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Genetics & Neurochemistry of Aggression: Normal and Abnormal
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Karen L. Overall, MA, VMD, PhD, DACVB
Center for Neurobiology and Behavior, Psychiatry Department, School of Medicine, University of Pennsylvania
Philadelphia, PA, USA

For the purposes of this topic aggression is defined as an appropriate or inappropriate, inter- or intra-specific challenge, threat, or contest resulting in deference or in combat and resolution [1,2]. The importance of context cannot be over-emphasized in any evaluation of aggression. Most abnormal aggressions are the result of underlying anxiety [2-4]. Canine and feline anxieties, particularly those involving more extreme responses, appear to have a genetic component. Because of the use of breeds of dogs for certain types of work, more is known about both canine aggression and the putative genetic mechanisms that underlie it than about feline aggression. The probability that any dog will be afflicted with a profoundly anxious or panicky response is, in part, associated with breed. Breeds are the result of selection for specific types of work. The first dogs identified with extreme freezing and social withdrawal, for example, were from a familial line selected for exquisitely developed pointing behaviors. One would expect that the extent to which anxiety was present and deleterious could depend on breed and the task, and that more 'reactive breeds' which are also expected to engage in more complex behaviors (e.g., explosives detection and patrol / human detainment) would be more at risk than are dogs selected for low reactivity, or those trained for and used in more singular tasks like explosives detection.

There is a growing body of evidence that anxiety can affect: (1) the rate at which learning progresses, and (2) various performance capabilities [5,6]. Additionally, there is evidence that treatment with monoamine re-uptake inhibitors speeds learning of specific tasks in dogs [6]. Similar results have been reported for mice for age-associated impairment in maze learning [7,8]. The best and most extensive data that reflect the effects of anxiety and aggression on canine behavior involve military and other patrol/detector/sniffer/working dogs; when the physical sequelae of conditions associated with anxiety are considered, behavioral problems are among the most common reasons that such dogs die or are euthanized [9]. The most common reason puppies, juveniles, and young adults are removed from all working / service dog training programs is performance failure based in anxiety-related conditions. The most commonly noted complaints include fear, 'unstable' temperament, uncontrollable aggression, or 'lack of drive' / shyness. In dogs, all of these conditions are based in underlying anxiety. It is important to remember that the criteria for working / service dogs are far more extensive than are the criteria for suitability as pets. Under 'normal' circumstances, many of the anxieties exhibited by service / working dogs would not become pathological; however, the stress of training for the work these dogs are to do contributes to worsening for all anxiety-related conditions. Additionally, only the best and most exceptional dogs are selected for deployment and, or breeding. Again, this reflects the role that selection for task suitability plays, and highlights the differences between dogs chosen for pets and those chosen for work. However, these populations of dogs may not be entirely separate, and to fully understand the genetic bases of canine aggression large phenotypic and genotypic surveys that includes all breed populations is necessary.

The mechanisms postulated for failed performance associated with anxiety and aggression involve the finding that chronic glucocorticoid excess interferes with LTP and other putative electrophysiological processes associated with learning [10,11]. This chronic exposure has also been proposed to affect hippocampal neuronal structure [12]. Viewed in this light chronic cortisol elevation may act as a translational gene regulator in regions of the hippocampus. In the large, but overwhelmingly non-experimental literature on working dogs, the single best predictor of failure in any working dog is fear, and the factor that prohibits most dogs from completing training programs is their aggressive / fearful / anxious / uncertain response to novel or complex environments [13-16]. Any tests that can help identify early aspects of fear and anxiety and their effects on aggression will lead to future research on intervention for, and effects of intervention on learning.
Some of our knowledge of canine aggression, in particular, will come from similar studies in humans. Dogs share both foraging mode and a virtually identical social system with humans [2], and have co-evolved for co-operative work with humans for approximately 135,000 years, with intense selection for specific suites of behavioral traits (e.g., the development of breeds) occurring in the last 12,000-15,000 years [17-21]. Dogs mirror humans in hallmarks of social development [2, 22]. Recent data indicate that dogs are significantly more comparable to humans than are chimpanzees and wolves with regard to the complex social cognition involved in understanding long-distance signals that indicate where food is hidden [23-27]. Dogs are further able to communicate this information to other dogs. Also, like humans, dogs suffer from what we recognize as maladaptive anxiety--that which interferes with normal functioning--which was selected against during the co-evolution of dogs and humans.

Dog breeds were developed on the basis of specific work or jobs (e.g., border collies, Australian shepherds, Australian cattle dogs [herding]; Labrador retrievers [retrieving in water]; beagles [alerting for hidden prey]; Jack Russell terriers [tracking and killing small prey], Belgian Malinois [herding, guarding, and flock protection], et cetera). If breeds selected for different behaviors or jobs express different manifestations of extreme anxiety characterization of the response for different pedigree lines may provide hypotheses to be tested about composition of "spectrum" disorders.

Paradoxically, some of the best data for aberrant or abnormal aggression involves one of the most controversial canine behavioral diagnoses: canine 'dominance' or impulse control aggression. This aggression is about control or access to control in direct social situations involving humans. The range of behaviors manifest in this condition includes postural threats and stares to sudden stiffening and bites [2, 28, 29]. This is the primary category of canine aggression in which no warning is given [30]. The classic afflicted dog growls, lunges, snaps or bites if they are stared at, physically manipulated--often when reaching over their head to put on a leash, physically disrupted or moved from a resting site--no matter how gently this is done, and when they are physically or verbally 'corrected'. Otherwise, clients report that these are perfectly wonderful and charming dogs for well over 95% of the time. Clients are further puzzled by the observation that the dog often seeks them out for attention and then bites them when they give it. As for most other behavioral conditions, this aggression commonly develops during social maturity when neurochemistry undergoes changes that will result in the individual's adult neurochemical profile; however dogs exhibiting this behavioral abnormality at social maturity tend to be male, whereas when females are affected they exhibit the behavioral pathology in puppyhood, suggesting that this is a multi-factorial disorder with different underlying mechanisms leading to similar phenotypes [31, 32]. The average age of onset for affected males is ~12 months, but is ~ 8 months for females, a statistically significant different. The range of ages of onset also varies significantly for the sexes [33].

Little work has been done either post-mortem on neuroanatomy or cytoarchitectural facets of these conditions, or ante-mortem using imaging studies of dominance aggression or impulsivity, per se, although limbic system structures, in general, have been related to impulsive risk-taking, behavioral timing, and time judgments [34]. The serotonin system has been implicated in both canine impulse control aggression and in human impulsivity. Affected dogs have lower CSF levels of 5-hydroxyindol acetic acid [5-HIAA] and homovanillic acid [HVA], metabolites of serotonin and dopamine, respectively, post-mortem than do control dogs [35]. Although there is evidence that CSF HVA level may be a function of breed, CSF 5-HIAA levels appear to be decreased irrespective of breed. Finally, these dogs differ from all other aggressive dogs based on data from urinary metabolic screens: these dogs consistently manifest excretion of glutamine, the metabolite of the excitatory amino acid glutamate, in their urine [36, 37]. Further refinement of amino acid identification is still needed to interpret these findings. Finally, these dogs respond to treatment with TCAs and SSRIs when combined with behavior modification. In the early stages of the condition, the dog improves quickly and dramatically if they are give a kind, reliable rule structure for interaction (e.g., they must sit and be calm before they get any kind of attention). This is a huge clue that the provocative behavior exhibited by the dog may be more about soliciting information from and about the social environment than it is about pushy, manipulative behavior. In fact, within the population of dogs developing the behavior at social maturity, at least 2 phenotypic groups have been identified: (1) those dogs that are not able to function using the social cues in the human environment and become explosive when they reach their stimulus threshold, and (2) those dogs that are uncertain of the human social environment and provoke it to gain information about what expected social responses and consequences could be. Both of these pathologic representations are forms of rule structures that have gone wrong. Keys to treatment include replacement with rule structures that clearly and humanely specify expectations.

Dogs affected with this condition appear to come from family lines were ~ ½ the dogs are afflicted by social maturity. Once identified within a breed or familial line the condition appears each generation. Breeds that have been commonly represented in specific populations include American cocker spaniels, Dalmatian, English springer spaniel, golden retriever, German shepherd dog, Labrador retriever, and rottweiler [2] in the USA, English cocker spaniels in the UK [28,29], and golden retrievers in Europe. Work is currently underway to use genome scans and mapping for this condition and others involving aggression and anxiety. Breeds, by definition, are the result of canalized genetic variation, and when a trait appears in a breed line it is likely that there is accompanying line breeding which can be identified by multi-generational pedigrees. It is not unusual to have 3 or 4 generations of dogs available for examination within any affected pedigree. Use of multi-generational dog families also allow us to examine individual differences instead of averaging across groups. Furthermore, families and breeds of dogs are also ideal for haplotype analysis in a way that is not possible in humans [38]. Such analyses may better link structure and function than do analyses of groups [39, 40]. Finally, although much of our information about canine aggression comes from breeds of dogs, none of this information implies that entire breeds are aggressive, nor does it support legislation that bans breeds [41].

References
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