Suicide is a major public health concern. Suicidal behavior occurs in the context of a diathesis that is characterized by traits in multiple domains: behavioral, clinical, personality, and biologic. While the complexity of suicidal behavior requires a multi-faceted prevention approach, the identification of neurobiological dysfunction is critical for the pharmacological interventions that may have protective effects against suicidal behavior. In this context, we have shown reduced BDNF gene expression and less activation of its cognate receptor TrkB in the brain of suicide subjects. In addition, we have found that p75NTR, a low affinity BDNF receptor is upregulated in the brain of these subjects. BDNF, which plays a critical role in neural plasticity and cell survival, essentially mediates its action via TrkB-mediated activation of extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide 3 kinase (PI3K) signaling pathways. Abnormalities in these two signaling systems at the upstream levels were also found in the same brain areas of suicide subjects in which abnormalities were noted in BDNF/TRKB/p75NTR. These changes were present in all suicide subjects regardless of psychiatric diagnosis. To better understand the functional significance of altered BDNF signaling at molecular and cellular levels and their implications in the neurobiology of suicide, we propose to test the hypothesis that hypoactive BDNF/TrkB-mediated ERK1/2 and PI3K/Akt and overexpressed p75NTR will lead to modifications in the interaction and activation of downstream scaffolding/regulatory proteins, translational machinery, chromatin remodeling, and structural plasticity in the suicide brain. To test our hypothesis, in brain areas implicated in suicidal behavior, i.e., dlPFC and hippocampus (cerebellum as negative control brain region) from well-characterized and well-matched depressed suicide and non-psychiatric control subjects (n = 30 in each group), we aim to examine whether: 1) hypoactive ERK1/2 will lead to altered activation of substrates p90 ribosomal S6 kinase (RSK) and mitogen- and stress-activated kinase (MSK) and their mediated transactivation of transcription factors and chromatin remodeling;2) hypoactive ERK1/2 and PI3K will lead to less active translational machinery, translation of postsynaptic genes, and altered dendritic morphology;and 3) altered PI3K/Akt and p75NTR will be associated with altered interactions of scaffolding proteins leading to c-Jun kinase (JNK) activation and altered expression and functional characteristics of downstream apoptotic regulatory proteins and neuronal apoptosis. To make sure that the effects are suicide specific, we will perform these studies in the same brain areas of an additional group of well-matched subjects who were depressed (no previous suicide attempt and no family history of suicide) and died by causes other than suicide (n = 30). Our proposed study will precisely and mechanistically assess the complexity of cellular signaling at the molecular, cellular, and functional levels in suicide brain and will have a significant impact in understanding not only the neurobiological basis of suicide but in designing more efficacious treatment strategies.

Public Health Relevance

Our proposed study will yield important information on the neurobiology of suicide and may indicate possible novel sites for therapeutic interventions, which may eventually lead to better treatment and possibly prevention of suicide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH101890-02
Application #
8733756
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2013-09-12
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Roy, Bhaskar; Wang, Qingzhong; Dwivedi, Yogesh (2018) Long Noncoding RNA-Associated Transcriptomic Changes in Resiliency or Susceptibility to Depression and Response to Antidepressant Treatment. Int J Neuropsychopharmacol 21:461-472
Ii Timberlake, Matthew; Dwivedi, Yogesh (2018) Linking unfolded protein response to inflammation and depression: potential pathologic and therapeutic implications. Mol Psychiatry :
Timberlake 2nd, Matthew; Prall, Kevin; Roy, Bhaskar et al. (2018) Unfolded protein response and associated alterations in toll-like receptor expression and interaction in the hippocampus of restraint rats. Psychoneuroendocrinology 89:185-193
Wang, Qingzhong; Shelton, Richard C; Dwivedi, Yogesh (2018) Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: A systematic review and meta-analysis. J Affect Disord 225:422-428
Ludwig, Birgit; Dwivedi, Yogesh (2018) The concept of violent suicide, its underlying trait and neurobiology: A critical perspective. Eur Neuropsychopharmacol 28:243-251
Wang, Qingzhong; Roy, Bhaskar; Turecki, Gustavo et al. (2018) Role of Complex Epigenetic Switching in Tumor Necrosis Factor-? Upregulation in the Prefrontal Cortex of Suicide Subjects. Am J Psychiatry 175:262-274
Ludwig, Birgit; Roy, Bhaskar; Dwivedi, Yogesh (2018) Role of HPA and the HPG Axis Interaction in Testosterone-Mediated Learned Helpless Behavior. Mol Neurobiol :
Roy, Bhaskar; Wang, Qingzhong; Palkovits, Miklos et al. (2017) Altered miRNA expression network in locus coeruleus of depressed suicide subjects. Sci Rep 7:4387
Wang, Qingzhong; Dwivedi, Yogesh (2017) Transcriptional profiling of mitochondria associated genes in prefrontal cortex of subjects with major depressive disorder. World J Biol Psychiatry 18:592-603

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