Plasticity of synapses and reward circuit function in the genesis and treatment of depression

In the paper

“We have observed that chronic, but not acute, administration of fluoxetine restores the strength of stress-weakened TA-CA1 excitatory synapses, concomitant with the recovery of normal hedonic behavior [44,120].”

What the sources say

• Not checked yetcites [44] Cai X, Kallarackal AJ, Kvarta MD, Goluskin S, Gaylor K, Bailey AM, et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci. 2013;16:464–72. source
• Not checked yetcites [120] Tomar A, Polygalov D, McHugh TJ. Differential impact of acute and chronic stress on CA1 spatial coding and gamma oscillations. Front Behav Neurosci. 2021;15:710725. source

In the paper

“The range of behaviors altered in depression suggests that multiple synaptic circuits are adversely affected, with no one synapse or circuit likely to be uniquely responsible for generating the entirety of the depressed phenotype.”

In the paper

“There are also circuits involving the lateral habenula that display a relatively selective processing of negative valence stimuli and feed forward to the VTA.”

In the paper

“These chronic stress models induce depressive-like behavioral states, resembling the symptom domains of human depression, and alter the putative underlying brain circuits in parallel with functional imaging findings in depressed humans [18,[37][38][39].”

What the sources say

• Not checked yetcites [18] Xia CH, Ma Z, Ciric R, Gu S, Betzel RF, Kaczkurkin AN, et al. Linked dimensions of psychopathology and connectivity in functional brain networks. Nat Commun. 2018;9:3003.
• Not checked yetcites [37] Strekalova T, Steinbusch HW. Measuring behavior in mice with chronic stress depression paradigm. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:348–61. source
• Not checked yetcites [38] Lammel S, Tye KM, Warden MR. Progress in understanding mood disorders: optogenetic dissection of neural circuits. Genes Brain Behav. 2014;13:38–51. source

In the paper

“All chronic stress protocols produce behavioral changes with face validity to the symptom domains of human depression.”

In the paper

“Impairment in these tasks is consistently observed after chronic stress and is clearly maladaptive.”

In the paper

“Hippocampal ensemble firing patterns also help animals correctly predict which direction they need to move in order to reach a chosen distant goal [62].”

What the sources say

• Not checked yetcites [62] Wikenheiser AM, Redish AD. Hippocampal theta sequences reflect current goals. Nat Neurosci. 2015;18:289–94. source

In the paper

“Importantly, receipt of a reward triggers an increase in the rate of spike-wave ripples [63], which are known to enhance place field stability, and may thereby promote learning of reward locations [64].”

What the sources say

• Not checked yetcites [63] Singer AC, Frank LM. Rewarded outcomes enhance reactivation of experience in the hippocampus. Neuron. 2009;64:910–21. source
• Not checked yetcites [64] Roux L, Hu B, Eichler R, Stark E, Buzsaki G. Sharp wave ripples during learning stabilize the hippocampal spatial map. Nat Neurosci. 2017;20:845–53. source

In the paper

“An impaired ability to think and concentrate, which encompasses deficits in memory, executive function, and attention, is one of the major symptom categories used to diagnose MDD and contributes significantly to the overall disability associated with depression [56,57].”

What the sources say

• Not checked yetcites [56] Ottowitz WE, Dougherty DD, Savage CR. The neural network for abnormalities of attention and executive function in major depressive disorder: implications for application of the medical disease model to psychiatric disorders. Harv Rev Psychiatry. 2002;10:86–99. source
• Not checked yetcites [57] Frodl T, Schaub A, Banac S, Charypar M, Jäger M, Kümmler P, et al. Reduced hippocampal volume correlates with executive dysfunctioning in major depression. J Psych Neurosci. 2006;31:316–23.

In the paper

“The hippocampus is well known to be essential in declarative and spatial memory formation from both animal studies and humans.”

In the paper

“It is also known to be an important regulator of the hypothalamic-pituitary axis, mediating negative feedback of stress hormone secretion.”

In the paper

“A grossly oversimplified overview of these circuits is that the prefrontal cortices and hippocampus are devoted to detecting and decoding specific features of stimuli and the environment, including the social environment, to guide decision-making and ensure adaptive, flexible, and predictive responses to rewarding stimuli, whereas the lateral hypothalamus-lateral habenula circuits predominantly En”

What the sources say

• Not checked yetcites [50] Sesack SR, Grace AA. Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacol. 2010;2010:27–47. source
• Not checked yetcites [51] Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25. source
• Not checked yetcites [52] Lammel S, Lim BK, Malenka RC. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacol. 2014a;76:351–9. source

In the paper

“There is also evidence that early life trauma can cause lifelong decreases in hippocampal volume [83], suggesting that preexisting hippocampal atrophy may predispose some people to the onset of depression later in life.”

What the sources say

• Not checked yetcites [83] Opel N, Redlich R, Zwanzger P, Grotegerd D, Arolt V, Heindel W, et al. Hippocampal atrophy in major depression: a function of childhood maltreatment rather than diagnosis? Neuropsychopharmacol. 2014;39:2723–31. source

In the paper

“McEwen and colleagues first discovered that chronic stress and administration of exogenous corticosteroids lead to neuronal death in the hippocampus in rodents, as well as atrophy of the distal pyramidal cell dendrites and loss of dendritic spines [69][70][71][72][73][74].”

What the sources say

• Not checked yetcites [69] Sapolsky R, Krey L, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985;5:1222–27. source
• Not checked yetcites [70] Woolley C, Gould E, McEwen BS. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res. 1990;531:225–31. source
• Not checked yetcites [71] Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341–5. source

In the paper

“As in animal models, human hippocampal atrophy can result solely from elevated corticosteroid levels.Selective atrophy of the hippocampus is observed in patients with Cushing's Syndrome and other diseases with chronically elevated cortisol levels, and these morphological changes are reversed by treatments that lower cortisol levels [82].”

What the sources say

• Not checked yetcites [82] Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, Schteingart DE. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol Psychiatry. 1999;46:1595–602. source

In the paper

“These effects are consistent in all principal cell types and across multiple forms of physical and social stress [75][76][77].”

What the sources say

• Not checked yetcites [75] Silva-Gómez AB, Rojas D, Juárez I, Flores G. Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res. 2003;983:128–36. source
• Not checked yetcites [76] Donohue HS, Gabbott PL, Davies HA, Rodríguez JJ, Cordero MI, Sandi C, et al. Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience. 2006;140:597–606. source
• Not checked yetcites [77] Maras PM, Molet J, Chen Y, Rice C, Ji SG, Solodkin A, et al. Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress. Mol Psychiatry. 2014;19:811–22. source

In the paper

“Treatment with conventional antidepressants diminishes the atrophy in human depression [84], including recent longitudinal studies in previously drug naïve patients [85,86], suggesting that the anatomical changes may underlie functional improvements.”

What the sources say

• Not checked yetcites [84] Sheline YI, Gado MH, Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516–8. source
• Not checked yetcites [85] Katsuki A, Watanabe K, Nguyen L, Otsuka Y, Igata R, Ikenouchi A, et al. Structural changes in hippocampal subfields in patients with continuous remission of drug-naive major depressive disorder. Int J Mol Sci. 2020;21:3032. source
• Not checked yetcites [86] Zarate-Garza PP, Ortega-Balderas JA, Ontiveros-Sanchez de la Barquera JA, Lugo-Guillen RA, Marfil-Rivera A, Quiroga-Garza A, et al. Hippocampal volume as treatment predictor in antidepressant naïve patients with major depressive disorder. J Psychiatr Res. 2021;140:323–8. source

In the paper

“The link between these phenomena and the genesis of depression was considerably strengthened with the finding that conventional antidepressants promote BDNF expression [87,93] and neurogenesis [94][95][96].”

What the sources say

• Not checked yetcites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source
• Not checked yetcites [93] Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15:7539–47. source
• Not checked yetcites [94] Malberg J, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult hippocampus. J Neurosci. 2000;20:9104–10. source

In the paper

“The dentate gyrus is a unique source of ongoing neurogenesis in the adult brain, at least in nonhuman animals, and there is preclinical evidence that the birth and maturation of new granule cells may play a role in depression and antidepressant drug actions [89].”

What the sources say

• Not checked yetcites [89] Tartt AN, Mariani MB, Hen R, Mann JJ, Boldrini M Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry. 2022;27:2689-99; https://doi.org/10.1038/s41380-022-01520-y. source

In the paper

“A neurotrophic hypothesis of depression has been proposed, which posits that a decrease in neurotrophic factor signaling as the root of dysgenesis of dentate granule cells and atrophy of dendrites and synapses in depressed brain [87,97,98].”

What the sources say

• Not checked yetcites [87] Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–27. source
• Not checked yetcites [97] Duman RS, Li N. A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists. Philos Trans R Soc Lond B Biol Sci. 2012;367:2475–84. source
• Not checked yetcites [98] Castrén E, Monteggia LM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. 2021;90:128–36. source

In the paper

“In area CA3, chronic stress enhances synaptic currents mediated by NMDARs but has no effect on AMPARs [109].”

What the sources say

• Not checked yetcites [109] Kole MHP, Swan L, Fuchs E. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats. Eur J Neurosci. 2002;16:807–16. source

In the paper

“This hypothesis is complementary to the suggestion that stimulation of neurotrophic signaling and neurogenesis by antidepressants explains their therapeutic actions [99][100][101].”

What the sources say

• Not checked yetcites [99] Dranovsky A, Hen R. Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry. 2006;59:1136–43. source
• Not checked yetcites [100] Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110–5. source
• Not checked yetcites [101] Anacker C, Zunszain PA, Cattaneo A, Carvalho LA, Garabedian MJ, Thuret S, et al. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Mol Psychiatry. 2011;16:738–50. source

In the paper

“Beyond dendritic atrophy, there are dramatic alterations in synaptic structure and function in animal models based on chronic stress [104], including altered synaptic currents [105], deficits in synaptic plasticity in CA1 and DG [106], and impaired local circuit function [107].”

What the sources say

• Not checked yetcites [104] Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;11:675–81. source
• Not checked yetcites [105] Karst H, Joëls M. Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons. J Neurophysiol. 2003;89:625–33. source
• Not checked yetcites [106] Alfarez DN, Joëls M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34. source

In the paper

“In contrast, chronic stress has no effect on basal synaptic strength at Schaffer collateral (SC) synapses in area CA1, although it does impair SC-CA1 long-term potentiation (LTP) [106,110].”

What the sources say

• Not checked yetcites [106] Alfarez DN, Joëls M, Krugers HJ. Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro. Eur J Neurosci. 2003;17:1928–34. source
• Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source

In the paper

“In contrast, at the temporoammonic (TA) synapses formed by entorhinal cortical afferents to the distal dendrites of CA1 pyramidal cells, where atrophy is most apparent, AMPARmediated basal synaptic transmission is impaired by chronic stress or exogenous corticosteroid administration, but LTP is unaffected [36,110].”

What the sources say

• Not checked yetcites [36] Kvarta MD, Bradbrook KE, Dantrassy HM, Bailey AM, Thompson SM. Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses. J Neurophysiol. 2015;114:1713–24. source
• Not checked yetcites [110] Kallarackal AJ, Kvarta MD, Cammarata E, Jaberi L, Cai X, Bailey AM, et al. Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses. J Neurosci. 2013;33:15669–74. source

In the paper

“The explanatory power of neurogenesis in depression and antidepressant drug effects is complicated by the fact that neurogenesis is only observed in the dentate gyrus, putting a severe limit on the possible depression symptom domains it can impact, and by recent findings that neurogenesis may be very limited or absent in humans [102].”

What the sources say

• Not checked yetcites [102] Franjic D, Skarica M, Ma S, Arellano JI, Tebbenkamp ATN, Choi J, et al. Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells. Neuron. 2022;110:452–69. source

In the paper

“In this regard, it is important to recognize that the effects of acute stress are generally adaptive and very different from the maladaptive consequences of chronic stress [104].”

What the sources say

• Not checked yetcites [104] Krugers HJ, Hoogenraad CC, Groc L. Stress hormones and AMPA plasticity and memory. Nat Rev Neurosci. 2010;11:675–81. source

In the paper

“In the hippocampus, several types of chronic stress cause a loss of distal apical dendritic branches in CA3 and CA1 pyramidal cells and a loss in the size and number of dendritic spines [71,74,108].”

What the sources say

• Not checked yetcites [71] Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 1992;588:341–5. source
• Not checked yetcites [74] Magariños AM, McEwen BS, Flügge G, Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534–40. source
• Not checked yetcites [108] Sousa N, Lukoyanov NV, Madeira MD, Almeida OFX, Paula-Barbosa MM. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience. 2000;97:253–66. source

In the paper

“How this compares to human GluA1 gene SNPs was not described, but this evidence converges with human data implicating AMPARs [115].Gene clusters associated with excitatory synaptic function are also commonly identified in genetic screens in suicide and depression [116][117][118] and in preclinical studies [119].”

What the sources say

• Not checked yetcites [115] Freed WJ, Dillon-Carter O, Kleinman JE. Properties of [3H]AMPA binding in postmortem human brain from psychotic subjects and controls: increases in caudate nucleus associated with suicide. Exp Neurol. 1993;121:48–56. source
• Not checked yetcites [116] Sequeira A, Mamdani F, Ernst C, Vawter MP, Bunney WE, Lebel V, et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One. 2009;4:e6585. source
• Not checked yetcites [117] Sokolowski M, Wasserman J, Wasserman D. Gene-level associations in suicide attempter families show overrepresentation of synaptic genes and genes differentially expressed in brain development. Am J Med Genet B Neuropsychiatr Genet. 2018;177:774–84. source

In the paper

“Chronic adolescent stress in female rats caused a decrease in hippocampal SC-CA1 synaptic strength in adults, accompanied by impaired cognitive flexibility [112].”

What the sources say

• Not checked yetcites [112] Hyer MM, Shaw GA, Goswamee P, Dyer SK, Burns CM, Soriano E, et al. Chronic adolescent stress causes sustained impairment of cognitive flexibility and hippocampal synaptic strength in female rats. Neurobiol Stress. 2021;14:100303. source

In the paper

“Serotonin increases phosphorylation of AMPA receptors and increases their delivery to the cell surface [123], an effect that is mimicked by the tricyclic antidepressant imipramine”

What the sources say

• Not checked yetcites [123] Andreetta F, Carboni L, Grafton G, Jeggo R, Whyment AD, van den Top M, et al. Hippocampal 5-HT7 receptors signal phosphorylation of the GluA1 subunit to facilitate AMPA receptor mediated-neurotransmission in vitro and in vivo. Br J Pharm. 2016;173:1438–51. source

In the paper

“The power of gamma oscillations contributes to working memory capacity, is reduced in patients with MDD, and is normalized with symptomatic remission [121].”

What the sources say

• Not checked yetcites [121] Arikan MK, Metin B, Tarhan N. EEG gamma synchronization is associated with response to paroxetine treatment. J Affect Disord. 2018;235:114–6. source

In the paper

“Together these data make a strong argument that disruption of hippocampal glutamatergic transmission, specifically AMPAR function, accompanies and may cause the depression-like behavioral state seen in preclinical models.”

In the paper

“We concluded that the antidepressant actions of SSRIs are mediated, in part, by a rapid insertion of AMPARs into synapses, due to 5HT 1B R-dependent activation of CaMK and phosphorylation of GluA1 subunits at serine 831, a mechanism shared with canonical NMDAR-dependent long-term potentiation, as well as a slower restoration in GluA1 expression levels.”

In the paper

“GABAergic inhibition is also affected by chronic stress [122] and may contribute to the altered balance of excitation and inhibition as well as defects in ensemble activity.”

What the sources say

• Not checked yetcites [122] Alaiyed S, McCann M, Mahajan G, Rajkowska G, Stockmeier CA, Kellar KJ, et al. Venlafaxine stimulates an MMP-9-dependent increase in excitatory/inhibitory balance in a stress model of depression. J Neurosci. 2020;40:4418–31. source

In the paper

“On a network level, chronic stress deceases the spatial tuning of hippocampal cell discharges, as well as the power of gamma oscillations in local field potentials [120].”

What the sources say

• Not checked yetcites [120] Tomar A, Polygalov D, McHugh TJ. Differential impact of acute and chronic stress on CA1 spatial coding and gamma oscillations. Front Behav Neurosci. 2021;15:710725. source

In the paper

“Fluoxetine also produces rapid disinhibition in hippocampal brain slices [128], which could also contribute to a net increase in excitation in vivo.”

What the sources say

• Not checked yetcites [128] Méndez P, Pazienti A, Szabo G, Bacci A. Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants. J Neurosci. 2012;32:16616–28. source

In the paper

“Extensive experience with human patients has established that ketamine exerts rapid, robust antidepressant, antianhedonic, and antisuicidal actions within two hours of administration that are sustained for at least seven days in patients with major depression following a single infusion or intranasal administration [129-133].”

What the sources say

• Not checked yetcites [129] Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4. source
• Not checked yetcites [130] Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64. source
• Not checked yetcites [131] DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, et al. Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. 2010;71:1605–11. source

In the paper

“Zanos et al. [153] reported that the behavioral actions of ketamine in mice could be eliminated by deuterating the molecule to greatly reduce its rate of hydrolysis, suggesting that ketamine's inhibition of NMDARs is not sufficient for its antidepressant actions.”

What the sources say

• Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source

In the paper

“This hypothesis cannot be readily applied to other fast acting antidepressant compounds that do not target NMDARs.It is also difficult to reconcile with findings that other NMDAR antagonists that do not appear to have antidepressant activity.”

In the paper

“Ketamine also exerts strong antidepressant-like actions in preclinical models, including restoration of reward behavior in chronically stressed animals, promotion of dendritic spine formation, restoration of synaptic strength, and promotion of expression of pro-synaptic genes [45].”

What the sources say

• Not checked yetcites [45] Zanos P, Thompson SM, Duman RS, Zarate CA, Gould TD. Convergent mechanisms underlying rapid antidepressant action. CNS Drugs. 2018;32:197–227. source

In the paper

“As predicted, acute inhibition of eEF2K increases mEPSC amplitude in cultured hippocampal cells and occludes the actions of ketamine on mEPSC amplitude [159].”

What the sources say

• Not checked yetcites [159] Suzuki K, Kim JW, Nosyreva E, Kavalali ET, Monteggia LM. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action. Cell Rep. 2021;37:109918. source

In the paper

“Finally, it was observed that five days of treatment with the monoaminergic antidepressant citalopram failed to produce antidepressant behavioral effects in mice but did decrease phosphorylation of eEF2 levels [160].”

What the sources say

• Not checked yetcites [160] Opal MD, Klenotich SC, Morais M, Bessa J, Winkle J, Doukas D, et al. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Mol Psychiatry. 2014;19:1106–14. source

In the paper

“Lastly, there is an exciting recent hypothesis that ketamine may exert its antidepressant actions not by blocking NMDARs, but rather by its neuroactive metabolites, particularly the hydroxynorketamines (HNKs).”

What the sources say

• Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source

In the paper

“This hypothesis posits that ketamine restores stress-impaired excitatory synapses by blocking a subset of NMDARs that are preferentially activated by spontaneous glutamate release.”

• Also stated in: § THE HIPPOCAMPUS · plain

  “As a result, synaptic AMPAR expression is increased [154, 159].”

What the sources say

• Not checked yetcites [154] Kavalali ET, Monteggia LM. Targeting homeostatic synaptic plasticity for treatment of mood disorders. Neuron 2020;106:715–26. source
• Not checked yetcites [155] Sutton MA, Taylor AM, Ito HT, Pham A, Schuman EM. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron. 2007;55:648–61. source
• Not checked yetcites [159] Suzuki K, Kim JW, Nosyreva E, Kavalali ET, Monteggia LM. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action. Cell Rep. 2021;37:109918. source

In the paper

“Loneliness, for example, is caused by perceived social isolation and absence of companionship and is associated with increased risk for depression and suicide [171].”

What the sources say

• Not checked yetcites [171] McClelland H, Evans JJ, Nowland R, Ferguson E, O’Connor RC. Loneliness as a predictor of suicidal ideation and behaviour: a systematic review and meta-analysis of prospective studies. J Affect Disord. 2020;274:880–96. source

In the paper

“Antidepressant relevant effects reported for AMPAkines include decreased immobility in the FST, promotion of BDNF expression, amplification of ketamine effects, and increased neurogenesis in the dentate gyrus [163][164][165][166].”

What the sources say

• Not checked yetcites [163] Li X, Tizzano JP, Griffey K, Clay M, Lindstrom T, Skolnick P. Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacol. 2001;40:1028–33. source
• Not checked yetcites [164] Bai F, Bergeron M, Nelson DL. Chronic AMPA receptor potentiator (LY451646) treatment increases cell proliferation in adult rat hippocampus. Neuropharmacol. 2003;44:1013–21. source
• Not checked yetcites [165] Farley S, Apazoglou K, Witkin JM, Giros B, Tzavara ET. Antidepressant-like effects of an AMPA receptor potentiator under a chronic mild stress paradigm. Int J Neuropsychopharmacol. 2010;13:1207–18. source

In the paper

“Direct administration of HNKs mimicked the behavioral actions of ketamine in mice, promoted EEG gamma oscillations, promoted expression of AMPARs and BDNF, and decreased phosphorylation of eEF2 levels in the hippocampus, providing plenty of mechanisms that could be triggered independently from NMDAR inhibition.”

What the sources say

• Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source

In the paper

“but it is important to recognize that there is strong evidence that their functions are not identical and may display sex differences [167].”

What the sources say

• Not checked yetcites [167] Wallace T, Myers B. Effects of Biological Sex and Stress Exposure on Ventromedial Prefrontal Regulation of Mood-Related Behaviors. Front Behav Neurosci. 2021;15:737960. source

In the paper

“An essential adaptive skill of all animals is to learn to associate a rewarding experience with the sensory cues and actions in the environment that can be used to predict their future occurrence.”

In the paper

“These cognitive maps of rewards underlie all goaldirected behaviors, providing an adaptive benefit of permitting flexible decision-making optimized for both interoceptive state and environmental availability.”

In the paper

“It also regulates the negative ruminative thinking that can indirectly have an adverse impact on cognition and mood [178].”

What the sources say

• Not checked yetcites [178] Lewis EJ, Blanco I, Raila H, Joormann J. Does repetitive negative thinking affect attention? Differential effects of worry and rumination on attention to emotional stimuli. Emotion. 2019;19:1450–62. source

In the paper

“Electrophysiological activity in the PFC encodes potential choice options and computes their comparison in the currently relevant environment.PFC output then turns these computations into actual actions [170].”

What the sources say

• Not checked yetcites [170] Klein-Flügge MC, Bongioanni A, Rushworth MFS. Medial and orbital frontal cortex in decision-making and flexible behavior, Neuron 2022; https://doi.org/10.1016/j.neuron.2022.05.022 source

In the paper

“Deficits in PFC synaptic excitation and imbalances between excitation and inhibition would have obvious impact on these calculations.”

In the paper

“On the other hand, social support is one of the strongest predictors of resilience and increasing social support can provide a beneficial component of effective therapeutic approaches [172].”

What the sources say

• Not checked yetcites [172] Pearce E, Myles-Hooton P, Johnson S, Hards E, Olsen S, Clisu D, et al. Loneliness as an active ingredient in preventing or alleviating youth anxiety and depression: a critical interpretative synthesis incorporating principles from rapid realist reviews. Transl Psychiatry. 2021;11:628. source

In the paper

“In the human brain, activity increases as cues and stimuli become relevant to decisions, with the magnitude of this increase directly proportional to the outcome and reliability of the decision [173].”

What the sources say

• Not checked yetcites [173] Grueschow M, Polania R, Hare TA, Ruff CC. Automatic versus choice-dependent value representations in the human brain. Neuron. 2015;85:874–85. source

In the paper

“Measured with fMRI, the PFC of depressed patients displays evidence of reduced volume, activity, and connectivity.”

In the paper

“Stress induced decision-making deficits in MDD patients are reversible: after one month of reduced stress, subjects were indistinguishable from controls [196].”

What the sources say

• Not checked yetcites [196] Soares JM, Sampaio A, Ferreira LM, Santos NC, Marques F, Palha JA, et al. Stress-induced changes in human decision-making are reversible. Transl Psychiatry. 2012;2:e131. source

In the paper

“Furthermore, co-administration of the mTOR inhibitor rapamycin prevented the induction of dendritic spines by ketamine, as well as ketamine's actions in the FST and other behaviors [202].”

What the sources say

• Not checked yetcites [202] Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source

In the paper

“As discussed above, inhibition of interneurons may promote the kinds of high frequency oscillatory activity in pyramidal cells that underlies gamma oscillations, as seen in human and rodent EEGs, and, in turn, promotes endogenous activity-dependent mechanisms that strengthen stress-impaired excitatory synapses, such as LTP and BDNF-trkB signaling.”

In the paper

“The nucleus accumbens in the ventral striatum is an essential integrator of input pathways from the prefrontal cortex, hippocampus, and amygdala and is critical for determining motivating and reinforcing responses to rewarding stimuli and avoidance responses to aversive stimuli [215][216][217].”

What the sources say

• Not checked yetcites [215] Volkow ND, Wise RA, Baler R. The dopamine motive system: implications for drug and food addiction. Nat Rev Neurosci. 2017;18:741–52. source
• Not checked yetcites [216] Floresco SB. The nucleus accumbens: an interface between cognition, emotion, and action. Annu Rev Psychol. 2015;66:25–52. source
• Not checked yetcites [217] Bayassi-Jakowicka M, Lietzau G, Czuba E, Steliga A, Waśkow M, Kowiański P. Neuroplasticity and multilevel system of connections determine the integrative role of nucleus accumbens in the brain reward system. Int J Mol Sci. 2021;22:9806. source

In the paper

“Many of these forms of activity-dependent plasticity are likely to be NMDAR-dependent, as supported by the antidepressant-like actions of the NMDAR positive allosteric modulator GLYX-13 (rapastinel) in preclinical models [213].”

What the sources say

• Not checked yetcites [213] Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacol. 2017;42:1231–42. source

In the paper

“The NAc is divided into two histologically distinct subregions, the core and the shell, which have unique patterns of inputs and outputs [218,219] and are thought to serve distinct, but similar functions [177].”

What the sources say

• Not checked yetcites [218] Heimer L, Zahm DS, Churchill L, Kalivas PW, Wohltmann C. Specificity in the projection patterns of accumbal core and shell in the rat. Neurosci. 1991;41:89–125. source
• Not checked yetcites [219] Brog JS, Salyapongse A, Deutch AY, Zahm DS. The patterns of afferent innervation of the core and shell in the “accumbens” part of the rat ventral striatum: immunohistochemical detection of retrogradely transported fluoro-gold. J Comp Neurol. 1993;338:255–78. source
• Not checked yetcites [177] Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015;86:646–64. source

In the paper

“Ketamine's disinhibitory action in dendrites also promotes dendritic Ca 2+ influx [214], providing an additional mechanism to drive endogenous activitydependent synaptic strengthening mechanisms.”

What the sources say

• Not checked yetcites [214] Ali F, Gerhard DM, Sweasy K, Pothula S, Pittenger C, Duman RS, et al. Ketamine disinhibits dendrites and enhances calcium signals in prefrontal dendritic spines. Nat Commun. 2020;11:72.

In the paper

“As in the hippocampus, ketamine inhibits the discharge of interneurons in the PFC and reduces spontaneous IPSCs in pyramidal cells acutely [210], while restoring inhibition at later timepoints corresponding to its behavioral actions [211].”

What the sources say

• Not checked yetcites [210] Gerhard DM, Pothula S, Liu RJ, Wu M, Li XY, Girgenti MJ, et al. GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions. J Clin Invest. 2020;130:1336–49. source

In the paper

“Activation of inputs to the NAc from the hippocampus and PFC is rewarding and reinforcing of rewarding stimuli [227,228].”

What the sources say

• Not checked yetcites [227] Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A. Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron. 2012;76:790–803. source
• Not checked yetcites [228] Otis JM, Namboodiri VM, Matan AM, Voets ES, Mohorn EP, Kosyk O, et al. Prefrontal cortex output circuits guide reward seeking through divergent cue encoding. Nature. 2017;543:103–7. source

In the paper

“Nevertheless, activity in D1 MSNs is more likely to be associated with motivation, reward, and positive responses [193,[223][224][225] and resilience to stress [226].”

What the sources say

• Not checked yetcites [193,[223][224][225]
• Not checked yetcites [226] Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22. source

In the paper

“In contrast, MSNs expressing D2-type dopamine receptors, canonically considered the 'indirect' pathway, project to GABAergic cells within the ventral pallidum, that then project to the interneurons within the VTA.Activation of D2-expressing MSNs thereby inhibits activation of dopamine projections back to the forebrain by disinhibiting the interneurons that silence them.”

What the sources say

• Not checked yetcites [220] Watabe-Uchida M, Eshel N, Uchida N. Neural circuitry of reward prediction error. Annu Rev Neurosci. 2017;40:373–94. source

In the paper

“As originally described in the dorsal striatum, MSNs expressing D1-type dopamine receptors, canonically considered the 'direct' pathway, project to and inhibit GABAergic interneurons within the VTA that, in turn, inhibit VTA dopamine releasing cells.Activation of D1-expressing MSNs thereby promotes activation of dopamine projections back to the forebrain by disinhibiting them [220].”

What the sources say

• Not checked yetcites [220] Watabe-Uchida M, Eshel N, Uchida N. Neural circuitry of reward prediction error. Annu Rev Neurosci. 2017;40:373–94. source

In the paper

“Dopamine receptor activation is not required for this potentiation but may be modulatory under physiological conditions [229].”

What the sources say

• Not checked yetcites [229] Yagishita S, Hayashi-Takagi A, Ellis-Davies GC, Urakubo H, Ishii S, Kasai H. A critical time window for dopamine actions on the structural plasticity of dendritic spines. Science. 2014;345:1616–20. source

In the paper

“Chronic, but not acute, administration of fluoxetine to stressed mice restores the strength of hippocampal excitatory synapses in D1 MSNs and their ability to undergo LTP, concomitant with restoration of sucrose preference [193].”

What the sources say

• Not checked yetcites [193] LeGates TA, Kvarta MD, Tooley JR, Francis TC, Lobo MK, Creed MC, et al. Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses. Nature. 2018;564:258–62. source

In the paper

“Lim et al. [236] demonstrated that preventing stress-induced AMPA receptor loss in D1 MSNs was sufficient to prevent stress-induced loss of hedonic responses in sucrose preference and cocaine-induced place preference (although not the FST).”

What the sources say

• Not checked yetcites [236] Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 2012;487:183–9. source

In the paper

“Susceptibility to chronic social defeat stress is accompanied by atrophy of MSN dendrites, specifically in D1 MSNs and not D2 MSNs, and a corresponding loss of dendritic spines [226,234,235].”

What the sources say

• Not checked yetcites [226] Francis TC, Chandra R, Friend DM, Finkel E, Dayrit G, Miranda J, et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol Psychiatry. 2015;77:212–22. source
• Not checked yetcites [234] 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;22:1512–19. source
• Not checked yetcites [235] 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. 2020;25:1022–34. source

In the paper

“There is evidence that the NAc is activated by reward anticipation and both motivational and hedonic aspects of reward processing [245].”

What the sources say

• Not checked yetcites [245] Pool ER, Munoz Tord D, Delplanque S, Stussi Y, Cereghetti D, Vuilleumier P, et al. Differential contributions of ventral striatum subregions to the motivational and hedonic components of the affective processing of reward. J Neurosci. 2022;42:2716–28. source

In the paper

“For example, Sterpinich et al. [251] observed that ketamine increased responses in a reward task and caused an accompanying increase in activity in the orbitofrontal cortex, ventral striatum, and the ventral tegmental area.”

What the sources say

• Not checked yetcites [251] Sterpenich V, Vidal S, Hofmeister J, Michalopoulos G, Bancila V, Warrot D, et al. Increased reactivity of the mesolimbic reward system after ketamine injection in patients with treatment-resistant major depressive disorder. Anesthesiol. 2019;130:923–35. source

In the paper

“Excitatory synapses onto LHb cells are characterized by a high ratio of AMPAR-to NMDAR-mediated synaptic responses [255], indicative of low levels of NMDAR expression.”

What the sources say

• Not checked yetcites [255] Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011;470:535–9. source

In the paper

“There is limited evidence of the effect of antidepressants on these measures of reward circuit function, but it has been shown that improvements in self-reported depression severity and negative affective bias are improved with chronic SSRI administration in depressed patients and are strongly correlated with increases in NAc activity and NAc-PFC connectivity [249].”

What the sources say

• Not checked yetcites [249] Heller AS, Johnstone T, Light SN, Peterson MJ, Kolden GG, Kalin NH, et al. Davidson RJ. Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment. Am J Psychiatry. 2013;170:197–206. source

In the paper

“Unmedicated MDD patients show deficits in reward learning, reduced responses in the ventral striatum for positive prediction errors in a reward task, and reduced NAc-VTA connectivity [247,248].”

What the sources say

• Not checked yetcites [247] 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. Neuropsychopharmacol. 2018;43:1581–8. source
• Not checked yetcites [248] Reinen JM, Whitton AE, Pizzagalli DA, Slifstein M, Abi-Dargham A, McGrath PJ, et al. Differential reinforcement learning responses to positive and negative information in unmedicated individuals with depression. Eur Neuropsychopharmacol. 2021;53:89–100. source

In the paper

“The lateral habenula (LHb) is another key node in regulation of reward behaviors that has been implicated in the genesis of depressive symptoms and reward dysregulation [252].”

What the sources say

• Not checked yetcites [252] Lecca S, Meye FJ, Mameli M. The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci. 2014;39:1170–8. source

In the paper

“LHb neurons fire in response to both aversive stimuli and the absence of an expected reward [257-260].”

What the sources say

• Not checked yetcites [257] Matsumoto M, Hikosaka O. Representation of negative motivational value in the primate lateral habenula. Nat Neurosci. 2009;12:77–84. source
• Not checked yetcites [258] Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, et al. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife. 2017;6:1–16. source
• Not checked yetcites [259] Cerniauskas I, Winterer J, de Jong JW, Lukacsovich D, Yang H, Khan F, et al. Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors. Neuron. 2019;104:899–915. source
• Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source

In the paper

“Optogenetic activation of LHb neurons via projections from the lateral hypothalamic nucleus (LH) triggers avoidance and escape behaviors, whereas optogenetic or pharmacological inhibition of LHb cell discharge impairs avoidance and escape in response to aversive stimuli [258][259][260].”

What the sources say

• Not checked yetcites [258] Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, et al. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife. 2017;6:1–16. source
• Not checked yetcites [259] Cerniauskas I, Winterer J, de Jong JW, Lukacsovich D, Yang H, Khan F, et al. Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors. Neuron. 2019;104:899–915. source
• Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source

In the paper

“With regard to behaviors typically used to study depression and antidepressant drugs, acute physical restraint, foot shock, tail suspension, forced swimming, and social defeat are all accompanied by strong LHb activation [258,260].”

What the sources say

• Not checked yetcites [258] Lecca S, Meye FJ, Trusel M, Tchenio A, Harris J, Schwarz MK, et al. Aversive stimuli drive hypothalamus-to-habenula excitation to promote escape behavior. Elife. 2017;6:1–16. source
• Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source

In the paper

“RMTg neurons, in turn, project to the VTA and are largely responsible for the predominantly inhibitory action of LHb projections onto VTA dopaminergic neurons [256].”

What the sources say

• Not checked yetcites [256] Ji H, Shepard PD. Lateral habenula stimulation inhibits rat midbrain dopamine neurons through a GABA(A) receptor-mediated mechanism. J Neurosci. 2007;27:6923–30. source

In the paper

“Increased numbers of burst-firing LHb neurons were observed in vitro and in vivo in both a rat strain with congenital learned helplessness and in wild type rats after chronic restraint stress, although no overall change in membrane potential was reported [266].”

What the sources say

• Not checked yetcites [266] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90. source

In the paper

“Lesioning or pharmacologically silencing the LHb can normalize learned helplessness responses [266,268], including inhibition of NMDAR-mediated LHb bursting [264].”

What the sources say

• Not checked yetcites [266] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90. source
• Not checked yetcites [268] Winter C, Vollmayr B, Djodari-Irani A, Klein J, Sartorius A. Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav Brain Res. 2011;216:463–5. source
• Not checked yetcites [264] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018a;554:317–22. source

In the paper

“Selective activity-dependent potentiation of synapses formed by axons of LH neurons with LHb neurons promoted LHb discharge and was sufficient to induce mimic the behavioral effects of chronic stress in the forced swim and sucrose preference tests [260, 267].”

What the sources say

• Not checked yetcites [260] Zheng Z, Guo C, Li M, Yang L, Liu P, Zhang X, et al. Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset. Neuron. 2022;110:1400–15. source
• Not checked yetcites [267] Li K, Zhou T, Liao L, Yang Z, Wong C, Henn F, et al. βCaMKII in lateral habenula mediates core symptoms of depression. Science. 2013;341:1016–20. source

In the paper

“Optogenetically induced increases in burst firing in LHb neurons increased mobility in the FST and decreased sucrose preference [266], like the effects of chronic stress.”

What the sources say

• Not checked yetcites [266] Yang LM, Hu B, Xia YH, Zhang BL, Zhao H. Lateral habenula lesions improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus. Behav Brain Res. 2008;188:84–90. source

In the paper

“Increased burst discharges [264] are attributed to dysregulation of the astrocytic K + channels that regulate extracellular K + concentrations, thereby promoting hyperpolarization of LHb neurons [265], although this hyperpolarization was not shown.”

What the sources say

• Not checked yetcites [264] Yang Y, Cui Y, Sang K, Dong Y, Ni Z, Ma S, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018a;554:317–22. source
• Not checked yetcites [265] Cui Y, Yang Y, Ni Z, Dong Y, Cai G, Foncelle A, et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature. 2018;554:323–7. source

In the paper

“Nevertheless, the evidence is plentiful and strong that the LHb is an important mediator of aversive behavioral responses via its outputs to the VTA and that its behavior is profoundly increased in a variety of chronic stress conditions used to model depression relevant behaviors in rodents (for excellent further reviews, see: [252, 269, 270]).”

What the sources say

• Not checked yetcites [252] Lecca S, Meye FJ, Mameli M. The lateral habenula in addiction and depression: an anatomical, synaptic and behavioral overview. Eur J Neurosci. 2014;39:1170–8. source
• Not checked yetcites [269] Yang Y, Wang H, Hu J, Hu H. Lateral habenula in the pathophysiology of depression. Curr Opin Neurobiol. 2018b;48:90–6. source
• Not checked yetcites [270] Mondoloni S, Mameli M, Congiu M. Reward and aversion encoding in the lateral habenula for innate and learned behaviours. Transl Psychiatry. 2022;12:3.

In the paper

“In contrast, hypoactive PFC circuits might be more heavily affected in patients with more prevalent cognitive and decision-making symptoms.”

In the paper

“There is also robust preclinical evidence that psilocybin can restore both reward behaviors and synapse structure and function.”

What the sources say

• Not checked yetcites [275] Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci. 2021;118:e2022489118. source
• Not checked yetcites [276] Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–.e4. source

In the paper

“Driving the LHb may overpower counterbalancing NAc inputs to the VTA, for example, regardless of whether they are fully functional or dysfunctional.”

In the paper

“In general, the synaptic changes result in a weakening of pathways that promote dopamine release by activating cells in the VTA, such as the direct and indirect weakening of excitatory drive of D1 MSNs in the NAc, and potentiation of pathways inhibiting dopamine secretion, such as those within the LH-LHb-RMTg.”

In the paper

“Although there is overlap, some favor activity-dependent synaptic strengthening mechanisms, such as ketamine and ketamine metabolites, whereas others, such as SSRIs, favor neurotrophic growth factor signaling.”

In the paper

“Considering emotional dysregulation [271], for example, an overactive LHb circuit may favor an increase in negative affect.”

What the sources say

• Not checked yetcites [271] Hofmann SG, Sawyer AT, Fang A, Asnaani A. Emotion dysregulation model of mood and anxiety disorders. Depress Anxiety. 2012;29:409–16. source

In the paper

“These concerted changes in synapses in response to chronic stress have been found in essentially every circuit in every reward pathway, providing a mechanistic explanation for the wide range of symptoms that together constitute the clinical definition of depression.”

In the paper

“Those antidepressants that restore synaptic strength slowly, such as SSRIs, restore synaptic strength slowly, whereas fast acting antidepressants do so rapidly.”

In the paper

“Excitatory synapses generally become reduced in number and weaker in areas devoted to directing attention and making decisions about cues and stimuli and stronger in the pathways processing negative valence stimuli.”

In the paper

“These synapses are the working elements of the circuits they are embedded in and hence are could be the cause of significant changes in the function of those circuits.”

In the paper

“Similarly, in the PFC, psilocybin administration to unstressed mice leads to an increase in the net formation of new dendritic spines in pyramidal cells, persisting for over one month, which is accompanied by an increase in the frequency of spontaneous mEPSCs [276].”

What the sources say

• Not checked yetcites [276] Shao LX, Liao C, Gregg I, Davoudian PA, Savalia NK, Delagarza K, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron 2021;109:2535–.e4. source

In the paper

“Taking hippocampal brain slices from these same mice revealed that psilocybin also restored the strength of the stress-sensitive TA-CA1 synapses, concurrent with the restoration of reward behavior, again much like other fastacting antidepressants.”

What the sources say

• Not checked yetcites [275] Hesselgrave N, Troppoli TA, Wulff AB, Cole AB, Thompson SM. Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proc Natl Acad Sci. 2021;118:e2022489118. source

In the paper

“such as AZD6765 [149], mGluR 2/3 antagonists [150], alpha5 subunit-selective GABA A R-NAMs [151, 152], and the ketamine metabolite (2 R,6 R)-HNK [153], all of which enhance EEG power in the gamma frequency band.”

What the sources say

• Not checked yetcites [149] Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, et al. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry. 2014;19:978–85. source
• Not checked yetcites [150] Ahnaou A, Ver Donck L, Drinkenburg WH. Blockade of the metabotropic glutamate (mGluR2) modulates arousal through vigilance states transitions: evidence from sleep-wake EEG in rodents. Behav Brain Res. 2014;270:56–67. source
• Not checked yetcites [153] Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533:481–6. source

In the paper

“Many of the same processes described above are likely to be involved, including neurotrophin signaling and enzymatic cascades promoting receptor trafficking and process outgrowth [278].”

What the sources say

• Not checked yetcites [278] Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 2018;23:3170–3182. source