TY - JOUR
T1 - TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice
AU - Cheng, Yuyan
AU - Desse, Sachi
AU - Martinez, Ana
AU - Worthen, Ryan J.
AU - Jope, Richard S.
AU - Beurel, Eleonore
N1 - Funding Information:
This research was supported by grants from the NIMH ( MH104656 , MH110415 , MH095380 ), a Merit Award from the Veterans Administration (BX003678), and a NARSAD Distinguished Investigator Grant from the Brain & Behavior Research Foundation. We thank Dr. Paul Smith, Novartis, for the gift of Fingolimod.
PY - 2018/3
Y1 - 2018/3
N2 - Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNFα, which contributes to impaired recovery from prolonged learned helplessness.
AB - Recovery from major depressive disorder is difficult, particularly in patients who are refractory to antidepressant treatments. To examine factors that regulate recovery, we developed a prolonged learned helplessness depression model in mice. After the induction of learned helplessness, mice were separated into groups that recovered or did not recover within 4 weeks. Comparisons were made between groups in hippocampal proteins, inflammatory cytokines, and blood brain barrier (BBB) permeability. Compared with mice that recovered and control mice, non-recovered mice displaying prolonged learned helplessness had greater hippocampal activation of glycogen synthase kinase-3 (GSK3), higher levels of tumor necrosis factor-α (TNFα), interleukin-17A, and interleukin-23, increased permeability of the blood brain barrier (BBB), and lower levels of the BBB tight junction proteins occludin, ZO1, and claudin-5. Treatment with the GSK3 inhibitor TDZD-8 reduced inflammatory cytokine levels, increased tight junction protein levels, and reversed impaired recovery from learned helplessness, demonstrating that prolonged learned helplessness is reversible and is maintained by abnormally active GSK3. In non-recovered mice with prolonged learned helpless, stimulation of sphingosine 1-phosphate receptors by Fingolimod or administration of the TNFα inhibitor etanercept repaired the BBB and reversed impaired recovery from prolonged learned helplessness. Thus, disrupted BBB integrity mediated in part by TNFα contributes to blocking recovery from prolonged learned helplessness depression-like behavior. Overall, this report describes a new model of prolonged depression-like behavior and demonstrates that stress-induced GSK3 activation contributes to disruption of BBB integrity mediated by inflammation, particularly TNFα, which contributes to impaired recovery from prolonged learned helplessness.
KW - Blood brain barrier
KW - Depression recovery
KW - GSK3
KW - Learned helplessness
KW - Neuroinflammation
KW - TNFα
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U2 - 10.1016/j.bbi.2018.02.003
DO - 10.1016/j.bbi.2018.02.003
M3 - Article
C2 - 29452218
AN - SCOPUS:85042192501
VL - 69
SP - 556
EP - 567
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
SN - 0889-1591
ER -