The molecular and cellular mechanisms of depression: a focus on reward circuitry

In the paper

“The stress-induced behavioral phenotypes are reversed by chronic, but not acute antidepressant treatment, and are thus posited to have both face and predictive validity [8].”

What the sources say

• Not checked yetcites [8] Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010;13:1161–9. source

In the paper

“Reward learning and connectivity between the VTA and striatum is impaired in MDD patients [18, 19].”

What the sources say

• Not checked yetcites [18] Kumar P, Goer F, Murray L, Dillon DG, Beltzer ML, Cohen AL, et al. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology. 2018;43:1581–8. source
• Not checked yetcites [19] Blood AJ, Iosifescu DV, Makris N, Perlis RH, Kennedy DN, Dougherty DD, et al. Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder. PLoS ONE. 2010;5:e13945. source

In the paper

“dopaminergic neurons in the VTA fire in response to unpredicted reward and in anticipation of impending reward [20]”

What the sources say

• Not checked yetcites [20] Schultz W. Reward prediction error. Curr Biol. 2017;27:R369–R371. source

In the paper

“rodents are exposed to a series of stressors such as cage tilting and disrupted lights for 8–12 weeks [10], after which animals show reduced sucrose preference.”

What the sources say

• Not checked yetcites [10] Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93. source

In the paper

“Approximately 70% of mice that undergo CSDS are termed “stress-susceptible,” displaying a robust depression-like phenotype marked by reduced social interaction, increased anhedonia, and significant body-weight changes [13].”

What the sources say

• Not checked yetcites [13] Krishnan V, Han M-HH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404. source

In the paper

“inhibiting VTA dopamine neurons that project to the NAc induces resilience but inhibiting VTA dopamine projections to medial prefrontal cortex (mPFC) promotes CSDS susceptibility [23].”

What the sources say

• Not checked yetcites [23] Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6. source

In the paper

“Increased Ih currents occur specifically in NAc, but not mPFC projecting VTA dopamine neurons [30]”

What the sources say

• Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source

In the paper

“Ih and intrinsic excitability are upregulated in CSDS-susceptible mice [30], but somewhat paradoxically, Ih is upregulated to a greater extent in resilient mice.”

What the sources say

• Not checked yetcites [30] Friedman AK, Walsh JJ, Juarez B, Ku SM, Chaudhury D, Wang J, et al. Enhancing depression mechanisms in midbrain dopamine neurons achieves homeostatic resilience. Science. 2014;344:313–9. https://doi.org/10.1126/science.1249240 . source

In the paper

“KCNQ channel Kv7.4 is an attractive target in depression, as this subtype is more selectively expressed in VTA (not substantia nigra) dopamine neurons and Kv7.4 currents are reduced in susceptible mice [27].”

What the sources say

• Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source

In the paper

“KCNQ overexpression or administration of KCNQ-openers rescues depressive behavior [25, 27] by reducing firing of NAc projecting, but not PFC projecting VTA dopamine neurons [25].”

What the sources say

• Not checked yetcites [25] Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671. source
• Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source

In the paper

“Ih potentiation with repeated lamotrigine increases K+ currents and decreases neuronal excitability in previously susceptible mice to reverse social and sucrose preference deficits [25].”

What the sources say

• Not checked yetcites [25] Friedman AK, Juarez B, Ku SM, Zhang H, Calizo RC, Walsh JJ, et al. KCNQ channel openers reverse depressive symptoms via an active resilience mechanism. Nat Commun. 2016;7:11671. source

In the paper

“Sucrose preference deficits, social avoidance, and VTA excitability are reduced by opening Kv7.4 channels with fasudil [27]”

What the sources say

• Not checked yetcites [27] Li L, Sun H, Ding J, Niu C, Su M, Zhang L, et al. Selective targeting of M-type potassium Kv 7.4 channels demonstrates their key role in the regulation of dopaminergic neuronal excitability and depression-like behaviour. Br J Pharmacol. 2017;174:4277–94. source

In the paper

“chronic stress increases extracellular signal-regulated kinase 2 (ERK2) activity in the VTA and inhibiting VTA ERK2 rescues CSDS-susceptibility and reduces forced-swim and tail-suspension immobility by reducing dopamine neuron excitability [47].”

What the sources say

• Not checked yetcites [47] Iñiguez SD, Vialou V, Warren BL, Cao J-L, Alcantara LF, Davis LC, et al. Extracellular signal-regulated kinase-2 within the ventral tegmental area regulates responses to stress. J Neurosci. 2010;30:7652–63. source

In the paper

“Rats exposed to chronic mild stress have fewer spontaneously active dopamine neurons [52, 53], an effect more pronounced in females [53].”

What the sources say

• Not checked yetcites [52] Moreines JL, Owrutsky ZL, Gagnon KG, Grace AA. Divergent effects of acute and repeated quetiapine treatment on dopamine neuron activity in normal vs. chronic mild stress induced hypodopaminergic states. Transl Psychiatry. 2017;7:1275. source
• Not checked yetcites [53] Rincón-Cortés M, Grace AA. Sex-dependent effects of stress on immobility behavior and VTA dopamine neuron activity: modulation by ketamine. Int J Neuropsychopharmacol. 2017;20:823–32. source

In the paper

“CB2 activation reduces VTA dopamine neuron firing [39] and immobility in forced-swim and tail-suspension tests [40].”

What the sources say

• Not checked yetcites [39] Zhang H-Y, Gao M, Liu Q-R, Bi G-H, Li X, Yang H-J, et al. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci USA. 2014;111:E5007–15. source
• Not checked yetcites [40] Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S. β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav. 2014;135:119–24. source

In the paper

“VTA firing is also reduced in mice exposed to CUS and optogenetic stimulation in this context reverses, instead of promotes, stress-induced behavioral deficits [54].”

What the sources say

• Not checked yetcites [54] Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai H-C, Finkelstein J, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–41. source

In the paper

“long-term activation of PPARα decreases β2-nAChR phosphorylation, increases dopamine neuron bursting, and rescues sucrose self-administration after stress [59].”

What the sources say

• Not checked yetcites [59] Scheggi S, Melis M, De Felice M, Aroni S, Muntoni AL, Pelliccia T, et al. PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors. Neuropharmacology. 2016;110:251–9. source

In the paper

“Peroxisome proliferator-activated receptor α (PPARα) signaling increases β2-nAChR phosphorylation, which subsequently decreases VTA dopamine neuron firing [58].”

What the sources say

• Not checked yetcites [58] Melis M, Carta S, Fattore L, Tolu S, Yasar S, Goldberg SR, et al. Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors. Biol Psychiatry. 2010;68:256–64. source

In the paper

“β-Cat regulates Dicer1, a microRNA regulator that, in turn, modulates other known pro-susceptibility genes such as Arc and Npas4 [127].”

What the sources say

• Not checked yetcites [127] Dias C, Feng J, Sun H, Shao NY, Mazei-Robison MS, Damez-Werno D, et al. β-catenin mediates stress resilience through Dicer1/microRNA regulation. Nature. 2014;516:51–5. source

In the paper

“FNDC5 induces thermogenesis and elevates mitochondrial gene expression [131], and resilient mice have increased NAc metabolism [132].”

What the sources say

• Not checked yetcites [131] Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481:463–8. source

In the paper

“In both male and female mice, NAc ERα overexpression increases sucrose preference and promotes CSDS-resilience in males [133].”

What the sources say

• Not checked yetcites [133] Lorsch ZS, Loh Y-HE, Purushothaman I, Walker DM, Parise EM, Salery M, et al. Estrogen receptor α drives pro-resilient transcription in mouse models of depression. Nat Commun. 2018;9:1116. source

In the paper

“Egr3 is upregulated specifically in D1-MSNs of susceptible mice and its knockdown can prevent altered synaptic activity and stress susceptibility [88].”

What the sources say

• Not checked yetcites [88] Francis TC, Chandra R, Gaynor A, Konkalmatt P, Metzbower SR, Evans B, et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry. 2017;22:1512–9. source

In the paper

“Social defeat increases NAc PGC1α and its downstream myokine FNDC5, and FNDC5 is upregulated more in resilient mice [130].”

What the sources say

• Not checked yetcites [130] Zhan G, Huang N, Li S, Hua D, Zhang J, Fang X, et al. PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat. Psychopharmacology (Berl). 2018;235:3351–8. source

In the paper

“RhoA is transcriptionally regulated by Egr3 [88] and in stress-naive mice, increased RhoA in D1-MSNs decreases sucrose preference in males, grooming behavior in females, and forced-swim immobility.”

What the sources say

• Not checked yetcites [138] Fox ME, Chandra R, Menken MS, Larkin EJ, Nam H, Engeln M, et al. Dendritic remodeling of D1 neurons by RhoA/Rho-kinase mediates depression-like behavior. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0211-5 . [Epub ahead of print]. source

In the paper

“Intra-NAc HDAC inhibition reverses social avoidance induced by CSDS, likely caused by increased Rac1 expression [141].”

What the sources say

• Not checked yetcites [141] Golden SA, Christoffel DJ, Heshmati M, Hodes GE, Magida J, Davis K, et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med. 2013;19:337–44. source

In the paper

“Repressive histone modifications are both up-and downregulated after social defeat stress, and these changes are linked to genes with known roles in CSDS-susceptibility.”

What the sources say

• Not checked yetcites [140] Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-Iinduced vulnerability to stress. Neuron. 2011;71:656–70. source

In the paper

“Subchronic stress also upregulates NAc Dnmt3a, but to a greater extent in stressed females.”

What the sources say

• Not checked yetcites [144] Hodes GE, Pfau ML, Purushothaman I, Ahn HF, Golden SA, Christoffel DJ, et al. Sex differences in nucleus accumbens transcriptome profiles associated with susceptibility versus resilience to subchronic variable stress. J Neurosci. 2015;35:16362–76. source

In the paper

“G9a overexpression promotes resilience, thought to occur by normalization of TrkB-CREB signaling [140].”

What the sources say

• Not checked yetcites [140] Covington HE, Maze I, Sun H, Bomze HM, DeMaio KD, Wu EY, et al. A role for repressive histone methylation in cocaine-Iinduced vulnerability to stress. Neuron. 2011;71:656–70. source

In the paper

“Expression of activity-dependent histone variant H3.3 (H3f3b) is increased in the NAc in postmortem MDD tissue, after early life stress, and in CSDS-susceptible mice, an effect prevented in mice by environmental enrichment [146].”

What the sources say

• Not checked yetcites [146] Lepack AE, Bagot RC, Peña CJ, Loh Y-HE, Farrelly LA, Lu Y, et al. Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior. Proc Natl Acad Sci USA. 2016;113:12562–7. source

In the paper

“Pro-susceptibility Dnmt3a overexpression [143] or constitutively active IκB kinase (IKK) [156, 157] both increase MSN spine density.”

What the sources say

• Not checked yetcites [143] LaPlant Q, Vialou V, Covington HE, Dumitriu D, Feng J, Warren BL, et al. Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nat Neurosci. 2010;13:1137–43. source
• Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
• Not checked yetcites [157] Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615–23. source

In the paper

“Histone acetylation on the Fosb promotor drives resilience in D1-MSNs, but susceptibility in D2-MSNs [124].”

What the sources say

• Not checked yetcites [124] Hamilton PJ, Burek DJ, Lombroso SI, Neve RL, Robison AJ, Nestler EJ, et al. Cell-type-specific epigenetic editing at the Fosb gene controls susceptibility to social defeat stress. Neuropsychopharmacology. 2018;43:272–84. source

In the paper

“In contrast, CUS increases dendritic length of NAc core MSNs, which is reversed by imipramine or fluoxetine treatment [154].”

What the sources say

• Not checked yetcites [154] Bessa JM, Morais M, Marques F, Pinto L, Palha JA, Almeida OFX, et al. Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry. 2013;3:e266–e266. source

In the paper

“Reduced dendritic complexity largely agrees with changes in other brain regions [151, 152] and is associated with reduced excitatory input but increased intrinsic excitability [88, 89], which may reflect homeostatic self-tuning [153].”

What the sources say

• Not checked yetcites [88] Francis TC, Chandra R, Gaynor A, Konkalmatt P, Metzbower SR, Evans B, et al. Molecular basis of dendritic atrophy and activity in stress susceptibility. Mol Psychiatry. 2017;22:1512–9. source
• Not checked yetcites [89] Francis TC, Gaynor A, Chandra R, Fox ME, Lobo MK. The selective RhoA inhibitor Rhosin promotes stress resiliency through enhancing D1-MSN plasticity and reducing hyperexcitability. Biol Psychiatry. 2019. https://doi.org/10.1016/j.biopsych.2019.02.007 . source

In the paper

“CSDS-susceptible mice upregulate cytokines IL-1β and CXCL1, and have more circulating leukocytes [175].”

What the sources say

• Not checked yetcites [175] Hodes GE, Pfau ML, Leboeuf M, Golden SA, Christoffel DJ, Bregman D, et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc Natl Acad Sci USA. 2014;111:16136–41. source

In the paper

“Mice lacking p11 [162], p11 reductions in NAc [163], or p11 knockout in NAc ChIs [158] is sufficient to reduce sucrose preference and increase forced-swim immobility (Fig. 2, top).”

What the sources say

• Not checked yetcites [162] Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, et al. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006;311:77–80. source
• Not checked yetcites [163] Alexander B, Warner-Schmidt J, Eriksson T, Tamminga C, Arango-Llievano M, Ghose S, et al. Reversal of depressed behaviors in mice by p11 gene therapy in the nucleus accumbens. Sci Transl Med. 2010;2:54ra76–54ra76. source
• Not checked yetcites [158] Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5. source

In the paper

“Silencing NAc cholinergic interneurons (ChIs) results in anhedonia and increases immobility in the forced-swim and tail-suspension tests [158].”

What the sources say

• Not checked yetcites [158] Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, et al. Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA. 2012;109:11360–5. source

In the paper

“IL-6 drives production of inflammatory T-helper 17 (Th17) cells, which promote learned helplessness and social avoidance, and mice unable to produce Th17 are resilient to learned helplessness [178].”

What the sources say

• Not checked yetcites [178] Beurel E, Harrington LE, Jope RS. Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry. 2013;73:622–30. source

In the paper

“At least 40% of cells in the rodent [171] and human [172] brain are non-neuronal, but how non-neuronal cells interact with reward circuitry in MDD is unknown.”

What the sources say

• Not checked yetcites [171] Herculano-Houzel S, Lent R. Isotropic fractionator: a simple, rapid method for the quantification of total cell and neuron numbers in the brain. J Neurosci. 2005;25:2518–21. source
• Not checked yetcites [172] von Bartheld CS, Bahney J, Herculano-Houzel S. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol. 2016;524:3865–95. source

In the paper

“Microglia found in healthy reward circuitry are incredibly diverse [196] and more work is needed to profile their function in pathologic states.”

What the sources say

• Not checked yetcites [196] De Biase LM, Schuebel KE, Fusfeld ZH, Jair K, Hawes IA, Cimbro R, et al. Local cues establish and maintain region-specific phenotypes of basal ganglia microglia. Neuron. 2017;95:341–.e6. source

In the paper

“Microglia in CUS mice have enhanced colony stimulating factor 1 receptor expression and enhanced phagocytotic activity, paralleled by CSF1 elevations in postmortem MDD tissue [185].”

What the sources say

• Not checked yetcites [185] Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49. source

In the paper

“Bacteria in the gastrointestinal tract directly influence neural activity through sensory neurons, or by modulating the function of the hypothalamic–pituitary–adrenal axis (reviewed in ref. [197]).”

What the sources say

• Not checked yetcites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source

In the paper

“In the absence of stress, constitutively active IKK increases thin spine density, increases forced-swim immobility, and decreases sucrose preference after acute stress [156, 157].”

What the sources say

• Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
• Not checked yetcites [157] Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615–23. source

In the paper

“CSDS increases IKK and NF-κB, along with the number of immature dendritic spines in the NAc of susceptible mice [156, 157].”

What the sources say

• Not checked yetcites [156] Christoffel DJ, Golden SA, Dumitriu D, Robison AJ, Janssen WG, Ahn HF, et al. IκB kinase regulates social defeat stress-induced synaptic and behavioral plasticity. J Neurosci. 2011;31:314–21. source
• Not checked yetcites [157] Christoffel DJ, Golden SA, Heshmati M, Graham A, Birnbaum S, Neve RL, et al. Effects of inhibitor of κB kinase activity in the nucleus accumbens on emotional behavior. Neuropsychopharmacology. 2012;37:2615–23. source

In the paper

“When lymphocytes from socially defeated mice are transplanted into Rag2−/− lymphopoenic mice, recipient mice exhibit more social interaction and less tail-suspension immobility [193].”

What the sources say

• Not checked yetcites [193] Brachman RA, Lehmann ML, Maric D, Herkenham M. Lymphocytes from chronically stressed mice confer antidepressant-like effects to naive mice. J Neurosci. 2015;35:1530–8. source

In the paper

“Mice that lack microglial autophagy-related protein 7 exhibit impaired social interaction and increased immature synapses [194].”

What the sources say

• Not checked yetcites [194] Kim H-J, Cho M-H, Shim WH, Kim JK, Jeon E-Y, Kim D-H, et al. Deficient autophagy in microglia impairs synaptic pruning and causes social behavioral defects. Mol Psychiatry. 2017;22:1576–84. source

In the paper

“Microglia from socially defeated mice have an increased inflammatory profile and produce more IL-6 after lipopolysaccharide (LPS) stimulation [191], similar to enhanced IL-6 release from the peripheral leukocytes of stressed mice [175].”

What the sources say

• Not checked yetcites [191] Wohleb ES, Hanke ML, Corona AW, Powell ND, Stiner LM, Bailey MT, et al. β-Adrenergic receptor antagonism prevents anxiety-like behavior and microglial reactivity induced by repeated social defeat. J Neurosci. 2011;31:6277–88. source

In the paper

“Ccl2 reduction with short hairpin RNA restores sucrose preference and increases swimming in the forced-swim test [192].”

What the sources say

• Not checked yetcites [192] Wu X-B, Jing P-B, Zhang Z-J, Cao D-L, Gao M-H, Jiang B-C, et al. Chemokine receptor CCR2 contributes to neuropathic pain and the associated depression via increasing NR2B-mediated currents in both D1 and D2 dopamine receptor-containing medium spiny neurons in the nucleus accumbens shell. Neuropsychopharmacology. 2018;43:2320–30. source

In the paper

“Viral knockdown of neuronal Csf1 attenuates dendritic spine pruning on mPFC neurons and prevents stress-induced anhedonia and forced-swim immobility [185].”

What the sources say

• Not checked yetcites [185] Wohleb ES, Terwilliger R, Duman CH, Duman RS. Stress-induced neuronal colony stimulating factor 1 provokes microglia-mediated neuronal remodeling and depressive-like behavior. Biol Psychiatry. 2018;83:38–49. source

In the paper

“Similarly, although we know changes to NAc D1-and D2-MSN function are bidirectional, most of this work was done solely in male rodents.”

In the paper

“Mice with reduced glutamate transporter GLT-1 expression in habenular astrocytes are more stress-susceptible and exhibit increased tail-suspension immobility at baseline [200], in agreement with reduced glutamate transporter expression in learned helpless rats [201].”

What the sources say

• Not checked yetcites [200] Cui W, Mizukami H, Yanagisawa M, Aida T, Nomura M, Isomura Y, et al. Glial dysfunction in the mouse habenula causes depressive-like behaviors and sleep disturbance. J Neurosci. 2014;34:16273–85. source

In the paper

“The gut microbiome controls gut permeability and inflammation, and may thus participate in the neuroimmune mechanisms of depression [197].”

What the sources say

• Not checked yetcites [197] Foster JA, McVey Neufeld K-A. Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36:305–12. source

In the paper

“These studies have revealed important adaptations in both dopaminergic and glutamatergic function within the VTA and NAc, and notably these adaptations can differ in directionality based on cell type or stress paradigm.”

In the paper

“Recent work indicates gut microbiota can also influence neural metabolism [198].”

What the sources say

• Not checked yetcites [198] Zheng P, Zeng B, Zhou C, Liu M, Fang Z, Xu X, et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol Psychiatry. 2016;21:786–96. source