Social Defeat

Since the end of WW2 much of the world has seen a sustained period of material, if not spiritual development. This brief historical anomaly is coming to an end. The developing macroeconomic crisis and pending ‘great reset’ are the threshold to a grim near future; the degrees of freedom laboriously accumulated by the last 4 or 5 generations look set to be trimmed back as we enter the golden age of crony capitalism, social credit and digital feudalism.

Not since the medieval period has there been such socioeconomic disparity.

The world’s 2,153 billionaires now control more wealth than the 4.6 billion people who make up 60 percent of the planet’s population (1), and just 8 of these plutocrats own as much as the poorer 50% of the world’s population (2). Gates, Bezos and their ilk are largely above the law. Their perversion of capitalism has degraded our political systems and funds the political vermin who infest them. 

The politicians then drive the Covid lockdowns that bleed income and opportunity from the entrepreneurial class and transfer it to the elites, including Big Pharma. The lockdowns have probably done little to affect Covid numbers (3), but have certainly killed many thousands; deaths of despair, caused by substance abuse and suicide, are on a tear (4). The loss of employment and social contacts, and the constant hectoring (and worse) by various enforcers causes the disorder known as social defeat.

I am not interested in the psychopathology of the ‘elite’. But I am interested in what current political, economic and nutritional shifts are doing to people’s hearts and minds.

I have written previously about the impact of poor nutrition on the brain. The modern, ultra-processed diet works via chronic inflammatory stress, Type B malnutrition and dysbiosis to lower IQ (5-8), reduce impulse control, impair mood and make us passive (9-17). It damages brain structures (18-21) and, over the long term, raises the risk of neurodegenerative disease (22, 23). That’s bad enough – but it gets worse, because the emerging thugocracy deals in social defeat.

Social defeat has mostly been studied in rodents. If, for example, you introduce a young male rat (or mouse) into the home cage of a dominant and aggressive older male, the outcomes are predictably negative. The newcomer is bullied into submission, develops neuro-inflammation (24) and shows all the signs of depression (25, 26). 

Metabolic pathways in the brain are distorted in ways that mimic the changes found in the brains of depressive patients (27). The ratling will develop multiple neurotic (displacement) behaviours, cultivate a taste for self-medication with street drugs (28, 29) and/or alcohol (30-32) and die before his time (33), due in most cases to autonomic dysregulation (34).

Social defeat in humans can be just as simple. The rodent experiment has obvious parallels with abusive relationships which increase the risk of depression and other mental illness in the abused partner, together with drug and alcohol abuse (35, 36). Children are even more vulnerable, and lose considerable health (37) and life (38) expectancy.

While it is possible to step outside an abusive relationship, it is far harder to step outside an abusive society. A far more pervasive form of social defeat is the loss of opportunity, income and freedom that is being ushered in by the globalists, using Covid as their excuse to enforce distancing, masking and social and economic privation.

Let’s return, momentarily, to the socially defeated Rattus norvegicus. Social defeat causes withdrawal, depression and impaired memory and cognition by inducing neuroinflammation (24, 39, 40); because immune cells in the central nervous system react to stress as if it were cellular damage (41). This is termed the Cell Danger Response, or CDR.

One could argue, teleologically, that the CDR exists because stress in animals is generally associated with physical trauma. The evolutionary process has therefore engineered a response to stress which not includes the flight and fight stuff, but also prepares the immune system for imminent physical damage and an associated microbial invasion.

If the stress is acute, this portfolio of responses is entirely protective. If the stresses are chronic (and humans are particularly good at creating chronic stress), they are entirely counter-productive. 

The CDR is directly controlled by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem, and which persist in human animals (42). Clinically, chronic activation of the CDR is believed to be involved in PTSD, depression, anxiety disorders, substance abuse and, in the longer term, degenerative diseases (42). 

There is good news and bad news. 

The good news is that the CDR is modulated by a population of gabaminergic neurones in the ventral tegmental area (VTA) and the closely connected dentate gyre of the hippocampus (43, 44), which link reward, punishment and discriminative memory circuits. These neurones can be favourably modified by GABA-targetting drugs such as erzogabine (45) and ketamine (46). They can also be modified by the considerably safer endocannabinoids (47) and the natural compounds found in saffron (48).

All the above compounds are effective in ameliorating social defeat in rats and mice (ie 49, 50), the cannabinoids have been specifically shown to down-regulate the CDR (49), and all of them are used to treat clinical depression and anxiety states. I have had some involvement with the validated extract Affron, which I happily recommend; together with physical exercise which supports the hippocampus and is anti-depressant (51-53) even under lockdown (54), and in defeated mice (55).

Innate immune cells are key players in the development of social defeat (56, 57). These include monocytes, which carry stress signals between the brain and the rest of the immune system (58) and the brain’s own immune cells, the microglia (59).

This suggests that a traditional diet, rich in antioxidants and anti-inflammatory compounds, will help to prevent social stress-induced depression – and clinical reality reflects this (60-63). 

I particularly enjoyed the Parletta et al study (60), which has input from the redoubtable Kerin O’Dea. I would add the 1-3, 1-6 beta glucans, which enhance innate immune cell function and in addition to reducing infection, reliably improve mood (ie 64, 65); and the prebiotic fibers (66).

Now for the bad news.

While a pre-transitional (traditional) diet supports resilience, by supporting a healthy hippocampus and creating a generally anti-inflammatory metabolism, the modern diet has the opposite effect. By creating chronic inflammation, dysbiosis and Type B malnutrition, it makes social defeat more likely.

The modern diet explains why PTSD, depression, anxiety and the neurodegenerative diseases are all trending up (67, 68). These and the other ‘diseases of civilization’ create medical dependence, leaving us at the toxic and not-so-tender mercies of Big Pharma, and even more disenfranchised. We are all Okies now.

In generations past, oppression generally bred subversion. Resilient individuals twisted, resisted and desisted from tyranny and tyrants always fell, eventually. Tyranny now comes increasingly in digital and fake news form, and can be hard to see let alone counter. At the same time we microserfs are becoming more malnourished, more medicated. more chronically inflamed, more prone to social defeat and less able to resist a Googleboot stamping on the human face, forever.

Cutting down on ultra-processed food, learning to cook and taking more exercise have become truly revolutionary activities.

The world’s 8 richest people:

1. Bill Gates: America founder of Microsoft (net worth $75 billion)

2. Amancio Ortega: Spanish founder of Inditex which owns the Zara fashion chain (net worth $67 billion)

3. Warren Buffett: American CEO and largest shareholder in Berkshire Hathaway (net worth $60.8 billion)

4. Carlos Slim Helu: Mexican owner of Grupo Carso (net worth: $50 billion)

5. Jeff Bezos: American founder, chairman and chief executive of Amazon (net worth: $45.2 billion)

6. Mark Zuckerberg: American chairman, chief executive officer, and co-founder of Facebook (net worth $44.6 billion)

7. Larry Ellison: American co-founder and CEO of Oracle (net worth $43.6 billion)

8. Michael Bloomberg: American founder, owner and CEO of Bloomberg LP (net worth: $40 billion)

Next week: a Konsideration of Konsciousness, Ketamine, Kellogs, the dawning of SkyNet and how to prune your memory bank.

References:

1. https://www.oxfam.org/en/press-releases/worlds-billionaires-have-more-wealth-46-billion-people

2. https://oi-files-d8-prod.s3.eu-west-2.amazonaws.com/s3fs-public/file_attachments/bp-economy-for-99-percent-160117-en.pdf

3. Chin V, Ioannidis JPA, Tanner MA, Cripps S. Effects of non-pharmaceutical interventions on COVID-19: A Tale of Three Models. medRxiv. doi: https://doi.org/10.1101/2020.07.22.20160341

4. https://wellbeingtrust.org/areas-of-focus/policy-and-advocacy/reports/projected-deaths-of-despair-during-covid-19/#:~:text=Alongside%20the%20thousands%20of%20deaths,Center%20for%20Policy%20Studies%20in

5. Woodley MA, Nijenhuis JT, Murphy R. Were the Victorians cleverer than us? The decline in general intelligence estimated from a meta-analysis of the slowing of simple reaction time. Intelligence 41(6), Nov–Dec 2013, pp 843-850

6. Pietschnig J, Gittler G. A reversal of the Flynn effect for spatial perception in German-speaking countries; Evidence from a cross-temporal IRT-based meta-analysis (1977-2014). Intelligence 53, Nov–Dec 2015, pp 145-153

7. Graves LV, Drozdick L, Courville T, Farrer TJ, Gilbert PE, Delis DC. Cohort differences on the CVLT-II and CVLT3: evidence of a negative Flynn effect on the attention/working memory and learning trials. Clin Neuropsychol. 2019 Dec 12:1-18.

8. Woodley MA, Nijenhuis JT, Murphy R. Is there a dysgenic secular trend towards slowing simple reaction time? Responding to a quartet of critical commentaries. Intelligence (46), September–October 2014, pp 131-147

9. Beilharz JE, Maniam J, Morris MJ. Short-term exposure to a diet high in fat and sugar, or liquid sugar, selectively impairs hippocampal-dependent memory, with differential impacts on inflammation. Behav Brain Res. 2016 Jun 1;306:1-7.

10. Jena PK, Sheng L, Di Lucente J, Jin LW, Maezawa I, Wan YY. Dysregulated bile acid synthesis and dysbiosis are implicated in Western diet-induced systemic inflammation, microglial activation, and reduced neuroplasticity. FASEB J. 2018 May;32(5):2866-2877.

11. Treadway M, Cooper JA, Miller AH. Can’t or won’t? Immunometabolic constraints on dopaminergic drive. Trends in Cognitive Sciences 2019, May 1, 435-448 (Review)

12.  Felger JC, Treadway MT. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine. Neuropsychopharmacology. 2017 Jan;42(1):216-241. 

13.  Felger JC. The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications. Curr Top Behav Neurosci. 2017;31:199-219.

14.  Furuyashiki T, Kitaoka S. Neural mechanisms underlying adaptive and maladaptive consequences of stress: roles of dopaminergic and inflammatory responses. Psychiatry Clin Neurosci. 2019 Jun 19. doi: 10.1111/pcn.12901. [Epub ahead of print] Review.

15.  Kohler O, Krogh J, Mors O, Benros ME. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr Neuropharmacol. 2016;14(7):732-42.

16.  Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: depression fans the flames and feasts on the heat. Am J Psychiatry. 2015 Nov 1;172(11):1075-91. 

17.  Majd M, Saunders EFH, Engeland CG. Inflammation and the Dimensions of Depression: A Review. Front Neuroendocrinol. 2019 Oct 22:100800.

18. Jacka FN, Cherbuin N, Anstey KJ, Sachdev P, Butterworth P. Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med. 2015 Sep 8;13:215.

19. Akbaraly T, Sexton C, Zsoldos E, Mahmood A, Filippini N, Kerleau C, Verdier JM, Virtanen M, Gabelle A, Ebmeier KP, Kivimaki M. Association of Long-Term Diet Quality with Hippocampal Volume: Longitudinal Cohort Study. Am J Med. 2018 Nov;131(11):1372-1381.e4.

20. Lindqvist A, Mohapel P, Bouter B, Frielingsdorf H, Pizzo D, Brundin P, Erlanson-Albertsson C. High-fat diet impairs hippocampal neurogenesis in male rats. Eur J Neurol. 2006 Dec;13(12):1385-8.

21. Stangl D, Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes Nutr. 2009 Dec; 4(4): 271–282.

22. Martínez Leo EE, Segura Campos MR. Effect of ultra-processed diet on gut microbiota and thus its role in neurodegenerative diseases. Nutrition. 2020 Mar;71:110609.

23. Camicioli R, Moore MM, Kinney A, Corbridge E, Glassberg K, Kaye JA. Parkinson’s disease is associated with hippocampal atrophy. Mov Disord. 2003 Jul;18(7):784-90.

24. Zhu Y, Klomparens EA, Guo S, Geng X. Neuroinflammation caused by mental stress: the effect of chronic restraint stress and acute repeated social defeat stress in mice. Neurol Res. 2019 Aug;41(8):762-769.

25. Hollis F, Kabbaj M. Social defeat as an animal model for depression. ILAR J. 2014;55(2):221-32.

26. Tornatzky W, Miczek KA. Long-term impairment of autonomic circadian rhythms after brief intermittent social stress. Physiol Behav. 1993 May;53(5):983-93.

27. Liu YY, Zhou XY, Yang LN, Wang HY, Zhang YQ, Pu JC, Liu LX, Gui SW, Zeng L, Chen JJ, Zhou CJ, Xie P. Social defeat stress causes depression-like behavior with metabolite changes in the prefrontal cortex of rats. PLoS One. 2017 Apr 28;12(4):e0176725.

28. Covington HE 3rd, Miczek KA. Repeated social-defeat stress, cocaine or morphine. Effects on behavioral sensitization and intravenous cocaine self-administration “binges”. Psychopharmacology (Berl). 2001 Dec;158(4):388-98.

29. García-Pardo MP, Blanco-Gandía MC, Valiente-Lluch M, Rodríguez-Arias M, Miñarro J, Aguilar MA. Long-term effects of repeated social stress on the conditioned place preference induced by MDMA in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Dec 3;63:98-109.

30. Deal AL, Konstantopoulos JK, Weiner JL, Budygen EA. Exploring the consequences of social defeat stress and intermittent ethanol drinking on dopamine dynamics in the rat nucleus accumbens. Sci Rep 8, 332 (2018).

31. Newman EL, Albrechet-Souza L, Andrew PM, Auld JG, Burk KC, Hwa LS, Zhang EY, DeBold JF, Miczek KA. Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism. Psychopharmacology (Berl). 2018 Jun;235(6):1807-1820.

32. Newman EL, Leonard MZ, Arena DT, de Almeida RMM, Miczek KA. Social defeat stress and escalation of cocaine and alcohol consumption: Focus on CRF. Neurobiol Stress. 2018 Sep 19;9:151-165.

33. Carnevali L, Mastorci F, Audero E, Graiani G, Rossi S, Macchi E, Callegari S, Bartolomucci A, Nalivaiko E, Quaini F, Gross C, Sgoifo A. Stress-induced susceptibility to sudden cardiac death in mice with altered serotonin homeostasis. PLoS One. 2012;7(7):e41184.

34. Brouillard C, Carrive P, Sévoz-Couche C. Social defeat: Vagal reduction and vulnerability to ventricular arrhythmias. Neurobiol Stress. 2020 Aug 3;13:100245.

35. Golding JM. Intimate partner violence as a risk factor for mental disorders: a meta-analysis. J Fam Violence. 1999;14(2):99–132.

36. Oram S, Trevillion K, Feder G, Howard LM. Prevalence of experiences of domestic violence among psychiatric patients: systematic review. Br J Psychiatry. 2013 Feb; 202():94-9.

37. Jia H, Lubetkin EI. Impact of adverse childhood experiences on quality-adjusted life expectancy in the U.S. population. Child Abuse Negl. 2020 Apr;102:104418.

38. Brown DW, Anda RF, Tiemeier H, Felitti VJ, Edwards VJ, Croft JB, Giles WH. Adverse childhood experiences and the risk of premature mortality. Am J Prev Med. 2009 Nov;37(5):389-96.

39. McKim DB, Niraula A, Tarr AJ, Wohleb ES, Sheridan JF, Godbout JP. Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat. J Neurosci. 2016 Mar 2;36(9):2590-604. 

40. Pfau ML, Russo SJ. Neuroinflammation Regulates Cognitive Impairment in Socially Defeated Mice. Trends Neurosci. 2016 Jun;39(6):353-355. 

41. Weber MD, Frank MG, Tracey KJ, Watkins LR, Maier SF. Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J Neurosci. 2015 Jan 7;35(1):316-24.

42. Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014 May;16:7-17.

43. Zhou Z, Liu X, Chen S, Zhang Z, Liu Y, Montardy Q, Tang Y, Wei P, Liu N, Li L, Song R, Lai J, He X, Chen C, Bi G, Feng G, Xu F, Wang L. A VTA GABAergic Neural Circuit Mediates Visually Evoked Innate Defensive Responses. Neuron. 2019 Aug 7;103(3):473-488.e6.

44. Deng SL, Hu ZL, Mao L, Gao B, Yang Q, Wang F, Chen JG. The effects of Kctd12, an auxiliary subunit of GABAB receptor in dentate gyrus on behavioral response to chronic social defeat stress in mice. Pharmacol Res. 2021 Jan;163:105355.

45. Treven M, Koenig X, Assadpour E, Gantumur E, Meyer C, Hilber K, Boehm S, Kubista H. The anticonvulsant retigabine is a subtype selective modulator of GABAA receptors. Epilepsia. 2015 Apr;56(4):647-57.

46. Silberbauer LR, Spurny B, Handschuh P, Klöbl M, Bednarik P, Reiter B, Ritter V, Trost P, Konadu ME, Windpassinger M, Stimpfl T, Bogner W, Lanzenberger R, Spies M. Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study. Front Psychiatry. 2020 Sep 8;11:549903.

47. Hirono M, Yanagawa Y. Endocannabinoids regulate cerebellar GABAergic transmission in a synapse type-dependent manner. J Neurosci Res. 2020 Dec 3. doi: 10.1002/jnr.24765. Epub ahead of print.

48. Pitsikas N, Tarantilis PA. The GABAA-Benzodiazepine Receptor Antagonist Flumazenil Abolishes the Anxiolytic Effects of the Active Constituents of Crocus sativus L. Crocins in Rats. Molecules. 2020 Nov 30;25(23):5647.

49. Lisboa SF, Niraula A, Resstel LB, Guimaraes FS, Godbout JP, Sheridan JF. Repeated social defeat-induced neuroinflammation, anxiety-like behavior and resistance to fear extinction were attenuated by the cannabinoid receptor agonist WIN55,212-2. Neuropsychopharmacology. 2018 Aug;43(9):1924-1933.

50. Mishra PK, Kumar A, Behar KL, Patel AB. Subanesthetic ketamine reverses neuronal and astroglial metabolic activity deficits in a social defeat model of depression. J Neurochem. 2018 Sep;146(6):722-734.

51. Kingston RC, Smith M, Lacey T, Edwards M, Best JN, Markham CM. Voluntary exercise increases resilience to social defeat stress in Syrian hamsters. Physiol Behav. 2018 May 1;188:194-198.

52. Gourgouvelis J, Yielder P, Murphy B. Exercise Promotes Neuroplasticity in Both Healthy and Depressed Brains: An fMRI Pilot Study. Neural Plast. 2017;2017:8305287.

53. Cooney GM, Dwan K, Greig CA, Lawlor DA, Rimer J, Waugh FR, McMurdo M, Mead GE. Exercise for depression. Cochrane Database Syst Rev. 2013 Sep 12; (9):CD004366.

54. Carlos AF, Poloni TE, Caridi M, Pozzolini M, Vaccaro R, Rolandi E, Cirrincione A, Pettinato L, Vitali SF, Tronconi L, Ceroni M, Guaita A. Life during COVID-19 lockdown in Italy: the influence of cognitive state on psychosocial, behavioral and lifestyle profiles of older adults. Aging Ment Health. 2021 Jan 15:1-10.

55. Reguilón MD, Ferrer-Pérez C, Ballestín R, Miñarro J, Rodríguez-Arias M. Voluntary wheel running protects against the increase in ethanol consumption induced by social stress in mice. Drug Alcohol Depend. 2020 Jul 1;212:108004.

56. Ramirez K, Fornaguera-Trías J, Sheridan JF. Stress-Induced Microglia Activation and Monocyte Trafficking to the Brain Underlie the Development of Anxiety and Depression. Curr Top Behav Neurosci. 2017;31:155-172.

57. Reader BF, Jarrett BL, McKim DB, Wohleb ES, Godbout JP, Sheridan JF. Peripheral and central effects of repeated social defeat stress: monocyte trafficking, microglial activation, and anxiety. Neuroscience. 2015 Mar 19;289:429-42.

58. Weber MD, Godbout JP, Sheridan JF. Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal. Neuropsychopharmacology. 2017 Jan;42(1):46-61.

59. Lehmann ML, Weigel TK, Poffenberger CN, Herkenham M. The Behavioral Sequelae of Social Defeat Require Microglia and Are Driven by Oxidative Stress in Mice. J Neurosci. 2019 Jul 10;39(28):5594-5605.

60. Parletta N, Zarnowiecki D, Cho J, Wilson A, Bogomolova S, Villani A, Itsiopoulos C, Niyonsenga T, Blunden S, Meyer B, Segal L, Baune BT, O’Dea K. A Mediterranean-style dietary intervention supplemented with fish oil improves diet quality and mental health in people with depression: A randomized controlled trial (HELFIMED). Nutr Neurosci. 2019 Jul; 22(7):474-487.

61. Jacka FN, O’Neil A, Opie R, Itsiopoulos C, Cotton S, Mohebbi M, Castle D, Dash S, Mihalopoulos C, Chatterton ML, Brazionis L, Dean OM, Hodge AM, Berk M. A randomised controlled trial of dietary improvement for adults with major depression (the ‘SMILES’ trial). BMC Med. 2017 Jan 30; 15(1):23.

62. Bayes J, Schloss J, Sibbritt D. Effects of Polyphenols in a Mediterranean Diet on Symptoms of Depression: A Systematic Literature Review. Adv Nutr. 2020 May 1; 11(3):602-615.

63. García-Toro M, Vicens-Pons E, Gili M, Roca M, Serrano-Ripoll MJ, Vives M, Leiva A, Yáñez AM, Bennasar-Veny M, Oliván-Blázquez B. Obesity, metabolic syndrome and Mediterranean diet: Impact on depression outcome. J Affect Disord. 2016 Apr; 194():105-8.

64. Talbott S, Talbott J. Effect of Beta 1, 3/1, 6 Glucan on Upper Respiratory Tract Infection Symptoms and Mood State in Marathon Athletes. J Sports Sci Med. 2009 Dec 1;8(4):509-15. 

65. Zabriskie HA, Blumkaitis JC, Moon JM, Currier BS, Stefan R, Ratliff K, Harty PS, Stecker RA, Rudnicka K, Jäger R, Roberts MD, Young K, Jagim AR, Kerksick CM. Yeast Beta-Glucan Supplementation Downregulates Markers of Systemic Inflammation after Heated Treadmill Exercise. Nutrients. 2020 Apr 19;12(4):1144.

66. Kennedy PJ, Cryan JF, Dinan TG, Clarke G. Kynurenine pathway metabolism and the microbiota-gut-brain axis. Neuropharmacology. 2017 Jan;112(Pt B):399-412.

67. https://www.mhanational.org/issues/state-mental-health-america

68. https://www.alz.org/alzheimers-dementia/facts-figures