Research ReportDistribution of the neuronal inputs to the ventral premammillary nucleus of male and female rats☆
Introduction
The ventral premammillary nucleus (PMV) is a small, compact group of neurons in the medial zone of the hypothalamus, located immediately caudal to the ventromedial nucleus of the hypothalamus and ventral to the dorsal premammillary nucleus (Canteras et al., 1992b, Donato and Elias, 2011). Initial studies using extensive electrolytic lesions of the premammillary area of rats suggested the involvement of the PMV in male conspecific aggression (van den Berg et al., 1983). These findings were later reinforced by neuroanatomical studies using Fos immunoreactivity as a marker of neuronal activation (Hoffman and Lyo, 2002). The PMV of male rats and hamsters shows increased Fos expression after aggressive conspecific encounters, but notably also after sexual behavior (Coolen et al., 1996, Kollack-Walker and Newman, 1995, Veening et al., 2005). In fact, conspecific opposite sex odors alone induce Fos expression in PMV neurons of rodents. These neurons coexpress nitric oxide synthases and cocaine- and amphetamine-regulated transcript (CART) (Cavalcante et al., 2006a, Donato et al., 2010, Yokosuka et al., 1999). We further demonstrated that CART mRNA is increased in the PMV of males following exposure to female odors and that PMV CART neurons project to areas controlling gonadotropin releasing hormone (GnRH) secretion (Cavalcante et al., 2006a, Rondini et al., 2004).
The PMV expresses high to moderate density of sex steroids receptors and projects to the sexually dimorphic circuitry, to nuclei of the vomeronasal system and reproductive control sites (Canteras et al., 1992b, Gautron et al., 2013, Merchenthaler et al., 2004, Rondini et al., 2004, Simerly et al., 1990). Therefore, PMV neurons may integrate external (odor) and internal (sex steroids) cues to modulate the downstream targets in neuroendocrine and behavioral responses. In agreement with this model, electrolytic lesions of the PMV abolished the luteinizing hormone (LH) rise induced by male odor or electrical stimulation of the medial nucleus of the amygdala (Beltramino and Taleisnik, 1985). Moreover, using excitotoxic lesions, we and others have shown that the PMV plays a role in female neuroendocrine regulation of estrous cycles, sexual behavior and maternal aggression (Donato et al., 2009, Donato et al., 2013, Motta et al., 2013).
The PMV also expresses receptors for several metabolic cues including leptin, insulin and ghrelin, and may represent a key integrative site for metabolic regulation (Donato and Elias, 2011, Elias et al., 2000, Elmquist et al., 1998, Frazao et al., 2014, Leshan et al., 2009, Zigman et al., 2006). Nutrition is fundamental to reproductive function (Frisch and McArthur, 1974, Hill et al., 2008, Kennedy and Mitra, 1963). States of negative energy balance decreases reproductive capacity and delays puberty. On the other hand, excess energy also disrupts fertility (Bluher and Mantzoros, 2004, Chan and Mantzoros, 2001). Leptin signaling-deficient mice and humans are obese and infertile, and the genetic deletion of insulin receptors in the brain disrupts fertility in mice (Bruning et al., 2000, Chua et al., 1996, Clement et al., 1998, Coleman, 1978, Farooqi et al., 2002, Tartaglia et al., 1995, Zhang et al., 1994). However, the exact brain sites involved in the metabolic control of reproduction are not completely known. We have shown that endogenous re-expression of leptin receptors only in the PMV of mice otherwise null for leptin receptor induces puberty and improves fertility (Donato et al., 2011). These findings indicate that the PMV plays a fundamental role in the integration of metabolism and reproduction. However, although the projections of PMV neurons have been well documented (Canteras et al., 1992b, Gautron et al., 2013, Leshan et al., 2009, Rondini et al., 2004), little is known about the neuronal inputs received by PMV neurons. To fill this gap and contribute to the understanding of the hypothalamic circuitry controlling complex physiological systems, we performed a systematic evaluation of the brain sites innervating the PMV neurons of male and female rats. In the present study, we chose to use a standard neuroanatomical tracer to acquire knowledge on the complete network of neuronal populations with the potential to modulate PMV output.
Section snippets
Results
Neurons projecting to the PMV from the entire brain were mapped using the cholera toxin b subunit (CTb) as a retrograde tracer. CTb is an efficient, allowing restricted injections combined with robust and consistent retrograde labeling with virtually no uptake from fibers of passage (Luppi et al., 1990). We observed that the projections to the PMV of male and female rats were predominantly ipsilateral with a few retrogradely labeled neurons in contralateral nuclei. The pattern of distribution
Discussion
In the present study, we showed that the PMV of males and females receive inputs from many areas throughout the brain, with a predominance of projections originating in the forebrain. No clear difference was noticed in the innervation pattern comparing both sexes. The MeA, the PA, the BSTpr and the MPN are the major sources of inputs. Moderate innervation originates from the ventral subdivision of the LS and the ventral subiculum. In the hypothalamus, moderate input to the PMV originates in the
Animals
Adult male and female Wistar rats (280–320 g) were housed two per cage in the animal facility of the Department of Anatomy, Institute of Biomedical Sciences, University of São Paulo, SP – Brazil. Animals were maintained on a 12-h light/dark cycle (lights on at 7 am) in a temperature-controlled environment (21±2 °C) and were given free access to rat chow and water. All experiments were carried out in accordance with the guidelines established by the National Institutes of Health Guide for the Care
Acknowledgments
We would like to thank Joelcimar Martins da Silva for expert technical assistance. Financial support was provided in the form of Grants and fellowships from the FAPESP (00/11569-4, 03/06022-4, 04/00585-0, and 05/50951-5).
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Support: This study was supported by grants and fellowships from the FAPESP (to J.C.C. fellowship 2001/11103-8, J.C.B. Grant 2004/13849-5 and C.F.E. Grant 05/59286-4) and the NIH (HD61539 and HD69702 to C.F.E.).