Abstract
Background
Studies have suggested that chronic social stress specifically downregulates endothelial
tight junction protein expression in the nucleus accumbens (NAc), thus increasing
blood-brain barrier (BBB) permeability and promoting depression-like behaviors. However,
the molecular mechanism underlying the reduction in tight junction protein, particularly
in the NAc, is largely uncharacterized.
Methods
We performed comparative metabolomic profiling of the nucleus accumbens, prefrontal
cortex, and hippocampus of social defeat–stressed mice to identify the molecular events
that mediate BBB breakdown.
Results
We identified the levels of cyclic adenosine monophosphate (cAMP) that were specifically
reduced in the NAc and positively correlated with the degree of social avoidance.
Replenishing cAMP in the NAc was sufficient to improve BBB integrity and depression-like
behaviors. We further found that cAMP levels were markedly decreased in neurons of
the NAc, rather than in endothelial cells, astrocytes, or microglia. RNA-sequencing
data showed that adenylate cyclase 5 (Adcy5), an enzyme responsible for the synthesis
of cAMP from adenosine triphosphate (ATP), was predominantly expressed in the NAc;
it also resided exclusively in neurons. Endogenous modulation of cAMP synthesis in
neurons through the knockdown of Adcy5 in the NAc regulated the sensitivity to social
stress. Moreover, deficient neuronal cAMP production in the NAc decreased the expression
of reelin, while supplementary injection of exogenous reelin into the NAc promoted
BBB integrity and ameliorated depression-like behaviors.
Conclusions
Chronic social stress diminished cAMP synthesis in neurons, thus damaging BBB integrity
in the NAc and promoting stress vulnerability. These results characterize neuron-produced
cAMP in the NAc as a biological mechanism of neurovascular pathology in social stress.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Biological PsychiatryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cross-national epidemiology of DSM-IV major depressive episode.BMC Med. 2011; 9: 90
- Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1789-1858
- Ketamine: A paradigm shift for depression research and treatment.Neuron. 2019; 101: 774-778
- Addressing the burden of mental, neurological, and substance use disorders: Key messages from Disease Control Priorities, 3rd edition.Lancet. 2016; 387: 1672-1685
- Inflammation-induced depression: Its pathophysiology and therapeutic implications.J Neuroimmunol. 2017; 313: 92-98
- Inflamed depression.Lancet. 2018; 392: 1189-1190
- From inflammation to sickness and depression: when the immune system subjugates the brain.Nat Rev Neurosci. 2008; 9: 46-56
- Anti-inflammatory treatments for mood disorders: Systematic review and meta-analysis.J Psychopharmacol. 2017; 31: 1137-1148
- Inflammation and vascular remodeling in the ventral hippocampus contributes to vulnerability to stress.Transl Psychiatry. 2017; 7e1160
- Repeated social defeat, neuroinflammation, and behavior: Monocytes carry the signal.Neuropsychopharmacology. 2017; 42: 46-61
- Social stress induces neurovascular pathology promoting depression.Nat Neurosci. 2017; 20: 1752-1760
- Social defeat induces depressive-like states and microglial activation without involvement of peripheral macrophages.J Neuroinflammation. 2016; 13: 224
- The brain reward circuitry in mood disorders.Nat Rev Neurosci. 2013; 14: 609-625
- The mesolimbic dopamine reward circuit in depression.Biol Psychiatry. 2006; 59: 1151-1159
- A standardized protocol for repeated social defeat stress in mice.Nat Protoc. 2011; 6: 1183-1191
- Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions.Cell. 2007; 131: 391-404
- Using the rat forced swim test to assess antidepressant-like activity in rodents.Nat Protoc. 2012; 7: 1009-1014
- Extraction and GC/MS analysis of the human blood plasma metabolome.Anal Chem. 2005; 77: 8086-8094
- Metabolomics-proteomics combined approach identifies differential metabolism-associated molecular events between senescence and apoptosis.J Proteome Res. 2017; 16: 2250-2261
- Orally administered crocin protects against cerebral ischemia/reperfusion injury through the metabolic transformation of crocetin by gut microbiota.Front Pharmacol. 2019; 10: 440
- Cell-type-specific role of delta FosB in nucleus accumbens in modulating intermale aggression.J Neurosci. 2018; 38: 5913-5924
- Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency.Mol Psychiatry. 2017; 22: 961-971
- Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse.J Psychopharmacol. 2013; 27: 386-395
- Isolation and culture of brain microvascular endothelial cells for in vitro blood-brain barrier studies.Methods Mol Biol. 2018; 1727: 315-331
- Integrated metabolomics and genomics: systems approaches to biomarkers and mechanisms of cardiovascular disease.Circ Cardiovasc Genet. 2015; 8: 410-419
- An integrative systems genetic analysis of mammalian lipid metabolism.Nature. 2019; 567: 187-193
- Live single cell mass spectrometry reveals cancer-specific metabolic profiles of circulating tumor cells.Cancer Sci. 2019; 110: 697-706
- Altered plasma arginine metabolome precedes behavioural and brain arginine metabolomic profile changes in the APPswe/PS1DeltaE9 mouse model of Alzheimer’s disease.Transl Psychiatry. 2018; 8: 108
- Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and -independent pathways.Exp Cell Res. 2003; 290: 275-288
- Thr(207) of claudin-5 is involved in size-selective loosening of the endothelial barrier by cyclic AMP.Exp Cell Res. 2004; 300: 202-212
- Molecular architecture of the mouse nervous system.Cell. 2018; 174: 999-1014.e1022
- Lateral diffusion of Gαs in the plasma membrane is decreased after chronic but not acute antidepressant treatment: Role of lipid raft and non-raft membrane microdomains.Neuropsychopharmacology. 2015; 40: 766-773
- Lipid raft microdomains and neurotransmitter signalling.Nat Rev Neurosci. 2007; 8: 128-140
- Endothelial Dab1 signaling orchestrates neuro-glia-vessel communication in the central nervous system.Science. 2018; 361
- Extracellular matrix and matrix receptors in blood-brain barrier formation and stroke.Dev Neurobiol. 2011; 71: 1018-1039
2004 Allen Institute for Brain Science. Allen Mouse Brain Atlas. Available at: mouse.brain-map.org. Accessed September 28, 2018.
- cAMP signaling in brain is decreased in unmedicated depressed patients and increased by treatment with a selective serotonin reuptake inhibitor.Mol Psychiatry. 2017; 22: 754-759
- Ablation of type III adenylyl cyclase in mice causes reduced neuronal activity, altered sleep pattern, and depression-like phenotypes.Biol Psychiatry. 2016; 80: 836-848
- Depression and adenylyl cyclase: Sorting out the signals.Biol Psychiatry. 2016; 80: 812-814
- Abnormality of the blood-cerebrospinal fluid barrier of patients suffering from a depressive illness.J Neurol Neurosurg Psychiatry. 1960; 23: 156-161
- Altered choroid plexus gene expression in major depressive disorder.Front Hum Neurosci. 2014; 8: 238
- Decoding microglia responses to psychosocial stress reveals blood-brain barrier breakdown that may drive stress susceptibility.Sci Rep. 2018; 8: 11240
- CSD, BBB and MMP-9 elevations: Animal experiments versus clinical phenomena in migraine.Expert Rev Neurother. 2009; 9: 1595-1614
- Aberrant expression of collagen gene family in the brain regions of male mice with behavioral psychopathologies induced by chronic agonistic interactions.Biomed Res Int. 2019; 20197276389
- Adult neurogenesis, glia, and the extracellular matrix.Cell Stem Cell. 2019; 24: 690-705
- Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway.Mol Psychiatry. 2014; 19: 417-426
- Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats.Sci Transl Med. 2017; 9
- The role of ventral striatal cAMP signaling in stress-induced behaviors.Nat Neurosci. 2015; 18: 1094-1100
- NMDAR-independent, cAMP-dependent antidepressant actions of ketamine.Mol Psychiatry. 2019; 24: 1833-1843
- The interface of depression and cardiovascular disease: Therapeutic implications.Ann N Y Acad Sci. 2015; 1345: 25-35
- Depression and coronary heart disease.Nat Rev Cardiol. 2017; 14
- Individual differences in the neurobiology of social stress: implications for depression-cardiovascular disease comorbidity.Curr Neuropharmacol. 2014; 12: 205-211
Article info
Publication history
Published online: October 07, 2019
Accepted:
September 21,
2019
Received in revised form:
September 9,
2019
Received:
June 5,
2019
Identification
Copyright
© 2019 Society of Biological Psychiatry.
