Page personnelle

Philippe CIOFI

Principal Investigator

Phone : 33(0)5 57 57 37 38 / 33(0)5 57 57 36 00
Send an email

1984-87: PhD Univ. Lille (France), Neuroanatomy - Neuroendocrinology
1987-90: Post-Doc, Univ. Calif. Irvine, Neuroanatomy - Neuroendocrinology
1991- :Inserm Investigator, Neuroanatomy - Neuroendocrinology

72 publication(s) since Décembre 1985:

Sort by

* equal contribution
The indicated IF have been collected by the Web of Sciences in

01/2011 | J Neuroendocrinol   IF 3.1
Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat.
True C, Kirigiti M, Ciofi P, Grove KL, Smith MS

Lactation results in negative energy balance in the rat leading to decreased gonadotrophin-releasing hormone (GnRH) release and anoestrus. Inhibited GnRH release may be a result of decreased stimulatory tone from neuropeptides critical for GnRH neuronal activity, such as kisspeptin (Kiss1) and neurokinin B (NKB). The present study aimed to identify neuronal projections from the colocalised population of Kiss1/NKB cells in the arcuate nucleus (ARH) using double-label immunohistochemistry to determine where this population may directly regulate GnRH neuronal activity. Additionally, the present study further examined lactation-induced changes in the Kiss1 system that could play a role in decreased GnRH release. The colocalised ARH Kiss1/NKB fibres projected primarily to the internal zone of the median eminence (ME) where they were in close proximity to GnRH fibres; however, few Kiss1/NKB fibres from the ARH were seen at the level of GnRH neurones in the preoptic area (POA). Arcuate Kiss1/NKB peptide levels were decreased during lactation consistent with previous mRNA data. Surprisingly, anteroventral periventricular (AVPV) Kiss1 peptide levels were increased, whereas Kiss1 mRNA levels were decreased during lactation, suggesting active inhibition of peptide release. These findings indicate ARH Kiss1/NKB and AVPV Kiss1 appear to be inhibited during lactation, which may contribute to decreased GnRH release and subsequent reproductive dysfunction. Furthermore, the absence of a strong ARH Kiss1/NKB projection to the POA suggests regulation of GnRH by this population occurs primarily at the ME level via local projections.

2011 | Front Endocrinol (Lausanne)
Sexual dimorphism of kisspeptin and neurokinin B immunoreactive neurons in the infundibular nucleus of aged men and women.
Hrabovszky E, Molnar CS, Sipos MT, Vida B, Ciofi P, Borsay BA, Sarkadi L, Herczeg L, Bloom SR, Ghatei MA, Dhillo WS, Kallo I, Liposits Z

The secretory output of gonadotropin-releasing hormone (GnRH) neurons is critically influenced by peptidergic neurons synthesizing kisspeptins (KP) and neurokinin B (NKB) in the hypothalamic infundibular nucleus (Inf). These cells mediate negative feedback effects of sex steroids on the reproductive axis. While negative feedback is lost in postmenopausal women, it is partly preserved by the sustained testosterone secretion in aged men. We hypothesized that the different reproductive physiology of aged men and women is reflected in morphological differences of KP and NKB neurons. This sexual dimorphism was studied with immunohistochemistry in hypothalamic sections of aged human male (>/=50 years) and female (>55 years) subjects. KP and NKB cell bodies of the Inf were larger in females. The number of KP cell bodies, the density of KP fibers, and the incidence of their contacts on GnRH neurons were much higher in aged women compared with men. The number of NKB cell bodies was only slightly higher in women and there was no sexual dimorphism in the regional density of NKB fibers and the incidence of their appositions onto GnRH cells. The incidences of NKB cell bodies, fibers, and appositions onto GnRH neurons exceeded several-fold those of KP-IR elements in men. More NKB than KP inputs to GnRH cells were also present in women. Immunofluorescent studies identified only partial overlap between KP and NKB axons. KP and NKB were colocalized in higher percentages of afferents to GnRH neurons in women compared with men. Most of these sex differences might be explained with the lack of estrogen negative feedback in aged women, whereas testosterone can continue to suppress KP, and to a lesser extent, NKB synthesis in men. Overall, sex differences in reproductive physiology of aged humans were reflected in the dramatic sexual dimorphism of the KP system, with significantly higher incidences of KP-IR neurons, fibers and inputs to GnRH neurons in aged females vs. males.

12/2010 | J Chem Neuroanat
Hypothalamic arcuate neuropeptide Y-neurons decrease periventricular somatostatin-neuronal activity before puberty in the female lamb: morphological arguments.
Tillet Y, Picard S, Bruneau G, Ciofi P, Wankowska M, Wojcik-Gladysz A, Polkowska J

It is assumed that hypothalamic somatostatin plays a dominant role in the regulation of growth of developing lambs. On the other side, neuropeptide Y (NPY) neurons of the arcuate (ARC) nucleus are potentially involved in the control of gonadotrophins in prepubertal lambs and also of growth hormone (GH) secretion in adults. This study therefore investigated whether the transition from the prepubertal to the peripubertal period is accompanied by changes in NPY-ir and NPY mRNA content in neurons of the ARC nucleus and their putative projections to somatostatin neurons in both the ARC and periventricular (PEV) nuclei. The hypothalami of prepubertal (17-week-old) and peripubertal (32-week-old) female lambs were compared using single and double-labelling immunohistochemistry, and hybridisation in situ for NPY. Single-labelling for NPY mRNA and NPY-ir was quantified by image analysis using a light microscope and expressed as the percent area stained and/or the integral density of the reaction. Double-labelling for NPY-somatostatin relationships was analysed by confocal microscopy. Our data suggest that there are no detectable changes in NPY-ir in the PEV nucleus in the period leading up to puberty, whereas both the distributional area and intensity of NPY-labelling in the ARC are significantly higher in peripubertal compared to prepubertal sheep. In contrast, NPY mRNA levels are higher in prepubertal than in peripubertal ewes in the ARC nucleus. Confocal microscopy suggests the existence of NPY-somatostatin axo-somatic contacts in both PEV and ARC nuclei. In the PEV nucleus, the number of close appositions between NPY-ir fibres and somatostatin-ir perikarya is higher in prepubertal than in peripubertal ewes, but in the ARC no such difference was observed. In conclusion, our observations suggest that there is decreased activity of the NPY neurons of the ARC nucleus closely related to somatostatin neurons in the PEV nucleus at the onset of puberty. The withdrawal of this NPY effect may allow a higher release of somatostatin, which consequently inhibits GH secretion and stops growth. Both peptides are involved in the transmission of signals leading to stop growth at puberty.

Human genetics indicate that kisspeptin and neurokinin B (NKB) signaling are necessary for generating pulsatile LH release and therefore for initiation of puberty and maintaining gonadal function. In the present study, male monkeys were employed to examine 1) whether activation of the NKB receptor (NK3R) is associated with GnRH release, and 2) hypothalamic localization of these peptides using immunofluorescence histochemistry. Agonadal juveniles, in which pituitary responsiveness to GnRH was heightened by GnRH priming, were employed to indirectly examine GnRH-releasing actions of NK3R and kisspeptin receptor agonists by tracking LH after their i.v. injection. Castrated adults were used for immunohistochemistry. Single i.v. injections of NKB or senktide (an NK3R agonist) elicited robust LH discharges that were abolished by GnRH receptor antagonism (acyline) confirming the ligands' hypothalamic action. Intermittent infusion of senktide (1-min pulse every hour for 4 h), in contrast to that of kisspeptin, failed to sustain pulsatile GnRH release. Repetitive senktide injections did not compromise the GnRH-releasing action of kisspeptin. NKB and kisspeptin were colocalized in perikarya of the arcuate nucleus and in axonal projections to the median eminence, confirming earlier findings in sheep. These results are consistent with the human genetics, and indicate that although brief activation of NK3R stimulates GnRH release, repetitive stimulation of this pathway, in contrast to that of kisspeptin receptor, fails to sustain pulsatile GnRH release. In addition, the data provide a platform for future elucidation of the interactions between NKB and kisspeptin that are required for generating pulsatile GnRH release in primates.

01/06/2010 | Eur J Neurosci
The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons.
Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, Kallo I


12/2009 | Endocrinology
Brain-endocrine interactions: a microvascular route in the mediobasal hypothalamus.
Ciofi P, Garret M, Lapirot O, Lafon P, Loyens A, Prevot V, Levine JE

Blood-borne hormones acting in the mediobasal hypothalamus, like those controlling food intake, require relatively direct access to target chemosensory neurons of the arcuate nucleus (ARC). An anatomical substrate for this is a permeable microvasculature with fenestrated endothelial cells in the ARC, a system that has awaited comprehensive documentation. Here, the immunofluorescent detection of endothelial fenestral diaphragms in the rat ARC allowed us to quantitate permeable microvessels throughout its rostrocaudal extent. We have determined that permeable microvessels are part of the subependymal plexus irrigating exclusively the ventromedial (vm) ARC from the subadjacent neuroendocrine median eminence. Unexpectedly, permeable microvessels were concentrated proximal to the pituitary stalk. This marked topography strongly supports the functional importance of retrograde blood flow from the pituitary to the vmARC, therefore making a functional relationship between peripheral long-loop, pituitary short-loop, and neuroendocrine ultra-short loop feedback, altogether converging for integration in the vmARC (formerly known as the hypophysiotrophic area), thereby so pivotal as a multicompetent brain endocrinostat.

09/2009 | Gene Expr Patterns
Spatiotemporal expression in mouse brain of Kiaa2022, a gene disrupted in two patients with severe mental retardation.
Cantagrel V, Haddad MR, Ciofi P, Andrieu D, Lossi AM, Maldergem L, Roux JC, Villard L

We previously identified an inactivating disruption of the X-linked KIAA2022 gene by a chromosomal rearrangement in two male patients with severe mental retardation. In order to determine if KIAA2022 has a role during the development of the central nervous system, we have cloned its murine ortholog, Kiaa2022, determined its genomic structure and studied its expression during mouse development. We show that Kiaa2022 is preferentially expressed in the central nervous system and that the transcript is highly expressed in postmitotic neurons. The expression of Kiaa2022 is first detectable at E10.5 to reach a maximum at P3 where it is notably expressed in the hippocampus, the entorhinal cortex and strongly in the ventral premammillary nucleus. After P3, the expression of Kiaa2022 decreases and maintains very low levels thereafter. Our results show that Kiaa2022 is expressed in the developing brain and that it may play a role in postmitotic, maturing neurons.

2009 | Pour la Science, Cerveau & Psycho
Programmés pour le sexe en été
Ciofi P


2009 | Pour la Science, Cerveau & Psycho
Homosexuels : une différence cérébrale
Ciofi P


2008 | Métabolisme Hormones et Nutrition
Brain sexual differentiation : an update
Ciofi P