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Social phobia - neurophysiological correlates


Social phobia - neurophysiological correlates

Mice that repeatedly experienced aggression from conspecifics developed a lifelong social phobia. This could be remedied by:

  • Elimination of BDNF in the VTA / nucleus accumbens pathway1
  • Permanent administration of antidepressants (fluoxetine)1
  • Single administration of ketamine, but less Rabastinel2
    • This also indicates the importance of BDNF in socially triggered stress

BDNF withdrawal in the VTA / nucleus accumbens pathway appears to have an antidepressant effect,34 5 , while conversely in the hippocampus BDNF administration has an antidepressant effect, antidepressants slowly increase BDNF in the hippocampus and ketamine rapidly increases BDNF in the hippocampus.6

Abnormalities in the social reward circuitry appear to contribute to the social deficit in ASD.
The social reward circuit consists mainly of:7

  • basolateral amygdala (blA)
  • Nucleus accumbens (Nac)
  • dorsal anterior cingulate cortex (dACC)
  • Hypothalamus
  • Midbrain

ASD sufferers show reduced activity in the reward circuit blA / Nac.8
An increase in 2-arachidonoylglycerol (2-AG, an endocannabinoid signal) appears to reduce presynaptic glutamate release in the blA / Nac signaling pathway. This alleviated social avoidance in Shank3-/- model mice.9
Vitamin D deficiency correlated with a reduced expression of cannabinoid receptors in the spinal cord and of 2-AG in the intestine of mice.10
Vitamin D receptors are found almost everywhere in the brain, including in the brain regions of the social reward circuit.
It is possible that vitamin D modulates the amount of 2-AG in the blA-Nac circuit and thus the ASD symptom of social withdrawal7

A lack of empathy is an important characteristic of ASD and impairs social functions.
The ACC-blA circuit, among others, is involved in emotional empathy.11
Children with ASD show reduced connectivity between the amygdala and ACC, the extent of which correlated with the degree of social deficits.12
Like almost all brain regions, blA and ACC also express vitamin D receptors and vitamin D deficiency correlated with a thinner ACC.
It is possible that vitamin D deficiency could affect the morphology of the ACC and thus contribute to a lack of emotional empathy.7

  1. Berton, McClung, Dileone, Krishnan, Renthal, Russo, Graham, Tsankova, Bolanos, Rios, Monteggia, Self, Nestler (2006): Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science. 2006 Feb 10;311(5762):864-8. doi: 10.1126/science.1120972. PMID: 16469931.

  2. Yang, Zhang, Han, Yao, Yang, Ren, Ma, Chen, Hashimoto (2016): Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression. Psychopharmacology (Berl). 2016 Oct;233(19-20):3647-57. doi: 10.1007/s00213-016-4399-2. PMID: 27488193; PMCID: PMC5021744.

  3. Wang, Fanous, Terwilliger, Bass, Hammer, Nikulina (2013): BDNF overexpression in the ventral tegmental area prolongs social defeat stress-induced cross-sensitization to amphetamine and increases ΔFosB expression in mesocorticolimbic regions of rats. Neuropsychopharmacology. 2013 Oct;38(11):2286-96. doi: 10.1038/npp.2013.130. PMID: 23689674; PMCID: PMC3773680.

  4. Eisch, Bolaños, de Wit, Simonak, Pudiak, Barrot, Verhaagen, Nestler (2003): Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry. 2003 Nov 15;54(10):994-1005. doi: 10.1016/j.biopsych.2003.08.003. PMID: 14625141.

  5. Wang, Bina, Wingard, Terwilliger, Hammer, Nikulina (2014): Knockdown of tropomyosin-related kinase B receptor expression in the nucleus accumbens shell prevents intermittent social defeat stress-induced cross-sensitization to amphetamine in rats. Eur J Neurosci. 2014 Mar;39(6):1009-1017. doi: 10.1111/ejn.12464. PMID: 24354924.

  6. Duman, Deyama, Fogaça (2021): Role of BDNF in the pathophysiology and treatment of depression: Activity-dependent effects distinguish rapid-acting antidepressants. Eur J Neurosci. 2021 Jan;53(1):126-139. doi: 10.1111/ejn.14630. PMID: 31811669; PMCID: PMC7274898. REVIEW

  7. Ye X, Zhou Q, Ren P, Xiang W, Xiao L. The Synaptic and Circuit Functions of Vitamin D in Neurodevelopment Disorders. Neuropsychiatr Dis Treat. 2023 Jul 3;19:1515-1530. doi: 10.2147/NDT.S407731. PMID: 37424961; PMCID: PMC10327924. REVIEW

  8. Dichter GS, Felder JN, Green SR, Rittenberg AM, Sasson NJ, Bodfish JW (2012): Reward circuitry function in autism spectrum disorders. Soc Cogn Affect Neurosci. 2012 Feb;7(2):160-72. doi: 10.1093/scan/nsq095. PMID: 21148176; PMCID: PMC3277365.

  9. Folkes OM, Báldi R, Kondev V, Marcus DJ, Hartley ND, Turner BD, Ayers JK, Baechle JJ, Misra MP, Altemus M, Grueter CA, Grueter BA, Patel S (2020): An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability. J Clin Invest. 2020 Apr 1;130(4):1728-1742. doi: 10.1172/JCI131752. PMID: 31874107; PMCID: PMC7108917.

  10. Guida F, Boccella S, Belardo C, Iannotta M, Piscitelli F, De Filippis F, Paino S, Ricciardi F, Siniscalco D, Marabese I, Luongo L, Ercolini D, Di Marzo V, Maione S (2020): Altered gut microbiota and endocannabinoid system tone in vitamin D deficiency-mediated chronic pain. Brain Behav Immun. 2020 Mar;85:128-141. doi: 10.1016/j.bbi.2019.04.006. PMID: 30953765.

  11. Kim SW, Kim M, Baek J, Latchoumane CF, Gangadharan G, Yoon Y, Kim DS, Lee JH, Shin HS (2023): Hemispherically lateralized rhythmic oscillations in the cingulate-amygdala circuit drive affective empathy in mice. Neuron. 2023 Feb 1;111(3):418-429.e4. doi: 10.1016/j.neuron.2022.11.001. Epub 2022 Dec 1. PMID: 36460007.

  12. Bartolotti J, Sweeney JA, Mosconi MW (2020): Functional brain abnormalities associated with comorbid anxiety in autism spectrum disorder. Dev Psychopathol. 2020 Oct;32(4):1273-1286. doi: 10.1017/S0954579420000772. PMID: 33161905; PMCID: PMC8081066.

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