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In the cat four different types of vocalization, mews, howls, cries, and hisses were generated by microstimulation in different parts of the periaqueductal gray (PAG). While mews imply positive vocal expressions, howls, hisses, and cries represent negative vocal expressions. In the intermediate PAG, mews were generated in the lateral column, howls, and hisses in the ventrolateral column. Cries were generated in two other regions, the lateral column of the rostral PAG and the ventrolateral column of the caudal PAG. In order to define the specific motor patterns of the mews, howls, and cries, the following muscles were recorded during these vocalizations; larynx (cricothyroid, thyroarytenoid, and posterior cricoarytenoid), tongue (genioglossus), jaw (digastric), and respiration muscles (diaphragm, internal intercostal, external, and internal abdominal oblique). During these mews, howls, and cries we analyzed the frequency, intensity, activation cascades power density, turns, and amplitude analysis of the electromyograms (EMGs). It appeared that each type of vocalization consists of a specific circumscribed motor coordination. The nucleus retroambiguus (NRA) in the caudal medulla is known to serve as the final premotor interneuronal output system for vocalization. Although neurochemical microstimulation in the NRA itself also generated vocalizations, they only consisted of guttural sounds, the EMGs of which involved only small parts of the EMGs of the mews, howls, and cries generated by neurochemical stimulation in the PAG. These results demonstrate that positive and negative vocalizations are generated in different parts of the PAG. These parts have access to different groups of premotoneurons in the NRA, that, in turn, have access to different groups of motoneurons in the brainstem and spinal cord, resulting in different vocalizations. The findings would serve a valuable model for diagnostic assessment of voice disorders in humans.

The nucleus retroambiguus (NRA) is a neuronal cell group in the medullary ventrolateral tegmentum, rostrocaudally between the obex and the first cervical spinal segment. NRA neurons are premotor interneurons with direct projections to the motoneurons of soft palate, pharynx, and larynx in the nucleus ambiguus in the lateral medulla as well as to the motoneurons in the spinal cord innervating diaphragm, abdominal, and pelvic floor muscles and the lumbosacral motoneurons generating sexual posture. These NRA premotor interneurons receive very strong projections from the periaqueductal gray (PAG) in the context of basic survival mechanisms as fight, flight, freezing, sound production, and sexual behavior. In the present study in rat we investigated the physiological motor patterns generated by NRA neurons, as the result of vagal, peripheral chemosensory, and nociceptive stimulation. The results show that the NRA contains phasic respiratory modulated neurons, as well as nonphasic tonically modulated neurons. Stimulation in the various rostrocaudal levels of the NRA generates site-specific laryngeal, respiratory, abdominal, and pelvic floor motor activities. Vagal and peripheral chemosensory stimulation induces both excitatory and inhibitory modulation of phasic NRA-neurons, while peripheral chemosensory and nociceptive stimulation causes excitation and inhibition of nonphasic NRA-neurons. These results are in agreement with the concept that the NRA represents a multifunctional group of neurons involved in the output of the emotional motor system, such as vomiting, vocalization, mating, and changes in respiration.

Vocalizations such as mews and cries in cats or crying and laughter in humans are examples of expression of emotions. These vocalizations are generated by the emotional motor system, in which the mesencephalic periaqueductal gray (PAG) plays a central role, as demonstrated by the fact that lesions in the PAG lead to complete mutism in cats, monkeys, as well as in humans. The PAG receives strong projections from higher limbic regions and from the anterior cingulate, insula, and orbitofrontal cortical areas. In turn, the PAG has strong access to the caudal medullary nucleus retroambiguus (NRA). The NRA is the only cell group that has direct access to the motoneurons involved in vocalization, i.e., the motoneuronal cell groups innervating soft palate, pharynx, and larynx as well as diaphragm, intercostal, abdominal, and pelvic floor muscles. Together they determine the intraabdominal, intrathoracic, and subglottic pressure, control of which is necessary for generating vocalization. Only humans can speak, because, via the lateral component of the volitional or somatic motor system, they are able to modulate vocalization into words and sentences. For this modulation they use their motor cortex, which, via its corticobulbar fibers, has direct access to the motoneurons innervating the muscles of face, mouth, tongue, larynx, and pharynx. In conclusion, humans generate speech by activating two motor systems. They generate vocalization by activating the prefrontal-PAG-NRA-motoneuronal pathway, and, at the same time, they modulate this vocalization into words and sentences by activating the corticobulbar fibers to the face, mouth, tongue, larynx, and pharynx motoneurons.

Neurochemical microstimulation in different parts of the midbrain periaqueductal gray (PAG) in the cat generates four different types of vocalization, mews, howls, cries, and hisses. Mews signify positive vocal expression, whereas howls, hisses, and cries signify negative vocal communications. Mews were generated in the lateral column of the intermediate PAG and howls and hisses in the ventrolateral column of the intermediate PAG. Cries were generated in two regions, the lateral column of the rostral PAG and the ventrolateral column of the caudal PAG. To define the specific motor patterns belonging to mews, howls, and cries, the following muscles were recorded during these vocalizations: larynx (cricothyroid, thyroarytenoid, and posterior cricoarytenoid), tongue (genioglossus), jaw (digastric), and respiration (diaphragm, internal intercostal, external abdominal oblique, and internal abdominal oblique) muscles. Furthermore, the frequency, intensity, activation cascades, and turns and amplitude analyses of the electromyograms (EMGs) during these vocalizations were analyzed. The results show that each type of vocalization consists of a specific, circumscribed motor coordination. The nucleus retroambiguus (NRA) in the caudal medulla serves as the final premotor interneuronal output system for vocalization. NRA neurochemical microstimulation also generated vocalizations (guttural sounds). Analysis of the EMGs demonstrated that these vocalizations consist of only small parts of the emotional voalizations generated by neurochemical stimulation in the PAG. These results demonstrate that motor organization of positive and negative emotional vocal expressions are segregated in the PAG and that the PAG uses the NRA as a tool to gain access to the motoneurons generating vocalization.

Achtergrond: Het is algemeen bekend dat Brodmanns area 17 (BA 17), de primaire visuele cortex, een fundamentele rol speelt in basale overlevingsmechanismen, aangezien visuele informatie van essentieel belang is bij het effectief reageren op gebeurtenissen in de directe omgeving van een individu. In de neuroimaging-studies waarin aan de vrijwilligers gevraagd wordt naar films te kijken, wordt de primaire visuele cortex op gelijke wijze gestimuleerd, ongeacht de inhoud van de visuele informatie. Alleen in sommige studies waarin de vrijwilligers gevraagd wordt zware niet-visuele taken te verrichten, is aangetoond dat de primaire visuele cortex gedeactiveerd wordt, ondanks dat de aangeboden hoeveelheid visuele informatie hetzelfde is. De vraag is dat of dat ook zo is wanneer de vrijwilligers naar zwak of sterk erotische films kijken, in vergelijking met neutrale films.

Introduction The physiological component of ejaculation shows parallels with that of micturition, as both are essentially voiding activities. Both depend on supraspinal influences to orchestrate the characteristic pattern of activity in the pelvic organs. Unlike micturition, little is known about the supraspinal pathways involved in ejaculation and female orgasm. Aim To identify brainstem regions activated during ejaculation and female orgasm and to compare them with those activated during micturition. Methods Ejaculation in men and orgasm in women were induced by manual stimulation of the penis or clitoris by the participants' partners. Positron emission tomography (PET) with correction for head movements was used to capture the pattern of brain activation at the time of sexual climax. Main Outcome Measures PET scans showing areas of activation during sexual climax. Results Ejaculation in men and orgasm in women resulted in activation in a localized region within the dorsolateral pontine tegmentum on the left side and in another region in the ventrolateral pontine tegmentum on the right side. The dorsolateral pontine area was also active in women who attempted but failed to have an orgasm and in women who imitated orgasm. The ventrolateral pontine area was only activated during ejaculation and physical orgasm in women. Conclusion Activation of a localized region on the left side in the dorsolateral pontine tegmentum, which we termed the pelvic organ‐stimulating center, occurs during ejaculation in men and physical orgasm in women. This same region has previously been shown to be activated during micturition, but on the right side. The pelvic organ‐stimulating center, via projections to the sacral parasympathetic motoneurons, controls pelvic organs involved in voiding functions. In contrast, the ventrolateral pontine area, which we term the pelvic floor‐stimulating center, produces the pelvic floor contractions during ejaculation in men and physical orgasm in women via direct projections to pelvic floor motoneurons. Huynh HK, Willemsen ATM, Lovick TA, and Holstege G. Pontine control of ejaculation and female orgasm. J Sex Med 2013;10:3038–3048.

The midbrain periaqueductal gray (PAG) is involved in many basic survival behaviors that affect respiration. We hypothesized that the PAG promotes these behaviors by changing the firing of preinspiratory (pre-I) neurons in the pre-Botzinger complex, a cell group thought to be important in generating respiratory rhythm. We tested this hypothesis by recording single unit activity of pre-Botzinger pre-I neurons during stimulation in different parts of the PAG. Stimulation in the dorsal PAG increased the firing of pre-I neurons, resulting in tachypnea. Stimulation in the medial part of the lateral PAG converted the pre-I neurons into inspiratory phase-spanning cells, resulting in inspiratory apneusis. Stimulation in the lateral part of the lateral PAG generated an early onset of the pre-I neuronal discharge, which continued throughout the inspiratory phase, while at the same time attenuating diaphragm contraction. Stimulation in the ventral part of the lateral PAG induced tachypnea but inhibited pre-I cell firing, whereas stimulation in the ventrolateral PAG inhibited not only pre-I cells but also the diaphragm, leading to apnea. These findings show that PAG stimulation changes the activity of the pre-Botzinger pre-I neurons. These changes are in line with the different behaviors generated by the PAG, such as the dorsal PAG generating avoidance behavior, the lateral PAG generating fight and flight, and the ventrolateral PAG generating freezing and immobility. J. Comp. Neurol. 521: 3083-3098, 2013. (c) 2013 Wiley Periodicals, Inc.

Introduction The brain has two goals: survival of the individual and survival of the species. It ensures that the body resides in safe circumstances and can obtain sufficient drink and food. It also has to produce and protect offspring. Its most important tool is its motor system, which consists of the voluntary and emotional motor systems. Aim To explain how the brain uses its emotional motor system to control the pelvic organs. Methods Anatomic and physiologic data in cats and humans are used to find out how this motor system works and what parts of the brain and brainstem are involved. Main Outcome Measures Main outcome is that the brain control of the pelvic organs is a specific descending system. Results The pelvic organs are innervated by the sacral parasympathetic motoneurons, which are controlled by a specific group of neurons in the pontine brainstem, the pelvic organ stimulating center (POSC). Through long descending pathways, this POSC generates micturition, defecation, and sexual activities by stimulating different groups of sacral parasympathetic motoneurons. In turn the POSC is driven by the periaqueductal gray (PAG), which receives, through the sacral cord, precise information regarding the situation in all pelvic organs. In addition, the PAG receives instructions from higher brain levels such as the amygdala, bed nucleus of the stria terminalis, and various regions of the hypothalamus. Notably, in humans, the most important brain region having access to the PAG is the medial orbitofrontal cortex, which is deactivated in women with hypoactive sexual desire disorder. Conclusion In women with hypoactive sexual desire disorder, deactivation of their medial orbitofrontal cortex produces a decrease in PAG-POSC activation, causing absence of vaginal vasocongestion and lubrication and decreased sexual behavior in general. It often leads to major problems in their personal circumstances. The question is whether new drugs can cure this.

Introduction The primary visual cortex, Brodmann's area (BA 17), plays a vital role in basic survival mechanisms in humans. In most neuro-imaging studies in which the volunteers have to watch pictures or movies, the primary visual cortex is similarly activated independent of the content of the pictures or movies. However, in case the volunteers perform demanding non-visual tasks, the primary visual cortex becomes de-activated, although the amount of incoming visual sensory information is the same. Aim Do low- and high-intensity erotic movies, compared to neutral movies, produce similar de-activation of the primary visual cortex? Methods Brain activation/de-activation was studied by Positron Emission Tomography scanning of the brains of 12 healthy heterosexual premenopausal women, aged 18–47, who watched neutral, low- and high-intensity erotic film segments. Main Outcome Measures We measured differences in regional cerebral blood flow (rCBF) in the primary visual cortex during watching neutral, low-intensity erotic, and high-intensity erotic film segments. Results Watching high-intensity erotic, but not low-intensity erotic movies, compared to neutral movies resulted in strong de-activation of the primary (BA 17) and adjoining parts of the secondary visual cortex. Conclusions The strong de-activation during watching high-intensity erotic film might represent compensation for the increased blood supply in the brain regions involved in sexual arousal, also because high-intensity erotic movies do not require precise scanning of the visual field, because the impact is clear to the observer. Huynh HK, Beers C, Willemsen A, Lont E, Laan E, Dierckx R, Jansen M, Sand M, Weijmar Schultz W, and Holstege G. High-intensity erotic visual stimuli de-activate the primary visual cortex in women. J Sex Med 2012;9:1579–1587.

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.

Micturition is, similar to all other movements of the body, the result of activation of the motor system in the central nervous system. This review explains how the brain and brainstem control micturition. The basic reflex system begins with a distinct cell group called Gert's Nucleus (GN) in the sacral cord. GN receives information about bladder contents via A-delta fibers from the bladder and bladder sphincter and relays this information to the central part of the midbrain periaqueductal gray (PAG), but not to the thalamus. The PAG, in turn, in case of substantial bladder filling, excites the pontine micturition center (PMC), which cell group, via its long descending pathways to the sacral cord, induces micturition. Higher brain regions in prefrontal cortex and limbic system, by means of its projections to the PAG are able to interrupt this basic reflex system. It allows the individual to postpone micturition until time and place are appropriate. Lesions in the pathways from prefrontal cortex and limbic system to the PAG probably cause urgeincontinence in the elderly. Neurourol. Urodynam. 29:42-48, 2010. (C) 2009 Wiley-Liss, Inc.

The role of the nucleus retroambiguus (NRA) in the context of respiration control has been subject of debate for considerable time. To solve this problem, we chemically (usingd,l-homocysteic acid) stimulated the NRA in unanesthetized precollicularly decerebrated cats and studied the respiratory effect via simultaneous measurement of tracheal pressure and electromyograms of diaphragm, internal intercostal (IIC), cricothyroid (CT), and external oblique abdominal (EO) muscles. NRA-stimulation 0–1 mm caudal to the obex resulted in recruitment of IIC muscle and reduction in respiratory frequency. NRA-stimulation 1–3 mm caudal to the obex produced vocalization along with CT activation and slight increase in tracheal pressure, but no change in respiratory frequency. NRA-stimulation 3–5 mm caudal to the obex produced CT muscle activation and an increase in respiratory frequency, but no vocalization. NRA-stimulation 5–8 mm caudal to the obex produced EO muscle activation and reduction in respiratory frequency. A change to the inspiratory effort was never observed, regardless of which NRA part was stimulated. The results demonstrate that NRA does not control eupneic inspiration but consists of topographically separate groups of premotor interneurons each producing detailed motor actions. These motor activities have in common that they require changes to eupneic breathing. Different combination of activation of these premotor neurons determines the final outcome, e.g., vocalization, vomiting, coughing, sneezing, mating posture, or child delivery. Higher brainstem regions such as the midbrain periaqueductal gray (PAG) decides which combination of NRA neurons are excited. In simple terms, the NRA is the piano, the PAG one of the piano players.

Are there limits to the duration of high quality of life? Are there limits to healthy life for a human brain? We have had the opportunity to evaluate the performance of a 112-113-year-old woman and perform full pathological examination of her body immediately after death at the age of 115. The psychological tests revealed that her general performance was above average of healthy adults of 60-75 years. The pathological observations revealed almost no atherosclerotic changes throughout the body. In the brain almost no beta-amyloid plaques or vascular changes were found and only slight accumulation of hyperphosphorylated tau protein with a Braak-stage 2. Counts of the number of locus coeruleus neurons corresponded with the number of neurons found in the brains of healthy people of 60-80 years old. Our observations indicate that the limits of human cognitive function extends far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentanarians, is not inevitable. (c) 2008 Published by Elsevier Inc.

Vocalizations such as mews and cries in cats or crying and laughter in humans are examples of expression of emotions. These vocalizations are generated by the emotional motor system, in which the mesencephalic periaqueductal gray (PAG) plays a central role, as demonstrated by the fact that lesions in the PAG lead to complete mutism in cats, monkeys, as well as in humans. The PAG receives strong projections from higher limbic regions and from the anterior cingulate, insula, and orbitofrontal cortical areas. In turn, the PAG has strong access to the caudal medullary nucleus retroambiguus (NRA). The NRA is the only cell group that has direct access to the motoneurons involved in vocalization, i.e., the motoneuronal cell groups innervating soft palate, pharynx, and larynx as well as diaphragm, intercostal, abdominal, and pelvic floor muscles. Together they determine the intraabdominal, intrathoracic, and subglottic pressure, control of which is necessary for generating vocalization. Only humans can speak, because, via the lateral component of the volitional or somatic motor system, they are able to modulate vocalization into words and sentences. For this modulation they use their motor cortex, which, via its corticobulbar fibers, has direct access to the motoneurons innervating the muscles of face, mouth, tongue, larynx, and pharynx. In conclusion, humans generate speech by activating two motor systems. They generate vocalization by activating the prefrontal-PAG-NRA-motoneuronal pathway, and, at the same time, they modulate this vocalization into words and sentences by activating the corticobulbar fibers to the face, mouth, tongue, larynx, and pharynx motoneurons.

The lower urinary tract is responsible for the storage and periodic elimination of liquid waste from the body in the form of urine. The lower urinary tract consists of the urinary bladder and its outlet, the urethra, and is controlled by a complex set of pre- and postsynaptic autonomic and somatic motoneurons, which are in turn controlled by neurons in the spinal cord, pons, and midbrain. Conscious control of the lower urinary tract is maintained by the midbrain periaqueductal gray, which receives specific sensory input from the lower urinary tract and from higher brain regions, including the medial orbitofrontal cortex, which determines whether it is appropriate to void. This chapter outlines the organization of the neural pathways that innervate the lower urinary tract, how these pathways interact to control micturition and how the higher brain centers, in turn, control these pathways to maintain continence or allow micturition to take place.

The infralimbic cortex (ILc) in cat is the ventralmost part of the anterior cingulate gyrus. The ILc, together with the amygdala, bed nucleus of the stria terminalis and lateral hypothalamus, is involved in the regulation of fear behavior. The latter three structures are thought to take part in triggering the fear response by means of their projections to the pontine and medullary lateral tegmental field (LTF). The LTF is a large region extending from the parabrachial nuclei rostrally to the spinal cord caudally. It contains almost all the premotor interneurons for the brainstem and for some upper spinal cord motoneurons innervating the muscles of face, head and throat. The question is whether ILc also projects to the LTF. Such a pathway would allow the ILc to influence the fear response by acting directly on these premotor interneurons. Anterograde tracer injections were made in the medial surface of the cortex in four cats. Only when the injection sites involved ILc were anterogradely labeled fibers observed throughout the rostrocaudal extent of the LTF. To verify whether these projections indeed originated from ILc, in two other cases retrograde tracer injections were made in the pontomedullary LTF. The results showed many retrogradely labeled neurons in ILc, but none in adjacent cortical regions. These results show that the ILc projects to the LTF in cat and can possibly modulate the fear response not only via indirect but also via direct routes to the premotor interneurons in the brainstem.

The spinothalamic tract (STT), well known for its role in the relay of information about noxe, temperature, and crude touch, is usually associated with projections from lamina 1, but spinothalamic neurons in other laminae have also been reported. In cat, no complete overview exists of the precise location and number of spinal cells that project to the thalamus In the present study the laminar distribution of retrogradely labeled cells in all spinal segments (C1-Coc2) was investigated after large WGA-HRP injections in the thalamus. The results show that this distribution of STT cells differed greatly between the different spinal segments. Quantitative analysis showed that there exist at least five separate clusters of spinothalamic neurons. Lamina I neurons in cluster A and lamina V neurons in cluster B are mainly found contralaterally throughout the length of the spinal cord. Cluster C neurons are located bilaterally in the ventrolateral part of laminae VI-VII and lamina VIII of the C1-C3 spinal cord. Cluster D neurons were found contralaterally in lamina VI in the C1-C2 segments, and cluster E neurons were located mainly contralaterally in the medial part of laminae VI-VII and lamina VIII of the lumbosacral cord. Most spinothalamic neurons are not located in the enlargements and most spinothalamic neurons are not located in lamina 1, as suggested by several other authors. The location of the spinothalamic neurons shows remarkable similarities, but also differences, with the location of spino-periaqueductal gray neurons.

Penile sensory information is essential for reproduction, but almost nothing is known about how sexually salient inputs from the penis are processed in the brain. We used positron emission tomography to measure regional cerebral blood flow (rCBF) during various stages of male sexual performance. Compared to a passive resting condition (without penile erection), sexual stimulation of the penis increased rCBF in an area of the right hemisphere encompassing the posterior insula and adjacent posterior part of the secondary somatosensory cortex (SII) and decreased rCBF in the right amygdala. No activation was observed in either the thalamus, genital part of primary somatosensory cortex (SI), or hypothalamus. Based on these results we put forward the concept that during sexual performance the salience of the stimulus, represented by activation of the insula and SII, is of greater significance than the exact location of the stimulus, encoded in SI. The absence of activation in the hypothalamus indicates that this region is more important for the onset of sexual arousal than for the resulting sexual performance. Deactivation of the amygdala during sexual stimulation of the penis corresponds with a decrease of vigilance during sexual performance.

The dorsolateral column of the mesencephalic periaqueductal gray (PAG) is a separate part of the PAG. Its afferent sources, efferent targets, and neurochemical properties differ from the adjacent PAG columns. The dorsolateral PAG is thought to be associated with aversive behaviors, but it is not yet understood how these behaviors are brought about. To elucidate the function of the PAG further, in the present study we investigated which brainstem regions project to the dorsolateral PAG. Wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injections involving the dorsolateral PAG, but extending into the lateral part, resulted in many retrogradely labeled cells in the pontine and medullary tegmentum bilaterally. However, it was concluded that these neurons were labeled from the lateral PAG, because no anterograde labeling was found in the dorsolateral PAG after a large injection into the tegmentum. Retrogradely labeled cells were also found in the nucleus prepositus hypoglossi (PPH), mainly contralaterally. Injections of [(3)H]leucine or WGA-HRP in the PPH resulted in anterogradely labeled fibers in the dorsolateral PAG. Two separate distribution patterns were found. The caudal and intermediate PPH projected to a small region on the dorsolateral edge of the dorsolateral column, whereas the supragenual PPH distributed labeled fibers to all other parts of the dorsolateral PAG, except the area on the dorsolateral edge. These separate PPH projections suggest that two subdivisions exist within the dorsolateral PAG. The present findings suggest a role for the dorsolateral PAG in the oculomotor system.

An overview is given of the regions in the spinal cord that are active during ejaculation. Motoneurons involved are the preganglionic sympathetic motoneurons in the upper lumbar spinal cord and the motoneurons in the nucleus of Onuf, located in the upper sacral cord. The first group is involved in the so-called emission phase of ejaculation, the last group in the expulsion phase. Both groups receive afferents from premotor interneurons in the so-called intermediomedial cell groups located at about the same level as the motoneurons themselves. A concept is put forward in which these premotor cell groups represent the central spinal pattern generators for ejaculation, one for the emission phase and one for the expulsion phase. Clinical observations in patients suffering from transection of the spinal cord indicate that the ejaculation motoneurons as well as their spinal central pattern generators are under strong influence of descending pathways originating in supraspinal parts of the brain. The various pathways possibly involved in ejaculation control are reviewed. Finally, the results of the brain activation of a PET-scan study in human males, ejaculating after penile stimulation by their female partner are discussed. Especially the ventral tegmental area and the cerebellum seem to be activated during ejaculation, while the amygdala region is deactivated. Apparently, a general lack of fear is necessary for ejaculation to occur.

By far, the strongest spinal cord projections to periaqueductal gray (PAG) and thalamus originate from the upper three cervical segments, but their precise organization and function are not known. In the present study in cat, tracer injections in PAG or in thalamus resulted in more than 2400 labeled cells, mainly contralaterally, in the first three cervical segments (C1-C3), in a 1:4 series of sections, excluding cells in the dorsal column and lateral cervical nuclei. These cells represent about 30% of all neurons in the entire spinal cord projecting to PAG and about 45% of all spinothalamic neurons. About half of the C1-C3 PAG and C1-C3 thalamic neurons were clustered laterally in the ventral horn (C1-3v1), bilaterally, with a slight ipsilateral preponderance. The highest numbers Of C1-3v1-PAG and C1-3v1-thalamic cells were found in C1, with the greatest density rostrocaudal ly in the middle part of C 1. A concept is put forward that C1-3v1 cells relay information from all levels of the cord to PAG and/or thalamus, although the processing of specific information from upper neck muscles and tendons or facet joints might also play a role. (c) 2005 Elsevier B.V. All rights reserved.

There is a close connection between micturition and emotion. Several species use micturition to signal important messages as territorial demarcation and sexual attraction. For this reason, micturition is coordinated not in the spinal cord but in the brainstem, where it is closely connected with the limbic system. In cat, bladder afferents terminate in a cell group in the lateral dorsal horn and lateral part of the intermediate zone. Neurons in this cell group project to supraspinal levels, not to the thalamus but to the central periaqueductal gray (PAG). Neurons in the lateral PAG, not receiving direct sacral cord afferents, project to the pontine micturition center (PMC). The PMC projects directly to the parasympathetic bladder motoneurons and to sacral GABA-ergic and glycinergic premotor interneurons that inhibit motoneurons in Onuf s nucleus innervating the external striated bladder sphincter. Thus, PMC stimulation causes bladder contraction and bladder sphincter relaxation, i.e., complete micturition. Other than the PAG, only the preoptic area and a cell group in the caudal hypothalamus project directly to the PMC. The ventromedial upper medullary tegmentum also sends projections to the PMC, but they are diffuse and also involve structures that adjoin the PMC. Neuroimaging studies in humans suggest that the systems controlling micturition in cat and human are very similar. It seems that the many structures in the brain that are known to influence micturition use the PAG as relay to the PMC. This basic organization has to be kept in mind in the fight against overactive bladder (OAB) and urge-incontinence.

During mating, the female golden hamster displays a stereotyped specific receptive posture, characterized by lordosis of the back, elevation of the tail, and extension of the legs. Muscles involved in this posture are thought to be iliopsoas, cutaneus trunci, lateral longissimus (LL), and quadratus lumborum (QL). Lesion studies in rats suggest that mating behavior is controlled by the mesencephalic periaqueductal gray (PAG). The PAG does not project directly to the motoneurons innervating the muscles involved in mating, but is thought to make use of the nucleus retroambiguus (NRA) as relay. The NRA is located ventrolaterally in the most caudal medulla, and projects directly to iliopsoas and cutaneus trunci motoneuronal cell groups. The question is whether this is also true for LL and QL muscles. Retrograde HRP tracing experiments revealed that LL and QL motoneurons are located medially in the ventral horn of the T12-L6 and T13-L4 segments, respectively. A subsequent ultrastructural study combined wheatgerm agglutinin-conjugated horseradish peroxidase injections in the NRA with cholera-toxin B-subunit injections in LL and QL muscles. The results revealed monosynaptic contacts between anterogradely labeled NRA-fiber terminals with retrogradely labeled dendrites of both LL and QL motoneurons. Almost all these terminals had asymmetrical synapses and contained spherical vesicles, suggesting an excitatory function of this NRA-motoneuronal pathway. These results correspond with the hypothesis that in hamster the PAG-NRA-motoneuronal projection not only involves motoneurons of iliopsoas and cutaneus trunci but also of LL and QL. (C) 2004 Wiley-Liss, Inc.

Lamina I neurons sending their axons into the spinothalamic tract are thought to play a crucial role in nociception, but many spinothalamic fibers do not originate from lamina I neurons. In cat, no consensus exists about what percentage of the spinothatamic tract cells are located in lamina I. After wheat germ agglutinin-conjugated horseradish peroxidase injections that covered large parts of the thalamus, retrogradely labeled cells were plotted and counted in all segments of the spinal cord. Results show that, averaged over all spinal segments, the percentage of labeled lamina I neurons was 4.9-14.2%. These results demonstrate that, in contrast to what is concluded in several previous studies, lamina I in the cat provides only a limited part of the total spinal input to the thalamus. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

The spinothalamic tract, well known for its role in nociception, is the most frequently studied ascending pathway originating from the spinal cord. It is known that spinothalamic neurons are located in all segments of the spinal cord, but in most mammals the total number of spinothalamic neurons is not known. In three cats, after large wheat germ agglutinin-conjugated horseradish peroxidase injections involving all parts (one case) or almost all parts of the thalamus (two cases), the number of retrogradely labeled profiles was counted in a 1:4 series of sections of all spinal segments from C I to Coc2. After applying the correction factor of Abercrombie (Anat. Rec. 94 (1946) 239), it appears that a total of 12,000 cells in the spinal cord project to the thalamus. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

Brain mechanisms that control human sexual behavior in general, and ejaculation in particular, are poorly understood. We used positron emission tomography to measure increases in regional cerebral blood flow (rCBF) during ejaculation compared with sexual stimulation in heterosexual male volunteers. Manual penile stimulation was performed by the volunteer's female partner. Primary activation was found in the mesodiencephalic transition zone, including the ventral tegmental area, which is involved in a wide variety of rewarding behaviors. Parallels are drawn between ejaculation and heroin rush. Other activated mesodiencephalic structures are the midbrain lateral central tegmental field, zona incerta, subparafascicular nucleus, and the ventroposterior, midline, and intralaminar thalamic nuclei. Increased activation was also present in the lateral putamen and adjoining parts of the claustrum.Neocortical activity was only found in Brodmann areas 7/40, 18, 21, 23, and 47, exclusively on the right side. On the basis of studies in rodents, the medial preoptic area, bed nucleus of the stria terminalis, and amygdala are thought to be involved in ejaculation, but increased rCBF was not found in any of these regions. Conversely, in the amygdala and adjacent entorhinal cortex, a decrease in activation was observed.Remarkably strong rCBF increases were observed in the cerebellum. These findings corroborate the recent notion that the cerebellum plays an important role in emotional processing. The present study for the first time provides insight into which regions in the human brain play a primary role in ejaculation, and the results might have important implications for our understanding of how human ejaculation is brought about, and for our ability to improve sexual function and satisfaction in men.

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.

Modulation of respiration is a prerequisite for survival of the individual and of the species. For example, respiration has to be adjusted in case of speech, strenuous exercise, laughing, crying, or sudden escape from danger. Respiratory centers in pons and medulla generate the basic respiratory rhythm or eupnea, but they cannot modulate breathing in the context of emotional challenges, for which they need input from higher brain centers. In simple terms, the prefrontal cortex integrates visual, auditory, olfactory, and somatosensory information and informs subcortical structures such as amygdala, hypothalamus, and finally the midbrain periaqueductal gray (PAG) about the results. The PAG, in turn, generates the final motor output for basic survival, such as setting the level of all cells in the brain and spinal cord. Best known in this framework is determining the level of pain perception. The PAG also controls heart rate, blood pressure, micturition, sexual behavior, vocalization, and many other basic motor output systems. Within this context, the PAG also changes the eupneic respiratory rhythm into a breathing pattern necessary for basic survival. This review examines the latest developments regarding of how the PAG controls respiration.

Respiration is a motor system essential for the survival of the individual and of the species. Because of its vital significance, studies on respiration often assume that breathing takes place independent of other motor systems. However, motor systems generating vocalization, coughing, sneezing, vomiting, as well as parturition, ejaculation, and defecation encompass abdominal pressure control, which involves changes in the respiratory pattern. The mesencephalic periaqueductal gray (PAG) controls all these motor systems. It determines the level setting of the whole body by means of its very strong projections to the ventromedial medullary tegmentum, but it also controls the cell groups that generate vocalization, coughing, sneezing, vomiting, as well as respiration. For this control, the PAG maintains very strong connections with the nucleus retroambiguus, which enables it to control abdominal and intrathoracic pressure. In this same context, the PAG also runs the pelvic organs, bladder, uterus, prostate, seminal vesicles, and the distal colon and rectum via its projections to the pelvic organ stimulating center and the pelvic floor stimulating center. These cell groups, via long descending projections, have direct control of the parasympathetic motoneurons in the sacral cord as well as of the somatic motoneurons in the nucleus of Onuf, innervating the pelvic floor. Respiration, therefore, is not a motor system that functions by itself, but is strongly regulated by the same systems that also control the other motor output systems.

Modulation of respiration is a prerequisite for survival of the individual and of the species. For example, respiration has to be adjusted in case of speech, strenuous exercise, laughing, crying, or sudden escape from danger. Respiratory centers in pons and medulla generate the basic respiratory rhythm or eupnea, but they cannot modulate breathing in the context of emotional challenges, for which they need input from higher brain centers. In simple terms, the prefrontal cortex integrates visual, auditory, olfactory, and somatosensory information and informs subcortical structures such as amygdala, hypothalamus, and finally the midbrain periaqueductal gray (PAG) about the results. The PAG, in turn, generates the final motor output for basic survival, such as setting the level of all cells in the brain and spinal cord. Best known in this framework is determining the level of pain perception. The PAG also controls heart rate, blood pressure, micturition, sexual behavior, vocalization, and many other basic motor output systems. Within this context, the PAG also changes the eupneic respiratory rhythm into a breathing pattern necessary for basic survival. This review examines the latest developments regarding of how the PAG controls respiration.

Respiration is not a separate motor system, but takes part in all basic survival mechanisms. This volume is the first that analyzes respiration in this framework.Respiration is one of the most basic motor activities crucial for survival of the individual. It is under total control of the central nervous system, which adjusts respiratory depth and frequency depending on the circumstances the individual finds itself. For this reason this volume not only reviews the basic control systems of respiration, located in the caudal brainstem, but also the higher brain regions, that change depth and frequency of respiration. Scientific knowledge of these systems is crucial for understanding the problems in the many patients suffering from respiratory failure.This well-established international series examines major areas of basic and clinical research within neuroscience, as well as emerging subfields.

Respiration is a motor system essential for the survival of the individual and of the species. Because of its vital significance, studies on respiration often assume that breathing takes place independent of other motor systems. However, motor systems generating vocalization, coughing, sneezing, vomiting, as well as parturition, ejaculation, and defecation encompass abdominal pressure control, which involves changes in the respiratory pattern. The mesencephalic periaqueductal gray (PAG) controls all these motor systems. It determines the level setting of the whole body by means of its very strong projections to the ventromedial medullary tegmentum, but it also controls the cell groups that generate vocalization, coughing, sneezing, vomiting, as well as respiration. For this control, the PAG maintains very strong connections with the nucleus retroambiguus, which enables it to control abdominal and intrathoracic pressure. In this same context, the PAG also runs the pelvic organs, bladder, uterus, prostate, seminal vesicles, and the distal colon and rectum via its projections to the pelvic organ stimulating center and the pelvic floor stimulating center. These cell groups, via long descending projections, have direct control of the parasympathetic motoneurons in the sacral cord as well as of the somatic motoneurons in the nucleus of Onuf, innervating the pelvic floor. Respiration, therefore, is not a motor system that functions by itself, but is strongly regulated by the same systems that also control the other motor output systems.

The somatic mutation burden in healthy white blood cells (WBCs) is not well known. Based on deep whole-genome sequencing, we estimate that approximately 450 somatic mutations accumulated in the nonrepetitive genome within the healthy blood compartment of a 115-yr-old woman. The detected mutations appear to have been harmless passenger mutations: They were enriched in noncoding, AT-rich regions that are not evolutionarily conserved, and they were depleted for genomic elements where mutations might have favorable or adverse effects on cellular fitness, such as regions with actively transcribed genes. The distribution of variant allele frequencies of these mutations suggests that the majority of the peripheral white blood cells were offspring of two related hematopoietic stem cell (HSC) clones. Moreover, telomere lengths of the WBCs were significantly shorter than telomere lengths from other tissues. Together, this suggests that the finite lifespan of HSCs, rather than somatic mutation effects, may lead to hematopoietic clonal evolution at extreme ages.

During micturition, according to the concept of Blok, Holstege, and colleagues ([1997] Neurosci. Lett. 233:109-112), the pontine micturition center (PMC) elicits bladder contraction by way of direct excitation of the parasympathetic bladder motoneurons. At the same time, the PMC elicits relaxation of the external urethral sphincter (EUS) by excitation of gamma -aminobutyric acid (GABA)-ergic interneurons in the sacral dorsal gray commissure (DGC), which, in turn, inhibit EUS motoneurons. The question is whether the inhibitory neurotransmitter glycine is also involved in this system. The present study investigated, first, whether there are glycine immunoreactive interneurons in the sacral DGC and, second, whether they receive direct PMC afferents. Finally, it was determined whether glycine and GABA are colocalized in DGC interneurons. In two adult male cats, the PMC was identified by electrical stimulation. Subsequently, the identified region was injected with the anterograde tracer WGA-HRP. Sections of sacral cord segments were processed for light and electron microscopic detection of anterograde labeling, as well as for glycine and GABA, using postembedding immunogold labeling with antibodies. In total 128 labeled PMC terminals were found in the DGC, which contained many round vesicles and asymmetric synapses. About 31.3% (40 of 128) made contact with glycine-immunoreactive dendrites. Eleven of them were selected for serial sectioning, which showed that 54.6% (6 of 11) of the glycine-immunoreactive dendrites were also immunoreactive for GABA. The results demonstrate that the PMC projects directly to dendrites of interneurons in the sacral DGC, which are immunoreactive for both glycine and GABA. These interneurons are thought to inhibit the EUS motoneurons during micturition. J. Comp. Neurol. 429:631-637, 2001. (C) 2001 Wiley-Liss, Inc.

The present retrograde tracing study in the cat describes the spinal cord projections to the periaqueductal gray (PAC), taking into account different regions of the PAG and all spinal segments. Results show that injecting different parts of the PAC leads to different laminar and segmental distributions of labeled spinal neurons. The impression was gained that at least five separate clusters of spinal neurons exist. Cluster I neurons are found in laminae I and V throughout the length of the cord and are probably involved in relaying nociceptive information to the PAG. Cluster II neurons lie in the ventrolateral part of laminae VI-VII of the C1-C4 spinal cord and were labeled by injecting the ventrolateral or lateral part of the rostrocaudal PAG or the deep tectum. Cluster III neurons are located in lamina X of the thoracic and upper lumbar cord and seem to target the PAG and the deep tectum. Cluster IV neurons are located in the medial part of laminae VI-VII of the lumbosacral cord and seem to project predominantly to the lateral and ventrolateral caudal PAC. These neurons may play a role in conveying tactile stimuli to the PAG during mating behavior. Neurons of cluster V are located in the lateral part of lamina I of L6-S2 and in laminae V-VII and X of S1-S3. They are labeled only after injections into the central portion of the lateral and ventrolateral caudal PAG and probably relay information concerning micturition and mating behavior. (C) 2000 Wiley-Liss, Inc.

The nucleus retroambiguus (NRA) consists of premotor neurons in the caudal medulla. It is involved in expiration, vomiting, vocalization, and probably reproductive behavior by means of projections to distinct motoneuronal cell groups. Because no information is available about the NRA and its efferent pathways in primates, the present study examines NRA projections to the lumbosacral spinal cord in female rhesus monkeys. To identify the NRA, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected into the lumbosacral cord in three monkeys. To study the distribution of NRA axons in the lumbosacral cord, WGA-HRP injections were made into the NRA in seven monkeys. To identify motoneuronal cell groups receiving input from the NRA, the same seven monkeys also received cholera toxin subunit b (CTb) injections into different hindlimb, axial, and pelvic floor muscles. The results show that NRA neurons projecting to the lumbosacral cord are mainly located between 1 to 4 mm caudal to the obex. They send numerous axons to external oblique and pelvic floor motoneurons, whereas projections to iliopsoas and axial motoneurons are less numerous. The projections are bilateral, but show a clear contralateral predominance in the iliopsoas, axial, and pelvic floor motoneuronal cell groups. At the ultrastructural level, NRA-terminal profiles make asymmetrical contacts with labeled and unlabeled dendrites in these motoneuronal cell groups and contain large amounts of spherical and a few dense core vesicles. It is concluded that the NRA is well developed in the monkey and that there exists a direct pathway from the NRA to lumbosacral motoneurons in this species. The finding that the NRA projects to a somewhat different set of motoneuronal cell groups compared with other species fits the concept that it is not only involved in expiration-related activities but also in species specific receptive and submissive behavior. J. Comp. Neurol. 424: 233-250, 2000. (C) 2000 Wiley-Liss, Inc.

The urinary bladder muscle and its external urethral sphincter are innervated, respectively, by the parasympathetic preganglionic motoneurons in the sacral intermediolateral cell column and somatic motoneurons in Onuf's nucleus. Neurons coordinating the activity of these muscles during micturition and urinary continence are not located in the sacral cord but in two pontine regions, the medial (M)-region (or pontine micturition center) and the lateral (L)-region (or pontine storage center). The M-region excites the bladder muscle through projections to its motoneurons and inhibits the urethral sphincter through excitatory projections to sacral cord gamma-amino butyric acid (GABA)-immunoreactive interneurons, which, in turn, inhibit urethral sphincter motoneurons. The L-region, through direct projections, excites urethral sphincter motoneurons. The present study investigated whether there are interconnections between the M- and L-regions. Anterograde tracing injections in the M-region resulted in labeled fibers to the intermediolateral cell column containing bladder motoneurons but not to Onuf's nucleus. No specific projections were found to the L-regions or to the contralateral M-region. L-region injections resulted in distinct projections to the Onuf's nucleus but not to the sacral intermediolateral cell column. No specific projections were observed either to the M-region or to the contralateral L-region. In conclusion, the M- and L-regions have direct long fiber projections, respectively, to the motoneurons of the bladder muscle and the external urethral sphincter, but they do not influence one another through direct pathways. The results strongly suggest that the M- and L-regions represent separate functional systems that act independently.

In the cat, the nucleus retroambiguus (NRA) projects to expiratory motoneurons in the brainstem and spinal cord. Recently, it has been demonstrated that the NRA sends fibers to a specific set of motoneurons in the lumbosacral cord, which pathway is thought to play a crucial role in mating behavior. The question is whether such projections exist in the hamster, because the female of this species displays a very distinctive receptive behavior. In the hamster, lumbosacral cord injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) combined with hemisection I or 2 segments rostral to injection sites in three of the five cases demonstrated retrogradely labeled neurons in the NRA at levels 1.0-2.25 mm caudal to the obex, contralateral to the injection sites. Injections of WGA-HRP into the NRA and adjoining reticular formation revealed that NRA fibers crossed the midline in the caudal medulla and descended in the contralateral lateral and ventrolateral funiculi to terminate bilaterally, but mainly contralaterally, in the motoneuronal cell groups of the abdominal wall and iliopsoas muscles. NRA. projections to levels caudal to lumbar segment 5 were virtually absent. Electron microscopic examination revealed that, of the 162 labeled NRA terminal profiles found in the ultrathin sections, 144 (89%) made monosynaptic contacts with retrogradely labeled dendrites of iliopsoas motoneurons. These NRA terminals formed asymmetrical synapses and contained spherical vesicles indicative of an excitatory function. The results indicate that, in the hamster, direct contralateral NRA projections exist to iliopsoas motoneurons. A concept is discussed in which this pathway plays a crucial role in mating behavior. (C) 1999 Wiley-Liss, Inc.