Limits...
Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress.

Licznerski P, Duric V, Banasr M, Alavian KN, Ota KT, Kang HJ, Jonas EA, Ursano R, Krystal JH, Duman RS, Traumatic Stress Brain Study Gro - PLoS Biol. (2015)

Bottom Line: Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models.These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction.Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

ABSTRACT
Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.

No MeSH data available.


Related in: MedlinePlus

Influence of viral expression of dnSGK1 on contextual memory recall.(A) Rats were infused with rAAV-dnSGK1 or rAAV-EGFP into the mPFC. Four weeks post infusion rats underwent auditory fear conditioning and then extinction training and testing according to the timeline schedule shown. (B) During extinction training, CS-elicited freezing was comparable between the dnSGK1 and EGFP groups (effect for group F(1,18) = 0.7033, p = 0.4127; for trial F(9,162) = 23.15, p < 0.0001; interaction F(9,162) = 0.3374, p = 0.9613, two-way repeated measures ANOVA). (C) During extinction recall, there was no significant difference in freezing between dnSGK1 and controls (effect for group F(1,18) = 0.01975, p = 0.8898; for trial F(4,72) = 20.27, p < 0.0001; interaction F(4,72) = 0.7638, p = 0.5523, two-way repeated measures ANOVA). (D) When reexposed to the original context, rats infused with dnSGK1 showed significantly higher freezing during the first 4 min of testing (t(18) = 1.787, one-tailed Student’s t test, *p < 0.05), but not during the second 4-min block. For underlying data, see S1 Data.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4623974&req=5

pbio.1002282.g004: Influence of viral expression of dnSGK1 on contextual memory recall.(A) Rats were infused with rAAV-dnSGK1 or rAAV-EGFP into the mPFC. Four weeks post infusion rats underwent auditory fear conditioning and then extinction training and testing according to the timeline schedule shown. (B) During extinction training, CS-elicited freezing was comparable between the dnSGK1 and EGFP groups (effect for group F(1,18) = 0.7033, p = 0.4127; for trial F(9,162) = 23.15, p < 0.0001; interaction F(9,162) = 0.3374, p = 0.9613, two-way repeated measures ANOVA). (C) During extinction recall, there was no significant difference in freezing between dnSGK1 and controls (effect for group F(1,18) = 0.01975, p = 0.8898; for trial F(4,72) = 20.27, p < 0.0001; interaction F(4,72) = 0.7638, p = 0.5523, two-way repeated measures ANOVA). (D) When reexposed to the original context, rats infused with dnSGK1 showed significantly higher freezing during the first 4 min of testing (t(18) = 1.787, one-tailed Student’s t test, *p < 0.05), but not during the second 4-min block. For underlying data, see S1 Data.

Mentions: To further analyze the role of SGK1 in relation to PTSD, we used fear conditioning and extinction as another model of PTSD-related behavior that can be tested in animals [27,28]. First, rAAV-dnSGK1 or rAAV-EGFP control virus were infused into the mPFC. After 4 wk, rats were subjected to an auditory fear conditioning and extinction paradigm (Fig 4A). Rats were fear conditioned (day 3) and then underwent extinction training (day 4) and recall testing (day 5) in a contextually distinct environment from that used for conditioning. During the extinction training session, there was no significant difference in levels of conditioned stimulus (CS)-elicited freezing between the dnSGK1 and EGFP controls (Fig 4B), indicating a similar rate and magnitude of extinction between both groups. Twenty-four hours later, the rats were returned to the extinction context in order to assess extinction recall (day 5, Fig 4C). The dnSGK1-expressing rats did not show significantly higher levels of overall freezing compared to EGFP controls, indicating that inhibition of SGK1 did not affect the acquisition of extinction or impair the consolidation of extinction learning. Twenty-four hours after the extinction recall session, the animals were reexposed to the context in which they were fear conditioned to examine context-dependent fear (day 6, Fig 4D). Rats infused with rAAV-dnSGK1 displayed higher levels of freezing compared to EGFP controls during the first 4 min of contextual memory recall test (Fig 4D), although there was no effect during the second block of 4 min. Taken together, the results demonstrate that inhibition of SGK1 enhances the memory of contextual cues associated with fear conditioning.


Decreased SGK1 Expression and Function Contributes to Behavioral Deficits Induced by Traumatic Stress.

Licznerski P, Duric V, Banasr M, Alavian KN, Ota KT, Kang HJ, Jonas EA, Ursano R, Krystal JH, Duman RS, Traumatic Stress Brain Study Gro - PLoS Biol. (2015)

Influence of viral expression of dnSGK1 on contextual memory recall.(A) Rats were infused with rAAV-dnSGK1 or rAAV-EGFP into the mPFC. Four weeks post infusion rats underwent auditory fear conditioning and then extinction training and testing according to the timeline schedule shown. (B) During extinction training, CS-elicited freezing was comparable between the dnSGK1 and EGFP groups (effect for group F(1,18) = 0.7033, p = 0.4127; for trial F(9,162) = 23.15, p < 0.0001; interaction F(9,162) = 0.3374, p = 0.9613, two-way repeated measures ANOVA). (C) During extinction recall, there was no significant difference in freezing between dnSGK1 and controls (effect for group F(1,18) = 0.01975, p = 0.8898; for trial F(4,72) = 20.27, p < 0.0001; interaction F(4,72) = 0.7638, p = 0.5523, two-way repeated measures ANOVA). (D) When reexposed to the original context, rats infused with dnSGK1 showed significantly higher freezing during the first 4 min of testing (t(18) = 1.787, one-tailed Student’s t test, *p < 0.05), but not during the second 4-min block. For underlying data, see S1 Data.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4623974&req=5

pbio.1002282.g004: Influence of viral expression of dnSGK1 on contextual memory recall.(A) Rats were infused with rAAV-dnSGK1 or rAAV-EGFP into the mPFC. Four weeks post infusion rats underwent auditory fear conditioning and then extinction training and testing according to the timeline schedule shown. (B) During extinction training, CS-elicited freezing was comparable between the dnSGK1 and EGFP groups (effect for group F(1,18) = 0.7033, p = 0.4127; for trial F(9,162) = 23.15, p < 0.0001; interaction F(9,162) = 0.3374, p = 0.9613, two-way repeated measures ANOVA). (C) During extinction recall, there was no significant difference in freezing between dnSGK1 and controls (effect for group F(1,18) = 0.01975, p = 0.8898; for trial F(4,72) = 20.27, p < 0.0001; interaction F(4,72) = 0.7638, p = 0.5523, two-way repeated measures ANOVA). (D) When reexposed to the original context, rats infused with dnSGK1 showed significantly higher freezing during the first 4 min of testing (t(18) = 1.787, one-tailed Student’s t test, *p < 0.05), but not during the second 4-min block. For underlying data, see S1 Data.
Mentions: To further analyze the role of SGK1 in relation to PTSD, we used fear conditioning and extinction as another model of PTSD-related behavior that can be tested in animals [27,28]. First, rAAV-dnSGK1 or rAAV-EGFP control virus were infused into the mPFC. After 4 wk, rats were subjected to an auditory fear conditioning and extinction paradigm (Fig 4A). Rats were fear conditioned (day 3) and then underwent extinction training (day 4) and recall testing (day 5) in a contextually distinct environment from that used for conditioning. During the extinction training session, there was no significant difference in levels of conditioned stimulus (CS)-elicited freezing between the dnSGK1 and EGFP controls (Fig 4B), indicating a similar rate and magnitude of extinction between both groups. Twenty-four hours later, the rats were returned to the extinction context in order to assess extinction recall (day 5, Fig 4C). The dnSGK1-expressing rats did not show significantly higher levels of overall freezing compared to EGFP controls, indicating that inhibition of SGK1 did not affect the acquisition of extinction or impair the consolidation of extinction learning. Twenty-four hours after the extinction recall session, the animals were reexposed to the context in which they were fear conditioned to examine context-dependent fear (day 6, Fig 4D). Rats infused with rAAV-dnSGK1 displayed higher levels of freezing compared to EGFP controls during the first 4 min of contextual memory recall test (Fig 4D), although there was no effect during the second block of 4 min. Taken together, the results demonstrate that inhibition of SGK1 enhances the memory of contextual cues associated with fear conditioning.

Bottom Line: Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models.These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction.Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, United States of America.

ABSTRACT
Exposure to extreme stress can trigger the development of major depressive disorder (MDD) as well as post-traumatic stress disorder (PTSD). The molecular mechanisms underlying the structural and functional alterations within corticolimbic brain regions, including the prefrontal cortex (PFC) and amygdala of individuals subjected to traumatic stress, remain unknown. In this study, we show that serum and glucocorticoid regulated kinase 1 (SGK1) expression is down-regulated in the postmortem PFC of PTSD subjects. Furthermore, we demonstrate that inhibition of SGK1 in the rat medial PFC results in helplessness- and anhedonic-like behaviors in rodent models. These behavioral changes are accompanied by abnormal dendritic spine morphology and synaptic dysfunction. Together, the results are consistent with the possibility that altered SGK1 signaling contributes to the behavioral and morphological phenotypes associated with traumatic stress pathophysiology.

No MeSH data available.


Related in: MedlinePlus