The limbic system is composed of both neocortical and phylogenetically older cortical areas (portions of the archicortex and paleocortex) and a number of nuclei. The cellular architecture of the archicortex and paleocortex differs from that of the neocortex. The major structures of the limbic system are the hippocampal formation, the parahippocampal gyrus and entorhinal area, the dentate gyrus, the cingulate gyrus, the mamillary body, and the amygdala. These structures are interconnected in the Papez circuit and also make extensive connections with other regions of the brain (neocortex, thalamus, and brainstem). The limbic system thereby enables communication between mesencephalic, diencephalic, and neocortical structures.
Through its connection with the hypothalamus, and thus with the autonomic nervous system, the limbic system participates in the regulation of drive and affective behavior. Its main function, teleologically speaking, is said to be the generation of behavior that promotes the survival of the individual and of the species. Important functions are ascribed to the amygdala in behavior associated with fear and anxiety. Moreover, the hippocampus plays a very important role in learning and memory. Lesions of the hippocampal formation, or of other structures that are functionally associated with it, produce an amnestic syndrome. Different disturbances of memory can arise, depending on the site of the lesion.
Anatomy
Broca, in 1878, described the ring of brain convolutions surrounding the corpus callosum, diencephalon, and basal ganglia, naming it the “grand lobe limbique” (great limbic lobe, from the Latin limbus, ring). In some respects, this complex of structures can be considered a zone of transition between the brainstem and the neocortex. The cortical areas within it are composed of archicortex (hippocampus and dentate gyrus), paleocortex (piriform cortex), and mesocortex (cingulate gyrus). Further limbic structures are the entorhinal and septal areas, the indusium griseum, the amygdala, and the mamillary bodies (▶Fig. 7.1). The extensive fiber connections linking all of these structures led Papez, in 1937, to propose that a loop, or circuit, of neural activation (the Papez circuit, see ▶Fig. 7.2) might be the anatomical substrate of emotional feeling and expression and of affective states corresponding to instinctual drive. This theory received support from the studies of Klüver and Bucy (Klüver–Bucy syndrome). Growing evidence of the anatomical and functional linkage of the various limbic structures led MacLean to coin the term limbic system.
More recently, however, the concept of the limbic system as a discrete functional unit has come into question, as further studies have shown that the limbic structures possess important neural connections not just with each other but with outside structures as well. Thus, the limbic system cannot be regarded as a closed system in either an anatomical or a functional sense. The functions associated with the limbic system, such as instinctual and affective behavior, motivation, and drive, as well as learning and memory (see ▶Functions of the Limbic System), should not be thought of as the preserve of the limbic system alone. These functions depend on an intact cooperation of the limbic system with many other areas of the brain.
Once this has been understood, there is no further objection to the use of the term limbic system, particularly because the anatomical connections between the various limbic structures, which originally motivated this term, are indeed present, robust, and functionally important. No uniform alternative terminology has yet come into general use. Pathological changes of the limbic structures are still described, in the clinical setting, as lesions of the limbic system.
Internal and External Connections
Papez Circuit
A group of limbic structures, including the hippocampus, are connected to one another in the so-called Papez circuit, which contains a number of neural relay stations arranged in a circuit or loop. Beyond the basic wiring diagram of the Papez circuit, as originally described, much further information has come to light regarding additional connections and the particular neurotransmitters used at various points in the circuit.
The Papez circuit runs as follows. From the hippocampus (Ammon’s horn), impulses travel through the great arch of the fornix to the mamillary body. This nucleus, in turn, is the site of origin of the mamillothalamic tract (of Vicq d’Azyr), which conveys impulses to the anterior nucleus of the thalamus. The anterior nucleus projects to the cingulate gyrus by way of the thalamocingulate radiation. From the cingulate gyrus, impulses travel by way of the cingulum back to the hippocampus, completing the circuit (▶Fig. 7.2).
Connections to Other Areas of the Brain
The mamillary body occupies a key position in the Papez circuit because it connects the limbic system with the midbrain (nuclei of Gudden and Bekhterev) and the reticular formation. The mamillotegmental tract and the peduncle of the mamillary body (see ▶Fig. 6.9 and ▶Fig. 6.10) form a regulatory circuit of their own. Impulses arising in the limbic system can travel by way of the anterior nucleus of the thalamus to the cingulate gyrus, but also, via association fibers, to the neocortex. Furthermore, impulses from the autonomic nervous system can travel through the hypothalamus and the medial dorsal nucleus of the thalamus to reach the orbitofrontal cortex.
Major Components of the Limbic System
Hippocampus
The hippocampal formation is the central structure of the limbic system. Its structure and neural connections and the clinical changes observed in patients with hippocampal lesions form the subject of this section.
Microanatomy of the Hippocampal Formation
The hippocampal cortex consists of archicortex, a phylogenetically old type of cerebral cortex, which possesses only three layers instead of the usual six. Because of this different structure, the hippocampus and a few other cortical areas are called allo cortex (as opposed to the six-layered iso cortex). The hippocampus proper (Ammon’s horn or cornu ammonis) is distinct from the dentate gyrus (fascia dentata, ▶Fig. 7.3a and ▶Fig. 7.3b). The principal cell type in the hippocampus is the pyramidal cell. There are different types of pyramidal cells in the individual regions of Ammon’s horn, designated CA1, CA2, and CA3 (“CA” stands for cornu ammonis) (▶Fig. 7.3c); some authors also describe a further CA4 region adjacent to the hilus of the dentate gyrus. The principal cells of the dentate gyrus are the granule cells, which connect the dentate gyrus with the hippocampus proper (CA4/CA3) through their axons, called mossy fibers. In addition to the principal cell types (pyramidal cells and granule cells) constituting the principal cell layers, the hippocampus and dentate gyrus also contain GABAergic interneurons that are not restricted to any particular cellular layer. These cells contain not only the inhibitory neurotransmitter GABA but also various neuropeptides and calcium-binding proteins.
Fig. 7.3 The hippocampal formation. (a) Major afferent and efferent projections of the hippocampal formation: the perforant path and the fornix, respectively. The perforant path penetrates the subiculum to link the entorhinal area with the dentate gyrus. (b) Cytoarchitecture of the hippocampal formation. (c) Diagram of the various cell types of the hippocampal formation and their connections. 1–3, Ammon’s horn regions CA1 through CA3; 4, perforant path; 5, pyramidal cells; 6, granule cells of the dentate gyrus; 7, mossy fibers; 8, alveus; 9, fimbria hippocampi; 10, recurrent Schaffer collaterals of the CA3 pyramidal cells, which form synapses with the dendrites of the CA1 pyramidal cells. (Reproduced with permission from Kahle W, Frotscher M. Taschenatlas der Anatomie. Vol. 3. 8th ed. Stuttgart: Thieme; 2002.)
Neural Connections of the Hippocampal Formation
Entorhinal afferent fibers. Like the hippocampus, the entorhinal area, too, is composed of allocortex. Recent studies have revealed the importance of this brain area, which is located lateral to the hippocampus in the parahippocampal gyrus (Brodmann area 28, ▶Fig. 7.1 and ▶Fig. 7.3) and borders the amygdala rostrally. The collateral sulcus marks the border between the entorhinal area and the temporal isocortex (see ▶Fig. 9.9). The entorhinal area receives afferent fibers from very widespread neocortical areas. It is thought to serve as a gateway to the hippocampus, which in turn analyzes incoming neocortical information with respect to its novelty. The fiber connection from the entorhinal cortex to the hippocampus is massive. Most of these fibers belong to the perforant path, which pierces the subiculum (▶Fig. 7.3a).
Septal afferent fibers. Cholinergic and GABAergic neurons from the medial septum and the diagonal band of Broca (septal area, cf. ▶Fig. 7.1) project to the hippocampus. The cholinergic projection is rather diffuse, while the GABAergic fibers specifically form synapses with hippocampal GABAergic neurons.
Commissural afferent fibers. Axons of the CA3 pyramidal cells and certain neurons in the hilar region of the dentate gyrus (mossy cells) connect the two hippocampi with each other, terminating on the proximal dendritic segments of the pyramidal and granule cells of the contralateral hippocampus.
Afferent fibers from the brainstem. Various brainstem nuclei send catecholaminergic fibers to the hippocampus, mostly in diffuse fashion.
Spread of Activation in the Hippocampus
As mentioned, the projection from the entorhinal cortex is the major afferent pathway to the hippocampus. The entorhinal fibers are glutamatergic and terminate on the distal dendritic segments of the granule and pyramidal cells. The following trisynaptic main pathway of excitation has been proposed (▶Fig. 7.3c): entorhinal cortex → granule cells of the dentate gyrus (first synapse) → mossy fiber system → CA3 pyramidal cells (second synapse) → recurrent Schaffer collaterals of the CA3 pyramidal cell axons → CA1 pyramidal cells (third synapse). At all three relay stations, the forward transfer of excitation is regulated by GABAergic inhibitory interneurons. GABAergic synapses onto the neurons of the main excitatory pathway are found either on the cell body (basket cells), at the initial segment of the pyramidal and granule cell axons (axo-axonal cells or chandelier cells), or at the dendrites.
The CA1 neurons project onward to the subiculum, whose efferent fibers, in turn, form the fimbria and fornix, which constitute the major efferent bundle of the hippocampal formation (▶Fig. 7.3c). The fornix arches over the diencephalon to terminate in the mamillary body. The fornix is the main connection of the hippocampus with the hypothalamus and thus with the autonomic nervous system (▶Fig. 7.2).
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