The nervous system, comprised of two major components, i.e., the peripheral nervous system (PNS) and the central nervous system (CNS), has three main functions: sensory input, integration of data, and motor output.4 The PNS is subdivided into sensory (afferent) and motor (efferent) divisions. Afferent sensory neurons conduct signals from the PNS to the CNS. Efferent motor neurons conduct signals from the CNS to the PNS.
The efferent motor division of the PNS is subdivided into somatic and autonomic systems. The somatic nervous system controls voluntary movements. The autonomic nervous system (ANS) controls involuntary responses. The sympathetic division of the ANS mobilizes body systems and is responsible for “fight or flight” responses. The parasympathetic division of the ANS conserves energy and is responsible for responses related to “calm and relaxation.”
The CNS has three functional levels: neocortical, limbic, and vegetative (Figure 1). The vegetative or lowest level consists of the brain stem and the reticular activation system that connect the brain to the spinal cord. The mid-level is the limbic system or the emotional center of the brain responsible for the biochemical events that constitute the stress response. The highest and most sophisticated level of the brain is the neocortex.
The neocortex consists of grey matter surrounding the white matter of the cerebrum. The cerebral hemispheres, which contain the cerebral cortex and basal ganglia, are connected by a bundle of nerve fibers called the corpus callosum. The cerebral cortex is responsible for high-level functions, such as sensory perception, generation of motor commands, spatial reasoning, conscious thought, and in humans, language.
The basal ganglia consist of three deep nuclei of gray matter and include the caudate and putamen nuclei - known as the striatum, and the globus pallidus. They help initiate and control cortical functions. These actions include intended movement, behavior, and certain aspects of cognition. Regions of the basal ganglia responsible for movement ensure that intended actions are carried out and irrelevant movements are inhibited.
The cerebral cortex contains parts of, and interacts with, elements of the limbic system. Significant structures of the limbic system include the cingulate gyrus, amygdala, hippocampus, thalamus, and hypothalamus. The cingulate gyrus coordinates smells and sights with pleasant memories of previous emotions and participates in the emotional reaction to pain and the regulation of aggressive behavior.
The hippocampus is involved in learning memory, i.e., the conversion of temporary memories into permanent memories; helps to analyze and remember special relationships essential for accurate movements; and facilitates the use of memory to modify behavior. The amygdala connects with the hippocampus, the septal area, and the thalamus and mediates such feelings as friendship, affection, and expression of mood.
Various nuclei of the thalamus link sensory pathways from the periphery to the cortex and structures of the limbic system and is associated with changes in emotional activity. The hypothalamus controls mood (e.g., expression of emotions such as pleasure, rage, aversion, and displeasure); motivated behaviors such as sexuality and hunger; regulates thirst and body temperature; and via the pituitary gland, controls hormonal processes.
The cerebellum receives information related to spatial positioning; and sends signals to the motor areas of the cortex via the thalamus and down the spinal cord to regulate proprioception. The cerebellum coordinates skeletal muscle activity in space and time; maintains balance; controls eye movement; and influences motor learning (e.g., eye-hand coordination) and cognitive functions (e.g., timing of repetitive events and language).
The brainstem (medulla, pons and midbrain) connects the spinal cord to the thalamus and the cortex. The medulla and pons contain control centers that direct the autonomic nuclei that regulate heart rate, respiration, digestive functions, and reflex reactions (e.g., coughing and vomiting). In the midbrain, neurons in the periaqeaductal gray send descending projections to the spinal cord and modulate pain perception.
The spinal cord is organized into white and gray matter. White matter consists of fiber tracts that connect the periphery and spinal cord to more rostral areas of the CNS. Gray matter consists of dorsal and ventral horns. The dorsal horn relays sensory information from the periphery to the CNS. The ventral horn relays signals from central motor areas to skeletal muscle. Interneurons connect sensory and motor neurons and mediate reflexes.
Distant areas of the nervous system connect to one another and relay signals between the PNS and the CNS via long-tract neurons. Local circuit neurons maintain connectivity within a localized area of the CNS and modulate signal transmission. Single-source divergent neurons originate in various nuclei of the brainstem, hypothalamus, and basal forebrain and innervate broad areas of the CNS (Figures 2‑7).4,6-11
Neurons communicate with one another and with other cells through the release of neurotransmitters.5 Neurotransmitters are synthesized by cytoplasmic enzymes and are stored in neuronal vesicles. When a nerve is stimulated its resting potential changes and the action potential generated causes an influx of Ca2+ ions into the presynaptic nerve terminal and the content of neurotransmitter-filled vesicles exocytose into the synaptic cleft.
The released neurotransmitter diffuses across the synaptic cleft and on the postsynaptic axonal membrane binds either to a neurotransmitter-gated ionotropic receptor and/or to a metabotropic receptor (e.g., a G protein-coupled receptor). Ionotropic receptor activation modulates ion channel function directly, while metabotropic receptor activation leads mainly to cAMP-dependent modulation of other ion channels.
A neurotransmitter may be excitatory or inhibitory and in some cases both (as a function of receptor subtypes). Excitatory neurotransmitters induce a net inward current by opening cation-specific ion channels, e.g., Na+ and Ca2+ ion channels; or by closing K+ ion “leak channels.” The net influx of Na+ and Ca2+ ions and the reduced outward flow of K+ ions across the neuronal membrane results in axonal membrane depolarization.
Inhibitory neurotransmitters induce a net outward current by opening K+ ion channels or Cl‑ ion channels and induce K+ efflux or Cl‑ influx, respectively. The loss of intracellular cations (i.e., K+ ions) and the gain of intracellular anions (i.e., Cl‑ ions) moves the membrane potential away from its threshold value, reduces the ability of inward current to depolarize the membrane, and results in neuronal membrane hyperpolarization.
Termination of ionotropic neurotransmission at postsynaptic neurons is accomplished by two mechanisms: (1) degradation of the neurotransmitter by enzymes in the synaptic cleft and/or by (2) neurotransmitter uptake into the presynaptic terminal by specific transporters allowing the neurotransmitter to be recycled into synaptic vesicles for storage. Termination of signaling by a G protein-coupled neurotransmitter also involves intracellular enzymes.
Neurotransmitters in the CNS include acetylcholine, amino acids, monoamines, and a number of neuroactive peptides and purines (Table 1). Major amino acids neurotransmitters include glutamate, gamma-aminobutyric acid (GABA), and others such as glycine and aspartate. Major monoamine neurotransmitters include the catecholamines dopamine and norepinephrine; and the indoleamine serotonin.4,6-11
|Neurotransmitter System||Receptor Types||Functional Class||Major Actions|
See Figure 2
|Excitatory (major)||Memory, learning|
mGlu1 and mGlu5
|mGlu2-4 and mGlu6-8||Inhibitory|
See Figure 3
|Inhibitory (major)||Sleep, muscle tone, source of well-being|
See Figure 4
D1 and D5
|Excitatory||Enables intended movement, attention, learning, emotional regulation, memory, motivation (reward system), executive functions|
|D2, D3, and D4||Inhibitory|
See Figure 5
α1, β1, β2, and β3
|Excitatory||Vigilance, alertness, responsiveness to unexpected stimuli, source of well-being, sleep-wakefulness, learning, memory, attention, consciousness, regulates temperature and pituitary function, reduced digestion, increased heartbeat|
See Figure 6
|Excitatory||Mood, arousal, modulates eating (appetite), pain perception, behavior, regulates body temperature, sexual behavior|
|5-HT2 and 5-HT4-7||Excitatory|
See Figure 7
|Excitatory||Alertness, sleep-wakefulness, skeletal muscle contraction, memory formation, learning and general intellectual functioning, sensory responses|
Muscarinic M1 and M5