Brain STAT5 signaling modulates learning and memory formation

Abstract

The signal transducer and activator of transcription 5 (STAT5) is a transcription factor recruited by numerous cytokines. STAT5 is important for several physiological functions, including body and tissue growth, mammary gland development, immune system and lipid metabolism. However, the role of STAT5 signaling for brain functions is still poorly investigated, especially regarding cognitive aspects. Therefore, the objective of the present study was to investigate whether brain STAT5 signaling modulates learning and memory formation. For this purpose, brain-specific STAT5 knockout (STAT5 KO) mice were studied in well-established memory tests. Initially, we confirmed a robust reduction in STAT5a and STAT5b mRNA levels in different brain structures of STAT5 KO mice. STAT5 KO mice showed no significant alterations in metabolism, growth, somatotropic axis and spontaneous locomotor activity. In contrast, brain-specific STAT5 ablation impaired learning and memory formation in the novel object recognition, Barnes maze and contextual fear conditioning tests. To unravel possible mechanisms that might underlie the memory deficits of STAT5 KO mice, we assessed neurogenesis in the hippocampus, but no significant differences were observed between groups. On the other hand, reduced insulin-like growth factor-1 (IGF-1) mRNA expression was found in the hippocampus and hypothalamus of STAT5 KO mice. These findings collectively indicate that brain STAT5 signaling is required to attain normal learning and memory. Therefore, STAT5 is an important downstream cellular mechanism shared by several cytokines to regulate cognitive functions.

Effects of growth hormone in the central nervous system

“…Importantly, GH action in the brain is impaired in these mice since the major intracellular pathway recruited by GHR is nonfunctional. We observed that brainspecific STAT5 ablation leads to impaired learning and memory formation, as determined by results from the novel object recognition test, Barnes maze and fear conditioning test (25). Although hippocampal neurogenesis is normal (25), these mutant mice exhibit decreased IGF-1 expression in the hippocampus, suggesting that GH-mediated hippocampal IGF-1 production is important for maintaining memory (Figure 2).…”

“…Since the activation of GHR, but not of IGF-1 receptor, recruits the STAT5 signaling pathway, manipulating this transcription factor may be an alternative way to study the effects of GH on the brain, regardless of circulating IGF-1 (25). Thus, our group generated a brain-specific STAT5-knockout mouse (25).…”

“…Since the activation of GHR, but not of IGF-1 receptor, recruits the STAT5 signaling pathway, manipulating this transcription factor may be an alternative way to study the effects of GH on the brain, regardless of circulating IGF-1 (25). Thus, our group generated a brain-specific STAT5-knockout mouse (25). A previous study had shown that these mice have normal body growth and serum IGF-1 levels, although brain-specific STAT5-knockout mice exhibit late onset obesity and insulin resistance (26).…”

Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice

“…Mice were anesthetized and perfused transcardially. The brains were sliced and processed as previously described 62 . The immunofluorescence staining was done in brain sections washed in 0.02 mol/L potassium PBS, pH 7.4 (KPBS) solution followed by 1 h incubation in 3% normal donkey serum.…”

Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons

“…G) Serum corticosterone levels {interaction between 2DG effect and GHR ablation [F(1,21) = 0.0183, P = 0.8936]; n = 6-7}. H ) Serum glucagon levels {interaction between 2DG effect and GHR ablation [F(1,23) = 0.6025, P = 0.4455]; n = 5-9}. I ) Serum GH levels {interaction between 2DG effect and GHR ablation [F(1,12) = 0.0928, P = 0.7658]; n = 4}.…”