Brain neurotrophin levels and mouse behavior : relationship to environmental influences

All normal functions over the lifetime of an animal are based on a dynamic balance of at least three fundamental elements: brain, environment and behaviour. This thesis investigated different aspects of these three elements and revealed novel interactions of brain neurotrophins, environmental influences and emotional behaviour in mice.

In the first two studies, we used C57BL6 mice housed in standard or enriched conditions to investigate anxiety- and fear-related behaviour and neurotrophin levels in different brain regions. We discovered: (a) The normal (steady state) levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein are differently distributed in dorsal and ventral parts of hippocampus in both male and female mice, with the dorsal hippocampal levels being consistently higher than those in ventral hippocampus. (b) Exposure to a series of behavioural tests induced complex changes on neurotrophin levels in selected brain regions. (c) Differential housing exerted significant influences on anxiety-related behaviour and brain neurotrophins; these changes were gender and brain region dependent. (d) Significant correlations between behavioural measures and postmortem brain regional neurotrophic factors contents were related: whereby the magnitude of anxiety-like behaviour in the elevated plus maze was positively related to dorsal hippocampal BDNF levels, but negatively related to NGF levels in dorsal hippocampus and in the amygdala, while the expression of conditioned fear is positively related to amygdala BDNF and NGF levels, and to dorsal hippocampus NGF levels.

The third and fourth studies further explored the interrelationship of environmental conditions, behaviour and brain neurotrophins, using BALB/c mice and BDNF knockout mice. The studies involved exposure to intermittent individual housing with or without access to physical exercise in anxious BALB/c mice and environmental enrichment (EE) in BDNF mutant mice. The results showed that: (a) Intermittent exposure to individual housing induced anxietylike behaviours with significantly enhanced motor activity, (b) Alternate social isolation caused down regulation of NGF and BDNF levels in frontal cortex, while up regulation of BDNF protein content in the amygdala and BDNF protein and mRNA levels in the hippocampus. (c) Access to running wheels for intermittently isolated mice normalized motor activity. Besides increased cerebellar BDNF and hippocampal NGF and BDNF protein levels, physical exercise did not attenuate down regulation of cortical NGF and BDNF protein levels induced by intermittent social isolation.

These results demonstrated for the first time that alternate housing had significant impact on behaviour and neurotrophin levels in selected brain regions in mice, which can be partially altered by voluntary physical exercise. It also suggested that substantial changes induced by intermittent social isolation are different from previous findings caused by sustained social isolation on behaviour and brain neurotrophin. (d) EE increased numbers of dendritic spines in the hippocampal dentate gyrus neurons in wild-type (WT) mice, whereas less impact was found in this brain region in the BDNF mutant mice. (e) Behavioural results showed that in enriched WT mice, there was increased exploration and faster habituation, while this effect was abolished or attenuated in BDNF mutant mice. These findings provided evidence for the involvement of BDNF in regulating emotional behaviour and neural plasticity associated with EE.

List of scientific papers

I. Zhu SW, Yee BK, Nyffeler M, Winblad B, Feldon J, Mohammed AH (2006). Influence of differential housing on emotional behaviour and neurotrophin levels in mice. Behav Brain Res. 169(1): 10-20.
https://doi.org/10.1016/j.bbr.2005.11.024

II. Yee BK, Zhu SW, Mohammed SH, Feldon J (2006). Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice. Journal of Neural Transmission. [Accepted]
https://doi.org/10.1007/s00702-006-0548-9

III. Zhu SW, Pham TM, Aberg E, Brene S, Winblad B, Mohammed AH, Baumans V (2006). Neurotrophin levels and behaviour in BALB/c mice: impact of intermittent exposure to individual housing and wheel running. Behav Brain Res. 167(1): 1-8.
https://doi.org/10.1016/j.bbr.2005.02.038

IV. Zhu SW, Codita A, Hjerling-Leffler J, Ernfors P, Bogdanovic N, Winblad B, Dickins DW, Mohammed AH (2006). Analysis of exploratory behaviour and hippocampal dendritic spines in BDNF knockout mice: influence of environmental manipulation. [Manuscript]

V. Mohammed AH, Zhu SW, Darmopil S, Hjerling-Leffler J, Ernfors P, Winblad B, Diamond MC, Eriksson PS, Bogdanovic N (2002). Environmental enrichment and the brain. Prog Brain Res. 138: 109-33.
https://doi.org/10.1016/S0079-6123(02)38074-9