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ACTA NEUROBIOL. EXP. 1979, 39: 503-516 Lecture delivered at the Warsaw Colloquium o n Instrumental Conditioning and Brain Research May 1979 THE EMOTIOGENIC BRAIN STRUCTURES IN CONDITIONING MECHANISMS: CONDITIONED EVOKED POTENTIALS AND MOTOR RESPONSES R. Yu.ILYUTCHENOK Institute of Physiology, Siberian Branch of the Academy of Medical Sciences of the USSR, Novosibirsk, USSR Abstract. The emotiogenic rnorphofunctional control system consists of the amygdaloid complex \(AM), the zona incerta, the peri- and paraventricular nuclei of the hypothalamus and the midbrain central gray matter (CG). The neuronal relationships between the structures of this system were established. Lesions of these structures prevented one-trial learning, whereas electrical stimulation of the AM or the CG permitted retrieval of a trace which was lower than threshold. AM stimulation accelerated learning 'by 5-10 times. The possible mechanisms of the emotiogenic control system of memory' are discussed. The contributim of the identified structures of the emotiogenic control system of memory was quantitatively estimated, by employing a matrix of the interaction of these structures during the performance of conditioned aeurographic responses of the radial nerve. The approach established the role of the emotiogenic control system in the spatial-temporal organization of brain structures needed for the retrieval of conditioned motor responses. Weakly trained cats, in which the AM-CG had been stimulated, did not differ from well trained ones in the patterns and correlation matrices of the conditioned evoked potentials. AM-CG activation may accelerate learning by reproducing such spatial-tkmporal relationships that are characteristic of well trained animals. Ample evidence for the important role of emotions in memory has come from recent studies. However, it is not clear how emotions contribute to this process. Specifically what makes the mechanisms of the emotions-memory interaction difficult to identify? Gaps exist in our knowledge of: 1. The spatial-temporal patterns of the system of emotiogenic structures involved in memory control. 2. The relative contribution of each emotiogenic structure and the interaction of these structures during conditioning. Further, there remain open questions of: 1. What changes are elicited by the excitation of emotiogenic structures, and in which brain regions? 2. What determines the i~nfluenceof emotiogenic structures on memory: the activation of the emotiogenic structures during the presentation of the unconditioned stimulus, or the brief residual process in these structures, or even long-term retention (perhaps, for life) of memory in the emotiogenic structures? It is difficult to provide an accuate assessment of the control system of memory because each brain structure contributes specifically to conditioning. To evaluate the structures composing this system, a more rigorous criterion is needed than the #degree of changes in conditioned responses acquired as the result of repeated pairings. The limit of memory trace control is information fixation at its first presentation, that is me-trial learning. Our analysis of one-trial learning was based on a model of the passive avoidance conditioned response. As a result, we identified those lesions of brain structures which disturb the elaboration of this response. It has been reported that the amygdaloid complex (AM) (11, 14) and the ventrolateral region of the midbrain central gray matter (CG) (7) are substrates for one-trial learning. In our laboratory L. Loskutova and I. Vinnitsky (unpublished) have shown that rats with lesions of CG become immuned to one-trial learning when shocked with moderately (0.75 mA) or even very painful (1.5 mA) current. This has also been observed in amygdalectomized rats. It has been suggested that these structures may be integrated into a structural-functional emotiogenic system that controls memory processes. What structures and pathways compose the amygdaloid complexcentral gray (AM-CG) system? Fibers, which connect the AM with the subcortical brain structures (Fig. I), are the ventral amygdalofugal pathway (VAF) and the stria terminalis (ST). The VAF ends in the lateral preoptic and anterior-hypothalamic regions. The ST ends in the medial preoptic and anterior-hypothalamic regions. L. Loskutova and RMYCDRLOID COMPLEX PEPI- R N D PAQAVENTQICULAP NUCLEI OF T H E ZONA INCERTA CENTRRL GRRY HYPOTHRLRMU3 STRIA TEPMINA~IS PATHWCN Fig. 1. The emotiogenic regulatory system of memory in the rat. Lesions of the AM, the ST, the HPV, the CG completely prevent one-trial learning. Lesions of the VAF and the ZI prevent it only under moderately aversive stimulation. Current intensity: I, 0.75 mA; 11. 1.5 mA. 1, third day of familarization; 2. testing 24 h after learning; 3, testing 48 h after learning. White columns, for control rats; black column, for lesioned rats. cn 0 Ur I. Vinnitsky demonstrated that sections of either of these two pathways make rats incapable of one-trial learning. Thus, it suffices to transect the VAF a t the level of the preoptic area and the anterior hypothalamus to prevent the emotional response and the elaboration of the passive avoidance conditioned response in rats that received moderate footshock (0.75 mA). The integrity of the VAF is most probably needed for the appearance of the emotional response and its autonomic component. There are other data supporting this suggestion. Thus, stimulation of the sites of passage of the VAF fibers eliclts a defensive response with components of alertness and fear. Sections of the VAF in the preoptic and the anterior hypothalamic regions prevent the development of the response to AM stimulation (4). However, in our experiments, section of the VAF at the level of the preoptic area did not prevent me-trial learning when a strong footshock (1.5 mA) was delivered. Rats also did not lose the capacity for multi-trial learning after section of the VAF. Section of the VAF at the level of the caudal hypothalamus had no effect on one-trial learning. Clearly, the VAF is not the only pathway through which the AM influences memory. Bilateral sections of the ST prevented me-trial learning as well (Fig. 1). It is important to note that such a section made rats incapable of one-trial learning, even under the stmng footshock condition (1.5 mA) that resulted in learning in all animals of the control group. Indeed, it 1s noteworthy that the peri- and paraventricular nuclei, that is the primary sites where the ST ends, are the critical nuclei of the preoptichypothalamic region in one-trial learning. Lesion of these nuclei prevented one-trial learning t m , in spite of stmng footshock (Fig. 1). The integrity of zona incerta (subthalamus) is another significant condition ensuring one-trial learning. It should be emphasized that lesions of zona incerta prevented one-trial leanning only when a moderate footshock was delivered (Fig. 1). Under stronger stimulation, (1.5 mA current), one-trial learning was still possible; however the elaboration of some autonomic and motor components of the conditioned defensive response was poorer, as observed by N. Volf and S. Tsvetovsky (unpublished) in our laboratory. Thus, the system of emotiogenic nuclei essential for one-trial learning (Fig. I), and comprising the AM, preoptic area; z. incerta, peri- and paraventricular hypothalamic nuclei, the CG (the AM-CG system). In the case of the fixation of emotionally colored information, its biological meaning is perceived at the first presentation. The role of the AM-CG system is manifest in the course of linkage between memory trace and the retrieval program. Ln the case of repetitive trials, the biological information is perceived as meaningful only after a series of presentations, and here the role of the system is not so crucial. Even amygdalectomized rats are capable of multi-trial learning. However, AM-CG control is not excluded entirely. What is decisive in the regulatory function of the AM-CG system? Not its participation in the registration of reinforcement and not the evaluation of the biological meaning of the information, although they are important initial steps. The biologically meaningful ilnformatim has to be retained in the brain after its first input. Consequently, the role of the AM-CG system is a determinant in that it produces conditions for the rapid fixation of a memory trace. Possibly, the activation of the AM-CG system gives rise to two parallel processes, that is the appearance of emotions and the reorganization of the functional properties of the neurons of other brain structures providing the rapid fixation of a memory trace. However, it cannot be excluded that such a reorganization of the functional properties of neurons may be a coinsequence of emotions. To understand the role of emotiogenic brain structures in memory control, we attempted to evaluate the relative contribution of each nuclear structure and to determine how the structures interact fmctimally. We proceeded from the assumption that one-trial learning is one extreme of the continuum of engram control. It so, the AM-CG system can presumably regulate the fixation and retrieval of a memory trace in a wide range from null to me-trial learning. Therefore, repetitive pairings of conditioned and unconditioned stimuli (CS-US) can also be used to evaluate the contribution of the structures identified. For this purpose, M. Gilinsky and I. Pukhov (unpublished) used the conditioned evoked $potential (CEP) as suggested by Adam (1). The CEP-method has been described in detail earlier (5). The CEP, which is an electrographic manifestation of a memory trace in brain structures, was compared with the conditioned neurographic response of the motor nerve, a n effector component of the conditioned response. It was impossible to establish any unambiguous functional relationship between the manifestation of the conditioned evoked potential and the conditioned neurographic response. For this reason, these relationships were expressed as binary signs reduced to a common table. This approach, developed in cooperation with the Computer Centre of the Siberian Branch of the USSR Academy of Sciences (V. Drobishev, T. Freidin, unpublished), permitted us to establish statistically the relationships between the manif estatims of the conditioned neurographic response and the respective set of the CEP in various brain structures. Quantitative estimates of the relative contribution of each brain structure demonstrated that the appearance of the CEP in the z, incerta, the preoptic area and the auditory cortex is most frequently accompanied by a conditioned neurographic response. This made necessary the building of a matrix of the interaction of the various brain structures Fig. 2. A matrix of the relationship between the distribution of the conditioned evoked potential (CEP) and the neurographic response. The conditioned neurographic response is constantly elicited when the CEP appears simultaneously in the ZI, the APO and the AC. Black areas are those in which the CEP is distributed during the registration of the neurographic response. Dashed areas indicate the expected area of the neurographic response. evoked conditioned response; -, no response. +, during the manifestation of the conditioned neurographic response (Fig. 2). Analysis of this interaction indicated that the conditioned meurographic response was a constant concomitant of the CEP in the zona incerta, the preoptic area and the auditory cortex. The response also appeared, but with much lower probability, when the CEP was elicited simultaneously in various other combinations with the involvement of some of these structures. Taken collectively the analysis of data on the brain structures providing one-trial learning, the CEP probability of occurrence in these structures and their correlation matrices, confirm that the AM-CG system (the amygdaloid complex, the preoptic area, the zona incerta, the periand paraventricular nuclei of the hypothalamus, the midbrain central gray) indeed controls memory. Ln the control of versatile memory processes, this system undoubtedly interacts with the thalarno-cortical and other brain structures. The AM-CG control system of the formation and retrieval of memory trace was also made apparent in studies of the stimulation of the AM. In experiments with immobilized cats, M. Gilinsky and I. Pukhov (unpublished) showed that AM stimulation (60 pulsesls, pulse duration oif 0.2 rns 3 V, stimulation for 3-5 min) before learning greatly accelerates it. Stimulated cats learned after 20-60 pairings of the CS-US (Fig. 3); whereas nonlesioned cats required 120-300 pairings for acquisi- . \J., - $ '1:: 4 : -) :- . . .A' ;!;:-: :; 1 ,>/ audttory cortex i: ) I i preopt L C area . . radtap nerve .- mpv L 2Wms Fig. 3. Accelerated learning after amygdala stimulation in cats. The conditioned evoked potentials after amygdala stimulation as the result of 20-60 pairings of CS and US, as compared with 120-300 pairings in the control. A, habituation; B, 20 CS-US pairings after AM stimulation; C, testing after 20 min. Arrows indicate the time when the CS-US were presented. tion. Moreover, by artificially modifying the rhythm of the AM neurons, one-trial learning was achieved in a situation requiring repetitive trials for learning (3, 5). A similar effect was observed only when current in the frequency range of 40-60 pulses/s was applied, that is when a rhythm of burst electrical AM activity developed during emotional tension (9, 10). It follows that the activation of one of the influential structures of the system, the AM, greatly accelerates and facilitates the formation of a memory trace. A.n obvious question might now be asked: does the AM-CG system participate in the control of memory trace retieval? M. Gilinsky, G. Abuladze, V. Masycheva and I. P u k h v (unpublished) studied the spatial distribution of the CEP in brain structures and the retrieval of the conditioned neurographic response after the stimulation of the AM and the CG. The AM was stimulated (3-5 mi~ntrain of pulses, 0.2 ms duration at 60 liHz, 3 V) or the CG (3-5 min train (of pulses, 0.1 ms duration a t 1 I f.$ ,li- ,' P! : ,rC liA,.' > , i i !\ . z gray ~ onlwi~ I : 'i area /-preopt.kc -:/ Lb i 4 :.- rr - .L-n.ventra~,s 01~vL200ms i! .. .. ,%-.-- :?centrap !!,- ;r, i - L r o d l o l nerve Fig. 4. Facilitation of the retrieval of the conditioned responses by amygdala stimulation. When trained cats do not show conditioned response, AM stimulation facilitates the retrieval of the conditioned neurographic responses and CEP in the AC, the ZI, the CG, the APO. A, habituation; B, 181 to 200 paired presentations; C, testing promptly after 200 CS-US pairings; D, 30 min after AM stimulation. Arrows indicate the time when the CS-US were presented. 100 Hz, 3 V) only in the case when the first test after learning (100-200 CS-US pairings) diid not elicit the neurographic response. In the first test for the CEP, the potential either did not appear at all or was restricted to one, two crr three brain structures. The conditioned neurographic response appeared in 75O/o of caCs repetitively tested 20-30 min after the AM stimulation. It is remarkable that the conditioned neurographic response was registered simultaneously with the CEP in the auditory cortex, the zona incerta and the preoptic area (Fig. 4). As already mentioned, this simultaneity is of decisive importance in the performance of the behavioral response. Stimulation of the CG resulted in retrieval of the conditioned neunographic respmse in 62.5OIo of cats; the CEP was registe~edin the zma incerta, the preoptic area and, as a rule, in the AM. Hence, the activation of the structures of the emotiogenic control system of memory creates a spatial-temporal organization of brain structures that promotes the appearance of the effector conditioned response. Through what mechanisms does the emotiogenic control system act on memory? There are three lines of experimental evidence of relevance to the understanding of the influence of emotiogenic structures on memory trace formation. 1. There is an increase in the number of cortical neurons with polysensory properties after AM stimulation (8). The enhancement of p l y sensory properties is characteristic of the acquisition of a conditioned response under the effect of a biologically meaningful reinforcement (6). However, the switching of converging mechanisms for the provision of the interaction of stimuli is insufficient for their stable linkage (12). 2. The shortening of the autonomic residual r e s p s e s to an US after amygdalwtomy, observed in the experiments of Volf and Tsvetovsky (unpublished), may be evidence for the important role of the AM in residual processes, especially in the retention of emotional responses. The response of amygdalectomized animals to the direct action of stimuli is retained. The involvement of the AM in the activation of convergence and residual processes does testify to its significance in the control over trace formation. However, the capacity for one-trial learning cannot be explained by such an influence of the AM. 3. The most weighty line of evidence concerns inhibitory amygdalofugal influences. The capacity of inducing a rhythm of neuronal discharges in the AM for prolonging inhibition of impulse flow in the CG is indicative of a modulating type of AM ilnfluence on the CG (2). Conceivably, the major influence of the emotiogeni~ccontrol system on memory trace formation is to facilitate the emergence of a dominat focus and to act on direct (lateral) and recurrent inhibition underlying interference. Activating afferent flows exciting the structures of the emotiogenic control system arise during the stimulation of CG (where the affectivemotivational component of a n aversive stimulus are first perceived). According to the data of Dubrovina, 86O/0 of reactive neurons of the zosa incerta are excited during CG stimulation (Fig. 5). It may be thought that the delivery of emotionally colored information activates the CG, the initial component of the system which modulates affective behavior. This activation may spread over to other nuclei of the emotiogenic control system (those of the AM, the zona incerta, the peri- and paraventricular nuclei of the hypothalamus). This activation of the entire emotiogenic control system can provide conditions for the dominant determining of the activity of the neuronal centers at a particular point in time. A dominant focus itself is one of the initial steps of the elaboration of conditioned responses as demonstrated by Rusinov (13). There are also data (6) indicatirng that the dominant state produced by a biologically meaningful reinforcement is of importance in the rate of meurmal activity reorganization of a signal type and in the maintenance of established relationships. Subsequent amygdalofugal inhibition may maintain the dominant state. Stimulation of the AM inhibited 72O/o of reactive neurons in the Fig. 5. Neuronal activity in the amygdaloid complex - midbrain central gray matter system. The CG has predominantly a n excitatory ascending effect on the ZI neurons (A), whereas the AM has an inhibitory effect on the neurons of the ZI (B)and the CG (C). Fig. 6. Functional relationships in the amygdaloid complex - the midbrain central gray matter system. Convergence of inhibitory i~nfluencesdescending from the AM (1) and of excitatory influences ascending from the CG (2) a t the ZI neurons. Convergence of predominantly inhibitory influences descending from the AM (3) and the ZI (4) a t the CG neurons. CG and 64O/o of those in the z. incerta (Fig. 5). It is noteworthy that impulses from the AM and the zona incerta have predominantly an inhibitory effect (71°/o) on the same CG neurons (Fig. 6); convergence of excitative impulses was observed only in 20°/o of neurons (2). As to mna incerta, 57O/o of the neurons show an inhibitory response to the influence of the AM and an excitatory one to that of the CG; 30°/o of its neurons respond only by excitation to the influences of either the AM or the CG. Possibly, after the registration of biologically meaningful information, which was evaluated earlier at the level of the CG and the AM,amygdalofugal influences inhibit the structures of the emotiogenic control system. The emerging pattern of retroactive and proactive ifnhilbition may facilitate the formation of a dominant, thereby promoting the fixation of a single information input. Rapid and secure fixation of a trace and its linkage with the established retrieval program are provided by the weakening of the effects of preceding traces by retroactive inhibition, the enhancement of the dominant and the weakening of the interfering effects of subsequent emotionally colored sensory input by proactive inhibition. However, the feasibility of subsequent trace formation after different time intervals depends on whether the trace is readable, but not an how it is fixed (short- or long-term memory). Interference may be m e of the causes of the rapid passage of a fixed trace to a subthreshold state which impedes its retrieval; this is outwardly seeming short-term memory. This memory is short for the only reason that its trace has become subthreshold and difficult to retrieve. One is confronted here not with the disappearance of a short-term memory trace, but rather with its rapid passage to a subthreshold level. Many factors may be causative: retroactive inhibition due to interference of subsequent signals, insufficient reinforcement, attention concentration, general setting and emotional concomitants, among others. The presentation of a single stimulus, without emotions is promptly followed by a sort of information loss, forgetting. These time intervals of trace retention can be subdivided into shorter ones. We can thus obtain transient, ultrashort and other "versions" of memory, which explains why the so-called short term memory lasts from 10 s to several hours according to data iln the literature. In multi-trial learning, the biological meaning of a neutral stimulus becomes apparent only after its repeated pairings with reinforcement. The production of a dominant is facilitated by the summation of incoming stimuli. Each subsequent stimulus can reinforce the !preestablished trace making it more stable. This may promote the maintenance of a trace 10 - Acta Neurobiol. Exp. 6179 at a threshold level in which it remains readable for a long time, that is one is confronted here with long-term memory. Long retention of a memory trace is also possible in one-trial learning, provided that information input was emotionally associated. The activation of the emotiogenic control system of memory at the time of me-trial learning may result in stronger retroactive inhibition attenuat b g the effects of the preceding traces. This may promote the rise of a new dominant. In turn, the promoted dominant helps the trace to remain superthreshold longer in the structures of this emotiogenic system. Thus, conditions may arise favorable for subsequent retrieval. One of these major conditions is the m t a n t availability of a memory trace in the structures of the emotiogenic control system. The trace of emotional memory is not erased, nor is it subjected to amnesia (5). The subsequent emotions activate these traces making them easier to read in the emotiogenic structures, and, as a result, the whole adaptive program, preestablished and trace-linked in these structures, is efficiently retrieved. REFERENCES 1. ADAM, G. 1987. Interoception and behaviour. Acad., Kiado, Budapest. 2. DUBROVINA, N. I. and ILYUTCHENOK, R. Yu. 1978. Neuronal activity of midbrain central gray substance under amygdaloid and subthalamical stimulation (in Russian). Neurophysiologiya 3: 245-251. 3. GOLD, P. E., HANKINS, L., EDWARDS, R. M., CHESTER, J. and McGAUGH, J. L. 1975. Memory interference and facilitation with posttrial amygdala stimulation effect on memory varies with footshock level. Brain Res. 86: 509-513. e 4. HILTON, S. M. and ZBROZYNA, A. W. 1963. Amygdaloid region for defence reactions and its efferent pathway to the brain stem. J. Physiol. (Lond.) 165: 160-173. 5. ILYUTCHENOK, R. Yu., VINNITSKY, I. M. and LOSKUTOVA, L: W. 1977. Neirokhimicheskie mekhanizmy mozga i pamyat'. Izdat. Nauka, Novosibirsk. 6. KOTLYAR, B. I. 1977. Mekhanizmy formirovanija vremennoi' svyazi: Izdat. Gosud. Moscow Univ., Moscow. 7. LIEBMAN, J. M., MAYER, F. J. and LIEBESKIND, J. C. 1970. Mesencephalic central gray lesions and fear-motivated behavior in rats. Brain R e . 23: 353-370. 8. MAKAROV, V. A. 1970. The role played by the amygdala in the mechanism of convergence of stimulations of different sensory modality on the neurons of the large hemisphere cortex (in Russian). Rep. Acad. Sci. Ukr. SSR. 194, 6 : 1454-1457. 9. McLENNAN, H. and CRAYSTONE, P. 1965. The electrical activity of the amygdala and its relationship to that of the olfactory bulb. Can. J. Physiol. Pharmacol. 43: 1009-1017. 10. ONIANI, T. N. and ORJONIKIDZE, Ts. A. 1968. Changes in electrical activity of some brain structures of the cat during general behavioural reactions. In Contemporary problems of activity and structure of the central nervous system. Mezniereba, Tbilisi, p. 5-13. 11. PELLEGRINO, L. 1968. Amygdaloid lesions and behavioral inhibition in the rat. J. Comp. Physiol. Psychol. 65: 483491. 12. RABINOVICH, M. Ya. 1975. Zamykatelnaya funktsiya mozga. Izdat. Meditsina, Moscow. 13. RUSINOV, V. S. 1969. Dominanta. Medicine, Moscow. 14. VINNITSKY, I. M. and ILYUTCHENOK, R. Yu. 1973. Elaboration of defensive conditioned reflexes in amygdalectomized rats. Zh. Vyssh. Nervn. Deyat. Im. I. P. Pavlova 23, 4: 766-770. R . Yu. ILYUTCHENOK, Institute of Physiology, Siberian Branch of the Academy of Medical Sciences of the USSR, Zolotodolinskaya 101, 630090 Novosibirsk, USSR. LIST OF ABBREVIATIONS AC auditory cortex AHA anterior hypothalamic area AM amygdaloid complex preoptic area APO bed n. Str. t. bed nucleus of the stria terminalis diagonal band of Broca Br bulbus olfactorius Bulb. olf. midbrain central gray matter CG peri- and paraventricular nuclei of the hypothalamus HPV medial forebrain bundle MFB midbrain reticular formation RT stria terminalis ST nucleus ventralis anterior VA ventral amygdalofugal pathway VAF ventromedial hypothalamus Vm zona incerta ZI