Unravelling the neurophysiological basis of aggression in a fish model

Abstract

BackgroundAggression is a near-universal behaviour with substantial influence on and implications for human and animal social systems. The neurophysiological basis of aggression is, however, poorly understood in all species and approaches adopted to study this complex behaviour have often been oversimplified. We applied targeted expression profiling on 40 genes, spanning eight neurological pathways and in four distinct regions of the brain, in combination with behavioural observations and pharmacological manipulations, to screen for regulatory pathways of aggression in the zebrafish (Danio rerio), an animal model in which social rank and aggressiveness tightly correlate.ResultsSubstantial differences occurred in gene expression profiles between dominant and subordinate males associated with phenotypic differences in aggressiveness and, for the chosen gene set, they occurred mainly in the hypothalamus and telencephalon. The patterns of differentially-expressed genes implied multifactorial control of aggression in zebrafish, including the hypothalamo-neurohypophysial-system, serotonin, somatostatin, dopamine, hypothalamo-pituitary-interrenal, hypothalamo-pituitary-gonadal and histamine pathways, and the latter is a novel finding outside mammals. Pharmacological manipulations of various nodes within the hypothalamo-neurohypophysial-system and serotonin pathways supported their functional involvement. We also observed differences in expression profiles in the brains of dominant versus subordinate females that suggested sex-conserved control of aggression. For example, in the HNS pathway, the gene encoding arginine vasotocin (AVT), previously believed specific to male behaviours, was amongst those genes most associated with aggression, and AVT inhibited dominant female aggression, as in males. However, sex-specific differences in the expression profiles also occurred, including differences in aggression-associated tryptophan hydroxylases and estrogen receptors.ConclusionsThus, through an integrated approach, combining gene expression profiling, behavioural analyses, and pharmacological manipulations, we identified candidate genes and pathways that appear to play significant roles in regulating aggression in fish. Many of these are novel for non-mammalian systems. We further present a validated system for advancing our understanding of the mechanistic underpinnings of complex behaviours using a fish model.

Assessment of fight outcome is needed to activate socially driven transcriptional changes in the zebrafish brain

“…These studies had found differential telencephalic and/or hypothalamic expression of nonapeptides, serotonin, hypothalamo-pituitarygonadal, and hypothalamo-pituitary-interrenal genes (26,27). In contrast, in the present study, when analyzed at the transcriptome level in whole brain samples, most of these genes for which a status-specific pattern was identified using a candidate gene approach were no longer detected as DE or overrepresented in the coexpression gene modules associated with specific social phenotypes.…”

“…Finally, there were also socially DE genes that interacted with histones and chromatin, thus having a potential role in epigenetic mechanisms [e.g., epc1, jdp2, msl1b, msl2a, ncapd3, jade3, Pim-1 proto-oncogene, serine/threonine kinase (pim1), rnf40]. Because previous studies have already documented the occurrence of DE genes between dominant and subordinate zebrafish, which included genes in the nonapeptides, serotonin, hypothalamo-pituitary-gonadal, and hypothalamo-pituitaryinterrenal pathways (26,27), we checked whether these genes were also responding to changes in status in our experiment. Interestingly, none of these genes were DE between winners and losers in our study (Table S2).…”

“…These results suggest the involvement of different transcriptional networks in the observed social phenotypes. We also checked whether the genes that have been reported to be DE between dominant and subordinate zebrafish in previous studies (26,27) were overrepresented in the coexpression gene modules associated with the social phenotypes studied in our experiment (Table S2). Despite the presence of some DE genes from these previous studies in the coexpression gene modules reported here (esr1 and gnrh3 in the light yellow module associated with losers and ar and esr2a in the light green module associated with noninteracting individuals), none of these modules were overrepresented in the gene dataset of the previous studies (light yellow: OR = 0.17, P = 0.99; light green: OR = 0.50, P = 0.90).…”

Modulation of Fgfr1a Signaling in Zebrafish Reveals a Genetic Basis for the Aggression–Boldness Syndrome

“…However, additional brain areas may also play an important role in linking aggression, boldness, and exploration. For example, a recent gene expression analysis of aggressive zebrafish identified gene expression changes in the telencephalon, optic tectum, hypothalamus, and hindbrain (Filby et al, 2010). It is clear that an in-depth analysis of the spd mutant brain is needed to resolve this issue.…”

Verapamil – L type voltage gated calcium channel inhibitor diminishes aggressive behavior in male Siamese fighting fish

“…Such effects were probably caused by inhibition of Ca 2+ entry into neurons preventing appearance of synaptic vesicles in axon terminals and release of neurotransmitter into the synaptic cleft. It was shown that verapamil inhibits release of dopamine, histamine and corticotropin-releasing factor (CRF) (Filby et al 2010), which may modulate fish behavior (aggressive display). Davis and Bauer (2012) have shown in experiments performed on rats, that activation of L-VGCCs is necessary for the long term retention of fear excitation.…”