Olfactory Inputs to Hypothalamic Neurons Controlling Reproduction and Fertility

Howard Hughes Medical Institute, Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Cell (Impact Factor: 32.24). 12/2005; 123(4):669-82. DOI: 10.1016/j.cell.2005.08.039
Source: PubMed


In order to gain insight into sensory processing modulating reproductive behavioral and endocrine changes, we have aimed at identifying afferent pathways to neurons synthesizing luteinizing hormone-releasing hormone (LHRH, also known as gonadotropin-releasing hormone [GnRH]), a key neurohormone of reproduction. Injection of conditional pseudorabies virus into the brain of an LHRH::CRE mouse line led to the identification of neuronal networks connected to LHRH neurons. Remarkably, and in contrast to established notions on the nature of LHRH neuronal inputs, our data identify major olfactory projection pathways originating from a discrete population of olfactory sensory neurons but fail to document any synaptic connectivity with the vomeronasal system. Accordingly, chemosensory modulation of LHRH neuronal activity and mating behavior are dramatically impaired in absence of olfactory function, while they appear unaffected in mouse mutants lacking vomeronasal signaling. Further visualization of afferents to LHRH neurons across the brain offers a unique opportunity to uncover complex polysynaptic circuits modulating reproduction and fertility.

Download full-text


Available from: Lynn Enquist,
    • "The response to urine pheromones, which is important for social recognition and initiation of aggressive behaviors, begins with pheromone detection in the vomeronasal organ (Chamero et al, 2007), and the information is then conveyed to the AOB. The AOB directly projects to the MeA, which itself projects to the BNST; the BNST also receives direct projections from the AOB (Yoon et al, 2005). Figure 4a schematically illustrates the flow of pheromonal information in the rodent. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabotropic glutamate receptor subtype 7 (mGluR7) is a member of group III mGluRs, which localize to the presynaptic active zones of the mammalian central nervous system. Although histological, genetic, and electrophysiological studies ensure the importance of mGluR7, its roles in behavior and physiology remain largely unknown. Using a resident-intruder paradigm, we found a severe reduction in intermale aggressive behavior in mGluR7 knockout (KO) mice. We also found alterations in other social behaviors in male mGluR7 KO mice, including sexual behavior toward male intruders. Because olfaction is critical for rodent social behavior, including aggression, we performed an olfaction test, finding that mGluR7 KO mice failed to show interest in the smell of male urine. To clarify the olfactory deficit, we then exposed mice to urine and analyzed c-Fos-immunoreactivity, discovering a remarkable reduction in neural activity in the bed nucleus of the stria terminalis (BNST) of mGluR7 KO mice. Finally, intra-BNST administration of the mGluR7-selective antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) also reproduced the phenotype of mGluR7 KO mice, including reduced aggression and altered social interaction. Thus, mGluR7 may work as an 'enhancer of neural activity' in the BNST and is important for intermale aggression. Our findings demonstrate that mGluR7 is essential for social behavior and innate behavior. Our study on mGluR7 in the BNST will shed light on future therapies for emotional disorders in humans.Neuropsychopharmacology accepted article preview online, 07 July 2015. doi:10.1038/npp.2015.198.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2015; DOI:10.1038/npp.2015.198 · 7.05 Impact Factor
  • Source
    • "Removal of the vomeronasal organs or lesioning of the accessory olfactory bulbs results in the disappearance of the effect of the partner ( Beltramino and Taleisnik , 1983 ) . However , this strict relationship between the accessory olfactory system and partner cues in rodents has been challenged by Yoon et al . ( 2005 ) who used transgenic mice to demonstrate the presence of direct pro - jections from the main olfactory bulbs to GnRH neurons but none from the accessory olfactory system . While much less research has been carried out in non - rodent mammals effects of olfactory cues from sexual partners appear to primarily involve air - born odors . T"
    [Show abstract] [Hide abstract]
    ABSTRACT: Reproduction in mammals is controlled by the hypothalamo-pituitary-gonadal (HPG) axis under the influence of external and internal factors such as photoperiod, stress, nutrition, and social interactions. Sheep are seasonal breeders and stop mating when day length is increasing (anestrus). However, interactions with a sexually active ram during this period can override the steroid negative feedback responsible for the anoestrus state, stimulate LH secretion and eventually reinstate cyclicity. This is known as the “ram effect” and research into the mechanisms underlying it is shedding new light on HPG axis regulation. The first step in the ram effect is increased LH pulsatile secretion in anestrus ewes exposed to a sexually active male or only to its fleece, the latter finding indicating a “pheromone-like” effect. Estradiol secretion increases in all ewes and this eventually induces a LH surge and ovulation, just as during the breeding season. An exception is a minority of ewes that exhibit a precocious LH surge (within 4h) with no prior increase in estradiol. The main olfactory system and the cortical nucleus of the amygdala are critical brain structures in mediating the ram effect since it is blocked by their inactivation. Sexual experience is also important since activation (increased c-fos expression) in these and other regions is greatly reduced in sexually naïve ewes. In adult ewes kisspeptin neurons in both arcuate and preoptic regions and some preoptic GnRH neurons are activated 2h after exposure to a ram. Exposure to rams also activates noradrenergic neurons in the locus coeruleus and A1 nucleus and increased noradrenalin release occurs in the posterior preoptic area. Pharmacological modulation of this system modifies LH secretion in response to the male or his odor. Together these results show that the ram effect can be a fruitful model to promote both a better understanding of the neural and hormonal regulation of the HPG axis in general and also the spec
    Frontiers in Neuroscience 05/2015; 9(111). DOI:10.3389/fnins.2015.00111 · 3.66 Impact Factor
  • Source
    • "Therefore, it was not clear whether activation of MeApd neurons would promote or inhibit attack. Moreover, while MeApd is activated by pheromonal signals (Chamero et al., 2007; Kollack-Walker and Newman, 1995; Veening et al., 2005), attack requires chemosensory input from the main as well as the accessory olfactory systems (Dhungel et al., 2011; Mandiyan et al., 2005; Stowers et al., 2002; Yoon et al., 2005). This raises the question of where in this circuitry such convergent sensory input is transformed into a coherent program of aggressive behavior. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Animals display a range of innate social behaviors that play essential roles in survival and reproduction. While the medial amygdala (MeA) has been implicated in prototypic social behaviors such as aggression, the circuit-level mechanisms controlling such behaviors are not well understood. Using cell-type-specific functional manipulations, we find that distinct neuronal populations in the MeA control different social and asocial behaviors. A GABAergic subpopulation promotes aggression and two other social behaviors, while neighboring glutamatergic neurons promote repetitive self-grooming, an asocial behavior. Moreover, this glutamatergic subpopulation inhibits social interactions independently of its effect to promote self-grooming, while the GABAergic subpopulation inhibits self-grooming, even in a nonsocial context. These data suggest that social versus repetitive asocial behaviors are controlled in an antagonistic manner by inhibitory versus excitatory amygdala subpopulations, respectively. These findings provide a framework for understanding circuit-level mechanisms underlying opponency between innate behaviors, with implications for their perturbation in psychiatric disorders.
    Cell 09/2014; 158(6):1348-61. DOI:10.1016/j.cell.2014.07.049 · 32.24 Impact Factor
Show more