What evidence exists showing the hormones directly impact aggressive behavior?

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Introduction

Behavioral endocrinology is the scientific study of the interaction between hormones and behavior. This interaction is bidirectional: hormones can affect behavior, and behavior can feedback to influence hormone concentrations. Hormones are chemical messengers released from endocrine glands that influence the nervous system to regulate the physiology and behavior of individuals. Over evolutionary time, hormones regulating physiological processes have been co-opted to influence behaviors linked to these processes. For example, hormones associated with gamete maturation such as estrogens are now broadly associated with the regulation of female sexual behaviors. Such dual hormonal actions ensure that mating behavior occurs when animals have mature gametes available for fertilization. Generally speaking, hormones change gene expression or cellular function, and affect behavior by increasing the likelihood that specific behaviors occur in the presence of precise stimuli. Hormones achieve this by affecting individuals’ sensory systems, central integrators, and/or peripherial effectors. To gain a full understanding of hormone–behavior interactions, it is important to monitor hormone values, as well as receptor interactions in the brain. Because certain chemicals in the environment can mimic natural hormones, these chemicals can have profound effects on the behavior of humans and other animals.

A Seasonal Obligate Migrant: White-Crowned Sparrow

The behavioral endocrinology of the migratory life history is best known from studies of songbirds that have been the focus of scientific investigations for well over 150 years. The descriptions that follow are based on the literature with a particular emphasis drawn from a long distance migratory subspecies of the White-crowned Sparrow (Zonotrichia leucophrys gambelii) (Fig. 8). Most seasonal migrants express phenotypic flexibility throughout 6 stages of the 12-month annual cycle (Fig. 9). The wintering stage occurs over the longest period and is followed by the prealternate molt that involves replacement of crown and body feathers. The cue for initiation of the molt is not well known though spring photoperiod is a likely candidate. Development of the vernal migratory stage for most north temperate species is the seasonal increase in day length in conjunction with endogenous rhythms. This stimulus activates gene expression, protein biosynthesis and cellular activation that will affect both the migratory and breeding stages. Duration of the developmental phase is at least a month, following which the mature capability phase sets in. Here testosterone and thyroid hormones contribute to hyperphagia, muscle and liver hypertrophy and physiological changes directing synthesis and deposition of fuel for flight, namely lipid and increased protein for enhance contractile forces for endurance flight and aerobic capacity for lipid utilization once migration begins (Pérez et al., 2016; Ramenofsky and Nemeth, 2014). Oxygen carrying capacity of the blood rises with increased synthesis of red blood cells (erythropoiesis) as measured by hematocrit (Krause et al., 2015). Synthesis of erythropoietin, a growth factor produced by the liver and kidney, is thought to be regulated by gonadal androgen and thyroid hormones. In a number of migrants, plasma corticosterone increases prior to departure and presumably contributes to the preparation for and transition to endurance flight. Timing of actual departure appears to be facultative and correlated with conducive weather conditions namely favorable tail winds and clear skies. After flight ensues, the levels of corticosterone remain elevated that in conjunction with other mediators of lipid and protein catabolism, all of which serve to meet the energetic demands of flight. Most migrants will undergo cycles of fueling and flight throughout the migratory period (Fig. 2). At stopovers, anabolic functions take over to replace the depleted stores of fuel experienced during flight. How quickly and effectively birds recover from flight, regain mass, fat and muscle lost en route are not known but such information along with the underlying endocrine mechanisms are vital for understanding the mechanisms regulating migratory patterns. Once birds arrive at the breeding destination and conditions allow initiation of breeding, migratory traits associated with movement cease, making way for the reproductive stage. The autumn stage of migration, though similar in terms of development, is distinct in terms of the environmental conditions and traits that typify it. Photoperiod is now declining, the reproductive system and gonadal steroids are basal, and corticosterone levels are lower and less dynamic that those of spring. The selective pressures on individuals to arrive on the wintering grounds are much reduced compared to those during spring. Once birds arrive on wintering grounds, migratory traits dissipate as the wintering stage ensues.

Taking a life cycle approach to the migratory life history provides information about the timing and duration. Each stage of the annual cycle in Fig. 9 represented by a trapezoid depicts the 3 phases: development (left triangle), mature capability (central rectangle) and termination (right triangle). What is obvious from the figure is that the stages appear distinct with relatively little contact or overlap as it is not energetically feasible to simultaneously express mature capability phases of two stages. For example, birds cannot migrate and breed simultaneously, but in some cases individuals may compromise by overlapping the development of one stage with the mature capability of the previous stage. This is evident with the vernal and breeding stages. For example, the environmental cue in spring initiates activation of the HPG for both migration and breeding stages. However, the expression of the mature capability phase of migration precedes that of breeding by at least 2 months. Given that preparation for breeding - gonadal development and gametogenesis – requires at least a month to complete, the development of the breeding axis must start during the migration stage. This is particularly critical for birds that breed at high latitude and altitude where windows of opportunity for breeding are shortened by the brevity of favorable conditions. With this kind of phenotypic flexibility, species can adjust the timing of development and expression of stages in response to demands of the environment. Other examples of overlap of phases of two stages across the annual cycle exist as well.

History

Traditionally the first study of behavioral endocrinology is reported to be that done by Arnold Adolph Berthold in 1846. It was well known that castration of young male cockerels prevents the development of male sexual traits including crowing and sexual behavior – an effect called caponization. Berthold showed that male typical behavior could be restored by reimplanting the testes in the same birds or in other castrated cockerels. Because the grafted testes did not build any tissue connection with the body of the host, Berthold concluded that some substances secreted by the testes – ‘androgens’ – were responsible for the activation of male sexual behavior. Soon afterwards, naturalists started to investigate the relationships between endocrine glands and behavior in free-living animals. In fact, already in 1802 George Montagu had noted that songbirds sing more at the times of the year when their testes are larger. By the end of the 1940s, the most important androgen and estrogen hormones, testosterone and estradiol, had been isolated and methods for their synthesis had been developed. These discoveries opened new perspectives in endocrinology as they allowed studying how specific hormones influence behavior. The founders of behavioral endocrinology, Frank A. Beach, Daniel Lehrman, and William C. Young, worked on a number of domestic or laboratory animals, building the conceptual bases for later extending behavioral endocrinology to the field. Initially, field endocrinology involved shooting the animals to measure the size of their endocrine glands. In 1960, Rosalyn Yalow and Solomon Aaron Berson published a new method called Radioimmunoassy, which allowed the measurement of hormones in relatively small blood samples. The birth of ‘modern’ field behavioral endocrinology can be traced to 1975, when John C. Wingfield and Donald S. Farner published a method for measuring five different steroid hormones in small blood samples taken from free-living songbirds which could be released immediately after sampling. This allowed studying behavioral interactions between conspecifics and correlate behavioral differences with hormonal ones. More importantly, because animals did not have to be killed to measure hormonal parameters, it was possible to study time-dependent changes in hormones in individual animals that could be sampled repeatedly.

History

Traditionally the first study of behavioral endocrinology is reported to be that done by Arnold Adolph Berthold in 1846. It was well known that castration of young male cockerels prevents the development of male sexual traits including crowing and sexual behavior – an effect called caponization. Berthold showed that male typical behavior could be restored by reimplanting the testes in the same birds or in other castrated cockerels. Because the grafted testes did not build any tissue connection with the body of the host, Berthold concluded that some substances secreted by the testes – “androgens” – were responsible for the activation of male sexual behavior (Berthold, 1849). Soon afterwards, naturalists started to investigate the relationships between endocrine glands and behavior in free-living animals. In fact, already in 1802 George Montagu had noted that songbirds sing more at the times of the year when their testes are larger (Montagu, 1802). By the end of the 1940s, the most important androgen and estrogen hormones, testosterone and estradiol, had been isolated and methods for their synthesis had been developed. These discoveries opened new perspectives in endocrinology as they allowed studying how specific hormones influence behavior.

The founders of behavioral endocrinology, Frank A. Beach, Daniel Lehrman, and William C. Young, worked on a number of domestic or laboratory animals, building the conceptual bases for later extending behavioral endocrinology to the field (Silver et al., 1973; Beach and Inman, 1965; Phoenix et al., 1959). Initially, field endocrinology involved shooting the animals to measure the size of their endocrine glands. In 1960, Rosalyn Yalow and Solomon Aaron Berson published the description of a new method called Radioimmunoassay, which allowed the measurement of hormones in relatively small biological samples (Yalow and Berson, 1960). The birth of “modern” field behavioral endocrinology can be traced to 1975, when John C. Wingfield and Donald S. Farner published a method for measuring five different steroid hormones in small blood samples taken from free-living songbirds which could be released immediately after sampling (Wingfield and Farner, 1975). This allowed studying behavioral interactions between conspecifics and correlate behavioral differences with hormonal ones. More importantly, because animals did not have to be killed to measure hormonal parameters, it was possible to study time-dependent changes in hormones in individual animals that could be sampled repeatedly.

3.02.1 Introduction and Overview

The major objective of research in behavioral endocrinology is to understand where and how hormones act in the brain to modify behavior. Among the most intensively studied steroid hormones at the cellular and molecular levels are the ovarian steroids – estradiol and progesterone. These hormones act in defined populations of central nervous system (CNS) neurons to regulate female reproductive physiology and behavior. The high degree of hormone dependence of female reproductive behavior, particularly the lordosis reflex, coupled with extensive knowledge of the underlying neural circuitry, has permitted investigators to apply a broad range of techniques to elucidate relevant sites and mechanisms of estrogen and progestin regulation of lordosis. However, estrogens also act in diverse brain regions to regulate a variety of nonreproductive behaviors and neuronal functions, including mood, cognition, pain, seizures, sensorimotor integration, energy homeostasis, and neural degeneration due to aging, ischemia, and other insults (McEwen and Alves, 1999; Chadwick and Goode, 2000; McEwen, 2001, 2002; Li and Shen, 2005; Craig and Murphy, 2007; Duckles and Krause, 2007). Therefore, experimental analysis of estrogen action in the brain has not been limited to the hypothalamus or to regulation of female reproductive behavior.

Because behavior is the product of activity in neural circuits or ensembles, it is rational to analyze the effects of hormones on the brain cells that comprise these neural circuits. An extension of this concept is that hormone-dependent changes in synaptic neurotransmission in specific neural circuits are likely to produce behavioral changes. This chapter summarizes the literature demonstrating that estrogens act at multiple presynaptic and postsynaptic levels, as well is in many (if not all) brain regions, to modify synaptic neurotransmission. We also note specific examples where progesterone acts in an estrogen-dependent manner to modulate neurotransmission. Because of increasing evidence that physiologically relevant crosstalk occurs among estrogen receptor (ER), neurotransmitter receptor, and growth-factor-receptor signal-transduction pathways, this chapter also reviews estrogen regulation of growth-factor signaling in the brain. Whether estrogens act genomically or nongenomically is considered in detail in several other chapters in this volume (see also 3.01, Membrane-Initiated Effects of Estradiol in the Central Nervous System and 3.03, Genetic and Epigenetic Mechanisms in Neural and Hormonal Controls over Female Reproductive Behaviors), and hence will not be a major issue for discussion in this chapter. Likewise, readers are referred to other sources for discussion of the hypothesis that estrogens synthesized locally in the brain can act in a neurotransmitter/neuromodulator fashion (Balthazart and Ball, 2006).

2.13.3.3 Rapid Actions of Estrogens on Aggressive Behavior

From the very beginning of the field of behavioral endocrinology, avian model systems have contributed to elucidating the relationship between steroid hormones and aggressive behavior. In 1849, pioneering work by Arnold Berthold established that castration eliminates (and transplantation of testes restores) intermale aggression in domestic chickens. More recently, John Wingfield et al. (1990) used laboratory and field studies of songbirds to demonstrate positive associations between plasma testosterone and territorial aggression, particularly during periods of social instability (i.e., the ‘Challenge Hypothesis’). Furthermore, such integrated laboratory and field studies of song sparrows have provided evidence that brain-derived estrogens rapidly modulate aggressive behavior.

In North America, some populations of song sparrows occupy and defend territories throughout the year. This includes the nonbreeding season (autumn and winter), when the gonads are fully regressed and plasma levels of testosterone are nondetectable. These observations raised the hypothesis that nonbreeding aggression is not regulated by sex steroids, such as T and E2. However, aromatase is expressed in behaviorally relevant brain regions in the nonbreeding season (Soma et al., 2003). Moreover, field experiments clearly demonstrated that both acute (24 h) and chronic (14 days) inhibition of aromatase reduces, and E2 replacement restores, territorial aggression in nonbreeding male song sparrows (Soma et al., 2000). Circulating testosterone and androstenedione levels are nondetectable in the nonbreeding season (Heimovics et al., 2012b) and thus cannot serve as substrates for brain aromatase. However, the androgen precursor (prohormone) dehydro-epiandrosterone (DHEA) is present in the blood and brain during the nonbreeding season (Soma and Wingfield, 2001; Heimovics et al., 2012a) and the enzyme that converts DHEA to androstenedione (3β-HSD) is present and active in the brain during the nonbreeding season (Pradhan et al., 2010). A field study showed that an STI during the nonbreeding season rapidly increases 3β-HSD activity in specific brain regions (Pradhan et al., 2010). Taken together with the fact that chronic administration of an aromatase inhibitor produces a nonsignificant decrease in aggressive behavior (Soma et al., 2000), these data suggest that neuroestrogen production may be more critical to the regulation of aggressive behavior in the nonbreeding season.

Neurosteroids can act via rapid nonclassical mechanisms in the avian brain (Pradhan et al., 2008, 2010; Schmidt et al., 2010). Thus, the rapid effects of E2 administration on aggressive behavior were examined in nonbreeding and breeding male song sparrows (Heimovics et al., 2015a). Notably, subjects in this experiment were tested in a seminatural setting: birds were caught locally and housed singly in cages placed in outdoor pens and thus they were exposed to ambient photoperiod, temperature, humidity, etc. Using a within-subjects design, male song sparrows were administered E2 or vehicle control noninvasively (solutions were injected into wax moth larva and subsequently fed to subjects). Ten minutes later, their aggressive behavior during a laboratory STI (L-STI) was quantified for 10 min. Acute E2 administration significantly increased aggressive behavior during the L-STI in nonbreeding but not in breeding subjects (Figure 5; Heimovics et al., 2015a). Given that the effects of E2 on nonbreeding aggression were seen within 20 min of E2 administration, these data strongly suggest that E2 activates aggressive behavior via a nongenomic mechanism in the nonbreeding season. Moreover, these data indicate that environmental cues associated with the nonbreeding season (e.g., short days, cool temperatures) may fundamentally alter the mechanisms by which E2 regulates the brain and behavior.

Brain sites that might mediate the rapid effects of E2 on song sparrow aggression were identified using immunohistochemistry for phosphoproteins associated with nongenomic estrogen signaling (Heimovics et al., 2012b). Membrane-associated estrogen receptors can modulate the extracellular signal-regulated kinase (ERK 1/2) pathway. When this pathway is activated, phosphorylated ERK (pERK) can go on to phosphorylate cAMP response element-binding protein (CREB) and tyrosine hydroxylase (TH, the rate-limiting enzyme in dopamine synthesis) (Heimovics et al., 2012b). Accordingly, staining for pERK, pCREB, and pTH was performed on brain tissue collected from breeding and nonbreeding male song sparrows (pretreated with the aromatase inhibitor fadrozole) that had been administered E2 or vehicle 15 min prior to euthanasia. E2 rapidly altered pERK, pCREB, and pTH immunoreactivity throughout much of the vertebrate ‘social behavior network’ including the POA, ventromedial hypothalamus (VMH), lateral septum (LS), nucleus taeniae (TnA, the avian homolog of the medial amygdala), and midbrain including the central gray (GCt) and ventral tegmental area (VTA). These nuclei are implicated in the neuroendocrine regulation of multiple forms of social behavior, including aggression. Thus, these data identify the POA, VMH, LS, TnA, GCt, and VTA as possible areas of the brain where E2 might act via rapid, nongenomic mechanisms to regulate aggression. Importantly, most of the rapid effects of E2 on intracellular signaling within the social behavior network were seen in both nonbreeding and breeding condition subjects. In fact, only pCREB in the medial POM (located within the POA) was found to be altered by E2 in nonbreeding subjects only. Future studies will focus on the role of estrogen signaling in the POM.

The aforementioned results indicate that both the nonbreeding and breeding song sparrow brain is responsive to the rapid effects of E2. Furthermore, high levels of aggressive behavior during a very brief (5 min) L-STI rapidly lowers DHEA levels in the anterior hypothalamus and medial striatum of both nonbreeding and breeding song sparrows (Heimovics et al., 2016). Taken together, these studies suggest that the production of steroids locally within the brain (neuroestrogens and/or neuroandrogens) is especially important for the regulation of aggressive behavior during the nonbreeding season, but there might be effects in the breeding season as well that are still unclear.

In summary, studies on birds have revealed new dimensions regarding how estrogens act acutely to regulate behaviors and brain circuits. In addition to important long-term regulation of seasonal plasticity in the brain of songbirds (Brenowitz, 2004; Meitzen et al., 2007; Caras et al., 2015), estrogens clearly exert a variety of rapid actions on auditory, sexual, and aggressive behaviors in avian species. Often, these two mechanistic roles (short-term vs long-term) are mediated by alternative receptor mechanisms, although they may in some cases occur in the same brain regions. As we have begun to learn about these rapid actions over the past decade or so, the underlying mechanisms have become important to consider for understanding the biology of birds, as well as moving further toward broader principles for vertebrates in general.

50 Years Ago

In 1959 a single publication by William C. Young and his colleagues changed the paradigm of behavioral endocrinology so much so that there has been little work on bisexuality of the brain since that time; this seminal paper set the trajectory of research on the neuroendocrinology of sexual behavior to the present day (Phoenix et al., 1959). Indeed, for the past 50 years almost all research in this area has focused on why males (or females) behave the way they do.

Drawing the analogy with the differential development of the accessory sex structures during embryogenesis as described by Alfred Jost a few years previously, Young and colleagues suggested that a similar dual anatomy exists in the brain, proposing that just as the early hormonal environment determined the fate of the ducts that transport eggs (Müllerian ducts) or sperm (Wolffian), these hormones also acted on the developing brain, specifically on the neural circuits subserving female- and male-typical sexual behaviors. In addition to its embryological foundation, the new perspective also built on the foundation laid earlier demonstrating that sexual behaviors were not simply dictated by sex steroid hormones, but reflected mechanisms intrinsic to the state of the brain itself. Although it was recognized that in some way the hormones were acting on the brain, the mechanism of this action was a mystery. It should be pointed out, however, that this new perspective in itself did not explain (nor did it seek to) the observation that individuals of either sex retain the capacity to, and commonly display, the behaviors typical of the opposite sex. The Organizational/Activational concept of Young and colleagues was further refined a few years later by Richard Whalen with the concept that the development of sex typical behaviors resulted from two independent processes, namely masculinization-demasculinization and feminization-defeminization (see below). Put simply, 1959 marked a time when the salient question transitioned from ‘why do males and females sometimes behave as the opposite sex’, to ‘why do males behave like males and females like females’.

Introduction

The study of female sexual behavior has been an active area of investigation within the field of Behavioral Endocrinology for over 80 years for a variety of reasons. Female sexual behavior is robust, reliable, and, at some levels, relatively easy to study. Furthermore, it lends itself to both behavioral analysis and mechanistic analysis. Sexual behavior is undoubtedly biologically important, and no inference is necessary to understand its relevance to the animal. Sexual behavior is also the prototypical model for sexual differentiation of the brain, since in most species the behavior is sexually dichotomous. Finally, although this was not clear in earlier years, female sexual behavior in some rodent species provides a useful model for understanding the role of hormones in certain aspects of human sexuality.

Female sexual behavior has also been used extensively as a model behavior for understanding the mechanisms by which hormonal and afferent neural signals from the social environment interact at the cellular level to modulate behavior. Some of the most interesting aspects of this model are the many ways in which behavioral response is shaped by environmental stimuli, as well as the ways in which behavioral output changes physiology. Although various components of these complex interactions can be studied in a reductionistic manner, they also lend themselves to analysis at all levels from organismic to cellular and molecular.

Introduction

The study of female sexual behavior has been an active, perhaps the most active, area of investigation within the field of Behavioral Endocrinology for over 75 years for a variety of reasons. Female sexual behavior is robust, reliable, and, at some levels, relatively easy to study. Furthermore, it lends itself to both behavioral analysis and mechanistic analysis. Sexual behavior is undoubtedly biologically important, and no inference is necessary to understand its relevance to the animal. Sexual behavior is also the prototypical model for sexual differentiation of the brain, since in most species the behavior is sexually dichotomous. Finally, although this was not clear in earlier years, female sexual behavior in some rodent species provides a useful model for understanding the role of hormones in certain aspects of human sexuality.

Female sexual behavior has also been used extensively as a model behavior for understanding the mechanisms by which hormonal and afferent neural signals from the social environment interact at the cellular level to modulate behavior. Some of the most interesting aspects of this model are the many ways in which behavioral response is shaped by environmental stimuli, as well as the ways in which behavioral output changes physiology. Although various components of these complex interactions can be studied in a reductionistic manner, they also lend themselves to analysis at all levels from organismic to cellular and molecular.

1.05.3.1 Introduction and Definitions

Psychoneuroendocrinology and psychoneuroimmunology deal with the study of the relationship between the hormonal and immune system and behavior, particularly in humans. Behavioral endocrinology and behavioral immunology use mostly animals for the same purpose. Several excellent texts are available for an in-depth review of both fields (cf., Ader, Felten, & Cohen, 1990; Becker, Breedlove, & Crews, 1992; Nelson, 1994). Here we provide a short overview of the main topics of both fields without a repetition of basic immunology or endocrinology. Both can be found in the textbooks on physiology and the above-mentioned introductions.

There are intricate relationships between the nervous system, the immune system, and the endocrine system. Behavior (on all three levels: motor, cognitive, and physiological) is not directly influenced by the two systems but hormones and immune factors enter the nervous system and change behavior through that system. It is important to note that there are reciprocal interactions between the nervous system and behavior: behavior is not only affected by the hormonal and immune system but together with environmental stimuli and the consequences of a particular behavior, behavior itself affects again the two “slow” bodily systems.

Hormones or immune factors can have organizing or activating effects. An organizing effect would, for example, be the specific formation of hypothalamic nuclei during intrauterine development which later in life cause heterosexual or homosexual behavior (see Section 1.05.9.3.6). An activating effect consists, for example, of the unspecific secretion of ACTH after stressful stimuli. Hormones influence sensory systems, the CNS, as well as the effectors. The hormonal and the immune system are phylogenetically very old systems (from insect to humans with similar structure and function) and act relatively slowly on behaviorally relevant structures. Slow means that the direct actions of the nervous system on muscles are usually much faster (in the millisecond range), whereas the “wet” bloodstream-dependent hormones and immune structures exert their effects within seconds, hours, days, or months. Both fields become increasingly important for clinical psychology and behavior modification: many clinical psychological and psychiatric disorders are caused or at least in some aspects influenced by endocrine and/or immunological agents. Additionally, the tailoring of psychological intervention strategies to endocrine and immunological changes in patients is extremely important, as can be seen from the intricate interplay of circadian hormonal rhythms and depression, sex hormones and sexual deviations, and in the modification of antisocial behavior, treatment of obesity and eating disorders, and stress-related disorders.