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GENETICS |
* Livestock Behavior Research Unit, USDA-Agricultural Research Service, West Lafayette, IN 47907; Purdue University, Department of Animal Science, West Lafayette, IN 47907; and School of Animal Science, Zheijiang University, Zheijiang, 310058, China
1 Corresponding author: Heng-wei.Cheng{at}ars.usda.gov
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: serotonin • aggression • genetic selection • chicken • hen
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Plasticity of neuronal structure and function in response to environmental change can alter both behavioral style (Sausa et al., 2000) and stress response (Pacak and Palkovits, 2001) including aggression. Adaptive alterations to the central neurotransmission, such as within the serotonergic system, have been used as indicators of stimulation-evoked reactions in mammals, including domestication of animals (Waterhouse et al., 1990; Popova et al., 1991, 1997). These changes functionally allow animals to adapt to their environments and are reflected as changes in the behavioral and physiological homeostasis of the animals. Serotonin (5-HT), one of the primary neurotransmitters involved in mammalian aggressiveness, functions as an inhibitory factor of aggression. Alterations of mammalian 5-HT and metabolite concentrations as well as density of its receptors have been used as indicators of aggression (Popova et al., 1997; Weiger, 1997). Aggressive rats have lower levels of 5-HT in the hypothalamus (Nikulina et al., 1991). Rodent-killing behavior can be blocked by experimental increase of 5-HT in the brain (Nikulina et al., 1991). In addition, aggressiveness can be increased due to impaired 5-HT receptor function (de Boer et al., 2000; Cleare and Bond, 2001) or by knockout of 5-HT1 receptor genes (Scearce-Levie et al., 1999). Functional changes of the serotonergic system are also found in humans with violent behaviors (Unis et al., 1997; George et al., 2006; Murakami et al., 2006; Zhou et al., 2006). Although, in mammals, aggression has been shown to be mediated through both the 5-HT1A and 1B pathways (Nelson and Chiavegatto, 2001), the exact role of each of these pathways in aggression mediation is still unclear.
To better examine the heritable mechanisms of serotonergic mediation of poultry aggressiveness, we examined 3 distinct strains of birds; 2 divergently selected strains characterized by high (HGPS) and low (LGPS) production and survivability resulted from cannibalism and a third strain, Dekalb XL (DXL), an aggressive commercial strain used as our out-group. Each of these strains is behaviorally distinct and show different levels of apparent well-being (Cheng et al., 2001). Our previous studies have shown that strain HGPS had a lower aggressive profile compared with their counterparts LGPS and DXL (Cheng et al., 2001). The differences in behavioral and physiological characteristics of these strains are reflected in changes in the capability of neuronal system in response to stimuli, including the neurotransmitter system (Dennis et al., 2006). That is, when selection was applied to production and specific behaviors (aggression and cannibalism) or disease resistance, selection was indirectly and simultaneously applied to the central nervous system neurons and resulted in the changes in the neurotransmitter systems that brought about the behavioral changes (Cheng et al., 2001; Dennis et al., 2004, 2006).
This study was designed to test our hypothesis that selection-induced changes of the serotonergic system play an important role in controlling animal behaviors and that this system is mediated differently in birds from high and low aggressive strains via the 5-HT1A and 1B receptors.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The 11th selected generation of chickens from the HGPS and LGPS as well as DXL strains were used in this study. The differences between the selected strains in productivity and survivability (Muir, 1996; Cheng et al., 2001) as well as immunology (Cheng et al., 2001) were previously reported. In the study, chicken care guidelines were in strict accordance with the rules and regulations set by the Federation of Animal Science Societies (Craig et al., 1999). Experimental protocols were approved by the Institutional Animal Care and Use Committee at Purdue University (protocol 00-008-03).
Aggression Testing and Drug Administration
At 22 wk of age, hens from each genetic strain were each randomly paired with a hen of the same strain in novel cages allowing 1,000 cm2/bird. All pairs were videotaped for the next 24 h to determine the least aggressive individual per pair. At 24 wk of age, the least aggressive individual from each pair received a daily i.p. injection of the 5-HT1A antagonist NAN-190 (0.5 mg/kg in 1 mL of saline; n = 7 per strain), 5-HT1B antagonist GR-127935 (0.5 mg/kg in 1 mL of saline; n = 7 per strain), or saline vehicle only (control; n = 8 per strain) for 5 consecutive days. Pairs were videotaped on d 0 (1 d preinjection) and d 1 through 5 of injection. Video recordings were analyzed for frequency and duration of aggressive pecks, threats, and feather pecking as described below.
Aggressive pecking: forceful downward pecks directed at the head or neck of other birds.Threat: One bird standing with its neck erect and hackle feathers raised (may only be slightly) in front of another bird.
Feather pecking: One bird pecks at feathers of another bird, can be gentle (nibbling or gentle pecking in which feathers are not removed or pulled) or severe (vigorous pecking to feathers in which feathers are often pulled, broken, or removed).
BW
Body weight was assessed 24 h before the first treatment on d 0 and again on d 5. The changes of BW were represented as weight gain after the treatment (BW gain = BW at d 5 of injection – BW at d 0).
Blood Sampling
A 5-mL blood sample was collected in an EDTA-coated tube from the birds after all treatments (24 h after final injection) by heart puncture using a 20-gauge needle after sedation with sodium phenobarbitol. The blood samples were centrifuged at 700 x g for 15 min at 4° C. Plasma and whole blood samples were kept at – 80° C until analysis by HPLC for 5-HT, amino acid, and catecholamine.
HPLC Assay: Dopamine, EP, and Norepinephrine
Dopamine, epinephrine (EP), and norepinephrine were measured, in duplicate, from plasma samples using a plasma catecholamine analysis kit (ESA Inc., Chelmsford, MA). Samples were deproteinized and acidified with 100 µL of 4 M perchloric acid. Samples were then centrifuged at 13,000 x g for 10 min at 4° C, and acid supernatants were added and absorbed onto an alumina minicolumn with internal standard, dihydroxybenzylamine. Minicolumns were set on a rocker to allow catecholamines to bind to the alumina. Columns were rinsed and eluted using solutions provided by ESA Inc. Eluents were injected into the reverse-phase columns where catecholamines were detected by HPLC with an ESA Coulochem II electrochemical detector (ICN Biomedicals Inc., Costa Mesa, CA). The mobile phase (75 mM Na2HPO4, 1.7 mM octanesulfonic acid, 25 µM EDTA, 10% CH3CN, and 100 uL/L of triethanolamine, adjusted to pH 3.00 with phosphoric acid) flow rate was 1.3 mL/min. An ESA HR-80 (80 mm in length) column with a pore size of 120 A was used in the study. Epinephrine concentrations were calculated from a reference curve constructed using the provided standards. Concentrations were obtained as nanograms per milliliter.
HPLC Assay: 5-HT and Trp
Serotonin and Trp were measured in duplicate from whole-blood samples. Samples were acidified in duplicate using 4 M perchloric acid and freshly prepared 3% ascorbic acid. After centrifugation, the acid supernatants were injected onto the columns. The mobile phase flow rate was 1.0 mL/min, and the concentration of 5-HT and Trp were calculated from a reference curve made using standard 5-HT and Trp. Concentrations were obtained as nanograms per milliliter.
Statistics
Behavior data were analyzed using a MIXED model repeated measure analysis of covariance (ANCOVA) for differences over time of d 1 through 5 of treatment. Baseline was assessed on d 0 (24 h before the first injection). For behavioral data analysis, day of observation was considered the repeated measure and was fit to an appropriate analysis structure for each behavior [heterogenous compound symmetry structure for pecks and first-order autoregressive covariance structure for threats and feather pecking] . Log transformation was used in ANOVA of catecholamine and amino acid data. Aggressive behaviors were compared across strains, antagonist treatment, and observation day. Least square means and SEM were reported for all groups. Contrasts were used to determine significance using the Bonferroni adjustment to maintain an experimental 
of 0.05 (0.10 was considered a trend). Data were analyzed using PROC MIXED of SAS 8.2 software (SAS Institute Inc., Cary, NC). Main effects included genetic strains, antagonist treatment, and observation day as the repeated measure; all interactions between main effects were considered.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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to 3, Table 1). After treatment with 5-HT1A antagonist, LGPS and DXL birds exhibited significantly more pecks than HGPS birds (P < 0.05). When treated with 5-HT1B antagonist, the birds of HGPS (P < 0.05) but not LGPS or DXL strains (P > 0.10) exhibited increased frequency of pecking. Subordinate birds showed no significant differences between strains in saline-treated control groups (P > 0.10). There were no time effects on aggressive behaviors in either the 5-HT1A- or 1B-treated groups from d 1 through 5 postinjection (P > 0.10).
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, Table 1). After treatment with 5-HT1A antagonist, birds of LGPS and DXL showed significantly increased frequency of threat behaviors compared with saline control and baseline (P < 0.05) and were significantly increased compared with treated HGPS birds (P < 0.05). The HGPS birds treated with 5-HT1B antagonist displayed increased threat behaviors compared with control and LGPS and DXL birds (P < 0.05). No differences were found in threat behaviors between d 1 through 5 post-5-HT1A or 1B antagonist treatment (P > 0.10) or between strains in threat frequency in saline-treated groups (P > 0.10).
Feather Pecking Behavior
There was a strong strain x receptor antagonist treatment interaction on frequency of feather pecking behavior (P < 0.0001; Figure 3, Table 1). Increases in feather pecking behavior were significant in HGPS birds after treatment with 5-HT1B antagonist and in LGPS birds after antagonism of the 5-HT1A receptor (P < 0.05). No differences in feather pecking behavior were found between d 1 through 5 of treatment (P > 0.10) or between strains in feather pecking frequency of birds during baseline determination or in saline-treated groups (P > 0.10).
5-HT, Amino Acid, and Catecholamine Analysis
Plasma 5-HT concentration was significantly altered by receptor antagonist treatment (P < 0.05). Birds of all strains treated with 5-HT1A and 1B antagonists exhibited decreased and elevated peripheral 5-HT (15.1 ± 0.21 and 17.3 ± 0.023 ng/mL), respectively, compared with saline-injected control birds (16.3 ± 0.20). Tryptophan, the amino acid precursor to 5-HT, also differed significantly by the strain (P < 0.01; Table 1), with DXL birds of both treatment and control groups having significantly lower levels of Trp in the blood (11.9 ± 0.21, P < 0.05, Table 1), compared with HGPS and LGPS birds (12.5 ± 0.21 and 12.6 ± 0.21, respectively). There was a strong trend for the interaction of strain x receptor antagonist treatment on plasma EP (P < 0.10; Figure 4, Table 1). The LGPS control birds tended to have elevated peripheral EP concentration compared with HGPS and DXL birds, respectively (P < 0.10). After treatment with 5-HT1B antagonist, LGPS birds exhibited decreased EP concentration (P < 0.05). There was no difference in either plasma dopamine or norepinephrine concentrations between strains (P > 0.10) or after 5-HT1A and 1B receptor antagonist treatments (P > 0.10).
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, Table 1). The 5-HT1B-treated birds showed significantly reduced BW over the 5-d treatment period compared with control birds, but not 5-HT1A-treated birds.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Previous studies have shown that concentration of 5-HT and metabolites (such as 5-hydroxyindoleacetic acid) have traits like heritable properties in mammals. Broad and narrow heritability of whole-blood 5-HT concentration were assessed in a human founder population to be 1.0 and 0.51, respectively (Abney et al., 2001). Mammals exhibiting relatively low central 5-HT concentrations or reduced cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid exhibited elevated or unrestrained aggressiveness (Higley and Linnoila, 1997; Coccaro, 1998). A similar heritable component of aggression and other stress-related behaviors has been shown in the present selected chicken strains with high and low aggressive profiles (Craig and Muir, 1996a,b; Cheng et al., 2001). Although the regulatory mechanisms that created these distinct phenotypes are unclear, the differential aggressive responsiveness and stress parameters after administration of 5-HT1A and 1B receptor antagonists (summarized in Table 1) may indicate that there are different functions of these receptors in the present high and low aggressive strains. Similarly, different functions of 5-HT1A and 1B receptors in regulating aggression have been seen in rodents (Olivier et al., 1995; de Boer and Koolhaas, 2005; Veening et al., 2005). It has been proposed that the differential functions between 5-HT1 subtype receptors could be related to the different hierarchically neural systems in the brain regions that are involved in the integration of behavioral outcome including aggressive behaviors, such as differences in receptor density and expression, mediating pathways, stimulus perception, pleotrophic effects, or epistatic interactions. Similar cellular mechanisms may be presented in the diversely selected chicken strains.
Although the amount of available Trp has been shown to influence 5-HT concentration, here we show no evidence that depletion or excess of Trp played any role in the peripheral 5-HT production. Antagonism of 5-HT1B increased the peripheral 5-HT levels in all strains, suggesting a role of the 5-HT1B receptor in preventing excess 5-HT production, either directly through feedback systems of the terminal autoreceptors or indirectly through more elaborate feedback mechanisms. Alternately, the 5-HT1A receptor-involved feedback mechanisms maintain serotonergic homeostasis by maintaining adequate 5-HT production. Suppressed levels of circulating 5-HT resulting from 5-HT1A antagonism may, in part, be responsible for elevated aggression in LGPS and DXL birds. However, the increased aggression in HGPS birds coincides with an increase in 5-HT, in opposition to the inhibitory effect that elevated levels of 5-HT has on aggression, suggesting there are additional mechanisms regulating the changes seen in this study. In the study by deBoer and Koolhass (2005), 5-HT1A receptor agonist inhibits aggressiveness by reducing rather than enhancing 5-HT neurotransmission, such that the traditional 5-HT deficiency hypothesis has been challenged. However, the absolute role of central neurotransmission in the behavioral responses seen here cannot be determined from peripheral measures alone.
The differential roles of serotonergic mediation of aggression through the 5HT1A and 1B receptors may be related to the unique stress-coping system of each strain (reported previously; Cheng et al., 2001; Dennis et al., 2006). Previous studies have determined that LGPS and DXL birds exhibited an inferior stress-coping ability compared with HGPS birds (Cheng et al., 2001). This is evidenced in the current study by the coincidental increase in both aggression and feather pecking behavior (a stress-related stereotypic behavior) in LGPS and HGPS birds with antagonism of 5-HT1A and 1B receptors, respectively. This pattern of coinciding changes in behavior is not evident in DXL birds, suggesting the possibility of different degrees of serotonergic control over stress-coping strategies such as feather pecking in different strains of highly aggressive birds. These alterations may be mediated at a cellular level by a combination of pleiotropy and epistatis, or heritable differences in the superior mesenteric artery axis, hypothalamic-pituitary-adrenal (HPA) axis, expression of genes regulating the serotonergic system, or receptor localization within the brain.
The genes regulating these receptor pathways could exhibit pleiotropic effects and epistatic interactions that alter aggression as well as other aspects of the stress-coping abilities of the birds. Additional effects of genetic and pharmacological alterations of these serotonergic pathways may alter other stress-regulating systems that affect the physiological homeostasis of the individual. Pleiotropic effects of the 5-HT1B receptor gene may cause the decreased weight gain and altered peripheral 5-HT concentrations seen in birds after receptor antagonism directly or indirectly through changes in these stress-coping mechanisms, independently of behavioral effects. Alternately, epistatic interactions between genes regulating the serotonergic pathways and metabolism have been shown to alter aggression and mental state in human patients diagnosed with anxiety and conduct disorders (Cadoret, 2003; Schinka et al., 2004).
Previous studies have demonstrated the importance of epistatic interactions in the function of the 5-HT system. Inherited polymorphisms of the 5-HT transporter gene have been shown to interact with other components of the 5-HT pathway such as monoamine oxidase (Urwin and Nunn, 2005) and the autoreceptors of 5-HT1A and 1B neurons (Stoltenberg, 2005). Different interaction effects of the somatodentridic 5-HT1A autoreceptor and the terminal 5-HT1B autoreceptor on aggressiveness and stress coping may become more apparent after antagonism of the alternate receptor causing the dramatic behavioral differences found in the present chicken strains.
Although both aggressive strains, DXL and LGPS, were found to have inferior stress-coping ability compared with HGPS birds, they exhibited different stress-coping mechanisms (Cheng et al., 2001; Dennis et al., 2006). In the present study, we show that in response to the same stressor, genetic lineage determines varied EP responses. The LGPS birds were found to have elevated EP concentrations without treatment and decreased EP concentrations in birds treated with 5-HT1B antagonist. Our findings show an extreme sensitivity of EP in LGPS birds to alterations in serotonergic activity. Similarly, 5-HT1B receptor knockout mice displayed extreme response to a mild stressor, including increased hyperactivity (Craig et al., 1999). The hyper-activity exhibited by LGPS birds may be related to the poor stress-coping ability of this strain.
The heritable differences in stress-coping ability may alter the serotonergic mediation of aggression indirectly through the HPA axis. Chronic stress and elevated corticosterone levels have been shown to have a regulatory function of 5-HT receptor binding and mRNA expression (Lopez et al., 1997). Downregulation of 5-HT1A receptor expression has also been linked with exposure to chronic stress in male mice (Flugge et al., 1998). Agonism of the 5-HT1A receptor has been linked to corticosterone stimulation in mice via an activation of the HPA axis (Bouwknecht et al., 2001). Highly aggressive mice were found to have increased receptor availability in the limbic and cortical regions of the brain (Korte et al., 1996). The inferior stress-coping ability of LGPS and DXL birds might negatively affect the aggression-mediating system of these birds via the 5-HT1A receptor pathway.
Serotonin 1A and 1B receptors are generally localized in specific parts of the brain; for instance, 5-HT1A receptors are found in the hippocampus in high-density concentrations, whereas 5-HT1B receptors are expressed more prominently in the substantia nigra and basal ganglia (Barnes and Sharp, 1999). Heritable differences in receptor density and expression in different areas of the brain have been shown to alter behavior and mood in mammals (Ramboz et al., 1998). Similar to the findings in rodents, different heritable expression of the 5-HT1A and 1B receptors in the brain regions that mediate aggression and other stress-related behaviors may be present in our experimental strains, by which 5-HT regulates behavior in different ways. For example, although it has not been tested, a smaller ratio of expression of 5-HT1A to 1B receptors in the hippocampus of HGPS birds may result in their aggressive response to 5-HT1B antagonist and lack of behavioral response to 5-HT1A antagonism. Alternately, different stimulus response mechanisms in the present strains may use different dominant pathways in regulating aggressive response to a stimulus, creating a situation under which the hippocampus, for example, has a greater regulatory role in aggressive responsiveness in LGPS and DXL birds, whereas aggressive response in HGPS birds may utilize the basal ganglia or the raphe nucleus to a greater extent. Differences in serotonergic modulation may also have neuronal effects on memory and sensory perception (Stutzmann et al., 1998; Kim and Camilleri, 2000). Alterations of perception of the social stimulus may in turn alter the response of the birds as well as the mechanisms used in regulation of aggression and feather pecking.
Our findings provide evidence for the heritable aggression mediation through genetic differences in the serotonergic system in chickens. Our results also show 2 distinct mediating pathways of aggression through the 5-HT1A and 1B receptors that are prominent in birds of low and high aggressiveness, respectively. Although the cellular mechanisms of these pathways are not fully understood, these pathways may be correlated with other aspects of the stress-coping mechanisms of the individual. The strains used in this study present a unique and essential animal model for the study and understanding of serotonergic regulation of both aggression and stress response and its interactions with other vital systems such as the HPA and superior mesenteric artery systems in regulating aggressive behaviors. Our findings further suggest the potential for neuronal indicators that can be utilized by the breeding industry to select for less aggressive, reduced feather pecking birds for production.
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ACKNOWLEDGMENTS |
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Received for publication September 17, 2007. Accepted for publication December 13, 2007.
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