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Do septal neurons pace the hippocampal theta rhythm?
Do septalneuronspace the hippocampaltheta rhythm? Mark Stewart and Steven E. Fox The hippocampal theta rhythm (rhythmical slow activity, RSA)is one of the most thoroughly studied EE5 phenomena. Much of this expenmental interest has been stimulated by suggestions that the mnemonic functions of the hippocampus may depend upon thetarelated neuronal activity. Inputs from the medial septa/ nuclei to the hippocampus were shown to be essenbalfor the theta rhythm in the 1950s, but the role of these basal forebrain projections has not been dearly defined. Four models of the septo-hippocampal connections involved in theta rhythm production are reviewed as the precise roles of these projections are discussed. In our final, consolidated model both cholinergicand 5ABAergic septa/projection cellsfire in rhythmic bursts that entrain hippocampal intemeurons. The resu/b'ngrhythmic inhibition of hippocampal projection cells, together with their excitatory interconnections, generatesat least one component of the theta rhythm.
Types of hippocampaltheta rhythm
Mark Stewartand The theta rhythm or rhythmical slow activity StevenE.Foxare at (RSA) has been studied in a number of non-primate the Departmentof species, including rodents, rabbits and carnivores. In PhysioloD,,State of New rats and rabbits, Vanderwolf and co-workers dis- University York, HealthScience tinguished two types of behavior during which this Center,Brooklyn,NY 4-10 Hz hippocampal slow wave can be recorded 112O3,USA. (reviewed in Refs 8, 9). The theta rhythm associated with certain movements of an animal, such as walking, rearing and struggling 1°, is apparently resistant to extremely large doses of muscarinic cholinergic receptor antagonists (atropine sulfate, 25-50 mg/kg i.p.) 11 or to cholinergic depletion 12. In contrast, the theta rhythm sometimes present during immobility is apparently abolished by similarly large doses of atropine or scopolamine 9,11. This atropine-sensitive theta activity also occurs spontaneously during urethane or ether anesthesia11. While theta activity recorded during periods of immobility or in anesthetized animals appears to be solely atropine-sensitive, movement-correlated theta rhythm actually comprises both atropineresistant and atropine-sensitive components 13. In this review, we will refer to the theta rhythm in terms of its atropine sensitivity or resistance whenever the distinction is clearly necessary. The hippocampus is one of several limbic cortical structures that is considered to be a generator of the theta rhythm. A brain region is considered a generator of a field potential such as the EEG if the transmembrane currents flowing through cells of that region sum to produce extracellular field potentials that can be recorded with macroelectrodes. Various experimental techniques have identified contributions to the hippocampal theta rhythm from the entorhinal cortices, hippocampal cornmissural and associational projections, and several subcortical regions ~4. The medial septal nuclei appear to be particularly important for the generation of the
Over 30 years ago, Scoville and Milner ~,2 reported a 'very grave recent memory loss' in patient HM, who had undergone a bilateral temporal lobectomy for the treatment of his epilepsy. Since then, the hippocampus has been the object of studies on many levels, from membrane channels to human behavior, in an effort to understand its presumed function in learning and memory and its common dysfunction in temporal lobe epilepsy. In the same year as Scoville's initial observations on HM, Green and Arduini 3 described rhythmic hippocampal electroencephalographic (EEG) activity in animals (Fig. 1). The 'synchronized' hippocampal activity, known as the 'theta rhythm', occurred simultaneously with 'desynchronized' neocortical EEG and 'arousal'. In addition to the theta rhythm being one of the largest amplitude EEG signals known, theta-related neuronal activity appears to be essential for the normal functioning of the hippocampus in many animal species. Manipulations that abolish the hippocampal theta rhythm in experimental animals produce behavioral impairments that are very similar to the impairments seen after lesions of the hippocampus itself 4-7. Efforts to determine the mechanisms underlying the generation of the hippocampal theta rhythm, important for an understanding of the EEG in general, could provide critical insights into the normal mnemonic functioning of the hippocampus as well as the pathological synchrony of epilepsy. Recent anatomical and electrophysiological findings regarding the cholinergic and GABAergic Fig. 1. Hippocampal theta rhythm recorded from a walking rat. EEG activity over 3 s is displayed. Top septo-hippocampal projections trace: recording from an electrode just dorsal to the pyramidal cell layer in area CA10.e. basal have led us to re-examine ~he dendritic side). Bottom trace: recording from an electrode located near the hippocampal fissure (i.e. 'pacemaker' role of the septum near the distal apical dendrites). The frequency of this theta activity is about 6.5 Hz. The theta in the production of the hippo- rhythm recorded during other behaviors or in anesthetized animals appears similar, but may have a slightly different frequency. Calibrations: 0.5 mV, 0.5 s. campal theta rhythm. TINS, Vol. 13, No. 5, 1990
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theta rhythm. In their original report, Green and Arduini 3 showed that lesions of the septal nuclei could abolish the hippocarnpal theta rhythm. This result, now replicated with many variations, indicated that the theta rhythm depended upon inputs originating in or passing through the septal nuclei. In 1962, Petsche, Stumpf and Gogol~k 15 recorded rhythmically bursting cells within the medial septal nucleus and the nucleus of the diagonal band (MSN-NDB), and suggested that projections to the hippocarnpus from these cells might directly generate the hippocarnpal theta rhythm 16. Vanderwolf has argued that the medial septal projections to the hippocampus are essential only for the atropine-sensitive component of the theta rhythm and that the atropine-resistant component is dependent upon a second set of hippocarnpal afferents, a serotonergic projection from the raphe nuclei (reviewed in Ref. 9). Identification of the actual roles the subcortical projections play in producing theta rhythm has been a surprisingly challenging endeavor. We will review four models of the medial septal inputs necessary for theta rhythm production to illustrate the development of ideas about the septo-hippocampal connections and their role in the functioning of the hippocampus.
The 'pacemaker' hypotheses The rhythmic activity of MSN-NDB cells (even during the absence of theta-related hippocampal activity) and the profound effects of septal lesions on the theta rhythm led to the suggestion that rhythmic septo-hippocampal projections directly generated the hippocampal theta rhythm. Gogol&k et al. ~6 postulated that the septal inputs ended on pyramidal cells (Fig. 2A), resulting in either rhythmic excitatory postsynaptic potentials in their basal dendrites or in rhythmic inhibitory postsynaptic potentials in their apical dendrites. As described above, this synaptic activity would be directly recorded as the theta rhythm. The term 'pacemaker' became associated with the MSN-NDB, primarily because of the rhythmic activity of septohippocampal neurons and the apparent absence of any ascending inputs to the septal nuclei having rhythmicity at the theta frequency. In spite of the 'pacemaker' label appearing to be completely appropriate, no data existed regarding the excitatory or inhibitory nature of the septal input, or the neuronal targets of this input. The possibility of septal inputs directly generating the theta rhythm lost support when medial septal stimulation failed to evoke any field potential activity, either excitatory or inhibitory, in the hippocampus 17. Buzsaki shifted attention away from the pyramidal and granule cells of the hippocarnpus and onto the interneurons ~8-2°. He reasoned that the septal projection responsible for the atropine-sensitive theta rhythm of urethane-anesthetized rats was an excitatory cholinergic input to the hippocampal interneurons (Fig. 2B). This hypothesis was based primarily on four pieces of data. (1) It appeared, from anatomical evidence, that the massive choli164
nergic septo-hippocampal projection 21,22 might terminate on interneurons 23. (2) Atropine or scopolamine could apparently eliminate the immobilityrelated or anesthesia-induced theta rhythm 9,11. (3) An increased firing rate in inhibitory hippocarnpal interneurons during theta rhythm was accompanied by a decreased firing rate in pyramidal cells19,24,2s. (4) Both pyramidal cells and interneurons discharge in phase with the theta rhythm; however, during atropine-sensitive theta rhythm they fire roughly 180° out of phase with each other (reviewed in Ref. 26). This phase difference, along with the changes in their respective firing rates, indicates that hippocarnpalinterneurons are not driven via the recurrent collaterals of pyramidal cells during atropine-sensitive theta rhythm. Cholinergic excitation of limbic interneurons has been demonstrated in vitro 27,28, is faster, and appears to be a more 'conventional' type of excitation than the well-known cholinergic suppression of pyramidal cell potassium (K+) currents such as the M-current 29,3°. The data listed above favored Buzsaki's hypothesis, even without direct evidence that the rhythmically bursting septal cells were cholinergic. According to his hypothesis, atropine-sensitive theta rhythm would result from the rhythmic excitation of hippocampal interneurons by cholinergic septal neurons. Periodic inhibition of pyramidal and granule cells by interneurons would generate at least a part of the EEG and also serve to synchronize the activity of other hippocampal neurons. Synaptic connections between and among pyramidal and granule cells would contribute to the EEG as well. Two pieces of data showed this hypothesis to be incomplete. A powerful excitatory input onto hippocarnpal interneurons should be detectable with septat stimulation. It was not ~7. In addition, a large fraction of the septo-hippocarnpal projection was found to be GABAergic31,32and clearly identified as terminating on interneurons 33 (cf. Ref. 34). Without strong tonic inhibitory activity to modulate, a disinhibitory action of septal stimulation might not be accompanied by a field potential. Emphasis on this GABAergic input suggests a third possible mechanism for septal production of the theta rhythm: the septal input might organize the activity of hippocampal projection cells via the rhythmic inhibition of hippocarnpal interneurons (Fig. 2C). The resulting synchronous activity throughout the hippocampus would produce the rhythmic EEG.
Our current hypothesis Efforts to account for the existing data, as well as new data from our laboratory, led to a fourth hypothesis. Recently, we found that there are two populations of rhythmically bursting MSN-NDB neurons that project to the hippocarnpus3s. We argued that both the cholinergic and GABAergic septo-hippocampal neurons are rhythmic and 'pace' the hippocarnpal theta rhythm via inputs to hippocampal intemeurons. Just as the inhibitory inputs to interneurons could escape detection with septal stimulation, so could a combination of excitatory and inhibitory inputs to the same cells. TINS, VoL 13, No. 5, 1990
When atropine is given systemically to a urethane-anesthetized rat, the hippocampal theta rhythm is apparently abolished. Under such conditions, recordings from rhythmically bursting MSNNDB cells reveal that some of these septal cells continue to burst rhythmically in the absence of the theta rhythm (atropine-resistant cells), while other cells lose their rhythmicity (atropine-sensitive cells). This is illustrated in Fig. 3. About two-thirds of the population of rhythmically bursting MSN-NDB cells are atropine-resistant while the remainder are atropine-sensitive 3s. Since the atropine-sensitive septal cells are not dependent upon feedback from the hippocampus (see Fig. 3B), blockade of a muscarinic synapse within the s.eptum probably accounts for their loss of rhythmicity. Is the theta rhythm abolished because of atropine's action within the hippocampus (at the terminals of either the atropine-sensitive or the atropine-resistant cells), or because of atropine's action within the septum? Application of atropine to the entire septal nucleus, making an effort to keep it from reaching the hippocampus, reversibly eliminated the hippocampal theta rhythm 3s. This indicated the importance of a septal site of action of atropine, but more importantly, it appeared that the loss of rhythmicity in the atropine-sensitive septal cells was sufficient to abolish the theta rhythm. Attempts to activate antidromically all electrophysiologically defined categories of MSN-NDB cells from the fimbria or fornix were successful only for the two types of rhythmically bursting cells, indicating that the atropine-sensitive and atropine-resistant cells are the principal projection cells of the MSN-NDB 36. The possible transmitter identities of the atropine-resistant and atropine-sensitive septal cells may then be inferred from the results of the septal application of atropine. During the application of atropine to the septum alone, the continued rhythmic input to the hippocampus from the atropine-resistant septal cells was not blocked, yet there was no hippocampal theta rhythm. This result indicates that the atropine-resistant septal cells are not likely to be the cholinergic cells, since their unblocked terminals in the hippocampus would be expected to produce rhythmic field potentials. If, on the other hand, the atropine-resistant MSN-NDB cells are GABAergic, they can account for the small component of the theta rhythm, resistant to high systemic doses of atropine, that was discovered in urethane-anesthetized rats by triggering an average of the hippocampal EEG on the rhythmic bursts of atropine-resistant septal cells37. Working on the assumption that one of the pharmacologically identified cell groups corresponds to one of the histochemically identified cell groups, the data are most consistent with the atropine-resistant cells being GABAergic and the atropine-sensitive cells cholinergic. How can the atropine-sensitive cells be cholinergic when they are the cells affected by atropine? Admittedly, without additional details of the interactions among septal cells, it is difficult to answer this question specifically. Several pieces of data can be TINS, VoL 13, No. 5, 1990
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Fig. 2. Three models of septo-hippocampal connections that might 'pace' the hippocampal theta rhythm. None of the models depicts all of the septal inputs to the hippocampus; only those connections that might pace the theta rhythm are shown. Excitatory endings are represented by open symbols and inhibitory endings by filled symbols. The different shapes reflect different transmitters: open triangles represent cholinergic terminals in all cases except in (A) where the transmitter is not specified; open rectangles are glutamatergic terminals; filled circles are GABAergic terminals. Connections mediating the recurrent inhibition of the pyramidal cell (pyr) by the intemeuron (int) are well established. Only the connections of septum with area CA1 of the hippocampus are illustrated. (A) The direct generation of hippocampal theta rhythm by rhythmic excitatory inputs to the basal dendrites of hippocampal pyramidal cells. This was one mechanism proposed by Gogol~k et al. 16. (B) Rhythmic cholinergic excitation of hippocampal interneurons as proposed by BuzsakiIa-2° This model would produce theta rhythm by rhythmic inhibition of pyramidal cells (via the interneurons) and by the inputs from other hippocampal formation neurons made synchronous by the septal control of intemeurons in those areas. (C) A model similar to (B), except that the rhythmic modulation of hippocampal interneuronal firing is accomplished by a GABAergic projection from the septum 33,34 offered to at least make this notion plausible. The septum appears to be an oscillatory network rather than a collection of independent oscillatory neurons. Spontaneous rhythmic bursting activity, similar to that seen in the intact septum, has been recorded in the deafferented septum 38, but has not been dem165
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J Fig. 3. Simultaneous extracellular recordings from a pair of rhythmically bursting MSN-NDB neurons before and during cooling of the fimbria-fomix and following systemic atropine injection. (A) Control activity in the pair of septal cells and accompanying hippocampal theta rhythm. The rhythmicity of each cell is apparent in the expectation density functions shown to the right. (B) Both cells remain rhythmic after the theta rhythm has been abolished by cooling of the fimbria-fornix, indicating that neither depends upon hippocampal feedback for their rhythmicity. In this example, the firing rates of both cells decreased, in particular that of the cell shown in the middle. Firing rate changes during cooling and after atropine were variable. Note that approximately one-fifth of the number of spikes was analysed for the expectation density functions during coofing. (C) After intravenous injection of atropine sulfate (25 mg/kg), the cell shown in the top trace was confirmed to be atropine-resistant and the cell shown in the middle trace atropine-sensitive. Note that the expectation density function for the atropine-sensitive cell is essentially flat. Calibrations: 0.25 s; 400 #V for top trace of each panel, 800 I~V for middle trace and for hippocampal EEG (bottom trace). Expectation density function binwidth: 10 ms. (Taken, with permission, from Ref. 35.)
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vivo and in septal slices showed that 70-100% of septal neurons could be excited via a muscarinic action of acetylcholine 39,43,44and all cells could be inhibited by GABA39,~4. Without speculating about the details of the mechanism by which atropine might eliminate the rhythmic firing pattern of cholinergic septal neurons, we maintain that postulating atropine-sensitive septal cells to be the cholinergic cells best fits the available data. In our model (Fig. 4), the rhythmic cholinergic projections of atropine-sensitive septal cells end on both pyramidal cells and interneurons. The cholinergic input to pyramidal cells mediates the slow disinhibitory effects of inactivating several K÷ conductances. The cholinergic input to interneurons mediates a more rapid excitation, relaying the rhythmic activity of the septal cells. The rhythmic excitation of hippocampal interneurons is coupled with rhythmic inhibition of the same cells by GABAergic inputs from the atropine-resistant septal cells. Just as the preferred phase of firing for a given septal cell is determined by its interconnections with other excitatory and inhibitory septal cells, so the preferred phase of firing for a hippocampal interneuron is set by firing phases of its excitatory and inhibitory septal inputs. These interconnections make the phase relation between any two cells (septal or hippocampal) extremely stable across isolated epochs of theta activity. Rhythmically driven and modulated by the atropine-sensitive and atropine-resistant septal inputs, hippocampal interneurons generate a portion of the theta rhythm via inhibitory endings on pyramidal and granule cells, and synchronize the activity of cells throughout the hippocampal formation. The rhythmic activity of cells that project to the hippocampus from those areas also contributes synaptic currents that generate other components of the field potentials we call the theta rhythm 14,45,46. While they are consistent with the available data, the two principal features of the model, that both cholinergic and GABAergic septal cells are rhythmic, and that the cholinergic cells are atropine-sensitive and the GABAergic cells atropine-resistant, remain to be tested directly. Strictly speaking, our model applies only to the atropine-sensitive component of the theta rhythm, since the details underlying the production of atropine-resistant theta rhythm are unknown. As mentioned above, a small component of the hippocampal theta rhythm driven by the atropineresistant septal cells could be extracted with spiketriggered averaging from the apparently nonrhythmic hippocampal EEG of the rat, even after nearly lethal doses of atropine (up to 100 mg/kg i.v.) 37. This result is consistent with the possibility that a few of the GABAergic septal fibers end directly on pyramidal cells. Alternatively, this component could arise from the continued rhythmic modulation of interneuronal firing. The presence of a small atropine-resistant component of the urethane-induced theta rhythm suggests that the atropine-resistant septal cells, modulated by a serotonergic projection from the raphe nuclei39,47, might pace the atropineresistant theta rhythm, rather than the raphe acting as a separate 'pacemaker' input to the hippocampus. TINS, VoL 13, No. 5, 1990
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Do septal neurons pace the hippocampal theta rhythm? Each of the four models of the 'pacemaker' mechanism has lacked one piece of data - a demonstration that the hippocampal theta rhythm is dependent upon the rhythmic activity of the septal cells. It is clear that the septal cells are rhythmic and tightly coupled with the theta rhythm, but no one has shown that the septal input must be rhythmic, and not tonic, for a theta rhythm to exist. In fact, oscillations of the theta frequency have been found in hippocampal slices bathed with cholinergic agonists48 as well as in computer-simulated networks of hippocampal cells49. These reduced preparations allow study of the local interactions contributing to rhythmic hippocampal activity at a level that is impossible in intact animals. However, it is clear that these oscillations are not identical to the hippocampal theta rhythm recorded in vivo (e.g. Ref. 50) because the naturally occurring theta rhythm includes the effects of numerous rhythmic and non-rhythmic inputs to the hippocampus, none of which are represented in the reduced preparations. The theta-like oscillations found in the in vitro preparations and computer models do, however, raise an important question regarding the role of the septum: do the septal nuclei act as a 'pacemaker' or as a 'gating device'? The abundant circumstantial data suggest that 'pacemaker' is the more appropriate label, but it must be kept in mind that this has not been proved. The recent discovery of subthreshold Na+-dependent rhythmic activity in layer II stellate cells in slices of entorhinal cortex sl indicates that the intrinsic membrane properties of these cells, like those of hippocampal pyramidal cells~2, can cause them to oscillate within the frequency range of the theta rhythm. However, it should be remembered that theta activity in both the hippocampus and entorhinal cortex is abolished by septal lesions in intact animals (e.g. Refs 3, 6), emphasizing the importance of the septum for the production of the naturally occurring theta rhythm. The role of a pacemaker is to set the frequency and synchronize the oscillations of an entire population of independent oscillators. Evidence in favor of a pacemaker function for the septum, as opposed to a gating function, comes from the observation that high-frequency (e.g. 100 Hz) stimulation of the brainstem afferents to the septum can induce theta rhythm in the hippocampus, but such stimulation of the septum itself cannot; patterning of the septal stimulation at the theta frequency is required (reviewed in Ref. 53). But theta-patterned septal stimulation probably produces synchronous activation of septo-hippocampal projections, fibers of passage, and hippocampo-septal projections. It is unlikely that such activity would induce a physiological hippocampal theta rhythm. It is more likely that this septal stimulation produces a mixture of long-duration field potentials resembling theta rhythm primarily due to the patterning of the stimulation. Similarly, high-frequency stimulation of this mixed population could actually block the gating of the theta rhythm that might otherwise have ~NS, VoL 13, No.~ 1990
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Fig. 4. Proposed connections of rhythmically bursting MSN-NDB neurons with the cells of the hippocampus. Symbols are as described in Fig. 2. Cholinergic and GABAergic projections from the medial septum to the hippocampus have been demonstrated anatomically. We propose that the cholinergic projection cells of the MSN-NDB are rhythmic and atropine-sensitive (as) and that these cells terminate on both pyramidal cells and interneurons. Terminations on pyramidal cells mediate the slow, decreased conductance depolarization of these cells, whereas endings on intemeurons mediate a much faster 'conventional' excitation of the interneurons. We further argue that the GABAergic projection cells of the septum are rhythmic and atropine-resistant (at) and that these cells terminate almost exclusively on intemeurons. Only the connections between septum and area CA I are illustrated. The interconnections between the cholinergic and GABAergic septal cells and the possible GABAergic septal input to the pyramidal cells are not shown. See text for additional details. (Taken, with permission, from Ref. 35.)
occurred with stimulation of a pure population (or subpopulation) of septo°hippocampal fibers. The results of the septal application of atropine that was described earlier also favor a pacemaker role for the MSN-NDB. Although atropine eliminates the rhythmic activity of the atropine-sensitive septal cells, it does not eliminate their activity altogether. The loss of hippocampal theta rhythm after septal application of atropine was attributed to the change in firing pattern, from rhythmic to nonrhythmic, of the atropine-sensitive cells. Although this is precisely the type of experimental data needed to justify the use of a 'pacemaker' label, not enough data exist to rule out completely another interpretation such as a net decrease in firing of the atropine-sensitive cells (hence a net decrease in acetylcholine delivered to the hippocampus). So the question of whether septal neurons act as a pacemaker for the theta rhythm remains open.
The 'function' of the hippocampal theta rhythm An association between the theta rhythm and 'learning' was originally made when surgical manipulations that eliminate the theta rhythm were found to produce behavioral deficits that were similar to the deficits obtained with lesions of the hippocampus itself 4-7. Long-lasting increases in synaptic efficacy can be produced in many cell types with appropriately patterned stimuli (reviewed in Ref. 54), and this phenomenon, called long-term potentiation, is currently a popular model of learning. The association between theta rhythm and 'learning' has been strengthened by reports that the frequency of 167
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Acknowled&ements Thiswork was supportedby National Institutesof Healthgrants NS17095to SEFand N507117 (neurophysiology traininggrant). We thank Dr JamesB. Ranck,Jr for helpful commentson the manuscript.
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the theta rhythm may be optimal for such synaptic enhancement in the hippocampus ~5-57. On the other hand, it is entirely possible that the rhythmic firing of septal and hippocampal neurons associated with the theta rhythm is an epiphenomenon. The theta rhythm might only be indicative of some 'state' change in hippocampal pyramidal and granule cells. For example, the location-specific firing of hippocampal neurons 4,~8 shows a greater spatial signal-to-noise ratio during theta rhythm 59. In addition, sustained potential changes have been found to be associated with the theta rhythm 45,46,6° and the long-lasting actions of acetylcholine on pyramidal cells substantially change the firing properties of these cells 27-3°. The apparent absence of hippocampal theta rhythm from primates (reviewed in Ref. 8) has also contributed to this concern, essentially forcing theta rhythm researchers to consider the inappropriateness of generalizing their data to humans, or to accept that some aspect of the septo-hippocampal system, other than the theta rhythm, is conserved along the evolutionary path to primates. However, recent recordings of theta activity in monkeys have helped to restore the ' r h y t h m ' as the focus of attention 61. This is i m p o r t a n t for t w o reasons. First, it means that experimental effort directed toward understanding the mechanisms of generation of the hippocampal theta rhythm can continue, appropriately, in non-primate mammals such as rats before being extended to monkeys or humans. Second, and more important, the hippocampal theta rhythm of monkeys (and presumably man) may represent a useful physiological indicator of the condition of the cholinergic and non-cholinergic projections from the basal forebrain to the hippocampus and other cortical areas.
Selected references 1 Scoville,w. B. (1954) J. Neurosurg. 11,64-66 2 Scoville, W. B. and Milner, B. (1957) J. Neurol. Neurosurg. Psychiatr 20, 11-21 3 Green, J. D. and Arduini, A. A. (1954) J. Neurophysiol. 17, 533-557 40'Keefe, J. and Nadel, L. (1978) The Hippocampus as a Cognitive Map Oxford University Press 5 Winson, J. (1978) Science 210, 160-163 6 Mitchell, S. J., Rawlins, J. N. P., Steward, O. and Olton, D. S. (1982) J. Neurosci. 2,292-302 7 Squire, L. R. and Zola-Morgan, S. (1988) Trends Neurosci. 11,170-175 8 Robinson, T. E. (1980) Brain Res. Rev. 2, 69-101 9 Vanderwolf, C. H. (1988) int. Rev. Neurobiol. 30, 225-340 10 Vanderwolf, C. H. (1969) EEG Clin. Neurophysiol. 26, 407-418 11 Kramis, R., Vanderwolf, C. H. and Bland, B. H. (1975) Exp. NeuroL 49, 58-85 12 Robinson, T. E. and Green, D. J. (1980) EEG Clin. Neurophysiol. 50,314-323 13 Vanderwolf, C. H. and Leung, L-W. S. (1983) in The Neurobiology of the Hippocampus (Seifert, W., ed.), pp. 275-302, Academic Press 14 Buzsaki, G., Czopf, J., Kondakor, I. and Kellenyi, L. (1986) Brain Res. 365, 125-137 15 Petsche, H., Stumpf, Ch. and Gogol&k, G. (1962) EEG Clin. Neurophysiol. 14,202-211 16 Gogol,ik, G., Stumpf, Ch., Petsche, H. and Sterc, J. (1968) Brain Res. 7,201-207 168
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17 Krnjevi(% K. and Ropert, N. (1982) Neuroscience 7, 2165-2183 18 Buzsaki,G. and Eidelberg, E. (1983) Brain Res. 266, 334-339 19 Buzsaki, G., Leung, L. S. and Vanderwolf, C. H. (1983) Brain Res. Rev. 6, 139-171 20 Buzsaki,G. (1984) Pro&. Neurobiol. 22,131-153 21 Lewis, P. R. and Shute, C. C. D. (1967) Brain90, 521-540 22 Lewis, P. R., Shute, C. C. D. and Silver, A. (1967) J. PhysioL (London) 191,215-224 23 Mosko, S., Lynch, G. and Cotman, C. W. (1973) J. Comp. NeuroL 152, 163-174 24 Ranck,J. B., Jr (1973) Exp. NeuroL 41,461-531 25 Fox, S. E. and Ranck, J. B., Jr (1981) Exp. Brain Res. 41, 399-410 26 Fox, S. E., Wolfson, S. and Ranck, J. B., Jr (1986) Exp. Brain Res. 62,495-508 27 Benardo, L. S. and Prince, D. A. (1982) Brain Res. 249, 315-331 28 McCormick, D. A. and Prince, D. A. (1986) J. Physiol. (London) 375,169-194 29 Halliwell, J. V. and Adams, P. R. (1982) Brain Res. 250, 71-92 30 Madison, D. V., Lancaster, B. and Nicoll, R. A. (1987) J. Neurosci. 7, 733-741 31 K6hler, C., Chan-Palay, V. and Wu, J-Y. (1984) Anat. Embryol. 169, 41-44 32 Peterson, G. M., Williams, L. R., Varon, S. and Gage, F. H. (1987) Neurosci. Lett. 76, 140-144 33 Freund, T. and Antal, M. (1988) Nature336, 170-173 34 Bilkey, D. K. and Goddard, V. G. (1985) Brain Res. 361, 99-106 35 Stewart, M. and Fox, S. E. (1989) J. NeurophysioL 61, 982-993 36 Stewart, M. and Fox, S. E. (1989) Exp. Brain Res. 77, 507-516 37 Stewart, M. and Fox, S. E. (1989) Brain Res. 500, 55-60 38 Vinogradova, O. S., Brazhnik, E. S., Karanov, A. M. and Zhadina, S. D. (1980) Brain Res. 187,353-368 39 Segal,M. (1986)J. Physiol. (London)379,309-330 40 AIvarez de Toledo, G. and L6pez-Barneo, J. (1988) J. PhysioL (London) 396,399-415 41 Griffith, W. H. (1988) J. NeurophysioL 59, 1590-1612 42 Bialowas, J. and Frotscher, M. (1987) J. Comp. NeuroL 259, 298-307 43 Dutar, P., Lamour, Y. and Jobert, A. (1983) Neurosci. Left. 43, 43-47 44 Lamour, Y., Dutar, P. and Jobert, A. (1984) Brain Res. 309, 227-239 45 Fox, S. E. and Stewart, M. (1986) Soc. Neurosci. Abstr. 12, 1527 46 Branka~k, J. and Fox, S. E. (1987) Soc. Neurosci. Abstr. 13, 1331 47 Crunelli, V. and Segal, M. (1985) Neuroscience 15, 47-60 48 Konopacki, J., Maciver, M. B., Bland, B. H. and Roth, S. H. (1987) Brain Res. Bull. 18, 25-27 49 Traub, R. D., Miles, R. and Wong, R. K. S. (1989) Science 243, 1319-1325 50 Konopacki, J., Bland, B. H. and Roth, S. (1987) Brain Res. 417,399-402 51 Alonso, A. and Llin,~s,R. R. (1989) Nature342, 175-177 52 Nefiez, A., Garcia-Austt, E. and BuEo, W., Jr (1987) Brain Res. 416, 289-300 53 Bland, B. H. (1986) Prog. Neurobiol. 26, 1-54 54 Teyler, T. J. and Discenna, P. (1984) Brain Res. Rev. 7, 15-28 55 Larson, J., Wong, D. and Lynch, G. (1986) Brain Res. 368, 347-350 56 Rose, G. M. and Dunwiddie, T. V. (1986) Neurosci. Lett. 69, 244-248 57 Greenstein, Y. J., Pavlides, C. and Winson, J. (1988) Brain Res. 438,331-334 58 Muller, R. U., Kubie, J. L. and Ranck, J. B., Jr (1987) J. Neurosci. 7, 1935-1950 59 Kubie, J. L., Muller, R. U. and Fox, S. E. (1985) in Electrical Activity of the Archicortex (Buzsaki, G. and Vanderwolf, C. H., eds), pp. 221-231, Akademiai Kiado 60 Gerbrandt, L. K. and Fowler, J. R. (1980) Prog. Brain Res. 54, 109-116 61 Stewart, M. and Fox, S. E. (1989) Soc. Neurosci. Abstr. 15, 1250 TINS, Vol. 13, No. 5, 1990
letter Neuroanatomical nomenclature SIR:
We were pleased to read Butcher and Semba's report 'Reassessing the cholinergic basal forebrain: nomenclature schemata and concepts '1. There is a critical need for a stable neuroanatomical nomenclature to convey information between neuroscientists accurately and intelligibly. In some areas of the brain, such as the cortex, there is such a multitude of synonyms that researchers need to use a table of equivalence of the different terms. Unfortunately, N o m i n a A n a t o m i c a 2 does not provide a comprehensive list of terms for
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the nervous system. For example, it lists three amygdaloid nuclei, while de Olmos eta/. 3 recognize 51. The initiative shown by Butcher and Semba and your willingness to publish their work will be welcome to those who find the proliferation of synonyms, and abbreviations thereof, an unnecessary obstacle to understanding. As cartographers, we are at times in the unenviable position of deciding between competing nomenclature schemes. Attention to nomenclature by the primary researchers in the area as well as by editors of journals should assist in arriving at a consensus. It should always be remem-
to
the
editor
bered that sharing nomenclature with others presents no risk of infection by communicative diseases. George Paxino$ Istvan T6rk Schools of Psychologyand Anatomy, The Universityof New South Wales,PC)Box 1, Kensington, NSW,Australia2033.
References 1 Butcher, L. L. and Semba, K. (1989) Trends NeuroscL 12,483-485 2 Anon. (1983) Nomina Anatomica (5th
edfT; 11th International Congress of Anatomists) Williams and Wilkins 3 de OImos, J., Alheid, G. F. and Beltramino, C. A. (1985) in The Rat
Nervous System VoL 1: Forebrain and Midbrain (Paxinos, G., ed.), pp. 223-334, Academic Press
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reviews
Ion condudancesaffectedby 5-HT receptorsubtypesin mammalianneurons Daniel H. Bobker and John T. Williams
5-Hydroxytryptamine (5-HT) has both excitatory and 5-HT caused a hyperpolarization of CA1 hippocampal inhibitory actions in the CNS and PNS. The develop- neurons. 8-OH-DPAT was a weak partial agonist (at ment of new 5-HT ligands has led to the expansion of micromolar concentrations) in one study 7 and an 5-HT receptor subtypes into three categories: 5-HT1, antagonist (at nanomolar concentrations) in the other s 5-HT2 and 5-1-17"3 (Ref 1). Each category has further indicating that there is an absence of 'spare' receptors subdivisions. The literature concerning the biochemical in the hippocampus. Both studies found that the basis of this division has been reviewed recently2. While 5-HT1n-mediated hyperpolarization was a result of an this approach has elucidated many of the pharmaco- increased conductance to potassium (K +) ions. Furlogical properties of 5-HT receptors, it has not addressed thermore, the K + current induced by 5-HT was the question of how 5-HT modulates cell excitability. blocked by pretreatment of the animal with pertussis Physiological studies have confirmed the existence of a toxin. The 5-HT1A receptor has therefore been mul@licity of 5-HT receptors that act through a variety included in the growing list of receptors that cause an of ionic mechanisms. The purpose of this review is to increase in K + conductance mediated by a pertussis summarize what is known of the ionic mechanisms toxin-sensitive G protein 9-n. A 5-HT-mediated hyperpolarization has also been associated with the activation of identified mammalian 5-HT receptor subtypes, as well as some effects of 5-HT reported in neurons of the dorsal raphe 12,13 (Fig. 1A), prepositus hypoglossi14, superior cervical ganglion 15, where the receptor could not be defined. and myenteric plexus TM. Additionally, a 5-HTmediated inhibitory postsynaptic potential (IPSP) has Increase in potassium conductance: 5-HTIA The 5-HTIA receptor has been localized throughout been reported in rat dorsal raphe 12,1s and in guineathe nervous system, with high concentrations in limbic pig prepositus hypoglossiTM neurons. As would be regions and in the dorsal raphe nucleus 3 (Table I). expected for a response mediated by the activation of Interest in this site has developed since the discovery 5-HT~A receptors, these IPSPs were blocked by of the selective 5-HTIA agonist, 8-hydroxy-(2-N,N- nanomolar concentrations of spiperone, prolonged by dipropylamino)-tetraline (8-OH-DPAT) 4. Unfortu- fluoxetine or cocaine (Fig. 1B,C), and reversed nately, in physiological studies, this compound can act polarity at the K + equilibrium potential 12,14,17,18. The as a full agonist, a partial agonist, or an antagonist time-course of the synaptic potential was slow (and depending on the receptor reserve of the tissue. similar in the two preparations), with a 1-2 s duration, Nevertheless, when used at concentrations under and so is comparable to the noradrenergic IPSP 1 ~w and in combination with the antagonist spiperone 5,6, mediated by oc2-adrenoceptors in the locus coeruleus 19 8-OH-DPAT identifies 5-HT~A receptor-mediated and the GABAB-mediated IPSP in the hippocampus 2°. actions. A remaining question concerning the 5-HT1A recepReports from two laboratories demonstrated that tor is the role of adenylate cyclase. Both stimulation of TINS, Vol. 13, No. 5, 1990
© 1990, EPsevieScience r PublishersLtd,(UK) 0166- 2236/90/$02.00
DanielH. Bobkerand John T. Williamsare at the Vollum Institute, Oregon HealthScience University,3181SW SamJacksonPark Road,Portland,OR 97201, USA.
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Types of hippocampaltheta rhythm
Mark Stewartand The theta rhythm or rhythmical slow activity StevenE.Foxare at (RSA) has been studied in a number of non-primate the Departmentof species, including rodents, rabbits and carnivores. In PhysioloD,,State of New rats and rabbits, Vanderwolf and co-workers dis- University York, HealthScience tinguished two types of behavior during which this Center,Brooklyn,NY 4-10 Hz hippocampal slow wave can be recorded 112O3,USA. (reviewed in Refs 8, 9). The theta rhythm associated with certain movements of an animal, such as walking, rearing and struggling 1°, is apparently resistant to extremely large doses of muscarinic cholinergic receptor antagonists (atropine sulfate, 25-50 mg/kg i.p.) 11 or to cholinergic depletion 12. In contrast, the theta rhythm sometimes present during immobility is apparently abolished by similarly large doses of atropine or scopolamine 9,11. This atropine-sensitive theta activity also occurs spontaneously during urethane or ether anesthesia11. While theta activity recorded during periods of immobility or in anesthetized animals appears to be solely atropine-sensitive, movement-correlated theta rhythm actually comprises both atropineresistant and atropine-sensitive components 13. In this review, we will refer to the theta rhythm in terms of its atropine sensitivity or resistance whenever the distinction is clearly necessary. The hippocampus is one of several limbic cortical structures that is considered to be a generator of the theta rhythm. A brain region is considered a generator of a field potential such as the EEG if the transmembrane currents flowing through cells of that region sum to produce extracellular field potentials that can be recorded with macroelectrodes. Various experimental techniques have identified contributions to the hippocampal theta rhythm from the entorhinal cortices, hippocampal cornmissural and associational projections, and several subcortical regions ~4. The medial septal nuclei appear to be particularly important for the generation of the
Over 30 years ago, Scoville and Milner ~,2 reported a 'very grave recent memory loss' in patient HM, who had undergone a bilateral temporal lobectomy for the treatment of his epilepsy. Since then, the hippocampus has been the object of studies on many levels, from membrane channels to human behavior, in an effort to understand its presumed function in learning and memory and its common dysfunction in temporal lobe epilepsy. In the same year as Scoville's initial observations on HM, Green and Arduini 3 described rhythmic hippocampal electroencephalographic (EEG) activity in animals (Fig. 1). The 'synchronized' hippocampal activity, known as the 'theta rhythm', occurred simultaneously with 'desynchronized' neocortical EEG and 'arousal'. In addition to the theta rhythm being one of the largest amplitude EEG signals known, theta-related neuronal activity appears to be essential for the normal functioning of the hippocampus in many animal species. Manipulations that abolish the hippocampal theta rhythm in experimental animals produce behavioral impairments that are very similar to the impairments seen after lesions of the hippocampus itself 4-7. Efforts to determine the mechanisms underlying the generation of the hippocampal theta rhythm, important for an understanding of the EEG in general, could provide critical insights into the normal mnemonic functioning of the hippocampus as well as the pathological synchrony of epilepsy. Recent anatomical and electrophysiological findings regarding the cholinergic and GABAergic Fig. 1. Hippocampal theta rhythm recorded from a walking rat. EEG activity over 3 s is displayed. Top septo-hippocampal projections trace: recording from an electrode just dorsal to the pyramidal cell layer in area CA10.e. basal have led us to re-examine ~he dendritic side). Bottom trace: recording from an electrode located near the hippocampal fissure (i.e. 'pacemaker' role of the septum near the distal apical dendrites). The frequency of this theta activity is about 6.5 Hz. The theta in the production of the hippo- rhythm recorded during other behaviors or in anesthetized animals appears similar, but may have a slightly different frequency. Calibrations: 0.5 mV, 0.5 s. campal theta rhythm. TINS, Vol. 13, No. 5, 1990
© 199o.ElsevierSciencePublishersLtd.(UK) 0166-2236/90/$02.00
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theta rhythm. In their original report, Green and Arduini 3 showed that lesions of the septal nuclei could abolish the hippocarnpal theta rhythm. This result, now replicated with many variations, indicated that the theta rhythm depended upon inputs originating in or passing through the septal nuclei. In 1962, Petsche, Stumpf and Gogol~k 15 recorded rhythmically bursting cells within the medial septal nucleus and the nucleus of the diagonal band (MSN-NDB), and suggested that projections to the hippocarnpus from these cells might directly generate the hippocarnpal theta rhythm 16. Vanderwolf has argued that the medial septal projections to the hippocampus are essential only for the atropine-sensitive component of the theta rhythm and that the atropine-resistant component is dependent upon a second set of hippocarnpal afferents, a serotonergic projection from the raphe nuclei (reviewed in Ref. 9). Identification of the actual roles the subcortical projections play in producing theta rhythm has been a surprisingly challenging endeavor. We will review four models of the medial septal inputs necessary for theta rhythm production to illustrate the development of ideas about the septo-hippocampal connections and their role in the functioning of the hippocampus.
The 'pacemaker' hypotheses The rhythmic activity of MSN-NDB cells (even during the absence of theta-related hippocampal activity) and the profound effects of septal lesions on the theta rhythm led to the suggestion that rhythmic septo-hippocampal projections directly generated the hippocampal theta rhythm. Gogol&k et al. ~6 postulated that the septal inputs ended on pyramidal cells (Fig. 2A), resulting in either rhythmic excitatory postsynaptic potentials in their basal dendrites or in rhythmic inhibitory postsynaptic potentials in their apical dendrites. As described above, this synaptic activity would be directly recorded as the theta rhythm. The term 'pacemaker' became associated with the MSN-NDB, primarily because of the rhythmic activity of septohippocampal neurons and the apparent absence of any ascending inputs to the septal nuclei having rhythmicity at the theta frequency. In spite of the 'pacemaker' label appearing to be completely appropriate, no data existed regarding the excitatory or inhibitory nature of the septal input, or the neuronal targets of this input. The possibility of septal inputs directly generating the theta rhythm lost support when medial septal stimulation failed to evoke any field potential activity, either excitatory or inhibitory, in the hippocampus 17. Buzsaki shifted attention away from the pyramidal and granule cells of the hippocarnpus and onto the interneurons ~8-2°. He reasoned that the septal projection responsible for the atropine-sensitive theta rhythm of urethane-anesthetized rats was an excitatory cholinergic input to the hippocampal interneurons (Fig. 2B). This hypothesis was based primarily on four pieces of data. (1) It appeared, from anatomical evidence, that the massive choli164
nergic septo-hippocampal projection 21,22 might terminate on interneurons 23. (2) Atropine or scopolamine could apparently eliminate the immobilityrelated or anesthesia-induced theta rhythm 9,11. (3) An increased firing rate in inhibitory hippocarnpal interneurons during theta rhythm was accompanied by a decreased firing rate in pyramidal cells19,24,2s. (4) Both pyramidal cells and interneurons discharge in phase with the theta rhythm; however, during atropine-sensitive theta rhythm they fire roughly 180° out of phase with each other (reviewed in Ref. 26). This phase difference, along with the changes in their respective firing rates, indicates that hippocarnpalinterneurons are not driven via the recurrent collaterals of pyramidal cells during atropine-sensitive theta rhythm. Cholinergic excitation of limbic interneurons has been demonstrated in vitro 27,28, is faster, and appears to be a more 'conventional' type of excitation than the well-known cholinergic suppression of pyramidal cell potassium (K+) currents such as the M-current 29,3°. The data listed above favored Buzsaki's hypothesis, even without direct evidence that the rhythmically bursting septal cells were cholinergic. According to his hypothesis, atropine-sensitive theta rhythm would result from the rhythmic excitation of hippocampal interneurons by cholinergic septal neurons. Periodic inhibition of pyramidal and granule cells by interneurons would generate at least a part of the EEG and also serve to synchronize the activity of other hippocampal neurons. Synaptic connections between and among pyramidal and granule cells would contribute to the EEG as well. Two pieces of data showed this hypothesis to be incomplete. A powerful excitatory input onto hippocarnpal interneurons should be detectable with septat stimulation. It was not ~7. In addition, a large fraction of the septo-hippocarnpal projection was found to be GABAergic31,32and clearly identified as terminating on interneurons 33 (cf. Ref. 34). Without strong tonic inhibitory activity to modulate, a disinhibitory action of septal stimulation might not be accompanied by a field potential. Emphasis on this GABAergic input suggests a third possible mechanism for septal production of the theta rhythm: the septal input might organize the activity of hippocampal projection cells via the rhythmic inhibition of hippocarnpal interneurons (Fig. 2C). The resulting synchronous activity throughout the hippocampus would produce the rhythmic EEG.
Our current hypothesis Efforts to account for the existing data, as well as new data from our laboratory, led to a fourth hypothesis. Recently, we found that there are two populations of rhythmically bursting MSN-NDB neurons that project to the hippocarnpus3s. We argued that both the cholinergic and GABAergic septo-hippocampal neurons are rhythmic and 'pace' the hippocarnpal theta rhythm via inputs to hippocampal intemeurons. Just as the inhibitory inputs to interneurons could escape detection with septal stimulation, so could a combination of excitatory and inhibitory inputs to the same cells. TINS, VoL 13, No. 5, 1990
When atropine is given systemically to a urethane-anesthetized rat, the hippocampal theta rhythm is apparently abolished. Under such conditions, recordings from rhythmically bursting MSNNDB cells reveal that some of these septal cells continue to burst rhythmically in the absence of the theta rhythm (atropine-resistant cells), while other cells lose their rhythmicity (atropine-sensitive cells). This is illustrated in Fig. 3. About two-thirds of the population of rhythmically bursting MSN-NDB cells are atropine-resistant while the remainder are atropine-sensitive 3s. Since the atropine-sensitive septal cells are not dependent upon feedback from the hippocampus (see Fig. 3B), blockade of a muscarinic synapse within the s.eptum probably accounts for their loss of rhythmicity. Is the theta rhythm abolished because of atropine's action within the hippocampus (at the terminals of either the atropine-sensitive or the atropine-resistant cells), or because of atropine's action within the septum? Application of atropine to the entire septal nucleus, making an effort to keep it from reaching the hippocampus, reversibly eliminated the hippocampal theta rhythm 3s. This indicated the importance of a septal site of action of atropine, but more importantly, it appeared that the loss of rhythmicity in the atropine-sensitive septal cells was sufficient to abolish the theta rhythm. Attempts to activate antidromically all electrophysiologically defined categories of MSN-NDB cells from the fimbria or fornix were successful only for the two types of rhythmically bursting cells, indicating that the atropine-sensitive and atropine-resistant cells are the principal projection cells of the MSN-NDB 36. The possible transmitter identities of the atropine-resistant and atropine-sensitive septal cells may then be inferred from the results of the septal application of atropine. During the application of atropine to the septum alone, the continued rhythmic input to the hippocampus from the atropine-resistant septal cells was not blocked, yet there was no hippocampal theta rhythm. This result indicates that the atropine-resistant septal cells are not likely to be the cholinergic cells, since their unblocked terminals in the hippocampus would be expected to produce rhythmic field potentials. If, on the other hand, the atropine-resistant MSN-NDB cells are GABAergic, they can account for the small component of the theta rhythm, resistant to high systemic doses of atropine, that was discovered in urethane-anesthetized rats by triggering an average of the hippocampal EEG on the rhythmic bursts of atropine-resistant septal cells37. Working on the assumption that one of the pharmacologically identified cell groups corresponds to one of the histochemically identified cell groups, the data are most consistent with the atropine-resistant cells being GABAergic and the atropine-sensitive cells cholinergic. How can the atropine-sensitive cells be cholinergic when they are the cells affected by atropine? Admittedly, without additional details of the interactions among septal cells, it is difficult to answer this question specifically. Several pieces of data can be TINS, VoL 13, No. 5, 1990
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Fig. 2. Three models of septo-hippocampal connections that might 'pace' the hippocampal theta rhythm. None of the models depicts all of the septal inputs to the hippocampus; only those connections that might pace the theta rhythm are shown. Excitatory endings are represented by open symbols and inhibitory endings by filled symbols. The different shapes reflect different transmitters: open triangles represent cholinergic terminals in all cases except in (A) where the transmitter is not specified; open rectangles are glutamatergic terminals; filled circles are GABAergic terminals. Connections mediating the recurrent inhibition of the pyramidal cell (pyr) by the intemeuron (int) are well established. Only the connections of septum with area CA1 of the hippocampus are illustrated. (A) The direct generation of hippocampal theta rhythm by rhythmic excitatory inputs to the basal dendrites of hippocampal pyramidal cells. This was one mechanism proposed by Gogol~k et al. 16. (B) Rhythmic cholinergic excitation of hippocampal interneurons as proposed by BuzsakiIa-2° This model would produce theta rhythm by rhythmic inhibition of pyramidal cells (via the interneurons) and by the inputs from other hippocampal formation neurons made synchronous by the septal control of intemeurons in those areas. (C) A model similar to (B), except that the rhythmic modulation of hippocampal interneuronal firing is accomplished by a GABAergic projection from the septum 33,34 offered to at least make this notion plausible. The septum appears to be an oscillatory network rather than a collection of independent oscillatory neurons. Spontaneous rhythmic bursting activity, similar to that seen in the intact septum, has been recorded in the deafferented septum 38, but has not been dem165
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onstrated in septal slices maintained in vitro 39-41. Based on extracellular recordings from rhythmically bursting septal neurons, each cell bears a remarkably stable phase relation to the hippocampal theta rhythm and to other rhythmic septal cells36, even across many separate epochs of the theta rhythm, indicating that they must be somehow linked. Eachof the four possible combinations of synapses between identified cholinergic and non-cholinergic septal cells has been visualized at the electron microscopic level42. There are cholinergic inputs to cholinergic septal cells, as well as to the non-cholinergic septal cells. Finally, iontophoretic studies conducted both in Control _ll
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166
vivo and in septal slices showed that 70-100% of septal neurons could be excited via a muscarinic action of acetylcholine 39,43,44and all cells could be inhibited by GABA39,~4. Without speculating about the details of the mechanism by which atropine might eliminate the rhythmic firing pattern of cholinergic septal neurons, we maintain that postulating atropine-sensitive septal cells to be the cholinergic cells best fits the available data. In our model (Fig. 4), the rhythmic cholinergic projections of atropine-sensitive septal cells end on both pyramidal cells and interneurons. The cholinergic input to pyramidal cells mediates the slow disinhibitory effects of inactivating several K÷ conductances. The cholinergic input to interneurons mediates a more rapid excitation, relaying the rhythmic activity of the septal cells. The rhythmic excitation of hippocampal interneurons is coupled with rhythmic inhibition of the same cells by GABAergic inputs from the atropine-resistant septal cells. Just as the preferred phase of firing for a given septal cell is determined by its interconnections with other excitatory and inhibitory septal cells, so the preferred phase of firing for a hippocampal interneuron is set by firing phases of its excitatory and inhibitory septal inputs. These interconnections make the phase relation between any two cells (septal or hippocampal) extremely stable across isolated epochs of theta activity. Rhythmically driven and modulated by the atropine-sensitive and atropine-resistant septal inputs, hippocampal interneurons generate a portion of the theta rhythm via inhibitory endings on pyramidal and granule cells, and synchronize the activity of cells throughout the hippocampal formation. The rhythmic activity of cells that project to the hippocampus from those areas also contributes synaptic currents that generate other components of the field potentials we call the theta rhythm 14,45,46. While they are consistent with the available data, the two principal features of the model, that both cholinergic and GABAergic septal cells are rhythmic, and that the cholinergic cells are atropine-sensitive and the GABAergic cells atropine-resistant, remain to be tested directly. Strictly speaking, our model applies only to the atropine-sensitive component of the theta rhythm, since the details underlying the production of atropine-resistant theta rhythm are unknown. As mentioned above, a small component of the hippocampal theta rhythm driven by the atropineresistant septal cells could be extracted with spiketriggered averaging from the apparently nonrhythmic hippocampal EEG of the rat, even after nearly lethal doses of atropine (up to 100 mg/kg i.v.) 37. This result is consistent with the possibility that a few of the GABAergic septal fibers end directly on pyramidal cells. Alternatively, this component could arise from the continued rhythmic modulation of interneuronal firing. The presence of a small atropine-resistant component of the urethane-induced theta rhythm suggests that the atropine-resistant septal cells, modulated by a serotonergic projection from the raphe nuclei39,47, might pace the atropineresistant theta rhythm, rather than the raphe acting as a separate 'pacemaker' input to the hippocampus. TINS, VoL 13, No. 5, 1990
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Do septal neurons pace the hippocampal theta rhythm? Each of the four models of the 'pacemaker' mechanism has lacked one piece of data - a demonstration that the hippocampal theta rhythm is dependent upon the rhythmic activity of the septal cells. It is clear that the septal cells are rhythmic and tightly coupled with the theta rhythm, but no one has shown that the septal input must be rhythmic, and not tonic, for a theta rhythm to exist. In fact, oscillations of the theta frequency have been found in hippocampal slices bathed with cholinergic agonists48 as well as in computer-simulated networks of hippocampal cells49. These reduced preparations allow study of the local interactions contributing to rhythmic hippocampal activity at a level that is impossible in intact animals. However, it is clear that these oscillations are not identical to the hippocampal theta rhythm recorded in vivo (e.g. Ref. 50) because the naturally occurring theta rhythm includes the effects of numerous rhythmic and non-rhythmic inputs to the hippocampus, none of which are represented in the reduced preparations. The theta-like oscillations found in the in vitro preparations and computer models do, however, raise an important question regarding the role of the septum: do the septal nuclei act as a 'pacemaker' or as a 'gating device'? The abundant circumstantial data suggest that 'pacemaker' is the more appropriate label, but it must be kept in mind that this has not been proved. The recent discovery of subthreshold Na+-dependent rhythmic activity in layer II stellate cells in slices of entorhinal cortex sl indicates that the intrinsic membrane properties of these cells, like those of hippocampal pyramidal cells~2, can cause them to oscillate within the frequency range of the theta rhythm. However, it should be remembered that theta activity in both the hippocampus and entorhinal cortex is abolished by septal lesions in intact animals (e.g. Refs 3, 6), emphasizing the importance of the septum for the production of the naturally occurring theta rhythm. The role of a pacemaker is to set the frequency and synchronize the oscillations of an entire population of independent oscillators. Evidence in favor of a pacemaker function for the septum, as opposed to a gating function, comes from the observation that high-frequency (e.g. 100 Hz) stimulation of the brainstem afferents to the septum can induce theta rhythm in the hippocampus, but such stimulation of the septum itself cannot; patterning of the septal stimulation at the theta frequency is required (reviewed in Ref. 53). But theta-patterned septal stimulation probably produces synchronous activation of septo-hippocampal projections, fibers of passage, and hippocampo-septal projections. It is unlikely that such activity would induce a physiological hippocampal theta rhythm. It is more likely that this septal stimulation produces a mixture of long-duration field potentials resembling theta rhythm primarily due to the patterning of the stimulation. Similarly, high-frequency stimulation of this mixed population could actually block the gating of the theta rhythm that might otherwise have ~NS, VoL 13, No.~ 1990
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Fig. 4. Proposed connections of rhythmically bursting MSN-NDB neurons with the cells of the hippocampus. Symbols are as described in Fig. 2. Cholinergic and GABAergic projections from the medial septum to the hippocampus have been demonstrated anatomically. We propose that the cholinergic projection cells of the MSN-NDB are rhythmic and atropine-sensitive (as) and that these cells terminate on both pyramidal cells and interneurons. Terminations on pyramidal cells mediate the slow, decreased conductance depolarization of these cells, whereas endings on intemeurons mediate a much faster 'conventional' excitation of the interneurons. We further argue that the GABAergic projection cells of the septum are rhythmic and atropine-resistant (at) and that these cells terminate almost exclusively on intemeurons. Only the connections between septum and area CA I are illustrated. The interconnections between the cholinergic and GABAergic septal cells and the possible GABAergic septal input to the pyramidal cells are not shown. See text for additional details. (Taken, with permission, from Ref. 35.)
occurred with stimulation of a pure population (or subpopulation) of septo°hippocampal fibers. The results of the septal application of atropine that was described earlier also favor a pacemaker role for the MSN-NDB. Although atropine eliminates the rhythmic activity of the atropine-sensitive septal cells, it does not eliminate their activity altogether. The loss of hippocampal theta rhythm after septal application of atropine was attributed to the change in firing pattern, from rhythmic to nonrhythmic, of the atropine-sensitive cells. Although this is precisely the type of experimental data needed to justify the use of a 'pacemaker' label, not enough data exist to rule out completely another interpretation such as a net decrease in firing of the atropine-sensitive cells (hence a net decrease in acetylcholine delivered to the hippocampus). So the question of whether septal neurons act as a pacemaker for the theta rhythm remains open.
The 'function' of the hippocampal theta rhythm An association between the theta rhythm and 'learning' was originally made when surgical manipulations that eliminate the theta rhythm were found to produce behavioral deficits that were similar to the deficits obtained with lesions of the hippocampus itself 4-7. Long-lasting increases in synaptic efficacy can be produced in many cell types with appropriately patterned stimuli (reviewed in Ref. 54), and this phenomenon, called long-term potentiation, is currently a popular model of learning. The association between theta rhythm and 'learning' has been strengthened by reports that the frequency of 167
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Acknowled&ements Thiswork was supportedby National Institutesof Healthgrants NS17095to SEFand N507117 (neurophysiology traininggrant). We thank Dr JamesB. Ranck,Jr for helpful commentson the manuscript.
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the theta rhythm may be optimal for such synaptic enhancement in the hippocampus ~5-57. On the other hand, it is entirely possible that the rhythmic firing of septal and hippocampal neurons associated with the theta rhythm is an epiphenomenon. The theta rhythm might only be indicative of some 'state' change in hippocampal pyramidal and granule cells. For example, the location-specific firing of hippocampal neurons 4,~8 shows a greater spatial signal-to-noise ratio during theta rhythm 59. In addition, sustained potential changes have been found to be associated with the theta rhythm 45,46,6° and the long-lasting actions of acetylcholine on pyramidal cells substantially change the firing properties of these cells 27-3°. The apparent absence of hippocampal theta rhythm from primates (reviewed in Ref. 8) has also contributed to this concern, essentially forcing theta rhythm researchers to consider the inappropriateness of generalizing their data to humans, or to accept that some aspect of the septo-hippocampal system, other than the theta rhythm, is conserved along the evolutionary path to primates. However, recent recordings of theta activity in monkeys have helped to restore the ' r h y t h m ' as the focus of attention 61. This is i m p o r t a n t for t w o reasons. First, it means that experimental effort directed toward understanding the mechanisms of generation of the hippocampal theta rhythm can continue, appropriately, in non-primate mammals such as rats before being extended to monkeys or humans. Second, and more important, the hippocampal theta rhythm of monkeys (and presumably man) may represent a useful physiological indicator of the condition of the cholinergic and non-cholinergic projections from the basal forebrain to the hippocampus and other cortical areas.
Selected references 1 Scoville,w. B. (1954) J. Neurosurg. 11,64-66 2 Scoville, W. B. and Milner, B. (1957) J. Neurol. Neurosurg. Psychiatr 20, 11-21 3 Green, J. D. and Arduini, A. A. (1954) J. Neurophysiol. 17, 533-557 40'Keefe, J. and Nadel, L. (1978) The Hippocampus as a Cognitive Map Oxford University Press 5 Winson, J. (1978) Science 210, 160-163 6 Mitchell, S. J., Rawlins, J. N. P., Steward, O. and Olton, D. S. (1982) J. Neurosci. 2,292-302 7 Squire, L. R. and Zola-Morgan, S. (1988) Trends Neurosci. 11,170-175 8 Robinson, T. E. (1980) Brain Res. Rev. 2, 69-101 9 Vanderwolf, C. H. (1988) int. Rev. Neurobiol. 30, 225-340 10 Vanderwolf, C. H. (1969) EEG Clin. Neurophysiol. 26, 407-418 11 Kramis, R., Vanderwolf, C. H. and Bland, B. H. (1975) Exp. NeuroL 49, 58-85 12 Robinson, T. E. and Green, D. J. (1980) EEG Clin. Neurophysiol. 50,314-323 13 Vanderwolf, C. H. and Leung, L-W. S. (1983) in The Neurobiology of the Hippocampus (Seifert, W., ed.), pp. 275-302, Academic Press 14 Buzsaki, G., Czopf, J., Kondakor, I. and Kellenyi, L. (1986) Brain Res. 365, 125-137 15 Petsche, H., Stumpf, Ch. and Gogol&k, G. (1962) EEG Clin. Neurophysiol. 14,202-211 16 Gogol,ik, G., Stumpf, Ch., Petsche, H. and Sterc, J. (1968) Brain Res. 7,201-207 168
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17 Krnjevi(% K. and Ropert, N. (1982) Neuroscience 7, 2165-2183 18 Buzsaki,G. and Eidelberg, E. (1983) Brain Res. 266, 334-339 19 Buzsaki, G., Leung, L. S. and Vanderwolf, C. H. (1983) Brain Res. Rev. 6, 139-171 20 Buzsaki,G. (1984) Pro&. Neurobiol. 22,131-153 21 Lewis, P. R. and Shute, C. C. D. (1967) Brain90, 521-540 22 Lewis, P. R., Shute, C. C. D. and Silver, A. (1967) J. PhysioL (London) 191,215-224 23 Mosko, S., Lynch, G. and Cotman, C. W. (1973) J. Comp. NeuroL 152, 163-174 24 Ranck,J. B., Jr (1973) Exp. NeuroL 41,461-531 25 Fox, S. E. and Ranck, J. B., Jr (1981) Exp. Brain Res. 41, 399-410 26 Fox, S. E., Wolfson, S. and Ranck, J. B., Jr (1986) Exp. Brain Res. 62,495-508 27 Benardo, L. S. and Prince, D. A. (1982) Brain Res. 249, 315-331 28 McCormick, D. A. and Prince, D. A. (1986) J. Physiol. (London) 375,169-194 29 Halliwell, J. V. and Adams, P. R. (1982) Brain Res. 250, 71-92 30 Madison, D. V., Lancaster, B. and Nicoll, R. A. (1987) J. Neurosci. 7, 733-741 31 K6hler, C., Chan-Palay, V. and Wu, J-Y. (1984) Anat. Embryol. 169, 41-44 32 Peterson, G. M., Williams, L. R., Varon, S. and Gage, F. H. (1987) Neurosci. Lett. 76, 140-144 33 Freund, T. and Antal, M. (1988) Nature336, 170-173 34 Bilkey, D. K. and Goddard, V. G. (1985) Brain Res. 361, 99-106 35 Stewart, M. and Fox, S. E. (1989) J. NeurophysioL 61, 982-993 36 Stewart, M. and Fox, S. E. (1989) Exp. Brain Res. 77, 507-516 37 Stewart, M. and Fox, S. E. (1989) Brain Res. 500, 55-60 38 Vinogradova, O. S., Brazhnik, E. S., Karanov, A. M. and Zhadina, S. D. (1980) Brain Res. 187,353-368 39 Segal,M. (1986)J. Physiol. (London)379,309-330 40 AIvarez de Toledo, G. and L6pez-Barneo, J. (1988) J. PhysioL (London) 396,399-415 41 Griffith, W. H. (1988) J. NeurophysioL 59, 1590-1612 42 Bialowas, J. and Frotscher, M. (1987) J. Comp. NeuroL 259, 298-307 43 Dutar, P., Lamour, Y. and Jobert, A. (1983) Neurosci. Left. 43, 43-47 44 Lamour, Y., Dutar, P. and Jobert, A. (1984) Brain Res. 309, 227-239 45 Fox, S. E. and Stewart, M. (1986) Soc. Neurosci. Abstr. 12, 1527 46 Branka~k, J. and Fox, S. E. (1987) Soc. Neurosci. Abstr. 13, 1331 47 Crunelli, V. and Segal, M. (1985) Neuroscience 15, 47-60 48 Konopacki, J., Maciver, M. B., Bland, B. H. and Roth, S. H. (1987) Brain Res. Bull. 18, 25-27 49 Traub, R. D., Miles, R. and Wong, R. K. S. (1989) Science 243, 1319-1325 50 Konopacki, J., Bland, B. H. and Roth, S. (1987) Brain Res. 417,399-402 51 Alonso, A. and Llin,~s,R. R. (1989) Nature342, 175-177 52 Nefiez, A., Garcia-Austt, E. and BuEo, W., Jr (1987) Brain Res. 416, 289-300 53 Bland, B. H. (1986) Prog. Neurobiol. 26, 1-54 54 Teyler, T. J. and Discenna, P. (1984) Brain Res. Rev. 7, 15-28 55 Larson, J., Wong, D. and Lynch, G. (1986) Brain Res. 368, 347-350 56 Rose, G. M. and Dunwiddie, T. V. (1986) Neurosci. Lett. 69, 244-248 57 Greenstein, Y. J., Pavlides, C. and Winson, J. (1988) Brain Res. 438,331-334 58 Muller, R. U., Kubie, J. L. and Ranck, J. B., Jr (1987) J. Neurosci. 7, 1935-1950 59 Kubie, J. L., Muller, R. U. and Fox, S. E. (1985) in Electrical Activity of the Archicortex (Buzsaki, G. and Vanderwolf, C. H., eds), pp. 221-231, Akademiai Kiado 60 Gerbrandt, L. K. and Fowler, J. R. (1980) Prog. Brain Res. 54, 109-116 61 Stewart, M. and Fox, S. E. (1989) Soc. Neurosci. Abstr. 15, 1250 TINS, Vol. 13, No. 5, 1990
letter Neuroanatomical nomenclature SIR:
We were pleased to read Butcher and Semba's report 'Reassessing the cholinergic basal forebrain: nomenclature schemata and concepts '1. There is a critical need for a stable neuroanatomical nomenclature to convey information between neuroscientists accurately and intelligibly. In some areas of the brain, such as the cortex, there is such a multitude of synonyms that researchers need to use a table of equivalence of the different terms. Unfortunately, N o m i n a A n a t o m i c a 2 does not provide a comprehensive list of terms for
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the nervous system. For example, it lists three amygdaloid nuclei, while de Olmos eta/. 3 recognize 51. The initiative shown by Butcher and Semba and your willingness to publish their work will be welcome to those who find the proliferation of synonyms, and abbreviations thereof, an unnecessary obstacle to understanding. As cartographers, we are at times in the unenviable position of deciding between competing nomenclature schemes. Attention to nomenclature by the primary researchers in the area as well as by editors of journals should assist in arriving at a consensus. It should always be remem-
to
the
editor
bered that sharing nomenclature with others presents no risk of infection by communicative diseases. George Paxino$ Istvan T6rk Schools of Psychologyand Anatomy, The Universityof New South Wales,PC)Box 1, Kensington, NSW,Australia2033.
References 1 Butcher, L. L. and Semba, K. (1989) Trends NeuroscL 12,483-485 2 Anon. (1983) Nomina Anatomica (5th
edfT; 11th International Congress of Anatomists) Williams and Wilkins 3 de OImos, J., Alheid, G. F. and Beltramino, C. A. (1985) in The Rat
Nervous System VoL 1: Forebrain and Midbrain (Paxinos, G., ed.), pp. 223-334, Academic Press
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reviews
Ion condudancesaffectedby 5-HT receptorsubtypesin mammalianneurons Daniel H. Bobker and John T. Williams
5-Hydroxytryptamine (5-HT) has both excitatory and 5-HT caused a hyperpolarization of CA1 hippocampal inhibitory actions in the CNS and PNS. The develop- neurons. 8-OH-DPAT was a weak partial agonist (at ment of new 5-HT ligands has led to the expansion of micromolar concentrations) in one study 7 and an 5-HT receptor subtypes into three categories: 5-HT1, antagonist (at nanomolar concentrations) in the other s 5-HT2 and 5-1-17"3 (Ref 1). Each category has further indicating that there is an absence of 'spare' receptors subdivisions. The literature concerning the biochemical in the hippocampus. Both studies found that the basis of this division has been reviewed recently2. While 5-HT1n-mediated hyperpolarization was a result of an this approach has elucidated many of the pharmaco- increased conductance to potassium (K +) ions. Furlogical properties of 5-HT receptors, it has not addressed thermore, the K + current induced by 5-HT was the question of how 5-HT modulates cell excitability. blocked by pretreatment of the animal with pertussis Physiological studies have confirmed the existence of a toxin. The 5-HT1A receptor has therefore been mul@licity of 5-HT receptors that act through a variety included in the growing list of receptors that cause an of ionic mechanisms. The purpose of this review is to increase in K + conductance mediated by a pertussis summarize what is known of the ionic mechanisms toxin-sensitive G protein 9-n. A 5-HT-mediated hyperpolarization has also been associated with the activation of identified mammalian 5-HT receptor subtypes, as well as some effects of 5-HT reported in neurons of the dorsal raphe 12,13 (Fig. 1A), prepositus hypoglossi14, superior cervical ganglion 15, where the receptor could not be defined. and myenteric plexus TM. Additionally, a 5-HTmediated inhibitory postsynaptic potential (IPSP) has Increase in potassium conductance: 5-HTIA The 5-HTIA receptor has been localized throughout been reported in rat dorsal raphe 12,1s and in guineathe nervous system, with high concentrations in limbic pig prepositus hypoglossiTM neurons. As would be regions and in the dorsal raphe nucleus 3 (Table I). expected for a response mediated by the activation of Interest in this site has developed since the discovery 5-HT~A receptors, these IPSPs were blocked by of the selective 5-HTIA agonist, 8-hydroxy-(2-N,N- nanomolar concentrations of spiperone, prolonged by dipropylamino)-tetraline (8-OH-DPAT) 4. Unfortu- fluoxetine or cocaine (Fig. 1B,C), and reversed nately, in physiological studies, this compound can act polarity at the K + equilibrium potential 12,14,17,18. The as a full agonist, a partial agonist, or an antagonist time-course of the synaptic potential was slow (and depending on the receptor reserve of the tissue. similar in the two preparations), with a 1-2 s duration, Nevertheless, when used at concentrations under and so is comparable to the noradrenergic IPSP 1 ~w and in combination with the antagonist spiperone 5,6, mediated by oc2-adrenoceptors in the locus coeruleus 19 8-OH-DPAT identifies 5-HT~A receptor-mediated and the GABAB-mediated IPSP in the hippocampus 2°. actions. A remaining question concerning the 5-HT1A recepReports from two laboratories demonstrated that tor is the role of adenylate cyclase. Both stimulation of TINS, Vol. 13, No. 5, 1990
© 1990, EPsevieScience r PublishersLtd,(UK) 0166- 2236/90/$02.00
DanielH. Bobkerand John T. Williamsare at the Vollum Institute, Oregon HealthScience University,3181SW SamJacksonPark Road,Portland,OR 97201, USA.
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