In addition to their well-defined role in regulating arousal, monoaminergic neurons also regulate cognitive performance during waking and affect a variety of other central nervous system functions. We illustrate these effects with four examples.
Cognitive Performance Is Optimized by Ascending Projections from Monoaminergic Neurons
Although the monoamines and acetylcholine each induce arousal, they have different effects on cognitive function during waking. This occurs in part because each of the monoamines, and acetylcholine, uses distinct intracellular signaling pathways that act on different complements of ion channels (Figure 46–5B). Thus, in addition to differences in regional distribution, each type of monoamine receptor has a unique cellular and subcellular distribution (Figure 46–6). Hence each part of the brain and each type of neuron is affected differently by monoamines and acetylcholine.
Different types of serotonin receptors are distributed differently within the brain.
The left images are positron emission tomography (PET) scans showing the density of two types of serotonin (5-HT) receptors in the brain of a normal person, and the right images are magnetic resonance imaging (MRI) scans showing the anatomy at the same level.
A. The 5-HT1a receptors are concentrated mainly in the medial temporal lobe (red), and less so in the neocortex (blue). (Modified, with permission, from Plenevaux et al. 2000.)
B. At the same level, 5-HT2a receptors are concentrated mostly in the frontal and temporal neocortex and less so in the medial temporal lobe. (Modified, with permission, from Smith et al. 1998.)
Neurons of the locus ceruleus, which release norep-inephrine, play an important role in attention. These neurons have a low baseline level of activity in drowsy monkeys. In alert monkeys the cells have two modes of activity that correspond to differences in behavior. In the phasic mode the baseline activity of the neurons is low to moderate. Just before the monkey responds to a stimulus to which it has been attentive, the cells are briefly excited. This pattern of activity correlates with and may facilitate selective attention. In contrast, in the tonic mode the baseline level of activity is elevated and does not change in response to external stimuli. This mode of firing may disrupt the ability to maintain attention on a single task and help to search for a new behavioral and attentional goal when the current task is no longer rewarding (Figure 46–7).
Locus ceruleus neurons exhibit different patterns of activity with different levels of attentiveness and task performance.
Inverted U curve shows the relationship between a monkey's performance on a target detection task and the level of locus ceruleus (LC) activity. Histograms show the responses of LC neurons to presentation of the target during different levels of task performance. Performance is poor at low levels of LC activity because the animals are not alert. Performance is also poor when baseline activity is high because the higher baseline is incompatible with focusing on the assigned task. Performance is optimal when baseline activity is moderate and phasic activation follows presentation of the target (arrow). The tonic mode (with high baseline activity) might be optimal for tasks (or contexts) that require behavioral flexibility instead of focused attention. If so, the LC could regulate the balance between focused and flexible behavior. (Reproduced, with permission, from Aston-Jones and Cohen 2005.)
Monoaminergic inputs to the dorsolateral prefrontal cortex improve working memory (see Chapters 65 and 67). Microinjection of dopamine-receptor antagonists into the dorsolateral prefrontal cortex of monkeys markedly reduces the animals' ability to remember a location for several seconds. In functional magnetic resonance imaging (fMRI) studies of humans, D1 agonist drugs increased activation of the dorsolateral prefrontal cortex during a memory task. Injection of agonists of the α2-adrenergic receptor into the dorsolateral prefrontal cortex of aging monkeys can also improve performance on working memory tasks.
Dopamine also has been linked to reward-based learning. Rewards are objects or events for which an animal will work (see Chapter 49) and are useful in reinforcing behavior. Activity of dopaminergic neurons increases when a reward (such as food or juice) is unexpectedly given. But after animals are trained to expect that a reward will follow a conditioned stimulus, the activity of the neurons increases immediately after the conditioned stimulus rather than after the reward. This pattern of activity indicates that dopaminergic neurons provide a reward-prediction error signal, an important element in reinforcement learning. The importance of dopamine in learning is also supported by observations that lesions of dopaminergic systems prevent reward-based learning. The same dopaminergic pathways that are important for reward and learning are involved in addiction to many drugs of abuse (see Chapter 49)
Monoamines Are Involved in Autonomic Regulation and Breathing
Neurons in the adrenergic C1 group in the rostral ventrolateral medulla play a key role in maintaining resting vascular tone as well as adjusting vasomotor tone necessitated by various behaviors. For example, an upright posture disinhibits neurons in the rostral ventrolateral medulla that directly innervate the sympathetic preganglionic vasomotor neurons, thus increasing vasomotor tone to prevent a drop in blood pressure (the baroreceptor reflex). Neurons in the noradrenergic A5 group in the pons inhibit the sympathetic preganglionic neurons and play a role in depressor reflexes (eg, the fall in blood pressure in response to deep pain).
Serotonin regulates many different autonomic functions including gastrointestinal peristalsis, thermoregulation, cardiovascular control, and breathing. Electrical stimulation of serotonergic neurons within the medullary raphe nuclei increases heart rate and blood pressure. Serotonergic neurons in the medulla also project to neurons in the medulla and spinal cord that regulate breathing (Figure 46–8A), and stimulation of the medullary raphe nuclei increases respiratory motor output (see Chapter 45). Some serotonergic neurons in the medulla are central chemoreceptors (CO2 sensors), firing faster in response to an increase in CO2 and in turn stimulating breathing to restore arterial acid/base homeostasis. Serotonergic neurons in the midbrain also sense arterial CO2 (Figure 46–8B). These neurons may induce arousal, anxiety, and changes in cerebral blood flow when blood CO2 increases, responses which are important for survival when airflow is obstructed. Consistent with these ideas, genetic deletion of all serotonergic neurons in mice leads to a large decrease in the ventilatory response to breathing air with increased CO2 (hypercapnia) and these mice no longer wake up when presented with the same stimulus while asleep.
Serotonergic neurons have a role in the response to a rise in CO2 levels as well as sudden infant death syndrome (SIDS).
A. Serotonergic neurons in the medulla are central respiratory chemoreceptors that are thought to stimulate breathing in response to an increase in arterial blood PCO2. The dendrites of these neurons wrap around large arteries and are stimulated by an increase in partial pressure of CO2 (PCO2) (see Figure 45–9). They project to and excite neurons in the medulla and spinal cord that control breathing.
B. Serotonergic neurons in the midbrain are also PCO2 sensors. Shown here is the increase in firing rate of a serotonergic neuron from the dorsal raphe nucleus in response to an increase in PCO2 (monitored by the resultant decrease in external pH). This increase in firing rate may convert thalamic and cortical neurons to single-spike mode and thus cause wakening from sleep, an important response to prevent airway obstruction during sleep when the airway is obstructed.
C. 1. Infants are at risk of death from SIDS when three conditions coincide (triple risk hypothesis). First, the infant must be vulnerable because of an underlying abnormality of the brain stem, such as a genetic predisposition or an environmental insult (eg, exposure to cigarette smoke). Second, the baby must be in the stage of development (usually less than 1 year of age) when it may be difficult to change position to escape airway obstruction. Third, there also must be an exogenous stressor (eg, lying face down in a pillow). (Reproduced, with permission, from Filiano and Kinney 1994.) 2. One proposed mechanism of SIDS is that the combination of abnormal serotonergic neurons (eg, caused by exposure to cigarette smoke) and postnatal immaturity of neurons involved in respiratory control may lead to the inability to respond effectively to airway obstruction. The infant then does not wake up and turn its head or breathe faster, either of which would correct the problem. As a result, severe decreases in blood oxygenation (hypoxia) and elevation of blood carbon dioxide (hypercapnia) occur. (Reproduced, with permission, from Richerson 2004.)
The role of serotonergic neurons as CO2 receptors may explain why defects in the serotonergic system have been linked to sudden infant death syndrome (SIDS). SIDS is the leading cause of postneonatal mortality in the Western world, responsible for six infant deaths every day in the United States. It was defined by an expert panel of pathologists and pediatricians as "the sudden and unexpected death of an infant under one year of age that remains unexplained after a complete clinical review, autopsy, and death scene investigation and occurs in seemingly healthy infants usually during a sleep period" (Figure 46–8C).
A widely held theory holds that some SIDS cases are due to defective CO2 chemoreception, breathing, and arousal. An increase in the number of serotonergic neurons with an immature morphology, a decrease in serotonin levels, and changes in serotonergic receptor density are found in the raphe nuclei of infants who die of SIDS. A plausible neurobiological mechanism for SIDS is that a defect in development of serotonergic neurons leads to reduced ability to detect a rise in partial pressure of CO2 when airflow is obstructed during sleep, thus blunting the normal protective response which should include arousal and increased ventilation (Figure 46–8C). Infants sleeping face down would be unable to arouse sufficiently to change position when bedding blocks the airway. This mechanism could explain the success of the Back to Sleep campaign that encourages mothers to place infants on their backs when put to sleep and has reduced the incidence of SIDS by 50%.
Pain and Anti-nociceptive Pathways Are Modulated by Monoamines
Although pain is necessary for an animal to avoid injury, continued pain following an injury may be maladaptive (eg, if the pain prevents vigorous escape from a predator). Hence the monoaminergic systems include important descending projections to the dorsal horn of the spinal cord that modulate pain perception (see Chapter 24).
The noradrenergic inputs to the spinal cord originate from pontine cell groups, including the locus ceruleus, A5, and A7 cell groups. Similarly, the serotonergic medullary raphe nuclei, particularly the nucleus raphe magnus, project to the dorsal horn where they modulate the processing of information about noxious stimuli. Direct application of serotonin to dorsal horn neurons inhibits their response to noxious stimuli, and intrathecal administration of serotonin attenuates the defensive withdrawal of the paw evoked by noxious stimuli. In addition, intrathecal administration of antagonists of serotonin receptors blocks the pain inhibition evoked by stimulation of the raphe nuclei.
Insight into the role of serotonin in pain processing has been used in treating migraine headaches. In particular, agonists to the 5-HT1D receptors, the triptans have been found to be therapeutically effective. One of the possible mechanisms of action of this family of tryptamine-based drugs includes presynaptic inhibition of pain afferents from the meninges, preventing sensitization of central neurons. Drugs that block monoamine reuptake, including both traditional antidepressants and selective serotonin reuptake inhibitors, are effective in limiting pain in patients with chronic pain and migraine headaches.
Monoamines Facilitate Motor Activity
The dopaminergic system is critical for normal motor performance. A massive projection ascends from the substantia nigra pars compacta to the striatum. As described in Chapter 43, dopaminergic fibers act on striatal neurons via D1 and D2 receptors to release inhibition on motor responses.
As would be expected, patients with Parkinson disease in whom midbrain dopaminergic neurons have degenerated have trouble initiating movement and difficulty sustaining their movements. Such patients speak softly, write with small letters, and take small steps. Conversely, drugs that facilitate dopaminergic transmission in the striatum can result in unintended behaviors ranging from motor tics (small muscle twitches), to chorea (large scale, jerky limb movements), to complex cognitive behaviors (such as compulsive gambling or sexual activity).
As first shown by Sten Grillner, serotonergic neurons play an important role in generating motor programs. Drugs that activate serotonin receptors can induce hyperactivity, myoclonus, tremor, and rigidity, which are all part of the "serotonin syndrome." Increases in the firing of raphe neurons have been observed in animals during repetitive motor activities such as feeding, grooming, locomotion, and deep breathing. Conversely, the atonia and lack of movement that occur during REM sleep are associated with near cessation of firing of raphe neurons.
Noradrenergic cell groups in the pons also send extensive projections to motor neurons. This modulatory input facilitates excitatory inputs to motor neurons by acting on β- and α1-adrenergic receptors. The sum of these effects is to facilitate motor neuron responses in stereotypic and repetitive behaviors such as rhythmic chewing, swimming, or locomotion. Conversely, increased β-adrenergic activation during stress can exaggerate motor responses and produce tremor. Drugs that block β-adrenergic receptors are used clinically to reduce certain types of tremor and are often taken by musicians prior to performances to minimize tremulousness.