Age-dependent deficits in fear learning in heterozygous BDNF knock-out mice

Abstract

Beyond its trophic function, the neurotrophin BDNF (brain-derived neurotrophic factor) is well known to crucially mediate synaptic plasticity and memory formation. Whereas recent studies suggested that acute BDNF/TrkB signaling regulates amygdala-dependent fear learning, no impairments of cued fear learning were reported in heterozygous BDNF knockout mice (BDNF +/2 ). Since brain BDNF levels are known to decline with aging, we hypothesized that BDNF +/2 mice might show reduced fear learning at older ages. Indeed, BDNF +/2 animals revealed an age-dependent deficit in fear learning 3 mo after birth and beyond. Since there were no alterations between the two genotypes during the conditioning training and when testing short-term memory, this learning deficit most likely reflects a deficit in memory consolidation. Importantly, there were no differences in spontaneous motor behavior and baseline anxiety in BDNF +/2 animals at any age tested. Following behavioral testing quantification of BDNF levels in the basolateral amygdala with a sensitive BDNF ELISA revealed a positive correlation between the levels of BDNF in the amygdala and the individual learning performance. However, the age-dependent decline in the efficiency of fear conditioning in BDNF +/2 mice was not accompanied by reduced BDNF expression in the amygdala. Thus, while reduced BDNF levels in general correlate with less efficient fear learning, this lack of BDNF can be compensated in young but not in older animals, suggesting that the cellular mechanisms responsible for fear learning consolidation become BDNF-dependent 3 mo after birth.

RETRACTED: BNDF heterozygosity is associated with memory deficits and alterations in cortical and hippocampal EEG power

“…Despite selective deficits in freezing at some CSs, all animals showed equivalent freezing at the anticipatory time point (Post CS), which suggests that all animals acquired the fear memory. This would be in line with other studies of KO animals that also do not show an impairment in acquisition [57–59]. Reduced freezing during the CS presentations in the KO animals may be related to reduced BDNF-related pain perception [60].…”

Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice

“…Other investigators have reported that BDNF +/− , BDNF Met/Met , and forebrain-inducible BDNFdeleted mice are impaired in contextual fear conditioning, whereas cued conditioning is retained (35,(43)(44)(45). Cued fear conditioning, however, can be deficient in older BDNF +/− animals (46). By contrast, transgenic overexpression of TrkB in cortical and hippocampal subfields augments contextual fear conditioning and taste aversion (36); the latter is a test of amygdala function.…”

Mice lacking TrkB in parvalbumin-positive cells exhibit sexually dimorphic behavioral phenotypes

“…While preclinical studies of behavior are biased towards male subjects, sex-related differences may strongly affect translation of these findings to human populations. This clinical reality warrants an examination of BNDF and TrkB manipulations in female animals, which have been neglected in previous investigations [2-7, 10, 11, 20, 22]. …”

“…In preclinical models, neural synchrony has been strongly correlated with the formation, retrieval, and extinction of emotional memories, processes that are disrupted by BNDF loss of function [2, 3, 7, 10, 11] and by optogenetic manipulation of PV-interneurons [12, 13]. Recent evidence indicates that cell-autonomous TrkB signaling in PV-positive cells promotes PV-interneuron maturation and entrainment of local networks [14].…”