BDNF restricted knockout mice as an animal model for aggression

Abstract

Mice with global deletion of one brain-derived neurotrophic factor (BDNF) allele or with forebrain-restricted deletion of both alleles show elevated aggression, but this phenotype is accompanied by other behavioral changes, including increases in anxiety and deficits in cognition. Here we performed behavioral characterization of conditional BDNF knockout mice generated using a Cre recombinase driver line, KA1-Cre, which expresses Cre in few areas of brain: highly at hippocampal area CA3 and moderately in dentate gyrus, cerebellum and facial nerve nucleus. The mutant animals exhibited elevated conspecific aggression and social dominance, but did not show changes in anxiety-like behaviors assessed using the elevated plus maze and open field test. There were no changes in depression-like behaviors tested in the forced swim test, but small increase in immobility in the tail suspension test. In cognitive tasks, mutants showed normal social recognition and normal spatial and fear memory, but exhibited a deficit in object recognition. Thus, this knockout can serve as a robust model for BDNF-dependent aggression and object recognition deficiency.

Chronic BDNF deficiency leads to an age-dependent impairment in spatial learning

“…Finally, a fourth study reported unaffected water maze learning in 3 months old BDNF +/À mice (Montkowski & Holsboer, 1997). Similarly, studies using region-specific, inducible BDNF knock out mouse models reported conflicting results for a role of endogenous BDNF in hippocampus-dependent learning: whereas two studies using hippocampus or forebrain-restricted BDNF knockout mice observed deficits in spatial learning (Gorski, Balogh, Wehner, & Jones, 2003;Heldt et al, 2007), another study using a mostly hippocampus-specific BDNF knock out mouse model reported intact spatial learning in the water maze (Ito, Chehab, Thakur, Li, & Morozov, 2011). In conclusion, it remains still unclear to what extent chronically reduced hippocampal BDNF levels affect spatial learning in transgenic mouse models.…”

Neural deletion of Sh2b1 results in brain growth retardation and reactive aggression

“…Notably, the aggression phenotype of brain-specific Sh2b1 KO mice is reminiscent of that seen in heterozygous Bdnfnull mice and mice with targeted disruption of Bdnf in specific brain regions (27)(28)(29). We, therefore, hypothesized that the effect of Sh2b1 on behavior may be mediated, in part, by modulating BDNF signaling.…”

Impaired social contacts with familiar anesthetized conspecific in CA3‐restricted brain‐derived neurotrophic factor knockout mice

“…10,11 In this study, we examine mice with the CA3-restricted knockout (KO) of BDNF, which exhibit elevated aggression and dominance toward cage mates but normal cognition and social memory. 12 As predicted, in the new test, mice did not show aggression toward unfamiliar conspecific and other forms of behaviors triggered by reciprocal activities, like following and escaping, which allowed comparisons between responses to social cues from familiar vs unfamiliar conspecific. To this end, we find a distinct social trait-sustained contact with the familiar, but not unfamiliar anesthetized conspecific-that was compromised in the BDNF KO mice, despite their normal sociability, when assayed in the three-chamber test.…”

“…Mice with the CA3-restricted KO of BDNF were generated by combining two mutant mouse lines, the floxed BDNF line 13 and the transgenic bacterial artificial chromosome KA1 Cre recombinase driver line 14 as previously described. 12 Before interline crossings, these lines were backcrossed to C57BL/6 background animals a minimum of 6 generations. To produce animals for experiments, homozygous BDNF-floxed Cre-positive (BDNF ff, Cre ) males were crossed with homozygous BDNF-floxed Cre-negative (BDNF ff ) females to obtain BDNF ff, Cre and BDNF ff male and female animals, further referred to as KO and wild-type (WT), respectively.…”