Experimental dissociation between wakefulness and paradoxical sleep hippocampal theta

Physiology & Behavior, Vol. 23, pp. 471-479. Pergamon Press and Brain Research Publ., 1979. Primed in the U.S.A.

Experimental Dissociation Between Wakefulness and Paradoxical Sleep Hippocampal Theta PAUL MONMAUR,

ODILE HOUCINE

AND JEAN DELACOUR

Laboratory o f Psychophysiology, University o f Paris VII, 7 Quai Saint Bernard, 75221 Paris Cedex 05, France R e c e i v e d 28 N o v e m b e r 1978 MONMAUR, P., O. HOUCINE AND J. DELACOUR. Experimental dissociation between wakefulness and paradoxical sleep hippocampal theta. PHYSIOL. BEHAV. 23(3) 471--479, 1979.--The effects of electrolytic lesions of the septum on the theta activity of the dorsal hippocampus were studied in the chronically implanted rat during both wakefulness and paradoxical sleep. The experimental results show that depending on their localization, septal lesions can either: (1) eliminate the wakefulness theta rhythm without suppressing that of paraoxical sleep; (2) eliminate the paradoxical sleep theta rhythm without suppressing that of wakefulness. These results suggest that there are two kinds of theta activity having different anatomophysiological bases and a different functional significance: one associated with wakefulness and the other, with paradoxical sleep. Septal lesions

Hippocampal theta rhythm

Wakefulness

Paradoxical sleep

MONMAUR, P., O. HOUCINE AND J. DELACOUR. Dissociation exp~rimentale entre I'activitg th~ta hippocampique de veille et l'activitd th~ta hippocampique du sommeil paradoxal chez le rat. PHYSIOL. BEHAV. 23(3) 471--479, 1979.-Les effets de la l~,sion 61ectrolytique du septum sur l'activit6 thfta de l'hippocampe dorsal ont 6tg 6tudi(~s chez le rat chroniquement implantf, au cours de la veille et du sommeil paradoxal. Les rgsultats exp~fimentaux montrent que la l(~sion septale peut, scion sa Iocalisation: (1) abolir le rythme thfta de veille sans supprimer celui du sommeil paradoxal; (2) abolir le rythmes thfta du sommeil paradoxal sans supprimer celui de veille. Ces rfsultats suggfrent tr~,s fortement I'existence de deux types distincts de rythmes thfta ayant des bases anatomophysiologiques et une signification fonctionnelle difffrentes: l'un de veille, l'autre de sommeil paradoxal. Lfsions septales

Rythme thfta hippocampique

Veille

IN T H E rat, it is well established that the dorsal hippocampus is the site of a slow electrophysiological activity, from 4 to 12 c/sec, that is highly synchronized and easily identifiable, called the theta rhythm. This rhythm clearly appears during the wakefulness state (W), associated with oriented or voluntary movements [31], as well as during paradoxical sleep (PS). The hypothesis according to which the theta rhythm might in each state have distinct anatomophysiological bases has been proposed once only [30], and no specific investigation has been devoted to it. Ordinarily, the hypotheses proposed in this regard are monist [25, 32, 37, 38]. Differences between the basic organization of W theta activity and PS theta activity have been described by some authors: in particular, the mean frequency [36], the amplitude [37] and the regularity of this rhythm [9] differ in the two states. Furthermore, the W and PS theta rhythms have been shown to be unequally sensitive to atropine [12, 30, 33, 35]. Until now, however, no direct argument has supported the existence of distinct anatomophysiologicai bases for W and PS theta rhythms. In demonstrating that lesion of the septal area can cause one of these rhythms to disappear while the other is maintained, the present results offer the first data that would uphold a dualist hypothesis.

Sommeil paradoxal

Part of these results have been briefly reported elsewhere [181. METHOD The experiments were performed on 23 male SpragueDawley rats, weighing about 300 g. They were stereotaxically implanted under Penthotal anesthesia (70 mg/kg, IP) with chronic bipolar electrodes placed unilaterally in the right dorsal hippocampus and at the level of the neocortex, of the eyeballs and of nuchal muscles. The b i p o l a r h i p p o c a m p a l e l e c t r o d e w a s m a d e o f stainless-steel wires, 0.12 mm in diameter, insulated except for the cross section of the tip. The wires were twisted together and cut so that one tip was 1.3 mm shorter than the other. One was aimed at the stratum oriens of CA1 and the other at the stratum moleculare of the fascia dentata. According to the atlas of Albe-Fessard et al, [1], coordinates for the hippocampal placement were: 4.9 mm anterior to lambda, 1.7 mm lateral and 3.5 mmm below the skull surface. At the same time a 0.4 mm diameter needle insulated except for 0.5 mm at the tip was implanted in the septal area.

C o p y r i g h t © 1979 B r a i n R e s e a r c h P u b l i c a t i o n s Inc.--0031-9384/79/090471-09501.40/1

472

MONMAUR. H ( ) U C I N E AN[) DELACOLrR

Septal electrodes were placed 8 to i0 mm anterior to lambda, 0 mm lateral and 6 to 7 mm below the skull surface. Lesions of the septum were carried out under Diethyl Ether anesthesia. A DC cathodal current ( 4 mA) was passed for 30 sec. One week after electrode implantation and one day prior to the septal lesion, a control recording was done. It was followed by another recording one day after the lesion, and then a recording every 7 days over 2 months. During the postlesion period, a supplementary recording was performed in the rats after intraperitoneal administration of lg/kg Ethyl Urethane. All the other recordings were taken after administration of isotonic saline. Urethane elicits a slow W theta activity in the immobile animal [ 12]. This drug also favors the appearance and maintenance of low frequencies of PS theta activity [25]. Considering these special effects, administration of this pharmacological agent to lesioned rats seemed an interesting way to test the effect of septal lesions on the E E G hippocampal activity. Recordings lasted 3 hours. They included the E E G activity associated with 100 sec of spontaneous exploratory behavior, 100 sec of exploratory behavior elicited by sensory stimulations and 200 sec of PS. Recordings performed before and after electrocoagulation of the septum were compared. For each rat the average amplitude and frequency of the theta rhythm were determined from 5 sec samples of theta recorded during exploration and PS.

W

At the completion of the experiments, the recording sites of the hippocampal theta rhythm were marked by passing small DC currents through each electrode. Then, the rats were intracardially perfused with 10% Formalin. After several days of fixation in formalin, the brains were then removed from the skulls, cut on a freezing microtome at I00 p~m section thickness, and stained with I%,, Thionine.

RESULTS

Lffects of the Lesions on Hippocampal Theta Activity Data on hippocampal EEG analysis following lesion of the septal area are yet incomplete. Those reported here essentially concern the initial postlesion period (4-5 weeks). The first results show that lesion of the septal area brought about three types of effect: - - t o t a l suppression or alteration of W theta activity and PS theta activity in 10 rats (group 1) (Fig. 13: - - s u p p r e s s i o n of W theta activity without that of PS in 4 rats (group 2) (Fig. 2); - - s u p p r e s s i o n of PS theta activity without notable alteration of that of W in 9 rats (group 3) (Fig. 3). As shown in Figs. 4 and 5, administration of urethane enhance these phenomena: when the theta rhythm was eliminated, the drug had no effect: when this rhythm was present but altered, the drug favored its appearance. This particular effect of urethane is well illustrated in Fig. 6: in rat 24, in

A

PS

pc

explore W

B

PS

-exploreFIG. 1. Electrophysiological activity of the dorsal hippocampus (h) and the fronto-parietal cortex (pc) during wakefulness (W) and paradoxical sleep (PS) of rat 32, before (A) and after (B) lesion of the septum. Septal lesion alters but does not suppress the W and PS theta rhythms. Note: pronounced amplitude reduction of theta waves. Calibrations: I sec and 100 gv.

S E P T A L L E S I O N S AND H I P P O C A M P A L T H E T A RHYTHM

473

A

PS

B

PS

explore W

-

explore

FIG. 2. Electrophysiological activity of the dorsal hippocampus (h) and the fronto-parietal cortex (pc) during wakefulness (W) and pardoxical sleep (PS) of rat 12, before (A) and after (B) lesion of the septum. Septal lesion suppress the W theta rhythm. In contrast, this rhythm can be easily identified during PS. It is often associated with fast and low voltage activity. Calibrations: 1 sec and 100 ~v.

which W and PS theta rhythms had been disrupted by the lesion, the administration of this drug allowed a transient but clear appearance of this rhythm during W and PS. During the initial postlesion period, and more especially on the first day, the lesion that did not disrupt hippocampal theta activity generally produced a substantial reduction of its amplitude and a slight decrease of its frequency. In all but one of these rats, the averag~ amplitude was reduced by 25-75 percent of the prelesion value. An example of such a reduction in amplitude is seen in Fig. 1. In rats of group 1, postlesion amplitude was less than 50 percent of the prelesion value. In rats of the two other groups, postlesion amplitude was always superior to 50 percent of the prelesion value. In all group 2 rats and 7 of the 9 group 3 rats, postlesion frequency was reduced by 0.5-1 c/s. On the contrary, frequency was unaffected by lesion in group 1. As shown in Fig. 1, 2 and 4, septal lesion could substantially alter the morphology of them waves. In this case, them waves were often associated with fast and low voltage activity (Fig. 4). These anomalies did not prevent the identification of theta rhythm by visual inspection; on the contrary they rendered more difficult amplitude and frequency measurements. Therefore, further experiments will be needed to confirm these preliminary data.

A systematic study of hippocampal theta rhythm recovery during the postlesion period was not undertaken. However, preliminary analysis shows that the phenomenon is complex: in some cases, the suppression or alteration of the W and PS theta rhythms was permanent for at least two months; in others, it lasted only a few days or a few weeks. W and PS theta rhythms reappeared either simultaneously (2 rats)or independently (4 rats). On account of both the theoretical importance and complexity of this phenomenon it is to become the main topic of another study. The effects of septal lesions on theta activity did not seem secondary to global behavioral modifications nor to an alteration of the wakefulness and sleep phenomena. The most constant behavioral effect of the lesion was hyper-reactivity, characterized by a strong startle reaction in response to familiar sensory stimuli. All the experimental animals displayed exploration and orientation behavior with which the W theta rhythm is normally associated. The general organization of the wakefulness and sleep phenomena was not modified, and more particularly the different phases of these two states succeeded each other normally. The behavioral aspects of sleep presented no anomalies; particularly, posture, eye movements and the clonic body movements, typical of paradoxical sleep appeared normal in the experimental subjects.

474

M O N M A U R , H O U C I N E A N D DEI,ACOUR

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explore FIG. 3. Electrophysiological activity of the dorsal hippocampus (h) and fronto-parietal cortex (pc) during wakefulness (W) and paradoxical sleep (PS) of rat 26, before (A) and after (B) lesion of the septum. Septal lesion eliminates the paradoxical sleep theta rhythm without notably altering that of wakefulness. Calibrations: 1 sec and 100 #V.

Histological Control Hippocampus. The approximate localization of electrodes in the dorsal hippocampus was examined in 16 rats. Systematic differences between recording sites of the theta rhythm in rats of the three groups were not observed. Septum. Histological examination of the septal lesions pointed out a clear-cut difference between the localization of lesions in group 1 and 2 animals on one hand and the localization of lesions in group 3 animals on the other: (a) Group 2 animals, the lesion of which suppressed the W theta rhythm without suppressing that of PS, underwent a subtotal lateral and medial destruction of the posterior septal area. This lesion differed very little from that which simultaneously eliminated or altered these two rhythms. It included varying proportions of the caudal p a r t of the dorso-lateral septal nuclei and the medial dorsal part of the medial septal nucleus, depending on the subjects. It was generally associated with a rather large destruction of the fornix and the anterior commissure (Fig. 7). (b) Group 3 animals, the lesion of which eliminated the PS theta rhythm without suppressing that of W, underwent destruction of the anterior septal area. The lesion especially affected the rostral part of the dorso-lateral septal nuclei and the dorsal part of the diagonal band of Broca (Fig 8). It was often associated with an alteration of the lower edge of the corpus callosum and the caudal region of the medial paroifactorial area.

DISCUSSION

Some of the results reported here confirm those obtained in the rat by other authors, according to which the destruction of the fornix or a more or less extensive lesion o f the septal area would cause a simultaneous suppression of the W and PS theta rhythms [4, 10, 28, 39. 40]. Moreover, our results bring out an important new fact: it is possible to dissociate the W them rhythm from that of PS by means of lesions of the septal area: that is, to cause these two activities to disappear independently of one another. Without completely proving it, these results strongly suggest that there are distinct anatomophysiological bases for the W and PS theta rhythms. This could have noteworthy consequences from two points of view: (1) F o r understanding the wakefulness and sleep phenomena in rat: the activation of the telencephalon, or at least of the limbic system, during PS could cause neurophysiologicai systems distinct from those of W to come into play. (2) F o r the functional interpretation of the theta rhythm: the chief difficulty in interpreting this rhythm is brought about by its association with two different functional states: W and PS. This difficulty vanishes if the W theta rhythm and the PS theta rhythm represent two distinct physiological phenomena.

SEPTAL LESIONS AND HIPPOCAMPAL THETA RHYTHM

W

475

A

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W

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i immobile FIG. 4. Electrophysiologicalactivity of the dorsal hippocampus (h) and the fronto-parietal cortex (pc) during wakefulness (W) and paradoxical sleep (PS)of rat 1, before (A) and after (B) lesion of the septum, septal lesion eliminates the wakefulness theta rhythm without suppressing that of paradoxical sleep. Administering urethane (Ur) favors the appearance of this rhythm during paradoxical sleep. On the contrary, it does not elicit this rhythm during wakefulness in the immobile animal. Note: morphology of theta waves is altered and fast activity increased in the hippocampus. (~bS): control administration of isotonic saline. Calibrations: 1 sec and 100/zv.

Several neurophysiological systems are capable of influencing the hippocampal theta activity of the rat [2, 3, 5, 6, 11, 17, 22, 26, 27, 29, 34]. Among them, solely the septohippocampal connections system has been clearly implicated in the genesis of this rhythm [4, 10, 28, 39, 40]. The possible implication of the hippocampal feedback circuit via the timbria and the lateral septum in the control of the hippocampal

theta activity [14,15] has not been confirmed [8]. Septal efferences innervating the hippocampus could, on the other hand, play an essential role in the production of this rhythm

[8]. Studies of the anatomical organization of septal projections onto the rat dorsal hippocampus indicate that this part of the hippocampal formation receives afferences

476

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immobile FIG. 5. Electrophysiological activity of the dorsal hippocampus (h) and the fronto-frontal cortex (fc) during wakefulness (W) and paradoxical sleep (PS) of rat 7, before (A) and after (B) lesion of the septum. Septal lesion eliminates the paradoxical sleep theta rhythm without notably altering that of wakefulness. Administering urethane (Ur) elicits this rhythm during wakefulness in the immobile animal. On the contrary, it is ineffective during paradoxical sleep: in this state, the activity of the hippocampus remains desynchronized. (thS): control administration of isotonic saline. Calibrations: 1 sec and 100/zv.

mainly coming from the diagonal band of Broca and the medial septal nucleus [16, 19, 21, 23, 24]. The most recent detailed informations on this subject shows that cells located along the medial septal line, within the vertical axis of the diagonal band and medial septal nucleus, project their axons onto all CA areas and onto the gyrus dentatus of the dorsal hippocampus, via the dorsal fornix [16]. Furthermore, animal data indicating that the cells of the medial septal nucleus

are morphologically different from those of the diagonal band [13] suggest that these two structures are functionally heterogenous. On the basis of these data and taking our results into account, complementary investigations will be necessary to determine whether the W theta rhythm depends u p o n the integrity of one of these two septal structures and whether the PS theta rhythm depends upon the integrity of the other.

SEPTAL LESIONS AND HIPPOCAMPAL

THETA RHYTHM

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explore FIG. 6. Electrophysioiogical activity of the dorsal hippocampus (h) and the fronto-parietal cortex (pc) during wakefulness (W) and paradoxical sleep (PS) of rat 24, before (A) and after (B) lesion of the septum. Septal lesion disrupts wakefulness and paradoxical theta rhythms. These rhythms are not identifiable on Day 23. Nevertheless, on Day 24 administration of urethane (Ur) causes both wakefulness and paradoxical theta rhythms to appear. Once again, these rhythms are not identifiable on Day 30. (&S): control administration of isotonic saline. Calibrations: 1 sec and 100/xv.

478

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FIG. 7. Histological reconstruction of representative lesions (stippled areas) according to the atlas of Albe-Fessard et al.. The lesion eliminates the wakefulness them rhythm without suppressing that of paradoxical sleep. A: distance (mm) from the lambda: apm: medial parolfaetorial area: bdb: diagonal band of Broca: ca: anterior commissure: cc: corpus callosum: chi: hippocampal commissure: fx: fornix: sdl: dorso-lateral septal nucleus: sm: medial septal nucleus: v: ventricle.

A7.2

FIG. 8. Histological reconstruction of representative lesions (stippled areas) according to the atlas of Albe-Fessard e t al. The lesion eliminates the paradoxical sleep theta rhythm without notably altering that of wakefulness. A: distance (mm) from the lambda; apm: medial parolfactorial area; bdb: diagonal band of Broca; ca: anterior commissure; cc: corpus callosum; chi: hippocampal commissure; fx: fornix; sdl: dorso-lateral septal nucleus; sm: medial septal nucleus; v: ventricle.

SEPTAL LESIONS AND HIPPOCAMPAL

THETA RHYTHM

479

REFERENCES

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