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The limbic system: An interface
BEHAVIORAL BIOLOGY, 12, 149-164 (1974), Abstract No. 4136
The Limbic System: An Interface
ERVIN WILLIAM POWELL and GARTH HINES 1
Department of Anatomy, University of Arkansas School of Medicine, Little Rock, Arkansas 72201 and Department of Psychology, University of Arkansas at Little Rock, Little Rock, Arkansas 72201
Much work has related limbic structure with hypothalamic function rather than with higher nervous system function. Most studies have dealt with single limbic structures rather than with several as interrelated functional systems. Upon consideration of the total limbic-strueture complex it would appear that the septum-hippocampus-amygdala form an interface between the isocortex and the thalamus. Our work relating to projections of the limbic system, especially the septal area, has directed our attention to the thalamus as a particularly important target of limbic system projections. Furthermore, our work on projections of the cingulate gyrus reveals that this cortical area projects strongly to other cortical regions as well as to thalamic nuclei. The orbital frontal cortex, eingulate gyms, and hippocampal gyrus are isocortical areas which then link the limbic system with other corticothalamic systems. This feature, plus strong thalamic connections from the hippocampus, septum, and amygdala provide a basis for considering the limbic system as an interface between the overlying cerebral isocortex and thalamic structures. This interface may be a key integrating system related to selective modulation of emotion and sensory mechanisms of the brain via a number of feedback circuits wherein recycling could be effected through the temporal and/or the frontal cortex.
There is still no satisfactory general concept of how the limbic system is organized. The hippocampus has been studied as a key structure of the limbic system by many investigators since Papez (1937) first proposed an anatomical framework for emotional mechanisms of the brain. Structurally, the hippocampus is known to project through the fornix to the hypothalamus 1This research was supported Lucas, Ture Sehoultz, and Robert Arkansas School of Medicine, for Geraldine Brown, Jean Galatzan, and
by NSF Grant GB32170. The authors thank Drs. Ed Skinner, Department of Anatomy, University of discussing and helping with the manuscript and Robert Leman for their technical assistance. 149
Copyright © 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
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(Simpson, 1952; Guillery, 1955; Powell et al., 1957; Raisman et al., 1966). This orientation has lead investigators to consider the hypothalamus as a primary center o f limbic function and main source o f cerebral feedback modulation (Feldman, 1962; Zanchetti, 1967; A n d y et aL, 1972; Clemente and Chase, 1973). Major inputs to the hypothalamus (Fig. 1) are via the fornix column, medial forebrain bundle, stria terminalis, substantia innominata, and mammillary peduncle. All o f these fiber connections originate in a limbic structure with but one possible exception, the mammillary peduncle. The mammillary
Fig. 1. Drawing of limbic pathways. There are many connections with the hypothalamus. The hypothalamus lies ventral to the hypothalamic sulcus (about the level of the most dorsal fibers of the medial forebrain bundle). The midpart of the optic chiasm and the posterior edge of the mammillary body mark the anterior and posterior boundaries respectively. Modified from Papez (1929) drawing of the olfactory brain in the rabbit. At-Anterior commissure; Ad-Anterodorsal nucleus of the thalamus; A g Amygdala; Ah-Anterior hypothalamus; Am-Anteromedial nucleus; An-Anterior thaiamic nuclei; Av-Anteroventral nucleus; Ca-Cornu ammonis; Cc-Corpus callosum; C d Caudate nucleus; Cg-Cingulate gyrus; Ci-Cingulum; Ch-Optic chiasm; Ct-Neocortex; Df-Dorsal fornix; D1-Dorsal longitudinal fasciculus; Fb-Fornix body; Fc-Fornix column; Fd-Fascia dentata; Fx-Fornix; Gp-Globus pallidus; Hb-Habenula; HgHippocampal gyrus; Hi-Habenulointerpeduncular tract; Hp-Hippocampus; Ic-lnternal capsule; Ip-Interpedunclular nucleus; Is-Insula; Ld-Lateral dorsal nucleus of thalamus; Ls-Longitudinal stria; Mb-MammiUary body; Me-Midbrain tegmentum; Mr-Medial forebrain bundle; Mp-Mammillary peduncle; Mt-MammiUothalamic tract; Ob-Olfactory bulb; Oc-Occipital cortex; Of-Orbital frontal cortex; O1-Olfactory tract; Ot-Olfactory tubercle; Pa-Paraventricular nucleus of hypothalamus; Pf-Precomissural fornix; P o Postcomissural fornix; Pv-Periventricular nucleus of thalamus; Pt-Parataenial nucleus of thalamus; Re-Reuniens nucleus; Rh-Rhomboid nucleus; Rt-Lateral reticular nucleus of the thalamus; Sb-Subiculum; Se-Septum; S1-Splenum of corpus callosum; Sm-Stria medullaris thalami; So-Supraoptic nucleus of hypothalarous; St-Stria terminalis; T a Temporoammonic tract; Th-Thalamus; T1-Temporal lobe; Tr-Thalamic radiations; U f Uncinate fasciculus; V-Ventricle; Va-Ventral anterior nucleus of thalamus; Vm-Ventral medial of hypothalamus; Zi-Zona incerta.
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peduncle is composed of fibers which are collaterals of sensory fiber systems and input from the midbrain tegmental nuclei, which are part of the midbrain limbic area (Fox, 1941, Nauta, 1958; Cowan et aL, 1964). The medial forebrain bundle contains projections from the septum, olfactory tubercle, orbital frontal cortex, and amygdala. The stria terminalis and substantia innominata contain the principal efferent projections of the amygdala to the hypothalamus. Thus, the hypothalamus has been emphasized as the main target of the limbic structures in spite of considerable work which reports connections to the thalamus and other areas, e.g., isocortex, olfactory tubercle, and midbrain (Powell et al., 1957; Johnson, 1959; Valenstein and Nauta, 1959; Powell, 1963; Raisman et al., 1966; Powell et al., 1970; Simmons and Powell, 1970; Siegel and Tassoni, 1971a, b). It would appear that such connections attest to the hypothalamic dependence on limbic system input but they do not necessarily reflect a reciprocal dependence of limbic system on hypothalamic function. Major effector pathways of the hypothalamus are via the dorsal longitudinal fasciculus, reticulospinal tracts, hypothalamohypophyseal tract, and neuroendocrine mechanisms. The mammillothalamic tract is a large hypothalamic efferent projection although it is not usually understood as an hypothalamic effector (motor) pathway. While the h3ipothalamus is the recipient of a number of inputs from the latter structures, they also have a number of other targets. A diagram of many of the limbic system structures and connections is shown in Fig. 2. The circuit
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Fig. 2. Diagram of the limbic system. The Papez circuit is indicated by the arrows. Other structures and connections shown have been added to the system since his initial proposal.
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initially proposed by Papez may be traced by following the arrows from structure to structure. Subsequently, it has been shown that the hippocampus is interconnected with other structures in addition to those originally proposed. Many of these structures are indicated in Fig. 2. In general, fibers originating in the hippocampus project to the septum, olfactory tubercle, anterior thalamus, and mammillary body (MacLean, 1949; Gfllery, •956; Valenstein and Nauta, 1959; Green, 1964; Livingston and Escobar, 1971; PoweU and Hines, in press). Subsequent to fomix transection we have observed degeneration in the dorsal septal nuclei of the squirrel monkey equal in density and area involved to that which was observed in the mammillary body (Powell, 1973). The septal area should include the dorsal, ventral, medial, and caudal group of nuclei listed by Andy and Stephan (1964) and Stephan and Andy (1964) plus the accumbens nucleus and hippocampal rudiment. The hippocampal rudiment appears to be a slightly hypertrophied anterior terminus of the indusium griseum (gray matter of the medial longitudinal stria) and is juxtaposed to the gyrus rectus and the dorsal septal nuclei. This relation is similar to that found posteriorly where the fascia dentata is juxtaposed to the hippocampus and also connected to the dorsal septal nuclei via the fornix. There are also a considerable number of projections from the septum to the hippocampus (Powell, 1963; Raisman et al., 1966). Other structures which project to septal nuclei, e.g., those from the midbrain limbic area (raphe nuclei) via the medial forebrain bundle (Guillery, 1957; Nauta, 1958; Powell, 1963; Raisman, 1966), may in turn be relayed to the hippocampus. Some rather detailed structural studies of septohippocampal interrelations indicate that a fine degree of regulation and topographic contact exists between these two structures (Raisman et al., 1965; Raisman, 1966; Siegel and Ta{soni, 1971a, b). Siegel and Tassoni generally relate the projections of the dorsal and ventral hippocampus to the medial and lateral septal nuclei, respectively, and return connections to the dorsal and ventral hippocampus from the lateral and medial septal nuclei. We have concluded from our studies of degeneration resulting from transections of the fornix body in the monkey that primary synaptic relations to the dorsal septal nuclei exist (Powell, 1973). A part of the septohippocampal interconnection is also formed by the hippocampal fascia dentata and its projection through the medial longitudinal stria to the hippocampal rudiment of the septum (Crosby et al., 1962). Our studies indicate that these connections are probably multisynaptic or indirect through other structures, e.g., cingulate gyrus. In experiments where the indusium griseum has been lesioned or injected with radioactive leucine, degeneration or terminals was not observed to extend far along the stria and indusium (PoweU, 1963; Powell and Robinson, 1974). The indusium griseum appears to be
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reciprocally connected with the cingulate gyms and septal nuclei (Powell, 1963; Raisman et al., 1965; Domesick, 1969; Siegel and Tassoni, 1971b). The septum has been shown to project to the cingulate gyrus (Powell, 1963; Cragg, 1965; Kemper et al., 1972) in addition to its projections to the hippocampus. It has also been shown since Zuckerkandl (1888) and Cajal (1911) to interconnect with the olfactory tubercle region. The septum is also interrelated with other cortices, especially those determined to be near the lateral fissure (Niemer et al., 1963; Powell, 1964; Johnson et al., 1968). In addition to projections of the hippocampus mentioned above, there are also sizeable ones with temporal lobe structures via the temporoammonic tract and its perforating fascicles (Votaw, 1959, 1960; Powell, 1963; Elul, 1964; Cragg, 1965; Hjorth-Simonsen, 1971; Siegel and Tassoni, 1971a; Hjorth-Simonsen and Jeune, 1972). These connections are distributed through a wider area and structurally are not as obvious as the fornix bundle. Thus, hippocampal efferents to the subiculum and cortices of the hippocampal gyrus are frequently overlooked. Hippocampal afferents from the hippocampal gyms, however, are better documented and have been reported by various workers (Cajal, 1911; Allen, 1948; Blackstad, 1958; Raisman et al., 1965; Hjorth-Simonsen and Jeune, 1972). Furthermore, connections between the hippocampal cortex and the amygdala have been demonstrated (Gloor, 1960; Nauta, 1962; Cowan et al., 1965). Thus, these pathways provide reciprocal connections between the hippocampus and the amygdala via the subiculum and hippocampal cortex. These latter cortical regions also connect the posterior part of the cingulate gyrus with the hippocampus (White, 1959; Raisman et al., 1965; Domesick, 1969; Powell et al., 1974). Recently, it has been shown that the hippocampus and the septum both project independently to the mammillary body and to the anterior thalamic nuclei (Simmons and Powell, 1972; Powell, 1973). Various workers have reported thalamic projections from the septum and the hippocampus (Valenstein and Nauta, 1959; Powell et al., 1957; Powell, 1963, 1966; Powell et al., 1970; Siegel and Tassoni, 1971a, b; Powell, 1973). There is evidence in the rat, cat, and monkey that the septum projects more strongly to the anteromedial nucleus while the hippocampus projects more strongly to the anteroventral nucleus (Fig. 3). Quantitative studies have also shown that the septum and the hippocampus both project more heavily to the thalamus than they do to the hypothalamus. Powell (1973) showed that degeneration was as great or greater in thalamic nuclei than it was in the mammillary body after lesion of the septum or transection of the fornix body. He also found that degeneration in the lateral dorsal nucleus, which appears to be equal in size to the mammillary body, was as dense as was that observed in the medial mammillary nucleus. The anterior thalamic nuclei are also larger than the mammillary body. Data reported by Blinkov and Glezer (1968) in4icate that
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Fig. 3. Illustration of degeneration in the anterior thalamic nuclei. A, B, and C show a preferential degeneration in the anteromedial nucleus of the thalamus (Am) after a lesion in the septum of the rat, cat, and monkey, respectively. A', B', and C' show a preferential degeneration in the anteroventral nucleus of the thalamus (Av) after a lesion in the fornix body of the rat, cat, and monkey, respectively. Modified from Powell, 1963; Powell, 1966; Powell, 1973.
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the anterior thalamic nuclei are about double the size of the medial mammillary nucleus. Hence, there are probably more connections with these nuclei than there are to the mammillary body. Thalamus, especially the anterior nuclear complex, is an excellent example of an area of anatomical convergence (Fig. 4). For example, the hippocampus, septum, mammillary body, and cingulate gyrus all project profusely to the anterior thalamic nuclei. Knook (1966)reported reciprocal connections in the mammillothalamic tract between the anterior nuclei and the mammillary body. Therefore, these structures could provide various types or levels of functional feedback bias through the thalamus. The cingulate cortex, which receives connections from thalamic nuclei, projects via association fibers to other cortical areas (frontal, parietal, and temporal cortices) as shown by various workers (Yakovlev and Locke, 1961; Krieg, 1963; Locke et al., 1964; Airapetyants and Sotnichenko, 1967; Domesick, 1972; Locke and Kerr, 1973; Powell et al., 1974). These other cortical receiving_ areas are known to project in turn to thalamic nuclei (Walker, 1966; Johnson et al., 1968; Robertson and Rinvik, 1973), as do some areas of the cingulate gyrus, (Domesick, 1969). Such anatomical evidence suggests that there may be a functional relevance to a limbic system interface between the cerebral cortex and thalamic nuclei in preference to one between cerebral cortex and hypothalamic nuclei.
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Fig. 4. Thalamic emphasis of limbic connections. Hippocampal connections are shown by solid lines. Septal connections are shown by dashed lines. Other connections, shown by dotted lines, arise mainly from the mammillary body, cingulate gyms, and, especially, cortical association areas.
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Electrophysiological experiments have shown that hippocampal theta activity (synchronized 4-8 Hz) originates in and is topographically related to septal nuclei (Anderson et aL, 1961; Green, 1964; Vanderwolf, 1969; BrustCarmona et aL, 1973). This is commensurate with various data relevant to septal lesion studies. Septal lesions prevent the development of hippocampal theta activity in the region of the hippocampus which receives projections from the dorsal and lateral septal nuclei (Green and Arduini, 1954; Anderson et aL, 1961; Brugge, 1965; Stumpf, 1965; Petsche et aL, 1965; Gogolak et al., 1968; Brust-Carmona, 1973). Theta activity and habituation as indicated by behavior and electroencephalographic recordings have been associated with learning and memory (Herrick, 1933; Green, 1964; Klemm, 1972; Landfield and McGaugh, 1972; Bennett et al., 1973; Stevens and Cowey, 1973; Vinogradova, 1973; Whishaw and Vanderwolf, 1973; Lucas et al., 1974). Habituation occurs as hippocampal theta returns to the electroencephalogram subsequent to a brief alert record induced by a novel stimulus (Karmos and Grastyan, 1962). If theta activity and habituation do not occur, a hypersensitive (overresponsive or confused) animal results (Vanegas and Flynn, 1968; Crowne et al., 1972; Simonov, 1972). Furthermore, animals failed to habituate to a novel stimulus if hippocampal theta activity was eliminated by lesions of the septum or hippocampus (Sanwald et al., 1970). This is consistent with the finding that animals with septal lesions which spared medial septal nuclei were less deficient in the position-reversal task than were those with the medial nuclei damaged (Hamilton et aL, 1970). Evidence indicating the concept that serotonin may be a neurotransmitter released by hippocampal terminals in the mammillary body nuclei has been reported, while the septum has been shown to be potentially related to three different neurotransmitter (Powell et al., 1972). Hence, the septum, through selective influence of its nuclei might in turn topographically modify neurotransmitters quantity and quality to differentially activate the hippocampus. The hippocampus might then exert an habituating influence as it projects to the thalamus and mammillary body. Thus far the emphasis has been placed on septal and hippocampal connections between the anterior limbic cortex and the thalamus. As anatomically inferred above, there is also a hippocampal-amygdala interface between the hippocampal cortex and the thalamus. The amygdala, like the septum, is a multinucleated thalamus-like structure with reciprocal hippocampal c~nnections via entorhinai cortex, subiculum, and temporoammonic tracts (Pribram et al., 1950; Gloor, 1960; Crosby et al., 1962; Hjorth-Simonsen, 1971; Chronister et al., 1974). Strong connections from the amygdala to the dorsal medial nucleus of the thalamus have been demonstrated (Fox, 1949; Nauta, 1961). Thus, both the septum and the amygdala have relatively intimate connections with the hippocampus and both structures form an interface between phylogenetically more complex cerebral cortex and
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the dorsal thalamus. Hence the emphasis on septohippocampal relations made above should appropriately be expanded to include the hippocampal reciprocity with the temporal lobe. Thus, a limbic system interface exists between the neocortex o f the cerebral hemispheres and the thalamus, as illustrated in Fig. 5. Such a perspective of the structural data strongly suggest that a considerable functional emphasis of the limbic system relates to thalamic nuclei and their cortical integrating mechanisms (capacity). Sierra and Fuster (1968) have indicated that limbic activity can modulate cortical evoked responses after visual stimulation. That the modulation was occurring at the cortical level was inferred by the absence of evoked potential change at the lateral geniculate body. This suggests the possibility that ongoing hypothalamic function could then be affected by the dynamics of corticothalamic circuit input or recycling. Such recycling via corticothalamic circuitry could modulate input phases as well as cancel output channels of cerebral pathways. That is, accentuation or inhibition of cerebral input would appear to be an efficient way to control and override cerebral output, circumventing the stopping of ongoing cerebral activity in order to arrest a motor or behavioral event. Such an emphasis is in agreement with physiological data on exteroceptive input (Powell et al., 1970; MacLean, 1972), the finding that stimulation of some central structures may function as either positive or negative reinforcement, depending on the nature of the environmental condition of the external input (Ellen and Powell, t966), and the
CEREBRAL OUTPUT
Fig. 5. Limbic system interface between the lobes of the cerebral hemisphere and the thalamus as discussed in the body of the text.
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observation that cortical responses associated with the acquisition of a classically conditioned response are closely associated with electrical activity changes in the hippocampus (Malcolm, 1958). We would thus like to present the limbic system as a quality-choice interface between an overlying cerebral cortex integrator (the cerebral override system which makes it possible to maintain an organized balance and sequencing of more than one modality) and an underlying brainstem implementor (the brainstem and spinal cord apparatus, including the final common pathway and analogous visceral output to muscle, blood vessels, and visceral organs which are essential to normal facilitation and inhibition of the particular function of the end Organ) (Fig. 5). The limbic system, imposed between the cerebral cortex and the brain stem, appears to have at least two phases, similar to that forwarded by Pribram (1960) for problem solving. He mentioned two classes of behavior: differentiative and intentional. Posterior and frontal cerebral systems were associated, respectively, with these two behavior classes. For example, the parietal and temporal lobe (posterior systems) lesions interfere with the ability to differentiate during searching activity, thus affecting problem delineation. Lesions of the frontal lobe (frontal systems) encumber the ability to volitionally implement a behavior, presumably subsequent to a preliminary completion of problem-delineation activity. Pribram further noted that Sherrington (1947) made this kind of general distinction in his description of the coordination of reflexes. Anteriorly the limbic system is composed of the dorsal hippocampus and the septum which are interconnected via the fornix. Posteriorly it is composed of the ventral hippocampus and the amygdala which are interconnected via the subicuhim and the temporoammonic tracts. The anterior phase is in close association with the anterior parts of the cingulate gyms and the prefrontal cortex, i.e., Brodmann areas 8, 10, 11, and 12 (DeVito and Smith, 1964; Johnson et al., 1968). The prefrontal Cortex is thought to be associated with higher nervous-system functions [abstraction and temporal sequencing] (Pribram 1960; Nauta 1971) which we shall designate as choice-integration. Other areas of the frontal cortex, i.e., Brodmann areas 4 and 6, relate to the integration of motor functions. The posterior limbic phase, consisting of the ventral hippocampus and amygdala, are in close association with the temporal lobe. Studies of memory and learning mechanisms, as stated above, frequently involve these structures, hence they may be presumed to function in memory integration (Fig. 5). The primary sensory cortices serve as the brain sensor or initial input areas. A large part of the parietal cortex is an area where the integration of primary sensory inputs probably occurs. Hence, the firststimulus thrust is probably from primary cortical sensory areas (Shumilina, 1973) and thence to a topographic modulation through the limbic interface to the thalamus and subsequent recycling through various feedback circuits including neocortical ones. The ventral hippocampus in connection with the
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Fig. 6. Diagram of some possible functional roles of the septal-hippocampal connections. The septum, hippocampus, and mammillary body project preferentially to the anteromedial, anteroventral, and anterodorsal nuclei respectively. The septum and hippocampus each have a different projection to the mammiUary body. The septum and hippocampus also have a different effect on motivation as measured by terminal response rate, i.e., septum was usually found to inhibit and the hippocampus to facilitate bar pressing (Ellen and Powell, 1962). The thalamic nuclei are in a position to integrate various sources of stimuli and cycle them as feedback through the subiculum to the hippocampus. This allows not only for disparate effects from particular structures but also for a multiplicity of secondary cues.
amygdala would likely be involved in defensive and learning orientation, similar to that suggested by Simonov (1972). The more global dynamics of memory and imagination could reciprocate through the thalamus via the dorsal medial nucleus and the frontal lobe, from whence the motor output of the cerebrum seems to be voluntarily generated, and then be transmitted through motor structures of the brain stem to appropriate somatic and visceral organs for expression. Thus, (assuming that the main function of the limbic system relates to lower autonomic effects and emotions, e.g., love, hate, fear, and rage), limbic connections, including those with the thalamus and overlying cerebral cortex, probably carry impulses which introduce and adjust (modulate) the emotion input into the total cerebral system (Fig. 6); while those limbic projections which traditionally have received considerable attention, i.e., those directed to the hypothalamus, probably elicit reflex-oriented mechanisms subject to little, if any, additional influence.
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Knook, H. L. (1966). "The Fibre-Connections of the Forebrain." Philadelphia: Davis. Pp. 230-255. Krieg, W. J. S. (1963). "Connections of the Cerebral Cortex." Evanston: Brain Books. Pp. 219-242. Landfield, P. W., and McGaugh, J. L. (1972). Theta rhythm and memory. Science 176, 1449. Livingston, K. E., and Escobar, A. (1971). Anatomical bias of the limbic system concept. Arch. Neurol. 24, 17-21. Locke, S., and Kerr, C. (1973). The projection of nucleus lateralis dorsalis of monkey to basomedial temporal cortex. J.. Comp. Neurol. 149, 29-42. Locke, S., Angevine, J. B., and Yakovlev, P. I. (1964). Limbic nuclei Of thalamus and connections of limbic cortex. VI. Thalamocortical projections of lateral dorsal nucleus in cat and monkey. Arch. Neurol. 1I, 1-12. Lucas, E. A.; Powell, E. W., and Murphree, O. D. (1974). Hippocampal theta in nervous pointer dogs. PhysioL Behav. 12, 609-613. MacLean, P. D. (1949). Psychosomatic disease and the "visceral" brain. Recent developments bearing on the Papez theory of emotions. Psychosom. Med. 11, 338-353. MacLean, P. D. (1972). Implications of microelectrode findings on exteroceptive inputs to the limbic cortex. In C. H. Hockman (Ed.), "Limbic System Mechanisms and Autonomic Function." Springfield: Thomas. Pp. 115-136. Malcolm, J. L. (1958). The electrical activity of cortical neurons in relation to behavior, as studied with microelectrodes in unrestrained cats. In G. E. W. Wolstenholme and C. M. O'Conner (Eds.), "Neurological Basis of Behavior," Ciba Foundation Symposium. Boston: Little, Brown. Pp. 295-302. Nauta, W. J. H. (1958). Hippocampal injections and related neural pathways to the midbrain in the cat. Brain 81, 319-340. Nauta, W. J. H. (1961). Fibre degeneration following lesions of the amygdaloid complex in the monkey. J. Anat. 95,515-531. Nauta, W. J. H. (1962). Neural associations of the amygdaloid complex in the monkey. Brain 85, 505-520. Nauta, W. J. H. (1971). The problem of the frontal lobe: A reinterpretation. J. Psychiat. Res. 8, 167-187. Niemer, W. T., Goodfellow, E. F., and Speaker, J. (1963). Neocorticolimbic relations in the cat. Electroencephalogr. Clin. Neurophysiol. 15,827-838. Papez, J. W. (1929). "Comparative Neurology." New York: Harrier. P. 313. Papez, J. W. (1937). A proposed mechanism of emotion. Arch. NeuroL Psychiat. (Chicago) 38, 725-743. Petsche, H., Gogolak, G., and Zweiten, P. A. (1965). Rhythmicity of septal cell discharge at various levels of reticular excitation. Electroencephalogr. Clin. Neurophysiol. 19, 25-33. Powell, E. W. (1963). Septal efferents revealed by axonal degeneration in the rat. Exp. Neurol. 8, 406-422. Powell, E. W. (1964). Corticolimbic interrelations revealed by evoked potential and degeneration techniques. Exp. Neurol. 10, 463-474. Powell, E. W. (1966). Septal efferents in the cat. Exp. NeuroL 14, 328-337. Powell, E. W. (1973). Limbic projections to the thalamus. Exp. Brain Res. 17, 394-401. PoweU, E. W., and Robinson, P. F. (1974). Cinguloseptal connections. Anat. Rec. 178, 440. Powell, E. W., and Hines, G. (in press). Septo-hippocampal interface. In R. L. Isaacson and K. H. Pribram (Eds.), "The Hippocampus: A Comprehensive Treatise," New York: Plenum Press.
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Powell, E. W., Akagi, K., and Hatton, J. B. (1974). Subcortical projections of the cingulate gyrus in cat. J. Hirnforsch. Powell, E. W., Furlong, L. D., and Hatton, J. B. (1970). Influence of the septum and inferior colliculus on medial geniculate body units. Electroencephalogr. Clin. Neurophysiol. 29, 74-82. Powell, E. W., Winter, C° G., Kirby, M. E., and Austin, B. (1972). Mammillary body fluorescence changes following septal or hippocampal lesions in the rat. Neurobiology 2, 149-153. Powell, T. P. S., Guillery, R. W., and Cowan, W. M. (1957). A quantitative study of the fornix-mamillo-thalamic system. J. Anat. 91,419-437. Pribram, K. H. (1960). The intrinsic systems of the forebrain. In J. Field, H. W. Magoun, and V. E. Hall (Eds.), "Handbook of Physiology," Section I, Neurophysiology, V. II. Baltimore: Williams & Wilkins. Pp. 1323-1344. Pribram, K. H., Lennox, M. A., and Dunsmore, R. H. (1950). Some connections of the orbito-fronto-temporal limbic and hippocampal areas of Macaca mulatta. J. NeurophysioL 13, 127-135. Raisman, G. (1966). The connexions of the septum. Brain 89, 317-348. Raisman, G., Cowan, W. M., and Powell, T. P. S. (1965). The extrinsic afferent, comimssural and association fibers of the hippocampus. Brain 88, 963-996. Raisman, G., Cowan, W. M., and Powell, T: P. S. (1966). An experimental analysis of the efferent projections of the hippocampus. Brain 89, 83-108. Robertson, R. T., and Rinvik~ E. (1973). The corticothalamic projections from parietal regions of the cerebral cortex. Experimental degeneration studies in the cat. Brain Res. 51, 61-79. Sanwald, J . C., Porzio, N. R., Dean, G. E.,and Donovick, P. J. (1970). The effects of septal and dorsal hippocampal lesions on the cardiac component of the orienting response. Physiol. Behav. 5, 883-888. Sherrington, C. S. (1947). "The Integrative Action of the Nervous System," (2nd ed.). New Haven: Yale University Press. Pp. 385-390. Shumilina, A. I. (1973). Afferent synthesis as the initial stage of behavioral act. Zh. Vyssh. Nerv. Deyatil. im. LP. Pavlova. 23, 282-288. Siegel, A., and Tassoni, J. P. (1971a). Differential efferent projections from the ventral and dorsal hippocampus of the cat. Brain Behav. Evol. 4, 185-200. Siegel, A., and Tassoni, J. P. (1971b). Differential efferent projections of the lateral and medial septal nuclei to the hippocampus in the cat. Brain Behav. Evol. 4, 201-219. Sierra, G., and Fuster, J. M. (1968). Facilitation of secondary visual evoked responses by stimulation of limbic structures~ Electroencephalogr. Clin. Neurophysiol. 25, 274-278. Simmons, H. J., and Powell, E. W. (1970). A quantitative analysis of septothalamie projections in the squirrel monkey. Anat. Rec. 166, 378. Simmons, H. J., and Powell, E. W. (1972). SeptomammiUary projections in the squirrel monkey. Acta. Anat. 82, 159-178. Simonov, P. V. (1972). On the role of the hippocampus in the integrative activity of the brain. Zh. Vyssh. Nerv. Deyatel. ira. LP. Pavlova. 22, 1119-1124. Simpson, D. A. (1952). The efferent fibers of the hippocampus in the monkey. J. Neurol. Neurosurg. Psychiat. 15, 79-92. Stephan, H., and Andy, O. J. (1964). Cytoarchitectonics of the septal nuclei in old world monkeys (Cercopithecus and Colobus). J. Hirnforsch. 7, 1-23. Stevens, R., and Cowey, A. (1973). Effects of dorsal and ventral hippocampal lesions on spontaneous alternation, learned alternation and probability learning in rats. Brain Res. 52, 203-224.
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Stumpf, C. (1965). The fast component in the electrical activity of rabbits' hippocampus. Electroencephalogr. Clin. Neurophysiol. 18, 477-486. Valenstein, E. S., and Nauta, W. J. H. (1959). A comparison of the distribution of the fornix system in the rat, guinea pig, cat and monkey. J. Comp. Neurol. 113, 337-363. Vanderwolf, C. H. (1969). Hippocampal electrical activity and voluntary movement in the rat. Electroencephalogr. Clin. Neurophysiol. 26, 207-218. Vanegas, H., and Flynn, J. P. (1968). Inhibition of cortically-elicited movement by electrical stimulation of the hippocampus. Brain Res. 11,489-506. Vinogradova, O. S. (1973). Some problems of memory and the role of the limbic systems in the registration of information. Zh. Vyssh. Nerv. DeyateL im. LP. Pavlova. 23, 305-314. Votaw, C. L. (1959). Certain functional and anatomical relations of the cornu ammonis of the Macaque monkey I. Functional relations. J. Comp. Neurol. 112, 353-382. Votaw, C. L. (1960). Certain functional and anatomical relations of the cornu ammonis of the Macaque monkey II. Anatomical relations. J. Cornp. Neurol. 114, 283-293. Walker, A. E. (1966). Internal structure and afferent-efferent relations of the thalamus. In D. P. Purpura and M. D. Yahr (Eds.), "The Thalamus." New York: Columbia University Press. Pp. 1-12. Whishaw, I. Q., and Vanderwolf, C. H. (1973). Hippocampal EEG and behavior: changes in amplitude and frequency of RSA (theta rhythm) associated with spontaneous and learned movement patterns in rats and cats. Behav. Biol. 8, 461-484. White, L. E. (1959). Ipsilateral afferents to the hippocampal formation in the albino rat. J. Comp. Neurol. 113, 1-42. Yakovlev, P. I., and Locke, S. (1961). Limbic nuclei of thalamus and connections of limbic cortex. III. Corticocortical connections of the anterior cingulate gyrus, the cingulum, and the subcallosal bundle in monkey. Arch. Neurol. 5, 364-400. Zanchetti, A. (1967). Subcortical and cortical mechanisms in arousal and emotional behavior. In G. C. Quarton, T. Melnichuk, and F. O. Schmitt (Eds.), "The Neurosciences." New York: Rockefeller University Press. Pp. 602-614. Zuckerkandl, E. (1888). Das Riechbandel des Ammonshornes. Anat. Anz. 3, 425-434.
The Limbic System: An Interface
ERVIN WILLIAM POWELL and GARTH HINES 1
Department of Anatomy, University of Arkansas School of Medicine, Little Rock, Arkansas 72201 and Department of Psychology, University of Arkansas at Little Rock, Little Rock, Arkansas 72201
Much work has related limbic structure with hypothalamic function rather than with higher nervous system function. Most studies have dealt with single limbic structures rather than with several as interrelated functional systems. Upon consideration of the total limbic-strueture complex it would appear that the septum-hippocampus-amygdala form an interface between the isocortex and the thalamus. Our work relating to projections of the limbic system, especially the septal area, has directed our attention to the thalamus as a particularly important target of limbic system projections. Furthermore, our work on projections of the cingulate gyrus reveals that this cortical area projects strongly to other cortical regions as well as to thalamic nuclei. The orbital frontal cortex, eingulate gyms, and hippocampal gyrus are isocortical areas which then link the limbic system with other corticothalamic systems. This feature, plus strong thalamic connections from the hippocampus, septum, and amygdala provide a basis for considering the limbic system as an interface between the overlying cerebral isocortex and thalamic structures. This interface may be a key integrating system related to selective modulation of emotion and sensory mechanisms of the brain via a number of feedback circuits wherein recycling could be effected through the temporal and/or the frontal cortex.
There is still no satisfactory general concept of how the limbic system is organized. The hippocampus has been studied as a key structure of the limbic system by many investigators since Papez (1937) first proposed an anatomical framework for emotional mechanisms of the brain. Structurally, the hippocampus is known to project through the fornix to the hypothalamus 1This research was supported Lucas, Ture Sehoultz, and Robert Arkansas School of Medicine, for Geraldine Brown, Jean Galatzan, and
by NSF Grant GB32170. The authors thank Drs. Ed Skinner, Department of Anatomy, University of discussing and helping with the manuscript and Robert Leman for their technical assistance. 149
Copyright © 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
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(Simpson, 1952; Guillery, 1955; Powell et al., 1957; Raisman et al., 1966). This orientation has lead investigators to consider the hypothalamus as a primary center o f limbic function and main source o f cerebral feedback modulation (Feldman, 1962; Zanchetti, 1967; A n d y et aL, 1972; Clemente and Chase, 1973). Major inputs to the hypothalamus (Fig. 1) are via the fornix column, medial forebrain bundle, stria terminalis, substantia innominata, and mammillary peduncle. All o f these fiber connections originate in a limbic structure with but one possible exception, the mammillary peduncle. The mammillary
Fig. 1. Drawing of limbic pathways. There are many connections with the hypothalamus. The hypothalamus lies ventral to the hypothalamic sulcus (about the level of the most dorsal fibers of the medial forebrain bundle). The midpart of the optic chiasm and the posterior edge of the mammillary body mark the anterior and posterior boundaries respectively. Modified from Papez (1929) drawing of the olfactory brain in the rabbit. At-Anterior commissure; Ad-Anterodorsal nucleus of the thalamus; A g Amygdala; Ah-Anterior hypothalamus; Am-Anteromedial nucleus; An-Anterior thaiamic nuclei; Av-Anteroventral nucleus; Ca-Cornu ammonis; Cc-Corpus callosum; C d Caudate nucleus; Cg-Cingulate gyrus; Ci-Cingulum; Ch-Optic chiasm; Ct-Neocortex; Df-Dorsal fornix; D1-Dorsal longitudinal fasciculus; Fb-Fornix body; Fc-Fornix column; Fd-Fascia dentata; Fx-Fornix; Gp-Globus pallidus; Hb-Habenula; HgHippocampal gyrus; Hi-Habenulointerpeduncular tract; Hp-Hippocampus; Ic-lnternal capsule; Ip-Interpedunclular nucleus; Is-Insula; Ld-Lateral dorsal nucleus of thalamus; Ls-Longitudinal stria; Mb-MammiUary body; Me-Midbrain tegmentum; Mr-Medial forebrain bundle; Mp-Mammillary peduncle; Mt-MammiUothalamic tract; Ob-Olfactory bulb; Oc-Occipital cortex; Of-Orbital frontal cortex; O1-Olfactory tract; Ot-Olfactory tubercle; Pa-Paraventricular nucleus of hypothalamus; Pf-Precomissural fornix; P o Postcomissural fornix; Pv-Periventricular nucleus of thalamus; Pt-Parataenial nucleus of thalamus; Re-Reuniens nucleus; Rh-Rhomboid nucleus; Rt-Lateral reticular nucleus of the thalamus; Sb-Subiculum; Se-Septum; S1-Splenum of corpus callosum; Sm-Stria medullaris thalami; So-Supraoptic nucleus of hypothalarous; St-Stria terminalis; T a Temporoammonic tract; Th-Thalamus; T1-Temporal lobe; Tr-Thalamic radiations; U f Uncinate fasciculus; V-Ventricle; Va-Ventral anterior nucleus of thalamus; Vm-Ventral medial of hypothalamus; Zi-Zona incerta.
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peduncle is composed of fibers which are collaterals of sensory fiber systems and input from the midbrain tegmental nuclei, which are part of the midbrain limbic area (Fox, 1941, Nauta, 1958; Cowan et aL, 1964). The medial forebrain bundle contains projections from the septum, olfactory tubercle, orbital frontal cortex, and amygdala. The stria terminalis and substantia innominata contain the principal efferent projections of the amygdala to the hypothalamus. Thus, the hypothalamus has been emphasized as the main target of the limbic structures in spite of considerable work which reports connections to the thalamus and other areas, e.g., isocortex, olfactory tubercle, and midbrain (Powell et al., 1957; Johnson, 1959; Valenstein and Nauta, 1959; Powell, 1963; Raisman et al., 1966; Powell et al., 1970; Simmons and Powell, 1970; Siegel and Tassoni, 1971a, b). It would appear that such connections attest to the hypothalamic dependence on limbic system input but they do not necessarily reflect a reciprocal dependence of limbic system on hypothalamic function. Major effector pathways of the hypothalamus are via the dorsal longitudinal fasciculus, reticulospinal tracts, hypothalamohypophyseal tract, and neuroendocrine mechanisms. The mammillothalamic tract is a large hypothalamic efferent projection although it is not usually understood as an hypothalamic effector (motor) pathway. While the h3ipothalamus is the recipient of a number of inputs from the latter structures, they also have a number of other targets. A diagram of many of the limbic system structures and connections is shown in Fig. 2. The circuit
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Fig. 2. Diagram of the limbic system. The Papez circuit is indicated by the arrows. Other structures and connections shown have been added to the system since his initial proposal.
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initially proposed by Papez may be traced by following the arrows from structure to structure. Subsequently, it has been shown that the hippocampus is interconnected with other structures in addition to those originally proposed. Many of these structures are indicated in Fig. 2. In general, fibers originating in the hippocampus project to the septum, olfactory tubercle, anterior thalamus, and mammillary body (MacLean, 1949; Gfllery, •956; Valenstein and Nauta, 1959; Green, 1964; Livingston and Escobar, 1971; PoweU and Hines, in press). Subsequent to fomix transection we have observed degeneration in the dorsal septal nuclei of the squirrel monkey equal in density and area involved to that which was observed in the mammillary body (Powell, 1973). The septal area should include the dorsal, ventral, medial, and caudal group of nuclei listed by Andy and Stephan (1964) and Stephan and Andy (1964) plus the accumbens nucleus and hippocampal rudiment. The hippocampal rudiment appears to be a slightly hypertrophied anterior terminus of the indusium griseum (gray matter of the medial longitudinal stria) and is juxtaposed to the gyrus rectus and the dorsal septal nuclei. This relation is similar to that found posteriorly where the fascia dentata is juxtaposed to the hippocampus and also connected to the dorsal septal nuclei via the fornix. There are also a considerable number of projections from the septum to the hippocampus (Powell, 1963; Raisman et al., 1966). Other structures which project to septal nuclei, e.g., those from the midbrain limbic area (raphe nuclei) via the medial forebrain bundle (Guillery, 1957; Nauta, 1958; Powell, 1963; Raisman, 1966), may in turn be relayed to the hippocampus. Some rather detailed structural studies of septohippocampal interrelations indicate that a fine degree of regulation and topographic contact exists between these two structures (Raisman et al., 1965; Raisman, 1966; Siegel and Ta{soni, 1971a, b). Siegel and Tassoni generally relate the projections of the dorsal and ventral hippocampus to the medial and lateral septal nuclei, respectively, and return connections to the dorsal and ventral hippocampus from the lateral and medial septal nuclei. We have concluded from our studies of degeneration resulting from transections of the fornix body in the monkey that primary synaptic relations to the dorsal septal nuclei exist (Powell, 1973). A part of the septohippocampal interconnection is also formed by the hippocampal fascia dentata and its projection through the medial longitudinal stria to the hippocampal rudiment of the septum (Crosby et al., 1962). Our studies indicate that these connections are probably multisynaptic or indirect through other structures, e.g., cingulate gyrus. In experiments where the indusium griseum has been lesioned or injected with radioactive leucine, degeneration or terminals was not observed to extend far along the stria and indusium (PoweU, 1963; Powell and Robinson, 1974). The indusium griseum appears to be
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reciprocally connected with the cingulate gyms and septal nuclei (Powell, 1963; Raisman et al., 1965; Domesick, 1969; Siegel and Tassoni, 1971b). The septum has been shown to project to the cingulate gyrus (Powell, 1963; Cragg, 1965; Kemper et al., 1972) in addition to its projections to the hippocampus. It has also been shown since Zuckerkandl (1888) and Cajal (1911) to interconnect with the olfactory tubercle region. The septum is also interrelated with other cortices, especially those determined to be near the lateral fissure (Niemer et al., 1963; Powell, 1964; Johnson et al., 1968). In addition to projections of the hippocampus mentioned above, there are also sizeable ones with temporal lobe structures via the temporoammonic tract and its perforating fascicles (Votaw, 1959, 1960; Powell, 1963; Elul, 1964; Cragg, 1965; Hjorth-Simonsen, 1971; Siegel and Tassoni, 1971a; Hjorth-Simonsen and Jeune, 1972). These connections are distributed through a wider area and structurally are not as obvious as the fornix bundle. Thus, hippocampal efferents to the subiculum and cortices of the hippocampal gyrus are frequently overlooked. Hippocampal afferents from the hippocampal gyms, however, are better documented and have been reported by various workers (Cajal, 1911; Allen, 1948; Blackstad, 1958; Raisman et al., 1965; Hjorth-Simonsen and Jeune, 1972). Furthermore, connections between the hippocampal cortex and the amygdala have been demonstrated (Gloor, 1960; Nauta, 1962; Cowan et al., 1965). Thus, these pathways provide reciprocal connections between the hippocampus and the amygdala via the subiculum and hippocampal cortex. These latter cortical regions also connect the posterior part of the cingulate gyrus with the hippocampus (White, 1959; Raisman et al., 1965; Domesick, 1969; Powell et al., 1974). Recently, it has been shown that the hippocampus and the septum both project independently to the mammillary body and to the anterior thalamic nuclei (Simmons and Powell, 1972; Powell, 1973). Various workers have reported thalamic projections from the septum and the hippocampus (Valenstein and Nauta, 1959; Powell et al., 1957; Powell, 1963, 1966; Powell et al., 1970; Siegel and Tassoni, 1971a, b; Powell, 1973). There is evidence in the rat, cat, and monkey that the septum projects more strongly to the anteromedial nucleus while the hippocampus projects more strongly to the anteroventral nucleus (Fig. 3). Quantitative studies have also shown that the septum and the hippocampus both project more heavily to the thalamus than they do to the hypothalamus. Powell (1973) showed that degeneration was as great or greater in thalamic nuclei than it was in the mammillary body after lesion of the septum or transection of the fornix body. He also found that degeneration in the lateral dorsal nucleus, which appears to be equal in size to the mammillary body, was as dense as was that observed in the medial mammillary nucleus. The anterior thalamic nuclei are also larger than the mammillary body. Data reported by Blinkov and Glezer (1968) in4icate that
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Fig. 3. Illustration of degeneration in the anterior thalamic nuclei. A, B, and C show a preferential degeneration in the anteromedial nucleus of the thalamus (Am) after a lesion in the septum of the rat, cat, and monkey, respectively. A', B', and C' show a preferential degeneration in the anteroventral nucleus of the thalamus (Av) after a lesion in the fornix body of the rat, cat, and monkey, respectively. Modified from Powell, 1963; Powell, 1966; Powell, 1973.
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the anterior thalamic nuclei are about double the size of the medial mammillary nucleus. Hence, there are probably more connections with these nuclei than there are to the mammillary body. Thalamus, especially the anterior nuclear complex, is an excellent example of an area of anatomical convergence (Fig. 4). For example, the hippocampus, septum, mammillary body, and cingulate gyrus all project profusely to the anterior thalamic nuclei. Knook (1966)reported reciprocal connections in the mammillothalamic tract between the anterior nuclei and the mammillary body. Therefore, these structures could provide various types or levels of functional feedback bias through the thalamus. The cingulate cortex, which receives connections from thalamic nuclei, projects via association fibers to other cortical areas (frontal, parietal, and temporal cortices) as shown by various workers (Yakovlev and Locke, 1961; Krieg, 1963; Locke et al., 1964; Airapetyants and Sotnichenko, 1967; Domesick, 1972; Locke and Kerr, 1973; Powell et al., 1974). These other cortical receiving_ areas are known to project in turn to thalamic nuclei (Walker, 1966; Johnson et al., 1968; Robertson and Rinvik, 1973), as do some areas of the cingulate gyrus, (Domesick, 1969). Such anatomical evidence suggests that there may be a functional relevance to a limbic system interface between the cerebral cortex and thalamic nuclei in preference to one between cerebral cortex and hypothalamic nuclei.
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Fig. 4. Thalamic emphasis of limbic connections. Hippocampal connections are shown by solid lines. Septal connections are shown by dashed lines. Other connections, shown by dotted lines, arise mainly from the mammillary body, cingulate gyms, and, especially, cortical association areas.
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Electrophysiological experiments have shown that hippocampal theta activity (synchronized 4-8 Hz) originates in and is topographically related to septal nuclei (Anderson et aL, 1961; Green, 1964; Vanderwolf, 1969; BrustCarmona et aL, 1973). This is commensurate with various data relevant to septal lesion studies. Septal lesions prevent the development of hippocampal theta activity in the region of the hippocampus which receives projections from the dorsal and lateral septal nuclei (Green and Arduini, 1954; Anderson et aL, 1961; Brugge, 1965; Stumpf, 1965; Petsche et aL, 1965; Gogolak et al., 1968; Brust-Carmona, 1973). Theta activity and habituation as indicated by behavior and electroencephalographic recordings have been associated with learning and memory (Herrick, 1933; Green, 1964; Klemm, 1972; Landfield and McGaugh, 1972; Bennett et al., 1973; Stevens and Cowey, 1973; Vinogradova, 1973; Whishaw and Vanderwolf, 1973; Lucas et al., 1974). Habituation occurs as hippocampal theta returns to the electroencephalogram subsequent to a brief alert record induced by a novel stimulus (Karmos and Grastyan, 1962). If theta activity and habituation do not occur, a hypersensitive (overresponsive or confused) animal results (Vanegas and Flynn, 1968; Crowne et al., 1972; Simonov, 1972). Furthermore, animals failed to habituate to a novel stimulus if hippocampal theta activity was eliminated by lesions of the septum or hippocampus (Sanwald et al., 1970). This is consistent with the finding that animals with septal lesions which spared medial septal nuclei were less deficient in the position-reversal task than were those with the medial nuclei damaged (Hamilton et aL, 1970). Evidence indicating the concept that serotonin may be a neurotransmitter released by hippocampal terminals in the mammillary body nuclei has been reported, while the septum has been shown to be potentially related to three different neurotransmitter (Powell et al., 1972). Hence, the septum, through selective influence of its nuclei might in turn topographically modify neurotransmitters quantity and quality to differentially activate the hippocampus. The hippocampus might then exert an habituating influence as it projects to the thalamus and mammillary body. Thus far the emphasis has been placed on septal and hippocampal connections between the anterior limbic cortex and the thalamus. As anatomically inferred above, there is also a hippocampal-amygdala interface between the hippocampal cortex and the thalamus. The amygdala, like the septum, is a multinucleated thalamus-like structure with reciprocal hippocampal c~nnections via entorhinai cortex, subiculum, and temporoammonic tracts (Pribram et al., 1950; Gloor, 1960; Crosby et al., 1962; Hjorth-Simonsen, 1971; Chronister et al., 1974). Strong connections from the amygdala to the dorsal medial nucleus of the thalamus have been demonstrated (Fox, 1949; Nauta, 1961). Thus, both the septum and the amygdala have relatively intimate connections with the hippocampus and both structures form an interface between phylogenetically more complex cerebral cortex and
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the dorsal thalamus. Hence the emphasis on septohippocampal relations made above should appropriately be expanded to include the hippocampal reciprocity with the temporal lobe. Thus, a limbic system interface exists between the neocortex o f the cerebral hemispheres and the thalamus, as illustrated in Fig. 5. Such a perspective of the structural data strongly suggest that a considerable functional emphasis of the limbic system relates to thalamic nuclei and their cortical integrating mechanisms (capacity). Sierra and Fuster (1968) have indicated that limbic activity can modulate cortical evoked responses after visual stimulation. That the modulation was occurring at the cortical level was inferred by the absence of evoked potential change at the lateral geniculate body. This suggests the possibility that ongoing hypothalamic function could then be affected by the dynamics of corticothalamic circuit input or recycling. Such recycling via corticothalamic circuitry could modulate input phases as well as cancel output channels of cerebral pathways. That is, accentuation or inhibition of cerebral input would appear to be an efficient way to control and override cerebral output, circumventing the stopping of ongoing cerebral activity in order to arrest a motor or behavioral event. Such an emphasis is in agreement with physiological data on exteroceptive input (Powell et al., 1970; MacLean, 1972), the finding that stimulation of some central structures may function as either positive or negative reinforcement, depending on the nature of the environmental condition of the external input (Ellen and Powell, t966), and the
CEREBRAL OUTPUT
Fig. 5. Limbic system interface between the lobes of the cerebral hemisphere and the thalamus as discussed in the body of the text.
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observation that cortical responses associated with the acquisition of a classically conditioned response are closely associated with electrical activity changes in the hippocampus (Malcolm, 1958). We would thus like to present the limbic system as a quality-choice interface between an overlying cerebral cortex integrator (the cerebral override system which makes it possible to maintain an organized balance and sequencing of more than one modality) and an underlying brainstem implementor (the brainstem and spinal cord apparatus, including the final common pathway and analogous visceral output to muscle, blood vessels, and visceral organs which are essential to normal facilitation and inhibition of the particular function of the end Organ) (Fig. 5). The limbic system, imposed between the cerebral cortex and the brain stem, appears to have at least two phases, similar to that forwarded by Pribram (1960) for problem solving. He mentioned two classes of behavior: differentiative and intentional. Posterior and frontal cerebral systems were associated, respectively, with these two behavior classes. For example, the parietal and temporal lobe (posterior systems) lesions interfere with the ability to differentiate during searching activity, thus affecting problem delineation. Lesions of the frontal lobe (frontal systems) encumber the ability to volitionally implement a behavior, presumably subsequent to a preliminary completion of problem-delineation activity. Pribram further noted that Sherrington (1947) made this kind of general distinction in his description of the coordination of reflexes. Anteriorly the limbic system is composed of the dorsal hippocampus and the septum which are interconnected via the fornix. Posteriorly it is composed of the ventral hippocampus and the amygdala which are interconnected via the subicuhim and the temporoammonic tracts. The anterior phase is in close association with the anterior parts of the cingulate gyms and the prefrontal cortex, i.e., Brodmann areas 8, 10, 11, and 12 (DeVito and Smith, 1964; Johnson et al., 1968). The prefrontal Cortex is thought to be associated with higher nervous-system functions [abstraction and temporal sequencing] (Pribram 1960; Nauta 1971) which we shall designate as choice-integration. Other areas of the frontal cortex, i.e., Brodmann areas 4 and 6, relate to the integration of motor functions. The posterior limbic phase, consisting of the ventral hippocampus and amygdala, are in close association with the temporal lobe. Studies of memory and learning mechanisms, as stated above, frequently involve these structures, hence they may be presumed to function in memory integration (Fig. 5). The primary sensory cortices serve as the brain sensor or initial input areas. A large part of the parietal cortex is an area where the integration of primary sensory inputs probably occurs. Hence, the firststimulus thrust is probably from primary cortical sensory areas (Shumilina, 1973) and thence to a topographic modulation through the limbic interface to the thalamus and subsequent recycling through various feedback circuits including neocortical ones. The ventral hippocampus in connection with the
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Fig. 6. Diagram of some possible functional roles of the septal-hippocampal connections. The septum, hippocampus, and mammillary body project preferentially to the anteromedial, anteroventral, and anterodorsal nuclei respectively. The septum and hippocampus each have a different projection to the mammiUary body. The septum and hippocampus also have a different effect on motivation as measured by terminal response rate, i.e., septum was usually found to inhibit and the hippocampus to facilitate bar pressing (Ellen and Powell, 1962). The thalamic nuclei are in a position to integrate various sources of stimuli and cycle them as feedback through the subiculum to the hippocampus. This allows not only for disparate effects from particular structures but also for a multiplicity of secondary cues.
amygdala would likely be involved in defensive and learning orientation, similar to that suggested by Simonov (1972). The more global dynamics of memory and imagination could reciprocate through the thalamus via the dorsal medial nucleus and the frontal lobe, from whence the motor output of the cerebrum seems to be voluntarily generated, and then be transmitted through motor structures of the brain stem to appropriate somatic and visceral organs for expression. Thus, (assuming that the main function of the limbic system relates to lower autonomic effects and emotions, e.g., love, hate, fear, and rage), limbic connections, including those with the thalamus and overlying cerebral cortex, probably carry impulses which introduce and adjust (modulate) the emotion input into the total cerebral system (Fig. 6); while those limbic projections which traditionally have received considerable attention, i.e., those directed to the hypothalamus, probably elicit reflex-oriented mechanisms subject to little, if any, additional influence.
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