Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior

Abstract

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response. Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region-specific, particularly involving the corticolimbic system, including the ventral tegmental area, nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology. In this review, we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression. We focused on associated molecular pathways and neural circuits, with special attention to the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway and the ventral tegmental area-nucleus accumbens dopamine circuit. We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature, severity, and duration of stress, especially in the above-mentioned brain regions of the corticolimbic system. Therefore, BDNF might be a biological indicator regulating stress-related processes in various brain regions.

Figure 1

The timeline for exploring the role of BDNF in the brain in social stress–induced depression. AMY: Amygdala; BDNF: brain-derived neurotrophic factor; CSDS: chronic social defeat stress; Gadd45b: growth arrest and DNA damage-inducible beta; HIPP: hippocampus; HPA: hypothalamic-pituitary-adrenal; mPFC: medial prefrontal cortex; NAc: nucleus accumbens; PFC: prefrontal cortex; TrkB: tropomyosin receptor kinase B; VTA: ventral tegmental area. This timeline figure was created with Adobe Illustrator CS6 based on Barde et al. (1982), Squinto et al. (1991), Nibuya et al. (1995), Smith et al. (1995), Siuciak et al. (1997), Eisch et al. (2003), Molnar et al. (2003), Pizarro et al. (2004), Schule et al. (2006), Tsankova et al. (2006), Thakker-Varia et al. (2007), Roth et al. (2009), Fanous et al. (2010), Walsh et al. (2014), Zhang et al. (2017a), Labonte et al. (2019), and Xu et al. (2021, 2023).

Figure 2

A flow diagram depicting a selection of studies. Created with Adobe Illustrator CS6.

Figure 3

Schematic diagram of social stress models used to explore the roles of brain-derived neurotrophic factor in rodents. Acute stress behavior paradigms include forced swimming and tail suspension tests. However, chronic stress models of depression, such as chronic social defeat stress and chronic mild stress, are more widely used because these models induce depression-like behavior and show sensitivity to antidepressant onset. Created with Adobe Illustrator CS6.

Figure 4

Schematic diagram of interactions among the brain areas and brain region–specific changes of BDNF in the corticolimbic system in social stress-induced depressive-like behavior. Exposure to stress and depression decreases BDNF expression in the HIPP and PFC but upregulates BDNF expression in the VTA-NAc pathway. Additionally, increased and decreased BDNF expression in the AMY have been reported in the literature. Created with Adobe Illustrator CS6. AMY: Amygdala; BDNF: brain-derived neurotrophic factor; HIPP: hippocampus; NAc: nucleus accumbens; PFC: prefrontal cortex; VTA: ventral tegmental area.