Chapter 31

The Limbic System

M.A. Willis and D.E. Haines

isthmus of the cingulate gyrus; the parahippocampal gyrus; and

Overview-457 the uncus (Fig. 31.2). The limbic lobe also includes the hippo-
Cytoarchitectural Definitions of the Limbic campal formation.
Cortex-457 In 1878, Broca (1824–1880) noted that the limbic lobe, which
is present in all mammals, represents a relatively large part of the
Early Functional Concepts-458 cerebral cortex in phylogenetically lower forms, and he postu-
Blood Supply to the Limbic System-459 lated that it might be related to olfaction. Because of this latter
point, the term rhinencephalon (“smell-brain”) was later coined
Hippocampal Formation-459 and used interchangeably with limbic lobe. However, it is now
Structure-460 known that the limbic lobe has little, if any, olfactory function in
Afferent Fibers-461 humans. Thus the term “rhinencephalon,” although historically
Efferent Fibers-461 interesting, is antiquated and has largely disappeared from use.
Complete Circuit of Papez-461 The second level includes structures of the limbic lobe plus a
Limbic System and Memory-462 variety of subcortical nuclei and tracts that collectively form the
limbic system (Fig. 31.1B). The subcortical nuclei of the lim-
Long-term Potentiation and Memory-462 bic system include, among others, the septal nuclei and nucleus
Amygdaloid Complex-463 accumbens (nucleus accumbens septi); various nuclei of the
Structure-463 hypothalamus, especially those associated with the mammillary
Afferent Fibers-463 body; the nuclei of the amygdaloid complex and adjacent sub-
Efferent Fibers-463 stantia innominata; and parts of the dorsal thalamus, particu-
larly the anterior and dorsomedial nuclei. Additional structures
Septal Region-464 connected with the limbic system include the habenular nuclei,
Nucleus Accumbens-465 ventral tegmental area, and periaqueductal gray. Furthermore,
the prefrontal cortex is considered by some investigators to be
Limbic System and Behavior-465 an important component of the limbic system, primarily because
Klüver-Bucy Syndrome-466 of its potential influence on various other cortical and subcorti-
Temporal Lobe Seizures-466 cal parts of the limbic system. Cortical targets of the prefrontal
cortex include the cingulate gyrus, whereas the hypothalamus,
Limbic System and Cognitive Function-466 dorsal thalamus, amygdaloid complex, and nuclei of the midbrain
Limbic System and Pain-467 represent subcortical targets.
The main efferent fiber bundles of the limbic system are the
fornix (primarily efferents of the hippocampus and subiculum),
Many complex brain systems are organized in a way that the stria terminalis and ventral amygdalofugal pathway (both
allows their function to be readily deduced. For example, are mainly efferents of the amygdaloid complex), and the mam-
although the connections of the somatosensory pathways with millothalamic tract (efferents of the medial mammillary nucleus;
the brainstem, thalamus, and cortex are complex, each com- Fig. 31.1B). A few additional nuclei and smaller tracts will be
ponent plays a straightforward role. The processing of somato- introduced as connections and functions of the limbic system.
sensory information is generally well understood. In contrast,
some systems are interconnected in such a way that a given CYTOARCHITECTURAL DEFINITIONS OF THE
function may be carried out by several components acting in LIMBIC CORTEX
cooperation, and a given component may participate in several The human cerebral cortex can be divided into several areas
functions. The limbic system is a case in point. This system on the basis of the number of cell layers present. Most of the
comprises structures that receive inputs from diverse areas of cerebral cortex (more than 90%) has six cell layers and is called
the neuraxis and participate in complicated and interrelated the neocortex (isocortex). Examples of neocortex include the
behaviors such as memory, learning, and social interactions. primary sensory, motor, and association cortices. The cortical
Thus lesions involving the limbic system generally result in a regions that have fewer than six layers are structurally and func-
wide range of deficits. tionally associated with the limbic system or with olfaction and
are classified as allocortex. Those structures that comprise three
OVERVIEW to five cellular layers are called the paleocortex (periallocortex)
The concept of a limbic system actually encompasses two levels and are represented by the cortex of the parahippocampal gyrus
of structural and functional organization. The first level consists (the entorhinal cortex), the uncus (the piriform cortex), and
of the cortical structures on the most medial edge (the limbus) the cortex overlying the termination of the lateral olfactory stria
of the hemisphere; these collectively form the limbic lobe (Fig. (lateral olfactory gyrus) (Fig. 31.2). The lateral olfactory stria is
31.1A). Beginning just anterior to the lamina terminalis and directly rostromedial to the piriform cortex. Structures having
proceeding caudally, these are the subcallosal area, containing only three cellular layers are classified as archicortex (allocortex)
the parolfactory and paraterminal gyri; the cingulate gyrus; the and are represented by the dentate gyrus and hippocampus.

457
458 Systems Neurobiology

Cingulate gyrus
Splenium of
corpus callosum

Cingulate sulcus

Isthmus of
cingulate gyrus
Genu of corpus
callosum

Subcallosal area

Uncus Parahippocampal gyrus

A Rhinal sulcus Collateral sulcus

Cingulum
Cingulate gyrus Stria medullaris thalami

Stria terminalis (ST)

Anterior thalamic nucleus

Fornix
Habenular nuclei
Habenulointerpeduncular tract
Anterior commissure

Medial forebrain bundle (MFB)

Septal nuclei Subiculum and hippocampus
Nucleus accumbens
Hypothalamic nuclei
Fimbria of hippocampus
Ventral amygdalofugal fibers MFB
Amygdaloid complex Ventral tegmental area
Mammillary nucleus
Brainstem nuclei
Mammillothalamic tract ST
B Interpeduncular nucleus

Cortical structures of limbic lobe

Nuclei of limbic system

Fiber bundles of limbic system

Fig. 31.1 Cortical structures forming the limbic lobe (A) and the subcortical structures (B, nuclei in pink,
fiber bundles in blue), which with the lobe represent the main components of the limbic system.

The separation between neocortex and allocortex is never of emotion was proposed. This pathway is now called the Papez
sharp but instead consists of transitional areas called periallocor- circuit in recognition of the anatomist James Papez (1883–1958),
tex, where one cortical region blends into the next. Such areas who initially described its components. This model, although sur-
are represented by caudal parts of the orbitofrontal cortex, the prisingly simple, has proved to be quite important in understand-
temporal pole, parts of the insula, and portions of the parahip- ing limbic function. The circuit suggested that emotion, mediated
pocampal and cingulate gyri. These important areas funnel input through the hypothalamus, is controlled and modulated by fibers
from association areas of the neocortex into the allocortex. from the fornix. Specifically, the cortical control of emotional
activity can be viewed as a pathway originating from the cingulate
EARLY FUNCTIONAL CONCEPTS gyrus (see Fig. 31.5). The Papez circuit consists of the following
In the late 1930s, two pivotal observations were made that formed structures and cell groups. The cingulate gyrus projects, via the
the basis for the concept of a limbic system. First, largely on the cingulum, to the hippocampal formation (mainly the subiculum
basis of the morphology of the brain, a circuit for the elaboration and the Ammon horn) as well as to the entorhinal cortex. The
 The Limbic System 459

Caudal Corpus
Olfactory bulb orbitofrontal callosum Hippocampal
and tract cortex formation

Rhinal
sulcus

Lateral olfactory stria

Uncus
A
Medial and lateral longitudinal
Collateral sulcus stria and indusium griseum
Parahippocampal
gyrus
Corpus
callosum
Isthmus of
cingulate gyrus

Occipitotemporal gyri

= Piriform cortex
Subcallosal Hippocampal
= Entorhinal cortex
area formation
Fig. 31.2 Cortical structures of the limbic lobe as seen on an anterior (ventral) B
view of the hemisphere.
Fig. 31.3 Developmental relationships between the corpus callosum (in red)
and the hippocampal formation (in green). As the corpus callosum expands cau-
hippocampus then projects, via the alveus and the various parts dally from the general area of the anterior commissure (A), the hippocampal
primordium migrates into the temporal lobe. In the adult brain, remnants of the
of the fornix, to the mammillary nuclei by coursing through the hippocampal formation left behind during development are located dorsal to the
postcommissural fornix. In turn, the medial mammillary nucleus corpus callosum (B).
projects to the anterior nucleus of the thalamus by way of the
mammillothalamic tract, and the anterior nucleus projects to the
cortex of the cingulate gyrus. This was the first time a specific the choroid plexus of the temporal horn, the hippocampal
anatomic substrate was proposed for a phenomenon as complex formation, parts of the amygdaloid complex, and adjacent
as emotion. structures, such as the tail of the caudate nucleus, the stria
The second pivotal observation was that bilateral removal of terminalis, and the sublenticular and retrolenticular limbs of
large parts of the temporal lobe in monkeys resulted in a constel- the internal capsule.
lation of dysfunctions that came to be known as the Klüver-Bucy Vessels serving hypothalamic nuclei that are functionally asso-
syndrome, in recognition of Heinrich Klüver (1897–1979) and ciated with the limbic system originate from the circle of Wil-
Paul Bucy (1904–1992). Whereas deficits in memory and behav- lis. In general, rostral areas of the hypothalamus are served by
ioral changes were initially described in animal experiments, branches from the anterior communicating artery and anterior
numerous cases of humans with bilateral temporal lobe injuries cerebral artery; posterior areas are served by branches from the
further elucidated the importance of the limbic system in the posterior communicating artery and proximal posterior cerebral
formation of new or recent memories. artery (see Fig. 8.17). The anterior nucleus of the thalamus, an
important synaptic station in the limbic system, is supplied by
BLOOD SUPPLY TO THE LIMBIC SYSTEM thalamoperforating arteries that arise from the P1 segment of
The blood supply to the limbic system originates from several the posterior cerebral artery.
sources. The main vessels serving the limbic system are the ante-
rior and posterior cerebral arteries, the anterior choroidal artery, HIPPOCAMPAL FORMATION
and branches arising from the circle of Willis. The hippocampal formation is composed of the subiculum,
The subcallosal area and rostral parts of the cingulate gyrus hippocampus (also called the hippocampus proper or horn of
are supplied by branches of the anterior cerebral artery as it Ammon), and dentate gyrus (see Fig. 31.4), all of which con-
loops around the genu of the corpus callosum (see Fig. 8.7). stitute the allocortex of Brodmann. The subiculum is laterally
Most of the cingulate gyrus and its isthmus receive blood sup- continuous with the cortex of the parahippocampal gyrus and an
ply via the pericallosal artery, a branch of the anterior cere- area of the periallocortex. Medially, the edge of the hippocampal
bral artery. Temporal branches of the posterior cerebral artery formation is formed by the dentate gyrus and the fimbria of the
(P3 segment) supply the parahippocampal gyrus. Although the hippocampus.
uncus may receive some small branches from the posterior Developmentally, the hippocampal formation originates dor-
cerebral artery, it is served primarily by uncal arteries, which sally and migrates into its ventral and medial positions in the
are branches of the M1 segment of the middle cerebral artery temporal lobe. During this migration, small remnants of the
(see Fig. 8.6). hippocampal formation remain behind to form the medial and
The anterior choroidal artery usually originates from the lateral longitudinal striae and their associated gray matter, the
internal carotid artery and follows the general trajectory of indusium griseum (Fig. 31.3). These structures are small in
the optic tract. It sends branches into the choroidal fissure of the human brain and extend rostrally along the dorsal aspect of
the temporal horn of the lateral ventricle. This vessel serves the corpus callosum into the subcallosal area.
460 Systems Neurobiology

Optic
tract Choroid plexus

Stria terminalis
Tail of caudate nucleus

Alveus

Temporal horn of
Fimbria of hippocampus lateral ventricle

Dentate gyrus: Hippocampus:

Polymorphic layer
Polymorphic layer
Granule cell layer Pyramidal layer
Molecular layer Molecular layer
Hippocampal fissure Alveus

Perforant pathway
Subiculum

Inputs from cingulate gyrus

Entorhinal cortex Inputs from olfactory bulb, cingulate gyrus,

basolateral amygdala, prelimbic
cortex (area 32), visual, auditory
and taste association cortices

CA3
CA2

CA1
CA4

Fig. 31.4 The basic structure of the hippocampal formation and its relation to adjacent structures. The
cell types of the dentate gyrus, hippocampus, and subiculum are shown diagrammatically. The general
locations of fields C1 to C4 are shown on the lower left; a Golgi stain of double pyramidal cells is shown
at the lower right.

Structure The dentate gyrus and the hippocampus are each composed of
The subiculum of the hippocampal formation is the transitional three layers (Fig. 31.4). The external layer is called the molec-
area between the three-layered hippocampus (allocortex) and ular layer and contains afferent axons and dendrites of cells
the five-layered entorhinal cortex (periallocortex) of the para- intrinsic to each structure. The middle layer, called the granule
hippocampal gyrus (Fig. 31.4). This transitional zone, although cell layer in the dentate gyrus and the pyramidal layer in the
small, can be divided into a prosubiculum, subiculum proper, hippocampus, contains the efferent neurons of each structure
presubiculum, and parasubiculum. These areas are essential for (Fig. 31.4). These layers are named according to the shape of
the flow of information into the hippocampal formation. the cell body of the principal type of neuron found therein. The
 The Limbic System 461

Cingulate cortex

Cingulum

Corpus callosum
Dorsomedial nucleus

Anterior nucleus

Postcommissural fornix Fornix

Precommissural fornix Habenula

MTTr
Anterior commissure
Medial frontal cortex Dentate gyrus
Hippocampus Hippocampal
Nucleus accumbens formation
Subiculum

Septal nuclei
Hypothalamic nuclei Entorhinal cortex
Optic chiasm
Corticohippocampal
cells and fibers
Mammillary body
Perforant pathway
Mammillotegmental fibers
Fig. 31.5 Semidiagrammatic representation of afferent and efferent connections of the hippocampal
formation. MTTr, mammillothalamic tract.

dendrites of granule and pyramidal cells radiate into the molec- Efferent Fibers
ular layer. The inner layer, called the polymorphic layer (also The outflow of the hippocampal formation originates primarily
called the stratum oriens in the hippocampus), contains the from cells of the subiculum and to a lesser degree from pyramidal
axons of pyramidal and granule cells, a few intrinsic neurons, cells of the hippocampus (Figs. 31.4 and 31.5). In both cases,
and many glial elements. In addition, the polymorphic layer of axons of these neurons enter the alveus, coalesce to form the fim-
the hippocampus contains the elaborate basal dendrites of some bria of the hippocampus, and then continue as the fornix. These
larger pyramidal somata that are located in the pyramidal layer. glutaminergic fibers traverse the entire extent of the fornix,
These are called double pyramidal cells because they have den- although some cross the midline in the hippocampal decussation
drites extending into both molecular and polymorphic layers just anterior (ventral) to the splenium of the corpus callosum.
(Fig. 31.4). The innermost part of the hippocampus borders At the level of the anterior commissure, the fornix divides into
on the wall of the lateral ventricle and is a layer of myelinated postcommissural and precommissural parts (Fig. 31.5). The fibers
axons arising from cell bodies located in the subiculum and hip- originating in the subiculum mainly form the postcommissural
pocampus. This layer, called the alveus, is continuous with the fornix. Most of these fibers terminate in the medial mammillary
fimbria of the hippocampus, which in turn becomes the fornix nucleus, although some enter the ventromedial nucleus of the
(Fig. 31.4). hypothalamus and the anterior nucleus of the dorsal thalamus
The hippocampus can be divided into four regions on the basis (Fig. 31.5). The precommissural fornix is composed of fibers
of a variety of cytoarchitectural criteria (Fig. 31.4). These areas arising primarily in the hippocampus. These fibers are somewhat
are designated CA1 to CA4, where CA stands for cornu ammo- diffusely organized and distribute to the septal nuclei, the medial
nis (horn of Ammon). Area CA1 (a parvocellular region that can areas of the frontal cortex, the preoptic and anterior nuclei of the
be separated into two cell layers in humans) is located at the hypothalamus, and the nucleus accumbens (Fig. 31.5).
subiculum-hippocampal interface. Area CA2 (a mixed zone) and
area CA3 (a magnocellular zone) are located within the hippo- Complete Circuit of Papez
campus. Area CA4 is located at the junction of the hippocampus As noted previously, the initial segment of the Papez circuit is
with the dentate gyrus but within the hilus of the dentate gyrus. a projection primarily from the subiculum (a part of the hip-
pocampal formation) to the medial mammillary nucleus via the
Afferent Fibers postcommissural fornix. The circuit is completed by the follow-
The major input to the hippocampal formation is from cells of ing connections (Fig. 31.5): (1) a mammillothalamic tract that
the entorhinal cortex via a diffuse projection called the perfo- connects the medial mammillary nucleus to the anterior nucleus
rant pathway (Figs. 31.4 and 31.5). Most fibers of the perforant of the thalamus; (2) thalamocortical fibers from the anterior
pathway terminate in the molecular layer of the dentate gyrus, nucleus to broad expanses of the cortex of the cingulate gyrus;
although a few terminate in the subiculum and hippocampus. and (3) a projection from the cingulate cortex, via the cingulum,
Granule cells in the dentate gyrus project into the molecular to the entorhinal cortex and also directly to the subiculum and
layer of the CA3 region of the hippocampus. CA3 neurons hippocampus. The subiculum, via the fornix, returns information
project into CA1 of the hippocampus, which in turn provides an to the mammillary body.
input to the subiculum. In addition, the subiculum also receives Other areas of the cerebral cortex are recruited into the vari-
a modest projection from the amygdaloid complex. Although the ous functions associated with the Papez circuit largely through
fornix is mainly an efferent path from the hippocampus, it also connections of the cingulate gyrus. For example, the cingulate
conveys cholinergic septohippocampal projections to the hippo- cortex receives input from premotor and prefrontal areas and
campal formation and entorhinal cortex. from visual, auditory, and somatosensory association cortices. In
462 Systems Neurobiology

Table 31.1 Categories of Memory and the Main Features

of Each Category
IMMEDIATE MEMORY SECONDS; SENSORY PERCEPTIONS
Short-term memory Minutes; limited capacity “scratch pad”
Long-term memory
Declarative Conscious; encoded by the hippocampus
Semantic Memory for facts, concepts
Episodic Memory for events, experiences
Procedural Unconscious; memory of skills encoded by the
cerebellum, basal ganglia, and motor cortex

turn, the cingulate cortex not only is a major source of afferent

fibers to the hippocampal formation but also projects to most
cortical areas from which it receives input. The cingulate gyrus
thus is not only an integral part of the Papez circuit but also an
important conduit through which a wide range of information
can reach the limbic system. A

LIMBIC SYSTEM AND MEMORY

The basic function of the hippocampal formation appears to be
the consolidation of long-term memories from immediate and
short-term memories, a point first observed in 1900 by Bechterew
(1857–1927) but essentially ignored until the 1950s. Immediate
(or sensory) memory and short-term memory refer to types of
memory that persist for seconds and minutes, respectively (Table
31.1). Normally, these memories can be incorporated into long-
term memory, which can be recalled days, months, or years later.
However, in persons with hippocampal lesions, this conversion
is not accomplished. Although patients may be able to recall
events or concepts for seconds or minutes, they are unable to
incorporate the short-term memory into long-term memory. The
redundancy and feedback in the hippocampus are ideal for this
imprinting of memory (Table 31.1).
Bilateral damage to the hippocampal formation sometimes
occurs after myocardial infarction, near-drowning, or severe
hypoglycemia as a result of cerebral ischemia (Fig. 31.6A). The
part of the hippocampal formation most vulnerable to anoxia B
during an ischemic episode is the CA1 area. The CA1-subiculum Fig. 31.6 Axial magnetic resonance image showing hyperintensities in both hip-
interface region is referred to as the Sommer sector in pathologic pocampi, slightly brighter on the right than on the left, due to severe hypoglyce-
conditions. Affected patients retain short-term memory but have mia (A). In B, a T1-weighted axial magnetic resonance image, note the atrophy
difficulty learning new concepts because the new information is of both hippocampi with enlarged temporal horns (arrows) and atrophy of the
not retained (remembered) long enough to become a long-term orbitofrontal cortex in a patient with Alzheimer dementia.
memory.
Another condition in which loss of memory and cognitive loss of neurons in the hippocampal formation (Fig. 31.7). These
function is particularly obvious is Alzheimer disease (AD). This patients with Korsakoff psychosis (alcoholic dementia) show a
disease is characterized, in part, by the presence of neurofibril- defect in short-term memory and consequently also in long-term
lary tangles, neuritic plaques, and neuronal loss in specific brain memory for events occurring since the onset of the disease. They
regions (Fig. 31.6B). The subiculum and entorhinal cortices are may appear demented, and they are prone to confabulation; that
among the first sites in which these abnormalities appear. As a is, they tend to string together fragments of memory from sev-
result, the relay of information through the hippocampal forma- eral different events to form a synthetic “memory” of an event
tion is impeded. It is believed that this damage is at least par- that never occurred (Table 31.2). Korsakoff psychosis is irrevers-
tially responsible for the difficulties with declarative memory ible. Thiamine deficiency may also be manifested more acutely
characteristic of AD. Poor recall of recent events or incorpora- as a triad of eye movement abnormalities, ataxia, and confusion
tion of new facts occurs early in AD. Long-term memory impair- known as Wernicke encephalopathy, which is reversible with thi-
ment and behavioral changes occur in later phases. Procedural amine replacement. Table 31.2 contrasts the acute and chronic
or implicit memory, the motor skills for performing tasks, is neurologic consequences of thiamine deficiency. In severe cases,
relatively spared because this type of memory is encoded by the patients may present with the Wernicke triad accompanied by
basal ganglia and cerebellum. profound memory loss; this condition is called Wernicke-Korsa-
Defects in memory can also result from prolonged thiamine koff syndrome.
deficiency. This vitamin B1 deficiency typically seen in the con-
text of chronic alcoholism, cancer cachexia, or any prolonged LONG-TERM POTENTIATION AND MEMORY
state of malnutrition causes a characteristic pattern of degenera- The process of long-term potentiation at individual synapses
tion in the brain (Fig. 31.7). Typically, the mammillary bodies is the probable mechanism that underlies the consolidation of
are involved, with some incursion into the dorsomedial nucleus short-term memory into long-term memory. When several syn-
of the thalamus and the columns of the fornix. There is also a apses are present on a single cell, the input from these synapses
 The Limbic System 463

current synaptic activity increases the probability that future

synaptic activity will take place. That is, the more the cir-
cuit is activated, the easier it is to activate. This mechanism
causes stimuli and responses to be paired in the process we call
memory.

AMYGDALOID COMPLEX
Structure
The amygdaloid complex is an almond-shaped group of cells
in the rostromedial part of the temporal lobe internal to the
uncus (Fig. 31.1). It is immediately rostral to the hippocam-
pal formation and the anterior end of the temporal horn of
the lateral ventricle. The amygdaloid complex is composed
of a number of nuclei. For our purposes, these nuclei can be
grouped into a larger basolateral group and a smaller corti-
comedial group (including the central nucleus). The cortico-
medial group is more closely related to olfaction, whereas the
basolateral group has extensive interconnections with cortical
structures.

Afferent Fibers
The basolateral cell groups of the amygdala receive inputs from
the dorsal thalamus, the prefrontal cortex, the cingulate and
parahippocampal gyri, the temporal lobe and insular cortex, and
the subiculum (Fig. 31.8A). These fibers supply a wide range of
somatosensory, visual, and visceral information to the amygdaloid
complex.
The corticomedial cell group receives olfactory input, fibers
Fig. 31.7 Axial computed tomography scan showing severe atrophy of temporal from the hypothalamus (ventromedial nucleus, lateral hypo-
and frontal lobes as well as prominent cerebellar folia (also a sign of atrophy) in thalamic area), and fibers from the dorsomedial and medial
a patient with alcohol dementia. Also note the enlarged temporal horns of the
lateral ventricles (arrows). nuclei of the dorsal thalamus (Fig. 31.8A). In addition, this
cell group, particularly its central nucleus, receives ascending
input from nuclei in the brainstem known to be involved in
Table 31.2 Neurologic Consequences of Thiamine visceral functions. Among others, these include the parabra-
Deficiency and a Comparison of Wernicke Encephalopathy chial nuclei, the solitary nucleus, and portions of the periaq-
with Korsakoff Psychosis ueductal gray.

WERNICKE ENCEPHALOPATHY KORSAKOFF PSYCHOSIS Efferent Fibers

Acute Chronic The two major efferent pathways of the amygdaloid complex are
Ophthalmoparesis, ataxia, confusion Confabulation, anterograde and the stria terminalis and the ventral amygdalofugal pathway (Figs.
retrograde amnesia 31.1B and 31.8B). The stria terminalis is a small fiber bundle that
Reversible Irreversible arises primarily from cells of the corticomedial group. Through
most of its course, this bundle lies in the groove between the cau-
date nucleus and the dorsal thalamus, where it is accompanied by
is integrated; that is, the small potential changes (excitatory the superior thalamostriate (terminal) vein. It is associated along
postsynaptic potential and inhibitory postsynaptic potential; see its length with discontinuous aggregations of cells, which collec-
Chapter 3) are added together. In long-term potentiation, one tively are called the bed nucleus of the stria terminalis. This
synapse fires in a particular temporal pattern (such as bursts or tract distributes to various nuclei of the hypothalamus (the pre-
trains of action potentials). This synaptic activity increases the optic nuclei, ventromedial nucleus, anterior nucleus, and lateral
likelihood that the target cells will be activated by that synapse hypothalamic area), to the nucleus accumbens and the septal
and other synapses. This increased likelihood may be due to an nuclei, and to the rostral areas of the caudate nucleus and puta-
increased probability that transmitter will be released from the men (Fig. 31.8B).
presynaptic cell or an increased response in the postsynaptic cell The ventral amygdalofugal pathway is the major efferent fiber
to the same amount of neurotransmitter, or both. Long-term bundle of the amygdaloid complex. These fibers arise from the
potentiation has been demonstrated at terminals of the perforant basolateral cell group and the central nucleus of the corticomedial
pathway in the dentate gyrus and at the synapses of CA3 pyrami- cell group and follow two general trajectories (Fig. 31.8B). Axons
dal cells on CA1 cells. These connections use the neurotransmit- primarily from the basolateral cells pass medially through the
ter glutamate. substantia innominata (in which some of these fibers terminate)
According to one current model, the release of glutamate to eventually synapse in the hypothalamus and septal nuclei. The
causes a change in the biochemistry of the N-methyl-d-aspar- substantia innominata gives rise to a diffuse cholinergic projection
tate (NMDA)–type glutamate receptors of the hippocampal to the cerebral cortex. It is probable that these fibers play a role
cells, allowing an increased number of calcium ions to enter the in the activation of the cerebral cortex in response to behavior-
cell. The calcium influx causes a second postsynaptic biochemi- ally significant stimuli. In addition, cells of the basolateral group
cal change. The gaseous neuromodulator nitric oxide is released also project diffusely to frontal and prefrontal, cingulate, insular,
and diffuses back to the presynaptic terminal. It acts on the and inferior temporal cortices (Fig. 31.8B). Other fibers, mainly
presynaptic terminal to permanently increase the release of glu- from the central nucleus, turn caudally and descend diffusely in
tamate. At this type of synapse, a brief, sustained increase in the brainstem to terminate in visceral (dorsal motor vagal) nuclei,
464 Systems Neurobiology

Cingulate cortex

Fornix
Bed nucleus of Cingulum
stria terminalis

Prefrontal
Dorsomedial
cortex
nucleus

Stria
terminalis

Lateral
Septal nuclei hypothalamic
area
Ventromedial nucleus
of hypothalamus

Olfactory: Brainstem nuclei:

Bulb Raphe, parabrachial,
Tract periaqueductal gray,
solitary, dorsal motor
Corticomedial amygdala vagal, locus ceruleus
Piriform cortex
Subiculum
Basolateral amygdala
Temporal lobe, insula,
parahippocampal gyrus,
Entorhinal cortex medial frontal lobe
A

Stria terminalis

Caudate nucleus Dorsomedial nucleus

Putamen Fornix

Stria terminalis
Preoptic area and anterior hypothalamus
Lateral hypothalamic area
Septal nuclei
Nucleus accumbens Brainstem targets:
Periaqueductal gray,
reticular formation,
Substantia innominata
locus ceruleus,
Ventromedial nucleus substantia nigra; raphe,
parabrachial, solitary,
Amygdalofugal pathway and vagal nuclei

Corticomedial amygdala Subiculum

Basolateral amygdala Prefrontal, motor,
Entorhinal cortex and insular cortices
B
Fig. 31.8 Semidiagrammatic representation of the afferent (A) and efferent (B) connections of the
amygdaloid complex.

raphe nuclei (magnus, obscurus, pallidus), and other areas such habenulointerpeduncular tract, which projects to the interpe-
as the locus ceruleus, parabrachial nuclei, and periaqueductal duncular nucleus and other midbrain sites, including the ventral
gray (Fig. 31.8B). As noted previously, most of those brainstem tegmental area and periaqueductal gray.
areas that receive input from the amygdala project back to this
structure. SEPTAL REGION
Another route by which hippocampal and amygdaloid effer- The septal region (septal nuclei), excluding the nucleus accum-
ents influence the brainstem is through the stria medullaris bens, is a small area just rostral to the anterior commissure and
thalami. This bundle conveys fibers from the septal nuclei (tar- in the medial wall of the hemisphere (Figs. 31.1B and 31.9A).
gets of amygdaloid and hippocampal inputs) to the habenular These nuclei extend into the base of the septum pellucidum.
nuclei (Fig. 31.9A). The latter cell groups, in turn, give rise to the Despite their relatively small size, the septal nuclei have been
 The Limbic System 465

Fornix

Stria
terminalis Stria medullaris
thalami

Anterior
commissure
Habenular nuclei
Septal nuclei
Habenulointerpeduncular
tract
Nucleus accumbens Ventral tegmental area

Optic chiasm Medial forebrain bundle

Hypothalamus
A

Stria terminalis

Bed nucleus of Fornix

stria terminalis

Globus pallidus Lateral hypothalamic

area

Ventral tegmental
Nucleus accumbens area

Septal nuclei Substantia nigra

Medial forebrain bundle

B
Fig. 31.9 Summary of the main afferent (red arrows) and efferent (green arrows) connections of the
septal nuclei (A) and of the nucleus accumbens (B).

implicated in myriad functions in animal models on the basis NUCLEUS ACCUMBENS

of the patterns of their inputs and outputs. In contrast, there is The nucleus accumbens (nucleus accumbens septi) is located in
little clinical information about their function in humans. Rage the rostral and ventral forebrain, where the head of the caudate
behavior has been seen in a small group of patients with midline nucleus and the putamen are continuous (see Fig. 26.4). These
infarcts in this area. cells receive input from the amygdaloid complex (primarily via
The principal afferent pathways to the septal nuclei include the ventral amygdalofugal pathway), from the hippocampal for-
fibers from the hippocampus (via the fornix), the amygdaloid mation (through the precommissural fornix), and from cells of
complex (via the stria terminalis and ventral amygdalofugal the bed nucleus of the stria terminalis (Fig. 31.9B). The ventral
pathways), and the ventral tegmental area of the midbrain (Fig. tegmental area also gives rise to ascending fibers that enter the
31.9A). Fibers also originate from the preoptic, anterior, and nucleus accumbens via the medial forebrain bundle. In addition,
paraventricular hypothalamic nuclei and from the lateral hypo- amygdalofugal fibers traversing the stria terminalis also enter the
thalamic area. Many of the fibers in the stria terminalis and for- nucleus accumbens.
nix also send branches into the nucleus accumbens. Cells within the nucleus accumbens have receptors for a vari-
The main efferent projections from the septal nuclei (Fig. ety of neurotransmitters, including endogenous opiates. The
31.9A) are septohippocampal fibers (in the fornix), projections nucleus accumbens may play an important role in behaviors
to the habenular nuclei, the medial thalamic nuclei (via the stria related to addiction and chronic pain. Recent observations in
medullaris thalami), and the ventral tegmental area (via the addicted humans likewise reinforce the concept that the nucleus
medial forebrain bundle). The preoptic, anterior, and ventrome- accumbens is a gratification site. These patients show marked
dial nuclei and the lateral hypothalamic areas also receive input binding of substances to cells in nucleus accumbens.
from the septal nuclei. Efferent projections of the nucleus accumbens include fibers
The medial forebrain bundle is a diffuse group of fibers that to the hypothalamus, nuclei of the brainstem, and the globus pal-
courses rostrocaudally through the lateral hypothalamic area lidus (Fig. 31.9B). Nucleus accumbens fibers to the last target
(Fig. 31.9A). This bundle is complex in that it conveys ascend- represent an important route through which the limbic system
ing inputs into the hypothalamus and through this area into the may access the motor system.
septal region. It also is a major conduit through which the sep-
tal nuclei and portions of the hypothalamus communicate with LIMBIC SYSTEM AND BEHAVIOR
the brainstem (Fig. 30.9). The dopamine-containing fibers in this In recent years, the term limbic system has been used mainly
area are thought to be related to perceptions of pleasure or drive in reference to emotion-related areas of the brain and the
reduction. pathways that interconnect them. These areas are generally
466 Systems Neurobiology

Table 31.3 Limbic Structures and Behavior: Main Behavioral and Clinical Characteristics of the Amygdala Contrasted with
Those of the Nucleus Accumbens
AMYGDALA NUCLEUS ACCUMBENS
Predominant function Aversion center Gratification center
Stimulation Fear Joy, pleasure
Lesion Placidity, hyperorality, hypermetamorphosis, Addiction, impulsive behavior
hyperphagia, hypersexuality
Principal neurotransmitter Glutamate > > serotonin, norepinephrine, Dopamine > > serotonin, norepinephrine,
epinephrine, dopamine epinephrine, glutamate

composed of sites that function to alter the emotions. These is appropriate), hyperphagia (eating excessive amounts even
sites, which are often interspersed in a given region of the when not hungry or when objects are not actually food), and
brain, are frequently called either aversion centers or gratifi- hypersexuality (suggestive behavior and talk with vague or ill-
cation centers. If an aversion center is stimulated, the person conceived attempts at sexual contact). In addition to these
will experience fear and sorrow. For example, some reports predictable deficits, these patients may also experience tactile
have linked activation of the amygdala during rapid eye move- agnosia (inability to recognize objects by touch despite intact
ment sleep with nightmares and posttraumatic stress disorder. proprioception and cutaneous sensation), auditory agnosia
On the other hand, stimulation of a gratification center will (inability to recognize or differentiate sounds despite intact
result in pleasure. Functional interconnections between aver- hearing), amnesia, dementia, or aphasia, depending on the
sion and gratification centers probably contribute to emotional extent of the lesion of the temporal lobe.
stability (Table 31.3).
Although most limbic structures contain both gratification and TEMPORAL LOBE SEIZURES
aversion centers, one or the other type of center seems to pre- Limbic structures are very sensitive to seizure activity. Dam-
dominate in some structures (Table 31.3). For example, the hip- age to the mesial temporal lobes, mesial temporal sclerosis (Fig.
pocampus and amygdala have an abundance of aversion centers, 31.10A), is the most common cause of complex partial seizures.
whereas the nucleus accumbens contains an abundance of grati- This type of seizure starts in a specific area of the brain, resulting
fication centers. Consequently, stimulation of the amygdala may in a wide range of physical and emotional behaviors with altera-
elicit fear, whereas stimulation of the nucleus accumbens results tion of consciousness. Partial seizures are often associated with a
in feelings of joy and pleasure. warning or an aura. For example, seizures that start in the area of
The emotion-related deficits resulting from small lesions in the uncus may be associated with olfactory or gustatory halluci-
the limbic system are difficult to predict. However, the effects nations referred to as uncinate fits. These sensations are explain-
of relatively large lesions are more stereotypic. They typically able given the functions of the amygdala and the destinations of
result in the flattening of emotions, as reflected by the fact the olfactory-gustatory fiber systems. Seizures starting in other
that emotional extremes (joy and anxiety) are reduced. This areas of the limbic system may be associated with visual illu-
phenomenon, presumably due to the loss of both aversion and sions, sensations of impending doom, déjà vu (unfamiliar seems
gratification centers, commonly results from large lesions in familiar), jamais vu (familiar seems unfamiliar), or even auto-
the amygdala, hippocampus, fornix, or cingulate or prefrontal nomic disturbances such as changes in heart rate or sweating. The
cortex. spectrum of physical and emotional behaviors seen with seizures
Bilateral lesions of the anterior part of the cingulate gyrus originating from this part of the brain led to the term psychomo-
greatly diminish the emotional responses of the patient and may tor seizure, which is seen in older literature.
result in akinetic mutism. This is a state in which the patient The temporal lobes may be damaged in a variety of ways, includ-
is immobile, mute, and unresponsive but not in a coma. Other ing trauma, hypoxia, and infection. The herpes simplex virus has
patients with cingulate damage may be alert but have no idea of a predilection for the temporal lobes (Fig. 31.10B). Patients with
who they are. Patients may also be unable to recall the order in herpes encephalitis typically have high fever, confusion, person-
which past events occurred. ality changes, and seizures. The viral infection causes hemorrhage
and necrosis of the temporal lobes, leaving most survivors with
Klüver-Bucy Syndrome permanent difficulty in forming new memories.
As mentioned previously, bilateral temporal lobe lesions that Epilepsy (recurrent seizure activity) is also related to the
largely abolish the amygdaloid complex cause a set of behavioral malfunction of the hippocampus. It is well established that
changes called the Klüver-Bucy syndrome. These deficits were most areas of the hippocampus are involved in the pathogen-
initially described in a series of animal experiments, but they esis of epilepsy and sustain damage as a result of recurrent sei-
have also been seen in patients as a result of either trauma to zures. Surprisingly, area CA2 is the most resistant to sustained
the temporal lobe or temporal lobe surgery for epilepsy. Damage seizure activity, whereas the Sommer sector and CA4 are the
to the amygdaloid complex frequently involves portions of adja- most vulnerable. Poorly controlled seizures may result in per-
cent structures and of the surrounding white matter, and these manent and progressive memory impairment and emotional
incursions into other structures may contribute to the clinical problems. The organization of the hippocampal subfields and
picture. Damage to the amygdala and the hippocampus results in the function of the amygdala are clinically apparent in the
a greater memory deficit than the deficit noted with damage to field of epilepsy.
either one alone.
The Klüver-Bucy syndrome is characterized by the follow- LIMBIC SYSTEM AND COGNITIVE FUNCTION
ing deficits: visual agnosia (inability to recognize an object by There is a trend to look at the limbic system as a set of structures
sight), hyperorality (tendency to examine objects by mouth), that influence not only emotion but also cognitive functions.
hypermetamorphosis (compulsion to intensively explore the The manner in which limbic structures and the cortex interact is
immediate environment or overreact to visual stimuli), pla- undergoing extensive revision both in terms of anatomy as well
cidity (may not show fear or anger even when such a reaction as molecular signaling. We know that visual information enters
 The Limbic System 467

the entorhinal cortex by first synapsing in the perirhinal cortex

(area 35) of the proisocortex. Thus visual place memories are
formed in the hippocampus by specific pathways only recently
elaborated. Undoubtedly, other sensory modalities enter the hip-
pocampus through similar transitional regions. Such inputs can
perhaps account for the cognitive deficits that follow selective
limbic system damage due to ischemia, toxicity, neurodegenera-
tion, or inflammation.

Limbic System and Pain

Chronic pain imparts a large socioeconomic burden for the gen-
eral population. Although most efforts in understanding the
development of chronic pain have focused largely on periph-
eral nerve and spinal cord reorganization, the role of the lim-
bic system has been brought to the forefront in recent years.
In response to fluctuations in chronic pain, the amygdala and
the nucleus accumbens are engaged through pathways begin-
ning in the medial prefrontal cortex. The same pathways are
not activated with acute pain. This understanding will undoubt-
edly result in varied therapeutic strategies for management of
chronic and acute pain.

Sources and Additional Reading

A The complete list is available online at www.studentconsult.com.

B
Fig. 31.10 Axial T1-weighted magnetic resonance image in coronal plane
showing hyperintensities, especially in the hippocampal formation, in the mesial
temporal areas bilaterally in a patient with intractable epilepsy (A). Image B is
an axial computed tomography scan showing hemorrhage (hyperdensities) and
necrosis (hypodensities) of the left temporal lobe resulting from herpes simplex
virus encephalitis.
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