Mean Genes
Authors: René Hen
Journal: Neuron (1996)

Aggressive behavior is displayed by most animal species and subserves functions that are essential for the survival of the species, such as defense of the territory, defense of the progeny, and access to females (26Lorenz K On Aggression. Methuen, London1966Google Scholar). For example, isolated male mice as well as lactating females will attack male intruders. Humans may display aggressive behavior in response to a threat or under the influence of alcohol. In its most extreme cases, aggressive behavior is considered a social ill, and the prevention of violence is a major concern of our societies. Social stressors such as poverty or a history of child abuse are likely to play a crucial role in many violent behaviors (14Dodge K.A Bates J.E Pittit G.S Mechanisms in the cycle of violence.Science. 1990; 250: 1678-1683Crossref PubMed Scopus (1248) Google Scholar). Environmental factors can trigger behavioral responses by influencing the activity of biological substrates. For example, in mice isolation results in an increase in aggressive behavior as well as changes in levels of neurotransmitters and hormones (45Valzelli L Bernasconi S Aggressiveness by isolation and brain serotonin turnover changes in different strains of mice.Neuropsychobiology. 1979; 5: 129-135Crossref PubMed Scopus (80) Google Scholar). In this review, we will focus on the molecular mechanisms that might underlie aggressive behavior, not because we believe that environment plays a minor role but because recent advances have pointed toward specific molecules as modulators of aggressive behavior. One way to classify aggressive behavior is to consider affective aggression as being directed toward members of the same species and predatory aggression as being directed toward other species. Affective aggression can itself be divided into offensive and defensive behaviors (16Eichelman B.S Aggressive behavior from laboratory to clinic.Arch. Gen. Psychiatry. 1992; 49: 488-492Crossref PubMed Scopus (81) Google Scholar). Classically, lesions and electric stimulations have been used to determine which parts of the brain are involved in a particular form of aggressive behavior (1Bandler, R. (1988). Brain mechanisms of aggression as revealed by electrical and chemical stimulation: suggestion of a central role for the midbrain periaqueductal grey region. In Progress in Psychobiology and Physiological Psychology, A. Epstein and J. Sprague, eds. (New York: Academic Press, Inc.), pp. 67–154.Google Scholar, 49Weiger B Bear D An approach to the neurology of aggression.J. Psychiatr. Res. 1988; 22: 85-98Abstract Full Text PDF PubMed Scopus (107) Google Scholar). In a number of species, including rats, cats, and monkeys, attacks can be elicited by electrical stimulation of the hypothalamus, amygdala, or periaqueductal gray. In cats, stimulation of the medial hypothalamus usually produces affective attacks, while stimulation of the lateral hypothalamus produces predation (44Siegel A Pott C.B Neural substrates of aggression and flight in the cat.Neurobiology. 1988; 31: 261-283Google Scholar). These effects appear to be mediated by neurons innervating the ventrolateral periaqueductal gray matter in the case of affective aggression and the ventral tegmental area in the case of predation. The basolateral amygdala also appears to facilitate affective attacks through its connections with the hypothalamus and periaqueductal gray matter. Aggressive behavior is also modulated by hormones, especially sex steroids. Androgens have organizational and activational effects on male aggressive behavior, just as they have on male sexual behavior (12Conner, R.L., and Levine, S. (1969). Hormonal influences on aggressive behaviour. In Aggressive Behaviour, S. Garattini and E. B. Sigg, eds. (New York: John Wiley and Sons), pp. 150–163.Google Scholar). In adult rats, castration reduces intermale aggression and injection of testosterone reinstates aggressiveness. However, testosterone injections are ineffective if castration is performed neonatally (vom48vom Saal, F.S. (1983). Models of early hormonal effects on intra-sex aggression in mice. In Hormones and Aggressive Behavior. B. B. Svare, ed. (New York: Plenum Press), pp. 197–222.Google Scholar). The secretion of testosterone early in development has therefore been suggested to stimulate the development of neural circuits that facilitate intermale aggression. Insights into the neurochemistry of aggressive behavior first came from animal studies which showed that aggressive behavior could be markedly altered through the modification of specific neurotransmitter systems such as the serotonergic system, and, to some extent, the dopaminergic, noradrenergic, and GABAergic systems (15Eichelman B.S Neurochemical and psychopharmacologic aspects of aggressive behavior.Annu. Rev. Med. 1990; 41: 149-158Crossref PubMed Scopus (67) Google Scholar, 30Miczek K.A Weerts E Haney M Tidey J Neurobiological mechanisms controlling aggression preclinical developments for pharmacotherapeutic interventions.Neurosci. Biobehav. Rev. 1994; 18: 97-110Crossref PubMed Scopus (155) Google Scholar). I will focus on the serotonergic system because recent evidence points to the involvement of specific components of the serotonergic system in the modulation of aggressive behavior. Early animal studies suggested an inverse relationship between the activity of the brain serotonergic system and aggressive behavior (38Pucilowski O Kostowski W Aggressive behavior and the central serotoninergic system.Behav. Brain Res. 1983; 9: 33-48Crossref PubMed Scopus (86) Google Scholar). Specifically, experimental manipulations that lowered brain levels of serotonin increased aggressive responding in some animal models of aggression (46Vergnes M Depaulis A Boehrer A Parachlorophenylalanine-induced serotonin depletion increases offensive but not defensive aggression in male rats.Physiol. Behav. 1986; 36: 653-658Crossref PubMed Scopus (96) Google Scholar). Conversely, manipulations that raised serotonin levels decreased aggressive responding (32Molina V Ciesielski L Gobaille S Isel F Mandel P Inhibition of mouse killing behavior by serotonin-mimetic drugs effects of partial alterations of serotonin neurotransmission.Pharmacol. Biochem. Behav. 1987; 27: 123-131Crossref PubMed Scopus (64) Google Scholar). In humans, several authors have reported an association between deficits in the central serotonergic system and impulsive aggressive behavior, irrespective of whether the behavior was directed at others or at self (suicide). Low brain serotonin turnover rates, or blunted neuroendocrine responses to serotonergic agonists, which might reflect a low central serotonin activity, have been found in some individuals who engage in impulsive fire setting, frequent impulsive violent behavior, or violent suicide attempts (9Coccaro E.F Siever L.J Klar H.M Maurer G Cochrane K Cooper T.B Mohs R.C Davis K.L Serotonergic studies in patients with affective and personality disorders.Arch. Gen. Psychiatry. 1989; 46: 587-599Crossref PubMed Scopus (1001) Google Scholar, 24Linnoila M Virkkunen M Scheninin M Nuutila A Rimon R Goodwin F.K Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from non-impulsive violent behavior.Life Sci. 1993; 33: 2609-2614Crossref Scopus (1075) Google Scholar, 47Virkkunen M Rowlings R Tokola R Poland R.E Guidotti A Neveroff C Bissette G Kalogeras K Karonen S.L Linnoila M Cerebrospinal fluid monoamine metabolite levels in male arsonists.Arch. Gen. Psychiatry. 1994; 51: 20-27Crossref PubMed Scopus (466) Google Scholar). Pharmacological studies have also pointed toward an involvement of specific serotonin receptors in modulating aggressive behavior. Agonists of the 5-hydroxytryptamine (5-HT) receptor subtypes 5-HT1A and 5-HT1B have been termed "serenics" because of their antiaggressive properties in several rodent models of aggressive behavior, including male territorial aggression and aggression displayed by lactating females toward male intruders (Figure 1) (35Olivier B Mos J van der Heyden J Hartog J Serotonergic modulation of social interactions in isolated male mice.Psychopharmacology. 1989; 97: 154-156Crossref PubMed Scopus (113) Google Scholar, 33Mos J Olivier B Tulp M.Th.M Ethopharmacological studies differentiate the effects of various serotonergic compounds on aggression in rats.Drug Dev. Res. 1992; 26: 343-360Crossref Scopus (20) Google Scholar). Pharmacological manipulations have, however, been limited by the complexity of the serotonergic system (at least 15 distinct receptors) and the lack of specific drugs (42Saudou F Hen R 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates.Neurochem. Int. 1994; 25: 503-532Crossref PubMed Scopus (159) Google Scholar, 20Hoyer D Clarke D.E Fozard J.R Hartig P.R Martin G.R Mylecharane E.J Saxena P.R Humphrey P.P.A International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin).Pharmacol. Rev. 1994; 46: 157-203PubMed Google Scholar). Recently, molecular genetic techniques have made it possible to manipulate the expression of specific components of the serotonergic system in the mouse (43Saudou F Ait Amara D Dierich A LeMeur M Ramboz S Segu L Buhot M.-C Hen R Enhanced aggressive behavior in mice lacking 5-HT1B receptor.Science. 1994; 265: 1875-1878Crossref PubMed Scopus (712) Google Scholar, 27Lucas J.J Hen R New players in the 5-HT receptor field genes and knockouts.Trends Pharmacol. Sci. 1995; 16: 246-252Abstract Full Text PDF PubMed Scopus (121) Google Scholar). These manipulations, which include ectopic gene expression in transgenic mice or gene ablation in so-called knockout mice, have yielded mice that display enhanced aggressive behavior. The contribution of these studies to our understanding of the biology of aggressive behavior will be discussed below. As a result of the serotonin hypothesis, it is tempting to speculate that mutations in genes encoding various components of the serotonergic system will have consequences on aggressive behavior. One such mutation was recently identified in a Dutch family with a new form of X-linked mild mental retardation (3Brunner H.G Nelen M Breakefield X.O Ropers H.H van Oost B.A Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A.Science. 1993; 262: 578-580Crossref PubMed Scopus (1168) Google Scholar, 4Brunner H.G Nelen M.R van Zandvoort P Abeling N.G.G.M van Gennip A.H Wolters E.C Kulper M.A Ropers H.H van Oost B.A X-linked borderline mental retardation with prominent behavioral disturbance in monamine metabolism.Am. J. Genet. 1993; 52: 1032-1039PubMed Google Scholar). Fourteen affected males in this family displayed variable degrees of impulsive aggressive behaviors, including murder attempt, rape, and arson. In each of these individuals, a point mutation was identified that resulted in the lack of a functional monoamine oxidase A (MAOA), one of the two enzymes that metabolizes 5-HT. Selective MAOA deficiency in this family led to a marked disturbance of monoamine metabolism, as evidenced by an increased urinary excretion of MAOA substrates, including 5-HT, and decreased concentrations of MAOA metabolites, including 5-hydroxyindole acetic acid (5-HIAA). However, given the limited sample size, it was not possible to conclude unambiguously whether aggressive behavior was a consequence of the MAOA mutation or the result of other genetic or environmental factors that might also be present in this family. Possibly in support of the MAO hypothesis is the fact that deficits in MAOB (the second enzyme involved in monoamine metabolism) are sometimes associated with sensation-seeking personalities and disorders of impulse control such as those found in pathological gamblers (5Carrasco J.L Saiz-Ruiz J Hollander E Cesar J Lopez-Ibor J.J Low platelet monamine oxidase activity in pathological gambling.Acta Psychiatr. Scand. 1994; 90: 427-431Crossref PubMed Scopus (75) Google Scholar). Independently, a knockout mouse was produced that lacked a functional MAOA gene as a result of a deletion in the coding sequence of this gene (6Cases O Seif I Grimsby J Gaspar P Chen K Pournin S Muller U Aguet M Babinet C Shih J.C De Maeyer E Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA.Science. 1995; 268: 1763-1766Crossref PubMed Scopus (972) Google Scholar). In pup brains, serotonin concentrations were increased by up to 9-fold and norepinephrine by 2-fold. Pup behavioral abnormalities, including trembling, difficulty in righting, and increased startle response, were reversed by the serotonin synthesis inhibitor parachlorophenylalanine, whereas none of these traits were affected by the catecholamine synthesis inhibitor α-methylparatyrosine. In adults, 5-HT and 5-HIAA levels returned to normal. Adults displayed a specific set of behavioral alterations including enhanced intermale aggressive behavior, increased attempts to mount nonreceptive females, and decreased immobility in a forced swim test. The enhanced aggressive behavior displayed by mice lacking MAOA is consistent with the violent behavior displayed by the few men lacking this enzyme. The phenotype of these individuals might therefore be a consequence of the MAOA mutation rather than the result of some unusual environmental or genetic background in that family. Increased aggressive behavior in mice or men lacking MAOA came as a surprise because aggressive behavior is often associated with decreases in 5-HT levels rather than increases such as those elicited by acute administration of MAOA inhibitors. In fact, MAOA inhibitors, which were widely used as antidepressants, have not been reported to induce aggressive behavior. There are even reports that in certain rodent models MAOA inhibitors decrease aggressive behavior (21Isel F Ciesielski L Gobaille S Molina V Mandel P Alterations of serotonin neurotransmission and inhibition of mouse killing behavior. II. Effects of selective and reversible monamine oxidase inhibitors of type A.Pharmacol. Biochem. Behav. 1988; 29: 97-104Crossref PubMed Scopus (10) Google Scholar). The phenotype of individuals lacking MAOA might therefore be a consequence of compensatory changes that took place during development. For example, to compensate for high 5-HT levels, postsynaptic 5-HT receptors might be down-regulated, which could in turn result in a phenotype similar to low 5-HT activity. Alternatively, the absence of MAOA during development might produce structural defects. Indeed, mice lacking MAOA display neuroanatomic abnormalities such as an absence of the cortical barrel field, which is a somatosensory representation of the vibrissae (7Cases O Vitalis T Seif I De Maeyer E Sotelo C Gaspar P Lack of barrels in the somatosensory cortex of monoamine oxidase A–deficient mice role of an excess of serotonin during the critical period.Neuron, in press. 1996; Google Scholar). In addition50Whitaker-Azmitia P.M Zhang X Clarke C Effects of gestational exposure to monoamine oxidase inhibitors in rats preliminary behavioral and neurochemical studies.Neuropsychopharmacology. 1994; 11: 125-132Crossref PubMed Google Scholar have reported that rats exposed to MAO inhibitors during development display significant changes in cortical serotonergic innervation. The MAOA mutation is the first example of a genetic alteration that appears to facilitate aggressive behavior in mice and men. Other mutations affecting aggressive behavior have been created in the mouse, but no human counterpart has been found so far. The 5-HT1Dβ receptor is one of the 15 mammalian 5-HT receptors that have been identified to date (42Saudou F Hen R 5-Hydroxytryptamine receptor subtypes in vertebrates and invertebrates.Neurochem. Int. 1994; 25: 503-532Crossref PubMed Scopus (159) Google Scholar). The rodent homolog of this receptor is called 5-HT1B because of a pharmacological difference between these receptors. The 5-HT1B/1Dβ receptors as well as the 5-HT1A receptors are candidates for modulating aggressive behavior because agonists of these receptors have antiaggressive properties in rodents. Mice lacking 5-HT1B receptors were generated by gene targeting (43Saudou F Ait Amara D Dierich A LeMeur M Ramboz S Segu L Buhot M.-C Hen R Enhanced aggressive behavior in mice lacking 5-HT1B receptor.Science. 1994; 265: 1875-1878Crossref PubMed Scopus (712) Google Scholar, 39Ramboz S Saudou F Aı̈t Amara D Belzung C Misslin R.M Segu L Buhot M.-C Hen R 5-HT1B receptor knockout physiological and behavioral consequences.Behav. Brain Res., in press. 1995; Google Scholar). The homozygous mutants developed normally and did not differ from their wild-type littermates anatomically. In a number of behavioral tests aimed at measuring feeding, locomotion, and reactivity to novel or aversive environments, no differences were found between wild-type and mutant mice. However, when analyzed in the isolation-induced aggression test, the male homozygous mutants displayed increased aggressive behavior. In this test, wild-type or mutant males that have been isolated for 4 weeks are confronted with a male intruder that has not been isolated. The wild-type mice attack the intruder after an observation period that includes sniffing and aggressive displays such as tail rattling; in contrast, the mutant mice attack immediately or after a short latency. In addition, the number and the intensity of the attacks were significantly higher in the case of the mutants. The short latency of attack displayed by these mutant mice is reminiscent of the impulsive behavior often associated with deficits in central serotonin in primates (24Linnoila M Virkkunen M Scheninin M Nuutila A Rimon R Goodwin F.K Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from non-impulsive violent behavior.Life Sci. 1993; 33: 2609-2614Crossref Scopus (1075) Google Scholar, 29Mehlman P.T Higley J.D Faucher I Lilly A.A Taub D.M Vickers J Suomi S.J Linnoila M Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates.Am. J. Psychiatry. 1994; 151: 1485-1491PubMed Google Scholar). Agonists of 5-HT1B receptor have been shown to decrease aggressive behavior in a number of rodent models including the isolation-induced aggression test. It is therefore consistent that mice lacking this receptor display the opposite phenotype. However, it is also possible that compensatory changes are responsible for the aggressive behavior of these mutant mice. Specific 5-HT1B antagonists as well as inducible and tissue-specific knockouts will soon be available (27Lucas J.J Hen R New players in the 5-HT receptor field genes and knockouts.Trends Pharmacol. Sci. 1995; 16: 246-252Abstract Full Text PDF PubMed Scopus (121) Google Scholar) and should allow a more precise study of the role of the 5-HT1B receptor in the modulation of aggressive behavior, such as where the relevant receptors are located. A candidate structure is the central gray, which is involved in aggressive behavior and has abundant 5-HT1B receptors. A number of other transgenic and knockout mice have been reported that display aggressive behavior. Mutant mice that are heterozygous for a mutation in the gene encoding the enzyme α-calmodulin-dependent protein kinase II (CaMKII) display increases in defensive aggression but not in offensive aggression in the resident–intruder paradigm (8Chen D Rainnie D.G Greene R.W Tonegawa S Abnormal fear response and aggressive behavior in mutant mice deficient for α-calcium-calmodulin kinase II.Science. 1994; 266: 291-294Crossref PubMed Scopus (235) Google Scholar). Interestingly, these mice were also shown to display decreased serotonin release, as measured by extracellular and whole-cell patch-clamp recordings from brainstem slices. CaMKII-mediated phosphorylation is required for activation of tryptophan hydroxylase, the rate-limiting enzyme for 5-HT synthesis. A reduction in tryptophan hydroxylase activity might therefore explain the aggressive phenotype of the CaMKII heterozygous mice. Interestingly, homozygous mutants that lack both copies of the CaMKII gene are not aggressive but display a large number of other behavioral abnormalities. Transgenic mice overexpressing transforming growth factor α (TGFα) were also shown to be aggressive and to display low 5-HIAA levels (19Hilakivi-Clarke L.A Corduban T.-D Taira T Hitri A Deutsch S Korpi E.R Goldberg R Kellar K.J Alterations in brain monoamines and GABAA receptors in transgenic mice overexpressing TGFα.Pharmacol. Biochem. Behav. 1995; 40: 593-600Google Scholar). In this case, the relation between TGFα and the serotonergic system is unknown. However, since TGFα is a growth factor that is expressed in the brain, it is possible that the phenotype of these transgenic mice is the result of abnormal brain development. Mice lacking the neuronal form of nitric oxyde synthase (nNOS) display enlarged stomachs as well as an increase in offensive aggressive behavior and altered sexual behavior (34Nelson R.J Demas G.E Huang P.L Fishman M.C Dawson D.L Dawson T.M Snyder S.H Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase.Nature. 1995; 378: 383-386Crossref PubMed Scopus (524) Google Scholar). In the resident–intruder paradigm, mutant males attack male intruders more often and more intensely than wild-type males, while the latency to the first attack is the same in both groups. Neuronal NOS is expressed widely both in the developing and in the adult nervous system. However, so far, studies administering NOS inhibitors have not implicated NO in aggressive or sexual behavior. It is therefore not clear whether the phenotype of these mutant mice reflects abnormal brain development or whether nNOS is directly involved in the modulation of aggressive and sexual behavior. Evidence has accumulated during the past 50 years that variations in aggressive behavior can be heritable. Selective breeding has yielded strains of mice and rats that originate from the same genetic background but differ reliably in particular aspects of aggressive behavior (22Lagerspetz K.M.J Lagerspetz K.Y.H Changes in the aggressiveness of mice resulting from selective breeding, learning, and social isolation.Scand. J. Psychol. 1971; 12: 241-248Crossref PubMed Scopus (68) Google Scholar, 37Popova N.K Nikulina E.M Kulikov A.V Genetic analysis of different kinds of aggressive behavior.Behav. Genet. 1993; 23: 491-497Crossref PubMed Scopus (37) Google Scholar, 23Lewis M.H Gariepy J.-L Gendreau P Nichols D.E Mailman R.B Social reactivity and D1 dopamine receptors studies in mice selectively bred for high and low levels of aggression.Neuropsychopharmacology. 1994; 10: 115-122Crossref PubMed Scopus (35) Google Scholar). With the use of recombinant inbred strains, quantitative trait locus analysis, and the increasing number of genetic markers that have been identified in the mouse genome, it is now possible to get an estimate of how many genes are responsible for behavioral differences between two inbred strains and approximately where these genes are located (36Plomin R McClearn G.E Quantitative trait loci (QTL) analysis and alcohol-related behavior.Behav. Genet. 1993; 23: 197-211Crossref PubMed Scopus (66) Google Scholar, 13Crabbe J.C Belknap J.K Buck K.J Genetic animal model of alcohol and drug abuse.Science. 1994; 264: 1715-1723Crossref PubMed Scopus (370) Google Scholar) (Figure 2). Such strategies have been successfully applied in the case of susceptibilities to hypertension, diabetes, epileptic seizures, alcohol preference (for a review, see13Crabbe J.C Belknap J.K Buck K.J Genetic animal model of alcohol and drug abuse.Science. 1994; 264: 1715-1723Crossref PubMed Scopus (370) Google Scholar), and emotionality (17Flint J Corley R DeFries J.C Fulker D.W Gray J.A Miller S Collins A.C A simple genetic basis for a complex psychological trait in laboratory mice.Science. 1995; 269: 1432-1435Crossref PubMed Scopus (342) Google Scholar) and are underway for intermale offensive aggressive behavior (Figure 2). Portions of the mouse Y chromosome as well as a locus on chomosome 17 have been suggested to be associated with offence in mice (40Roubertoux P.L Carlier M Degrelle G Haas-Dupertuis M.C Phillips J Moutier R Co-segregation of intermale aggression with the pseudoautosomal region of the Y chromosome in mice.Genetics. 1994; 136: 225-230PubMed Google Scholar, 28Maxson S.C Candidate genes for mouse offense.Behav. Genet., in press. 1996; Google Scholar). However, these loci encompass usually a few million base pairs, and thus many genes. The identification of the relevant genes by conventional techniques can therefore still be a formidable task. However, if a candidate gene has been mapped at the same chromosomal locus as one of the quantitative trait loci, it will be possible to generate knockout mice lacking this gene and test their behavior. For example, one of the loci on the Y chromosome possibly involved in aggressive behavior contains a gene encoding the enzyme steroid sulphatase (41Roubertoux P.L Degrelle H Maxson S.C Phillips J Trodjman S Moutier R Dupertuis-Hass M.-C Alleles of the microsomal steroid sulfatase gene (Sts) in the pseudoautosomal region of the heterosomes of the mouse.CR Acad. Sci. (Paris). 1995; 317: 523-527Google Scholar). In humans, the contribution of genetic factors has been much more difficult to establish. Adoption and twin studies have revealed both environmental and genetic modulators for aggressive behavior in humans (Bohman et al., 1988; 25Loehlin J.C Partitioning environmental and genetic contributions to behavioral development.Am. Psychol. 1989; 44: 1285-1292Crossref PubMed Scopus (118) Google Scholar, 10Coccaro E.F Bergeman C.S McClearn G.E Heritability of irritable impulsiveness.J. Psychiatr. Res. 1993; 48: 229-242Abstract Full Text PDF Scopus (114) Google Scholar, 11Coccaro E.F Silverman J.M Klar H.M Horvath T.B Siever L.J Familial correlates of reduced central serotonergic system function in patients with personality disorders.Arch. Gen. Psychiatry. 1994; 51: 318-324Crossref PubMed Scopus (104) Google Scholar). Thus far, the only characterized mutation that might be associated with violent behavior is the mutation in the MAOA gene that has been identified in a Dutch family. It is unclear whether mutations in the MAOA gene are frequent and whether they will be associated with aggressive behavior in violent individuals from other pedigrees. A number of genetic disorders such as the Cornelia de Lange and the Prader–Willi syndromes are often associated with aggressive behavior (18Gualtieri C.T Neuropsychiatry and Behavioral Pharmacology. Springer Verlag, Berlin1991Crossref Google Scholar); however, the specific genetic defects have not yet been identified. The gene knockout and the transgenic strategies will provide useful animal models for mutations that might occur in the human population. For example, the availability of mice lacking MAOA will make it possible to study the developmental events that might underlie an increase in aggressive behavior later in life. Conversely, the fact that mice lacking the 5-HT1B receptor are aggressive makes this gene a candidate for mutations that might increase aggressive behavior in humans. The mouse studies also exemplify the fact that many genes can influence aggressive behavior, including totally unexpected ones such as TGFα. This should not be much of a surprise given the fact that aggressive behavior is a complex set of behaviors and that lesions and pharmacological studies have pointed toward the involvement of several brain structures and neurotransmitter systems. In its excessive forms, aggressive behavior might be compared to cancer. There are many oncogenes that when mutated can lead to cancer because there are many proteins that control or modulate cell division. There are also many environmental factors such as smoking that can increase the probability of developing tumors. Lung cancer, for example, might result from a combination of tumor promoters like nicotine and mutations such as those inactivating tumor suppressor genes (31Minna J.D The molecular biology of lung cancer pathogenesis.Chest. 1993; 103: 449S-456SCrossref PubMed Scopus (115) Google Scholar). Like cell division, aggressive behavior appears to be a finely tuned system that can be modulated at many levels and that can therefore be deregulated in many ways. If the quest for genetic causes for aggressive behavior resembles in any way the quest for oncogenes, we are in for a long ride. I wish to thank C. Lappi and Charles Lam for help in preparing this manuscript and J. Crabbe, B. Eichelman, M. Heath, S. Maxson, C. Mendelsohn, K. Miczek, K. Scearce, and I. Seif for comments and discussions.