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Vocal flexibility is a hallmark of the human species, most particularly the capacity to speak and sing. This ability is supported in part by the evolution of a direct neural pathway linking the motor cortex to the brainstem nucleus that controls the larynx ¬– the primary sound source for communication. Early brain imaging studies demonstrated that larynx motor cortex at the dorsal end of the orofacial division of motor cortex (dLMC) integrated laryngeal and respiratory control, thereby coordinating two major muscular systems that are necessary for vocalization. Neurosurgical studies have since demonstrated the existence of a second larynx motor area at the ventral extent of the orofacial motor division (vLMC) of motor cortex. The vLMC has been presumed to be less relevant to speech motor control, but its functional role remains unknown. We employed a novel ultra-high field (7T) magnetic resonance imaging paradigm that combined singing and whistling simple melodies to localise the larynx motor cortices and test their involvement in respiratory motor control. Surprisingly, whistling activated both ‘larynx areas’ more strongly than singing despite the reduced involvement of the larynx during whistling. We provide further evidence for the existence of two larynx motor areas in the human brain, and the first evidence that laryngeal-respiratory integration is a shared property of both larynx motor areas. We outline explicit predictions about the descending motor pathways that give these cortical areas access to both the laryngeal and respiratory systems and discuss the implications for the evolution of speech.

Subramanian HH, Holstege G. Midbrain and medullary control of postinspiratory activity of the crural and costal diaphragm in vivo. J Neurophysiol 105: 2852-2862, 2011. First published March 30, 2011; doi:10.1152/jn.00168.2011.-Studies on brain stem respiratory neurons suggest that eupnea consists of three phases: inspiration, postinspiration, and expiration. However, it is not well understood how postinspiration is organized in the diaphragm, i.e., whether postinspiration differs in the crural and costal segments of the diaphragm and what the influence is of postinspiratory neurons on diaphragm function during eupnea. In this in vivo study we investigated the postinspiratory activity of the two diaphragm segments during eupnea and the changes in diaphragm function following modulation of eupnea. Postinspiratory neurons in the medulla were stereotaxically localized extracellularly and neurochemically stimulated. We used three types of preparations: precollicularly decerebrated unanesthetized cats and rats and anesthetized rats. In all preparations, during eupnea, postinspiratory activity was found in the crural but not in the costal diaphragm. When eupnea was discontinued in decerebrate cats in which stimulation in the nucleus retroambiguus induced activation of laryngeal or abdominal muscles, all postinspiratory activity in the crural diaphragm was abolished. In decerebrate rats, stimulation of the midbrain periaqueductal gray abolished postinspiration in the crural diaphragm but induced activation in the costal diaphragm. In anesthetized rats, stimulation of medullary postinspiratory neurons abolished the postinspiratory activity of the crural diaphragm. Vagal nerve stimulation in these rats increased the intensity of postinspiratory neuronal discharge in the solitary nucleus, leading to decreased activity of the crural diaphragm. These data demonstrate that three-phase breathing in the crural diaphragm during eupnea exists in vivo and that postinspiratory neurons have an inhibitory effect on crural diaphragm function.

The distribution pattern of estrogen receptors in the rodent CNS has been reported extensively, but mapping of estrogen receptors in primates is incomplete. In this study we describe the distribution of estrogen receptor alpha immunoreactive (ER-alpha 1R) neurons in the brainstem and spinal cord of the rhesus monkey.In the midbrain, ER-alpha IR neurons were located in the periaqueductal gray, especially the caudal ventrolateral part, the adjacent tegmentum, peripeduncular nucleus, and pretectal nucleus. A few ER-alpha IR neurons were found in the lateral parabrachial nucleus, lateral pontine tegmentum, and pontine gray medial to the locus coeruleus. At caudal medullary levels, ER-alpha IR neurons were present in the commissural nucleus of the solitary complex and the caudal spinal trigeminal nucleus. The remaining regions of the brainstem were devoid of ER-alpha IR neurons. Spinal ER-alpha IR neurons were found in laminae I-V, and area X, and were most numerous in lower lumbar and sacral segments. The lateral collateral pathway and dorsal commissural nuclei of the sacral cord and the thoracic intermediolateral cell column also contained ER-a IR neurons. Estrogen treatment did not result in any differences in the distribution pattern of ER-alpha IR neurons.The results indicate that ER-alpha IR neurons in the primate brainstem and spinal cord are concentrated mainly in regions involved in sensory and autonomic processing. Compared with rodent species, the regional distribution of ER-alpha IR neurons is less widespread, and ER-a IR neurons in regions such as the spinal dorsal horn and caudal spinal trigeminal nucleus appear to be less abundant. These distinctions suggest a modest role of ER-a in estrogen-mediated actions on primate brainstem and spinal systems. These differences may contribute to variations in behavioral effects of estrogen between primate and rodent species. (c) 2009 IBRO. Published by Elsevier Ltd. All rights reserved.

Pharynx and soft palate are muscles for respiration, vocalization, swallowing, and vomiting. In cat, motoneurons innervating pharynx/soft palate are located in the dorsal group of the nucleus ambiguus (dgNA) in the medulla oblongata. In cat, dgNA is the only part of nucleus ambiguus that can be distinguished as a separate cell group, which makes it possible to study its afferent input. In two cats, WGA-HRP injections in dgNA and surrounding tegmentum resulted in retrogradely labeled cells at several levels of the neuraxis. In 170 cases anterograde tracers were injected in areas in which the cells of origin were identified, Results demonstrate that dgNA afferents originate from the tegmentum dorsolateral to the superior olivary complex, medullary ventromedial tegmentum, caudal raphe nuclei, medullary lateral tegmental field, nucleus retroambiguus (NRA), and adjoining tegmentum, extending into the first cervical segment of the spinal cord. In order to determine whether periaqueductal gray (PAG) and parabrachial nuclei (PB) make synaptic contacts with dgNA, ultrastructural studies combined anterograde tracing from PAG, PB, and NRA with retrograde tracing of pharyngeal and soft palate motoneurons. The results showed that PB, but not PAG, projects to the dgNA and that NRA afferent synapses are three times as numerous as those from PB. The morphology of PB and NRA synapses is consistent with excitatory input. In conclusion, pharyngeal and soft palate motoneurons receive their afferents almost exclusively from the pontine and medullary tegmentum and first cervical spinal segment. (c) 2005 Wiley-Liss. Inc.

The periaqueductal gray (PAG) contains numerous estrogen receptor-alpha immunoreactive (ER-alpha IR) neurons that are distributed in a species-specific way. These neurons might modulate different types of behavior that are mediated by the PAG such as active and passive coping responses, analgesia, and reproductive behavior. In primates, it is not known whether ER-c, IR PAG neurons represent local interneurons and/or neurons that project to brainstem areas that control these behaviors. In this double labeling study, we asked whether ER-alpha IR neurons in the PAG of the rhesus monkey project to the nucleus retroambiguus (NRA), an area in the ventrolateral caudal medulla oblongata that is involved in expiration, vocalization, and reproductive behavior.Tracer was injected into the caudal lateral medulla oblongata to retrogradely label PAG neurons, and ER-alpha was visualized immunohistochemically. Although ER-alpha IR neurons and NRA-projection neurons were present at similar levels of the PAG, their distributions hardly overlapped. ER-alpha IR PAG neurons that project to the lateral caudal medulla represented less than 2% of ER-alpha IR PAG neurons. These double-labeled neurons were mainly located in the ipsilateral caudal PAG. The cluster of neurons in the medial part of the lateral PAG that projects specifically to the NRA-region did not contain double-labeled cells.The results indicate that only a few ER-alpha IR PAG neurons project to the NRA-region. This might be related to the modest effects of estrogen on mating-related behavior in primates compared most other mammalian species. Remaining ER-alpha. IR PAG neurons might act locally on other PAG neurons, or they might represent neurons that project to other areas. Furthermore, the finding that the distributions of ER-alpha IR neurons and neurons that project to premotor neurons in the NRA-region scarcely overlap illustrates that the PAG in primates is very highly organized into anatomically distinct regions compared with other species. (C) 2004 IBRO. Published by Elsevier Ltd. All rights reserved.

The nucleus retroambiguus (NRA) of the caudal medulla is a relay nucleus by which neurons of the mesencephalic periaqueductal gray (PAG) reach motoneurons of pharynx, larynx, soft palate, intercostal and abdominal muscles, and several muscles of the hindlimbs. These PAG-NRA-motoneuronal projections are thought to play a role in survival behaviors, such as vocalization and mating behavior. In the present combined antero- and retrograde tracing study in the cat, we sought to determine whether the NRA, apart from the neurons projecting to motoneurons, also contains cells projecting back to the PAG. After injections of WGA-HRP in the caudal and intermediate PAG, labeled neurons were observed in the NRA, with a slight contralateral. preponderance. In contrast, after injections in the rostral PAG or adjacent deep tectal layers, no or very few labeled neurons were present in the NRA. After injection of [(3)H]leucine in the NRA, anterograde labeling was present in the most caudal ventrolateral and dorsolateral PAG, and slightly more rostrally in the lateral PAG, mainly contralaterally. When the [(3)H]leucine injection site extended medially into the medullary lateral tegmental field, labeling was found in most parts of the PAG as well as in the adjoining deep tectal layers. No labeled fibers were found in the dorsolateral PAG, and only a few were found in the rostral PAG. Because the termination pattern of the NRA fibers in the PAG overlaps with that of the sacral cord projections to the PAG, it is suggested that the NRA-PAG projections play a role in the control of motor functions related to mating behavior. J. Comp. Neurol. 445:47-58, 2002. (C) 2002 Wiley-Liss, Inc.

Reproductive behavior in most mammalian species consists of a highly stereotyped pattern of movements, is elicited by specific sensory stimuli and is sex steroid dependent. The present paper describes a concept of the pathways in the midbrain, brainstem and spinal cord which control the receptive posture of the female cat. The midbrain periaqueductal gray (PAG), which is an important structure in the Emotional Motor System (EMS), receives direct input from a distinct group of neurons in the dorsal horn of the lumbosacral cord. This cell group overlaps with the location of pelvic and to lesser extent, pudendal nerve primary efferents, which convey information from the pelvic viscera and sex organs to the central nervous system. The FAG, in turn, controls various motor components of female receptive behavior using different pathways. For example, immobility, which is one of the characteristics of receptive behavior, might be mediated by a diffuse pathway from the FAG, via the ventral part of the medial medullary tegmentum, to all parts of the spinal ventral hem. More specific components, such as hindlimb treading, lateral deviation of the tail and elevation of the lower back, are thought to be controlled by a circumscribed projection from the FAG to the nucleus retroambiguus (NRA). The NRA is a group of interneurons at the transition between brainstem and spinal cord and projects directly to distinct lumbosacral motoneuronal cell groups, which innervate muscles that are likely to be involved in the female receptive posture. Estrogen induces axonal sprouting of the NRA-lumbosacral pathway in adult female cats, which explains why female cats only display receptive behavior when estrogen levels are high. (C) 1998 Elsevier Science B.V. All rights reserved.

In 1995, we discovered a new pathway in the cat, which originates from the nucleus retroambiguus (NRA) and terminates in a distinct set of lumbosacral hindlimb, axial, and pelvic floor motoneuronal cell groups [VanderHorst VG.JM, Holstege G (1995) Caudal medullary pathways to lumbosacral motoneuronal cell groups in the cat: evidence for direct projections possibly representing the final common pathway for lordosis. J Comp Neurol 359:457-475]. The NRA is a compact group of interneurons located laterally in the caudal medulla oblongata. Its projection to lumbosacral moloneurons is thought to represent the final common pathway for male mounting and for female receptive or lordosis behavior. However, females only display lordosis behavior when they are in estrus, which suggests that the NRA-lumbosacral pathway is only active during estrus. This raised the question of whether estrogen affects this pathway. The effect of estrogen on the NRA-lumbosacral projection was studied light microscopically, using wheat-germ agglutinin horseradish peroxidase (WGA-HRP) as a tracer. The rubrospinal pathway served as control. The density of labeled NRA fibers in their target hindlimb motoneuronal cell groups appeared abundant in estrous and very weak in nonestrous cats. Such differences were not found in the rubrospinal pathway. For electron microscopical study, the NRA projection to the semimembranosus motoneuronal cell group was selected. In this cell group, an almost ninefold increase of labeled profiles was found in estrous versus nonestrous cats. Moreover, the semimembranous motoneuronal cell group contained labeled growth cones in estrous, but not in nonestrous, cats. The present study is the first to show that estrogen induces axonal outgrowth of a precisely identified pathway in the adult mammalian central nervous system. The possible mechanisms underlying this outgrowth are discussed.

In cats, there exists a descending system that controls the posture necessary for mating behavior. A key role is played by the mesencephalic periaqueductal gray (PAG), which maintains strong specific projections to the nucleus retroambiguus located laterally in the most caudal medulla. The NRA, in turn, has direct access to motoneurons in the lumbosacral cord that produce the mating posture. This pathway is slightly different in males and females, but in females its strength fluctuates strongly depending on whether or not the cat is in heat. This way the PAG determines whether or not mating can take place. Via the PAG many other regions in the limbic system as well as in the prefrontal cortex and insula can influence mating behavior. In humans, the brain also controls responses to sexual stimulation as well as ejaculation in men and orgasm in women. Neuroimaging techniques show activations and de-activations but are not able to verify whether the PAG has a similar effect as in cats. PET-scanning results revealed that there is activation in the upper brainstem and cerebellum, as well as insula in men and in the somatomotor and somatosensory cortex in women. During sexual stimulation, but especially during ejaculation and orgasm there was strong de-activation mainly on the left side in the temporal lobe and ventral prefrontal cortex. These neuroimaging results show the importance of lowering the level of alertness regarding your immediate environment (left hemisphere) to have proper sexual behavior. (C) 2011 Elsevier Inc. All rights reserved.

Anatomical studies have shown a monosynaptic projection from nucleus retroambiguus (NRA) to semimembranosus (Sm) motor nucleus in female cats, which is stronger in oestrus. Expiratory bulbospinal neurones are the best documented functional cell type in the NRA. If these cells participate in this projection, an expiratory drive would be expected in Sm motoneurones and this drive would be expected to be stronger in oestrus. In anaesthetized, paralyzed, ovariohysterectormized female cats, artificially ventilated to produce a strong respiratory drive (as monitored by phrenic nerve discharges), intracellular recordings were made from Sm motoneurones and from motoneurones in the surrounding hindlimb motor nuclei that are outside the focus of the NRA projection. The animals comprised two groups: either treated for 7 days with oestradiol benzoate (oestrous) or untreated (non-oestrous).Central respiratory drive potentials (CRDPs) were observed in most motoneurones of both groups, with amplitudes larger for the oestrous than for the non-oestrous group (1.58 +/- 1.34 mV versus 0.89 +/- 0.79 mV, mean +/- S.D.). However, the CRDPs most often consisted of a maximum depolarization in early expiration, which declined in late expiration and into inspiration. This pattern is different from the incrementing firing pattern of most expiratory bulbospinal neurones. The CRDPs in Sm and semitendinosus motoneurones (located in the same motor column) were of similar size and frequency to CRDPs in motoneurones outside that column. The hypothesis that expiratory bulbospinal neurones are significantly involved in the projection was rejected. Alternative sources and possible functional roles for the CRDPs are discussed. (c) 2006 Elsevier Inc. All rights reserved.

Our laboratory has proposed that the nucleus retroambiguus (NRA) generates the specific motor performance displayed by female cats during mating and that it uses direct pathways to the motoneurons of the lower limb muscles involved in this activity. In the hamster a similar NRA-projection system could generate the typical female mating posture, which is characterized by lordosis of the back as well as elevation of the tail. The present study attempted to determine whether this elevation of the tail is also part of the NRA-mating control system. The basic assumption was that elevation of the tail is a function of the cutaneus trunci muscle (CTM), which was verified by bilateral tetanic stimulation of the lateral thoracic nerves innervating the CTM. It resulted in upward movement of the tail to a position similar to the tail-up position during the lordosis posture. Retrograde tracing results showed that CTM motoneurons are located in the ventral and ventrolateral part of the C7–C8 ventral horn, those innervating the tail region ventrolateral to those innervating the axillary region. Anterograde tracing studies showed that NRA fibers terminate bilaterally in both parts of the CTM motoneuronal cell groups. Electron microscopical studies revealed that labeled NRA terminals make monosynaptic contacts with retrogradely labeled dendrites of CTM motoneurons. Almost all of these terminal profiles had asymmetric synapses and contained spherical vesicles, which suggests an excitatory function. The observation that 15% of the labeled NRA terminals make more than one synaptic contact with a retrogradely labeled CTM motoneuronal dendrite within the same section indicates how powerful the NRA-CTM projection is. The results indicate that during mating the NRA not only could generate the lordosis posture but also the elevation of the tail.

In 1995, we discovered a new pathway in the cat, which originates from the nucleus retroambiguus (NRA) and terminates in a distinct set of lumbosacral hindlimb, axial, and pelvic floor motoneuronal cell groups [VanderHorst VGJM, Holstege G (1995) Caudal medullary pathways to lumbosacral motoneuronal cell groups in the cat: evidence for direct projections possibly representing the final common pathway for lordosis. J Comp Neurol 359:457-475]. The NRA is a compact group of interneurons located laterally in the caudal medulla oblongata. Its projection to lumbosacral motoneurons is thought to represent the final common pathway for male mounting and for female receptive or lordosis behavior. However, females only display lordosis behavior. However, females only display lordosis behavior when they are in estrus, which suggests that the NRA-lumbosacral pathway is only active during estrus. This raised the question of whether estrogen affects this pathway. The effect of estrogen on the NRA-lumbosacral projection was studied light microscopically, using wheat-germ agglutinin horseradish peroxidase (WGA-HRP) as a tracer. The rubrospinal pathway served as control. The density of labeled NRA fibers in their target hindlimb motoneuronal cell groups appeared abundant in estrous and very weak in nonestrous cats. Such differences were not found in the rubrospinal pathway. For electron microscopical study, the NRA projection to the semi-membranosus motoneuronal cell group was selected. In this cell group, an almost ninefold increase of labeled profiles was found in estrous versus nonestrous cats. Moreover, the semimembranous motoneuronal cell group contained labeled growth cones in estrous, but not in nonestrous, cats. The present study is the first to show that estrogen induces axonal outgrowth of a precisely identified pathway in the adult mammalian central nervous system. The possible mechanisms underlying this outgrowth are discussed.

The nucleus retroambiguus (NRA) projects to distinct brainstem and cervical and thoracic cord motoneuronal cell groups. The present paper describes NRA projections to distinct motoneuronal cell groups in the lumbar enlargement. Lumbosacral injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) were made to localize and quantify the retrogradely labeled neurons in the caudal medullary lateral tegmentum. These injections were combined with spinal hemisections to distinguish between neurons having ipsi- or contralaterally descending axons. The NRA-lumbosacral fibers descend almost exclusively contralaterally, but neurons in areas surrounding the NRA project mainly ipsilaterally.In an anterograde tracing study, injections of WGA-HRP or tritiated leucine were made in the region of the NRA to determine the NRA. targets in the lumbosacral cord. Hemisections in C2 made it possible to distinguish between NRA projections and projections from neurons in the adjoining lateral tegmentum. The results show delicate NRA projections to distinct lumbosacral motoneuronal cell groups innervating specific hindlimb muscles (iliopsoas, adductors, and hamstrings) as well as axial muscles (medial longissimus and proximal tail muscles). The projection is bilateral, with a contralateral predominance. Ipsilaterally terminating fibers are derived from NRA neurons whose axons cross the midline at the level of the obex, descend through the contralateral spinal white matter, and recross at the level of termination. A conceptual description is presented in which the periaqueductal gray-NRA-lumbosacral projections form the final common pathway for lordosis in the cat. (C) 1995 Wiley-Liss, Inc.