CDNF Exerts Anxiolytic, Antidepressant-like, and Procognitive Effects and Modulates Serotonin Turnover and Neuroplasticity-Related Genes – PubMed Black Hawk Supplements
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Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse…
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CDNF Exerts Anxiolytic, Antidepressant-like, and Procognitive Effects and Modulates Serotonin Turnover and Neuroplasticity-Related Genes
Anton Tsybko et al. Int J Mol Sci. .
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor because it does not bind to a known specific receptor on the plasma membrane and functions primarily as an unfolded protein response (UPR) regulator in the endoplasmic reticulum. Data on the effects of CDNF on nonmotor behavior and monoamine metabolism are limited. Here, we performed the intracerebroventricular injection of a recombinant CDNF protein at doses of 3, 10, and 30 μg in C57BL/6 mice. No adverse effects of the CDNF injection on feed and water consumption or locomotor activity were observed for 3 days afterwards. Decreases in body weight and sleep duration were transient. CDNF-treated animals demonstrated improved performance on the operant learning task and a substantial decrease in anxiety and behavioral despair. CDNF in all the doses enhanced serotonin (5-HT) turnover in the murine frontal cortex, hippocampus, and midbrain. This alteration was accompanied by changes in the mRNA levels of the 5-HT1A and 5-HT7 receptors and in monoamine oxidase A mRNA and protein levels. We found that CDNF dramatically increased c-Fos mRNA levels in all investigated brain areas but elevated the phosphorylated-c-Fos level only in the midbrain. Similarly, enhanced CREB phosphorylation was found in the midbrain in experimental animals. Additionally, the upregulation of a spliced transcript of XBP1 (UPR regulator) was detected in the midbrain and frontal cortex. Thus, we can hypothesize that exogenous CDNF modulates the UPR pathway and overall neuronal activation and enhances 5-HT turnover, thereby affecting learning and emotion-related behavior.
Keywords: 5-HT; CDNF intracerebroventricular injection; CREB; UPR gene; anxiety; behavioral despair; c-Fos; learning; mouse.
Conflict of interest statement
The authors declare no conflicts of interest.
Figures
Daily (A) and total (B) distance traveled were not affected by i.c.v. injection of the CDNF protein. CDNF i.c.v. injection failed to affect either daily (C) or total (D) feed consumption. * p ˂ 0.05 and ** p ˂ 0.01 as compared with the first day of the experiment (repeated-measures analysis of variance [ANOVA]). Daily (E) and total (F) water consumption were not affected by i.c.v. injection of CDNF. * p ˂ 0.05 and ** p ˂ 0.01 vs. the first day of the experiment (repeated-measures ANOVA). All data are presented as means ± SEMs; n ≤ 8.
Body weight change (delta, Δ) after PBS or CDNF i.c.v. injection at 4 days (A) or 10 days (B) post treatment. * p ˂ 0.05 and *** p ˂ 0.001 vs. the PBS group (one-way ANOVA). The comparison of groups in panel (B) was performed with Student’s t test. All data are presented as means ± SEMs; n ≤ 8.
Average sleep duration in the light and dark phases of the day in mice after PBS or CDNF i.c.v. injection (A). *** p ˂ 0.001 for the dark phase vs. light phase; ## p ˂ 0.01 for 3 μg of CDNF vs. other groups (two-way ANOVA). (B) Daily dynamics of sleep duration in mice after PBS or CDNF i.c.v. injection throughout the experiment. # shows marginal significance (p = 0.06), * p ˂ 0.05, and ** p ˂ 0.01 for 3 μg of CDNF vs. the PBS group (repeated-measures ANOVA). (C) The average numbers of sleep episodes during the light and dark phases of the day in mice after PBS or CDNF i.c.v. injection. ** p ˂ 0.01 and *** p ˂ 0.001 for the dark phase vs. light phase (two-way ANOVA). (D) Daily dynamics of the numbers of sleep episodes in mice after PBS or CDNF i.c.v. injection throughout the experiment. All data are presented as means ± SEMs; n ≤ 8. L: the light phase of the day; D: the dark phase of the day. In panels (B,D), the dark time of the day is marked with a gray color.
The i.c.v. injection of CDNF improved associative learning in the operant wall, as evidenced by increases in the number of nose pokes (A), total time of nose pokes (B), and the number of obtained pellets (as reward) (C). * p ˂ 0.05 and ** p ˂ 0.01 vs. the PBS group (one-way ANOVA). All data are presented as means ± SEMs; n ≤ 8.
Injection of 10 μg of CDNF did not affect the number of nose pokes (A) or the number of pellets obtained (as reward) (C) but reduced the total time of nose pokes (B) in the operant wall 10 days after treatment. * p ˂ 0.05 vs. the PBS group (Student’s t test). All data are presented as means ± SEMs; n ≤ 8.
The total distance traveled (A), explored area of the arena (B), time spent at the center of the arena (C), the number of rearings (D), and the number of groomings (E) in mice after PBS or 3, 10, or 30 μg CDNF i.c.v. injection. * p ˂ 0.05, ** p ˂ 0.01, and *** p ˂ 0.001 (one-way ANOVA). Panels (A–D) show means ± SEMs, n ≤ 8, and panel (E) is a violin plot because these data were analyzed by the nonparametric Kruskal–Wallis test.
The total distance traveled (A), time in closed (B) and open (C) arms of the maze, explored area of closed (D) and open (E) arms, and the number (F), total duration (G), and latency (H) of peeks from a closed arm of the maze in mice after PBS or CDNF i.c.v. injection. * p ˂ 0.05, ** p ˂ 0.01, and *** p ˂ 0.001 as compared with the PBS group (one-way ANOVA). All data are presented as means ± SEMs; n ≤ 8.
The immobility time was shorter in the forced swim test after i.c.v. injection of the CDNF protein. * p ˂ 0.05 and ** p ˂ 0.01 vs. the PBS group (unpaired t test). All data are presented as means ± SEMs; n ≤ 8.
5-HT and 5-HIAA levels and the 5HIAA/5-HT ratio in the midbrain (A), frontal cortex (B), hippocampus (C) and hypothalamus (D) of control and CDNF-treated animals. Levels of 5-HT and 5-HIAA are expressed in ng/(mg of total protein). * p ˂ 0.05, ** p ˂ 0.01, and *** p ˂ 0.001 as compared with the PBS group; ### p ˂ 0.001 vs. the 30 μg group (one-way ANOVA). All data are presented as means ± SEMs; n ≤ 8.
mRNA levels of genes Tph2 (A), Slc6a4 (C), and Maoa (E), as well as TPH2 (B), 5-HTT (D), and MAOA (F) protein levels after i.c.v. injection of different doses of CDNF or PBS. Each mRNA level is displayed as the number of a gene’s cDNA copies per 100 copies of Polr2 cDNA. Each protein level is indicated as the ratio of chemiluminescence intensity of a target protein to that of GAPDH. * p ˂ 0.05 and ** p ˂ 0.01 vs. the PBS group (one-way ANOVA). All data are presented as means ± SEMs; n ≤ 8.
mRNA levels of genes Htr1a (A), Htr2a (C), and Htr7 (E), as well as 5-HT1A (B), 5-HT2A (D), and 5-HT7 (F) receptors’ protein levels after i.c.v. injection of CDNF or PBS. Each mRNA level is displayed as the number of a gene’s cDNA copies per 100 copies of Polr2 cDNA. Each protein level is indicated as the ratio of chemiluminescence intensity of a target protein to that of GAPDH. ** p ˂ 0.01 and *** p ˂ 0.001 vs. the PBS group (one-way ANOVA). All data are presented as means ± SEMs; n ≤ 8.
mRNA levels of genes c-Fos (A) and Creb (E), as well as c-Fos (B), phospho-c-Fos (C), Creb (F), and phospho-CREB (G) protein levels after i.c.v. injection of CDNF or PBS. * p ˂ 0.05, ** p ˂ 0.01, and *** p ˂ 0.001 vs. the PBS group (one-way ANOVA). The phosphorylation of c-Fos and CREB is depicted as the ratio of the nonphosphorylated to phosphorylated protein form (D,H). * p ˂ 0.05 and ** p ˂ 0.01 as compared with the PBS group (unpaired t test). The mRNA level is represented by the number of a gene’s cDNA copies per 100 copies of Polr2 cDNA. Each protein level is indicated as the ratio of chemiluminescence intensity of a target protein to that of GAPDH. All data are presented as means ± SEMs; n ≤ 8.
The influence of CDNF injection on both mRNA levels of UPR genes Grp78 (A), Ire1α (B), Atf6 (C), uXbp1 (D), and sXbp1 (E) as well as on the sXbp1/uXbp1 ratio (F). Each mRNA level (A–C) is displayed as the number of cDNA copies of a gene per 100 copies of Polr2 cDNA. In panels (D,E), expression is depicted as a ratio of sXbp1 and uXbp1 expression levels to the Polr2 expression level. * p ˂ 0.05, ** p ˂ 0.01 and *** p ˂ 0.001 vs. the PBS group (one-way ANOVA, Kruskal–Wallis test for sXbp1 and sXbp1/uXbp1 in the midbrain). All data are presented as means ± SEMs; n ≤ 8.
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