely to be a consequence of electrode placement. In addition, during the period of intense locomotion there was no change in the onset latency of the population spike, despite the attenuation in EPSP slope. These observations suggest

105 that only the modified component of the population EPSP is subject to the locomotion induced transient suppression. These relationships were similarly evaluated in the present experiment in order to determine the possible effects of septal lesions. The magnitude of momentary EPSP reduction was computed for each animal by subtracting the mean EPSP slope for the minute following placement into the moving treadmill from the mean Pre-lesion 100

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Fig. 2. Expt. 1: effects of septal lesions on alterations in evoked responses associated with environmental exploration and treadmill walking. This figure presents group means for exploratory behavior, power of hippocampal theta, evoked EPSP magnitude and evoked population spike area plotted as a function of time for the 10 animals in this experiment. Left: prelesion data. Note the gradual increase in the EPSP slope accompanying (hut outlasting) exploration, and the transient attenuation in the EPSP during periods of vigorous locomotion on the treadmill (depicted by the solid bar). Right: postlesion data. Exploratory activity was comparable to that observed prior to the lesion, but hippocampal theta associated with exploration and treadmill walking was depressed. Despite the reduction in hippocampal theta, animals exhibited levels of EPSP slope changes quite similar to those observed prior to the septal lesion.

EPSP slope immediately prior to being placed into the treadmill. These values were then plotted as a function of: (1) the normalized EPSP slope just prior to treadmill activation; and (2) the raw magnitude of EPSP slope (in mV/ms). The data were fitted using a linear regression model. The EPSP slope reduction was proportional to the net EPSP slope increase just prior to walking (r = 0.677, P < 0.05), and not to the absolute value of the EPSP slope itself (r = 0.153, P > 0.25). The period of treadmill walking was also associated with a modest increase in spike area, particularly in the minute following the animal's transfer to the treadmill (P < 0.05). The results of previous experiments have indicated that such spike area increases can be observed following changes in room illumination, changes in treadmill speed and environmental transitions, and may thus be related to environmental novelty12. Following the return of animals from the treadmill to the tub, EPSP values recovered immediately to pretreadmill levels. Over the last 10 min of the session, hippocampal theta and exploratory behavior declined gradually, while EPSP values remained fairly stable. Postlesion recording sessions. Exploratory behavior during the first two postlesion recording sessions was similar to that observed in the last prelesion recording session (i.e. quite modest). However, during the last postlesion testing session conducted under red light (postlesion session 3), the animals explored more vigorously than in the first two postlesion sessions, and at levels quite similar to those observed on prelesion session 1 (mean percent exploration prelesion = 39.9 _+ 2.3, postlesion = 36.9 _+ 2.4). Thus, the data from this test session were used for comparison purposes, and are illustrated in the right column of Fig. 2. Despite comparable levels of exploration, there was a substantial reduction in the power of hippocampal theta (6-8 Hz) relative to that observed prior to the lesion. Theta recorded during the first 10 rain of postlesion day 3 was significantly attenuated relative to that observed during an equivalent period in prelesion session 1 (P < 0.01). The severe attenuation in exploration-related theta was not associated with any significant alterations in the amplitude of evoked responses. EPSP and spike values at the beginning of the postlesion recording sessions did not differ from those observed prior to the lesion. In addition, the increase in the EPSP slope after the first 15 min reached about the same level as on the first day of prelesion testing (24.2 _+ 3.0% growth; pre- vs postlesion, P > 0.23). Over the same period, population spike areas declined to 69 + 8% of their initial value, a value nearly identical to that observed prior to the septal lesion (pre- vs postlesion, P > 0.32). The.reductions in latency to population spike onset which are associated with exploration-related increases in

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The extent of medial septal damage averaged 60 ± 11% (S.E.M.) and ranged from 2.8 to 90.2% in various animals. Damage to the lateral septum was minor. Damage to the diagonal band was substantial in one animal, moderate in two others, and minimal in the remaining animals. The possible relationship between alterations in evoked responses and septal lesion size was evaluated by plotting the change in relative EPSP slope increase over the first 15 min of the last postlesion recording session (postlesion slope increase - prelesion slope increase/ postlesion slope increase + prelesion slope increase) as a function of the septal damage for each animal. Linear regressions applied to these data indicated that neither the EPSP slope increase, spike area decline, or the spike onset latency reduction was significantly related to the extent of medial septal damage (all Ps > 0.05). The relationship between medial septal damage and hippocampal theta recorded during the 2.5 min period of treadmill walking was evaluated in a similar manner. A linear regression performed on these data indicated that the attenuation in theta observed following the lesion was significantly correlated with medial septal damage (r = 0.70, P = 0.023).

36

Fig. 3. Expt. 2: cumulative effects of sensory theta on evoked responses. The top panel shows power (linear scale) integrated over the 3-5 Hz frequency range, plotted as a function of time. The second through fourth panels show normalized values for the evoked EPSP, spike area, and spike latency plotted as a function of time. Theta was elicited by delivering intermittent tail pinches during the period indicated by the dashed vertical lines. The right column shows the spectral characteristics of the hippocampal EEG during the period of intermittent tail pinches (top panel), and during the prepineh baseline period (bottom panel). The insets are samples of EEG epochs collected during these periods. Sensory theta, elicited under urethane anesthesia, did not lead to the pattern of evoked potential alterations observed during exploration-related theta. Calibration: 1.5 mV, 1 s. EPSP slope were also not significantly affected by septal lesions (pre- vs postlesion, P > 0.44). Transfer to the moving treadmill produced a slight increase in hippocampal theta, although this was substantially reduced in comparison to prelesion treadmill values (mean theta reduction = 73.9%, pre- vs postlesion, P < 0.01). Treadmill walking was accompanied by a relative reduction in evoked EPSP which, as in prelesion sessions, was proportional to the net EPSP slope increase just prior to walking (r = 0.88, P < 0.01) rather than to the absolute value of the EPSP itself (r = 0.198, P > 0.25). Following removal of animals from the treadmill, EPSP values recovered immediately to pretreadmill levels, and remained fairly stable over the last 10 min of the session.

Experiment 2: cumulative effects of theta on evoked responses In this experiment we sought to determine whether theta, in the absence of movement, is sufficient to produce the pattern of evoked response alterations observed during exploration. The experiments were conducted in acute, urethane-anesthetized preparations, in which hippocampal theta can be elicited by sensory stimulation 8,15. In each experiment an attempt was made to mimic, as closely as possible, the pattern of E E G changes observed in freely moving animals subsequent to environmental transitions. This was accomplished by collecting baseline E E G and evoked responses during a long period in which hippocampal electrical activity was dominated by large amplitude irregular activity. Tail pinches of varying duration were then delivered intermittently for 8-20 min while responses were collected at 0.i Hz. Evoked responses and E E G were also collected during longer periods (10-30 min) which were characterized by occasional bouts of spontaneous theta. Alterations in evoked responses associated with theta were assessed by comparing response values for the 1 min period just prior to tail pinch with the peak change in the response (also a 1 min epoch) observed during hippocampal theta. There was no reliable cumulative effect of tail pinchinduced theta on EPSP or spike measures in these experiments. Theta was accompanied by small, non-

107 significant reductions in both EPSP slope (0.4 + 1.4%; P > 0.5), and population spike area (7.9 + 6.8%; P > 0.25). During baseline (no pinch) periods there were occasional bouts of spontaneous theta of varying amplitude and duration, but these were never accompanied by any significant alterations in EPSP amplitude. Fig. 3 shows representative results from an experiment in which high levels of theta were maintained by intermittent tail pinches over an 8 min period. Tail pinch produced a robust increase in theta at frequencies between 3 and 5 Hz. The slope of EPSP responses remained relatively stable across the baseline and tail pinch time periods in every experiment. DISCUSSION In accordance with previous reports, transfer of animals between environments was accompanied by a period of environmental exploration, gradual growth in the slope of the evoked EPSP, and a corresponding reduction in the area and onset latency of the evoked population spike. During intense locomotion on the treadmill, animals exhibited a relative attenuation in EPSP slope which was superimposed upon the EPSP slope increase associated with recent exploratory activity. This attenuation was strictly proportional to the EPSP slope increase just prior to locomotion on the treadmill. Electrolytic lesions produced significant damage to the medial septum and substantially reduced the amplitude of hippocampal theta recorded during both spontaneous exploration and treadmill walking. Nevertheless, baseline evoked responses were unchanged, and exploratory activity during postlesion testing sessions was accompanied by levels of EPSP slope increase and spike decline which were essentially identical to those exhibited prior to the lesion. Furthermore, septal lesions failed to alter significantly the relationship between exploration-related EPSP slope increase and the momentary attenuation of EPSP amplitude observed during vigorous locomotion on the treadmill. Finally, theta elicited under urethane anesthesia had no significant effect on evoked population EPSP or spike measures. It is important to note that the EPSP slope increase and spike decline observed following exploration in our experiments can be distinguished from the momentary 'gating' of evoked response amplitudes studied by Winson and colleagues 9'33-37. Those investigators observed significantly larger perforant path-evoked EPSPs in rats REFERENCES 1 Alvarez-Leefmans, EJ. and Gardner-Medwin, A.R., Influences of the septum on the hippocampal dentate area, J. Physiol., 249 (1975) 14P-16P.

during 'still alert' (SA) behaviors relative to when the rats were in slow wave sleep (SWS). Evoked spikes were larger during SWS than when animals were in SA. Values for evoked EPSPs and spikes during theta behaviors were quite variable, the average being intermediate between those observed in SWS and SA. The response changes observed in the present experiments were of approximately the same order of magnitude as those reported by Winson and colleagues, but did not require a transition from SWS to waking behavior (as confirmed by careful monitoring of the hippocampal EEG and behavior of the animals). Moreover, the alterations reported in our studies develop gradually and substantially outlast the exploratory behaviors which appear to produce them. Such changes are not characteristic of the gating phenomenon, which involves more transient response alterations depending upon the momentary behavioral state of the animal. Indeed, the variable EPSP and spike values associated with theta behaviors in the Winson experiments may be attributable, at least in part, to more persistent EPSP and spike changes such as those described in the present experiments. A previous study demonstrated that continuous theta associated, with locomotion in a treadmill does not produce EPSP slope increases 12. The present experiments extend these results by indicating that the evoked response alterations are not produced by continuous theta in anesthetized rats, nor are they attenuated by the near elimination of theta in septaUy lesioned rats. Taken together, the studies provide strong evidence that hippocampal theta is neither necessary nor sufficient for the expression of the exploration-related growth in the evoked EPSP slope, nor does it appear that the changes reflect other possible influences of septal afferents. Thus, the evoked response alterations associated with exploratory behavior can be completely dissociated from both the hippocampal EEG state and locomotion per se. This conclusion is consistent with the hypothesis that such changes are related to the processing of spatial sensory information in the awake animal. Although it remains to be demonstrated, this leaves open the possibility that the alterations in synaptic responses reflect a form of information storage. Acknowledgements. This work was supported by BNS-8617464 to B.L.M. and AG-03376 to C.A.B.E.J.G. was supported by NRSA postdoctoral fellowshipF32 AG05345. We thank C.A. Erickson and J. Meltzer for their assistance in various phases of these experiments.

2 Andersen, P., Bland, B.H., Myhrer, T. and Schwarzkroin,P.A., Septo-hippocampal pathway necessaryfor dentate theta production, Brain Research, 79 (1979) 13-22. 3 Barnes, C.A., Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat, J. Comp.

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Role of the medial septum and hippocampal theta rhythm in exploration-related synaptic efficacy changes in rat fascia dentata.

Animals transferred from their home cages to a different environment exhibited an increase in exploratory behavior which was accompanied by a substant...
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