Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms

Pittenger, Christopher; Duman, Ronald S.

doi:10.1038/sj.npp.1301574

Cited by 1,537 publications

(1,194 citation statements)

References 253 publications

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“…Pathological changes in monoamine synapses, hypothalamus‐pituitary‐adrenal axis, and brain‐derived neurotrophic factor are believed to cause neuronal atrophy in the ventral tegmental area, nucleus accumbens, and prefrontal cortex from depressive patients and depression‐like animals (Banasr, Dwyer, & Duman, 2011; Bennett et al, 2008; Duman, 2010; Elizalde et al, 2008; Ma, Xu, et al, 2016; Pittenger & Duman, 2008; Sandi & Haller, 2015; Xu, Cui, & Wang, 2016). In addition, major depression may be caused by a lack of reward in life to lower the use in the function of brain reward circuits including the ventral tegmental area, nucleus accumbens, and prefrontal cortex (Wang & Cui, 2015; Zhu, Wang, Ma, Cui, & Wang, 2017).…”

Section: Introductionmentioning

confidence: 99%

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Song

Sun

et al. 2018

American J of Med Genetics Pt B

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Major depression in negative mood is presumably induced by chronic stress with lack of reward. However, most individuals who experience chronic stress demonstrate resilience. Molecular mechanisms underlying stress‐ induced depression versus resilience remain unknown, which are investigated in brain reward circuits. Mice were treated by chronic unpredictable mild stress (CUMS) for 4 weeks. The tests of sucrose preference, Y‐maze, and forced swimming were used to identify depression‐like emotion behavior or resilience. High‐throughput sequencing was used to analyze mRNA and miRNA quantity in the nucleus accumbens (NAc) harvested from the mice in the groups of control, CUMS‐induced depression (CUMS‐MDD), and CUMS‐resistance to identify molecular profiles of CUMS‐MDD versus CUMS‐resilience. In data analyses and comparison among three groups, 1.5‐fold ratio in reads per kilo‐base per million reads (RPKM) was set to judge involvements of mRNA and miRNA in CUMS, MDD, or resilience. The downregulations of serotonergic/dopaminergic synapses, MAPK/calcium signaling pathways, and morphine addiction as well as the upregulations of cAMP/PI3K‐Akt signaling pathways and amino acid metabolism are associated with CUMS‐MDD. The downregulations of chemokine signaling pathway, synaptic vesicle cycle, and nicotine addiction as well as the upregulations of calcium signaling pathway and tyrosine metabolism are associated with CUMS‐resilience. The impairments of serotonergic/dopaminergic synapses and PI3K‐Akt/MAPK signaling pathways in the NAc are associated with depression. The upregulation of these entities is associated with resilience. Consistent results from analyzing mRNA/miRNA and using different methods validate our finding and conclusion.

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Section: Introductionmentioning

confidence: 99%

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Song

Sun

et al. 2018

American J of Med Genetics Pt B

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“…The NAC has been heavily implicated in stress responses, mood disorders, and processing natural rewards 2,5,[11][12][13][16][17][18][19][20][21] . Moreover, pathophysiological dysfunction of the NAcc in response to various stressors has been implicated in anhedonia and reward conditioning [18][19][20][21] .…”

mentioning

confidence: 99%

Activating positive memory engrams suppresses depression-like behaviour

Ramirez¹,

Liu²,

MacDonald³

et al. 2015

Nature

327

256

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Stress is considered a potent environmental risk factor for many behavioral abnormalities, including anxiety and mood disorders 1,2 . Animal models can exhibit limited but quantifiable behavioral impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioral challenges, and anhedonia 3-5 . The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stressinduced impairments 2,3,5 , though the neuronal underpinnings sufficient to support behavioral improvements are largely unknown. Here, we acutely rescue stress-induced, depression-related behaviors by optogenetically reactivating DG cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projectionspecific optogenetic blockade experiments, identified glutamatergic activity in the hippocampusamygdala-nucleus accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in a rescue of stress-induced behavioral impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviors and point to DG engram cells as potential therapeutic nodes for intervening with maladaptive behavioral states.Our recent studies have demonstrated that DG cells that express c-Fos during fear or reward conditioning define an active neural population that is sufficient to elicit both aversive and Reprints and permissions information is available at www.nature.com/reprints.

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“…Chronic antidepressant administration enhances the coupling of GPCRs to adenylyl cyclase, PKA activation, and expression of CREB [19] . Furthermore, the cAMP-PKA-CREB signaling cascade is critical for long-lasting forms of synaptic plasticity, notably late-LTP, and for long-term memory formation [84] .…”

Section: Brain-derived Neurotrophic Factormentioning

confidence: 99%

“…Modulatory neurotransmitters such as 5-HT, NE, and dopamine increase the intracellular cyclic adenosine monophosphate (cAMP) concentration and activate cAMP-dependent protein kinase (PKA) through G-protein coupled receptors (GPCRs) [83] . Chronic antidepressant administration enhances the coupling of GPCRs to adenylyl cyclase, PKA activation, and expression of CREB [19] . Furthermore, the cAMP-PKA-CREB signaling cascade is critical for long-lasting forms of synaptic plasticity, notably late-LTP, and for long-term memory formation [84] .…”

Section: Creb Signaling Cascade Under Monoamine-based Antidepressantsmentioning

confidence: 99%

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Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms

Cited by 1,537 publications

References 253 publications

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

microRNA and mRNA profiles in nucleus accumbens underlying depression versus resilience in response to chronic stress

Activating positive memory engrams suppresses depression-like behaviour

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

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