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Central Autonomic Control
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Central Autonomic Control Eduardo E. Benarroch Department of Neurology Mayo Clinic Rochester, Minnesota
The central autonomic control areas are distributed throughout the neuroaxis. They include the insular cortex, anterior cingulate gyrus, amygdala, and bed nucleus of the stria terminalis; hypothalamus; periaqueductal gray (PAG) matter of the midbrain, parabrachial nucleus (PBN); nucleus tractus solitarii (NTS); ventrolateral medulla (VLM) and caudal raphe nuclei. These areas are reciprocally interconnected, receive converging visceral and nociceptive information, contain neurons that are affected by visceral inputs, and generate patterns of autonomic responses through direct or indirect inputs to preganglionic sympathetic and parasympathetic neurons [1–3].
“preparatory” reactions in response to emotionally significant stimuli [4]. The amygdala plays a critical role in emotional responses, including conditioned fear. It has reciprocal interactions with the cerebral cortex, basal forebrain, and limbic striatum. The central nucleus of the amygdala (CeNA) projects to the hypothalamus PAG and autonomic areas of the brainstem and integrates autonomic, endocrine, and motor responses associated with emotion [6]. The preoptic–hypothalamic unit is subdivided into three functionally distinct longitudinal zones: periventricular, medial, and lateral. The periventricular zone includes the suprachiasmatic nucleus, involved in circadian rhythms and nuclei-controlling endocrine function. The median preoptic nucleus, the paraventricular nucleus (PVN), and arcuate nucleus produce regulatory hormones that control anterior pituitary function. Magnocellular neurons in the supraoptic nucleus and PVN produce vasopressin (AVP) and oxytocin. The medial preoptic nucleus contains thermosensitive and osmosensitive neurons, and the arcuate and ventromedial nuclei are involved in regulation of appetite and reproductive function. The lateral hypothalamus controls food intake, sleep wake cycle and motivated behavior. Neurons of the posterior lateral hypothalamus secrete hypocretin/orexin and regulate the switch between wakefulness and sleep through projections to monoaminergic and cholinergic brainstem nuclei. The PVN, dorsomedial nucleus, and lateral hypothalamic innervate separate subsets of preganglionic sympathetic and parasympathetic neurons. The PVN gives rise to the most widespread autonomic output of the hypothalamus. The lateral hypothalamic area relays influences of the insula and amygdala on autonomic nuclei [7].
ANATOMY OF CENTRAL AUTONOMIC AREAS Forebrain The insular cortex is the primary visceral sensory cortex. It contains an organotropic visceral sensory map; the anterior insula is the primary area for taste, whereas the posterior insula is the general visceral afferent area [3, 4]. The insular cortex has reciprocal, topographically, and functionally specific interconnections with the NTS and PBN, which relay viscerosensory information carried by the vagus and other cranial afferents to the insular cortex, through projections to the parvicellular subdivisions of the ventral posterior medial nucleus of the thalamus. The posterior dorsal insula is also the primary cortical area receiving pain, temperature, and spinal visceroceptive information from lamina I of the spinal cord, through a spinothalamic connection with the posterior portion of the ventromedial nucleus of the thalamus, which projects to the insular cortex [3, 5]. The anterior cingulate cortex is critically involved in initiation, motivation, and execution of emotional and goaldirected behaviors. Through its widespread interconnections with central autonomic regions, it participates in high-level regulation of autonomic and endocrine function. The ventromedial prefrontal cortex also has extensive reciprocal connections with the amygdala, and these interactions modulate emotional responses. Bilateral lesions of the ventromedial prefrontal cortex selectively impair autonomic
Brainstem The PAG integrates autonomic, motor, and antinociceptive responses to stress. It receives multiple input from the amygdala, preoptic area, and dorsal horn of the spinal cord. It is subdivided into longitudinal columns, with specific inputs and outputs and specific functions. The lateral PAG initiates opioid-independent analgesia and sympathoexcitatory responses through projection to the VLM. The
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Part II. Pharmacology
ventrolateral PAG initiates opioid-dependent analgesia and sympathoinhibitory responses through its projection to the medullary raphe nuclei [8]. The PBN includes several subnuclei that receive visceral inputs through the NTS and inputs from nociceptors, thermoreceptors, and muscle receptors through the spinoparabrachial tract originating in lamina I of the dorsal horn. The PBN projects to the hypothalamus, amygdala, and the thalamus and is involved in taste, salivation, gastrointestinal activity, cardiovascular activity, respiration, osmoregulation, and thermoregulation. This region includes the KöllikerFuse nucleus (pontine respiratory group), which regulates activity of respiratory and cardiovascular neurons of the medulla. The dorsal pons also contains the Barrington nucleus, corresponding to the “pontine micturition center.” It innervates sacral preganglionic neurons innervating the bladder, bowel, and sexual organs, as well as the Onuf nucleus motor neurons innervating the pelvic floor and external sphincters. It is critical for coordinated contraction of the bladder detrusor and relaxation of the external sphincter during micturition [2, 3]. The NTS is the first relay station for general visceral and taste afferents [2, 3]. It is critically involved in medullary reflexes and relays viscerosensory information to all central autonomic regions. The NTS consists of several subnuclei with specific inputs and outputs and has a viscerotropic organization. Taste afferents relay in its rostral, gastrointestinal afferents in its intermediate portion, and cardiovascular and respiratory afferents in the caudal half of the NTS. The NTS sends descending projections to spinal respiratory and preganglionic parasympathetic and sympathetic neurons; propriobulbar projections to neuronal cell groups of the medullary reticular–mediating baroreceptor, chemoreceptor, cardiopulmonary, and gastrointestinal reflexes; and ascending projections to all other rostral components of the central autonomic network, including the PBN, PAG, amygdala, medial preoptic, paraventricular, dorsomedial, and lateral hypothalamic nuclei, subfornical organ, and medial orbitofrontal cortex. The area postrema is a chemosensitive region with abundant connections with other central autonomic areas. It has long been considered the “chemoreceptor trigger zone” for vomiting and contains receptors for circulating angiotensin II, AVP, natriuretic peptides, and other humoral signals involved in cardiovascular regulation. The VLM contains the premotor neurons controlling vasomotor tone, cardiac function, and respiration. Neurons of the rostral VLM provide a major excitatory input to sympathetic preganglionic vasomotor neurons of the intermediolateral cell column (IML) [9]. Neurons of the caudal VLM are an integral component of several medullary reflexes. The VLM contains catecholaminergic neurons corresponding to the rostral C1 (adrenergic) and caudal A1 (noradrenergic) groups. C1 neurons project to the IML and A1 neurons to the hypothalamus. The VLM contains the ventral respiratory
group (VRG), including the pre-Bötzinger complex, which has a critical role in generation of the respiratory rhythm. Inspiratory neurons of the rostral VRG and expiratory neurons of the caudal VRG project to phrenic, intercostal, and abdominal spinal motor neurons [2]. The central chemosensitive region, located in the ventral surface of the medulla, contains neurons that respond to increased Pco2 and decreased pH in the cerebrospinal fluid. Neurons of the rostral ventromedial medulla, including the caudal raphe nuclei, also provide direct inputs to the sympathetic preganglionic neurons and may contribute to control of arterial pressure. The function of the raphe–spinal pathway is complex and includes both sympathoexcitatory and sympathoinhibitory influences. These neurons may be involved in sympathetic control to endocrine organs and to skin effectors for thermoregulation.
LEVELS OF INTEGRATION OF CENTRAL AUTONOMIC CONTROL Bulbospinal Level Baroreceptor, cardiac receptor, chemoreceptor, and pulmonary mechanoreceptor afferents preferentially activate neurons located on separate NTS subnuclei. These neurons generate several medullary reflexes by projecting to sympathoinhibitory neurons of the caudal VLM, sympathoexcitatory neurons of the rostral VLM, vagal cardiomotor neurons of the nucleus ambiguus and the dorsal vagal nucleus, respiratory neurons of the VRG and dorsal respiratory group, and AVP-producing magnocellular hypothalamic neurons [2].
Pontomesencephalic Level The PBN is a site of viscerosomatic convergence and serves as a substrate for integration of noxious, thermoreceptive, metaboreceptive, and viscerosensitive inputs with motivational, emotional, and homeostatic responses [3]. The lateral PAG initiates integrated sympathoexcitatory “fight or flight” responses, whereas the ventrolateral PAG elicits hyporeactive immobility and sympathoinhibition (the “playing death” response) [8].
Forebrain Level The cortical autonomic areas, the amygdala, hypothalamus, and PAG form a functional unit involved both in the assessment of emotional content of stimuli and initiation and regulation of emotional autonomic, endocrine, and motor responses. The PVN plays a central role in the integrated response to stress, because it secretes corticotrophin releasing factor (CRF) and AVP and projects to the rostral
4. Central Autonomic Control
VLM and to the preganglionic sympathetic and sympathoadrenal neurons. It is activated by hypoglycemia, hypovolemia, cytokines, or other internal stressors. The CRF neurons of the PVN are involved in reciprocal excitatory interactions with the noradrenergic neurons of the locus ceruleus, which selectively respond to novel, potentially threatening external stimuli. The CeNA, lateral hypothalamus, and PAG are involved in the cardiovascular, visceromotor, somatomotor, and antinociceptive components of the defense response [8].
References 1. Benarroch, E. E. 1997. Central autonomic network: Functional organization and clinical correlations. Armonk, NY: Futura. 2. Blessing, W. W. 1997. The lower brainstem and bodily homeostasis. New York: Oxford University Press. 3. Saper, C. B. 2002. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu. Rev. Neurosci. 25:433–469.
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4. Verberne, A. J., and N. C. Owens. 1998. Cortical modulation of the cardiovascular system. Prog. Neurobiol. 54:149–168. 5. Craig, A. D. 1996. An ascending general homeostatic afferent pathway originating in lamina I. In Progress in brain research, Vol. 107. ed. G. Holstege, R. Bandler, and C. B. Saper, 225–242. Amsterdam: Elsevier. 6. Amaral, D. G., J. I. Price, A. Pitkanen, and S. T. Charmichael. 1992. Anatomical organization of the primate amygdaoid complex. In The amygdala: Neurobiological aspects of emotion, ed. J. P. Aggleton, 1–66. New York: Wiley-Lyss. 7. Swanson, L. W. 1991. Biochemical switching in hypothalamic circuits mediating responses to stress [Review]. Prog. Brain Res. 87:181–200. 8. Bandler, R., and M. T. Shipley. 1994. Columnar organization in the midbrain periaqueductal gray: Modules for emotional expression? Trends Neurosci. 17:379–389. 9. Guyenet, P. G. 1990. Role of the ventral medulla oblongata in blood pressure regulation. In Central regulation of autonomic functions, ed. A. D. Loewy and K. M. Spyer, 145–167. New York: Oxford University Press.
Central Autonomic Control Eduardo E. Benarroch Department of Neurology Mayo Clinic Rochester, Minnesota
The central autonomic control areas are distributed throughout the neuroaxis. They include the insular cortex, anterior cingulate gyrus, amygdala, and bed nucleus of the stria terminalis; hypothalamus; periaqueductal gray (PAG) matter of the midbrain, parabrachial nucleus (PBN); nucleus tractus solitarii (NTS); ventrolateral medulla (VLM) and caudal raphe nuclei. These areas are reciprocally interconnected, receive converging visceral and nociceptive information, contain neurons that are affected by visceral inputs, and generate patterns of autonomic responses through direct or indirect inputs to preganglionic sympathetic and parasympathetic neurons [1–3].
“preparatory” reactions in response to emotionally significant stimuli [4]. The amygdala plays a critical role in emotional responses, including conditioned fear. It has reciprocal interactions with the cerebral cortex, basal forebrain, and limbic striatum. The central nucleus of the amygdala (CeNA) projects to the hypothalamus PAG and autonomic areas of the brainstem and integrates autonomic, endocrine, and motor responses associated with emotion [6]. The preoptic–hypothalamic unit is subdivided into three functionally distinct longitudinal zones: periventricular, medial, and lateral. The periventricular zone includes the suprachiasmatic nucleus, involved in circadian rhythms and nuclei-controlling endocrine function. The median preoptic nucleus, the paraventricular nucleus (PVN), and arcuate nucleus produce regulatory hormones that control anterior pituitary function. Magnocellular neurons in the supraoptic nucleus and PVN produce vasopressin (AVP) and oxytocin. The medial preoptic nucleus contains thermosensitive and osmosensitive neurons, and the arcuate and ventromedial nuclei are involved in regulation of appetite and reproductive function. The lateral hypothalamus controls food intake, sleep wake cycle and motivated behavior. Neurons of the posterior lateral hypothalamus secrete hypocretin/orexin and regulate the switch between wakefulness and sleep through projections to monoaminergic and cholinergic brainstem nuclei. The PVN, dorsomedial nucleus, and lateral hypothalamic innervate separate subsets of preganglionic sympathetic and parasympathetic neurons. The PVN gives rise to the most widespread autonomic output of the hypothalamus. The lateral hypothalamic area relays influences of the insula and amygdala on autonomic nuclei [7].
ANATOMY OF CENTRAL AUTONOMIC AREAS Forebrain The insular cortex is the primary visceral sensory cortex. It contains an organotropic visceral sensory map; the anterior insula is the primary area for taste, whereas the posterior insula is the general visceral afferent area [3, 4]. The insular cortex has reciprocal, topographically, and functionally specific interconnections with the NTS and PBN, which relay viscerosensory information carried by the vagus and other cranial afferents to the insular cortex, through projections to the parvicellular subdivisions of the ventral posterior medial nucleus of the thalamus. The posterior dorsal insula is also the primary cortical area receiving pain, temperature, and spinal visceroceptive information from lamina I of the spinal cord, through a spinothalamic connection with the posterior portion of the ventromedial nucleus of the thalamus, which projects to the insular cortex [3, 5]. The anterior cingulate cortex is critically involved in initiation, motivation, and execution of emotional and goaldirected behaviors. Through its widespread interconnections with central autonomic regions, it participates in high-level regulation of autonomic and endocrine function. The ventromedial prefrontal cortex also has extensive reciprocal connections with the amygdala, and these interactions modulate emotional responses. Bilateral lesions of the ventromedial prefrontal cortex selectively impair autonomic
Brainstem The PAG integrates autonomic, motor, and antinociceptive responses to stress. It receives multiple input from the amygdala, preoptic area, and dorsal horn of the spinal cord. It is subdivided into longitudinal columns, with specific inputs and outputs and specific functions. The lateral PAG initiates opioid-independent analgesia and sympathoexcitatory responses through projection to the VLM. The
17
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Part II. Pharmacology
ventrolateral PAG initiates opioid-dependent analgesia and sympathoinhibitory responses through its projection to the medullary raphe nuclei [8]. The PBN includes several subnuclei that receive visceral inputs through the NTS and inputs from nociceptors, thermoreceptors, and muscle receptors through the spinoparabrachial tract originating in lamina I of the dorsal horn. The PBN projects to the hypothalamus, amygdala, and the thalamus and is involved in taste, salivation, gastrointestinal activity, cardiovascular activity, respiration, osmoregulation, and thermoregulation. This region includes the KöllikerFuse nucleus (pontine respiratory group), which regulates activity of respiratory and cardiovascular neurons of the medulla. The dorsal pons also contains the Barrington nucleus, corresponding to the “pontine micturition center.” It innervates sacral preganglionic neurons innervating the bladder, bowel, and sexual organs, as well as the Onuf nucleus motor neurons innervating the pelvic floor and external sphincters. It is critical for coordinated contraction of the bladder detrusor and relaxation of the external sphincter during micturition [2, 3]. The NTS is the first relay station for general visceral and taste afferents [2, 3]. It is critically involved in medullary reflexes and relays viscerosensory information to all central autonomic regions. The NTS consists of several subnuclei with specific inputs and outputs and has a viscerotropic organization. Taste afferents relay in its rostral, gastrointestinal afferents in its intermediate portion, and cardiovascular and respiratory afferents in the caudal half of the NTS. The NTS sends descending projections to spinal respiratory and preganglionic parasympathetic and sympathetic neurons; propriobulbar projections to neuronal cell groups of the medullary reticular–mediating baroreceptor, chemoreceptor, cardiopulmonary, and gastrointestinal reflexes; and ascending projections to all other rostral components of the central autonomic network, including the PBN, PAG, amygdala, medial preoptic, paraventricular, dorsomedial, and lateral hypothalamic nuclei, subfornical organ, and medial orbitofrontal cortex. The area postrema is a chemosensitive region with abundant connections with other central autonomic areas. It has long been considered the “chemoreceptor trigger zone” for vomiting and contains receptors for circulating angiotensin II, AVP, natriuretic peptides, and other humoral signals involved in cardiovascular regulation. The VLM contains the premotor neurons controlling vasomotor tone, cardiac function, and respiration. Neurons of the rostral VLM provide a major excitatory input to sympathetic preganglionic vasomotor neurons of the intermediolateral cell column (IML) [9]. Neurons of the caudal VLM are an integral component of several medullary reflexes. The VLM contains catecholaminergic neurons corresponding to the rostral C1 (adrenergic) and caudal A1 (noradrenergic) groups. C1 neurons project to the IML and A1 neurons to the hypothalamus. The VLM contains the ventral respiratory
group (VRG), including the pre-Bötzinger complex, which has a critical role in generation of the respiratory rhythm. Inspiratory neurons of the rostral VRG and expiratory neurons of the caudal VRG project to phrenic, intercostal, and abdominal spinal motor neurons [2]. The central chemosensitive region, located in the ventral surface of the medulla, contains neurons that respond to increased Pco2 and decreased pH in the cerebrospinal fluid. Neurons of the rostral ventromedial medulla, including the caudal raphe nuclei, also provide direct inputs to the sympathetic preganglionic neurons and may contribute to control of arterial pressure. The function of the raphe–spinal pathway is complex and includes both sympathoexcitatory and sympathoinhibitory influences. These neurons may be involved in sympathetic control to endocrine organs and to skin effectors for thermoregulation.
LEVELS OF INTEGRATION OF CENTRAL AUTONOMIC CONTROL Bulbospinal Level Baroreceptor, cardiac receptor, chemoreceptor, and pulmonary mechanoreceptor afferents preferentially activate neurons located on separate NTS subnuclei. These neurons generate several medullary reflexes by projecting to sympathoinhibitory neurons of the caudal VLM, sympathoexcitatory neurons of the rostral VLM, vagal cardiomotor neurons of the nucleus ambiguus and the dorsal vagal nucleus, respiratory neurons of the VRG and dorsal respiratory group, and AVP-producing magnocellular hypothalamic neurons [2].
Pontomesencephalic Level The PBN is a site of viscerosomatic convergence and serves as a substrate for integration of noxious, thermoreceptive, metaboreceptive, and viscerosensitive inputs with motivational, emotional, and homeostatic responses [3]. The lateral PAG initiates integrated sympathoexcitatory “fight or flight” responses, whereas the ventrolateral PAG elicits hyporeactive immobility and sympathoinhibition (the “playing death” response) [8].
Forebrain Level The cortical autonomic areas, the amygdala, hypothalamus, and PAG form a functional unit involved both in the assessment of emotional content of stimuli and initiation and regulation of emotional autonomic, endocrine, and motor responses. The PVN plays a central role in the integrated response to stress, because it secretes corticotrophin releasing factor (CRF) and AVP and projects to the rostral
4. Central Autonomic Control
VLM and to the preganglionic sympathetic and sympathoadrenal neurons. It is activated by hypoglycemia, hypovolemia, cytokines, or other internal stressors. The CRF neurons of the PVN are involved in reciprocal excitatory interactions with the noradrenergic neurons of the locus ceruleus, which selectively respond to novel, potentially threatening external stimuli. The CeNA, lateral hypothalamus, and PAG are involved in the cardiovascular, visceromotor, somatomotor, and antinociceptive components of the defense response [8].
References 1. Benarroch, E. E. 1997. Central autonomic network: Functional organization and clinical correlations. Armonk, NY: Futura. 2. Blessing, W. W. 1997. The lower brainstem and bodily homeostasis. New York: Oxford University Press. 3. Saper, C. B. 2002. The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. Annu. Rev. Neurosci. 25:433–469.
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4. Verberne, A. J., and N. C. Owens. 1998. Cortical modulation of the cardiovascular system. Prog. Neurobiol. 54:149–168. 5. Craig, A. D. 1996. An ascending general homeostatic afferent pathway originating in lamina I. In Progress in brain research, Vol. 107. ed. G. Holstege, R. Bandler, and C. B. Saper, 225–242. Amsterdam: Elsevier. 6. Amaral, D. G., J. I. Price, A. Pitkanen, and S. T. Charmichael. 1992. Anatomical organization of the primate amygdaoid complex. In The amygdala: Neurobiological aspects of emotion, ed. J. P. Aggleton, 1–66. New York: Wiley-Lyss. 7. Swanson, L. W. 1991. Biochemical switching in hypothalamic circuits mediating responses to stress [Review]. Prog. Brain Res. 87:181–200. 8. Bandler, R., and M. T. Shipley. 1994. Columnar organization in the midbrain periaqueductal gray: Modules for emotional expression? Trends Neurosci. 17:379–389. 9. Guyenet, P. G. 1990. Role of the ventral medulla oblongata in blood pressure regulation. In Central regulation of autonomic functions, ed. A. D. Loewy and K. M. Spyer, 145–167. New York: Oxford University Press.