Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus
Abstract
:1. Introduction
2. Results
2.1. Early Life Stress Selectively Increases Anxiety-Like Behavior in rTgFKBP5 Mice
2.2. Sex and Genotype Modestly Affect the Prepulse Inhibition Response
2.3. FKBP5 Induces Spatial Reversal Learning Deficits in the Morris Water Maze (MWM) Test
2.4. Early Life Stress Affects the pAKT/AKT Ratio in the Hippocampus
2.5. FKBP5 Differentially Regulates AKT Phosphorylation in the Dorsal Hippocampus in the Presence Or Absence of ELS
2.6. AKT and GSK-3β Expression in the VH and Amygdala (AMYG) is not Affected by the FKBP5 x ELS Interaction
3. Discussion
3.1. Sex as a Confounding Factor that Effects Stress Susceptibility
3.2. Early Life Stress Modestly Interacted with Genotype
3.3. Genotype Influences Learning Processes at the Behavioral and Molecular Levels
3.4. FKBP5 Overexpression Modulates AKT in Selective Brain Structures
3.5. Concluding Remarks
4. Materials and Methods
4.1. Animal Subjects
4.2. Early Life Stress (ELS) Model
4.3. Elevated Plus Maze (EPM)
4.4. Prepulse Inhibition (PPI)
4.5. Morris Water Maze (MWM)
4.6. Tissue Collection, IHC, and Western Blot
4.7. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AKT | Protein kinase B |
AMYG | Amygdala |
ANOVA | Analysis of variance |
BLA and CeA | Basolateral and central nuclei of the amygdala |
CAMKII | Ca2+/calmodulin-dependent protein kinase II |
DH | Dorsal hippocampus |
ELS | Early life stress |
EPM | Elevated plus maze |
FKBP5 | FK506-binding protein 5/FK506-binding protein 51 |
GAPDH | Glyceraldehyde 3-phosphate dehydrogenase |
GR | Glucocorticoid receptor |
GSK-3β | Glycogen synthase kinase 3 |
HPA | Hypothalamic-pituitary-adrenal axis |
HPC | Hippocampus |
MWM | Morris water maze |
pAKTSer473 | Phosphorylated AKT at Serine 473 |
pGSK-3βSer9 | Phosphorylated GSK-3β phosphorylation at Serine 9 |
P1 | Postnatal Day 1 |
P21 | Postnatal Day 2 |
PPI | Prepulse inhibition |
PTSD | Post-traumatic stress disorder |
PVDF | Polyvinylidene fluoride or polyvinylidene difluoride |
SDS-PAGE | Sodium dodecyl sulfate polyacrylamide gel electrophoresis |
SEM | Standard error of the mean |
VH | Ventral hippocampus |
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Figure | Measured Condition | Groups Analyzed | Gen. x ELS | Factor | F Statistic and p-Value |
---|---|---|---|---|---|
1B | EPM: Anxiety levels (open arms) See 1D-E for sex differences | 3-way ANOVA, All groups | F(2, 48) = 1.078, p = 0.347 | Genotype | F(2, 48) = 4.610, p = 0.014 |
ELS | F(1, 48) = 3.28, p = 0.075 | ||||
Sex | F(1, 48) = 0.308, p = 0.582 | ||||
Sex/Gen/ELS | F(2, 48) = 1.968, p = 0.151 | ||||
2-way ANOVA, Non-stressed | F(2, 48) = 1.548, p = 0.233 | Genotype | F(2, 48) = 1.442, p = 0.256 | ||
Sex | F(1, 48) = 0.617, p = 0.439 | ||||
2-way ANOVA, ELS | F(2, 48) = 3.089, p = 0.06 | Genotype | F(2, 48) = 4.015, p = 0.031 | ||
Sex | F(1, 48) = 4.003, p = 0.05 | ||||
Number entries to open arms | 3-way ANOVA, All groups | F(2, 48) = 0.351, p = 0.705 | Genotype | F(2, 48) = 1.283, p = 0.285 | |
ELS | F(1, 48) = 0.049, p = 0.824 | ||||
Sex | F(1, 48) = 1.478, p = 0.230 | ||||
Sex/Gen/ELS | F(1, 48) = 0.541, p = 0.585 | ||||
Anxiety levels (closed arms) | 3-way ANOVA, All groups | F(2, 48) = 1.181, p = 0.316 | Genotype | F(2, 48) = 0.010, p = 0.989 | |
ELS | F(1, 48) = 0.850, p = 0.360 | ||||
Sex | F(1, 48) = 0.638, p = 0.428 | ||||
Sex/Gen/ELS | F(2, 48) = 1.096, p = 0.342 | ||||
2-way ANOVA, Males | F(2,24) = 0.228, p = 0.797 | Genotype | F(2,24) = 3.509, p = 0.049 | ||
ELS | F(1,24) = 0.002, p = 0.958 | ||||
2-way ANOVA, Females | F(2,24) = 1.865, p = 0.176 | Genotype | F(2,24) = 1.649, p = 0.213 | ||
ELS | F(1,24) = 0.354, p = 0.557 | ||||
1C | EPM: Locomotion | 3-way ANOVA, All groups | F(2,48) = 0.353, p = 0.704 | Genotype | F(2,48) = 1.657, p = 0.200 |
ELS | F(1,48) = 0.205 p = 0.652 | ||||
Sex | F(1,48) = 0.399, p = 0.673 | ||||
Sex/Gen/ELS | F(2,24) = 1.649, p = 0.213 | ||||
2-way ANOVA, Males | F(2,24) = 0.137, p = 0.879 | Genotype | F(2,24) = 0.714, p = 0.499 | ||
ELS | F(1,24) = 0.465 p = 0.501 | ||||
2-way ANOVA, Females | F(2,24) = 0.336, p = 0.717 | Genotype | F(2,24) = 1.327, p = 0.284 | ||
ELS | F(1,24) = 0.0 p = 1 | ||||
1D | Anxiety levels (open arms) | 2-way ANOVA, Males | F(2,24) = 0.089, p = 0.914 | Genotype | F(2,24) = 8.900, p = 0.001 |
ELS | F(1,24) = 0.001, p = 0.971 | ||||
1E | 2-way ANOVA, Females | F(2,24) = 3.069, p = 0.065 | Genotype | F(2,24) = 0.747 p = 0.294 | |
ELS | F(1,24) = 6.449, p = 0.018 | ||||
2A | Startle response | 3-way ANOVA, All groups | F(2, 48) = 0.997, p = 0.377 | Genotype | F(2, 48) = 1.058 p = 0.355 |
ELS | F(1, 48) = 0.609, p = 0.439 | ||||
Sex | F(1, 48) = 0.388, p = 0.536 | ||||
Sex/Gen/ELS | F(1, 48) = 0.395, p = 0.676 | ||||
2-way ANOVA, Males | F(2,24) = 0.691, p = 0.511 | Genotype | F(2,24) = 0.770, p = 0.475 | ||
ELS | F(1,24) = 0.199, p = 0.660 | ||||
2-way ANOVA, Females | F(2,24) = 0.464, p = 0.634 | Genotype | F(2,24) = 0.791, p = 0.464 | ||
ELS | F(1,24) = 0.789, p = 0.383 | ||||
2B,C | PPI | 3-way RM-ANOVA, All groups | F(2, 48) = 0.629, p = 0.537 | Genotype | F(2, 48) = 7.658, p = 0.001 |
ELS | F(1, 48) = 0.272, p = 0.605 | ||||
Sex | F(1, 48) = 4.532, p = 0.038 | ||||
Sex/Gen/ELS | F(1, 48) = 0.620, p = 0.542 | ||||
3A,C | MWM, Reversal training | 3-way RM-ANOVA, All groups | F(2, 54) = 0.688, p = 0.507 | Genotype | F(2, 54) = 2.685, p = 0.078 |
ELS | F(1, 54) = 0.123, p = 0.727 | ||||
Sex | F(1, 54) = 0.021, p = 0.886 | ||||
Sex/Gen/ELS | F(2, 54) = 0.385, p = 0.683 | ||||
2-way RM-ANOVA, Non-Stressed | Genotype | F(2, 24) = 1.456, p = 0.253 | |||
Sex | F(1, 24) = 0.101, p = 0.753 | ||||
Training | F(2, 23) = 28.02, p < 0.001 | ||||
2-way RM-ANOVA, ELS | Genotype | F(2, 24) = 1.913, p = 0.169 | |||
Sex | F(1, 24) = 0.006, p = 0.941 | ||||
Training | F(2, 23) = 17.53, p < 0.001 | ||||
2-way ANOVA, Males | F(2,24) = 0.812, p = 0.456 | Genotype | F(2,24) = 3.454, p = 0.048 | ||
ELS | F(1,24) = 0.003, p = 0.456 | ||||
2-way ANOVA, Females | F(2,24) = 0.054, p = 0.947 | Genotype | F(2,24) = 0.091, p = 0.913 | ||
ELS | F(1,24) = 0.245, p = 0.625 | ||||
3B,D | MWM, Reversal Probe | 3-way RM-ANOVA, All groups | F(2, 54) = 0.135, p = 0.873 | Genotype | F(2, 54) = 3.827, p = 0.027 |
ELS | F(1, 54) = 0.170, p = 0.681 | ||||
Sex | F(1, 54) = 0.183, p = 0.670 | ||||
Sex/Gen/ELS | F(2, 54) = 0.244, p = 0.784 | ||||
2-way ANOVA, Males | F(2,24) = 0.076, p = 0.927 | Genotype | F(2,24) = 1.208, p = 0.316 | ||
ELS | F(1,24) = 0.712, p = 0.407 | ||||
2-way ANOVA, Females | F(2,24) = 0.289, p = 0.752 | Genotype | F(2,24) = 0.012, p = 0.988 | ||
ELS | F(1,24) = 2.547, p = 0.124 | ||||
S1A | Percent of open arm entries | 3-way ANOVA, All groups | F(2, 48) = 1.560, p = 0.219 | Genotype | F(2, 48) = 3.956, p = 0.026 |
ELS | F(1, 48) = 0.000, p = 0.998 | ||||
Sex | F(1, 48) = 0.348, p = 0.558 | ||||
Sex/Gen/ELS | F(1, 48) = 1.720, p = 0.097 | ||||
S1B | Percent of open arm entries | 2-way ANOVA, Males | F(2, 48) = 2.753, p = 0.042 | Genotype | F(2, 48) = 5.423, p = 0.01 |
ELS | F(1, 48) = 1.493, p = 0.234 | ||||
S1C | Percent of open arm entries | 2-way ANOVA, Females | F(2, 48) =0.854, p = 0.526 | Genotype | F(2, 48) = 0.199, p = 0.821 |
ELS | F(1, 48) = 1.627, p = 0.214 | ||||
S2A | 2-way RM-ANOVA, Males | F(2,24) = 0.412, p = 0.668 | Genotype | F(2,24) = 0.614, p = 0.552 | |
ELS | F(1,24) = 0.879, p = 0.360 | ||||
S2B | 2-way RM-ANOVA, Females | F(2,24) = 7.092, p = 0.004 | Genotype | F(2,24) = 0.692, p = 0.511 | |
ELS | F(1,24) = 3.903, p = 0.061 | ||||
S3A | MWM, Visible | 3-way ANOVA, All groups | F(2, 54) = 0.107, p = 0.898 | Genotype | F(2, 54) = 2.062, p= 0.137 |
ELS | F(1, 54) = 0.110, p= 0.740 | ||||
Sex | F(1, 54) = 1.289, p = 0.262 | ||||
Sex/Gen/ELS | F(2, 54) = 0.099, p = 0.906 | ||||
2-way ANOVA, Males | F(2,24) = 0.352, p = 0.707 | Genotype | F(2,24) = 5.372, p = 0.012 | ||
ELS | F(1,24) = 0.488, p = 0.492 | ||||
2-way ANOVA, Females | F(2,24) = 0.008, p = 0.992 | Genotype | F(2,24) = 0.370, p = 0.694 | ||
ELS | F(1,24) = 0.002, p = 0.961 | ||||
S3B,D | MWM, Training | 3-way RM-ANOVA, All groups | F(2, 54) = 0.407, p = 0.668 | Genotype | F(2, 54) = 0.434, p = 0.650 |
ELS | F(1, 54) = 1.231, p = 0.272 | ||||
Sex | F(1, 54) = 0.003, p = 0.954 | ||||
Sex/Gen/ELS | F(2, 54) = 0.195, p = 0.823 | ||||
2-way RM-ANOVA, Non-Stressed | Genotype | F(2, 24) = 0.020, p = 0.981 | |||
Sex | F(1, 24) = 0.053, p = 0.821 | ||||
Training | F(2, 23) = 14.27, p < 0.001 | ||||
2-way RM-ANOVA, ELS | Genotype | F(2, 24) = 0.847, p = 0.441 | |||
Sex | F(1, 24) = 0.028, p = 0.868 | ||||
Training | F(2, 23) = 26.49, p < 0.001 | ||||
2-way ANOVA, Males | F(2,24) = 0.174, p = 0.841 | Genotype | F(2,24) = 0.092, p = 0.912 | ||
ELS | F(1,24) = 0.838, p = 0.369 | ||||
2-way ANOVA, Females | F(2,24) = 0.402, p = 0.673 | Genotype | F(2,24) = 0.534, p = 0.593 | ||
ELS | F(1,24) = 0.313, p = 0.581 | ||||
S3C,E | MWM, Probe | 3-way ANOVA, All groups | F(2, 54) = 7.047, p = 0.002 | Genotype | F(2, 54) = 7.018, p = 0.002 |
ELS | F(1, 54) = 9.118, p = 0.004 | ||||
Sex | F(1, 54) = 0.057, p = 0.813 | ||||
Sex/Gen/ELS | F(1, 54) = 0.362, p = 0.698 |
Figure | Brain Area | Protein | Groups | Gen. x ELS | Gen. | ELS |
---|---|---|---|---|---|---|
Figure 4A | HPC | pAKTSer473 | All groups | F(2, 24) = 0.077, p = 0.926 | F(2, 24) = 5.903, p = 0.007 | F(1, 24) = 4.373, p = 0.046 |
Figure 4C | HPC | GSK-3β | All groups | F(2, 24) = 0.079, p = 0.923 | F(2, 24) = 1.639, p = 0.215 | F(1, 24) = 0.083, p = 0.774 |
Figure 5A | DH | FKBP5 | All groups | F(2, 24) = 3.563, p = 0.045 | F(2, 24) = 27.23, p < 0.001 | F(1, 24) = 3.068, p = 0.093 |
Figure 5B | DH | pAKTSer473/AKT ratio | All groups | F(2, 22) = 6.304, p = 0.006 | F(2, 22) = 1.110, p < 0.347 | F(1, 22) = 0.965, p = 0.336 |
Figure 5C | DH | pGSK-3 βSer9/GSK-3β | All groups | F(2, 22) = 0.575 p = 0.570 | F(2, 22) = 0.703, p < 0.505 | F(1, 22) = 0.812, p = 0.376 |
Figure 5E | VH | FKBP5 | All groups | F(2, 22) = 0.898, p = 0.421 | F(2, 22) = 15.51, p < 0.001 | F(1, 22) = 1.041, p = 0.318 |
Figure 5F | VH | pAKTSer473/AKT ratio | All groups | F(2, 22) = 0.746, p = 0.487 | F(2, 22) = 0.057, p < 0.944 | F(1, 22) = 0.159, p = 0.694) |
Figure 5G | VH | pGSK-3βSer9/GSK-3β | All groups | F(2, 22) = 0.185, p = 0.832 | F(2, 22) = 1.175, p < 0.329 | F(1, 22) = 1.219, p = 0.286 |
Figure 5I | AMYG | FKBP5 | All groups | F(2,18) = 1.485, p = 0.253 | F(2, 18) = 118.6, p < 0.001 | F(1, 18) = 0.645, p = 0.432 |
Figure 5J | AMYG | pAKTSer473/AKT ratio | All groups | F(2, 18) = 1.446, p = 0.263 | F(2, 18) = 2.502, p < 0.115 | F(1, 18) = 0.774, p = 0.391 |
Figure 5K | AMYG | pGSK-3βSer9/GSK-3β | All groups | F(2, 18) = 0.374, p = 0.693 | F(2, 18) = 1.322, p < 0.291 | F(1, 18) = 0.462, p = 0.505 |
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Criado-Marrero, M.; Gebru, N.T.; Gould, L.A.; Smith, T.M.; Kim, S.; Blackburn, R.J.; Dickey, C.A.; Blair, L.J. Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus. Int. J. Mol. Sci. 2019, 20, 2738. https://doi.org/10.3390/ijms20112738
Criado-Marrero M, Gebru NT, Gould LA, Smith TM, Kim S, Blackburn RJ, Dickey CA, Blair LJ. Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus. International Journal of Molecular Sciences. 2019; 20(11):2738. https://doi.org/10.3390/ijms20112738
Chicago/Turabian StyleCriado-Marrero, Marangelie, Niat T. Gebru, Lauren A. Gould, Taylor M. Smith, Sojeong Kim, Roy J. Blackburn, Chad A. Dickey, and Laura J. Blair. 2019. "Early Life Stress and High FKBP5 Interact to Increase Anxiety-Like Symptoms through Altered AKT Signaling in the Dorsal Hippocampus" International Journal of Molecular Sciences 20, no. 11: 2738. https://doi.org/10.3390/ijms20112738