Chapter 16: The Limbic System and Cerebral Circuits for Reward, Emotions, and Memory

The limbic system is a diverse collection of cortical and subcortical regions that are crucial for normal human behavior. Who you are—your memories, your unique personality, your thoughts, your emotions—in large measure is determined by the functions of the diverse brain regions that comprise the limbic system. Virtually all psychiatric diseases involve dysfunction of these structures.

Nineteenth century neurologists and anatomists recognized that damage to particular parts of the human brain was associated with disorders of emotion and memory. These lesions, unlike those of the cerebellum, occipital lobe, or cortical regions around the central sulcus, for example, spared perception and movement. This research led to the understanding that the neural systems for reward, emotions, and memory are distinct from the sensory and motor systems and, hence, are grouped into a single system called the limbic system. The term limbic derives from the Latin word limbus for "border," because many of the structures engaged in these functions encircle the diencephalon on the medial brain surface and are at the border between subcortical nuclei and the cerebral cortex.

However, the more that is understood about the myriad functions of limbic system structures, the less helpful it is to adhere to the notion of a single system. It becomes more meaningful to consider the component functional systems. As a consequence, the term limbic system is gradually being abandoned in favor of a more functionally descriptive terminology. Nevertheless, the notion of the limbic system has some utility. Brain structures that comprise the limbic system have been conserved throughout much of vertebrate evolution, reflecting the common and important need for the functions they serve.

The basic organizational plan of the circuits for reward, emotions, and memory appears to be different from the sensory and motor systems. The different sensory and motor systems consist of structurally and functionally independent regions that are interconnected only at the highest levels of processing. This functional independence makes sense. For example, although perceptions are enriched when information from different modalities is combined, you can nevertheless identify an apple by touch alone or a dog by the sound of a bark. In contrast, circuits for reward, emotions, and memory are highly integrated from the start. This no doubt reflects the fact that reward and emotion depend on the concurrent analysis of diverse sensory information and actions, and therefore are highly integrated behaviors. So, too, are memories. The sight of an old house and children playing in the yard can evoke vivid recollection of times spent during childhood.

This chapter first considers the components of the limbic system in relation to their generalized roles in reward, emotions, and memory. Then the chapter reexamines the same structures from the perspective of their spatial interrelations, their tracts, and their connections.

The circuits for reward, emotions, and memory have tremendous anatomical and functional diversity, involving an interplay between cortical and subcortical structures (Table 16–1). Components of the limbic system are highly interconnected, just as their functions are interdependent. And not surprisingly, it is difficult to categorically assign one or another function to each component of the limbic system. Even so, major functional distinctions emerge after disturbance to one or another structure, such as after removal for intractable epilepsy or after stroke.

The hippocampal formation is central to memory and the amygdala, to emotions (Figure 16–2A). In addition, the amygdala participates in the acquisition, consolidation, and recall of emotional memories. Two other subcortical structures— the ventral tegmental area and the ventral striatum and other components of the emotional loop of the basal ganglia (see Figure 14–2)—are key to reward and other reward-related behaviors, punishment, and aspects of decision. Recall that the ventral striatum comprises the nucleus accumbens and adjoining parts of the ventral caudate nucleus and putamen. And all of these structures are interconnected with the limbic association cortex (Figures 16–3 and 16–4). These cortical areas receive information from integrative thalamic nuclei, higher-order sensory areas; and from the other cortical association areas. In turn, they project to the subcortical limbic system structures.

The Limbic Association Cortex Is Located on the Medial Surface of the Frontal, Parietal, and Temporal Lobes

There are three major cortical association areas: (1) the parietal-temporal-occipital area, (2) the dorsolateral prefrontal association cortex (Figure 16–3, inset), and (3) the limbic association cortex. The limbic association cortex consists of morphologically and functionally diverse regions on four sets of gyri primarily on the medial and orbital surfaces of the cerebral hemisphere (Figures 16–3 and 16–4): the cingulate gyrus, the parahippocampal gyrus, the orbitofrontal and medial frontal gyri, and the gyri of the temporal pole. On the ventral brain surface (Figure 16–4), the lateral boundary of the limbic association cortex corresponds approximately to the collateral sulcus.

The cingulate gyrus, receiving its major thalamic input from the anterior nucleus, comprises three functional regions: rostral, middle, and posterior (Figure 16–3). The rostral portion of the cingulate gyrus is important in emotions, with connections with the amygdala, orbitofrontal, and insular cortex. We learned that a portion of this cortex receives information about physically painful stimuli. This portion is also involved in "emotional pain" of certain social situations (Figure 2–7). We also learned in Chapter 5 that the anterolateral system projects to the medial dorsal nucleus of the thalamus to convey physical pain information to the anterior cingulate gyrus. The portion under the genu of the corpus callosum, sometimes termed the subgenual region of the cingulate gyrus, is associated with the mood disorder, depression. This region is the target of therapeutic brain stimulation to ameliorate depression in patients who are refractory to pharmacological antidepressant therapy. The middle portion corresponds to the cingulate motor areas (see Chapter 10; Figure 10–7B). This portion may be involved in aspects of movement control driven by emotions and reward. The posterior cingulate appears to be more related to higher-order sensory functions and memory. The parahippocampal gyrus contains several subdivisions that provide information to the hippocampal formation (Figure 16–4). These areas are discussed below. Together, the cingulate and parahippocampal gyri form a C-shaped ring of cortex that partially encircles the corpus callosum, diencephalon, and midbrain (Figure 16–2). The cingulum (or cingulum bundle) is a collection of axons that courses in the white matter deep within the cingulate and parahippocampal gyri. Cortical association fibers course in the cingulum and terminate in the parahippocampal gyrus.

Rostral to the cortical ring are the medial frontal and orbitofrontal gyri. These areas are central to reward and decision making. A famous case study called attention to the orbitofrontal cortex in emotions. Phineas Gage was a railway foreman who was seriously injured in an accident in which an explosion drove a metal rod through his skull, largely ablating the orbitofrontal cortex and adjoining prefrontal cortex on one side of the brain. He survived but was a changed man. He was no longer a responsible worker, he became "short-tempered, capricious, and profane;" he was "no longer Gage." These changes occurred without major defects in intellect. Frontal lobe research led to development of the prefrontal lobotomy—whereby physical removal of orbitofrontal cortex and adjacent areas or section of its connections—to quell the disruptive behaviors of psychiatric disease. The orbitofrontal cortex receives information from all sensory modalities, typically via higher-order sensory cortical regions, together with inputs from subcortical reward centers (see below). It is thought to integrate this information for decision making and to evaluate the hedonic value of stimulation.

The cortex of the temporal pole, corresponding to Brodmann's area 38 (Figures 16–3 and 16–4; see Figure 2–19) is interconnected with the orbitofrontal cortex and subcortically with the amygdala and hypothalamus. Lesion of this part of the temporal lobe can produce personality changes, such as social withdrawal. In this chapter's case study, the person with degeneration of the temporal pole changed from being highly extroverted and empathetic to introverted and cold. Indiscriminate eating habits also are reported.

The Hippocampal Formation Plays a Role in Consolidating Explicit Memories

Important insights into the function of the hippocampal formation have been obtained by studying the behavior of patients whose medial temporal lobe either was damaged because of a stroke or was ablated to ameliorate the serious symptoms of temporal lobe epilepsy. In one of the most extensively examined cases, this region was removed bilaterally from a patient referred to as H.M. After surgery, H.M. lost the capacity for consolidating short-term memory into long-term memory, but he retained the memory of events that occurred before the lesion. This is termed anterograde amnesia. The impairment was selective for consolidating explicit memories (also termed declarative memories), such as the conscious recollection of facts. By contrast, H.M. and other patients with hippocampal (or medial temporal lobe) damage are capable of remembering procedures and actions (ie, implicit or nondeclarative memory), and they retain the capacity for a variety of simple forms of memory. More common than surgical ablation, sometimes after a severe heart attack, patients suffer bilateral damage to a key part of the hippocampal formation. During a heart attack, circulation of blood to the brain can become compromised because of insufficiency in the pumping action of the heart. This brain injury results because certain neurons in the hippocampal formation require consistently high circulating blood oxygen levels. What has emerged from this research is that the hippocampal formation is involved in the long-term consolidation of explicit memory. It is thought that the memories themselves reside in the higher-order association areas of the cerebral cortex.

Whereas the hippocampal formation is best known for its role in memory consolidation, it has also been implicated in the body's response to stress and emotions. Interestingly, animal and human fMRI studies suggest that the posterior part of the hippocampal formation is more important for explicit memory, cognition, and spatial memory, while the anterior portion is more related to stress and emotions. Interestingly, London taxicab drivers, who must master the complex London street map, have a larger posterior hippocampal formation than control subjects. Located anteriorly, there is a division related to stress and emotions. Further, the size of the hippocampal formation is reduced in schizophrenia, linking it with human psychiatric disease.

The hippocampal formation comprises three anatomical components, each with distinctive morphologies and connections (Figure 16–5; Table 16–1; see Box 16–1): the dentate gyrus, the hippocampus proper, and the subiculum. (The nomenclature of the hippocampal formation is variable, and exactly which components are considered to be part of this structure may differ, depending on the source.) The three components are organized roughly as parallel strips running antero-posteriorly within the temporal lobe and together forming a cylinder (Figure 16–5). These strips are initially a flattened sheet located on the brain surface, but during prenatal development they become buried within the cortex (see Figure 16–16A). The flat sheet also folds in a complex manner to assume its mature configuration, which resembles a jelly-roll pastry. The dentate gyrus—together with the subventricular zone of the lateral ventricle, which was discussed in Chapter 9 (see Box 9–1)—are the two brain sites for neurogenesis in the mature brain.

The hippocampal formation has serial and parallel circuits

The hippocampal formation receives complex sensory and cognitive information from a portion of the limbic association cortex termed the entorhinal cortex (Figures 16–3, 16–4, and 16–5). In fact, the hippocampal formation works so closely with the adjoining entorhinal cortex that the two are functionally inseparable. The entorhinal cortex, located on the parahippocampal gyrus adjacent to the hippocampal formation, collects information from other parts of the limbic association cortex (perirhinal and parahippocampal cortex) as well as from other association areas (Figure 16–6A). Extensive processing of information occurs within the hippocampal formation, within a prominent serial circuit, in which information is projected in sequential steps (see Box 16–1). There is also a parallel circuit, in which information from the entorhinal cortex projects directly to each hippocampal component. Combined serial and parallel processing within neural circuits is also a feature of sensory and motor pathways.

The output neurons of the hippocampal formation are pyramidal neurons, similar to the neocortex covering most of the cerebral hemisphere, and they are located in the hippocampus and subiculum. The dentate gyrus contains neurons, termed granule cells, that make connections only within the hippocampal formation. Pyramidal neurons have axon branches that collect on the surface of the hippocampal formation. Eventually these axons form a compact fiber bundle, the fornix (Figures 16–2 and 16–5), which projects to other subcortical telencephalic and diencephalic structures. The hippocampal formation, together with the fornix, has a C-shape. Two output systems can be distinguished within the fornix, from the subiculum and the hippocampus (Figures 16–6B and 16–7B). Although these systems are involved in the cognitive aspects of memory, it is not yet understood how their functions differ.

From the subiculum, axons synapse mostly in the mammillary bodies of the hypothalamus (Figures 16–2 and 16–6B). This projection completes an anatomical loop: Via the mammillothalamic tract, the mammillary body projects to the anterior nuclei of the thalamus, which project to the cingulate gyrus (Figure 16–6B). The cingulate gyrus provides information to the entorhinal cortex, which projects to the hippocampal formation. In 1937, James Papez postulated that this pathway plays an important role in emotion. It is now known that the circuit named in his honor is part of a complex network of bidirectional connections and that many components of this network play an important role in memory. Some fornix fibers from the subiculum project to the amygdala. This may be part of the circuit for consolidating emotional memories.

From the hippocampus, most axons do not synapse in the mammillary bodies, but rather, in several other locations, including the septal nuclei, located more rostrally in the forebrain in close apposition to the septum pellicudum (Figure 16–6B). Little is known about the function of septal nuclei. In a fascinating series of experiments in the early 1950s, laboratory rats, when given the choice of receiving either electrical stimulation of the septal nuclei or food and water, preferred the electrical stimulation. Investigators reasoned that this region is a so-called pleasure center that likely plays an important role in regulating highly motivated behaviors, such as reproductive behaviors or feeding. The septal nuclei give rise to a cholinergic (see Figure 2–3A) and GABAergic projection, via the fornix, back to the hippocampal formation. This return septal projection is important in regulating hippocampal activity during certain active behavioral states.

The hippocampal formation has diverse cortical projections

The fornix is an extremely large tract, with over one million heavily myelinated axons on each side. This number is comparable to the number of myelinated axons in one medullary pyramid or an optic nerve. Despite its size, a major target of axons of the fornix is the ipsilateral mammillary body, whose output is also highly focused, on the anterior thalamic nuclei. How can the hippocampal formation, with such a focused subcortical projection, have a generalized role in memory? One answer is that the fornix is not the only major output of the hippocampal formation. The subiculum and hippocampus also project back to the entorhinal cortex (Figure 16–6C), which, in turn, has diverse efferent corticocortical connections to the prefrontal cortex, orbitofrontal cortex, parahippocampal gyrus, cingulate gyrus, and insular cortex (Figure 16–6B). And collectively these cortical areas also have widespread projections. Through the divergence of connections emerging from the entorhinal cortex to cortical association areas, the hippocampal formation can influence virtually all association areas of the temporal, parietal, and frontal lobes, as well as some higher-order sensory areas, after as few as three synapses. The divergence in the cortical output of the hippocampal formation parallels the widespread convergence of its inputs, also via the entorhinal cortex, from association areas.

The Amygdala Contains Three Major Functional Divisions for Emotions and Their Behavioral Expression

The amygdala (sometimes termed the amygdaloid complex) is a collection of morphologically, histochemically, and functionally diverse nuclei. Located largely within the rostral temporal lobe (Figure 16–2), the main portion of the amygdala is almond-shaped (amygdala is Greek for "almond"). One of its output pathways, however, the stria terminalis, and one of its component nuclei, the bed nucleus of the stria terminalis, are C-shaped (Figure 16–7). Axons of the other output pathway of the amygdala, the ventral amygdalofugal pathway, take a somewhat more direct route to their targets.

Amygdala circuits are preferentially involved in emotions and their overt behavioral expressions. The functions of amygdala circuits are therefore similar to the functions originally proposed for the entire limbic system. What stimuli are responded to, how overt responses to these stimuli are organized, and the internal responses of the body's organs are all dependent on this subcortical structure. Following damage to the amygdala, people lose the ability to recognize the affective meaning of facial expression, especially threatening faces. People also fail to recognize the emotional content of speech. Given the defects observed with its damage, it is not surprising that the amygdala is a central figure in emotion regulation, especially in relation to fear. For example, analysis of staring eyes, a vocalization, and body posture can lead to a set of potential emotional outcomes, such as fear or anxiety, and a set of possible actions, such as fleeing or attacking a potential foe. In animals, electrical stimulation of the amygdala, depending on the particular site, can evoke diverse defense reactions and visceral motor responses. The numerous nuclei of the amygdala can be divided into three principal nuclear groups (Figure 16–8): basolateral, central, and cortical. Each group has different connections and functions.

The basolateral nuclei are reciprocally connected with the cerebral cortex

The basolateral nuclei (Figure 16–7A) comprise the largest division of the amygdala. These nuclei are thought to attach emotional significance to a stimulus. The basolateral nuclei receive information about the particular characteristics of a stimulus from higher-order sensory cortical areas in the temporal and insular cortical areas and from association cortex. Limbic association cortex conveys this information to the amygdala to link particular stimuli, such as seeing a particular object or hearing a certain sound, with particular emotions. The amygdala is an important target of the ventral stream for object recognition (see Figures 7–15 and 7–16). Importantly, the amygdala and hippocampal formation receive somewhat different kinds of sensory information. Whereas the amygdala receives highly processed sensory information, it retains its modality characteristics (eg, visual or auditory). On the other hand, the hippocampal formation receives more integrated sensory information that is thought to reflect complex features of the environment, such as spatial relationships and contexts. For example, when you see a snake, you may feel threatened and fearful. Visual pathways through the ventral portion of the temporal lobe convey information about the snake to the amygdala. The amygdala uses this information to organize your response, both the emotions you feel and your overt behavior to this potential danger. The hippocampal formation is thought to be important in learning the complex environmental setting, or context, in which the snake was seen.

The major efferent connections of the basolateral amygdala are directed back to the cerebral cortex, either directly or indirectly. The cortical areas receiving a direct projection from the basolateral amygdala are the limbic association cortex—which includes the cingulate gyrus, temporal pole, and medial orbitofrontal cortex—and the dorsolateral prefrontal cortex. The amygdala also projects directly to the hippocampal formation, which, as discussed earlier, is thought to be important in learning the emotional significance of complex stimuli or the context in which emotionally charged stimuli are experienced. In addition to direct cortical projections, the basolateral division has extensive subcortical projections that give rise, indirectly, to connections to the cortex. Via the ventral amygdalofugal pathway, the basolateral amygdala projects to the thalamic relay nucleus for association areas in the frontal lobe, the medial dorsal nucleus. It also has a major projection to cholinergic forebrain neurons located in the basal nucleus (of Meynert), which itself has widespread cortical projections (see next section and Figure 2–3A). Finally, neurons of the basolateral nuclei also project to the central amygdala nuclei (see section below on the basal forebrain), which are important in mediating behavioral responses to emotional stimuli.

The central nuclei project to autonomic control centers in the brain stem and hypothalamus

An important function of the central nuclei (Figure 16–7B) is to mediate emotional responses. In regulating the autonomic nervous system, the central nuclei receive viscerosensory input from brain stem nuclei, in particular the solitary nucleus and the parabrachial nucleus (see Chapter 6). In turn, the central nuclei project via the ventral amygdalofugal pathway to the dorsal motor nucleus of the vagus as well as to other brain stem parasympathetic nuclei and nearby portions of the reticular formation. The central nuclei also regulate the autonomic nervous system through projections to the lateral hypothalamus (see Chapter 15). As discussed earlier in this chapter, the central nuclei receive an input from the basolateral nuclei. This is the key path for fear conditioning, which helps to shape responses to emotional stimuli.

The central nuclei of the amygdala are part of the collection of nuclei that share morphological, histochemical, and connection characteristics, called the extended amygdala. These nuclei extend caudally within the basal forebrain and beneath the basal ganglia. Included in this group is the bed nucleus of the stria terminalis. Together with parts of the ventral striatal circuits, this is an important structure in substance abuse and dependence. They may help organize drug-seeking and drug-taking behaviors that are characteristics of addiction.

The cortical nuclei are reciprocally connected with olfactory structures

As discussed in Chapter 9, the cortical nuclei receive olfactory information from the olfactory bulb (Figure 16–7C; see Figure 9–9). The piriform cortex, along with the lateral orbitofrontal cortex, is thought to be important in olfactory perception. In animals, the cortical nuclei play a role in behaviors triggered by olfactory stimuli, especially sexual responses.

The Mesolimbic Dopamine System and Ventral Striatum Are Important in Reward

The brain has two major dopamine systems. One originates from the substantia nigra pars compacta (Figure 16–8B) and projects primarily to two parts of the striatum, the caudate and the putamen, and less so to the nucleus accumbens. This is termed the nigrostriatal dopaminergic system. The other is the mesolimbic (sometimes termed mesocorticolimbic) dopaminergic system, which originates from the ventral tegmental area (Figure 16–8B). This system provides the principal dopaminergic innervation of the nucleus accumbens (Figure 16–8A; see Figures 16–10 and 16–11), the amygdala, and various parts of the cortex, especially the prefrontal cortex. The mesolimbic dopaminergic axons travel in the medial forebrain bundle (Figure 16–8A). Whereas dysfunction of the nigrostriatal system is associated with Parkinson disease, dysfunction of the mesolimbic dopaminergic system is implicated in schizophrenia and depression.

The dopaminergic systems are important in responding to natural rewarding stimuli for survival, such as feeding and reproduction. However, dopaminergic neurons do not simply signal the hedonic (ie, subjective experience of pleasure) value of events, because novel negative reinforcing stimuli can also activate the dopaminergic systems. Nevertheless, the mesolimbic dopaminergic system is central to the brain's reward circuit. Most drugs of abuse—like psychostimulants (such as cocaine, methamphetamine, and MDMA), sedative-hypnotics (including ethanol), nicotine, THC (tetrahydrocannabinol, the active compound in marijuana), and opiates—produce an increase in dopamine in several target areas of the mesocorticolimbic dopaminergic system. (Note that opiates also use nondopaminergic mechanisms.) Several substance-specific mechanisms account for this effect, including decreased reuptake of dopamine at synaptic sites and disinhibition of ventral tegmental neurons so that they can release more dopamine and, hence, have a stronger reinforcing effect. The nucleus accumbens, which is part of the ventral striatum, is a particularly important area because the reinforcing effects of drugs of abuse are greatly diminished or eliminated when dopamine transmission is blocked there. Another area important for the reinforcing actions of drugs, especially ethanol, is the central amygdala nuclei (see Figure 16–13).

The nucleus accumbens is also a key site for neural interactions responsible for drug reinforcement and the motivation to seek drugs. Release of dopamine in the nucleus accumbens is critically involved in forming the associations between drug-related cues and rewarding experiences. The nucleus accumbens is a striatal component of the limbic loop (see Chapter 14). This loop can provide an emotional context for planning motor behavior. The output nucleus of the limbic loop is the ventral pallidum, which projects to the anterior and medial dorsal thalamic nuclei and then to the medial orbitofrontal and medial prefrontal cortex, and cingulate cortex (Figure 16–8C). The various frontal association areas project to premotor areas to influence movements directly (see Figure 10–2B). This circuit could mediate the flexible responses to cues associated with drug use and abuse.

Connections Exist Between Components of the Limbic System and the Three Effector Systems

The limbic system is difficult to study partly because a bewilderingly large number of interconnections exist between its many structures. What might be the functions of these myriad interconnections? Many of the connections relate to the behavioral expression of emotions. Complex polysynaptic pathways ultimately link limbic system structures with the three effector systems for the behavioral expression of emotion: the endocrine, autonomic, and somatic motor systems (Figure 16–9).

Paths by which the limbic system may influence pituitary hormone secretion involve indirect connections between the amygdala and the periventricular hypothalamus (Figure 16–9A). One such path, for example, involves the projection from the cortical amygdala, via the stria terminalis, to the ventromedial nucleus (Figure 16–7C). This nucleus projects to a key component of the parvocellular neurosecretory system, the arcuate nucleus (see Chapter 15).

The visceral consequences of emotions are mediated by direct and indirect connections to brain stem and spinal nuclei of the autonomic nervous system (Figure 16–9B). As discussed earlier, the central nuclei of the amygdala project directly to brain stem autonomic centers (Figure 16–7B). The amygdala also affects autonomic function indirectly, through projections to the lateral hypothalamus, which influences autonomic function through neural circuits of the reticular formation and other parts of the hypothalamus. Recall that the hypothalamus, including part of the paraventricular nucleus and the lateral hypothalamus, gives rise to descending pathways that regulate autonomic function (see Figure 15–8).

The overt behavioral signs of emotion, such as flight or fight reactions, are mediated by the actions of the limbic system on the somatic motor systems (Figure 16–9C), especially the reticulospinal tracts (see Figure 10–5B). For example, projections from the hippocampus, septal nuclei, and amygdala to the lateral hypothalamus can influence the reticulospinal system (Figure 16–9C). These connections may be important in triggering stereotypic responses, such as defense reactions and reproductive behaviors. Experimental studies in animals have also shown that the periaqueductal gray matter mediates motor behaviors typical of particular species, such as growling and hissing in carnivores responding to environmental threats. The periaqueductal gray matter receives inputs from the central amygdala nuclei and the hypothalamus.

The limbic system can also influence somatic motor functions in more complex and behaviorally flexible ways through the limbic loop of the basal ganglia, which includes the ventral striatum, ventral pallidum, and thalamic medial dorsal nucleus (see Figure 16–15B; see Figure 14–8). Cortical inputs to this loop derive from the limbic association areas, hippocampal formation, and basolateral nuclei of the amygdala. As noted in Chapter 14, the output of the limbic loop is to the limbic association areas of the frontal lobe. These areas can influence the planning of movements through projections to premotor areas and possibly the execution of movements through projections to the cingulate motor areas (see Figure 10–7B).

All Major Neurotransmitter Regulatory Systems Have Projections to the Limbic System

The innervation of the limbic system by the major neurotransmitter regulatory systems (see Chapter 2; Figure 2–3) is particularly important for normal thoughts, moods, and behaviors. This conclusion is based on the observation that many of the drugs used to treat psychiatric illness—the disorders of thought, such as schizophrenia, and of mood, such as depression and anxiety—selectively affect one of the neurotransmitter systems. These neurotransmitter systems have direct and widespread connections with the limbic system:

• The ventral tegmental area influences many limbic system structures, as indicated earlier (Figure 16–8). Coursing through the medial forebrain bundle, the dopaminergic fibers synapse on neurons in the dorsolateral prefrontal association area, medial orbitofrontal cortex, cingulate gyrus, ventral striatum, amygdala, and hippocampal formation. An important hypothesis for the pathophysiology of schizophrenia is that an exaggerated dopamine response leads to prefrontal cortex dysfunction, which is a key region for organization of thoughts and behaviors.

• Serotonergic projections to limbic system structures of the telencephalon and diencephalon originate from the dorsal and median raphe nuclei (see Figure 16–19B, C). Coursing within three tracts—the medial forebrain bundle, the dorsal longitudinal fasciculus, and the medial longitudinal fasciculus—the ascending serotonergic projection synapses on neurons in the amygdala, hippocampal formation, all areas of the striatum, and cerebral cortex. Drugs that block serotonin reuptake mechanisms are effective in treating mood disorders, including anxiety and obsessive-compulsive disorders.

• The noradrenergic projection, which originates from the locus ceruleus (see Figure 16–19C), influences the entire cerebral cortex, including the limbic association areas, as well as limbic and other subcortical structures. This system, together with the serotonergic system, may play a role in depression because drugs that ameliorate depression result in elevations of these two monoamines.

• The cholinergic projection originates from large neurons in the basal nucleus, the medial septal nucleus, and the nucleus of the diagonal band of Broca (see Figure 16–12). Additional brain stem cholinergic cell groups with widespread cortical (and thalamic) projections are found near the pedunculopontine nucleus (see Figure 16–19B). As discussed in Chapter 14, the pedunculopontine nucleus is an important output nucleus of the basal ganglia, and is a target of deep brain electrical stimulation to ameliorate signs of Parkinson disease. Targets of the cholinergic projection include the entire neocortex (including the limbic association cortex), the amygdala, and the hippocampal formation. Alzheimer disease, characterized by progressive dementia, begins with a loss of these basal forebrain cholinergic neurons. As the disease progresses, other neurotransmitter systems are also affected.

Knowledge of the three-dimensional configuration of individual limbic system structures is essential for understanding their location in two-dimensional slices. As noted earlier in this chapter, three components of the limbic system have a C-shape: (1) the hippocampal formation and its output pathway, the fornix (Figure 16–2), (2) part of the amygdala and one of its pathways, the stria terminalis (Figure 16–7), and (3) the limbic association cortex, especially the cingulate and parahippocampal gyri (Figure 16–3). As a consequence of their C-shape, a coronal section through the cerebral hemisphere may transect these structures twice: first dorsally and then ventrally. In horizontal sections, C-shaped structures are located rostrally and caudally.

The Nucleus Accumbens and Olfactory Tubercle Comprise Part of the Basal Forebrain

Sections through the rostral forebrain cut through components of the limbic loop of the basal ganglia. The input side of the loop (see Figures 14–5 and 14–8) is the ventral striatum, consisting of the nucleus accumbens, the olfactory tubercle, and the ventromedial parts of the caudate nucleus and putamen (Figures 16–10 and 16–12). The ventral striatum receives information from all of the nuclear divisions of the amygdala as well as from the hippocampal formation and limbic association cortex. The output nucleus of the limbic loop is the ventral pallidum (Figure 16–12), which projects to parts of the medial dorsal nucleus of the thalamus (see Figure 16–14B) and from there to the dorsolateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate gyrus. The ventral striatum also has direct projections to the amygdala. Recall that the dorsal parts of the striatum are important in skeletal motor and oculomotor functions and cognition. Their outputs are focused on the internal and external segments of the globus pallidus and the substantia nigra pars reticulata. Nevertheless, as discussed in Chapter 14, there are ways the limbic and motor loops can interact, which allow the limbic loop to influence movement control.

Other than receiving olfactory input from the olfactory bulb and tract, little is known of the functions of the olfactory tubercle. The olfactory tubercle corresponds to the region on the ventral surface termed the anterior perforated substance (Figure 16–4). This is where penetrating branches of the middle and anterior cerebral arteries (the lenticulostriate arteries) enter the basal brain surface to supply parts of the basal ganglia and internal capsule. The slice shown in Figure 16–10 also cuts through the most anterior portions of the cingulate and parahippocampal gyri.

This is the level of the temporal pole, which has connections with orbitofrontal cortex and the amygdala; it also has direct projections to the hypothalamus. As discussed earlier, temporal pole cortex is important for personality. Connections with the orbitofrontal lobe are made by axons that travel within the uncinate fasciculus (Figure 16–12).

Basal Forebrain Cholinergic Systems Have Diffuse Limbic and Neocortical Projections

The septal nuclei are adjacent to the septum pellucidum (Figures 16–10 and 16–12), a nonneural structure that separates the anterior horns of the lateral ventricles of the two cerebral hemispheres. Animal studies have revealed that the septal nuclei consist of separate medial and lateral components. In humans, the lateral septal nucleus may correspond to neurons located near the ventricular surface, whereas the medial septal nucleus, to those near the septum pellucidum. Moreover, these medial cells are continuous with the gray matter on the medial surface of the cerebral hemisphere, just rostral to the lamina terminalis. This region, termed the paraterminal gyrus (Figure 16–3), merges with the nucleus of the diagonal band of Broca, which is located on the basal forebrain surface (Figures 16–4, 16–11, and 16–12).

The lateral septal nucleus is a target of the projection from the hippocampus, via the fornix. The medial septal nucleus receives its major input from the lateral septal nucleus and projects to three sites: (1) to the hippocampal formation, (2) to the periaqueductal gray matter and reticular formation, and (3) to the habenula, a portion of the diencephalon. The projection to the hippocampal formation, via the fornix, is important in regulating hippocampal neuronal activity. The projection to the periaqueductal gray matter and reticular formation, via the medial forebrain bundle, is thought to be important in evoking stereotypic behaviors in response to environmental stimuli. Finally, the projection to the habenula, located lateral and ventral to the pineal gland (Figure 16–11; see Figure AI–7), is part of a circuit with the midbrain medial dopaminergic and serotonergic systems. The habenulopeduncular tract (see Figure AII–15) is the highly myelinated output tract of the habenula.

The basal forebrain is located on the ventral surface of the cerebral hemisphere. It includes the paraterminal gyrus, nucleus of the diagonal band of Broca, and anterior perforated substance. The septal nuclei are continuous with many basal forebrain structures. On Figure 16–4, the basal forebrain is located approximately anterior to and beneath the optic chiasm and tracts. Large neurons are located here that use acetylcholine as their principal neurotransmitter. In addition to the medial septal nucleus, cholinergic neurons are located in the nucleus of the diagonal band of Broca and the basal nucleus (Figure 16–12). The various cholinergic neurons form a continuous band, from dorsomedially in the septal nuclei to ventrolaterally in the basal nucleus (Figure 16–12, orange shading). Other large cholinergic neurons are dispersed between the lamina of the globus pallidus and putamen and adjacent to the internal capsule. Some are present in the lateral hypothalamus. The basal forebrain cholinergic neurons (including those in the medial septal nucleus) excite their targets primarily through muscarinic receptors; such responses to acetylcholine are important in integrating information because they facilitate responses to other inputs. These cholinergic neurons, through widespread cortical projections, may also modulate overall cortical excitability.

The Cingulum Courses Beneath the Cingulate and Parahippocampal Gyri

Two cortical limbic areas, the cingulate and parahippocampal gyri, are seen in a series of coronal sections (Figures 16–10 and 16–12, 16–13, 16–14, 16–15, 16–16): The cingulate gyrus is located dorsally, and the parahippocampal gyrus is located ventrally. The pathway that connects regions of the dorsolateral prefrontal cortex, the orbitofrontal gyri and the cingulate gyrus with the parahippocampal gyrus, including the entorhinal cortex, is termed the cingulum. This pathway is located in the white matter beneath the cingulate gyrus (Figure 16–12). Unlike the cingulum, another limbic system cortical association pathway, the uncinate fasciculus (Figures 16–12 and 16–13), has a more direct trajectory for interconnecting anterior portions of the temporal lobe with medial orbital gyri of the frontal lobe.

The Three Nuclear Divisions of the Amygdala Are Revealed in Coronal Section

The amygdala is located in the rostral temporal lobe beneath the cortex of the parahippocampal gyrus (Figures 16–12, 16–13, 16–14A). The amygdala is rostral and slightly dorsal to the hippocampal formation. (Compare the parasagittal section in Figure 16–18B with the drawing in Figure 16–2.) The arrow in Figure 16–12 shows the approximate plane of section in Figure 16–18B. The amygdala and the rostral hippocampal formations form the uncus (Figures 16–3 and 16–14). Expanding space-occupying lesions above the tentorium cerebelli (see Figure 3–15), especially those of the temporal lobe, may displace the uncus medially. This uncal herniation compresses midbrain structures, ultimately resulting in coma and even death. Initially uncal herniation can compress the oculomotor nerves, which exit from the ventral midbrain surface. This results in third nerve dysfunction, including paralysis of extraocular muscles and loss of pupillary light reflexes.

The three nuclear divisions of the amygdala are schematically depicted in the inset to Figure 16–13. The cortical division of the amygdala merges with the overlying cortex of the medial temporal lobe. This division receives a major input directly from the olfactory bulb. The two other nuclear divisions, basolateral and central, are also shown. The bed nucleus of the stria terminalis is the C-shaped nuclear component of the amygdala. It has connections with brain stem autonomic and visceral afferent nuclei and thus has connections similar to those of the central nuclear division. Along with the central nucleus and several smaller nuclei, they form the extended amygdala. A portion of the bed nucleus of the stria terminalis is thought to be sexually dimorphic.

The stria terminalis and the ventral amygdalofugal pathway are the two output pathways of the amygdala

The stria terminalis carries output from the amygdala, predominantly from the cortical nuclei. The stria terminalis and its bed nucleus are located medial to the caudate nucleus, in a shallow groove formed at the junction of the thalamus and the caudate nucleus (Figures 16–11 and 16–14), termed the terminal sulcus. Running along with the stria terminalis and bed nucleus is the thalamostriate vein (or terminal vein), which drains portions of the thalamus and caudate nucleus. The stria terminalis does not stain darkly because its axons are not heavily myelinated. A major target of the axons running in the stria terminalis is the ventral medial nucleus of the hypothalamus, which is important in feeding.

The other efferent pathway of the amygdala, the ventral amygdalofugal pathway (Figure 16–13), runs ventral to the anterior commissure and globus pallidus (see Chapter 14). The projections of the central and basolateral nuclei course primarily in this efferent pathway. The ventral pathway has four major targets:

1. The medial dorsal nucleus of the thalamus (Figures 16–15B and 16–16) links synaptically the basolateral amygdala indirectly with the frontal lobe. Separate portions of the medial dorsal nucleus project to the dorsolateral prefrontal and orbitofrontal cortical areas.

2. The ventral amygdalofugal pathway links the central nuclei of the amygdala with the lateral hypothalamus for autonomic nervous system control and with parvocellular neurons for neuroendocrine control. The central nuclei of the amygdala influence corticotropin hormone release by parvocellular neurosecretory neurons of the paraventricular nucleus (Chapter 15). This control is exerted by disinhibition: GABAergic output neurons of the central nuclei synapse on GABAergic neurons in the hypothalamus that control the neurosecretory neurons. Disinhibition is an important feature of circuitry in the cerebellar cortex (Chapter 13) and basal ganglia (Chapter 14).

3. The basal forebrain, including the ventral striatum and the cholinergic neurons of the basal nucleus and nucleus of the diagonal band of Broca, links the amygdala synaptically with the cortex.

4. The brain stem, which contains parasympathetic preganglionic nuclei, receives a projection from the central nuclei.

The Hippocampal Formation Is Located in the Floor of the Inferior Horn of the Lateral Ventricle

Coronal sections through the temporal lobe, from rostral to caudal directions, slice first through the amygdala, then through both the amygdala and hippocampal formation, and finally through the hippocampal formation alone. (Figures 16–14 and 16–15 show these rostrocaudal relationships.) The hippocampal formation forms part of the floor of the inferior horn of the lateral ventricle. In coronal section (eg, Figure 16–15), the hippocampal formation is located ventrally and the fornix is located dorsally. In horizontal section (Figure 16–11), the hippocampal formation (which here is quite small) is caudal and the fornix is rostral. There is a minuscule portion of the hippocampal formation dorsal to the corpus callosum that is vestigial; in the mature brain, it is termed the indusium griseum (see Figure AII–16). Some schizophrenic individuals exhibit degeneration of the hippocampal formation and other medial temporal lobe neural structures. In consequence, this produces an increase in the size of the lateral ventricle.

During development the hippocampal formation undergoes an infolding into the temporal lobe (Figure 16–16). The simple sequence of the component parts of the temporal lobe, from the parahippocampal gyrus on the lateral surface to the dentate gyrus on the medial surface, becomes more complex later in development. As the hippocampal sulcus forms, the dentate gyrus and the subiculum become apposed; the pial surfaces of these two structures fuse, and a hippocampal afferent pathway (the perforant pathway) courses through this fusion (Figure 16–17B).

The morphology of the hippocampal formation, as well as many of the limbic association areas, differs from that of the rest of the cortex. As we learned in Chapter 9, the principal cortex is neocortex (eg, primary somatic sensory cortex or posterior parietal association cortex), which has six major cell layers (Figure 16–16B1). The other type of cortex is allocortex (Figure 16–16B2), which has fewer than six layers and is more variable. The hippocampal formation is a kind of allocortex termed archicortex; regions in the parahippocampal gyrus and the cingulate gyrus under the corpus callosum are the other kind of allocortex, termed paleocortex.

The three divisions of the hippocampal formation—the dentate gyrus, hippocampus, and subiculum—are shown in the inset in Figure 16–15. Each division has three principal cell layers, conforming to the common allocortex plan (Figure 16–16B). The pyramidal layer—or granule cell layer in the dentate gyrus—contains the projection neurons of the region. The other layers contain interneurons. Whereas the output neurons of the pyramidal layer (pyramidal neurons) in the hippocampus and subiculum can project outside the hippocampal formation (see Box 16–1), the granule cells of the dentate gyrus connect only within the hippocampal formation.

Pyramidal cells of the hippocampus and subiculum have extrinsic connections, sending their axons to cortical and subcortical targets (Figure 16–6). The hippocampus and subiculum have extensive "back" projections to the entorhinal cortex that, in turn, project widely to other cortical regions (Figure 16–6). The principal subcortical targets are the mammillary bodies, which receive a projection from pyramidal cells mostly of the subiculum, and the lateral septal nucleus, which receives a projection primarily from the hippocampus. These axons course in the fornix. In addition to extrinsic connections, both sides of the hippocampal formation are interconnected through commissural neurons whose axons course in the ventral portion of the fornix.

A Sagittal Cut Through the Mammillary Bodies Reveals the Fornix and Mammillothalamic Tract

Structures that have a C-shape are oriented approximately in the sagittal plane. The sagittal section in Figure 16–18A is located close to the midline and transects the fornix, although not through its entire length. The sagittal section in Figure 16–18B is located farther laterally and cuts through the long axis of the hippocampal formation.

Pyramidal cell axons of the hippocampus and subiculum form the alveus, the myelinated envelope surrounding the hippocampal formation (Figure 16–18B). These axons collect on the medial side of the hippocampal formation to form the first of the four anatomical parts of the fornix, termed the fimbria. The other three parts—the crus (where the axons are separate from the hippocampal formation), the body (where the axons from both sides join at the midline), and the column (where axons descend toward their targets)—bring the axons of the fornix to neurons in the diencephalon and rostral telencephalon.

The body and column of the fornix can be seen in Figure 16–18A. Note how the column of the fornix descends caudal to the anterior commissure to terminate in the mammillary body; this is the postcommissural fornix (see also Figure 16–11, where the columns of the fornix are caudal to the anterior commissure). The mammillary body comprises the medial and lateral mammillary nuclei (Figure 16–14A), and the fornix terminates in both components. The major output, the mammillothalamic tract, originates from both the medial and lateral mammillary nuclei. Axons of the mammillothalamic tract also can be seen leaving the mammillary body in Figure 16–18A. These axons are coursing toward the anterior thalamic nuclei (Figure 16–14B). The lateral mammillary nucleus (Figure 16–14A) also gives rise to the mammillotegmental tract, which descends to the midbrain and rostral pontine reticular formation. Degeneration of the mammillary bodies, along with portions of the medial thalamus, occurs in Korsakoff syndrome. These patients have profound memory loss, attributable to impairment in expressin g the functions of the subiculum. This condition results from thimamine deficiency, typically accompanying alcoholism.

Fibers of the fornix also terminate in locations other than the mammillary bodies. Some of these fibers terminate directly in the anterior thalamic nuclei; others project to the amygdala and nucleus accumbens. Moreover, rostral to the anterior commissure, the precommissural fornix, which is smaller than the postcommissural portion, courses away from the midline. (It cannot be seen in the section in Figure 16–18A.) An important projection of the hippocampus is to the lateral septal nucleus through the precommissural fornix. A portion of the stria medullaris, which has a predominantly rostrocaudal course, is also revealed in this section (Figure 16–18A). As discussed earlier, the medial septal nucleus projects axons into the stria medullaris. These axons synapse in the habenula (see Figures AI–7 and AII–18).

Nuclei in the Brain Stem Link Telencephalic and Diencephalic Limbic Structures With the Autonomic Nervous System and the Spinal Cord

The periaqueductal gray matter and reticular formation (Figure 16–19) are thought to be important in the behavioral expression of emotions, such as stereotypic defense reactions or the body's response to stress. Septal neurons project to the midbrain reticular formation via neurons of the lateral hypothalamus. Neurons of the lateral hypothalamus are interspersed throughout the medial forebrain bundle (see Chapter 15). From these midbrain regions, the actions of neurons in wide areas of the reticular formation can be modified by the limbic system. The hypothalamus also projects to the periaqueductal gray matter. Chapter 5 considered the projection of the periaqueductal gray matter to the raphe nuclei (see Figure 5–8), which give rise to a spinal cord projection for regulating pain transmission.

General Anatomy of the Limbic System

The limbic system comprises a set of structures located predominantly on the medial surface of the cerebral hemisphere (Figures 16–2 and 16–3). The diverse functions of the limbic system include important roles in reward, memory, and emotions—and their behavioral and visceral consequences. Many of the structures have a C-shaped configuration. The limbic system has three C-shaped components (Figures 16–2, 16–3, 16–4, 16–5): (1) the limbic association cortex, (2) the hippocampal formation and fornix, and (3) part of the amygdala (stria terminalis and bed nucleus of the stria terminalis).

Limbic Association Cortex

The limbic cortical areas include the following structures (Figures 16–3 and 16–4): the medial orbital gyri of the frontal lobe, the cingulate gyrus in the frontal and parietal lobes, the parahippocampal gyrus in the temporal lobe, and the cortex of the temporal pole. The limbic cortical areas receive input from higher-order sensory areas in the temporal lobe and from the other cortical association areas, the prefrontal association cortex and the parietal-temporal-occipital association area. The two principal pathways carrying cortical association axons to and from other limbic system structures are the cingulum (located beneath the cingulate gyrus; Figure 16–12) and the uncinate fasciculus (Figure 16–12). The cytoarchitecture of limbic association cortex differs from that of other cortical regions. The cortex on the external surface of the parahippocampal gyrus lateral to the collateral sulcus (Figure 16–4) has at least six layers (neocortex), whereas the cortex medial to the sulcus is more variable and typically has fewer than six cell layers (allocortex) (Figure 16–16B). Cholinergic projections to limbic cortex, the hippocampal formation, and lateral cortical areas originate from the basal forebrain, including the basal nucleus, the nucleus of the diagonal band of Broca, and the medial septal nucleus (Figure 16–12).

Hippocampal Formation

The hippocampal formation (Figures 16–2 and 16–5) includes three cytoarchitectonically distinct subdivisions (Figures 16–5, 16–13, and 16–17): the dentate gyrus, the hippocampus, and the subiculum. The hippocampal formation plays an essential role in consolidation of explicit and spatial memory. The limbic association cortex provides the major input to the hippocampal formation. The entorhinal cortex, a specific portion of the rostral parahippocampal gyrus, projects directly to the hippocampal formation (Figure 16–6A). Other portions of the limbic association cortex influence the hippocampal formation indirectly, via the entorhinal cortex. The dentate gyrus, hippocampus, and subiculum are separate processing stages in a sequence of intrinsic connections in the hippocampal formation (Figure 16–17). The flow of information through the hippocampal formation is largely unidirectional.

Hippocampal efferents originate from the subiculum and the hippocampus proper; the dentate gyrus projects only to part of the hippocampus. Cortical projections from the hippocampus and subiculum terminate in the entorhinal cortex, and from there information is widely distributed throughout the cerebral cortex (Figure 16–6B). Subcortical projections are via the fornix. Most of the axons in the fornix are those of pyramidal cells of the subiculum and hippocampus. Axons from the subiculum synapse in the mammillary body (Figures 16–6B, 16–14A, and 16–18A). These axons course in the postcommissural fornix (Figure 16–19A). The mammillary bodies project, via the mammillothalamic tract (Figures 16–14A and 16–18A), to the anterior thalamic nuclei (Figure 16–14B), which project to the cingulate gyrus (Figures 16–3 and 16–11). The hippocampus projects, via the precommissural fornix, to the lateral septal nucleus (Figures 16–6B and 16–12). The medial septal nucleus, which contains cholinergic and GABAergic neurons, projects back to the hippocampal formation, via the fornix.

Amygdala

The amygdala has three major nuclear divisions (Figures 16–7 and 16–13), which collectively are involved in emotions and their behavioral expression: the basolateral nuclei, the central nuclei, and the cortical nuclei. The basolateral nuclei receive a major input from the cerebral cortex and project to the medial dorsal nucleus of the thalamus, the basal nucleus, the ventral striatum, and back to the cortex (temporal, orbitofrontal, and prefrontal association areas). The central nuclei, important for the visceral expression of emotion and reward/addiction, are reciprocally connected with viscerosensory and visceral motor nuclei of the brain stem. They also project to the hypothalamus to regulate neuroendocrine functions. The cortical nuclei receive direct olfactory input. They may play a role in appetitive behaviors and neuroendocrine functions through their projections to the ventromedial nucleus of the hypothalamus.

The amygdala has two output pathways: (1) The stria terminalis (Figures 16–7C and 16–13), which is C-shaped, carries the efferent projection primarily from the cortical nuclei, and (2) the ventral amygdalofugal pathway (Figure 16–13) carries the efferents from the central nuclei, which descend to the brain stem, and those from the basolateral nuclei, which ascend to the thalamus, the ventral striatum, and the basal nucleus (Figures 16–12 and 16–13). The bed nucleus of the stria terminalis runs along with the stria.

Limbic Loop of the Basal Ganglia and Ventral Tegmental Area

The limbic loop of the basal ganglia comprises the ventral striatum (nucleus accumbens, and adjoining ventral portions of the caudate nucleus and putamen; Figures 16–8 and 16–10). Its output is directed to the ventral pallidum (Figure 16–12). The medial dorsal nucleus of the thalamus, which is a target of the ventral pallidum, projects to orbitofrontal, medial frontal, and dorsolateral prefrontal cortex. The ventral tegmental area (Figures 16–8 and 16–19A) contains dopaminergic neurons that project to the ventral striatum and prefrontal, medial frontal, and orbitofrontal cortex and is key to reward, punishment, and decision signaling in the brain.