On the Functional Significance of the Hippocampal θ–Rhythm*

On the Functional Significance of the Hippocampal &Rhythm* PIER LUIGI PARMEGGIANI * * Isstituio di Fisiologia umana dell'universita, Bologna (Italy)

In 1938, Jung and Kornmuller reported that, in the rabbit, low-frequency waves appear in the hippocampal recordings upon stimulation of peripheral nerves. These and similar findings of other authors (MacLean et at., 1952) remained practically unnoticed until Green and Arduini (1954) stressed the importance of this pattern of response. Indeed, they pointed out the very peculiar fact that in arousal the bioelectrical patterns of hippocampal activation are the reverse of those exhibited by the neocortex. That these low-frequency waves (&rhythm) can be elicited by a great variety of stimuli or by the electrical stimulation of central and peripheral nervous structures, was shown by several authors (Liberson and Cadilhac, 1954; Liberson and Akert, 1955; Passouant et al., 1955; Rimbaud et at., 1955; Gangloff and Monnier, 1956; Grastyan et al., 1959; Tokizane et al., 1959; Iwata and Snider, 1959; Brucke et al., 1959a, b ; Beteleva and Novikova, 1960; Torii and Kawamura, 1960; Corazza and Parmeggiani, 1960a, b ; Parmeggiani and Zanocco, 1961,1963). The afferent pathways involved have also been studied (Green and Arduini, 1954; Mayer and Stumpf, 1958; Briicke et al., 1959a, b ; Corazza and Parmeggiani, 1960a, b, 1961a, b, 1963; Torii, 1961 ;Kawamura et al., 1961 ;Petsche et al., 1962, 1965; Stumpf, 1965; Brugge, 1965). Furthermore, unitary analysis has shown that not only is each of the &waves generally associated with a burst of unit activity (Arduini and Pompeiano, 1955; Green and Machne, 1955), but also that fixed phase relationships may be maintained between spikes and waves (Green et at., 1960, 1961; Fujita and Sato, 1964). Many other important contributions to the electrophysiology of the hippocampus should be mentioned, but because they cover a larger field than is desirable for this condensed paper, the reader is referred to the recent review of Green (1964) as a further source of information and references. A short account of recent findings is presented here with the view of clarifying certain aspects of the functional significance of the hippocampal &rhythm. Although this rhythm appears to be a typical feature of the hippocampograms of lower mammalsIonly, a better understanding of its significance would improve our knowledge of the physiology of the hippocampus of both lower and higher mammals. In lower mam-

* Dedicated to Prof. W. R. Hess. ** Present address: Istituto di Fisiologia urnana delI'Universita, Piazza S. Donato 2, Bologna (Italy). References p. 4 3 8 4 4 1

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mals, the effects of such a stereotyped and synchronized output as that of the hippocampus during the appearance of the &rhythm can be detected more easily than those of outputs related to any other physiological condition of hippocampal activity. In higher mammals, the depression or suppression of the 8-rhythm appears to be the final step of an evolutionary trend already apparent in lower mammals. The differences between the hippocampograms of the rabbit and the cat need not to be stressed here: it can be simply stated that these differences seem to be related to the development of the neocortex. What has been gained and what has been lost by higher mammals can only be clarified if the functional significance of the hippocampal &rhythm in lower mammals becomes clear. The following working hypothesis has been derived from the experimental data already mentioned. It seems reasonable to suppose that the hippocampal output during the &rhythm exerts a synchronizinginfluence on the activity of subcortical and neocortical neurones and therefore counteracts the desynchronizing effects of the reticular activating system. In fact, the bursts of hippocampal unit activity associated with the &waves allow one to predict that the hippocampal output in turn may induce a rhythmic firing of neurones receiving projections directly or indirectly from the hippocampus. Furthermore, because such synchronizing action would occur in arousal, an antagonistic role against the effects of the reticular activating system has been tentatively attributed to the hippocampal output during the &rhythm. The validity of this working hypothesis was supported by the results of behavioral experiments (Parmeggiani, 1958, 1962a). Repetitive electrical stimulation of the midbrain reticular formation in unrestrained cats, besides increasing the arousal level, also elicits an amazing rebound sleep behavior. After the arousal the animal yawns, grooms itself, looks for somewhere to lie down, curls up and finally goes more or less deeply to sleep. Because such patterns of sleep behavior occur in a primary fashion during direct stimulation of the hippocampus (Parmeggiani, 1959,1960), the origin of the rebound sleep could itself be due to the intervention of the hippocampus indirectly activated by the reticular stimulation. As shown by Green and Arduini (1954), reticular stimulation elicits the hippocampal &rhythm, which may last longer than the stimulation period. In the present exposition the following points will be considered : (A) Mechanisms underlying the appearance of the hippocampal &rhythm in arousal; (B) Neocortical influences of the hippocampal output associated with the 8-rhythm ; (C) Thalamic influences exerted by the hippocampal output during low-frequency stimulation of the hippocampus dorsalis; (D) Interaction phenomena appearing at the thalamic level between hippocampal and reticular iniluences; (E) Behavioral effects of the suppression of the hippocampal &rhythm; (F) Behavioral effects of the repetitive stimulation of the hippocampus dorsalis, the fimbria and the fornix.

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(A) Mechanisms underlying the appearance of the hippocampal @-rhythmin arousal A simple method for the elicitation of the hippocampal 0-rhythm in curarized* cats consists in the repetitive stimulation** of the sciatic nerve (Corazza and Parmeggiani, 1960a, b). This method of activation is preferred because it provides at the same time reliable and physiological input to both the reticular formation and the hippocampus dorsalis. In curarized cats (Corazza and Parmeggiani, 1961a, b), low-frequency sciatic stimulation (4-2O/sec, 1 msec, 0.5-3 V) elicits the hippocampal 0-rhythm, whereas with higher frequencies (20-100/sec, 1 msec) the type of hippocampal response depends upon the voltage of the stimuli (0.5-3 V). In the latter instance, by increasing the voltage from 0.5 to 3 V the 0-waves become smaller and smaller in amplitude up to clear-cut desynchronization of the hippocampogram during stimulation (Fig. 1).

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Fig. 1. Effects exerted on the bioelectrical activity of the hippocampus by repetitive electrical stimulation of the sciatic nerve. Unanesthetized, curarized cat. Effects of sciatic stimulation (lOO/sec, 1 msec) of increasing voltage (A, 0.6 V; B, 0.8 V; C, 1 V; D, 1.4 V). Note that the 8-waves are smaller in amplitude during the stimulation period of B and C than during that of A. Note also in D the overt desynchronization during the stimulation period, and that the hippocampal @-rhythmappears in a rebound-like manner. The nerve stimulation is marked by the line at the bottom of the tracings; hd, right hippocampus dorsalis; hs, left hippocampus dorsalis. (From Corazza and Parmeggiani, 1961b.)

However, following the end of the stimulation period the &rhythm appears in a rebound-like manner.

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Barbiturate or chloralose anesthesia suppresses the &rhythm (cf. also Green and Arduini, 1954).

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In our experimental conditions full activation of group I11 fibers was avoided.

References p. 438-441

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After coagulation of the septum the hippocampogram becomes very similar to the neocorticogram, and sciatic stimulation elicits, at all frequencies and voltages used, only desynchronizationof the bioelectrical activity of the hippocampus (Figs. 2 and 3).

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These results are consistent with the idea that there are two separate afferent systems to the hippocampus dorsalis, the one synchronizing(&rhythm), the other desynchronizing (Corazza and Parmeggiani, 1961a, b; cf. also Torii, 1961). At the hippocampal level, the two systems act concomitantly; consequently, mixed frequency patterns are seen in the absence of any predominant driving influence. A clear-cut prevalence of the effects of the one or of the other system results in the synchronization or desynchronization of the hippocampogram for a limited time, during and/or after peripheral stimulation. The central course of the pathway eliciting the &rhythm in the cat’s hippocampus dorsalis upon sciaticstimulationwas subjectedto further study(Corazza and Parmeggiani, 1963). The results can be summarized as follows. (i) The hippocampal &rhythm elicited by sciatic stimulation is unaffected after unilateral or bilateral coagulation of any one of the following bulbo-pontine structures: fibrae arcuatae internae, n. cuneatus, n. dorsalis nervi vagi, n. gracilis, nn. pontis, n. raphes, n. reticularis gigantocellularis, n. reticularis paramedianus, n. reticularis parvocellularis, n. reticularis pontis caudalis, n. reticularis pontis oralis, reticularis tegmenti pontis, n. reticularis ventralis, n. tractus solitarius, tractus spino-thalamicus. (ii) At the midbrain level, coagulation of the formatio reticularis depresses the hippocampal &rhythm only when placed bilaterally*. As to the other structures explored, unilateral or bilateral coagulations proved to be ineffective when placed in any one of the following structures : commissura posterior, fasciculus longitudinalis

* The fact is here recalled that in these experiments the coagulation was never so extensive as to involve the whole formatio reticularis.

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dorsalis (Schutz), lemniscus medialis, n. interpeduncularis, n. limitans, n. paralemniscalis, n. tegmenti, nn. tegmenti Guddenii, praetectum, substantia grisea centralis, substantia nigra, tractus habenulo-peduncularis. (iii) Coagulations (uni- or bilateral) of diencephalic structures showed that the appearance of the 6-rhythm in the hippocampus dorsalis upon sciatic stimulation is only dependent on the integrity of structures of the hypothalamus medialis (Fig. 4): area hypothalamica anterior, area hypothalamica dorsalis, area hypothalamica posterior, area tuberalis, n. ventralis medialis hypothalami, pars anterior n. paraventricularis, pars tuberalis n. periventricularis. On the other hand the 0-rhythm is unaffected by unilateral or bilateral coagulation of the following structures : area hypothalamica lateralis, campi Forelii, fasciculus medialis telencephali (median forebrain bundle), fornix, n. mammillaris medialis (pars centralis), n. mammillaris medialis (pars intermedia), n. paraventricularis (pars dorsalis), n. praemammillaris, n. subthalamicus, n. supramammillaris, n. supraopticus, n. tuberomammillaris, pedunculus mammillaris, tractus mammillo-thalamicus, zona incerta. The 8-rhythm is equally unmodified after coagulation of the thalamic nuclei, either specific or non-specific.

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Fig. 3. Effects exerted on the bioelectrical activity of the hippocampus by repetitive electrical stimulation of the sciatic nerve before and after septa1coagulation. Unanesthetized, curarized cat. Note that the same stimuli (20/sec, 1 msec, 2 V) exerting synchronizing effects on the bioelectrical activity of the hippocampus before coagulation (A), after coagulation (B), desynchronize the hippocampogram in a way comparable to that of the neocortical arousal. The nerve stimulation is marked by the line at the bottom of the tracings; os, left occipital; ps, left parietal; fs, left frontal; hs, left hippocampus dorsalis; fd, right frontal; pd, right parietal; od, right occipital. (From Corazza and Parmeggiani, 1961b.)

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The results reported here indicate that the neural elements responsible for the appearance of the &rhythm in the hippocampogram undergo recognizable structural grouping only from the mesencephalic-hypothalamiclevel, and run upwards to the septum : the synchronizing afferent system to the hippocampus seems, therefore, to originate from the reticular formation of the midbrain. On the basis of the experiments of sciatic stimulation in the cat it appears, moreover, that the &rhythm results from moderate reticular activity, and desynchronization occurs during strong reticular activation. The functional significance of the hippocampal 8-rhythm can be fully understood only if the desynchronization of the bioelectrical activity of the hippocampus dorsalis is also taken into account. Further research has to be performed to solve the hodological problem underlying this desynchronization. However, the data already available show that hippocampal desynchronization can still be obtained in cats after hypothalamic, thalamic and septa1lesions, and that hippocampal and neocortical desynchronization are probably closely interrelated. In the rabbit, the cat and the monkey, the

Fig. 4. Effects exerted on the bioelectricalactivity of the hippocampus by repetitive electrical stimulation of the sciatic nerve before and after coagulation of hypothalamic structures. Unanesthetized, curarized cats. A X , D-F, G-I refer to three different preparations. In A, D, G and in C, F: I (respectively before and after coagulation) EEG tracings are recorded from the neocortex and hippocampus (RF, right frontal; RH, right hippocampus dorsalis; LH, left hippocampus dorsalis; LF, left frontal). The nerve stimulation (20/sec, 1 msec, 1 V) is marked by the line at the bottom of the tracings. In B, E, H histological sections are reproduced (Nissl staining)to illustrate the location and the extent of the coagulations in the hypothalamus of the three animals. (From Corazza and Parmeggiani, 1963.)

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ease with which the hippocampal 0-rhythm can be observed is inversely related to the development of the neocortex, so that it can be surmised that the desynchronization of the hippocampogram and the depression of the 0-rhythm depend a t least in part on the increased influence of the neocortex on the bioelectrical activity of the hippocampus. In higher mammals, the reticulo-neocortico-hippocampal system may possibly become so dominant that the activity of the hippocampus is maintained desynchronized also at moderate levels of reticular activation.

(B) Neocortical influences of the hippocampal output associated with the 8-rhythm The influence of the hippocampal output, when the &rhythm is observed in the hippocampogram, was detected in the bioelectrical activity of the neocortex of curarized cats. In fact: (i) during the appearance of the hippocampal &rhythm low-frequency recruiting waves depending upon impulses originating in the hippocampus itself wax and wane in the neocorticogram (Corazza and Parmeggiani, 1960a, b); (ii) the amplitude and course of induced neocortical d.c. potential shifts are modified by the hippocampal output during &rhythm (Parmeggiani and Rabini, 1964); and (iii) the nature of the changes in the evoked responses of the auditory and visual cortex which accompany induced arousal reactions depends upon the presence or absence of the hippocampal output associated with the &rhythm (Parmeggiani and Salvatorelli, 1961; Parmeggiani, 1962b, c). (i) Hippocampal &rhythm and neocortical low-frequency recruiting waves. The effects upon the bioelectrical activity of the hippocampus and neocortex (monopolar recording technique) elicited by repetitive electrical stimulation (4-20-1 OO/sec, 1 msec, 0.5-3 V) of the sciatic nerve were investigated, and the following evidence was assembled: ( a ) With variable latency (0.1 to 15 sec) with respect to the beginning of the hippocampal synchronization (@-rhythm)the neocortical recordings show, besides the fast activity typical for the arousal reaction, a rhythm of low-frequency waves (Figs. 5 , 6 and 7) increasing in voltage (100-200 pV, 2-5/sec), and often subjected to regular variations in amplitude (waxing and waning); (b) It may be inferred that the neocortical low-frequency waves are local in origin and not due to physical spread of hippocampal events, because of the above-mentioned latency (Fig. 8), and because the waves are suppressed by neocortical cooling (Fig. 9) and strongly depressed by topical application of cocaine; (c) Furthermore, coagulation experiments (Fig. 10) of rhinencephalic structures (septum, fornix and mammillo-thalamic tracts) and of non-specific thalamic nuclei show that the neocortical low-frequency waves related to the &rhythm depend upon impulses fired by the hippocampus itself and that thalamic non-specific nuclei are involved in the origin of such waves. The same phenomenon that is observed in curarized cats (i.e. $-waves in the hippocampogram and low-frequency waves in the neocortical recordings) could also be proved to occur in unrestrained cats, in attentive or excited wakefulness and particularly during activated sleep (low-voltage fast EEG phase of sleep). In such conditions, on a background of fast activity, both the neocortical recordings and the leads from subcortical structures show low-frequency (4-6/sec) waves (Figs. 11 and 12). Discrete References p. 438-441

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septa1 lesions, preventing the &rhythm from appearing in the hippocampogram, also suppress the neocortical and subcortical low-frequency waves. It is interesting to note that, if one accepts the oneiric correlate of activated sleep (Aserinsky and Kleitman, 1955; Dement and Kleitman, 1957a, b; Dement, 1958), one might infer that the appearance of the hippocampal &rhythm and of archicortically-induced low-frequency waves in neocortical and subcortical recordings during this phase of sleep reveals the

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importance of the archicortical component (affective, visceral) in the activity of the dreaming brain. In summary, these results support the hypothesis that the hippocampal &rhythm is related to a synchronizing hippocampal influence which counteracts the desynchronizing effects of the reticular activating system on the activity of neocortical and subcortical structures. (ii) Hippocampal &rhythm and induced neocortical d.c. potential shifts. The neocortical d.c. potential shifts elicited by sciatic stimulation (&2&100/sec, 1 msec, 0.5-3 V) were studied both before and after the appearance of the hippocampal &rhythm was prevented by means of septa1 coagulation. The results can be summarized by References p. 438441

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Fig. 9. Effects exerted by topical cooling of the neocortex on the low-frequency waves elicited by repetitive electrical stimulation of the sciaticnerve. Unanesthetized, curarized cat. The temperature of the right occipital neocortex was reduced from 37 to 29". Note the effects of sciatic stimulation (100/sec, 1 msec, 1 V) after cooling: the rhythm of low-frequency waves is absent in the lead from the cooled neocortical area. (From Corazza and Parmeggiani, 1960b.)

stating that: (a) in the normal animal sciatic stimulation elicits surface-negative shifts (0.15-1 mV, 10-100 sec) of the neocortical d.c. potential; and (b) after septal coagulation the shiftselicited by the same stimuli are smaller in amplitude (20-60 %) than before the septal lesion (Fig. 13). This depression of the negative shifts does not depend upon variations of the effects of sciatic stimulation on the systemic arterial pressure, but appears to be related to the suppression of the hippocampal &rhythm as a consequence of septal coagulation. These results further support the hypothesis that during &rhythm the hippocampal output consistently influences the neocortical activity. (iii) Hippocampal 8-rhythm and neocortical evoked responses. The influence on the responsiveness of the primary auditory area exerted by repetitive electrical stimulation (100/sec, 1 msec, 0.5-3 V) of the sciatic nerve has been investigated. During and after the nerve stimulation the first positive component of the auditory responses to clicks is depressed, whereas the second positive (cf. Goldstein et al., 1959; Cenacchi and Par-

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Fig. 10. Effects exerted on the bioelectrical activity of the hippocampus and neocortex by repetitive electrical stimulation of the sciatic nerve before and after coagulation of rhinencephalic structures. Unanesthetized, curarized cat. In A, sciatic stimulation (20/sec, 1 msec, 2 V) beforecoagulation. InB, histological sections (Nissl staining) showing the lesions produced by coagulation of the basal region of the septum. In C , sciatic stimulation (20/sec, 1 msec, 3 V) after coagulation. Note that after coagulation both the hippocampal 8-rhythm and the neocortical low-frequency waves are absent. (From Corazza and Parmeggiani, 1960b.)

meggiani, 1962, 1963) and the main negative components are enhanced. In such experimental conditions the sciatic stimulation does not depress in toto the auditory response to receptor stimulation (cf. also Bremer et al., 1960; Steriade and Demetrescu, 1962), as has been observed by others (Bremer and Bonnet, 1950; Gauthier et al., References p . 438-441

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Fig. 11. Bioelectrical activity of cortical and subcorticalstructuresin the cat during relaxed or excited wakefulness. Unanesthetized, unrestrained cat. In A, the animal is relaxed at the beginning of the recording period, and becomes attentive towards the end. During the relaxed state, note: absence of h a v e s , lower frequency of neocortical activity, and spindle-like envelopes. Durhg the attentive state, note: clear-cut hippocampal &rhythm, low-frequency waves in central gray, subthalamus,parietal and occipital leads, and higher frequency of neocortical activity. In B, the animal is very excited and mewing. Note the hippocampal @-rhythmand low-frequency waves in subcortical and neocortical recordings. F, frontal; P, parietal; 0, occipital; CG, substantia grisea centralis; Ht, hypothalamus; Hp, hippocampus dorsalis; St, subthalamus. (From Parmeggiani and Zanocco, 1963.)

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1956; Desmedt and La Grutta, 1957; Bremer and Stoupel, 1958, 1959; Bremer et ul., 1960). The observed changes are not only due to the ascending influences of the reticular system, as pointed out by many authors (Bremer and Stoupel, 1958, 1959; Dumont and Dell, 1958,1960; Bremer et al., 1960; Steriade and Demetrescu, 1962; Demetrescu et ul., 1965), but also to hippocampal influences effective when the 0-rhythm appears

in the hippocampogram. In fact, as soon as the 8-rhythm resulting from sciatic stimulation is prevented from appearing by coagulating the septum, the auditory responses are no longer modified by sciatic stimulation as they had been before the septa1lesion. Furthermore, the second positive and the main negative components of the response

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425

Fig. 13. Effects of septal coagulation on neocortical d.c. potential shifts elicited by sciatic stimulation. Unanesthetized, curarized cat. Upper tracings in A, B, D, E show surface-negative shifts (upward deflections) elicited by sciatic stimulation, and lower tracings respectively show the effects of sciatic stimulation on hippocampal activity (A, D) and systemic arterial pressure (B, E). The tracings of A and B refer to the intact animal; those of D and E were recorded after septal coagulation. The nerve stimulation (4/sec, 1 msec, 1 V) is marked by the line at the bottom of the tracings. In C, a histological section is reproduced (Nissl staining) to illustrate the location and the extent of the coagulation in the septum of this animal. Note the depression of the d.c. shifts after coagulation. (From Parmeggiani and Rabini, 1964.)

appear depressed (Figs. 14 and 15). The nature of the changes induced in the auditory responses by the hippocampal output during the &rhythm shows that this output has modified the activity of neocortical inhibitory and excitatory circuits (Cenacchi and Parmeggiani, 1963). Other experiments have shown that the neocortical responses to photic stimuli are enhanced by the hippocampal output during the appearance of the 8-rhythm (Parmeggiani, 1962~). In summary, the accumulated evidence indicates that impulses from the hippocampus intervene in the regulation of sensory mechanisms. It is, therefore, significant that the 0-rhythm appears in the hippocampogram during the orientation reaction (Grastyhn et al., 1959; RadulovaEki and Adey, 1965), conditioning (Grastyan et al., 1959) and approach behavior (Holmes and Adey, 1960; Adey, 1961;Grastykn et al., 1965). Moreover, among other factors, the effects of the hippocampal output during the 0-rhythm should also be taken into account to explain the nature of the changes in the evoked neocortical and thalamic responses occurring in arousal and activated sleep. (cf. Jouvet, 1962; Cordeau et al., 1965; Favale et al., 1965; Rossi et al., 1965). ( C ) Thalamic influences exerted by the hippocampal output during low-frequency stimulation of the hippocampus dorsalis The indirect evidence of the hippocampal influences on the neocortex, as shown previously by the modification of various kinds of neocortical activity during the appearance of the hippocampal &rhythm, made it appear profitable to study the subcortical mechanisms involved. To provide information about this problem, the effects exerted by repetitive electrical stimulation (2-5/sec, 0.5 msec, 2-12 V) of the hippocampus dorsalis on thalamic unit activity were studied on curarized cats (Manzoni and Parmeggiani, 1964a, 1965). The frequency of repetitive stimulation was chosen within the range of the rhythm References p.^438-441

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Fig. 15. Schematic representation of the variations elicited in the components of the primary auditory responses by repetitive electrical stimulation of the sciatic nerve before and after septal coagulation. Unanesthetized, curarized cat. Variations in amplitude of the first positive, second positive and negative components of the response, as calculated before (A, B, and C respectively)and after (A1, B1, and CI respectively) septal coagulation, are compared with the mean amplitude of each component. The mean amplitude is calculated from 12 responses recorded immediately before the sciatic sthulation, and is shown in each graph by the horizontal heavy line, the two broken lines giving the standard deviation. The segments on the abscissa indicate the periods during which three auditory responses were recorded, the time being computed from the beginning of sciatic stimulation. Such a stimulation is marked by the segment with two arrows. For each group of three responses, the mean amplitude of each component is plotted in the proper graph as a filled circle, the standard deviation being given by the vertical bar. (From Parmeggiani, 1962b.)

observed for the 6-waves in order to evaluate the driving power of the hippocampal output at physiological levels of activity. It is worth while recalling that bursts of hippocampal unit activity are associated with such waves, a condition that would be similar to that realized artificially in the present research by repetitive low-frequency stimulation of the hippocampus. References p . 438441

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Fig. 16. Hippocampal influence on the activity of thalamic neurones. Unanesthetized, curarized cats. In A-E, responses to stimulation of the left hippocampus dorsalis (A, B, 8 V; C, 10 V; D, DI, Dz, 6 V; E, El, 8 V) recorded respectively from the n. lateralis dorsalis (A, B) and the n. anterior ventralis (C, D, D1, D2, E, El) of the left-side thalamus. Note that in B, upper tracing shows the response recorded from the right hippocampus dorsalis and lower tracing the response from the n. lateralis dorsalis; D, D1 and Dz, were recorded respectively at the beginning, during and at the end of hippocampal stirnulation; E and El are a continuous sequence. In F, the left column shows seizure waves of the right hippocampus dorsalis, and the right column the unit activity recorded simultaneously from the n. anterior ventralis of the left-side thalamus. In all tracings, upward deflections indicate negativity of active electrode. For further explanation see text. (From Manzoni and Parmeggiani, 1964a.)

Unit responses to repetitive hippocampal stimulation have been recorded thus far from the following ipsilateral thalamic nuclei : anterior ventralis, anterior medialis, ventralis anterior, medialis dorsalis, paracentralis, centralis lateralis, lateralis dorsalis and habenularis. Two principal types of response were observed. (i) Each shock delivered to the hippocampus elicits a triphasic or diphasic wave on

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which a unit response is often superimposed as a burst (20&500/sec) of spikes (0.3-1.2 mV). The unit responses often wax and wane* or completely disappear during the stimulation period (Fig. 16). The latency of the first spike of the burst is variable and ranges from 6 to 72 msec**. (ii) Hippocampal stimulation influences the unit activity in the thalamus in such a way that random spikes (0.3-1.2 mV) become grouped in bursts (200-400/sec), and/or previously silent neurones are recruited (Fig. 16). The latency of the first spike of the bursts described ranges from 5 to 160 msec**. Concerning the functional relationship between the hippocampus and the previously mentioned nuclei of the thalamus, some other data deserve mention. During hippocampal seizures induced by repetitive electrical stimulation at higher frequency (loo/ sec, 0.5 msec, 2-12 V) of the ipsilateral hippocampus, each hippocampal seizure-wave is seen to be related to a burst of thalamic unit activity (Fig. 16). If the seizure spreads to the thalamus itself, then each hippocampal spike and wave complex is associated with a spike and wave complex in the thalamus. In our experimental conditions the hippocampal output is able to induce rhythmic variations in the activity of thalamic neurones. Besides the nuclei of the anterior group (see also Green and Adey, 1956; Adey et al., 1958; Cazard, 1963), many others are affected by hippocampal stimulation (see also Green and Adey, 1956; Adey et al., 1958). Therefore, not only the neurones which underlie the regulation of the activity of the gyrus cinguli, but also those projecting to other neocortical regions are influenced by the hippocampus. It follows, finally, that the cortical fields of projection of such thalamic neurones must in turn be affected by the hippocampal output. The hippocampal control of cortical neurones has already been proved for units of the gyrus cinguli (Manzoni and Parmeggiani, 1964b), whereas for other neocortical areas only indirect evidence suggests that a similar condition exists (Green and Morin, 1953; Elul, 1964). As far as the hippocampal &rhythm is concerned, the nature of the thalamic responses to repetitive hippocampal stimulation studied in the present research allows one to propose that a periodical activation of the non-specific nuclei of the thalamus underlies the rhythms of low-frequency recruiting waves which appear in the neocortical recordings during the hippocampal &rhythm (cf. Bi, p. 419). Since, as previously shown, such neocortical waves depend on impulses fired by the hippocampus, there is good reason to relate these impulses with the rhythmic bursts of hippocampal unit activity associated with the 0-waves (Arduini and Pompeiano, 1955; Green and Machne, 1955; Green et al., 1960, 1961 ; Fujita and Sato, 1964). All this, in electrophysiological terms, means that the hippocampal action during the appearance of the hippocampal &rhythm is a synchronizing one (Corazza and Parmeggiani, 1960a, b). A hippocampal rhythmic activation of the thalamic non-specific nuclei may also explain the fact that the neocortical low-frequency recruiting waves (cf. Bi, p. 419) and the

* Referring to the number of spikes of the unit response. ** The actual latency figures for each nucleus explored are given in Table I of the original paper

(Manzoni and Parmeggiani, 1965). References p. 438441

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components of the neocortical evoked responses that are modified during the appearance of the hippocampal 6-rhythm (cJ Biii, p. 422), depend on the activity of the superficial layers of the neocortex (Corazza and Parmeggiani, 1960b; Cenacchi and Parmeggiani, 1963), where the non-specific afferents terminate. Finally, the data concerning the neocortical d.c. shifts (cf. Bii, p. 421) may fit into this line of thinking in so far as dendritic mechanisms may underlie their origin (Brookhart et al., 1958;Caspers, 1959; O'Leary and Goldring, 1964). ( D ) Interaction phenomena appearing at the thalamic level between hippocampal and reticular influences

The study of the interaction between hippocampal and reticular influences (Manzoni and Parmeggiani, 1964b, 1965) was performed because of the working hypothesis that the hippocampus operates in opposition to the reticular activating system during the appearance of the &rhythm. The effects of contemporary hippocampal and sciatic repetitive stimulation were studied in some of those thalamic nuclei where the discharge was previously seen to be modified or elicited by hippocampal stimulation (cf. C, p. 425). The stimulation of the sciatic nerve (20-100/sec, 1 msec, 0.5-3 V) was preferred to the direct stimulation of the midbrain reticular formation with the view of achieving a more physiologicalactivation of the ascending reticular system. The results obtained under such experimental conditions can be grouped as follows. (i) The unit responses elicited by low-frequency stimulation of the hippocampus dorsalis in the nuclei anterior ventralis (Fig. 17), lateralis dorsalis and medialis dorsalis are not consistently modified during contemporary sciatic stimulation. Sometimes a moderate enhancement of the unit responses to hippocampal stimulation can be observed during and for a few seconds after the sciatic stimulation. (ii) Stimulation of the sciatic nerve resulted in the depression or abolition of the unit responses to contemporary low-frequency hippocampal stimulation in the nuclei ventralis anterior (Fig. 18), centralis lateralis and sometimes in the nucleus medialis dorsalis. This study has shown that the thalamic limbic pathway to the gyrus cinguli is relatively independent from any reticular control and therefore is able to convey to this cortex patterns of activity that closely resemble those of the hippocampal output. The conditions do exist for the reactivation of the hippocampus via the gyrus cinguli (cf. Brodal, 1947; Adey, 1959): so a circuit is closed which is capable of carrying and maintaining stable patterns of activity. Also the projections of the nuclei dorsalis lateralis, and in part medialis dorsalis, are not subjected to apparent reticular influence. On the contrary, as far as the nuclei ventralis anterior, centralis lateralis, and in part medialis dorsalis are concerned, the hippocampal effects interact with those of the ascending reticular system. In this event it must be assumed that at the subcortical level integration phenomena might already occur, and that the hippocampal influence on the neocortex could in turn be modulated or suppressed outright by the reticular system.

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Fig. 17. Interaction phenomena between the effects of contemporary hippocampal and sciatic stimulation appearing at the thalamic level. Unanesthetized, curarized cat. In A-Az, responses of the n. anterior ventralis to repetitive stirnulation (5/sec, 0.5 msec, 4 V) of the left hippocampus dorsalis respectively before (A), during (A1) and after (Az) repetitive stimulation (20/sec, 1 msec, 2V) of the sciatic nerve. Dots indicate the beginning and the end of sciatic stimulation. Note that during sciatic stimulation the unit responses are not depressed. (From Manzoni and Parmeggiani, 1965.) References p. 438441

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Fig. 18. Interaction phenomena between the effects of contemporary hippocampalandsciaticstimulation appearing a t the thalamic level. Unanesthetized, curarized cat. In A-A4, responses of the n. ventralis anterior to repetitive stirnulation (5/sec, 0.5 msec, 8 V) of the left hippocampus dorsalis respectively before (A), during (A1 and As) and after (A3, 11 sec; A4, 20 sec) repetitive stimulation (2O/sec, 1msec, 2V) of thesciaticnerve. Dotsindicatethebeginningandtheend of sciaticstimulation; A1 and A2 are a continuous sequence. Note that during and after sciatic stimulation the unit responses are markedly depressed. (From Manzoni and Parmeggiani, 1965.)

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(E) Behavioral eflects of the suppression of the hippocampal @rhythm The behavioral implications of the working hypothesis were studied by experiments performed on unrestrained cats before and after discreteseptalcoagulation suppressing the hippocampal @rhythm (Parmeggiani and Zanocco, 1963; Lena and Parmeggiani, 1964). After such lesion (cf. also Brady and Nauta, 1953, 1955; Green and Arduini, 1954; Harrison and Lyon, 1957; King, 1958; Brugge, 1965; Nielson et al., 1965) the waking behavior of the animal is scarcely modified at all. However, it is noteworthy that certain environmental situations or stimuli, which do not seem to annoy a normal cat, can irritate one with a septal lesion. In fact, a certain hyper-reactivity is visible in its relations with the experimenter and with other cats, towards which it often adopts a rather aggressive attitude. At times it may be no less docile than any normal cat, provided it is treated gently, since the aggressive behavior is always in reply to stimuli and is short-lived. However, the fact that such stimuli are usually insufficient to trigger off a reaction in the cat before coagulation of the septum, must certainly be given considerable weight. When placed in the experimental cage in the non-soundproof room the animal remains motionless, and gives the impression of being apprehensive and of encountering some difficulty in curling up and in falling asleep. Once asleep, the slow-wave EEG phase is less frequently followed by activated sleep, than it was in the same animal and environmental situation before the septal coagulation. It can be observed that the cat wakes up suddenly during the flattening of the EMG, instead of entering the activated sleep phase. If activated sleep develops, it lasts in general for a shorter period of time than jn the normal animal. During activated sleep there is always desynchronized activity in the hippocampogram and never &rhythm patterns. Low-frequency waves are also no longer apparent either in neocortical or subcortical recordings, which only show low-voltage fast waves. The EMG of the neck muscles appears flat. In factual terms, after the septal lesion, the average number and mean total duration of the activated sleep phases recorded during each standard session fall approximately to 60 % of the average values observed before septal coagulation (Fig. 19). As to the results yielded by the experimental sessions in a soundproof room, their evaluation shows that in such conditions the effects of septal lesions on activated sleep are generally less clear-cut than when the animal is not shielded, or in certain conditions completely fail to appear. As regards the effects on waking behavior of septal lesions preventing the &rhythm from appearing in the hippocampogram, these observations incline one to the view that the hippocampal mechanism related to the &rhythm, and operating as a negative feedback with respect to the reticular activating system, might be important above all in relation to the control of the reactivity to environmental stimuli. It would seem that such a feedback improves the animal's adaptation to its surroundings and favors the appearance of behavioral patterns of trophotropic* character (Parmeggiani, 1960; cf. also MacLean, 1958a, b). Actually, it is well known that sleep has a particularly important role among such patterns. One may note in this connection that the animal

*

This term is used according to the concepts developed by Hess (1948, 1949).

References p . 438441

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Fig. 19. Effects of septal coagulation on activated sleep. Unanesthetized, unrestrained cat. In A and C , bioelectrical patterns of activated sleep before and after coagulation respectively. In B, histological section showing extent and location ofthecoagulation. In D, the first group ofhistograms refers to the average number of activated sleep phases per session (frequency), and the second one to their mean total duration per session (duration). In both groups the first histogram (a) refers to average values (equated to 100) before coagulation, the second one (b) to average values (percentage of a) after coagulation. Vertical bars indicate standard error. Lettering is as follows: P, parietal; 0, occipital; RHp, right hippocampus; LHp, left hippocampus; EMG, electrogram of the neck muscles. Note that after coagulation the hippocampal 0-rhythm is suppressed and that both frequency and duration of activated sleep phases are markedly reduced. (From Lena and Parmeggiani, 1964.)

with a septal lesion is less likely to curl up than the normal one. This observation agrees with the results of recent research, attributing to the hippocampus a pre-eminent function in the preparatory phase of sleep (Parmeggiani, 1959, 1960, 1962a). The fact that septal coagulation, which suppresses the hippocampal &rhythm, is followed by a consistent reduction both in the average number and in the mean total duration of the periods of activated sleep during sessions of standard duration in cats placed in the non-soundproof room, seems to indicate that the hippocampus stabilizes and maintains this phase of sleep when its bioelectrical activity is characterized by the

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&rhythm. In the normal animal the increased reticular activity during the phase of activated sleep (Parmeggiani and Zanocco, 1963) would be counterbalanced by the opposite action of the hippocampus, while such action would be absent or depressed in the animal with the septal lesion. On the other hand, it is noteworthy that in the soundproof room the reduction in the average number of phases of activated sleep and in their mean total duration per session as a result of the septal lesion may be less pronounced or absent altogether. On the basis of the foregoing results it seems justifiable to conclude that the imbalance of the central regulating mechanism, due to suppression of the hippocampal feedback after septal coagulation, is practically latent both in the waking state and in activated sleep if adequate stimuli are not present to reveal it.

( F ) Behavioral effects of repetitive electrical stimulation of the hippocampus dorsalis, the Jimbria and the fornix The very complex results of this study are only briefly summarized here to show that, in the unrestrained cat, discrete activation of the hippocampus dorsalis can elicit behavioral responses as significant as those observed during hippocampal seizures. The experiments were performed by means of the Hess technique (1932). Electrical stimulation was carried out using delayed condenser discharges with a rising phase of 10 msec duration (Wyss, 1950). The reader is referred to the original papers for more details on technique and results (Parmeggiani, 1959, 1960). The nature of the behavioral effects of repetitive stimulation of the hippocampus dorsalis, the fimbria and the fornix is strictly dependent on the stimulation intensity. (i) With low intensity (0.2-2 V, depending on the frequency u s e d 4 or 8.5/sec) a wide spectrum of reactions is obtained such as: orientation reactions, motor activity to change the position of the body, vegetative responses as salivation, protrusion of the nictitating membranes, mydriasis, increase in the respiratory rate etc., as well as somatomotor patterns of trophotropic character (grooming, scratching etc.) or related to sleep behavior (stretching, yawning, rolling up) and to affective behavior (mewing, purring, friendliness,apprehension, restlessness etc.). The responses that are components of the sleep behavior may appear isolated or in a well defined sequence which gives way to sleep. In general, the stimulation effects previously described are variably combined together in patterns changing from stimulation to stimulation and from animal to animal. The resulting global behavior appears, however, very natural. (ii) Strong stimulation (1-3 V, depending on the frequency used-8.5-17/sec) elicits a stereotyped response which is initially characterized by arousal followed by an arrest reaction and successively by a relatively constant sequence of many of the effects obtainable at random with low-intensity stimulation. There is no reason to go into the details of this response, because it is evidently the result of a hippocampal seizure (cf. also MacLean, 1957). The behavioral effects of low-frequency, low-intensity stimulation of the hippocampus dorsalis, the fimbria and the fornix show that during discrete rhythmic activation of these structures, similar to that occurring with the &rhythm, the hippocampal References p. 438-441

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output can also elicit significant responses in the somatic, vegetative and affective spheres. Because these responses are organized into variable patterns of global behavior, a goal-directed and integrative activity of the hippocampus seems to underlie the expressiveness of the behavior. CONCLUSIONS

On the basis of the preceding review of experimental data and related discussion, it is now possible to present a unitary view on some aspects of the functional significance of the hippocampal &rhythm. This effort can be considered valuable only within the limits of a working hypothesis stimulating research to prove or to reject it. The bioelectrical activity of the hippocampus is regulated by at least two afferent non-specific systems, the one synchronizing (0-rhythm), the other desynchronizing. In the rabbit, a tonic prevalence of the first is observed, whereas in the cat the effects of' the two systems appear to be in balance. In higher mammals, the condition of equilibrium is lost in favor of the desynchronizing system, which prevails tonically. This reversal in the influence of the two afferent systems seems to be related to the development of the neocortex. As far as concerns the cat, the animal providing the experimental evidence, some further conclusions can be drawn. The appearance of the 0-rhythm in the hippocampogram depends on a moderate level of reticular activation (Fig. 20). In this condition the hippocampal output elicits a rhythmic firing of subcortical neurones. Via the anterior thalamic nuclei and the

Fig. 20. Schematic drawing illustrating some of the functional relations discussed in the text. CA, commissura anterior; CC, corpus callosum; CM, corpus mammillare; CS, colliculus superior; FR, formatio reticularis; GC, gyrus cinguli; HB, habenula; HP, hippocampus; PO, pons; SGC, substantia grisea centralis; SP, septum; TH, thalamus.

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gyrus cinguli a hippocampo-hippocampal circuit is closed, and reactivation of the hippocampus at the same rate is quite possible. This circuit as well as the other thalamo-neocortical circuits of the nuclei lateralis dorsalis and in part medialis dorsalis are not consistently affected by the ascending influences of the activating reticular formation. It follows that the hippocampal influences can reach without interference the neocortical neurones of the corresponding projection areas. On the contrary, at the level of the nuclei of the non-specific thalamo-neocortical system, such as the nuclei ventralis anterior, paracentralis, and centralis lateralis, the effects of the hippocampal output during the &rhythm could be depressed or suppressed outright by the reticular influences. Probably this does not happen in conditions of moderate reticular activation, because the hippocampal effects appear at the neocortical level also in the realm of the projections of the thalamic non-specific system. In fact, under the hippocampal influence, low-frequency recruiting waves appear in the neocorticogram, and the neocortical d.c. potential and the neocortical evoked responses show impressive changes. The nature of the changes in the evoked responses shows that the activity of neocortical inhibitory and excitatory mechanisms is modified : sensorial, perceptual and possibly mnemonic processes may in turn be affected by the hippocampal output. In conditions of moderate arousal the hippocampal output during the appearance of the &rhythm has enough driving power taexert definite control on the bioelectrical activity of subcortical and neocortical structures. In terms of behavior a central tendency is translated into behavioral patterns of hippocampal type which are directed to improve the animal's adaptation to its surroundings and to fulfil trophotropic goals. The &rhythm appears, therefore, as the bioelectrical correlate of a hippocampal negative feedback regulating and counterbalancing the effects of the reticular activating system and related ergotropic mechanisms. On the other hand, in conditions of strong reticular activation, the hippocampal desynchronization betrays an increased dominance of the ergotropic mechanisms. However, as soon as the level of reticular activation drops, the hippocampal &rhythm may appear as a rebound effect, giving way to the bioelectrical changes in the activity of subcortical and neocortical structures and to the behavioral patterns mentioned above. It is evident that the preceding considerations cannot be directly extended to higher mammals. The emphasis for regulation is now shifted from the hippocampus to the neocortex. The depression or suppression of the hippocampal &rhythm does not necessarily mean that the hippocampus has lost or basically changed its functional significance. The hippocampal action may only become more discrete and modulated. In conditions of normal or pathological synchronization of the hippocampal activity, however, the hippocampus may again acquire the relevant driving power lost through the development of the neocortex and may, therefore, elicit bioelectrical and behavioral effects, and possibly related contents of consciousness, revealing similarities with those appearing in lower mammals.

As has happened in the past, we are once again obliged to recognize the scholarly foresight of C. J. Herrick who proposed many of these functional relations hypothetically in 1933. References p . 438-441

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This work was supported by grants from the Consiglio Nazionale delle Ricerche (Rome, Italy) and the SchweizerischenNationalfond zur Forderung der wissenschaftlichen Forschung (Bern, Switzerland).

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