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Chapter 9 The ventromedial nucleus (VMN; nucleus of Cajal)
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Handbook of Clinical Neurology, Vol. 79 (3rd Series Vol. 1) The Human Hypothalamus: Basic and Clinical Aspects, Part I D.F. Swaab, author © 2003 Elsevier B.V. All rights reserved
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CHAPTER 9
The ventromedial nucleus (VMN; nucleus of Cajal)
The VMN is generally presumed to play a role in various sexually dimorphic functions such as female mating behavior, gonadotropin secretion, feeding and aggression, as appears both from animal experiments and from observations in patients with neoplasms and other lesions in the VMN region (Bauer, 1959; Reeves and Plum, 1969; Matsumoto and Arai, 1983; Schumacher et al., 1990; Chapter 26.3). PET studies have indicated that the human VMN may be involved in reactions to pheromones in a sexually dimorphic way. In contrast to men, women smelling an androgen-like pheromone activate this region (Savic et al., 2001). In connection with its sexually dimorphic functions, it is of great interest that the nuclear receptor steroidogenic factor 1 is essential for the formation of the VMN in mice of both sexes (Ikeda et al., 1995). The VMN is presumed to be involved in eating behavior and metabolism. Tumors in this area cause a tetrad of symptoms such as hyperphagia, episodic rage, emotional lability and intellectual deterioration (Chapter 26.3). In a boy who was obese for 1 year, the neurons of the VMN had strongly decreased in number and diffuse astrocytosis, and perivascular cuffing was observed in this area, probably due to a viral infection (Wang and Huang, 1991). In relation to its function in eating, it should be noted though that precise experimental lesions restricted to the rat VMN were neither necessary nor sufficient for hypothalamic obesity. It is presumed that damage of the nearby noradrenergic bundle or its terminals rather than the VMN itself might be responsible for obesity after less accurately placed VMN lesions (Gold, 1973). Moreover, the histaminergic system (Chapter 13) innervates the VMN and H1 receptor antagonists elicit feeding when injected into the VMN (Brown et al., 2001). Electrical stimulation of the VMN in rhesus monkey elicits penile erections (Perachio et al., 1979).
(a) Possible functions In 1904, Cajal was the first to distinguish the ventromedial nucleus (VMN; Morgane and Panksepp, 1979). The pear-shaped VMN is a noticeable structure in the tuberal region of the human hypothalamus, with a cell density that is higher in the peripheral portions than in the center of the nucleus. It features a narrow, cell-sparse zone surrounding the nucleus, which facilitates its delineation from adjoining nuclear grays (Braak and Braak, 1992; Fig. 9.1). The VMN consists of two parts, the largest of which is the ventromedial part. A smaller part lies closer to the fornix (Saper, 1990). 239
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The ventromedial nucleus is interconnected with many neighboring areas and also generates major projections to the magnocellular nuclei of the basal forebrain in primates (Jones et al., 1976). These nuclei in turn send axons to virtually all parts of the cerebral cortex and it can therefore be assumed that the ventromedial nucleus may also influence higher cortical functions and behavior through these pathways (Braak and Braak, 1992). In this respect it is also interesting that fewer VMN neurons were found in Down’s syndrome subjects (Wisniewski and Bobinski, 1991), and neuropil threads and amyloid are found in the VMN of Alzheimer patients (Fig. 9.2; Tables 29.1 and 29.2). Moreover, numerous swollen axon terminals (spheroids) were found in the VMN of autistic patients (Weidenheim et al., 2001).
Fig. 9.1. Coronal section through the human hypothalamus in the tuberal region. Lying most ventrally is the infundibular (tuberoinfundibular) nucleus (IN). Above it is the ventromedial nucleus (VM), then the dorsomedial nucleus (DM) and, highest, the dorsal hypothalamic nucleus (D). The lateral hypothalamic zone (LH), containing the tuberomamillary nucleus, is well demarcated from the medial hypothalamic zone. In the inferior portion of the lateral hypothalamic region, near the pia, is the rostral end of one of the nuclei tuberis laterales (TL). Two parts of the supraoptic nucleus (SO), the dorsolateral and the ventromedial, are shown. F, fornix; OT, optic tract; 3V, third ventricle. (From Nauta and Haymaker, 1969; Fig. 4.7, with permission.)
In rats, the size of the VMN is sexually dimorphic. The VMN is larger in male than in female rats, a difference which is determined in early neonatal development by sex hormones (Matsumoto and Arai, 1983). In addition, the number of shaft and spine synapses in the rat ventrolateral part of the VMN were also significantly greater in intact males than in intact females (Matsumoto and Arai, 1986). Estradiol, progesterone and testosterone induce changes in the distribution and binding of oxytocin receptors in the rat VMN (Schumacher et al., 1990; Johnson et al., 1991). No human data of this kind are available as yet, but we did find more nuclear androgen receptor staining in the male VMN than in the female VMN (Fernández-Guasti et al., 2000; Figs. 6.2 and 6.4). Women showed a stronger estrogen receptor (ER)- staining in the VMN, and men a stronger ER- staining (Kruijver et al., 2002, 2003; Table 6.1 and 6.2). Animal experiments have shown projections from the VMN to the cerebellum that may be involved in motor activity and visceromotor functions (Haines et al., 1997).
(b) Chemoarchitecture The VMN contains a dense network of somatostatin fibers. While somatostatin-containing neurons have been reported to be present in childhood (Bouras et al., 1986, 1987; Najimi et al., 1989), the somatostatinergic network of the VMN is considered to come mainly from the central subnucleus of the amygdala (Mufson et al., 1988). We found somatostatinergic fibers but no positive cell bodies in the adult human VMN (Fig. 12.2). A similar somatostatinergic innervation of the VMN as observed after staining for somatostatin is found following staining by Alz-50 (Fig. 9.2) because of the cross-reaction of this antibody with a somatostatin-like compound (Van de Nes et al., 1994). Both antibodies, i.e. the one against somatostatin and the one against hyperphosphorylated tau (Alz-50), can be used to delineate the VMN in thin paraffin sections, also in non-Alzheimer patients. The density of this somatostatinergic amygdalofugal projection does not clearly change in Alzheimer’s disease (Mufson et al., 1988; Van de Nes et al., 1993), in spite of the presence in the VMN of senile plaques (Rudelli et al., 1984), /A4 staining Congo-negative amorphic plaques (Van de Nes et al., 1997) and dystrophic neurites in these patients. In addition to somatostatin fibers (Van de Nes et al., 1994), thyrotropin-releasing hormone (TRH) fibers (Fliers et al., 1994; Fig. 8.38b), luteinizing hormone-releasing hormone (LHRH) cells and fibers are present in the VMN (Stopa et al., 1991; Dudas and Merchenthaler, 2002). LHRH is often colocalized with delta sleep-inducing peptide (Vallet et al., 1990). There are also delta sleep-inducing fibers (Najimi et al., 2001b)
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Fig. 9.2. (a and b) Alzheimer patient, 90 years of age. (a) A dense pattern of somatostatin-reactive beaded fibers (f) was found in the ventromedial nucleus (VMH) following incubation with anti-somatostatin SOMAAR. (b) In addition to the beaded fibers containing an unknown somatostatin-like compound, Alz-50 also stained dystrophic neurites (D) and perikarya (P) representing AD pathology. (c and d) Alzheimer patient, 40 years of age. Adjacent sections taken from the ventral part of the bed nucleus of the stria terminalis (BSTv) stained with the somatostatin antiserum K107 and Alz-50, respectively. Two senile plaque-like structures (1,2) were present. (c) Staining with anti-somatostatin15-28 K107 showed a distinct pattern of beaded fibers (f) and some cell bodies (p). (d) On the other hand, Alz-50 showed the pattern of short, thickened non-beaded dystrophic neurites (D), but not that of beaded fibers. Note that the cell body present in senile plaque-like structure 1 (p!) stained with Alz-50 (d) was also detected by K107 (c). Bars = 100 m. (From Van de Nes et al., 1994; Fig. 4, with permission.)
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and hypocretin fibers (Moore et al., 2001) present in the VMN. Moreover, neurons containing substance-P (Mai et al., 1986; Chawla et al., 1997), preproenkephalin, preprodynorphin (Abe et al., 1988; Sukhov et al., 1995), brain-derived neurotrophic factor (Murer et al., 1999) and cocaine- and amphetamine-regulated transcript (CART; Charnay et al., 1999) are found in the VMN. Also the neurokinin-1 receptor by which substance-P exerts its actions is present in the VMN (Caberlotto et al., 2003). In addition to CART, the neuropeptide-Y5 receptor in the VMN may be related to its function in feeding behavior (Jacques et al., 1998). Oxytocin binding was demonstrated in the human VMN by autoradiography. The binding did not show any correlation with age or sex (Loup et al., 1991). High densities of the angiotensin IV receptor were observed in the VMN (Chai et al., 2000). It is presumed to be involved in memory processes and also present in many other parts of the human brain, but it is not clear what the function of this receptor may be in the VMN. Vasoactive intestinal peptide (VIP) receptors (Sarrieau et al., 1994), benzodiazepinebinding sites (Najimi et al., 1999, 2001) and NADPH diaphorase (Sangruchi and Kowall, 1991) have also been found in the VMN. Some growth hormone-releasing hormone-containing neurons have been observed in the ventral part of the VMN (Ciofi et al., 1988), which was confirmed by us. Both VMN and PVN contain a higher concentration of TRH, but not of LHRH, on the left-hand side (Borson-Chazot et al., 1986), which proves the necessity of taking the possibility of laterality into consideration in studies on the human hypothalamus, too (see Chapter 1.4a). (c) Sexual behavior The ventromedial nucleus has been the target of German neurosurgical stereotactic lesions (Roeder and Müller, 1969; Müller et al., 1973; Orthner, 1982). This operation was motivated by Dörner’s observations in the rat on sexual activity, experiments that did not, however, involve tests for sexual orientation. In spite of this important point, Müller et al. (1973) operated on a group of 22 male patients, 20 of whom were called “sexually deviant”, one of whom suffered from “neurotic pseudo-homosexuality” and one from “intractable addiction to alcohol and drugs”. The group of “sexual deviants” contained 14 cases of “pedo- or ephebophilic homosexuality” and 6 cases with
“disturbances of heterosexual behavior” (hypersexuality, exhibitionism, pedophilia). In 12 homosexual patients and patients with “morbid” heterosexuality, the lesion was restricted to the right-hand-side VMN. In one patient of this group, a bilateral lesion was made. According to this paper, 15 of the “sexual deviants” obtained a “good” result, and 3 patients a “fair” result. Only one case was classified as “poor”. The authors claimed that the VMN lesions caused changes both in sexual orientation and sexual drive. Following the operation “a vivid desire for full heterosexual contacts” occurred in 6 homosexual patients according to the authors. In one homosexual patient all interest in sexual activity completely vanished following bilateral VMN lesion. It should be said, however, that the amazingly superficial evaluation of the results of this very controversial operation, which, from the start, was not based on experimental data concerning the possible role of the VMN in sexual orientation, raised serious questions on both its ethical aspects and on the scientific value of these observations (see also Schorsch and Schmidt, 1979). These doubts are reinforced by a later paper (Dieckmann et al., 1988) stating that sexual orientation following unilateral stereotactic lesioning of the VMN in 14 cases treated for aggressive sexual delinquency did not alter, although sexual drive was diminished. A common side effect of the operation was an increased appetite, which is in agreement with the function this region has in feeding (see earlier and Chapter 26.3). Morphometric determinations of volume and cell number in relation to sex or sexual orientation of the human VMN have, so far, not been performed. Recently we investigated whether the function of VMN neurons depends on sex or age, using the size of the Golgi apparatus relative to cell size as a measure of neuronal metabolic activity. The VMN neurons appeared to be more active in young women than in young men and more active in elderly men than in young men. In addition, the Golgi apparatus/cell size ratio correlated significantly with age in men but not in women. These observations suggest an inhibitory role of androgens on the neuronal metabolic activity of human VMN neurons (Ishunina et al., 2001). This possibility is in agreement with the observations in VMN neurons, which appeared to have more androgen receptor staining in young men than in young women (Fernández-Guasti et al., 2000; Figs. 6.2 and 6.4). The exact role of the VMN in human sexual behavior still has to be established.
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1 2 3 4 5 6 7 8 9 101 1 2 3 4 5 6 7 8 9 201 1 2 3 4 5 6 7 8 9 301 1 2 3 4 5 6 7 8 9 401 1 2 3 4 5 6 7 8 911
CHAPTER 9
The ventromedial nucleus (VMN; nucleus of Cajal)
The VMN is generally presumed to play a role in various sexually dimorphic functions such as female mating behavior, gonadotropin secretion, feeding and aggression, as appears both from animal experiments and from observations in patients with neoplasms and other lesions in the VMN region (Bauer, 1959; Reeves and Plum, 1969; Matsumoto and Arai, 1983; Schumacher et al., 1990; Chapter 26.3). PET studies have indicated that the human VMN may be involved in reactions to pheromones in a sexually dimorphic way. In contrast to men, women smelling an androgen-like pheromone activate this region (Savic et al., 2001). In connection with its sexually dimorphic functions, it is of great interest that the nuclear receptor steroidogenic factor 1 is essential for the formation of the VMN in mice of both sexes (Ikeda et al., 1995). The VMN is presumed to be involved in eating behavior and metabolism. Tumors in this area cause a tetrad of symptoms such as hyperphagia, episodic rage, emotional lability and intellectual deterioration (Chapter 26.3). In a boy who was obese for 1 year, the neurons of the VMN had strongly decreased in number and diffuse astrocytosis, and perivascular cuffing was observed in this area, probably due to a viral infection (Wang and Huang, 1991). In relation to its function in eating, it should be noted though that precise experimental lesions restricted to the rat VMN were neither necessary nor sufficient for hypothalamic obesity. It is presumed that damage of the nearby noradrenergic bundle or its terminals rather than the VMN itself might be responsible for obesity after less accurately placed VMN lesions (Gold, 1973). Moreover, the histaminergic system (Chapter 13) innervates the VMN and H1 receptor antagonists elicit feeding when injected into the VMN (Brown et al., 2001). Electrical stimulation of the VMN in rhesus monkey elicits penile erections (Perachio et al., 1979).
(a) Possible functions In 1904, Cajal was the first to distinguish the ventromedial nucleus (VMN; Morgane and Panksepp, 1979). The pear-shaped VMN is a noticeable structure in the tuberal region of the human hypothalamus, with a cell density that is higher in the peripheral portions than in the center of the nucleus. It features a narrow, cell-sparse zone surrounding the nucleus, which facilitates its delineation from adjoining nuclear grays (Braak and Braak, 1992; Fig. 9.1). The VMN consists of two parts, the largest of which is the ventromedial part. A smaller part lies closer to the fornix (Saper, 1990). 239
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The ventromedial nucleus is interconnected with many neighboring areas and also generates major projections to the magnocellular nuclei of the basal forebrain in primates (Jones et al., 1976). These nuclei in turn send axons to virtually all parts of the cerebral cortex and it can therefore be assumed that the ventromedial nucleus may also influence higher cortical functions and behavior through these pathways (Braak and Braak, 1992). In this respect it is also interesting that fewer VMN neurons were found in Down’s syndrome subjects (Wisniewski and Bobinski, 1991), and neuropil threads and amyloid are found in the VMN of Alzheimer patients (Fig. 9.2; Tables 29.1 and 29.2). Moreover, numerous swollen axon terminals (spheroids) were found in the VMN of autistic patients (Weidenheim et al., 2001).
Fig. 9.1. Coronal section through the human hypothalamus in the tuberal region. Lying most ventrally is the infundibular (tuberoinfundibular) nucleus (IN). Above it is the ventromedial nucleus (VM), then the dorsomedial nucleus (DM) and, highest, the dorsal hypothalamic nucleus (D). The lateral hypothalamic zone (LH), containing the tuberomamillary nucleus, is well demarcated from the medial hypothalamic zone. In the inferior portion of the lateral hypothalamic region, near the pia, is the rostral end of one of the nuclei tuberis laterales (TL). Two parts of the supraoptic nucleus (SO), the dorsolateral and the ventromedial, are shown. F, fornix; OT, optic tract; 3V, third ventricle. (From Nauta and Haymaker, 1969; Fig. 4.7, with permission.)
In rats, the size of the VMN is sexually dimorphic. The VMN is larger in male than in female rats, a difference which is determined in early neonatal development by sex hormones (Matsumoto and Arai, 1983). In addition, the number of shaft and spine synapses in the rat ventrolateral part of the VMN were also significantly greater in intact males than in intact females (Matsumoto and Arai, 1986). Estradiol, progesterone and testosterone induce changes in the distribution and binding of oxytocin receptors in the rat VMN (Schumacher et al., 1990; Johnson et al., 1991). No human data of this kind are available as yet, but we did find more nuclear androgen receptor staining in the male VMN than in the female VMN (Fernández-Guasti et al., 2000; Figs. 6.2 and 6.4). Women showed a stronger estrogen receptor (ER)- staining in the VMN, and men a stronger ER- staining (Kruijver et al., 2002, 2003; Table 6.1 and 6.2). Animal experiments have shown projections from the VMN to the cerebellum that may be involved in motor activity and visceromotor functions (Haines et al., 1997).
(b) Chemoarchitecture The VMN contains a dense network of somatostatin fibers. While somatostatin-containing neurons have been reported to be present in childhood (Bouras et al., 1986, 1987; Najimi et al., 1989), the somatostatinergic network of the VMN is considered to come mainly from the central subnucleus of the amygdala (Mufson et al., 1988). We found somatostatinergic fibers but no positive cell bodies in the adult human VMN (Fig. 12.2). A similar somatostatinergic innervation of the VMN as observed after staining for somatostatin is found following staining by Alz-50 (Fig. 9.2) because of the cross-reaction of this antibody with a somatostatin-like compound (Van de Nes et al., 1994). Both antibodies, i.e. the one against somatostatin and the one against hyperphosphorylated tau (Alz-50), can be used to delineate the VMN in thin paraffin sections, also in non-Alzheimer patients. The density of this somatostatinergic amygdalofugal projection does not clearly change in Alzheimer’s disease (Mufson et al., 1988; Van de Nes et al., 1993), in spite of the presence in the VMN of senile plaques (Rudelli et al., 1984), /A4 staining Congo-negative amorphic plaques (Van de Nes et al., 1997) and dystrophic neurites in these patients. In addition to somatostatin fibers (Van de Nes et al., 1994), thyrotropin-releasing hormone (TRH) fibers (Fliers et al., 1994; Fig. 8.38b), luteinizing hormone-releasing hormone (LHRH) cells and fibers are present in the VMN (Stopa et al., 1991; Dudas and Merchenthaler, 2002). LHRH is often colocalized with delta sleep-inducing peptide (Vallet et al., 1990). There are also delta sleep-inducing fibers (Najimi et al., 2001b)
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Fig. 9.2. (a and b) Alzheimer patient, 90 years of age. (a) A dense pattern of somatostatin-reactive beaded fibers (f) was found in the ventromedial nucleus (VMH) following incubation with anti-somatostatin SOMAAR. (b) In addition to the beaded fibers containing an unknown somatostatin-like compound, Alz-50 also stained dystrophic neurites (D) and perikarya (P) representing AD pathology. (c and d) Alzheimer patient, 40 years of age. Adjacent sections taken from the ventral part of the bed nucleus of the stria terminalis (BSTv) stained with the somatostatin antiserum K107 and Alz-50, respectively. Two senile plaque-like structures (1,2) were present. (c) Staining with anti-somatostatin15-28 K107 showed a distinct pattern of beaded fibers (f) and some cell bodies (p). (d) On the other hand, Alz-50 showed the pattern of short, thickened non-beaded dystrophic neurites (D), but not that of beaded fibers. Note that the cell body present in senile plaque-like structure 1 (p!) stained with Alz-50 (d) was also detected by K107 (c). Bars = 100 m. (From Van de Nes et al., 1994; Fig. 4, with permission.)
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and hypocretin fibers (Moore et al., 2001) present in the VMN. Moreover, neurons containing substance-P (Mai et al., 1986; Chawla et al., 1997), preproenkephalin, preprodynorphin (Abe et al., 1988; Sukhov et al., 1995), brain-derived neurotrophic factor (Murer et al., 1999) and cocaine- and amphetamine-regulated transcript (CART; Charnay et al., 1999) are found in the VMN. Also the neurokinin-1 receptor by which substance-P exerts its actions is present in the VMN (Caberlotto et al., 2003). In addition to CART, the neuropeptide-Y5 receptor in the VMN may be related to its function in feeding behavior (Jacques et al., 1998). Oxytocin binding was demonstrated in the human VMN by autoradiography. The binding did not show any correlation with age or sex (Loup et al., 1991). High densities of the angiotensin IV receptor were observed in the VMN (Chai et al., 2000). It is presumed to be involved in memory processes and also present in many other parts of the human brain, but it is not clear what the function of this receptor may be in the VMN. Vasoactive intestinal peptide (VIP) receptors (Sarrieau et al., 1994), benzodiazepinebinding sites (Najimi et al., 1999, 2001) and NADPH diaphorase (Sangruchi and Kowall, 1991) have also been found in the VMN. Some growth hormone-releasing hormone-containing neurons have been observed in the ventral part of the VMN (Ciofi et al., 1988), which was confirmed by us. Both VMN and PVN contain a higher concentration of TRH, but not of LHRH, on the left-hand side (Borson-Chazot et al., 1986), which proves the necessity of taking the possibility of laterality into consideration in studies on the human hypothalamus, too (see Chapter 1.4a). (c) Sexual behavior The ventromedial nucleus has been the target of German neurosurgical stereotactic lesions (Roeder and Müller, 1969; Müller et al., 1973; Orthner, 1982). This operation was motivated by Dörner’s observations in the rat on sexual activity, experiments that did not, however, involve tests for sexual orientation. In spite of this important point, Müller et al. (1973) operated on a group of 22 male patients, 20 of whom were called “sexually deviant”, one of whom suffered from “neurotic pseudo-homosexuality” and one from “intractable addiction to alcohol and drugs”. The group of “sexual deviants” contained 14 cases of “pedo- or ephebophilic homosexuality” and 6 cases with
“disturbances of heterosexual behavior” (hypersexuality, exhibitionism, pedophilia). In 12 homosexual patients and patients with “morbid” heterosexuality, the lesion was restricted to the right-hand-side VMN. In one patient of this group, a bilateral lesion was made. According to this paper, 15 of the “sexual deviants” obtained a “good” result, and 3 patients a “fair” result. Only one case was classified as “poor”. The authors claimed that the VMN lesions caused changes both in sexual orientation and sexual drive. Following the operation “a vivid desire for full heterosexual contacts” occurred in 6 homosexual patients according to the authors. In one homosexual patient all interest in sexual activity completely vanished following bilateral VMN lesion. It should be said, however, that the amazingly superficial evaluation of the results of this very controversial operation, which, from the start, was not based on experimental data concerning the possible role of the VMN in sexual orientation, raised serious questions on both its ethical aspects and on the scientific value of these observations (see also Schorsch and Schmidt, 1979). These doubts are reinforced by a later paper (Dieckmann et al., 1988) stating that sexual orientation following unilateral stereotactic lesioning of the VMN in 14 cases treated for aggressive sexual delinquency did not alter, although sexual drive was diminished. A common side effect of the operation was an increased appetite, which is in agreement with the function this region has in feeding (see earlier and Chapter 26.3). Morphometric determinations of volume and cell number in relation to sex or sexual orientation of the human VMN have, so far, not been performed. Recently we investigated whether the function of VMN neurons depends on sex or age, using the size of the Golgi apparatus relative to cell size as a measure of neuronal metabolic activity. The VMN neurons appeared to be more active in young women than in young men and more active in elderly men than in young men. In addition, the Golgi apparatus/cell size ratio correlated significantly with age in men but not in women. These observations suggest an inhibitory role of androgens on the neuronal metabolic activity of human VMN neurons (Ishunina et al., 2001). This possibility is in agreement with the observations in VMN neurons, which appeared to have more androgen receptor staining in young men than in young women (Fernández-Guasti et al., 2000; Figs. 6.2 and 6.4). The exact role of the VMN in human sexual behavior still has to be established.