The effect of microinfusions of drugs into the accessory olfactory bulb on the olfactory block to pregnancy

doi:10.1016/0306-4522(88)90053-X

Neuroscience

Volume 25, Issue 3, June 1988, Pages 1007-1011

https://doi.org/10.1016/0306-4522(88)90053-X Get rights and content

Abstract

Female mice which have mated and are subsequently exposed to the odour (pheromones) of a strange male undergo hormonal changes resulting in a block to their pregnancy. The fact that the stud male's odours can also block pregnancies, that is other than his own, implies the formation of a memory or some form of recognition process by the female for this male's pheromones at the time of mating. The purpose of this study was to evaluate the effect of microinfusions of drugs which interfere with neural transmission, into the accessory olfactory bulbs. This was carried out immediately after mating over a 4-h period during which the “memory” to the stud male's pheromones is formed. Infusions of the α-blocker, phentolamine, blocked the formation of the olfactory memory, while the GABA receptor blocker, bicuculline, itself blocked pregnancy, but was without effect on memory formation. Protein synthesis inhibition or calpain inactivation in the accessory bulb was without effect on memory formation at any of the doses used.

These studies demonstrate that GABAergic transmitter blockade in the accessory olfactory bulb at the time of mating can prevent subsequent blastocyst implantation some 3 days later, while α-noradrenergic blockade can prevent the formation of an olfactory memory to the stud male.

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The Bruce effect: Representational stability and memory formation in the accessory olfactory bulb of the female mouse
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In the context of the BE, imprinting involves an interaction between individual recognition and the hypothalamic circuits that mediate basic physiological and endocrine responses. A series of studies has shown that both pregnancy block and the learning that selectively circumvents it involve sensory detection by the vomeronasal system (VNS), a chemosensory system devoted to processing cues from other organisms (Kaba et al., 1989; Kaba and Keverne, 1988; Lloyd-Thomas and Keverne, 1982). More specifically, it was suggested that activation of the VNS by unfamiliar male chemosignals would trigger a cascade of events involving the amygdala and hypothalamic dopamine (Li et al., 1989, 1990) neurons that block secretion of prolactin, which in turn is required for maintenance of pregnancy during the initial stages (Li et al., 1994).
In the Bruce effect, a mated female mouse becomes resistant to the pregnancy-blocking effect of the stud. Various lines of evidence suggest that this form of behavioral imprinting results from reduced sensitivity of the female’s accessory olfactory bulb (AOB) to the stud’s chemosignals. However, the AOB’s combinatorial code implies that diminishing responses to one individual will distort representations of other stimuli. Here, we record extracellular responses of AOB neurons in mated and unmated female mice while presenting urine stimuli from the stud and from other sources. We find that, while initial sensory responses in the AOB (within a timescale required to guide social interactions) remain stable, responses to extended stimulation (as required for eliciting the pregnancy block) display selective attenuation of stud-responsive neurons. Such temporal disassociation could allow attenuation of slow-acting endocrine processes in a stimulus-specific manner without compromising ongoing representations that guide behavior.
Noradrenergic circuits
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The norepinephrine/noradrenergic system has been implicated in substance use disorders for decades, but its importance has been somewhat overshadowed by its precursor molecule dopamine. In this chapter we explore norepinephrine and how noradrenergic signaling contributes to various aspects of substance use disorder. We begin by describing the system, anatomy and development of norepinephrine neurons, norepinephrine in physiological behavior, how to monitor/measure norepinephrine, and how noradrenergic circuits have been assayed and manipulated. We then describe what is known about noradrenergic function and involvement in major misused substances: opioids, alcohol, psychostimulants, nicotine, and cannabis. We finish with examining the role of norepinephrine in non-drug related rewards, such as food and psychosocial rewards.
Neural circuits regulating sexual behaviors via the olfactory system in mice
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Thus, the working hypothesis is that vomeronasal inputs from the AOB activate the arcuate dopaminergic neurons through the MeA, which results in inhibition of prolactin release, and ultimately abortion. For the second question, studies have suggested that the memory of the first mate is represented as changes in synaptic connectivity between mitral-tufted cells and granule cells in the AOB (Brennan et al., 1990; Kaba, 2005; Kaba and Keverne, 1988; Kaba et al., 1989, 1994). The working hypothesis is as follows.
Reproduction is essential for any animal species. Reproductive behaviors, or sexual behaviors, are largely shaped by external sensory cues exchanged during sexual interaction. In many animals, including rodents, olfactory cues play a critical role in regulating sexual behavior. What exactly these olfactory cues are and how they impact animal behavior have been a central question in the field. Over the past few decades, many studies have dedicated to identifying an active compound that elicits sexual behavior from crude olfactory components. The identified substance has served as a tool to dissect the sensory processing mechanisms in the olfactory systems. In addition, recent advances in genetic engineering, and optics and microscopic techniques have greatly expanded our knowledge of the neural mechanisms underlying the control of sexual behavior in mice. This review summarizes our current knowledge about how sexual behaviors are controlled by olfactory cues.
Roles for learning in mammalian chemosensory responses
2015, Hormones and Behavior
Citation Excerpt :
Depletion of olfactory bulb noradrenaline following local injections of the catecholaminergic neurotoxin, 6-hydroxy-dopamine six days prior to mating prevents memory formation to the mating male chemosignals (Rosser and Keverne, 1985). Moreover, local infusions of the α-adrenergic antagonist, phentolamine, but not the β-adrenergic antagonist, propranolol, during the sensitive period prevent memory formation (Kaba and Keverne, 1988). This dependence of memory formation on noradrenergic transmission in the AOB is further supported by in vitro studies.
This article is part of a Special Issue “Chemosignals and Reproduction”.
A rich variety of chemosignals have been identified that influence mammalian behaviour, including peptides, proteins and volatiles. Many of these elicit innate effects acting either as pheromones within species or allelochemicals between species. However, even innate pheromonal responses in mammals are not as hard-wired as the original definition of the term would suggest. Many, if not most mammalian pheromonal responses are only elicited in certain behavioural or physiological contexts. Furthermore, certain pheromones are themselves rewarding and act as unconditioned stimuli to link non-pheromonal stimuli to the pheromonal response, via associative learning. The medial amygdala, has emerged as a potential site for this convergence by which learned chemosensory input is able to gain control over innately-driven output circuits. The medial amygdala is also an important site for associating social chemosensory information that enables recognition of conspecifics and heterospecifics by association of their complex chemosensory signatures both within and across olfactory chemosensory systems. Learning can also influence pheromonal responses more directly to adapt them to changing physiological and behavioural context. Neuromodulators such as noradrenaline and oxytocin can plasticise neural circuits to gate transmission of chemosensory information. More recent evidence points to a role for neurogenesis in this adaptation, both at the peripheral level of the sensory neurons and via the incorporation of new neurons into existing olfactory bulb circuits. The emerging picture is of integrated and flexible responses to chemosignals that adapt them to the environmental and physiological context in which they occur.
Expression profiling reveals differential gene induction underlying specific and non-specific memory for pheromones in mice
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Citation Excerpt :
As a complementary approach to microarray studies on the AOB from mice that underwent physiological induction of pheromone memory, we carried out expression profiling on mice that were subjected to an artificial memory induction protocol. Previous work has established that infusion of bicuculline into the AOB causes formation of memory which is similar in behavioral manifestation to that induced by pheromones except that it is generalized to all pheromones and thus constitutes a non-specific memory (Kaba and Keverne, 1988). At the level of AOB, the memory induced by bicuculline which theoretically would result in modification of all the mitral–granule reciprocal synapses in the AOB.
Memory for the mating male’s pheromones in female mice is thought to require synaptic changes in the accessory olfactory bulb (AOB). Induction of this memory depends on release of glutamate in response to pheromonal exposure coincident with release of norepinephrine (NE) in the AOB following mating. A similar memory for pheromones can also be induced artificially by local infusion of the GABA_A receptor antagonist bicuculline into the AOB. The natural memory formed by exposure to pheromones during mating is specific to the pheromones sensed by the female during mating. In contrast, the artificial memory induced by bicuculline is non-specific and results in the female mice recognizing all pheromones as if they were from the mating male. Although protein synthesis has been shown to be essential for development of pheromone memory, the gene expression cascades critical for memory formation are not known. We investigated changes in gene expression in the AOB using oligonucleotide microarrays during mating-induced pheromone memory (MIPM) as well as bicuculline-induced pheromone memory (BIPM). We found the set of genes induced during MIPM and BIPM are largely non-overlapping and Ingenuity Pathway Analysis revealed that the signaling pathways in MIPM and BIPM also differ. The products of genes induced during MIPM are associated with synaptic function, indicating the possibility of modification at specific synapses, while those induced during BIPM appear to possess neuron-wide functions, which would be consistent with global cellular changes. Thus, these results begin to provide a mechanistic explanation for specific and non-specific memories induced by pheromones and bicuculline infusion respectively.
Muscarinic receptor type 1 (M1) stimulation, probably through KCNQ/Kv7 channel closure, increases spontaneous GABA release at the dendrodendritic synapse in the mouse accessory olfactory bulb
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Citation Excerpt :
Female mice learn to give up responding to a mated male's pheromone at a critical period just after the mating and thereafter become insensitive to the pheromone (Leinders-Zufall et al., 2004). Noradrenaline released during mating has been proposed to facilitate this learning (Rosser and Keverne, 1985; Kaba and Keverne, 1988; Keverne and de la Riva, 1982). However, the learning is also possible in noradrenaline-deficient mice (Thomas and Palmiter, 1997).
Cholinergic modulation of spontaneous GABAergic currents (mIPSC) was studied using whole-cell patch methods in mouse accessory olfactory bulb slices. Carbachol (above 100 µM) administration produced an increase in the mIPSC frequency in mitral cells, but did not affect the responses of mitral cells to GABA. The carbachol effect persisted in the presence of combined ionotropic and metabotropic glutamatergic receptor antagonists. The carbachol effect was reduced by the muscarinic receptor type-1 and -4 (M1 and M4) antagonist pirenzepine (10 µM), but not by the M2 and M4 antagonist himbacine (10 µM). The KCNQ/Kv7 potassium channel openers retigabine (80 µM) and diclofenac (300 µM) blocked the carbachol action, while the KCNQ potassium channel blocker XE-911 (20 µM) increased the mIPSC frequency. XE-911's action persisted in the presence of glutamate receptor blockers. In the presence of carbachol, mIPSCs were abolished by Ni (200 µM), while being insensitive to the calcium channel blocker nimodipine (30 µM), suggesting a role for R-type calcium channels in the GABA release. These results suggest that carbachol closed KCNQ channels by stimulating M1 receptors on granule cell dendrites, and the resulting depolarized and unstable membrane promoted calcium influx, thus increasing the GABA release. The possible role of acetylcholine in facilitating formation of a pheromone memory in mice is also discussed.

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^*: Present address: Kochi Medical School, Okohcho, Nankoku, Kochi 781-51, Japan.

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The effect of microinfusions of drugs into the accessory olfactory bulb on the olfactory block to pregnancy

Abstract

Brain. Res.

Neuroscience

Neuroscience

Neuroscience

Brain. Res.

Brain. Res.

Involvement of the vomeronasal organ and prolactin in pheromonal induction of delayed implantation in mice

J. Reprod. Fert.

Selective immunocytochemical staining of mitral cells in rat olfactory bulb with affinity purified antibodies against N-acetyl-aspartate-glutamate

Brain. Res.

A block to pregnancy in the mouse caused by proximity to strange males

J. Reprod. Pert.

Infantile experience with suckling odours determines adult sexual behaviour in male rates

Science, N.Y.

Olfactory regulation of maternal behaviour in the rat

J. comp. physiol. Psychol.