Douglas W. Wacker

Rapid inhibition of female sexual behavior by gonadotropin-inhibitory hormone (GnIH).

Gonadotropin-releasing hormone (GnRH) is largely responsible for the initiation of sexual behaviors; one form of GnRH activates a physiological cascade causing gonadal growth and gonadal steroid feedback to the brain, and another form is thought to act as a neurotransmitter to enhance sexual receptivity. In contrast to GnRH, gonadotropin-inhibitory hormone (GnIH) inhibits gonadotropin release. The distribution of GnIH in the avian brain suggests that it has not only hypophysiotropic actions but also unknown behavioral actions. GnIH fibers are present in the median eminence (ME) and are in apparent contact with chicken GnRH (cGnRH)-I and -II neurons and fibers. In birds, cGnRH-I regulates pituitary gonadotropin release, whereas cGnRH-II enhances copulation solicitation in estradiol-primed females exposed to male song. In the present study, we determined the effects of GnIH administered centrally to female white-crowned sparrows. A physiological dose of GnIH reduced circulating LH and inhibited copulation solicitation, without affecting locomotor activity. Using rhodaminated GnIH, putative GnIH binding sites were seen in the ME close to GnRH-I fiber terminals and in the midbrain on or close to GnRH-II neurons. These data demonstrate direct effects of GnIH upon reproductive physiology and behavior, possibly via separate actions on two forms of GnRH.

An intrinsic vasopressin system in the olfactory bulb is involved in social recognition

Many peptides, when released as chemical messengers within the brain, have powerful influences on complex behaviours. Most strikingly, vasopressin and oxytocin, once thought of as circulating hormones whose actions were confined to peripheral organs, are now known to be released in the brain, where they have fundamentally important roles in social behaviours. In humans, disruptions of these peptide systems have been linked to several neurobehavioural disorders, including Prader–Willi syndrome, affective disorders and obsessive–compulsive disorder, and polymorphisms of V1a vasopressin receptor have been linked to autism. Here we report that the rat olfactory bulb contains a large population of interneurons which express vasopressin, that blocking the actions of vasopressin in the olfactory bulb impairs the social recognition abilities of rats and that vasopressin agonists and antagonists can modulate the processing of information by olfactory bulb neurons. The findings indicate that social information is processed in part by a vasopressin system intrinsic to the olfactory system.

Aggressive interactions rapidly increase androgen synthesis in the brain during the non-breeding season.

In male song sparrows (Melospiza melodia), territorial challenges during the breeding season can rapidly increase circulating levels of testosterone (T). During the non-breeding season, male song sparrows are highly aggressive, but the gonads are regressed and plasma T levels are non-detectable and unaffected by territorial challenges. The pro-hormone dehydroepiandrosterone (DHEA) is elevated in song sparrow plasma and brain during the non-breeding season and may be locally converted to sex steroids in the brain to regulate aggression. The enzyme 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) converts DHEA to androstenedione (AE) using the cofactor NAD(+), and this is a critical rate-limiting step. We predicted that brain 3beta-HSD activity varies seasonally and is rapidly modulated by aggressive challenges. In the first study, brain 3beta-HSD activity was highest in the non-breeding season in specific regions. In the second study, a simulated territorial challenge rapidly increased aggressive behavior in non-breeding song sparrows. Brain 3beta-HSD activity, when measured without exogenous NAD(+), increased by approximately 250 to 500% in telencephalic regions of challenged subjects. When brain 3beta-HSD activity was measured with exogenous NAD(+), these effects of territorial challenges were not observed. These data suggest that territorial challenges rapidly increase endogenous NAD(+) levels or increase 3beta-HSD activity specifically within a NAD-rich subcellular compartment. Together, these two studies suggest a shift from systemic to local sex steroid signaling in the non-breeding season. Local steroid signaling produces high spatial and temporal specificity of steroid signals and avoids the costs of high systemic T levels during the non-breeding season.

Vasopressin, oxytocin, and social odor recognition

Central vasopressin and oxytocin, and their homologues, modulate a multitude of social behaviors in a variety of animal taxa. All social behavior requires some level of social (re)cognition, and these neuropeptides exert powerful effects on an animals ability to recognize and appropriately respond to a conspecific. Social cognition for many mammals, including rodents, begins at the main and accessory olfactory systems. We recently identified vasopressin expressing neurons in the main and accessory olfactory bulb and in the anterior olfactory nucleus, a region of olfactory cortex that transmits and processes information in the main olfactory system. We review this and other work demonstrating that both vasopressin and oxytocin modulate conspecific social recognition at the level of the olfactory system. We also outline recent work on the somato-dendritic release of vasopressin and oxytocin, and propose a model by which the somato-dendritic priming of these neuropeptides in main olfactory regions may facilitate the formation of short-term social odor memories. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Seasonal Differences of Gene Expression Profiles in Song Sparrow (Melospiza melodia) Hypothalamus in Relation to Territorial Aggression

Background Male song sparrows (Melospiza melodia) are territorial year-round; however, neuroendocrine responses to simulated territorial intrusion (STI) differ between breeding (spring) and non-breeding seasons (autumn). In spring, exposure to STI leads to increases in luteinizing hormone and testosterone, but not in autumn. These observations suggest that there are fundamental differences in the mechanisms driving neuroendocrine responses to STI between seasons. Microarrays, spotted with EST cDNA clones of zebra finch, were used to explore gene expression profiles in the hypothalamus after territorial aggression in two different seasons. Methodology/Principal Findings Free-living territorial male song sparrows were exposed to either conspecific or heterospecific (control) males in an STI in spring and autumn. Behavioral data were recorded, whole hypothalami were collected, and microarray hybridizations were performed. Quantitative PCR was performed for validation. Our results show 262 cDNAs were differentially expressed between spring and autumn in the control birds. There were 173 cDNAs significantly affected by STI in autumn; however, only 67 were significantly affected by STI in spring. There were 88 cDNAs that showed significant interactions in both season and STI. Conclusions/Significance Results suggest that STI drives differential genomic responses in the hypothalamus in the spring vs. autumn. The number of cDNAs differentially expressed in relation to season was greater than in relation to social interactions, suggesting major underlying seasonal effects in the hypothalamus which may determine the differential response upon social interaction. Functional pathway analyses implicated genes that regulate thyroid hormone action and neuroplasticity as targets of this neuroendocrine regulation.

Seasonal changes in aromatase and androgen receptor, but not estrogen receptor mRNA expression in the brain of the free-living male song sparrow, Melospiza melodia morphna

Free‐living male song sparrows experience three annually repeating life history stages associated with differential expression of sex steroid‐dependent reproductive and aggressive behavior. In the breeding stage, they display reproductive and aggressive behavior and have elevated circulating testosterone levels. During molt, males show little or no aggression and no reproductive behavior, and have basal levels of circulating testosterone. In the non‐breeding stage, they display high levels of aggression and no reproductive behavior, and have basal levels of circulating testosterone. In order to understand more fully the neural regulation of seasonal aggressive and reproductive behavior, birds were collected during all three life history stages, and levels of neural aromatase, androgen receptor (AR), and estrogen receptor α (ERα) and β (ERβ) mRNA expression were measured. Breeding males had the highest levels of aromatase expression in both the preoptic area (POA) and medial preoptic area/medial bed nucleus of the stria terminalis (mPOA/BSTm), and the highest AR expression levels in the POA, consistent with the well‐established role these regions play in the regulation of male reproductive behavior. Aromatase expression in the ventromedial nucleus of the hypothalamus (VMH) was higher during breeding and non‐breeding compared with molt, suggesting that the VMH may play a role in the estrogen‐dependent regulation of aggression in this species. AR expression also varied in medial HVC and pvMSt, a newly described periventricular region in the medial striatum. ERα and ERβ mRNA expression did not vary seasonally in any brain region examined, suggesting that estrogen‐dependent changes in behavior are mediated by differences in neural estrogen synthesis. J. Comp. Neurol. 518:3819–3835, 2010.

The role of androgen receptors in regulating territorial aggression in male song sparrows.

This paper examines the role that androgen receptors (ARs) play in modulating aggressive behavior in male song sparrows, Melospiza melodia morphna. Song sparrows are seasonally breeding, territorial birds that maintain year-round territories with male-female pair bonds formed during the spring breeding season. Plasma testosterone levels peak as territories are established and mates acquired. In late summer, testosterone levels fall and remain basal during the non-breeding season. We examined the role of ARs in regulating territorial aggression in captive song sparrows under short- and long-day conditions as well as just prior to, and at the start of the breading season in freely living birds using the nonsteroidal antiandrogen flutamide to block AR function. Birds were implanted with either empty or drug filled silastic implants for 18 to 42 days and then challenged with a novel male decoy to assess the individual birds level of male-male aggression. Freely living birds remained on their home territory and underwent a simulated territorial intrusion, whereas laboratory-held birds were assessed using a laboratory simulated territorial intrusion and remained in their home cage. Experimental treatment of male song sparrows decreased aggressive behavior during the pre-breeding life history substage (March-April) in freely living birds as well as in laboratory-held birds under long-day (16L:8D) conditions. During the early breeding substage (April-May) there was no measurable effect of flutamide treatment on aggressive behavior, nor was there a difference in behavior in the (8L:16D) laboratory birds. This demonstrates that ARs are an important component of the neuroendocrine control of aggressive behavior. Given that flutamide only affected aggression during the pre-breeding substage and in LD birds, the results suggest that AR dependent control of aggressive behavior changes as song sparrow life history states change.

Vasopressin and social odor processing in the olfactory bulb and anterior olfactory nucleus.

Central vasopressin facilitates social recognition and modulates numerous complex social behaviors in mammals, including parental behavior, aggression, affiliation, and pair‐bonding. In rodents, social interactions are primarily mediated by the exchange of olfactory information, and there is evidence that vasopressin signaling is important in brain areas where olfactory information is processed. We recently discovered populations of vasopressin neurons in the main and accessory olfactory bulbs and anterior olfactory nucleus that are involved in the processing of social odor cues. In this review, we propose a model of how vasopressin release in these regions, potentially from the dendrites, may act to filter social odor information to facilitate odor‐based social recognition. Finally, we discuss recent human research linked to vasopressin signaling and suggest that our model of priming‐facilitated vasopressin signaling would be a rewarding target for further studies, as a failure of priming may underlie pathological changes in complex behaviors.

Combined effects of DHEA and fadrozole on aggression and neural VIP immunoreactivity in the non-breeding male song sparrow

The male Song Sparrow, Melospiza melodia morphna, shows high levels of aggression in its non-breeding season, concomitant with basal levels of circulating testosterone (T) and estradiol (E(2)). However, administration of fadrozole, an aromatase inhibitor, decreases non-breeding aggression in the field. Circulating levels of dehydroepiandrosterone (DHEA), an androgen/estrogen precursor, correspond to the seasonal expression of aggression in this species, with high levels in the breeding and non-breeding seasons when aggression is also high, and lower levels during the molt when aggression is low. We test the hypothesis that circulating DHEA up-regulates non-breeding aggression via an aromatase-mediated mechanism. We also hypothesize that this up-regulation of aggression is partially mediated by changes in vasoactive intestinal polypeptide (VIP) in the lateral extent of the bed nucleus of the stria terminalis (BSTl) and lateral septum (LS). Birds were administered either DHEA, fadrozole, or both for 2 weeks and tested for aggression in a lab-based paradigm. As predicted, birds given DHEA were significantly more aggressive. However, fadrozole did not block this effect, and, when administered without DHEA, also led to increased aggression over controls. These results may be explained by the fact that the behaviors measured in field tests, which include more direct attack behaviors, may be under different hormonal regulation than the behaviors measured in the lab paradigm, which represent warning, or threat, behaviors. VIP immunoreactivity (VIP-ir) changed across multiple brain regions with this treatment regimen, most notably in the LSO/VFI subdivision of the lateral septum.

Expression of early growth response protein 1 in vasopressin neurones of the rat anterior olfactory nucleus following social odour exposure

The anterior olfactory nucleus (AON), a component of the main olfactory system, is a cortical region that processes olfactory information and acts as a relay between the main olfactory bulbs and higher brain regions such as the piriform cortex. Utilizing a transgenic rat in which an enhanced green fluorescent protein reporter gene is expressed in vasopressin neurones (eGFP‐vasopressin), we have discovered a population of vasopressin neurones in the AON. These vasopressin neurones co‐express vasopressin V1 receptors. They also co‐express GABA and calbinin‐D28k indicating that they are neurochemically different from the newly described vasopressin neurons in the main olfactory bulb. We utilized the immediate early gene product, early growth response protein 1 (Egr‐1), to examine the functional role of these vasopressin neurons in processing social and non‐social odours in the AON. Exposure of adult rats to a conspecific juvenile or a heterospecific predator odour leads to increases in Egr‐1 expression in the AON in a subregion specific manner. However, only exposure to a juvenile increases Egr‐1 expression in AON vasopressin neurons. These data suggest that vasopressin neurones in the AON may be selectively involved in the coding of social odour information.