What is a specialized cell responsible for converting external stimuli to neural activity for a specific sensory system?

9.13 Interoceptors

Interoceptors, including internal nociceptors, chemoreceptors, and stretch receptors, inform the CNS about the internal state of the body. The carotid body, a specialized chemoreceptor for detecting carbon dioxide (in a hypoxic state) or to a lesser extent low blood pH resulting in increased respiration, is associated with afferent axons of CN IX that project to the caudal nucleus solitarius in the medulla. The carotid sinus, a thin-walled region of the carotid artery, contains encapsulated and bare nerve endings that act as stretch receptors. These stretch receptors respond to increased arterial pressure as baroreceptors, send primary afferents to the caudal nucleus solitarius via CN IX, and elicit reflex bradycardia and decrease in blood pressure.

4.3.1 Enteroceptor specifity

The problem now faced by neurophysiology is how to identify the type of interoceptors in which these various kinds of messages are elicited. Do receptors respond specifically to only one stimulus? Or are they non-specific or polymodal? These questions are not easy to answer because of the technical difficulties involved in controlling and using intestinal stimuli, especially the chemical ones (see Leek, 1972, 1977).

Nevertheless, in the present state of the art, distinct types of receptor function seem to be present in the digestive tract, including several types of mechanoreceptors, chemoreceptors and thermoreceptors (Fig. 4.3;Meï, 1983, 1985). However, the existence also of truly polymodal receptors has been clearly demonstrated (Andrews and Andrews, 1971; Davison, 1972).

Circuitry Supporting Hypothalamic Drives

Homeostatic drives require both access to sensory inputs from the body, as described above, as well as interoceptors, or neuronal receptors that are internal to the brain. These include neurons within the hypothalamus that are especially responsive to local temperature (Boulant and Bignall, 1973; Hori et al., 1986), glucose (Oomura, 1988; Lee et al., 1999; Shiraishi et al., 1999), osmolality (Bourque and Oliet, 1998), or sodium (Voisin et al., 1999), as discussed below. In addition, the brain must have access to information about the levels of various nutrients and hormones in the blood stream. Direct access for these molecules to the brain is prohibited by the blood–brain barrier, consisting of tight junctions between capillary endothelial cells that lack fenestrations. This arrangement prevents any hydrophilic compounds from entering the brain from the blood stream unless they are specifically transported in. To overcome this barrier, the brain maintains a set of small “windows” on the circulation. These circumventricular organs are specialized neuro-hemal contact zones, along the borders of the ventricular system of the brain (Broadwell and Brightman, 1976; Oldfield and McKinley, 1990). The subfornical organ, at the foramen of Monro; the organum vasculosum of the lamina terminalis, at the anteroventral tip of the third ventricle; the median eminence, at the midline in the floor of the tuberal hypothalamus; and the area postrema, at the caudal end of the fourth ventricle all have fenestrated capillaries. Even large proteins in the blood stream can enter the circumventricular organs, where they can interact with neurons that are just outside the blood–brain barrier (Broadwell and Brightman, 1976; Fitzsimmons, 1998). Small amounts of blood-borne substances can penetrate the borders of the circumventricular organs and enter the brain for a millimeter or two, but most of the substances that gain entry are washed away in the cerebrospinal fluid. Specific homeostatic signals and their targets will be discussed below as we consider different functional systems in the hypothalamus.

Circadian rhythms in the brain are organized by the suprachiasmatic nucleus. This structure is difficult to identify in Nissl-stained sections of human brain, as it is far less prominent than it appears in rats and even in other primate brains (Moore, 1997). However, many neurons in the suprachiasmatic nucleus in rats contain vaspressin or vasoactive intestinal peptide, and the same peptides may be used as markers for identifying the human suprachiasmatic nucleus as well (Stopa et al., 1984; Hofman et al., 1996; Dai et al., 1997).

Lesions of the suprachiasmatic nucleus result in loss of daily rhythms of wake–sleep activity, feeding, body temperature, and a variety of hormones, including melatonin and cortisol (see Moore, 1997). However, humans (e.g., shift workers) and animals (e.g., when food availability is restricted to normal sleeping hours) can entrain to activity cycles that are dictated by social or physiological necessity, rather than the light cycle (Gooley et al., 2006). These observations suggest that, while the suprachiasmatic nucleus may be the pacemaker for circadian activity, there may be mechanisms downstream that are capable of modifying the output of the circadian clock and reorganizing activity, metabolic, and hormonal patterns.

One candidate for this function is the subparaventricular zone. In rats, the suprachiasmatic nucleus projects massively to the subparaventricular zone, which stretches from the dorsal surface of the suprachiasmatic nucleus, back into the area just ventral to the paraventricular nucleus, and caudally into the dorsomedial nucleus (Watts and Swanson, 1987). A similar pathway has been identified using post-mortem tracing in human brains (Dai et al., 1998). This column of tissue receives intense input from the suprachiasmatic nucleus throughout its course. Recent work in rodents suggests that lesions in the subparaventricular zone can profoundly interrupt circadian cycles of wakefulness and sleep, activity, and body temperature (Lu et al., 2001), but do not prevent entrainment to food. On the other hand, lesions of the dorsomedial nucleus also disrupt circadian rhythms of wake–sleep, locomotor activity, feeding, and corticosteroid secretion (Chou et al., 2003). In mice with deletion of the Bmal1 clock gene, who have no circadian rhythms, the entrainment to food, but not light, can be restored by restoring the Bmal1 gene only in the dorsomedial nucleus (Fuller et al., 2008). However, similar work in primates is so far lacking.

Allostatic drives are activated by perception of physiological challenges that are discrete and potentially of overwhelming importance (as opposed to the graded and often smaller challenges that constitute homeostatic challenges). McEwen (2000) defines allostatic challenges as those that produce stress, and which require change, rather than return to equilibrium. Attack by a predator or competitor could be examples of allostatic challenges, but so could the presence of a potential mate. Such external allostatic challenges are detected by the classical sensory systems and identified by higher cognitive systems in the cerebral cortex. Access to the hypothalamus in primates is likely to involve cortical, amygdaloid, or hippocampal pathways.

Other allostatic challenges may be of internal origin. For example, extensive tissue injury or blood loss is sensed by visceral afferent systems. Responses to invading microorganisms, however, require additional sensory mechanisms. In response to a variety of immune challenges, white blood cells in various parts of the body make cytokines (see Breder and Saper, 1994). These hormones, which attract and recruit other immune system cells to battle the invader, also act upon the nervous system. Prostaglandins play a key role in this process, as inhibiting their synthesis blocks most of the CNS response to inflammation (Elmquist et al., 1997). Prostaglandins made in various organs may act upon local branches of the vagus nerve, thus signaling the brain. In addition, circulating cytokines or other inflammatory signals may cause the secretion of prostaglandins by the endothelial cells and perivascular microglia lining small venules at the borders of the brain (Laflamme et al., 1999). Prostaglandins are lipids, and they can diffuse across the blood–brain barrier to activate CNS responses, which will be described below.

Sensory neurons

Sensory neurons form the afferent division of the PNS. They transmit impulses from sensory receptors in the skin or internal organs toward the CNS. A ganglion is a group of neuron cell bodies located in the PNS. Cell bodies in the brain and spinal cord (CNS) form nuclei. Examples include the trigeminal nuclei. Sensory neurons are unipolar. Virtually all of their cell bodies are located in peripheral sensory ganglia. The processes of sensory neurons are known as afferent fibers. They extend between sensory receptors and the CNS. Information moves from sensory receptors to the spinal cord or brain. There are about 10 million sensory neurons in the body, each collecting information about the external and internal environments. Somatic sensory neurons monitor the external environment. Visceral sensory neurons monitor the internal environment and organ systems. In the peripheral nerves the somatic fibers innervate skin, muscle, joints, and body walls. Similarly, the visceral fibers innervate the blood vessels and internal organs.

Sensory fibers are called afferent and motor fibers are called efferent. Sensory receptors may be classified into three groups:

Interoceptors monitor the cardiovascular, digestive, reproductive, respiratory, and urinary systems. They provide signals to contract or distend visceral structures. General visceral afferent fibers carry interoceptive data from the receptors of visceral organs.

Exteroceptors provide pressure, temperature, and touch information, and the senses of equilibrium (balance), hearing, sight, smell, and taste.

Proprioceptors monitor skeletal muscle and joint movement and positioning.

Somatic afferent fibers carry data from proprioceptors and exteroceptors.

II INTRODUCTION

Mechanical sensitivity plays an essential role in cells and higher organisms. Specialized exteroceptors transduce external stimuli such as sound, vibration, touch, and local gravity. Interoceptors regulate for the voluntary musculature and the filling of the hollow organs, as in regulation of blood pressure. MSCs may serve as sensors for local control of blood flow, regulation of cell volume, deposition of bone, and so on (Sachs and Morris, 1998; Hamill and Martinac, 2001). The channels may also drive some of the hormonally coupled mechanical systems, such as renin‐angiotensin and atrial natriuretic peptide that regulate fluid volume. They may also serve some of the autocrine and paracrine transducers that generate second messengers such as endothelin (ET) (Ostrow et al., 2000; Ostrow and Sachs, 2005).

Mechanical transduction is ubiquitous and is present in cells of all phyla. In higher plants, mechanical transducers guide root, stem, and leaf growth in response to gravity. MSCs serve as sensory transducers in bacteria and other microorganisms where they may be the sensors for volume regulation (Martinac, 2001; Sachs, 2002). The fact that E. coli has as many as five dif- ferent MSCs argues for their functional importance (Sachs, 2002). Mechanical transduction is presumed to have developed early in evolution, probably as a necessity for controlling cell volume when conducting metabolism in a membrane‐limited compartment.

The pervasive nature of MSCs indicates that we will find genetic and environmental factors that create human pathologies related to MSC malfunction. For example, studies on dystrophic muscle cells show that the dystrophin mutations lead to weakening of the membrane, thereby activating a Ca2+ influx through MSCs (Patel et al., 2001; Yeung et al., 2003). This influx can be blocked by gadolinium (Yeung et al., 2003) and the peptide GsMTx4 (Yeung et al., 2005).

Although mechanical sensitivity of ion channels appears across phyla (Martinac and Kloda, 2003), there appears to be no homology associated with the primary structure. For example, in E. coli, the two dominant mechanosensitive channels MscL and MscS (generically noted MSCs) differ fundamentally in sequence and structure. MscL is a pentamer (Chang et al., 1998) and MscS is a heptamer (Bass et al., 2003), and the primary sequences have little homology. The only well‐characterized MSC cloned from eukaryotes is the K+ selective 2P channels such as TREK‐1 (Patel et al., 2001), and these channels have no sequence homology to the bacterial channels. Thus, mechanosensitivity, while universal, does not obey the delightful homologies of many of the voltage‐ and ligand‐gated channels, an example of convergent evolution. Moreover, from a mechanistic viewpoint, bacterial MSCs are almost certainly different from eukaryotic channels given the difference in cytoskeletal structure that influences the mechanics. What we learn from bacteria does not necessarily apply to eukaryotic MSCs. Within the phenotypic MSC families, however, there appears to be a useful discriminator—channels that are stimulated by stress in the cytoskeleton and extracellular matrix (Corey, 2003a,b), as in the cochlea, and those that are stimulated by stress in the bilayer, as in bacterial MSCs.

The intrinsic mechanosensitivity of channels depends on dimensional changes between the closed and open states (Sachs and Morris, 1998; Sukharev et al., 1999; Hamill and Martinac, 2001). One detailed kinetic study of MscL shows that these prototype channels require at least eight rate constants to characterize the gating reaction, but only a single rate constant is significantly sensitive to tension (Sukharev et al., 1999). While most MSCs appear to be stretch‐activated channels (SACs), stretch‐inactivated channel (SIC) activity has also been described (Vandorpe et al., 1994), although this may be an artifactual response from SACs subjected to stress at rest (Honore et al., 2006). Only recently have cationic MSCs from nonspecialized tissues, TRPC1, been cloned or reconstituted (Maroto et al., 2005).

Mechanosensitivity is not the domain of a particular class of ion channels. Any channel that changes dimensions between closed and open states may be mechanosensitive, in the same way that most ion channels are voltage sensitive. Ligand‐gated and voltage‐sensitive channels have been shown to be mechanically sensitive (Gu et al., 2001; Calabrese et al., 2002; Laitko and Morris, 2004; Morris, 2004; see Chapter 11). The generality of mechanosensitivity poses an intriguing problem in evolution: how to design structures with the necessary flexibility to support large conformational changes (Jiang et al., 2003a,b) while avoiding unnecessary mechanical activation.

MSCs are phenotypically described as channels whose kinetics are substantially altered by mechanical input. The key parameter that makes channels mechanosensitive is that they have large dimensional changes between the closed and open conformations (Howard and Hudspeth, 1988; Sachs et al., 1998; Sukharev et al., 1999; Hudspeth et al., 2000; Hamill et al., 2001; see chapter by Markin and Sachs in this series, vol. 58, pp. 87–119). MSCs are embedded in a heterogeneous, non‐Newtonian mechanical structure consisting of the extracellular matrix, the bilayer and its embedded proteins, and the cytoskeleton (Garcia‐Anoveros and Corey, 1996; Gillespie and Walker, 2001). The stress that activates MSCs may come from the lipid bilayer (Akinlaja and Sachs, 1998), but that tension depends on the cytoskeleton, the preparation geometry, and the boundary conditions (Suchyna and Sachs, 2004). Despite this complexity, it appears that MSCs from nonspecialized tissues are activated by tension in the lipid bilayer (Sukharev et al., 1994; Suchyna et al., 2004). The tension depends on the cortical structure, since the applied stresses are borne by cytoskeletal elements in parallel and in series with MSCs (Wan et al., 1995; Mills and Morris, 1998). This is also true not only for patch clamp experiments but also for global stimuli such as hypotonic or shear stress. To define an absolute sensitivity of a channel requires working in lipid bilayers where the stress is reasonably well defined (Sukharev et al., 1999; Suchyna et al., 2004).

The physiological function of MSCs in nonspecialized tissues has not been demonstrated. One common ground (Sachs, 2002), however, may be volume regulation (Christensen, 1987), although preliminary data using GsMTx4 suggests that the volume sensor is not a cationic MSC (Hua, Gottlieb, and Sachs, in preparation). In general, to test the physiological role of a channel requires that one activate or inactivate the target by nonphysiological stimuli. Pharmacologic agents are one approach and genetic knockouts the other (Corey, 2003b). There is only one specific pharmacological agent for MSCs to date: GsMTx4 and its mutants (Suchyna et al., 2000). The search has been hampered, in part, by technical difficulties in defining the stimulus (Hamill and McBride, 1995; Besch et al., 2002). While stimulators for electrically gated and ligand‐gated channels have long been available (ALA Scientific Instruments Inc., Westbury, NY), until recently none were available for mechanically gated channels. However, even with controlled pressure stimuli for patch clamp experiments, defining the stimulus that actually reaches the channel requires knowledge of preparation geometry and constitutive mechanical properties of the cell cortex (Sachs and Morris, 1998; see chapter by Markin and Sachs in this series, vol. 58, pp. 87–119), factors that are generally unknown.

The focus of this chapter is the peptide GsMTx4 and how it affects MSCs. The initial part will describe our effort to characterize its chemical and structural properties. We then detail the biophysical properties as well as issue of specificity. These results have shown the peptide to work on MSCs in an unconventional manner. Finally, we survey some potential therapeutic uses that may emerge for this peptide and similar compounds which remain undiscovered.

Sherrington’s Scheme

Charles Sherrington9 proposed a classification of sensation that has application for the sensory control of speech. He divided the sensory receptors into three broad classes: exteroceptors, proprioceptors, and interoceptors. Exteroceptors mediate sight, sound, smell, and cutaneous sensation. Cutaneous superficial skin sensation includes light touch or pressure, fine touch (also known as two-point or discriminative touch), superficial pain, temperature, itching, and tickling. Proprioceptors mediate deep somatic sensation from receptors beneath the skin, in muscles and joints, and in the inner ear. Proprioception includes the senses of movement, vibration, position, and equilibrium. Interoceptors mediate sensation from the viscera as well as visceral pain and pressure or distention. Pain receptors, either from cellular or tissue injury, are known as nociceptors.

Neurophysiologists have classified the senses as special and general. The term special senses reflects the traditional layperson’s concept that certain senses are primary. For the neurophysiologist, hearing, vision, taste, smell, and balance are the special senses. The general senses, in this classification scheme, include the remainder of the senses. Further breakdown into visceral and somatic sensations has also been added to the classification schemes. General visceral afferent interoceptors monitor events within the body, including bladder distention and pH changes in the blood. Special visceral afferent receptors are those of taste and smell (olfaction). Special somatic afferent receptors are concerned with vision, audition, and balance or equilibrium.

Sensory Arms of the Sympathetic Nervous System

To maintain homeostasis, the sympathetic nervous system responds to several different types of sensory inputs. Some of these inputs are somatosensory, including nociceptive signals, whereas others – viscerosensory inputs – arise from interoceptors in the internal organs. They may reach spinal and supraspinal receptors by neural or humoral ways. Inputs which influence the activity of the sympathetic preganglionic or premotor sympathetic neurons (Figure 1) are called sympathetic sensory afferents. They represent the sensory (also called ascending or afferent) arm of the sympathetic regulatory circuit.

The sympathetic visceral afferent fibers enter the dorsal horn of the spinal cord through the dorsal roots and innervate the sympathetic preganglionic neurons in the IML via interneurons located in lamina V and lamina VII of the spinal cord (Figure 2). Some sensory fibers that project to the spinal cord also send a branch to sympathetic ganglia forming reflex circuits that may control some visceral autonomic functions.

Viscerosensory signals to supraspinal premotor sympathetic neurons are relayed in the nucleus of the solitary tract (NTS), which represents the primary viscerosensory center in the central nervous system. Viscerosensory fibers travel in cranial nerves (mainly in the trigeminal, glossopharyngeal, and vagal nerves) or in ascending spinal fibers (spino-solitary tract) and terminate in the NTS. The sensory afferents terminate in a topographically and functionally organized manner in the different subdivisions of the nucleus. The ascending fibers from the NTS may reach both the catecholaminergic and the noncatecholaminergic premotor sympathetic neurons in the brain stem and the hypothalamus. Some of them influence the activity of limbic and cortical structures that may respond to these signals through the activation of hypothalamic or brain stem premotor sympathetic neurons.

Beyond the Five Senses

In 1907, Charles Scott Sherrington introduced the terms proprioception, interoception, and exteroception. The exteroceptors are the organs responsible for detecting information from outside the body – the traditional five senses. The interoceptors give information about the internal organs. Proprioception is awareness of movement derived from muscular, tendon, and articular (joint) tensions and pressures. Joint receptors are located in the capsules of joints. Stretching the capsule deforms the endings, leading to a receptor potential, and the extent of the depolarization determines the frequency of the action potentials that are generated. It is now recognized that joint angle is sensed from composite signals from joint receptors, muscle length receptors, and skin receptors. Much of the research on this topic has focused on the finger and hand sensors, which are of particular interest to hands-on therapists who rely on their hands and fingers for sensation and dexterous movements (Johnson, 2004). Kinesthesia is often used interchangeably with proprioception, although kinesthesia places greater emphasis on motion. The kinesthetic sense enables us to touch the tip of our nose with our eyes closed or to reach to and scratch a part of our body that is itchy.

The proprioceptive sense also includes information from sensory neurons located in the inner ear (motion and orientation) and in the stretch receptors located in the muscles and joint-supporting tendons and ligaments (stance). Humans therefore have awareness of balance and motion that can involve the coordinated use of a number of sensory organs. Our sense of balance results from the complex interaction of visual inputs, the proprioceptive sensors (those that are affected by gravity and the stretch sensors found in muscles, skin, and joints), the inner ear vestibular system, pressure sensors on the soles of the feet, and the central nervous system.

Sherrington's Scheme

Charles Sherrington proposed a classification of sensation that is in wide use today and has application for the sensory control of speech. He divided the sensory receptors into three broad classes: (1) exteroceptors, (2) proprioceptors, and (3) interoceptors. Exteroceptors mediate sight, sound, smell, and cutaneous sensation. Cutaneous superficial skin sensation includes touch, superficial pain, temperature, itching, and tickling. Proprioceptors mediate deep somatic sensation from receptors beneath the skin, in muscles and joints, and in the inner ear. Proprioception includes the following senses: pressure, movement, vibration, position, deep pain, and equilibrium. Interoceptors include sensation from the viscera, as well as visceral pain and pressure or distension. Pain receptors, either from cellular or tissue injury, are known as nociceptive receptors.

In addition, multisensory functions have been called the higher sensations. The higher sensations include recognition of form, size, and texture, as well as weight and two-point discrimination.

Neurophysiologists have classified the senses as special and general senses. The term special senses reflects the traditional layperson's concept that certain of the senses are primary. For the neurophysiologist, hearing, vision, taste, smell, and balance are the special senses. The general senses, in this classification scheme, include the remainder of the senses.

Publisher Summary

This chapter discusses the methods for producing experimental neurogenic lesions. Lesions of the heart can be produced at various levels of the nervous system, both central and peripheral. Myocardium is very sensitive to stimulation applied to different reflexogenic regions. It is known that functional and structural cardiac damage occurs after strong and prolonged stimulation of the reflexogenic region of the aortic arch, sensory nerves, ganglia, and interoceptors of internal organs. However, all these methods have considerable drawbacks: either the irregular occurrence and poor manifestation of damage or the complex and traumatic operations. Myocardial dystrophies, caused by excessive stimulation of the aortic arch, have a neurogenic nature. The efferent pathways are the sympathetic cardiac nerves. Myocardial damage can develop as a result of the action of large concentrations of catechol-amines on both α and β-adrenoreceptors. Electrical stimulation of the aortic arch of adrenalectomized rats produces myocardial lesions similar to those observed in control animals with intact adrenal glands. The secretion of catecholamines by the adrenal gland is not the main cause of the myocardial lesions resulting from excessive stimulation. The leading role in lesion development is played by noradrenaline secreted from the endings of the sympathetic nerves.