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.
Table 16–1Components of the limbic system ||Download (.pdf) Table 16–1 Components of the limbic system
|Major brain division ||Structure ||Component part |
|Cerebral hemisphere (telencephalon) ||Limbic association cortex ||Orbitofrontal |
| || ||Cingulate |
| || ||Entorhinal |
| || ||Temporal pole |
| || ||Perirhinal |
| || ||Parahippocampal |
| ||Hippocampal formation ||Hippocampus (Ammon's horn) |
| || ||Subiculum |
| || ||Dentate gyrus |
| ||Amygdala ||Corticomedial |
| || ||Basolateral |
| || ||Central nucleus1 |
| ||Ventral striatum ||Nucleus accumbens |
| || ||Olfactory tubercle |
| || ||Ventromedial caudate and putamen |
|Diencephalon ||Thalamus ||Anterior nucleus |
| || ||Medial dorsal nucleus |
| || ||Midline nuclei |
| ||Hypothalamus ||Mammillary nuclei |
| || ||Ventromedial nucleus |
| || ||Lateral hypothalamic area |
| ||Epithalamus2 ||Habenula |
|Midbrain ||Portions of the periaqueductal gray matter and reticular formation || |
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.
Three-dimensional view of the amygdala and the hippocampal formation. The fornix, which is the output pathway of the hippocampal formation, and the mammillary body, a target to which it projects, are also illustrated.
Midsagittal view of the right cerebral hemisphere, with the brain stem removed. The limbic association areas are indicated by the different shaded regions. The lines drawn on the cingulate cortex roughly divide it into anterior, middle, and posterior regions, as described in the text. The inset shows the prefrontal association cortex and the parietal-temporal-occipital association cortex.
Ventral surface of the cerebral hemispheres, showing key components of the limbic association cortex (shaded area) as well as other basal forebrain structures. The collateral sulcus extends rostrally as the rhinal sulcus (sometimes termed fissure).
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 general spatial relations of components of the hippocampal formation, its efferent pathway (fornix), and the entorhinal cortex are shown. The middle portion of the hippocampal formation is distinguished in the schematic view. A coronal slice through the hippocampal formation (cut end, anteriorly) reveals a cylindrical shape and circular sequence of component structures (i.e., dentate gyrus, hippocampus, and subiculum). These components are present at all anterior-to-posterior levels; each forming a longitudinal strip along the antero-posterior axis of the cylinder.
Box 16–1 Circuits of the Hippocampal Formation and Entorhinal Cortex Are Important for Memory
Memory impairment after damage to the hippocampal formation and certain adjoining cortical structures is selective for explicit memories (also termed declarative memories). Consolidation of both forms of explicit memories is impaired: semantic memory, such as knowledge of facts, people, and objects, including new word meaning, and the episodic memory of events that have a specific spatial and temporal context, such as meeting a friend last week. Formation of spatial memories is also impaired, such as being able to navigate around a familiar city. By contrast, 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 learning and memory.
The three divisions of the hippocampal formation—the dentate gyrus, hippocampus, and subiculum, and any component parts—each have a relatively simple circuit, compared with other cerebral cortical areas. Moreover, the basic circuit is the same from anterior in the temporal lobe, posteriorly. In this way, it is much like that of the cerebellum in which local circuits were the same for the different cerebellar cortical regions. In a slice through the hippocampal formation (Figure 16–17), we see that pyramidal cells of the entorhinal cortex send their axons to the dentate gyrus, roughly in the same coronal plane as the hippocampal formation, to synapse on granule cells. This is the perforant pathway. Granule cell axons, termed mossy fibers, synapse on pyramidal cells of one subregion of the hippocampus, termed the CA3 region, where neurons, in turn, send their axons (called the Schaefer collaterals) to neurons of the CA1 region. (These axon collaterals spare the CA2 region.) The subiculum receives the next projection in the sequence, from the CA1 region, and it projects back to the entorhinal cortex. Both CA1 and the subiculum also project axons into the fornix, primarily to the septal nuclei and mammillary bodies, respectively. Additional parallel projections from entorhinal cortex to the hippocampus and subiculum are also important. It is not yet known how the myriad connections of the entorhinal cortex and hippocampal formation are organized to play a pivotal role in memory consolidation, spatial memory and navagation, and other aspects of cognition. However, an important clue exists: The strength of many synapses in the hippocampal formation can be modified under various experimental conditions.
A model for the functional organization of the hippocampal formation is based on its anatomical circuitry. Information that is first processed in the higher-order association areas on the lateral surface of the cerebral hemisphere, such as the parietal-temporal-occipital association area, is next processed in the limbic association cortex on the medial temporal lobe. This processing takes place in three key areas: the perirhinal cortex, the parahippocampal cortex, and the entorhinal cortex (Figure 16–3). From here, information is transmitted to the hippocampal formation (Figure 16–6), where further processing results in changes in the amount or timing of activity of certain populations of neurons. The complex neural responses comprise a "representation" of the memory, which unfortunately is not well understood. Finally, via two sets of return projections to the cortex—back to entorhinal cortex directly and, via the fornix, to the mammillary bodies and anterior thalamus to the cingulate cortex—this hippocampal memory representation enables consolidation of explicit and spatial memories in the association areas.
Serial and parallel hippocampal circuits. A. Cortical inputs to the hippocampal formation. B. Subcortical outputs via the fornix. There are also cortical projections from the hippocampal formation back to the entorhinal cortex, which projects back to the cortical areas from which it received input.
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.
Principal connections of the amygdala. The inset shows schematically the three divisions of the amygdala. A. The basolateral nuclei are reciprocally connected with the cortex of the temporal lobe, including higher-order sensory areas and association cortex. The basolateral amygdala also projects to the medial dorsal nucleus of the thalamus, the basal nucleus, and the ventral striatum. B. The central nuclei receive input from the brain stem, especially from visceral afferent relay nuclei (ie, solitary nucleus and parabrachial nucleus). The targets of its efferent projections include the hypothalamus and autonomic nuclei in the brain stem. C. The cortical nuclei have reciprocal connections with the olfactory bulb and efferent projections via the stria terminalis to the ventromedial nucleus of the hypothalamus.
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.
Brain regions important in addiction and reinforcement. A. The ventral tegmental area gives rise to a dopaminergic projection to the amygdala and ventral striatum that is important in various aspects of addiction. The ventral tegmental area also projects to the prefrontal cortex. B. Transverse section through the midbrain-diencephalon junction, showing the location of the ventral tegmental area and substantia nigra, both of which contain dopaminergic neurons. C. An expanded view of the region containing components of the limbic loop of the basal ganglia.
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.
Relations between the limbic system and effector systems. A. Neuroendocrine control is mediated by the amygdala via the periventricular hypothalamus. B. Autonomic control is mediated by both the amygdala and the lateral hypothalamus, via descending pathways that originate from the central nucleus of the amygdala and the middle and lateral hypothalamus. C. Somatic motor control is mediated by relatively direct projections to the reticular formation, for stereotypic behaviors, and through more complex telencephalic and diencephalic circuitry (not shown), for more flexible control.
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.
Myelin-stained coronal section through the rostral forebrain (A) and MRI (B). The inset shows the plane of section. (B, Courtesy of Dr. Joy Hirsch, Columbia University.)
Myelin-stained horizontal section through the anterior commissure.
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).
Myelin-stained coronal section through the septal nuclei, basal nucleus, (A) and amygdala and MRI (B). The arrow points to the plane of section of this image in Figure 16-18B. The inset shows the plane of section. (B, Courtesy of Dr. Joy Hirsch, Columbia University.)
Myelin-stained coronal section through the column of fornix and amygdala. The inset shows the approximate location of the nuclear divisions in the amygdala.
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).
Myelin-stained coronal section through the mammillary bodies (A) and through the mammillothalamic tract (B). In B, the mammillothalamic tract is seen on the right side only because the section is asymmetric. The inset shows the planes of section.
Myelin-stained coronal section through the medial dorsal nucleus of the thalamus. The divisions of the hippocampal formation are shown in the inset.
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.