Projections of the septum to the lateral hypothalamus

Evoked potentials recorded in the lateral hypothalamus (LH) of the rat to stimulation of the septum were observed to have response components of 3–6, 10–14, and 18–23 msec. These components were elicited from different regions of the septum; the 3–6 and 10–14 msec components from dorsal and midline regions corresponding to the projection field of the precommissural fornix from the hippocampus and the 18–23 msec component from a ventrolateral region corresponding to projections of the stria terminalis. Stimulation of the hippocampus and stria terminalis evoked responses in the LH of similar configuration but with latencies longer than the 10–14 and 18–23 msec components, respectively. Lesions in the dorsal midline and ventrolateral septum attenuated these responses suggesting that the precommissural fornix and stria terminalis are the pathways mediating the septal evoked components. These data provide a neuroanatomical framework for the dual role of the septum on response patterns elicited from the hypothalamus.     

Behavioral effects of lesions of precommissural and postcommissural fornix

Lesions which sever different parts of precommissural or postcommissural fornix were compared to the effects of control lesions in several behavioral tasks. Spatial learning and avoidance was impaired by lesions of the descending columns, or by lesions which sever the precommissural communications passing to and from medial septum. Damage to precommissural fibers through lateral septum produced a measurable change only on the avoidance task. This pattern of deficits, considered together with the anatomical relationship of the system, suggests a model in which the medial septum relays kinesthetic information to dorsal hippocampus, which in turn serves as a memory system in the performance of spatial habits. It is less clear what kind of information is relayed by lateral septum, but it may communicate with ventral hippocampus regarding the consequences of punishment, and thus serve as part of a system for defensive suppression of behavior.     

Hypothalamic afferent connections mediating adrenocortical responses that follow hippocampal stimulation

This study identified some neural pathways which mediate the adrenocortical responses that follow hippocampal stimulation. The increase in plasma corticosterone following dorsal hippocampus stimulation, in rats with electrodes chronically implanted under pentobarbital anesthesia, was blocked by dorsal fornix and lateral septal lesions and by small posterior hypothalamic deafferentation. Fimbria transection, lateral septal lesions, and posterior hypothalamic deafferentation, but not midbrain reticular formation lesions, also blocked the adrenocortical responses to ventral hippocampus stimulation. Our present and previous studies indicate that the dorsal and ventral hippocampal effects on the hypothalamus, which increase plasma corticosterone concentrations, are mediated by the dorsal fornix and fimbria, respectively, as well as by the lateral septum. A posterior hypothalamic input, which does not involve the medial forebrain bundle or the midbrain reticular formation is also essential for the activation of this response.     

Efferent connections of the hippocampal formation in the rat.

In this investigation the projections of the hippocampal formation to the septal area and hypothalamus were studied in the rat with the combined use of 3H-amino acid radioautography and horseradish peroxidase histochemistry. The results indicate that all of the fibers which project to the hypothalamus and the majority of fibers which project to the septum arise from the subicular cortex and not from hippocampal pyramidal cells. The projection to both of these areas are topographically organized along the longitudinal axis of the hippocampal formation. Specifically, fibers from subicular cortical cells situated at the septal end of the hippocampal formation which project through the medial part of the dorsal fornix terminate in the dorsomedial quadrant of the lateral septal nucleus and in the dorsal portion of the pars posterior of the medial mammillary nucleus. Fibers from progressively more posteroventral levels of the hippocampal formation which project through more lateral portions of the dorsal fornix and fimbria terminate in progressively lateral and ventral quadrants of the lateral septal nucleus and in progressively more ventral portions of the pars posterior. Concerning the specific origin of the fornix system, fibers from only the prosubiculum and subiculum project through both the pre- and postcommissural fornix. Hippocampal pyramidal cells from all CA fields have a restricted projection through the precommissural fornix and terminate in the caudal half of the septum while the presubiculum projects solely through the postcommissural fornix. The medial corticohypothalamic tract (MCHT) was found to arise from cells located in anterior ventral levels of the subicular cortex. Fibers from this tract appeared to be distributed throughout the pericellular region of the entire ventromedial extent of the hypothalamus from the level of the suprachiasmatic nucleus through the level of the medial mammillary nucleus. In this way, the mammillary bodies receive input from the subicular cortex via two routes: the descending column of the fornix and the MCHT.     

The topographical organization of the hippocampal projection to the septal area: a comparative neuroanatomical analysis in the gerbil, rat, rabbit, and cat

An experiment was performed to determine the origin of the projection from the hippocampus to the septal area in the subrimate mammalian nervous system. Lesions were made by aspiration or by radio frequency in 4 gerbils, 17 rats, 8 rabbits, and 7 cats. Survival times varied from 2–5 days. Tissues were stained principally with the Fink Heimer I method for identification of degenerating axons and their terminals. Following lesions destroying any one or more of the fields of the dorsal hippocampus of the gerbil, rat, rabbit, or cat, terminal degeneration was observed only in the medial septal area, olfactory tubercle, and adjacent portions of the diagonal band. In addition, lesions producing total destruction of all dorsal hippocampal fields also resulted in the presence of terminal degeneration restricted to the medial septal area. In contrast, superficial lesions of field CA1 of the ventral hippocampus produced terminal degeneration in the lateral septal area, nucleus accumbens, olfactory tubercle, and adjacent portions of the diagonal band. Similar findings were also observed following more widespread lesions of the ventral hippocampus which produced damage to other CA fields as well. Superficial lesions of the posterior crus of the hippocampus (i.e., a position midway between dorsal and ventral hippocampus) resulted in terminal degeneration localized to an intermediolateral region of the septum. Combined lesions of the dorsal hippocampus and fimbria produced widespread terminal degeneration in both the lateral and medial septum indicating that the axons contained within the fimbria arise only from the ventral hippocampus. Finally, lesions of the medial and lateral segments of the fornix of the cat produced terminal degeneration in the medial and lateral regions of the septum, respectively. These findings, collectively, indicate that the origin of the topographical projection to the medial and lateral septum are the dorsal and ventral hippocampus, respectively. This projection is unrelated to cytoarchitectonic fields within the hippocampus and is also invariant among the species considered in this study.     

Memory dysfunction following unilateral transection of the fornix: a hippocampal disconnection syndrome

This study presents a case with a discrete nondischarging lesion of the left fornix that resulted in a marked anterograde memory deficit that was defined by the same material, modality and methodologically specific features characteristic of unilateral lesions of the hippocampus. Since the fornix is the major efferent pathway of the hippocampus to the mamillary bodies, septal nuclei and anterior thalamic nuclei, this patient could be considered to have a hippocampal disconnection syndrome.     

T-maze alternation,response patterning,and septo-hippocampal circuitry in rats

The effects of small electrolytic lesions in the posterodorsal septal area (aimed at the precommissural fornix) on acquisition and retention of either a spatio-temporal task (contingently reinforced T-maze alternation) or a temporal task (response patterning in a straight runway) were investigated in Long-Evans rats. Acquisition of T-maze alternation was impaired following posterodorsal septal lesions, but with extensive training there was evidence of learning. Postoperative retention of T-maze alternation was also impaired by posterodorsal septal lesions but, again, with continued practice the experimental animals relearned the task and came to perform as well as controls. Postoperative acquisition of response patterning in a runway was significantly but not greatly impaired by posterodorsal septal lesions. The experimental animals did pattern, but not as well as controls, even after substantial practice. Retention of response patterning was severely impaired following lesions in the posterodorsal septum but, as in the T-maze task, experimental animals improved significantly in performance with postoperative practice. The results were interpreted in the light of two recent formulations of the functions of the septo-hippocampal system: cognitive mapping and working memory. However, the data are not conclusive and suggest that inhibition theories of septo-hippocampal function are possibly relevant.     

Neural systems and the inhibitory modulation of agonistic behavior: a comparison of mammalian species

The olfactory bulb, lateral septum, medial accumbens, medial hypothalamus, dorsal and median raphe, and amygdala are known from experiments in rats to participate in the inhibitory modulation of defensiveness and predation but not social aggression. The present paper surveys the influence of these structures in the inhibitory control of these same dimensions of agonistic behavior in other species. The existing evidence suggests that lesions in the lateral septum, medial accumbens, medial hypothalamus, or the dorsal and median raphe (or PCPA-induced depletion or serotonin) induce hyperreactivity to the experimenter in mice, rats, cats, dogs, and humans in every instance where they have been tested with one exception. The exception is that lesions in the medial hypothalamus of mice do not induce heightened reactivity. The same lesions do not cause this dramatic increase in reactivity to the experimenter in gerbils, hamsters, guinea pigs, or rabbits but do heighten some other species typical patterns of defensiveness such as alarm calls and avoidance of contact with conspecifics. Lesions in these same areas in monkeys have not been observed to heighten defensive behaviors. Predatory killing or killing of young conspecifics has been observed in hamsters, mice, rats, and cats in every instance where they have been examined following lesions of the olfactory bulbs, lateral septum, medial accumbens, medial hypothalamus, or the dorsal and median raphe nuclei (or PCPA-induced depletion of serotonin). Social aggression has been decreased with these same lesions in each case where they have been examined except for septal lesions in hamsters which have been reported to heighten social aggression. Across species, the consistency with which lesions of the olfactory region, lateral septum, medial accumbens, medial hypothalamus, and dorsal and median raphe nuclei alter defensiveness and predation but not social aggression supports the inference that neural systems exist which subserve the inhibitory modulation of these dimensions of behavior. Finally, the evidence that the disruption of functioning within these structures in humans results in increased agonistic responses to environmental stimuli serves to further establish the important role of this neural circuitry in the normal inhibitory modulation of agonistic behavior in humans.     

The septo-hippocampal pathways and their relevance to human memory: a case report.

The interaction between the septal region and the hippocampal formation appears indispensable for the maintenance of normal memory and learning mechanisms in humans. The disruption of some combination of septo-hippocampal pathways, especially the disruption of the "dorsal route", deteriorates explicit memory functions. The case of a 25-year-old male patient is presented who developed anterograde and to a certain extent retrograde amnesia following rupture and repair of an arteriovenous malformation in the atrium of the left ventricle. A left-sided lesion of the dorsal route involving the posterior cingulate bundle, the longitudinal striae (as part of the supracommissural hippocampus) and the fornix appeared responsible for his mnemonic deficits. The implications of these findings for the understanding of other clinical cases, particularly those with lesions of the septal region, the anterior and posterior singular gyrus/cingulate bundle and the fornix are discussed.     

An HRP study of the connections of the subfornical organ of the rat

The connections of the subfornical organ (SFO) wer investigated by using the HRP technique. Injections into the SFO labeled neurons in the medial septum, but not in lateral septum nor in the diagonal band nucleus. Labeled cells were observed in the median preoptic nucleus, below the ependyma of the third ventricle, in the dorsal preoptic region near the anterior commissure, and diffusely throughout the medial preoptic and anterior bypothalamic areas. Fibers were followed from the ventral stalk of the SFO. Precommissural fibers enter the median preoptic nucleus where many of them appear to terminate. Others continue on to the medial septum, the OVLT, the supraoptic nucleus, and the suprachiasmatic nucleus, HRP injections into the median preoptic nucleus labled many neurons in the SFO. Postcommissural fibers reach the hypothalamus by descending along the walls of the ventricle in the subependymal space, by traveling in the columns of the fornix and the medial corticohypothalamic tract, or by passing through the paraventricular nucleus of the thalamus. Some postcommissural fibers turn rostrally and enter the median preoptic nucleus while others join precommissural fibers bound for the supraoptic nucleus. More caudally directed fibers appear to innervate the paraventricular nucleus of the hypothalamus and the medial preoptic and anterior hypothalamic areas. HRP injections into the paraventricular nucleus of the hypothalamus labeled neurons in the SFO. These finding corroborate and extend previous work in describing neural connections between two brain regions that are important for fluid blance.     

The role of the medial septal nucleus in mediating adrenocortical responses to somatosensory stimulation

In view of the demonstrated involvement of the hippocampus in the mediation of adrenocortical responses following sciatic nerve stimulation, the role of the septum and the preoptic area in the transmission of this response was investigated. Changes in plasma corticosterone following ether stress and photic, acoustic, or sciatic nerve stimulation were studied in intact rats and in animals with lesions in the medial septal nucleus and the preoptic area. The response to ether stress and to photic and acoustic stimulation was normal in these animals. However, the adrenocortical response to sciatic nerve stimulation was partially reduced in the rats with lesions in the superior, but not in the inferior preoptic area, and it was completely blocked in those with medial septal lesions. Our previous and present experiments indicate that the ventral hippocampus, the fimbria, the septum, and anterior hypothalamic afferents mediate the adrenocortical response to somatosensory stimulation.     

Medial septal modulation of hippocampal theta cell discharges

The effect of small electrolytic lesions in various areas of the septum on the behavioral correlates and firing repertoires of hippocampal theta cells, was investigated in the freely moving rabbit. Lesions localized to the medial septum were found to abolish both slow wave theta and the rhythmic firing of CA1 and dentate layer theta cells, in both the type 1 theta (movement) and type 2 theta (sensory processing) behavior conditions. Small lesions of the diagonal band, lateral septum and fimbria/fornix regions only affected rhythmicity to the extent that they also involved the medial septal region. The same medial septal lesions that abolished rhythmicity were also shown to reduce the mean discharge rate of theta cells occurring during the type 1 movement condition by approximately 50%, while the discharge rate occurring during the type 2 sensory processing condition did not change significantly. Behavioral changes were also only observed for lesions involving the medial septum. The importance of afferent input from the medial septum in the generation of hippocampal theta cell rhythmicity was discussed.     

Projections of the ventral subiculum to the amygdala, septum, and hypothalamus: a PHAL anterograde tract-tracing study in the rat.

The projections of the ventral subiculum are organized differentially along the dorsoventral (or septotemporal) axis of this cortical field, with more ventral regions playing a particularly important role in hippocampal communication with the amygdala, bed nuclei of the stria terminalis (BST), and rostral hypothalamus. In the present study we re-examined the projection of the ventral subiculum to these regions with the Phaseolus vulgaris leucoagglutinin (PHAL) method in the rat. The results confirm and extend earlier conclusions based primarily on the autoradiographic method. Projections from the ventral subiculum course either obliquely through the angular bundle to innervate the amygdala and adjacent parts of the temporal lobe, or follow the alveus and fimbria to the precommissural fornix and medial corticohypothalamic tract. The major amygdalar terminal field is centered in the posterior basomedial nucleus, while other structures that appear to be innervated include the piriformamygdaloid area, the posterior basolateral, posterior cortical, posterior, central, medial, and intercalated nuclei, and the nucleus of the lateral olfactory tract. Projections from the ventral subiculum reach the BST mainly by way of the precommissural fornix, and provide rather dense inputs to the anterodorsal area as well as the transverse and interfascicular nuclei. The medial corticohypothalamic tract is the main route taken by fibers from the ventral subiculum to the hypothalamus, where they innervate the medial preoptic area, "shell" of the ventromedial nucleus, dorsomedial nucleus, ventral premammillary nucleus, and cell-poor zone around the medial mammillary nucleus. We also observed a rather dense terminal field just dorsal to the suprachiasmatic nucleus that extends dorsally and caudally to fill the subparaventricular zone along the medial border of the anterior hypothalamic nucleus and ventrolateral border of the paraventricular nucleus. The general pattern of outputs to the hypothalamus and septum is strikingly similar for the ventral subiculum and suprachiasmatic nucleus, the endogenous circadian rhythm generator.     

Corticotropin releasing factor-containing afferents to the lateral septum of the rat brain

Corticotropin releasing factor (CRF)-containing afferents to the rat lateral septum (LS) have been determined by means of cobalt-enhanced immunohistochemistry, tracing of retrograde transport of horseradish peroxidase (HRP), and by lesioning experiments. When unilateral lesions included the rostral part of the hypothalamus, CRF-like immunoreactive (CRFI) ipsilateral fibers in the LS decreased in number. Lesions in other brain regions did not cause alterations in the septal CRFI fibers. These findings suggest that the septal CRFI fibers originate in the rostral part of the hypothalamus. Furthermore, combined HRP and immunohistochemical staining on the same sections demonstrated double-labeled cells in two discrete areas within the rostral hypothalamus: one was the perifornical hypothalamic area (PeF) at the level of the paraventricular hypothalamic nucleus, and the other was the most caudal part of the anterior hypothalamic nucleus (AHc). These findings show that a large proportion of the CRFI projections to the LS have their origins in the PeF and AHc.     

Evidence for a functional and anatomical relationship between the lateral septum and the hypothalamus in the control of flank marking behavior in Golden hamsters

Golden hamsters with established dominant/subordinate relationships communicate their social status by rubbing pheromone-producing flank glands against objects in the environment. This behavior, called flank marking, is controlled by vasopressin-sensitive neurons localized to the anterior hypothalamus. Vasopressinergic magnocellular neurons in the nucleus circularis and medial aspect of the supraoptic nucleus are thought to be a source of neurotransmitter for the initiation of flank marking. The present study was undertaken to examine the extrahypothalamic control of flank marking. The anatomical and functional connections between the lateral septum and the vasopressin-containing nuclear groups in and around the anterior hypothalamus were examined by: (1) tracing afferent and efferent connections following microinjection of horseradish peroxidase and Phaseolus vulgaris-leucoagglutinin into the lateral septum, and (2) recording odor-induced flank marking prior to and following ibotenate lesions in the septum. The greatest number of perikarya retrogradely labeled with horseradish peroxidase were found lateral to the anterior hypothalamus and ventral to the fornix in the area of the lateral hypothalamus. The vasopressin-containing nuclear groups, e.g., paraventricular, supraoptic, suprachiasmatic nuclei, and the nucleus circularis, were devoid of labeled perikarya. Nerve terminals anterogradely labeled with Phaseolus vulgaris-leucoagglutinin were primarily localized to the anterior hypothalamus, in and around the nucleus circularis, and the medial aspect of the supraoptic nucleus. The lateral aspect of the supraoptic nucleus was devoid of nerve terminals as were the paraventricular and suprachiasmatic nuclei. The anatomical connections between the lateral septum and the hypothalamus appear to be necessary for the control of flank marking, since the microinjection of ibotenate into this limbic site significantly reduced odor-induced flank marking as compared to control microinjections of 0.9% NaCl.     

Effect of septohippocampal lesions on thyrotropin-releasing hormone antagonism of pentobarbital narcosis

Thyrotropin-releasing hormone (TRH) has been shown to antagonize pentobarbital narcosis in a variety of mammalian phylogeny, and many lines of evidence indicate that TRH action in the septum to modulate the septohippocampal system may be the neuroanatomical substrate mediating this effect. To further examine this hypothesis, the analeptic response following injection of TRH into the lateral ventricles or ventromedial septum was measured after lesions of the septum, fimbria or hippocampus. Lesions were induced using either radiofrequency current, aspiration or microinjection of kainic acid. Bilateral electrolytic lesions of the fimbria were found to block the antagonism of pentobarbital narcosis by intraseptal injection of 500 ng TRH, indicating that intraseptal TRH is acting via the septohippocampal system. In contrast, complete aspiration of the dorsal hippocampi did not attenuate intracerebroventricular (i.c.v.) administration of TRH. However, large electrolytic septal lesions effectively blocked i.c.v. TRH. These findings indicate first that i.c.v. TRH can cause arousal from pentobarbital narcosis via interaction with alternative neuroanatomical substrates from the septohippocampal system, and secondly, that these alternative substrates have axons which either synapse in or pass through the septum. The fact that injection of kainic acid into the ventromedial septum did not antagonize i.c.v. TRH supports the likelihood that the effectiveness of electrolytic septal lesions results from disruption of fibers in passage and not destruction of neuron perikarya in the septum.     

An autoradiographic study of the organization of the efferent connections of the hippocampal formation in the rat.

The efferent connections of the hippocampal formation of the rat have been re-examined autoradiographically following the injection of small quantities of 3H-amino acids (usually 3H-proline) into different parts of Ammon's horn and the adjoining structures. The findings indicate quite clearly that each component of the hippocampal formation has a distinctive pattern of efferent connections and that each component of the fornix system arises from a specific subdivision of the hippocampus or the adjoining cortical fields. Thus, the precommissural fornix has been found to originate solely in fields CA1-3 of the hippocampus proper and from the subiculum; the projection to the anterior nuclear complex of the thalamus arises more posteriorly in the pre- and/or parasubiculum and the postsubicular area; the projection to the mammillary complex which comprises a major part of the descending columns of the fornix has its origin in the dorsal subiculum and the pre- and/or parasubiculum; and finally, the medial cortico-hypothalamic tract arises from the ventral subiculum. The lateral septal nuclei (and the adjoining parts of the posterior septal complex) constitute the only subcortical projection field of the pyramidal cells in fields CA1-3 of Ammon's horn. There is a rostral extension of the pre-commissural fornix to the bed nucleus of the stria terminalis, the nucleus accumbens, the medial and posterior parts of the anterior olfactory nucleus, the taenia tecta, and the infralimbic area, which appears to arise from the temporal part of field CA1 or the adjacent part of the ventral subiculum. The projection of Ammon's horn upon the lateral septal complex shows a high degree of topographic organization (such that different parts of fields CA1 and CA3 project in an ordered manner to different zones within the lateral septal nucleus). The septal projection of "CA2" and field CA3 is bilateral, while that of field CA1 is strictly unilateral. In addition to its subcortical projections, the hippocampus has been found to give rise to a surprisingly extensive series of intracortical association connections. For example, all parts of fields CA1, CA2 and CA3 project to the subiculum, and at least some parts of these fields send fibers to the pre- and parasubiculum, and to the entorhinal perirhinal, retrosplenial and cingulate areas. From the region of the pre- and parasubiculum there is a projection to the entorhinal cortex and the parasubiculum of both sides. That part of the postsubiculum (= dorsal part of the presubiculum) which we have examined has been found to project to the cingulate and retrosplenial areas ipsilaterally, and to the entorhinal cortex and parasubiculum bilaterally.     

Anxiety is functionally segregated within the septo-hippocampal system

Previous lesion studies have suggested that the septal-hippocampal system is involved in fear and anxiety. In this study we examined the effects on anxiety of temporary neuronal inhibition of various aspects of the septo-hippocampal system in rats. Infusions of tetrodotoxin (TTX) were used to induce reversible lesions in the fimbria fornix, medial septum, dorsal hippocampus, and ventral hippocampus. To assess anxiety we used the elevated plus-maze and the shock-probe burying tests. A reduction in anxiety in the elevated plus-maze is indicated by increased open arm exploration, whereas a reduction in anxiety in the shock-probe burying test is indicated by decreased burying behavior or increased contacts with the shock-probe. The results suggested that inhibition of the septal-hippocampal system induced site-specific anxiolytic effects that vary in nature. Tetrodotoxin lesions of the fimbria fornix increased both open arm exploration and the number of shocks taken by the rats, while having no effect on burying behavior. Both septal and ventral hippocampal lesions increased open arm exploration and decreased burying behavior, but had no effect on the number of probe shocks. Finally, TTX lesions of the dorsal hippocampus increased the number of shocks taken by the rats, but did not affect open arm activity or burying behavior. Neuroanatomical studies indicated that the effect on the number of shocks induced by dorsal hippocampal TTX lesions was not likely mediated by the amygdala. Collectively, the data suggest that the control of specific anxiety reactions is functionally segregated within different aspects of the septo-hippocampal system.