R E V I E W Eur J Anat, 6 (1): 47-57 (2002) in the cat diencephalon: II. Hypohalamus

R. Coveñas 1, M. de León 1, M. Belda 1,P. Marcos 2, J.A. Narváez 3, J.A. Aguirre 3, G. Tramu4 and S. González-Barón 3

1 - Instituto de Neurociencias de Castilla y León (INCYL), Laboratorio de Neuroanatomía de los Sistemas Pep- tidérgicos, Salamanca, Spain 2- Un i v e r sidad de Castilla-La Mancha, Facultad de Medicina, De p a r tamento de Ciencias de la Salud, Al b a c e t e , Sp a i n 3 - Universidad de Málaga, Facultad de Medicina, Departamento de Fisiología, Málaga, Spain 4- Un i v e r sité de Bordeaux I, Laboratoire de Neurocytochimie Fon c t i o n e l l e , C. N . R . S . , U.R.A. 339, Tal e n c e , Fra n c e

SUMMARY INTRODUCTION

We have reviewed the distribution and func- The hypothalamus is part of the dien- tions of neuropeptides in the cat hypothalamus. cephalon. Along the animal scale, it is one of the Our review focuses in the cat hypothalamus on most preserved zones of the central nervous sys- the following points: 1) the distribution and tem (CNS). This shows that the findings coexistence of neuropeptides; 2) the anatomical observed in the hypothalamus of animals used relationships among the different neuropeptides; for experimental research can be extrapolated to 3) the peptidergic pathways (afferences and humans. It is a centre that is connected with the efferences); 4) comparison of the distribution of limbic system, which is involved in autonomic neuropeptides in the mammalian hypothalamus; and homeostasis functions. In this sense, the and 5) the physiological functions of neuropep- hypothalamus has been considered as the “great tides. Although at present the distribution of ganglion” of the autonomic nervous system, many neuropeptides in the hypothalamus of the since it integrates autonomic function at central cat is known, there is little information about level (Kupfermann, 1981). In addition, the hypo- other aspects of neuropeptides in the same dien- thalamus has been implicated in a large number cephalic region. Thus, in order to know more of very important functions, such as drinking, the distribution and functions of neuropeptides food intake, thermoregulation, neuroendocrine in the cat hypothalamus in detail, in the future control of the hypophysis (by means of releasing appropriate methodologies must be applied in and inhibiting factors), defence (immunoregula- order to determine, for example, the distribution tion), circadian rhythms, blood pressure, emo- of the receptors, the distribution of tions, stress, reproduction, aggressive behaviour, neuropeptidases, the peptidergic synaptic con- sexual orientation, as well as in the production nections, the coexistence of neuropeptides and of neurohormones (, ,…) the physiological actions of the neuropeptides in (see Swaab, 1997). In sum, it is a small centre in the cat hypothalamus. the CNS, but is involved in very important func- tions. Thus, it has been indicated that lesions in Key Words: Neuropeptides – Hypothalamus – the hypothalamus could elicit several diseases/ Diencephalon – Cat alterations: depression, anorexia nervosa, bulim-

Correspondence to: Dr. R. Coveñas. Instituto de Neurociencias de Castilla y León (INCYL), Laboratorio de Neu- roanatomía de los Sistemas Peptidérgicos, Facultad de Medicina, c/ Alfonso X El Sabio Submitted: November 23, 2001 s/n, 37007-Salamanca, Spain. Phone: 923-294400 ext. 1856; Fax: 923-294549. E-mail: Accepted: February 15, 2002 [email protected]

47 R. Coveñas, M. de León, M. Belda, P. Marcos, J.A. Narváez, J.A. Aguirre, G. Tramu and S. González-Barón

ia, changes in sexual orientation, diabetes neuropeptides studied showed a widespread dis- insipidus, Cushing’s disease, alterations in sleep tribution throughout the cat hypothalamus. At and temperature, sudden-infant-death-syndrome, present, the distribution of thirteen neuropep- Wolfram’s syndrome, Prader-Willi’s syndrome, tides has been fully studied in the cat hypothal- malignant syndrome, aggressive behaviour, alter- amus. In this sense, the distribution has been ations in the emotions, as well as alterations in studied of methionine- (Micevych the release of hormones into the hypophysis. and Elde, 1980; Coveñas et al., 1988; Yoshimoto M o re o v e r, hypothalamic modifications have et al., 1989), (Burgos et al., 1988; been reported in neurodegenerative diseases, Yoshimoto et al., 1989), (Hu et al., such as Alzheimer’s, Parkinson’s, Huntington’s, 1988; Yoshimoto et al., 1989; de León et al., multiple sclerosis,… (see Swaab, 1997). 1991a), -28 (1-12) (de León et al., Moreover, the hypothalamus is connected to 1991b), (Ueda et al., 1986; Hu et a large number of other CNS centres (Carpenter, al., 1987; Léger et al., 1987), endorphin (1-27) 1980; Saper, 1990). Thus, the hypothalamus (Coveñas et al., 1996a), -endorphin (1-31) receives inputs from the hippocampus, the (Micevych and Elde, 1982), -melanocyte-stimu- amygdala, the cerebral cortex, the retina, the lating hormone (Micevych and Elde, 1982; Rao et spinal cord, the ventrolateral medulla, the nucle- al., 1987; Coveñas et al., 1996b), adrenocorti- us of the solitary tract, the parabrachial nucleus, cotropin hormone (Kitahama et al., 1984, 1986; the locus coeruleus and the raphe, whereas Rao et al., 1986; Coveñas et al., 1996c), luteiniz- hypothalamic neurons send projections into the ing horm o n e - releasing hormone (Barry and amygdala, the periaqueductal gray, the reticular Dubois, 1975; Belda et al., 2000), formation of the mesencephalon, the thalamus, (Velasco et al., 1993), delta sleep-inducing pep- the hypophysis, the nucleus of the solitary tract, tide (Charnay et al., 1990) and vasoactive intesti- the parabrachial nucleus, the locus coeruleus, nal polypeptide (Obata-Tsuto et al., 1983, 1984) the nucleus ambiguus, the area postrema, the (see Figure 1). Also, there are very few data con- spinal cord, the nucleus accumbens and the cerning the distribution of another seven neu- median eminence. ropeptides (not shown in Table 1): , cor- As mentioned in a previous article (Part I: t i c o t ro p i n - releasing factor, somatostatin-14, Thalamus) (Coveñas et al., 2001), a large number vasopressin, oxytocin, octapep- of neuroanatomical, neurophysiological, neu- tide and thyro t ro p i n - releasing horm o n e ropharmacological and behavioural data have (Micevych and Elde, 1980; Kawata et al., 1982; been reported for the cat. However, until the Graybiel and Elde, 1983; Wahle and Albus, 1985; eighties research on the distribution of neu- Caverson et al., 1987; Yoshimoto et al., 1989). ropeptides in the cat diencephalon has received Thus, immunoreactive cell bodies containing little attention. Here, our aim is to review, in the galanin were observed in the hypothalamus ven- cat, currently available morphological and phys- tromedialis and in the regio praeoptica; those iological data concerning neuropeptides that containing corticotropin-releasing factor in the have emerged over the past eighteen-twenty hypothalamus posterior, hypothalamus lateralis, years concerning one of the most important nucleus supraopticus, nucleus periventricularis functional areas of the CNS: the hypothalamus. hypothalami and in the regio praeoptica; those We also compare the results obtained on neu- containing thyrotropin-releasing hormone in the ropeptides in the cat hypothalamus with those regio praeoptica and around the anterior hypo- found in the same diencephalic area of others thalamic nucleus; those containing vasopressin mammalian species (e.g., rat, monkey, human). in the nuclei periventricularis hypothalami, suprachiasmaticus and supraopticus, hypothala- mus lateralis and in the regio praeoptica; those NEUROPEPTIDES IN THE CAT HYPOTHALAMUS containing oxytocin in the hypothalamus dorso- medialis, hypothalamus lateralis, regio praeopti- The hypothalamus can be divided according ca and in the nuclei periventricularis hypothala- to topographic criteria into several re g i o n s mi and supraopticus, and those containing (Kupfermann, 1981): mamillar, periventricular, cholecystokinin in the nuclei arcuatus and medial, lateral and preoptic (see Table 1). In this periventricularis hypothalami, as well as in the review, we use the terminology of the hypothal- hypothalamus lateralis. In addition, somatostatin- amic nuclei according to the stereotaxic atlas of 14-, galanin-, corticotropin-releasing factor-, and the diencephalon of the cat carried out by Jasper t h y ro t ro p i n - releasing horm o n e - i m m u n o re a c t i v e and Ajmone-Marsan (1966). Table 1 shows the fibers were observed in the hypothalamus pos- distribution of fibers and cell bodies containing terior, whereas fibers containing vasopressin and neuropeptides in the cat hypothalamus, using oxytocin have been described in the nuclei immunocytochemical methods. In general, as periventricularis hypothalami and supraopticus. can be seen in the table, the immunoreactive Furthermore, using a microdissection tech- structures (fibers and cell bodies) containing the nique combined with radioimmunoassay the

48 Neuropeptides in the cat diencephalon: II. Hypothalamus

Table 1.- Distribution of neuropeptides in the nuclei of the cat hypothalamus.

MET-E SP NT SOM NPY b-END a -MSH ACTH LH-RH NKA b-END DSIP VIP (1-31) F CB F CB F CB F CB F CB F CB F CB F CB F CB F CB F CB F CB F CB

MAMILLAR REGION Ml ++-+----+-+-+---+-++ +- Mm -+ -+----+-+- RIA + - - - + - - - + - PERIVENTRICULAR REGION Arc ++ +++++-++++ RIA +++++++-++ ++++ MEDIAL REGION aHd ++ +++++++-+- RIA +++-+-++-- +-- Ha -+ +-+--++-+- RIA +-+-+++- ++- Hdm -+ --+-+++-+- +++---+++- -- Hp ++ +++++++-+- RIA +-+---++------Hvm ++ +++++-++++ RIA +++++-+++- +--- PVH -+ +++--++-+- RIA +-+-+-++-- +-++ Sch ++ +++++++-+- RIA +-+-+-+--- ++++ LATERAL REGION HL ++ +++++-+-+- +++-+-++-- +-++ So ++ +++++++-+- RIA +-+-+++--- ++++ PREOPTIC REGION RPO ++ -+-++++-+- RIA +-+-+++--- ++ TRACTS Fx +- +------+- +-+-+----- +- MFB -- +------RIA + - - - + - - - - - TMT +- --+---+--- RIA --+-+------

ACTH : adrenocorticotropin hormone (18-39); DSIP: delta sleep-inducing ; b-END: b-endorphin (1-27); b-END (1-31): b-endorphin (1-31); LH-RH : luteinizing hormone-releasing hormone; MET-E: methionine-enkephalin; a -MSH: a -melanocyte-stimulating hormone; NKA: neurokinin A; NPY: neuropeptide Y; NT: neurotensin; RIA : radioimmunoassay; SOM: somatostatin-28 (1-12); SP: substance P; VIP: vasoac- tive intestinal peptide. For the nomenclature of the hypothalamic nuclei, see list of abbreviations. CB: immunoreactive cell bodies; F: fibres; +: presence; -: ausence; no sign : no studied. concentration of -melanocyte-stimulating hor- (thirteen) was observed in fibers and/or cell mone has been measured in several regions of bodies was the nucleus arcuatus, whereas in the cat hypothalamus (O’donohue et al., 1979), other nuclei, such as the hypothalamus ventro- and the concentration of neurotensin and medialis, periventricularis hypothalami, kassinin in the whole cat hypothalamus has also suprachiasmaticus, hypothalamus lateralis and been measured (Goedert and Emson, 1983; supraopticus, twelve neuropeptides were seen in Hunter et al., 1985). Finally, the localization of each of them. -, and neurokinin-1 binding sites has been demonstrated in the cat hypothalamus (Guidobono et al., 1987; Yao et al., 1999). COEXISTENCE OF NEUROPEPTIDES IN THE CAT Except for -endorphin (1-31) and vasoactive HYPOTHALAMUS intestinal polypeptide, the other neuropeptides studied (eleven) in the cat hypothalamus As indicated in the previous chapter, the showed a widespread distribution in this dien- presence of at least seven neuropeptides in each cephalic region (see Table 2). Thus, in all the of the hypothalamic nuclei has been reported. hypothalamic nuclei of the cat, immunoreactive This indicates a possible interaction among such fibers and/or cell bodies containing methionine- neuropeptides and an elaborate modulation of enkephalin, neuropeptide Y, -endorphin (1-27) functions in which the hypothalamic nuclei are and -melanocyte-stimulating hormone were involved. In addition, the localization of several observed, whereas substance P-, luteinizing hor- different neuropeptides in the same hypothalam- mone-releasing hormone- and neurokinin A- ic nuclei indicates the possibility that two or immunoreactive fibers and/or cell bodies were more of them may coexist in the same neuron. found in twelve of the thirteen hypothalamic This research line must be developed in the nuclei and in eleven of the thirteen nuclei fibers future, since only a few data showing the coex- and/or cell bodies containing neuro t e n s i n , istence of neuropeptides in the neurons of the somatostatin-28 (1-12), adrenocorticotropin hor- cat hypothalamus are available. Thus, Micevych mone and delta sleep-inducing peptide. and Elde (1982) reported that -melanocyte-stim- Finally, in all the hypothalamic nuclei of the ulating hormone and -endorphin coexist in cat, seven or more neuropeptides were neurons located in the cat nucleus arcuatus, described (Table 3). The hypothalamic nucleus whereas the coexistence of delta sleep-inducing in which the highest number of neuropeptides peptide and luteinizing hormone-releasing hor-

49 R. Coveñas,M. de León, M. Belda, P. Marcos, J.A. Narváez, J.A. Aguirre, G. Tramu and S. González-Barón

mone has also been described in the cat hypo- thalamus (Charnay et al., 1990). Moreover, the possible coexistence of neurotensin and - melanocyte-stimulating hormone can be suggest- ed for cell bodies located in the nucleus arcua- tus because the morphological characteristics of perikarya containing - m e l a n o c y t e - s t i m u l a t i n g hormone are similar to the neuronal population containing neurotensin (de León et al., 1991a; Coveñas et al., 1996b). By contrast, in the cat nucleus arcuatus, the existence of cell bodies containing substance P, neuropeptide Y and neu- rotensin has been described (Léger et al., 1987; Bu r gos et al., 1988; de León et al., 1991a). How- ev e r , although there is an identical localization of im m u n o r eactive perikarya containing such neu- ropeptides and -endorphin (1-27)-immunorea c - tive cell bodies in the nucleus arcuatus of the cat (Coveñas et al., 1996a), the possible coexistence of -endorphin (1-27) with some of the three above-mentioned neuropeptides can not be sug- gested in this nucleus since the morphological characteristics of -endorphin (1-27)-immunore- active perikarya are quite diffe r ent from those shown by the neuronal populations containing substance P, neuropeptide Y or neurot e n s i n .

ANATOMICAL RELATIONSHIPS AMONG NEUROPEP- TIDES IN THE CAT HYPOTHALAMUS

T h e re is a close anatomical re l a t i o n s h i p among the neuropeptides in the cat hypothala- mus, since as shown in Table 4, the lowest level found was 76.92%. This value indicates that in 76.92% of the cat hypothalamic nuclei, for exam- ple, substance P-immunoreactive fibers and/or cell bodies and neuro t e n s i n - i m m u n o re a c t i v e fibers and/or cell bodies have been observed. The percentage was calculated taking the total number of the cat hypothalamic nuclei (thirteen) as 100%. In addition, this Table also indicates that in all the hypothalamic nuclei of the cat (100%) methionine-enkephalin and neuropeptide Y- im m u n o r eactive structures were observed, and this was also the case for methionine-enkephalin and -endorphin, methionine-enkephalin and - melanocyte-stimulating hormone, neurop e p t i d e Y and -endorphin, neuropeptide Y and - melanocyte-stimulating hormone and -e n d o r - phin and -melanocyte-stimulating hormo n e .

PEP T I D E R G I C PATH W AYS IN TH E CA T HY P O T H A L A M U S

Fig. 1.- Neuropeptides in the cat hypothalamus. A: Immunoreac- Yoshimoto et al. (1989) have reported the fol- tive fibers and cell bodies (arrowheads) containing adrenocorti- cotropin hormone (ACTH) in the nucleus arcuatus (Arc). D: dor- lowing afferent peptidergic pathways to the cat sal; M: medial; V: ventricle. x 125. B: Immunoreactive cell bodies posterior hypothalamus: (arrowheads) containing -endorphin (1-27) (END) in the nucleus arcuatus (Arc). D: dorsal; M: Medial; V: ventricle. x 160. C: Neu- rokinin A (NKA)-immunoreactive fibers and cell bodies (arrow- 1. Fr om the medial preoptic area, medial heads) located around the fornix (Fx). D: dorsal; M: medial. x 100. amygdaloid nucleus and nucleus of the stria D : I m m u n o reactive cell bodies (arrowheads) containing - te r minalis to the ventrol a t e r a l / d o r s o l a t e r a l melanocyte-stimulating hormone (MSH) in the area hypothalamica dorsalis (aHd). D: dorsal; M: medial; V: ventricle. x 100. posterior hypothalamus: containing galanin.

50 Neuropeptides in the cat diencephalon: II. Hypothalamus

Table 2.- Percentanges of hypothalamic nuclei of the cat that contain a neuropeptide located in fibers and/or cell bodies (F and/or CB), in fibers (F) or in cell bodies (CB). For a nomenclature of the neuropeptides, see Table 1. The total number of hypothalamic nuclei is: 13.

Table 3.- Presence of neuropeptides in the cat hypothalamic Table 4.- Anatomical relationships between the neuropeptides in nuclei and tracts. the cat hypothalamus.

Arc 13/13 100% % Hvm, PVH, Sch, HL, So 12/13 92.30% MET-E/NPY; MET-E/ b-END; MET-E/a -MSH Ha, RPO 11/12 91.66 % NPY/b-END; NPY/a -MSH; b-END/a -MSH 100 aHd 11/13 84.61% Hp 10/13 76.92 % MET-E/SP; MET-E/LH-RH; MET-E/NKA; Hdm 9/12 75% SP/NPY; SP/b-END; SP/a -MSH; SP/LH-RH; 92.30 Ml 8/11 72.72 % NPY/LH-RH; NPY/NKA; b-END/LH-RH; Mm 7/11 63.63 % b-END/NKA; a -MSH/LH-RH; a -MSH/NKA Fx 7/12 58.33% MET-E/NT; MET-E/SOM; MET-E/ACTH; TMT 6/12 50 % SP/NKA; NT/SOM; NT/NPY; NT/b-END MFB 3/11 27.27 % NT/a -MSH; NT/ACTH; NT/NKA; SOM/NPY b a 84.61 For nomenclature of the hypothalamic nuclei, see list of abbrevia- SON/ -END; SOM/ -MSH; SOM/ACTH; tions. For example, 10/13: indicates that of 13 neuropeptides stud- SOM/NKA; NPY/ACTH; b-END/ACTH; ied, 10 were found in fibers and /or cell bodies in the Hp. Their a -MSH/ACTH; ACTH/NKA; LH-RH/NKA percentages are also indicated. SP/NT; SP/SOM; SP/ACTH; NT/LH-RH; SOM/LH-RH; ACTH/LH-RH 76.92 2. From the anterior hypothalamus and medi- al preoptic area to the posterior hypothal- For a nomenclature of the neuropeptides, see Table 1. amus: containing corticotro p i n - re l e a s i n g factor. 3. From the medial preoptic area, dorsal 6. From the medial preoptic area and around hypothalamic nucleus and ventrolateral the anterior hypothalamic nucleus to the posterior hypothalamus to the posterior posterior hypothalamus: containing thy- hypothalamus: containing neurotensin. rotropin-releasing hormone. 4. From the medial preoptic area and the 7. From the nucleus of the stria terminalis to mamillary region to the posterior hypo- the posterior hypothalamus: containing thalamus: containing methionine- substance P or methionine-enkephalin. enkephalin. 5. F rom the medial amygdaloid nucleus, In addition, in the cat Yanagihara and Niimi medial preoptic area and lateral/dorsal and (1989) have described a projection containing posterior hypothalamic areas to the poste- substance P from the posterior hypothalamus to rior hypothalamus: containing substance P. the hippocampal formation. Kitahama et al.

51 R. Coveñas, M. de León, M. Belda, P. Marcos, J.A. Narváez, J.A. Aguirre, G. Tramu and S. González-Barón

Table 5.- Possible peptidergic afferents to the cat hypothalamic Table 6.- Possible peptidergic projecting neurons in the cat thala- nuclei (F: +++/++; CB: -). mic nuclei (F: -; CB: +++/++).

ACTH b-END NPY MET-E NT

aHd (+++) aHd (++) aHd (+++) Hdm (++) RPO (+++) Ha (+++) Ha (++) Ha (+++) Mm (+++) SP Hdm (+++) Hdm (++) Hdm (+++) PVH (++) Ml (++) HL (++) Hp (++) HL (++) SOM Mn (+++) Hp (++) PVH (+++) Hp (+++) Ha (+++) RPO (+++) PVH (+++) RPO (+++) Hp (+++) PVH (+++) Sch (++) Sch (++) Ml (+++) DSIP LH-RH PVH (+++) Hvm (+++) Hp (++) Sch (++) For nomenclature of the neuropeptides and the hypothalamic b-END (1-31) Ml (++) So (++) nuclei, see respectively, Table 1 and list of abbreviations. CB: Hvm (++) PVH (++) NT immunoreactive cell bodies (+++: high density; ++: moderate den- sity); F: immunoreactive fibers (-: absence). a -MSH Sch (++) PVH (++) Ha (+++) NKA SOM

Hp (++) RPO (++) Hvm (+++) PVH (+++) So (+++) These data indicate that the hypothalamic nuclei shown in Table 5 could receive peptidergic affer- For nomenclature of the neuropeptides and the hypothalamic nuclei, see respectively, Table 1 and list of abbreviations. CB: ents arising from neurons located inside and/or immunoreactive cell bodies (-: absence); F: immunoreactive fibers outside the hypothalamus, whereas the nuclei (+++: high density; ++: moderate density). included in Table 6 could contain projecting neurons, which could send projections to other hypothalamic nuclei and/or other parts of the (1984, 1986) have demonstrated that several central nervous system. According to these data, peptidergic pathways come from the nucleus the following peptidergic pathways can be sug- arcuatus of the cat. The peptidergic projections gested in the cat (in order to demonstrate these described, containing adrenocorticotropin hor- pathways, the use of both immunocytochemical mone, coursed from the nucleus arcuatus to the and tract-tracing techniques is required): midline of the thalamus, the nucleus periventric- ularis anterior, the locus coeruleus, the periforni- 1. From the hypothalamus lateralis to the cal region, the zona incerta, the hypothalamus parabrachial nuclei, the locus coeruleus, posterior, lateralis, anterior, dorsomedialis and the nucleus of the solitary tract, the nucle- ventromedialis and to the nuclei supraopticus, us medialis dorsalis, and to the nucleus suprachiasmaticus and periventricularis hypo- habenularis lateraris: containing - thalami. These authors also indicated that all the melanocyte-stimulating hormone. This p e p t i d e rgic fibers and terminals containing pathway could be possible, since in the adrenocorticotropin hormone observed in the brainstem and thalamic nuclei referred to, cat central nervous system come from the cell fibers containing -melanocyte-stimulating bodies located in the nucleus arcuatus. In addi- h o rmone were observed but no tion, Kitahama et al. (1986) showed that all the immunoreactive cell bodies (Coveñas et fibers and terminals containing adre n o c o r t i- al., 1996b, 2000), whereas in the hypothal- cotropin hormone in the cat nucleus ventrome- amus lateralis a high density of cell bodies dialis hypothalami come from cell bodies locat- containing -melanocyte-stimulating hor- ed in the nucleus arcuatus. These data suggest mone was described (Coveñas et al., that the adre n o c o r t i c o t ropin horm o n e - 1996b). Moreover, this observation is in immunoreactive cell bodies observed later in the agreement with previous works carried out nucleus ventromedialis hypothalami of the cat in the cat, in which, using horseradish and (Coveñas et al., 1996c) would be projecting neu- autoradiographic techniques, researchers rons. At present, in the cat central nervous sys- have described pathways from the hypo- tem the only sites in which cell bodies contain- thalamus lateralis to the five brain areas ing adrenocorticotropin hormone have been mentioned above (Ono and Niimi, 1985; described are the nucleus arcuatus (Kitahama et Holstege, 1987). al., 1986; Rao et al., 1986; Coveñas et al., 1996c) 2. From the pars ventralis of the corpus and the nucleus ventromedialis hypothalami geniculatum laterale to the nucleus (Coveñas et al., 1996c). suprachiasmaticus: containing neuropep- Tables 5 and 6 show the nuclei of the cat tide Y. In this case, a moderate density of hypothalamus in which peptidergic fibers but no i m m u n o reactive cell bodies containing cell bodies have been observed (Table 5), as neuropeptide Y was found in the thalamic well as the nuclei in which a moderate/high den- nucleus (Coveñas et al., 1990), whereas in sity of immunoreactive cell bodies has been the hypothalamic nucleus neuropeptide Y- found, but no immunoreactive fibers (Table 6). immunoreactive fibers, but no cell body

52 Neuropeptides in the cat diencephalon: II. Hypothalamus

Table 7.- Comparative study of the distribution of fibers and su, 1984; Pelletier et al., 1984; Ronnekleiv et al., cell bodies containing neuropeptides in the hypothalamus of 1984; Barry et al., 1985; Chronwall et al., 1985; mammals. Mezey et al., 1985; Smith et al., 1985; Bennet- Clark et al., 1986; Bouras et al., 1986; Mai et al., F CB 1986; Rao et al., 1986; Bouras et al., 1987; Hu et MET-E C = R > H C = R > M > H al., 1987; Léger et al., 1987; Mai et al., 1987; Rao SP C = R > H =M C = R > H = M et al., 1987; Burgos et al., 1988; Coveñas et al., NT C = R = H C = R = H SOM C = R = H R = H > C 1988; Palkovits, 1988; Léger et al., 1990; de León NPY C = R = M = H C = R = M = H et al., 1991a, b; Zaphiropoulos et al., 1991; Rance b-END C = R C = R et al, 1994; Coveñas et al., 1996a, b, c; Belda et a -MSH C = R C = R ACTH C = R = H C = R = H al., 2000). Thus, Table 7 indicates whether there LH-RH C > R M = H > C = R is or there is not a more or less widespread dis- tribution of the immunoreactive structures in the For nomenclature of the neuropeptides, see Table 1. C: cat; CB: hypothalamus of the four species studied. In this distribution of immunoreactive cell bodies; F: distribution of sense, the distribution of fibers containing neu- immunoreactive fibers; H: human; M: monkey; R: rat. rotensin, somatostatin, neuropeptide Y, -endor- phin, -melanocyte-stimulating hormone and adrenocorticotropin hormone in the mammalian containing this neuropeptide was hypothalamus is in general quite similar. How- observed (Hu et al., 1987). This possible ever, in the case of methionine-enkephalin and pathway containing neuropeptide Y is in substance P, distribution is similar in the cat and agreement with the results obtained by in the rat, but is more widespread in comparison Swanson et al. (1974), since these authors with that observed in humans (for methionine- demonstrated an anatomical pro j e c t i o n enkephalin) and in humans and monkey (for from the pars ventralis of the corpus genic- substance P). Moreover, the distribution of fibers ulatum laterale to the nucleus suprachias- containing luteinizing hormone-releasing hor- maticus. mone in the cat hypothalamus is more wide- 3. From the hypothalamus lateralis to the spread than that found in the rat. In general, the superior colliculus: containing - distribution of cell bodies in the mammalian melanocyte stimulating hormone. This hypothalamus containing neurotensin, neu- anatomical pathway has been demonstrat- ropeptide Y, -endorphin, -melanocyte-stimu- ed previously in the cat (Rieck et al., lating hormone and adrenocorticotropin hor- 1986). The peptidergic pathway could be mone shows a similar distribution. However, the possible, since a high density of distribution is more widespread in the rat and cat immunoreactive cell bodies and a low in comparison with the distribution found in the density of fibers containing -melanocyte- monkey and humans for methionine-enkephalin stimulating hormone has been observed in and substance P. In addition, the distribution of the hypothalamus lateralis (Coveñas et al., cell bodies containing somatostatin in the human 1996b), whereas immunoreacive fibers and rat hypothalamus is more widespread in containing the neuropeptide were only comparison with that found in the same dien- found in the superior colliculus (Coveñas cephalic area of the cat, and the distribution of et al., 2000). cell bodies containing luteinizing horm o n e - releasing hormone in the monkey and human hypothalamus is more widespread in compari- COMPARATIVE STUDY OF THE DISTRIBUTION OF son with the distribution observed for the same NE U R O P E P T I D E S IN TH E MA M M A L I A N HY P O T H A L A- neuropeptide in the hypothalamus of the cat and MUS rat. Finally, the discrepancies found in the distrib- The distribution of the neuropeptides in the ution of neuropeptides in the mammalian hypo- mammalian hypothalamus has mainly been stud- thalamus could be due to species differences ied in humans, the monkey, cat and rat. Table 7 and/or technical considerations (e.g., antisera compares the distribution of fibers and cell bod- used, injections of colchicine,…). ies containing neuropeptides in the four species studied, and depicts the neuropeptides that have been most extensively studied in the hypothala- PHYSIOLOGICAL FUNCTIONS OF NEUROPEPTIDES mus of mammals (Barry and Carette, 1975; Hök- IN THE CAT HYPOTHALAMUS felt et al., 1977; Ljungdahl et al., 1978; Sar et al., 1978; Bennet-Clark et al., 1980; Finley et al., As we have shown in Tables 3 and 4, numer- 1981a, b; Haber and Elde, 1982; Jennes et al., ous neuropeptides have been located in the 1982; Micevych and Elde, 1982; Bouras et al., same hypothalamic nuclei of the cat. This indi- 1984; Johanson et al., 1984; Krukoff and Calare- cates that in those hypothalamic nuclei there is

53 R. Coveñas, M. de León, M. Belda, P. Marcos, J.A. Narváez, J.A. Aguirre, G. Tramu and S. González-Barón

an elaborate modulation of functions in which visual and stress mechanisms (Fuchs at al., 1985; these nuclei are involved, and that in these Pickard, 1985; Gray et al., 1989; Preston et al., hypothalamic nuclei a possible interaction 1989). Also, the presence of immunoreactive between the neuropeptides localized in them structures containing luteinizing hormone-releas- could occur. In this sense (see Table 4), it is ing hormone in the nuclei arcuatus, re g i o known that inhibit the release of praeoptica, hypothalami ventro m e d i a l i s , substance P from hypothalamic slices (Micevych suprachiasmaticus and in the median eminence et al., 1982) and that the opiate receptors medi- indicates that the neuropeptide could play a role ate the inhibition of cholecystokinin and sub- in regulating the release of luteinizing hormone stance P release in the cat hypothalamus and follicle-stimulating hormone from the anteri- (Micevych et al., 1984). The release of methion- or pituitary, in sexual behavior, in circadian ine-enkephalin by -endorphin has also been rhymths, in visual mechanisms and in the regu- demonstrated (Tseng, 1989). In addition, the lation of thermogenesis (Kow and Pfaff, 1988; regulation of pro-opiomelanocortin gene expres- Pan et al., 1988; Merchenthaler et al., 1989). sion by neuropeptide Y has been described and Moreover, in the cat, it has been described that neuropeptide Y may act as a melanocyte- that hypothalamic vasopressin and oxytocin stimulating horm o n e - release inhibiting factor immunoreactive neurons are activated during the and that neuropeptide Y modulates the release pressor reflex exercise and that vasopressin is of luteinizing hormone-releasing hormone from involved in the regulation of evaporative water the hypothalamus. This suggests that neuropep- loss and body temperature, and it is known that tide Y could be a component of the luteinizing the release of cholecystokinin in the cat hypo- h o rm o n e - releasing hormone pulse-generating thalamus is involved in nutrient and volume system (Verburg-Van Kemenade et al., 1987; loading (Doris, 1982; Schick et al., 1989; Li et al., McDonald, 1990; de Yébenes et al., 1995). 1997). The presence of cell bodies containing Finally, it is known that the destruction of the methionine-enkephalin in the nuclei periventric- preoptic area, in which cell bodies containing ularis hypothalami and supraopticus suggests delta sleep-inducing peptide have been found in that such neurons could project to the median the cat (Charnay et al., 1990), result in a strong eminence and posterior pituitary, where they decrease or disappearance of both paradoxical might regulate the release of oxytocin and vaso- sleep and deep slow-wave sleep (Szymusiak and pressin in the neurohypophysis and probably McGinty, 1986; Sallanon et al., 1989). This sug- participate in cardiovascular control (Micevych gests that the neuropeptide could be involved in and Elde, 1980). Moreover, the presence of the hypothalamic control of sleep. methionine-enkephalin in the nucleus suprachi- asmaticus, as well as the localization of cell bod- ies containing the neuropeptide in the hypothal- FUTURE RESEARCH ON NEUROPEPTIDES IN THE amus dorsomedialis and in the regio praeoptica CAT HYPOTHALAMUS indicates that the neuropeptide could be involved in the control of circadian rhythms As we have indicated in a previous work on and/or in visual processes, as well as in control- the neuropeptides in the cat thalamus (Coveñas ling somatostatin release into the blood of the et al., 2001), in the hypothalamus there is also portal plexus (Tramu et al., 1981; Pickard, 1985; much to be done in order to know the distribu- Swaab et al., 1985). tion and the physiological functions of the neu- The presence of substance P in the nuclei ropeptides in this diencephalic region of the cat. periventricularis hypothalami, supraopticus, Thus, in addition to studying the distribution of hypothalami ventromedialis and in the suprachi- other neuropeptides that, at the present, have asmaticus indicates that the neuropeptide could not been studied in detail in the cat hypothala- play a role, respectively, in synaptic control of mus, in the future radioimmunoassay and in situ the vasopressinergic neurons of the nucleus hybridization techniques should be carried out periventricularis hypothalami, in increasing the in order to compare the results obtained after firing frecuency of neurons located in the nucle- using both techniques in the cat hypothalamus us supraopticus, in feeding behavior, and in with those described for the distribution of neu- visual processes (Clarke et al., 1980; Heike et al., ropeptides in the same diencephalic area of the 1986). In addition, the localization of immunore- cat. In addition, however, in the future the fol- active structures containing -endorphin and - lowing aspects should be explored in greater melanocyte-stimulating hormone in the nuclei depth in the cat hypothalamus, since they have hypothalami ventromedialis, periventricularis not received sufficient attention: 1) The distribu- hypothalami and suprachiasmaticus indicates tion of the receptors of the neuropeptides; 2) that both neuropeptides could be involved in The distribution of the neuropeptidases; 3) The feeding, affective defense behavior, the regula- location of the cell bodies that originate pep- tion of thermogenesis, circadian rhymths, and in tidergic afferences to the hypothalamus; 4) The

54 Neuropeptides in the cat diencephalon: II. Hypothalamus projections of the peptidergic neurons observed BOURAS C, TABAN CH and CONSTANTINIDIS J (1984). Mapping in the hypothalamus; 5) Knowledge of the of enkephalins in human brain. An immunofluores- synaptic connections; 6) The coexistence of neu- cence study on brains from patients with senile and pre- senile dementia. Neuroscience, 12: 179-190. ropeptides and 7) The physiological functions of BOURAS C, VALLET PG, DOBRINOV H, DE ST-HILAIRE S and CON- the neuropeptides. In sum, the application of STANTINIDIS J (1986). Substance P neuronal cell bodies in other methodologies (combining immunocyto- the human brain: complete mapping by immunohisto- chemical and tract-tracing methods, immunocy- fluorescence. Neurosci Lett, 69: 31-36. tochemical and electron microscopic methods, BOURAS C, MAGISTRETTI PJ, MORRISON JH and CONSTANTINIDIS J immunofluorescence methods, microinjections (1987). An immunohistochemical study of pro-somato- statin-derived in the human brain. Neuro - of neuropeptides…) is required in order to gain science, 22: 781-800. further insight into the distribution and functions BURGOS C, AGUIRRE JA, ALONSO JR and COVEÑAS R (1988). of the neuropeptides in the cat hypothalamus. Immunocytochemical study of substance P-like fibres and cell bodies in the cat diencephalon. J Hirnforsch, 29: 651-657. CARPENTER MB (1980). Fundamentos de neuroanatomía, El CKNOWLEDGEMENTS A Ateneo, Buenos Aires. CAVERSON MM, CIRIELLO J, CALARESUA FR and KRUKOFF TL This work has been supported by the (1987). Distribution and morphology of vasopressin-, D . G . I . C . Y. T. (PB 96/1467; PM 99/0159; PM neurophysin II-, and oxytocin-immunoreactive cell bod- 99/0160). The authors wish to thank N. Skinner ies in the forebrain of the cat. J Comp Neurol, 259: 211- for stylistic revision of the English text. 236. CHARNAY Y, LEGER L, GOLAZ J, SALLANON M, VALLET PG, GUN- TERN R, BOURAS C, CONSTANTINIDIS J, JOUVET M and TISSOT R (1990). Immunohistochemical mapping of delta sleep- ABBREVIATIONS USED inducing peptide in the cat brain and hypophysis. Rela- tionships with the LHRH system and corticotropes. J aHd: Area hypothalamica dorsalis Chem Neuroanat , 3: 397-412. Arc: Nucleus arcuatus CHRONWALL BM, DIMAGGIO DA, MASSARI VJ, PICKEL VM, RUG- GIERO DA and O’DONOHUE (1985). The anatomy of neu- Fx: Fornix ropeptide Y-containing neurons in rat brain. Neuro - Ha: Hypothalamus anterior science, 15: 1159-1181. HL: Hypothalamus lateralis CLARKE G, KIRBY PJC and THOMSON AM (1980). Effects on Hdm: Hypothalamus dorsomedialis vasopressinergic and oxytocinergic neurons of intraven- Hp: Hypothalamus posterior tricular substance P. J Physiol (London), 307: 59P-60P. Hvm: Hypothalamus ventromedialis COVEÑAS R, BURGOS C and CONRATH M (1988). 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