Elsevier

Neuroscience

Volume 284, 22 January 2015, Pages 297-310
Neuroscience

Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment

https://doi.org/10.1016/j.neuroscience.2014.10.009Get rights and content

Highlights

  • We tested effects of a ‘two hit’ combination of BDNF deficiency and stress in rats.

  • BDNF mutant rats showed disrupted short-term spatial memory and PPI.

  • Corticosterone induced object-recognition memory deficits in both groups.

  • Corticosterone disrupted fear conditioning extinction in BDNF mutant rats only.

  • Findings help understanding of BDNF-stress interactions in psychiatric illness.

Abstract

Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin involved in neurodevelopment, neuroprotection and synaptic plasticity. It is also implicated in a range of psychiatric disorders such as schizophrenia, depression and post-traumatic stress disorder. Stress during adolescence/young adulthood can have long-term psychiatric and cognitive consequences, however it is unknown how altered BDNF signaling is involved in such effects. Here we investigated whether a congenital deficit in BDNF availability in rats increases vulnerability to the long-term effects of the stress hormone, corticosterone (CORT).

Compared to wildtype (WT) littermates, BDNF heterozygous (HET) rats showed higher body weights and minor developmental changes, such as reduced relative brain and pituitary weight. These animals furthermore showed deficits in short-term spatial memory in the Y-maze and in prepulse inhibition and startle, but not in object-recognition memory. CORT treatment induced impairments in novel-object recognition memory in both genotypes but disrupted fear conditioning extinction learning in BDNF HET rats only.

These results show selective behavioral changes in BDNF HET rats, at baseline or after chronic CORT treatment and add to our understanding of the role of BDNF and its interaction with stress. Importantly, this study demonstrates the utility of the BDNF HET rat in investigations into the pathophysiology of various psychiatric disorders.

Introduction

The effects of chronic stress or allosteric overload (McEwen, 2008) during the adolescent and young-adult phase of neurodevelopment is known to have long-term consequences which may manifest in adulthood as various psychiatric disorders (Kaufman et al., 2000). The vulnerability of the brain during this period is due to the ongoing and fragile process of brain modeling in response to a multitude of internal and external cues (Eiland and Romeo, 2013). The hypothalamic–pituitary axis (HPA) is the main response system to the effects of stress and numerous studies have shown that in adolescents the release of glucocorticoids such as corticosterone (CORT) by the adrenal glands is greater compared to adults, suggesting increased sensitivity to stress during this period of growth (McCormick and Mathews, 2007). CORT binds to mineralocorticoid (MR) or glucocorticoid receptors (GR) which are located in several brain regions including the prefrontal cortex (PFC), amygdala and hippocampus. The hippocampus in particular has a significant role in regulating basal tone of the HPA-axis and its response to stress (Vazquez et al., 1996). Upon CORT binding to MRs or GRs, a range of genomic and non-genomic responses are initiated, such as hippocampal feedback to the HPA, modulation of synaptic plasticity, and influencing the expression of various proteins such as brain-derived neurotrophic factor (BDNF) (Joels and Baram, 2009).

BDNF is expressed widely throughout the brain and plays a major role in neurodevelopment, and plasticity. It is initially synthesized as the larger precursor prepro-BDNF (30–35 kDa) which is proteolytically converted to proBDNF (28 kDa) and then to BDNF (Huang and Reichardt, 2001). The effects of BDNF are mediated predominantly by binding to the tropomyosin-related kinase B (TrkB) receptor. Neuronal release of proBDNF is a highest during the early stages of brain development and then reduces in adolescence and adulthood (Yang et al., 2009). Interestingly, we have shown that levels of BDNF rise and fall in a sex-dependent manner at these developmental time points (Hill et al., 2012).

We have previously reported on the long-term effects of chronic CORT treatment in male and female BDNF heterozygous (HET) mice, which have approximately 50% reductions of brain BDNF levels (Klug et al., 2012). In adulthood, male, but not female BDNF HET mice treated with CORT showed significant deficits in short-term spatial memory and markedly elevated levels of the NR2B subunit of the N-methyl-d-aspartate (NMDA) receptor in the dorsal hippocampus (Klug et al., 2012) which is involved in spatial memory (Fanselow and Dong, 2010). This previous work suggested that a deficiency in BDNF renders the brain more vulnerable to the effects of chronic stress during adolescence in a sex-specific manner (Wu et al., 2013) and that consequent alterations in glutamatergic neurotransmission could underlie some of the behavioral effects. However, similar studies have not been done in rats, even though this is the preferred species for the study of psychiatric disorders (Parker et al., 2014). Rats have a richer behavioral repertoire than mice and the similarities they have with human neurophysiology make them a more translationally relevant species. We therefore used BDNF HET rats, with the aim to phenotype the animals for a number of behavioral measures and to assess the effect of chronic young-adult CORT treatment.

We recently reported on the genotype and CORT treatment effects on anxiety and depression-like behavior (Gururajan et al., 2014). Here we present findings from tests of cognition and other behaviors. Because few studies have been done with this model, we also verified body weight and organ weights. Lastly, as we had previously done for BDNF HET mice we examined effects on BDNF, TrkB and NMDA receptor subunit level expression in the dorsal hippocampus.

Section snippets

Animals

All rats were obtained from a breeding colony at the institute which was set up with wildtype (WT) Sprague–Dawley and BDNF HET rats on a Sprague–Dawley genetic background (SD-BDNFtm1sage) from SAGE® Labs. After weaning, male offspring were housed by genotype in individually ventilated cages in groups of three to four with free access to tap water and standard pellet food. They were kept in a temperature-controlled environment (22 °C) on a 12/12-h light/dark cycle (lights on 0700–1900 h). All

Organ weights

We have previously reported on the effects of genotype and treatment on body weight over the course of the experimental protocol (Gururajan et al., 2014). Here we present findings from the analysis of organ weights.

There were no group differences in absolute brain weights or pituitary weights (Table 1). However, heart weight was higher in BDNF HET rats compared to controls [F(1,54) = 6.4, p = 0.014] irrespective of CORT treatment. In contrast, seminal vesicle weights were lower in BDNF HET rats [F

Organ weights

The observation of reduced relative brain size in the BDNF HET has not been reported in BDNF HET mice and suggests a species-specific morphological effect of reduced BDNF levels. We observed no long-term effect of CORT treatment on relative adrenal gland or pituitary gland weight. Chronic stress and chronic dexamethasone treatments have been shown to induce adrenal hypertrophy (Chappell et al., 1986) and reduction in BDNF levels in the anterior pituitary, respectively (Kononen et al., 1994).

Acknowledgments

This work was supported by a National Health and Medical Research Council of Australia (NHMRC) project grant 566879 to MvdB, a postdoctoral training fellowship to RH and a senior research fellowship 509156 to MvdB. Additional support was obtained by way of operational infrastructure funding from the Victorian State Government. These funding sources had no role in the study’s design, the collection, analysis and interpretation of the data, the writing of the report, or the decision to submit the

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