The Limbic System (Integrative Systems) Part 1

The limbic system includes the phylogenetically older regions of the brain and consists of the hippocampal formation, septal area, and amygdala. In discussing the limbic system, most authors also include the prefrontal cortex and cingu-late gyrus as components within this system. Some authors also include the hypothalamus as part of the limbic system, but in the present context, we have limited our analysis of these structures based on criteria described in the following paragraph. It should also be pointed out that the expression "limbic system" implies that the component structures making up this system have similar or identical functions. However, this is not the case. The structures that are discussed in this topic are not uniform in their functions and differ with respect to physiological, pharmacological, and behavioral properties. Nevertheless, we use the term "limbic system" because of the overriding common features of the different structures and because this term has been in use for over 40 years.

As an overall defining property, limbic structures either directly or indirectly communicate with the hypothalamus or midbrain periaqueductal gray (PAG). Thus, a critical property of limbic structures is to modulate the functions normally attributed to the hypothalamus and/or midbrain PAG. Accordingly, one of the primary objectives of this topic is to examine how each of the limbic structures can regulate processes associated with the hypothalamus and PAG. It should also be pointed out that limbic structures also serve other functions, such as short-term memory and epileptogenic activity, that do not relate to functions of the hypothalamus. These functions are also considered separately in this topic.


One of the major themes regarding functions of the limbic system relates to its role in modulating processes normally associated with the hypothalamus. To gain a better understanding of the functional properties of the various limbic structures, it is important to consider their input-output relationships. These relationships are depicted in Figure 25-1. As a general rule, limbic structures receive inputs from at least two sources: (1) from one or more sensory systems, either directly or indirectly through interneurons in the cerebral cortex, and (2) from brainstem monoaminergic fiber systems. Limbic neurons then project directly or indirectly to the hypothalamus (and/or midbrain PAG). These projections enable the lim-bic structures to modulate the outputs of the hypothala-mus and PAG that are directed on somatic motor and autonomic neurons of the lower brainstem and spinal cord for the integration of specific forms of visceral responses. Feedback signals can also reach the limbic system from the hypothalamus. Similarly, limbic structures can send feedback signals to the cerebral cortex, which provide the cortex with visceral signals that are contiguous with other sensory signals that initially caused excitation of limbic nuclei. It is likely that the contiguity of these signals helps to provide the emotional quality to sensory signals.

Information flow to and from the limbic system. Note that the limbic system receives inputs from sensory systems, including the cerebral cortex, and monoamine neuronal groups of the brainstem reticular formation. Primary outputs of the limbic system are directed to the hypothalamus. This arrangement allows the limbic system to alter the activity of the hypothalamus in response to sensory input. Because the hypothalamus provides the integrating mechanism for different forms of emotional behaviors as well as for other visceral and autonomic responses, the limbic system serves as a key modulating region of these processes by virtue of its inputs to the hypothalamus. Inputs to the limbic system from monoamine pathways can provide the substrates underlying mood changes. PAG = periaqueductal gray matter.

FIGURE 25-1 Information flow to and from the limbic system. Note that the limbic system receives inputs from sensory systems, including the cerebral cortex, and monoamine neuronal groups of the brainstem reticular formation. Primary outputs of the limbic system are directed to the hypothalamus. This arrangement allows the limbic system to alter the activity of the hypothalamus in response to sensory input. Because the hypothalamus provides the integrating mechanism for different forms of emotional behaviors as well as for other visceral and autonomic responses, the limbic system serves as a key modulating region of these processes by virtue of its inputs to the hypothalamus. Inputs to the limbic system from monoamine pathways can provide the substrates underlying mood changes. PAG = periaqueductal gray matter.

Hippocampal Formation

Histology and Local Anatomical Connections

The hippocampal formation consists of the hippocampus, dentate gyrus, and subicular cortex (Fig. 25-2A). The primary cell type within the hippocampus is the pyramidal cell, which has both basal and apical dendrites. The basal dendrites extend laterally and slightly in the direction of the ventricular surface. The apical dendrites extend away from the ventricular surface toward the dentate gyrus. The axon of the pyramidal cell, which constitutes the primary efferent process of the hippocampal formation, passes into the superficial layer of the hippocampus, called the alveus (a fiber layer adjacent to the inferior horn of the lateral ventricle) and, ultimately, into either the fimbria-fornix or entorhinal cortex (Fig. 25-2B).

The hippocampus can be viewed as a primitive form of three-layered cortical tissue. Accordingly, it has the following layers extending from the ventricular surface to the dentate gyrus: (1) an external plexiform layer, situated adjacent to the inferior horn of the lateral ventricle, which contains axons of pyramidal cells that project outside the hippocampus as well as hippocampal afferent fibers from the entorhinal cortex (i.e., the alvear pathway); (2) stratum oriens, which contains basal dendrites and basket cells; (3) a pyramidal cell layer, which contains the pyramidal cells of the hippocampus; and (4) the stratum radiatum and stratum lacunosum-moleculare, which are two layers that contain the apical dendrites of the pyramidal cells and hippocampal afferents from the entorhinal cortex (i.e., perforant pathway [Fig. 25-2, A and B]).

Hippocampal anatomy and internal circuitry. (A) Diagram illustrates the histological appearance of the cell layers within the hippocampus and loci of the hippocampal fields, dentate gyrus, and subicular cortex. (B) Semischematic diagram illustrates: (1) inputs from the entorhinal region, which include the perforant and alvear pathways; (2) internal circuitry, which includes the connections of the mossy fibers and Schaffer collaterals; and (3) efferent projections of the hippocampal formation through the fimbria-fornix system of fibers. CA1-CA4 denote the four sectors of the hippocampus.

FIGURE 25-2 Hippocampal anatomy and internal circuitry. (A) Diagram illustrates the histological appearance of the cell layers within the hippocampus and loci of the hippocampal fields, dentate gyrus, and subicular cortex. (B) Semischematic diagram illustrates: (1) inputs from the entorhinal region, which include the perforant and alvear pathways; (2) internal circuitry, which includes the connections of the mossy fibers and Schaffer collaterals; and (3) efferent projections of the hippocampal formation through the fimbria-fornix system of fibers. CA1-CA4 denote the four sectors of the hippocampus.

As shown in Figure 25-2A, the pyramidal cells of the hippocampus are arranged in a C-shaped fashion, which is interlocked with another C-shaped arrangement of the dentate gyrus. The hippocampus is divided into a number of distinct fields. The fields, according to one classification, include four sectors (i.e., CA1, CA2, CA3, and CA4). The pyramidal cells situated closest to the subicu-lum are referred to as the CA1 field, whereas the CA4 field is located within the hilus of the dentate gyrus. The CA2 and CA3 fields are located between the CA1 and CA4 fields. Collaterals of axons arising from CA3 pyramidal cells (called recurrent or Schaffer collaterals) project back to the CA1 field. The CA1 field is of particular interest because the pyramidal cells are highly susceptible to anoxia, especially during periods of temporal lobe epilepsy. This region is referred to as Sommer’s sector.

The dentate gyrus can also be thought of as a primitive three-layered cortical structure. It is multilayered, and the principal cell type is the granule cell. The axon of the granule cell, called a mossy fiber, makes synaptic contact with pyramidal cells in the CA3 region. A polymorphic cell layer, composed of modified pyramidal cells, lies deep to the granule cell layer. External to the granule cell layer lies the molecular cell layer, which is apposed to the molecular layer of the hippocampus. The molecular layer mainly contains axons of hippocampal afferent fibers.

The last component of the hippocampal formation is the subicular cortex. It constitutes a transitional region between the entorhinal cortex and hippocampus. The primary histological distinction between the hippocampus and subicular cortex is that the pyramidal cell layer is considerably thicker in the subicular cortex than in the hippocampus (Fig. 25-2A).

Afferent Connections

There are a variety of sources that contribute afferent fibers to the hippocampal formation. One major source of inputs includes the entorhinal cortex. Separate groups of fibers arising from the lateral and medial parts of the entorhinal cortex pass through the alveus and molecular layers of the hippocampus and dentate gyrus, respectively, to supply much of the hippocampus. The lateral pathway is called the lateral perforant pathway and passes from the lateral entorhinal cortex into the molecular layer of the hippocampus. The medial pathway is called the medial perforant pathway and enters the alveus of the hippocampus after passing through the white matter adjoining the subiculum (Fig. 25-2B). Many of these inputs represent tertiary olfactory, visual, and auditory fibers that reach the hippocampus after making synaptic connections within the entorhinal region. A second group of fibers arises from the diagonal band of Broca (of the septal area) and supplies much of the hippocampal formation.These fibers may be viewed as a feedback circuit to the hippocampal formation from the septal area, which, in turn, receives inputs from the hippocampal formation via the precommissural fornix. Other sources of hippocam-pal afferent fibers include the prefrontal cortex, anterior cingulate gyrus, and premammillary region. A final source of hippocampal afferent fibers includes monoamine neuronal projections from the brainstem reticular formation (i.e., locus ceruleus, ventral tegmental area, and pontine and midbrain raphe neurons). These projections of the brainstem, which also supply other parts of the limbic system, provide the anatomical and physiological substrates that regulate mood changes. Thus, by receiving inputs from these varied sources, the hippocampal formation can respond to sudden changes in brainstem and cortical events and relay such changes to the hypothalamus, which then provides a visceral (and/or emotional) quality to these events.

Efferent Connections

The efferent connections of the hippocampal formation arise from pyramidal cells located in both the hippocampus and subicular cortex. The axons of these cells contribute the largest component to the fornix system of fibers. With respect to efferent connections of the hippocampal formation, there are three components of the fornix system. One component, called the precommissural fornix (Fig. 25-3), passes rostral to the anterior commissure and supplies the septal area. The precommissural fornix projection is topographically organized in that fibers situated near the anterior pole of the hippocampal formation project to the lateral aspect of the lateral septal nucleus, whereas neurons situated more posteriorly in the hippoc-ampal formation project to progressively more medial aspects of this nucleus.

A second component, called the postcommissural for-nix, innervates the diencephalon. The postcommissural fornix innervates the anterior thalamic nucleus, mammil-lary bodies, and adjoining regions of the medial hypothalamus (Fig. 25-3). Whereas the precommissural fornix arises from the hippocampus and subicular cortex, the postcom-missural fornix arises solely from the subicular cortex. Neurons located in the subiculum also project to the entorhinal cortex, cingulate cortex, and various parts of the prefrontal cortex. The entorhinal cortex, in turn, projects to the amygdala and adjoining regions of temporal neocortex. Taken collectively, the significance of the projections of the subic-ular and entorhinal cortex is that they enable the hippoc-ampal formation to communicate with widespread regions of neocortex, including areas that receive different modalities of sensory information. Such projections may constitute the substrate by which signals from limbic regions of the brain serve to provide affective properties to various modalities of sensory signals.

The third component of the fornix system is its com-missural component, which provides connections between the hippocampus on each side of the brain. In general, the hippocampal fibers that provide commissural connections arise mainly from the CA3-CA4 region and terminate in the homotypical region of the contralateral hippocampus. The presence of a commissural connection has important clinical significance. It may provide the structural basis by which seizures spread from the hippocampus on one side of the brain to the hippocampus on the other side, allowing for the formation of secondary epileptogenic foci on the side of the temporal lobe contralateral to the site where the primary focus is present.

Major projection targets of the hippocampal formation. The primary output is through the fornix to the diencephalon (i.e., medial hypothalamus, mammillary bodies, and anterior thalamic nucleus) via the postcommissural fornix and to the septal area via the precommissural fornix. Other connections shown include efferent fibers that synapse in entorhinal cortex, which, in turn, project to amygdala and cingulate gyrus.

FIGURE 25-3 Major projection targets of the hippocampal formation. The primary output is through the fornix to the diencephalon (i.e., medial hypothalamus, mammillary bodies, and anterior thalamic nucleus) via the postcommissural fornix and to the septal area via the precommissural fornix. Other connections shown include efferent fibers that synapse in entorhinal cortex, which, in turn, project to amygdala and cingulate gyrus.

Functions and Dysfunctions of the Hippocampal Formation

The hippocampal formation has been linked to a number of different functions. These include modulation of aggressive behavior, autonomic and endocrine functions, and certain forms of learning and memory. Modulation of aggression and autonomic and endocrine functions likely results from direct or indirect hippocampal inputs to different regions of the hypothalamus. The underlying anatomical substrates and functional mechanisms for learning and memory remain largely unknown.

Aggression and Rage

Experimental studies in animals and human clinical reports have indicated that the hippocampal formation plays an important role in the control of aggression and rage behavior. Electrical stimulation of the hippocampal formation of the cat at current levels below threshold for elicitation of seizure activity significantly alters the propensity for elici-tation of aggressive responses from the hypothalamus.As is true with several other regions of the limbic system, the hippocampal formation differentially modulates aggressive reactions. For example, activation of the part of the hippocampal formation closest to the amygdala (i.e., temporal pole) facilitates predatory attack behavior, whereas activation of the portion closest to the septal pole suppresses this form of aggression. It is important to note that the fibers arising from each of these regions of the hippocampal formation project to different regions of the septal area. That such fibers likely mediate hippocampal control of aggressive responses is further suggested by the fact that the septal area projects extensively to the hypothalamus. In this manner, the septal area may be viewed, in part, as a relay nucleus of the hippocampal formation of signals that are ultimately transmitted to the hypothalamus.

In humans, there have been a number of published reports linking lesions, tumors, and epileptogenic activity of the hippocampal formation with aggressive reactions. These responses vary in content but include reactions such as hostility and explosive acts of physical violence. It is difficult to know whether tumors have stimulation-like or lesion-like properties and whether the effects of such trauma originate directly from the hippocampal formation or are a result of secondary effects generated elsewhere in the limbic system. Nevertheless, these clinical findings provide support for the view that, in humans, the hippoc-ampal formation contributes to the regulation of aggressive forms of behavior. It is likely that such effects are mediated on the hypothalamus via interneurons in the septal area.

Endocrine Functions

The hippocampal formation (like other regions of the lim-bic system) has significant inputs to different parts of the hypothalamus, so it is not surprising that this region can also modulate endocrine functions normally associated with the hypothalamus. The supporting evidence is as follows: (1) estradiol-concentrating neurons are densely packed in the ventral regions of the hippocampal formation, (2) corticosterone is also localized in heavy concentrations in the hippocampal formation and has inhibitory effects on these neurons, (3) stimulation of the hippocam-pal formation inhibits ovulation in spontaneously ovulat-ing rats, and (4) lesions of the hippocampus or section of the fornix disrupt the diurnal rhythm for adrenocortico-tropic hormone (ACTH) release.

One possible mechanism guiding these effects is that the hippocampal formation may be selectively sensitive to various hormone levels and, therefore, serve as part of a feedback pathway to the pituitary via its direct and indirect projections to the hypothalamus. Such effects may be mediated by a direct pathway called the medial corticohy-pothalamic tract. This pathway arises from the subiculum near the temporal pole of hippocampus and projects directly to the ventromedial region of the hypothalamus. It terminates in the region between suprachiasmatic and arcuate nuclei, which contain hypophysiotrophic hormones that control anterior pituitary function. As we have indicated, the hippocampal formation can also indirectly communicate with the medial hypothalamus. It does so through a synaptic relay in the septal area.

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