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Cited by 230Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionNeuroscience and Neuropharmacology Research

Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression

Open access
Francis, T. Chase, Lobo, Mary Kay·2017·Biological Psychiatry
DOI 10.1016/j.biopsych.2016.09.007PMC PMC5352537
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Abstract

The ventral striatum (nucleus accumbens- NAc) and its role in mood, reward, and motivation has been the focus of significant research. Despite this interest, very little work has addressed cell-type specific distinctions in medium spiny neurons (MSNs), the main projection neurons in the NAc and dorsal striatum, and their function in relation to stress and depression. Previous work demonstrates opposing roles for Dopamine 1 receptor (D1) and dopamine 2 receptor (D2) MSN subtypes, in depression-like outcomes to stress, particularly in regards to repeated neuronal stimulation and excitatory transmission. Yet the mechanisms of action are still unknown. We discuss potential mechanisms by which MSN subtype function promotes dichotomous behavioral outcomes due to differences in cellular plasticity, subcellular signaling pathways, and genetic expression. This review aims to address our current understanding about the role of nucleus accumbens MSN subtypes in stress-related depression behavior and speculates on how currently understood mechanisms contribute to factors which control activity of MSNs.

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Cites

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Claims the paper makes

0 of 172 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Repeated high frequency stimulation of all nucleus accumbens neurons alleviates depression-like outcomes to chronic social defeat stress.

    “Like DBS, repeated high frequency stimulation of all NAc neurons alleviated depression-like outcomes to CSDS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Francis, 2015, Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress, Biol Psychiatry source

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  • Findingcitation

    Repeated, but not acute, stimulation is necessary for the behavioral effect of nucleus accumbens stimulation.

    “Furthermore, repeated, but not acute stimulation is necessary for this behavioral effect.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Francis, 2015, Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress, Biol Psychiatry source

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  • Findingcitation

    D2 medium spiny neuron stimulation promotes depressive-like outcomes.

    “D2-MSN stimulation promotes depressive-like outcomes (41), suggesting an imbalance in firing of MSN subtypes could mediate these symptoms.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Francis, 2015, Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress, Biol Psychiatry source

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  • Findingown data

    Our results show increased excitatory signaling to D2 medium spiny neurons after stress.

    “This outcome would be consistent with our results showing enhanced excitatory signaling to D2-MSNs following stress and other results showing overexpression of a constitutively active CaMKII promotes plasticity (89), while developmental inhibition of CaMKII reduces functional numbers of synapses (90).”
    Quote in the paperSubstantial claim
  • Premisecitation

    About 30% of depressed patients do not respond to common antidepressant treatments.

    “Studies examining antidepressant efficacy reveal 30% of depressed patients fail to respond to common antidepressant treatment (1)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Gaynes, 2009, What did STAR*D teach us? Results from a large-scale, practical, clinical trial for patients with depression, Psychiatr Serv source

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  • May combine two claims. 32
  • Classified as probably not a substantial claim. 8

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    Findingcitation

    In chronic social defeat stress susceptible mice, D1 medium spiny neurons show reduced miniature excitatory postsynaptic current frequency and D2 medium spiny neurons show enhanced frequency.

    “We recently found D1-MSNs display reduced mEPSC frequency and D2-MSNs display enhanced frequency of mEPSCs in CSDS susceptible mice (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Francis, 2015, Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress, Biol Psychiatry source

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    Findingown data

    D2 medium spiny neuron miniature excitatory postsynaptic current frequency negatively and strongly correlates with social interaction time, while D1 medium spiny neurons show no correlation.

    “We found D2-MSN mEPSC frequency negatively and strongly correlates with interaction time, while no correlation is observed in D1-MSNs (FIGURE 2A).”
    Quote in the paperSubstantial claim

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    Findingown data

    Interaction behavior strongly negatively correlates with D1 medium spiny neuron action potential firing, but not with D2 medium spiny neuron firing.

    “Additionally, a strong negative correlation was observed between interaction behavior and D1-MSN, but not D2-MSN action potential firing (FIGURE 2C).”
    Quote in the paperSubstantial claim

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    Findingown data

    Interaction time positively correlates with D1 medium spiny neuron intrinsic excitability, while D2 medium spiny neurons show no change in intrinsic properties.

    “A positive correlation is observed between interaction time and intrinsic excitability of D1-MSNs, while D2-MSNs display no change in intrinsic properties (FIGURE 2B), linking D1-MSN intrinsic excitability to susceptibility.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Stress produces central and peripheral adaptations through the hypothalamic-pituitary-adrenal axis, which feeds back on the brain via corticosteroid release.

    “Stress promotes central and peripheral adaptations in body systems via the hypothalamic-pituitary-adrenal (HPA) axis, which feeds back on the brain through corticosteroid release (12).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Pariante, 2008, The HPA axis in major depression: Classical theories and new developments, Trends Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nucleus accumbens integration of excitatory input triggers emotionally motivated behaviors through corticostriatal thalamic loops and drives the dorsolateral striatum to facilitate action-related behaviors.

    “NAc integration of this excitatory input triggers emotionally motivated behaviors through corticostriatal thalamic loops within the basal ganglia, eventually driving the dorsolateral striatum to facilitate action-related behaviors (14, 15).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Floresco, 2015, The nucleus accumbens: An interface between cognition, emotion, and action, Annu Rev Psychol source

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    • cites [15] Voorn, 2004, Putting a spin on the dorsal-ventral divide of the striatum, Trends Neurosci source

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    Premisecitation

    Medium spiny neurons make up more than 95% of the cells in the nucleus accumbens.

    “The NAc is composed of a vast array of transcriptionally distinct neuronal subtypes, where medium spiny neurons (MSNs) make up the majority (>95%) of the cells (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Gerfen, 1990, D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons, Science source

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    Interpretationreasoning

    Nucleus accumbens circuit interactions mediate motivated and emotional behavior, making the region an attractive therapeutic target.

    “These local and global NAc circuit interactions mediate motivated and emotional behavior making it an attractive target for therapeutics.”
    Quote in the paperSubstantial claim

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    Premisecitation

    D1 medium spiny neurons project to the ventral tegmental area and ventral pallidum, while D2 medium spiny neurons project to the ventral pallidum.

    “NAc D1-MSN and D2-MSNs are also distinguished by their projections to target regions: D1-MSNs target the ventral tegmental area (VTA) and ventral pallidum (VP), while D2-MSNs specifically target the VP (FIGURE 1) (19–21).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Koob, 1988, The functional output of the mesolimbic dopamine system, Ann N Y Acad Sci source

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    • cites [20] Smith, 2013, Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways), Curr Opin Neurobiol source

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    • cites [21] Kupchik, 2015, Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections, Nat Neurosci source

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    Premisecitation

    The nucleus accumbens core and dorsolateral regions project mainly to the dorsolateral ventral pallidum and substantia nigra, while the medial shell projects mainly to the ventromedial ventral pallidum and ventral tegmental area.

    “NAc core and dorsolateral regions of the NAc project mainly to the dorsolateral VP and substantia nigra (SN) while NAc medial shell projects mainly to the ventromedial VP and VTA (20).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Smith, 2013, Cocaine-induced adaptations in D1 and D2 accumbens projection neurons (a dichotomy not necessarily synonymous with direct and indirect pathways), Curr Opin Neurobiol source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Nucleus accumbens input and output follow a dorsolateral to ventromedial topology.

    “Input and output from the NAc follows a dorsolateral to ventromedial topology (15).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Voorn, 2004, Putting a spin on the dorsal-ventral divide of the striatum, Trends Neurosci source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Nucleus accumbens medium spiny neurons are defined by transcriptional profiles including dopamine receptor 1 versus dopamine receptor 2 expression, substance P, enkephalin, and other enriched genes.

    “These neurons are defined by their transcriptional profiles, including dopamine receptor 1 (D1) vs. dopamine receptor 2 (D2) expression, substance P and enkephalin, and other enriched genes (16–18).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Gerfen, 1990, D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons, Science source

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    • cites [17] Lobo, 2006, FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains, Nat Neurosci source

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    • cites [18] Heiman, 2008, A translational profiling approach for the molecular characterization of CNS cell types, Cell source

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  • May combine two claims.

    Premisecitation

    In nucleus accumbens shell, D1 medium spiny neuron mushroom spines from resilient animals show enhanced synaptic strength, while D2 medium spiny neuron mushroom spines show reduced strength.

    “Cell-type specific analysis of NAc shell thin and mushroom spines display enhanced synaptic strength of D1-MSN mushroom spines from resilient animals and reduced strength of D2-MSN mushroom spines (40).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Khibnik, 2016, Stress and cocaine trigger divergent and cell type-specific regulation of synaptic transmission at single spines in nucleus accumbens, Biol Psychiatry source

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    Premisecitation

    Human depressed patients show reduced nucleus accumbens activity and overall volume in imaging studies.

    “These excitatory deficits extend to NAc in human depressed patients, where reduced activity and overall volume is observed in imaging studies (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Drevets, 1992, A functional anatomical study of unipolar depression, J Neurosci source

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    Premisecitation

    Susceptible mice have an increased number of stubby spines in nucleus accumbens medium spiny neurons, which correlates with increased miniature excitatory postsynaptic current frequency.

    “Susceptible mice display an increased number of stubby spines NAc MSNs, which correlates with an increased frequency of miniature excitatory post synaptic currents (mEPSCs) (39).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Christoffel, 2011, IkappaB kinase regulates social defeat stress-induced synaptic and behavioral plasticity, J Neurosci source

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  • May combine two claims.

    Premisenone given

    Electrical deep brain stimulation targets cells without subtype specificity and may stimulate afferents such as medial prefrontal or ventral hippocampal inputs.

    “Electrical DBS targets cells without regard to subtype specificity and may stimulate afferents within these regions, such as mPFC or vHipp inputs.”
    Quote in the paperSubstantial claim

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    Premisecitation

    High frequency deep brain stimulation of the nucleus accumbens shows promise for alleviating treatment-resistant depression, although its mechanism is unclear.

    “High frequency DBS of the NAc, among other regions, shows great promise in alleviating treatment-resistant depression, though its mechanism is still unclear (5, 8, 10).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Bewernick, 2012, Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: Evidence for sustained efficacy, Neuropsychopharmacology source

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    • cites [8] Schlaepfer, 2008, Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression, Neuropsychopharmacology source

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    • cites [10] Williams, 2015, Good vibrations with deep brain stimulation, Nat Neurosci source

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    Premisecitation

    In mice, prefrontal cortex stimulation is specific to medial prefrontal cortex to nucleus accumbens input, but not medial prefrontal cortex to amygdala input.

    “This stimulation in mice is specific to mPFC-NAc, but not mPFC-amygdala input (45).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Vialou, 2014, Prefrontal cortical circuit for depression- and anxiety-related behaviors mediated by cholecystokinin: Role of DeltaFosB, J Neurosci source

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  • May combine two claims.

    Interpretationreasoning

    Increased miniature excitatory postsynaptic current frequency may enhance baseline activity of D2 medium spiny neurons in susceptible mice, while D1 medium spiny neuron excitatory activity is dampened.

    “Further, increased frequency may enhance baseline activity of D2-MSNs in susceptible mice, while D1-MSN excitatory activity is dampened.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    D1 medium spiny neurons likely mediate the antidepressant effect of non-specific nucleus accumbens stimulation because D1 medium spiny neuron-specific stimulation mimicked it.

    “It is likely D1-MSNs mediate this effect as cell-type specific stimulation of D1-MSNs mimicked non-specific NAc neuronal stimulation (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Francis, 2015, Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress, Biol Psychiatry source

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    Interpretationcitation

    Larger NMDA currents may enhance the probability of plasticity because NMDA receptors drive spike-timing dependent calcium-dependent potentiation on medium spiny neuron subtypes.

    “Additionally, these synapses display larger NMDA currents which may enhance the probability of plasticity as NMDA receptors drive spike-timing dependent calcium-dependent potentiation on MSN subtypes (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Shen, 2008, Dichotomous dopaminergic control of striatal synaptic plasticity, Science source

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  • May combine two claims.

    Interpretationreasoning

    Repeated stimulation of D1 and D2 medium spiny neuron subtypes may act through different but overlapping mechanisms, with a homeostatic mechanism favored for antidepressant D1 stimulation and an imbalanced excitatory signaling mechanism for depressant D2 stimulation.

    “Consequently, repeated stimulation of these subtypes may act through different but overlapping mechanisms in which a homeostatic mechanism is favored in antidepressant D1-MSN stimulation and an imbalanced excitatory signaling mechanism favors depressant D2-MSN stimulation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The nucleus accumbens and its targets contain potential modulatory drug targets including peptides, growth factors, and other neuromodulatory factors that modify cell firing properties and synaptic transmission.

    “The NAc and its targets are littered with potential modulatory drug targets including peptides, growth factors, and other neuromodulatory factors that modify cell firing properties and synaptic transmission (59).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Covington, 2010, From synapse to nucleus: Novel targets for treating depression, Neuropharmacology source

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  • May combine two claims.

    Premisecitation

    Repeated ventral tegmental area optogenetic stimulation dampens phasic firing of ventral tegmental area neurons through alterations in Ih potassium conductance and promotes resilience in chronic social defeat stress mice.

    “For instance, repeated VTA optogenetic stimulation is sufficient to dampen phasic firing of VTA neurons through alterations in Ih potassium conductance (54), promoting resilience in CSDS mice, and providing a potential parallel in mechanism.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Friedman, 2014, Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience, Science source

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  • May combine two claims.

    Interpretationreasoning

    D1 medium spiny neurons may provide a reversible switch for depression-like behavior, while aberrant D2 medium spiny neuron activity may be involved in the transition to or expression of a depression state.

    “This bidirectional manipulation of behavior promotes the idea that D1-MSNs may provide a reversible switch for depression-like behavior, while aberrant D2-MSN activity may be involved in the transition to or expression of a depression state.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Dopamine may oppositely regulate subtype-specific medium spiny neuron output following stress because medium spiny neurons are enriched with D1 or D2 receptors and dopamine receptor signaling cascades are opposing.

    “MSN enrichment with either D1 or D2 receptors, and the opposing nature of DA receptor signaling cascades suggests DA may act to oppositely regulate subtype-specific MSN output following stress.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Brain stimulation or deep brain stimulation may act as a neuromodulator for excitatory activity, facilitating or inhibiting neuronal transmission directly or through release of modulatory neurotransmitters and peptides.

    “Brain stimulation or DBS itself may also act as a neuromodulator for excitatory activity, facilitating or inhibiting neuronal transmission directly or by release of modulatory neurotransmitters and peptides.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nucleus accumbens D1 medium spiny neuron-specific knockout of Cdk5 reduces cAMP levels, increases PKA activity, and promotes antidepressant outcomes.

    “NAc D1-MSN specific knockout of Cdk5 reduces cAMP levels, increases PKA activity, and promotes antidepressant outcomes (63).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Plattner, 2015, The role of ventral striatal cAMP signaling in stress-induced behaviors, Nat Neurosci source

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  • May combine two claims.

    Interpretationreasoning

    Dopamine tone is enhanced following chronic stress, and lower affinity D1 receptors would be activated by phasic dopamine release, thereby preferentially enhancing D1 medium spiny neuron activity.

    “Thus, it would seem appropriate to conclude DA tone is enhanced following chronic stress and lower affinity D1 receptors would be activated by phasic DA release, thereby preferentially enhancing activity of D1-MSNs.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The hypothalamic-pituitary-adrenal axis releases corticosterone in mice, which can feed back on neurons in the brain.

    “The HPA-axis acts to release corticosterone in mice, which can feedback on neurons within the brain (12).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Pariante, 2008, The HPA axis in major depression: Classical theories and new developments, Trends Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of kappa opioid receptors promotes aversion, potentially through regulation of dopamine terminals in the nucleus accumbens.

    “Activation of kappa opioid receptors promotes aversion, potentially through regulation of dopamine terminals in the NAc (76).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] Chefer, 2013, Kappa opioid receptors on dopaminergic neurons are necessary for kappa-mediated place aversion, Neuropsychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This interpretation is consistent with observed excitatory changes on nucleus accumbens medium spiny neuron subtypes and with stimulation-mediated antidepressant outcomes.

    “This interpretation would be consistent with observed excitatory changes on NAc MSN subtypes as well as stimulation-mediated antidepressant outcomes (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Francis, 2015, Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress, Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Dynorphin signaling may oppose and balance D1 medium spiny neuron firing, while enkephalin signaling may oppose enhanced D2 medium spiny neuron activity.

    “That is, dynorphin signaling may oppose and provide balance for D1-MSN firing and enkephalin signaling may oppose enhanced D2-MSN activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The resilience produced by the 11A line is mainly caused by ΔFosB enrichment in D1 medium spiny neurons and by facilitated excitatory activity.

    “Interestingly, the 11A mouse line serendipitously expresses ΔFosB in D1-MSNs, suggesting this resilience effect is primarily due to D1-MSN enrichment of ΔFosB (83) and a facilitation of excitatory activity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Kelz, 1999, Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Expressing ΔFosB in all nucleus accumbens neurons increases overall resilience and excitatory transmission.

    “Despite enhancements in overall resilience and excitatory transmission following expression of ΔFosB in all NAc neurons, overexpression in a stress naïve mice decreased excitatory synaptic strength in D1-MSNs via an increased number of silent synapses and stubby spines, while in D2-MSNs, overexpression increased excitatory transmission in the shell and decreased silent synapses (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Grueter, 2013, FosB differentially modulates nucleus accumbens direct and indirect pathway function, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In stress-naïve mice, overexpressing ΔFosB raises excitatory transmission in the shell and reduces silent synapses in D2 medium spiny neurons.

    “Despite enhancements in overall resilience and excitatory transmission following expression of ΔFosB in all NAc neurons, overexpression in a stress naïve mice decreased excitatory synaptic strength in D1-MSNs via an increased number of silent synapses and stubby spines, while in D2-MSNs, overexpression increased excitatory transmission in the shell and decreased silent synapses (85).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Grueter, 2013, FosB differentially modulates nucleus accumbens direct and indirect pathway function, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These effects occur through an epigenetic mechanism that lowers acetylation and raises H3meK9 methylation.

    “These effects are through an epigenetic mechanism of reducing acetylation and increasing H3meK9 methylation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Robison, 2014, Fluoxetine epigenetically alters the CaMKIIalpha promoter in nucleus accumbens to regulate DeltaFosB binding and antidepressant effects, Neuropsychopharmacology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpressing constitutively active CaMKII promotes plasticity.

    “This outcome would be consistent with our results showing enhanced excitatory signaling to D2-MSNs following stress and other results showing overexpression of a constitutively active CaMKII promotes plasticity (89), while developmental inhibition of CaMKII reduces functional numbers of synapses (90).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Pi, 2010, Autonomous CaMKII can promote either long-term potentiation or long-term depression, depending on the state of T305/T306 phosphorylation, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Both medium spiny neuron subtypes appear to be involved in and control stress-related depression symptoms.

    “While both subtypes appear to be involved in and control stress-mediated depression symptomology, the degree to which each subtype is involved.”
    Quote in the paperSubstantial claim
39 of 39

  • The paper relies on this without support.

    Most depression models use repeated stress to produce depression-like symptoms in rodents and primates.

    “The overwhelming majority of depression models utilize repeated stress to produce depression-like symptomology in rodent and primate models.”

  • The paper relies on this without support.

    The nucleus accumbens receives dense innervation from the ventral tegmental area, which supplies dopamine, GABA, and brain-derived neurotrophic factor.

    “The NAc receives dense innervation from the VTA, which supplies the region with dopamine (DA), GABA, and brain derived-neurotrophic factor (BDNF).”

  • The paper relies on this without support.

    Dynorphin is enriched in D1 medium spiny neurons of the striatum.

    “Dynorphin is enriched in D1-MSNs of the striatum.”

  • The paper relies on this without support.

    Enkephalin is thought to be antidepressant.

    “In contrast, enkephalin, which is highly enriched in striatal D2-MSNs (17), is thought to be antidepressant.”

  • The paper relies on this without support.

    Very little research has examined how nucleus accumbens medium spiny neuron subtypes are regulated after stress.

    “Despite a wide array of research displaying differential and often opposing roles of D1- and D2-MSNs in motivation and reinforcement (24–31), very little research has been devoted to understanding how theses MSN subtypes are regulated following stress (TABLE 1).”

  • The paper relies on this without support.

    D1 and D2 medium spiny neuron subtypes can be differentially targeted using drug ligands for unique receptors and other molecular targets or expression constructs in both animals and humans.

    “Despite this complication, expression dissimilarity provides an exceptional opportunity to differentially target cell types using drug ligands for unique receptors and other molecular targets or expression constructs in both animals and humans.”

  • The paper relies on this without support.

    cAMP/PKA signaling, activated by dopamine receptor signaling, plays a role in stress.

    “Further, cAMP/PKA signaling, activated by dopamine receptor signaling, plays a role in stress.”

  • The paper relies on this without support.

    BDNF is highly involved in structural remodeling and plasticity.

    “BDNF is highly involved in structural remodeling and plasticity.”

  • The paper relies on this without support.

    β-catenin is activated by the non-phosphorylated form of GSK3β.

    “β-catenin is activated by the non-phosphorylated form of GSK3β.”

  • The paper relies on this without support.

    Most studies of medium spiny neuron subtypes and stress have used male rodents.

    “The majority of these studies were conducted in male rodents despite the higher female incidence of depression (93).”

  • The paper relies on this without support.

    ΔFosB interacts with molecules that regulate plasticity.

    “ΔFosB has been found to interact with molecules that regulate plasticity.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Chronic stress causes plastic changes in rodent nucleus accumbens medium spiny neurons that alter VTA dopaminergic release to the forebrain and responses to rewarding and aversive stimuli.

    “In response to chronic stress, rodent NAc MSNs display an array of plastic changes that act in concert to alter forebrain dopaminergic release from the VTA and, thereby, alter the responses to rewarding and aversive stimuli [233].”

    From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [233]

  • Neuromodulators including dopamine, serotonin, and enkephalins likely gate synaptic strength and the balance between D1 and D2 medium spiny neuron activity.

    “Neuromodulators, including dopamine itself, serotonin, and enkephalins are also likely to play a significant role in gating synaptic strength and the balance between D1 and D2 MSN activity [217,233,237].”

    From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [233]

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Authors
Francis, T. C., & Lobo, M. K.
Affiliations
University of Maryland, Baltimore (US)
Corresponding author
Lobo, Mary Kay
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2017-04
Volume
81
Issue
8
Pages
645-653
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2016.09.007
PMC
PMC5352537
OpenAlex
W2520064463
Semantic Scholar
49a101822315140a688019cb04b55bdeed01edc8
Cited by
230
References
97
Citations by year
2026: 18 · 2025: 16 · 2024: 33 · 2023: 29 · 2022: 26 · 2021: 26 · 2020: 21 · 2019: 29 · 2018: 16 · 2017: 16
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (R01MH106500)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nucleus accumbens, medium spiny neurons, depression, ventral striatum, dopamine D1 receptor, dopamine D2 receptor, stress, neuroplasticity, subcellular signaling, gene expression, excitatory synaptic transmission, reward, motivation
MeSH terms
Animals, Brain, Depression, Depressive Disorder, Female, Humans, Male, Mice, Inbred C57BL, Neural Pathways, Neurons, Nucleus Accumbens, Social Behavior, Stress, Psychological, Receptors, Dopamine D1, Receptors, Dopamine D2, Excitatory Postsynaptic Potentials, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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