Abstract Background Aggressive behavior is an ancient and conserved trait, habitual for most animals in order to eat, protect themselves, compete for mating and defend their territories. Genetic factors have been shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. Although such types of behaviors have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, selected for tameness. Results A total of 918 up-regulated and 278 down-regulated differentially expressed genes (DEG) were identified, representing above-chance overlap with genes previously identified in studies of aggression across species, as well as those implicated in recent human evolution. The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as Alzheimer disease-presenilin, integrins and the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, are up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions associated with PFC activity, are down-regulated, promoting the development of the aggressive responses selected for in Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression. Conclusions These transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors. This analysis constitutes a first important step towards the identification of the genes and metabolic pathways that promote aggression in cattle and, providing a novel model species to disentangle the mechanisms underlying variability in aggressive behavior. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07505-5. Background Aggression, an evolutionary well-conserved trait, is part of the behavioral repertoire across species, as most animals need this skill in order to eat, protect themselves and their families against predators, compete for mates, and acquire resources and territory [[35]1]. In contrast, scientific interest in human aggression is often centered on abnormal manifestations of the behavior, including violence associated with dementias or neuropsychiatric disorders, such as manic depression, bipolar disorder, schizophrenia, as well as conduct and antisocial personality disorders [[36]2, [37]3]. Research has shown that the expression of aggressive behavior depends on the interaction between environmental and genetic factors, with a genetic additive component ranging around 50% in humans [[38]4]. A large number of preclinical studies using different animal species as models has been encouraged on the reasoning that molecular correlates of animal aggressive behaviors resemble varying biological mechanisms in human pathological aggression [[39]5]. Several attempts have been made to mold abnormal forms of aggressiveness, mainly using murine models, and to a lesser extent dogs and semi-domesticated species such as the silver fox, in order to display a contrast between docile or tame behaviors and escalated levels of aggressiveness [[40]6]. However, relating these mechanisms to the human condition is not simple, given the polygenic basis and diverse instantiations of aggressive behaviors. In animals, aggressive responses consist of a combination of fight, chase, bite and ram, whereas aggression in humans involves both verbal and physical forms. Despite this, the identification of similar components of aggression across species can help to better understand its etiology and to further improve its diagnosis, prognosis and intervention strategies, which currently lack in effectiveness [[41]7]. Domesticated species offer particularly interesting models for research into human aggression. Over recent years, genomic, transcriptomic, behavioral, and archaeological evidence has begun to accumulate, indicating that anatomically modern humans and domesticated species have followed convergent evolutionary processes compared to their respective archaic and wild counterparts [[42]8–[43]10]. Our species exhibits craniofacial alterations reminiscent of those typical in the “domestication syndrome”, including reduced tooth size, contraction of the skull, and flattening of the face (comparable to the shortened muzzles of domesticates) [[44]11]. The Russian farm-fox experiment has shown that such broad phenotypical changes can emerge from selection for reduced reactive aggression towards humans, a trait ubiquitous across domesticated species [[45]12]. In conjunction with findings that our species has markedly reduced intraspecific reactive aggression when compared to extant primates, this has helped to spur research into the hypothesis that, relative to archaic hominins, modern humans have undergone positive selection for a reduction in reactive aggression towards each other [[46]13]. Similarly to farm foxes selected for aggressive behaviors, a reduction in reactive aggression is exceptionally absent in the case of the Lidia breed of cattle. Lidia bovines belong to a primitive population, selected for centuries to develop agonistic-aggressive responses by means of a series of traits that are registered by breeders on a categorical scale, which classifies aggression and fighting capacity, reporting moderate to high heritability estimates for the Lidia (0.20–0.36) [[47]14, [48]15]. Thus, within the bovine species, Lidia cattle may constitute a useful tool for studying the genomic makeup of aggressive behavior. The utility of cattle as a model for human aggression is further underscored by exploratory findings that selective sweeps implicated in cattle domestication have above-chance intersection with those identified in modern humans relative to archaics [[49]10]. A recent study has identified significant divergence in genomic regions containing genes associated with aggressive behavior in the Lidia breed [[50]16]. This includes a polymorphism in the promoter of the monoamine oxidase A (MAOA) gene, an important locus widely associated with pathological forms of aggression which, in humans, manifests in a broad spectrum of psychiatric conditions, such as manic and bipolar disorders and schizophrenia, among others [[51]17, [52]18]. Similarly, the kainite glutamate receptor GRIK3 is associated with heightened aggression in Lidia cattle. This gene has been targeted in modern human evolution and in multiple domestication events, including in dogs, sheep, yaks, and across multiple cattle breeds [[53]16, [54]19, [55]20]. However, no studies on gene expression differences for behavioral features have been conducted so far in cattle. Gene expression in the prefrontal cortex (PFC) has been shown to play a crucial role in the regulation of aggressive behavior [[56]21, [57]22]. The PFC role in aggression has been studied in different species, e.g. PFC lesions result in impulsive and antisocial behaviors in humans [[58]23] and offensive aggression in rodents [[59]17]. Moreover, a catalogue of gene-specific sequence variants was detected as differentially expressed between a strain of silver fox selected for aggressive behaviors when compared to its tame counterpart [[60]24]. Similar results are reported in RNA-seq profiles of different dog breeds [[61]25]. The goal of our study is to uncover genes that are differentially expressed in the PFC of aggressive and non-aggressive bovines using as models the Lidia and the Wagyu breeds as aggressive and non-aggressive cohorts respectively. The two breeds differ significantly in their agonistic responses, the Lidia being known as one of the most aggressive bovine breeds, whereas Wagyu bovines are docile animals, selected and bred by farmers with the aim of easing their handling [[62]26]. These divergent phenotypes, in conjunction with the potential relevance of domestication events to recent human evolution, make our populations of study as suitable for research into the biological underpinnings of aggressive behavior in animals, as well as abnormal aggression in humans. Methods This study did not involve purposeful killing of animals, thus, no special permits were required to conduct the research. Samples were collected from bovines after slaughter following standard procedures approved by the Spanish legislation applied to abattoirs [[63]27]. No ethical approval was deemed necessary. Animals, sample retrieval and tissue processing Post mortem PFC tissue samples were collected (in May 2019) from 16 non-castrated male bovines aged 3 to 4 years, 8 belonging to the Lidia breed, considered aggressive (n = 8), and 8 belonging to the Wagyu breed, considered tamed (n = 8). Animals from the aggressive Lidia group belong to two batches: one from “La quinta” farm (N = 4, coordinates: 37°44′39″N 5°17′32″O) and the other from “Montealto” farm (N = 4, coordinates: 40°49′35″N 3°38′30″W) (Supplementary Table [64]1), both affiliated to the Lidia Breeders Association (UCTL, [65]https://torosbravos.es/), whose genealogical and behavioral data have been previously studied and recorded [[66]15]. From the docile cohort, the batch of 8 Wagyu bulls belong to the farm “Nuestro Buey” ([67]https://www.fincasantarosalia.com/, coordinates: 42°16′24″N 4°09′23″W) and were raised exclusively for meat production purposes. The study is designed on the basis of the differences in aggressiveness reached through intensive human selection over the last centuries; whereas the Lidia breed has been selected exclusively for aggressive behavior related traits, the tamed Wagyu breed has been selected for meat quality traits and docile behaviors in order to facilitate handling [[68]26]. Among the wide variety of docile cattle breeds, we opted for the Wagyu breed due to its age at slaughter, higher than 36 months, like that of Lidia breed bulls [[69]28]. All of the selected Lidia individuals belonged to an “elite” group of aggressive bulls, selected by their breeders according to the standardized traits of aggressiveness, ferocity, face hiding and nobility on a categorical scale from 1 to 10 for each trait [[70]14, [71]28]. The genealogical and behavioral scores of these traits have been recorded between 1984 and 2010 and analyzed by Menéndez-Buxadera et al. [[72]15], using multi-trait reaction norm models, which revealed heritability values ranging between 0.230 and 0.308, with aggressiveness attaining the highest heritability score. Non-related Lidia individuals were raised under an extensive farming system, pasture fed until 6–8 months prior to their sacrifice. At this stage bulls were separated into wide-fenced enclosures and fed with a fattening supplementary diet of ad-libitum high energy and highly digestible concentrates [[73]29]. The Wagyu cattle handling practices are to raise animals freely grazing within the farm’s pastures at a young age to produce quality meat that satisfies consumer preferences