CoChat
Sign Up
PreprintCited by 30Neurotransmitter Receptor Influence on BehaviorStress Responses and CortisolMemory and Neural Mechanisms

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Long-term impact of early life stress on serotonin connectivity

Open access
Ramkumar, Raksha, Edge-Partington, Moriah, Adigun, Kabirat, Ren, Yi, Terstege, Dylan J, Khan, Nazmus S, Rouhi, Nahid, Jamani, Naila F, Tsutsui, Mio, Epp, Jonathan R, Sargin, Derya·2023·Biological Psychiatry
DOI 10.1101/2023.08.01.551573

Preprint — published as 10.1016/j.biopsych.2024.01.024 · Paper page

Open this paper in CoChat — free accountOpen PDF

Abstract

Chronic childhood stress is a prominent risk factor for developing mood disorders, yet mechanisms underlying this association remain unclear. Serotonin (5-HT) plays a crucial role in neurodevelopment and vulnerability to mood disorders. Maintenance of optimal 5-HT levels during early postnatal development is critical for the maturation of brain circuits. Developmental stress can alter the serotonin system, leading to chronic behavioral deficits. Yet, our understanding of the long-term impact of early life stress (ELS) on serotonin connectivity remains incomplete. Using a mouse model of chronic developmental stress, we sought to determine how ELS impacts brain-wide serotonin activity and behavior in adulthood. We established that adult female and male mice exposed to ELS during the first postnatal week show heightened anxiety-like behavior. Using in vivo fiber photometry and c-fos dependent activity mapping, we found that ELS enhances susceptibility to acute stress by disrupting the brain-wide functional connectivity of the raphe nucleus and the activity of dorsal raphe serotonin neuron population, in conjunction with a profound increase in the orbitofrontal cortex (OFC) activity. We further identified that 5-HT release in the medial OFC during environmental challenge is disrupted in mice exposed to ELS. Optogenetic stimulation of 5-HT terminals in the mOFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner. Our findings hold significant insight into the mechanisms underlying long-term brain connectivity deficits induced by ELS, with potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1101/2023.08.01.551573

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 71

  1. 2019, The Effect of Early Life Stress on Adult Psychiatric Disorders, Innov. Clin. Neurosci, 16, 35
  2. 10.1097/NMD.0000000000000049 · DOI · Paper page
  3. Syed, S. A. & Nemeroff, C. B. Early Life Stress, Mood, and Anxiety Disorders. Chronic Stress (Thousand Oaks) 1, (2017). · DOI
  4. 10.1016/j.neuron.2016.01.019 · DOI · Paper page
  5. 2015, The Intergenerational Transmission of Anxiety: A Children-of-Twins Study, AJP, 172, 630, 10.1176/appi.ajp.2015.14070818 · DOI
  6. 10.1038/npp.2015.252 · DOI · Paper page
  7. 2020, Early Childhood Parenting Predicts Late Childhood Brain Functional Connectivity During Emotion Perception and Reward Processing, Child Dev, 91, 110, 10.1111/cdev.13126 · DOI
  8. 10.1037/a0024892 · DOI · Paper page
  9. 10.1016/j.jad.2003.12.013 · DOI · Paper page
  10. 10.1016/S0006-3223(03)00231-2 · DOI · Paper page
  11. 10.1038/nrn2639 · DOI · Paper page
  12. 10.1037/0033-2909.128.2.230 · DOI
  13. 10.1016/j.biopsych.2010.05.028 · DOI · Paper page
  14. 2016, Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks, Neuropsychopharmacology, 41, 197, 10.1038/npp.2015.181 · DOI · Paper page
  15. 10.3389/fnbeh.2018.00114 · DOI
  16. 10.1007/s00213-010-2009-2 · DOI · Paper page
  17. 10.1016/S0149-7634(03)00007-1 · DOI · Paper page
  18. 10.1016/j.neuroscience.2006.04.036 · DOI · Paper page
  19. 10.1038/nrn1256 · DOI · Paper page
  20. 10.1016/S0074-7742(04)59006-2 · DOI
  21. 10.1016/0165-3806(88)90163-0 · DOI
  22. 10.1016/j.neuroscience.2006.12.007 · DOI
  23. 10.1016/j.bbr.2006.08.002 · DOI
  24. 2014, Early-life stress induces persistent alterations in 5-HT1A receptor and serotonin transporter mRNA expression in the adult rat brain, Front. Mol. Neurosci, 7, 24
  25. 10.1523/JNEUROSCI.3245-10.2010 · DOI
  26. 10.1176/appi.ajp.162.9.1658 · DOI
  27. 10.1073/pnas.1416065112 · DOI
  28. 10.1098/rstb.2012.0223 · DOI · Paper page
  29. 10.1126/science.1101678 · DOI · Paper page
  30. 10.1038/mp.2014.10 · DOI
  31. 2012, The influence of neonatal serotonin depletion on emotional and exploratory behaviours in rats, Behav. Brain Res, 226, 87, 10.1016/j.bbr.2011.08.030 · DOI
  32. Ren, J. et al. Single-cell transcriptomes and whole-brain projections of serotonin neurons in the mouse dorsal and median raphe nuclei. Elife 8, (2019). · DOI · Paper page
  33. 2016, Conditional anterograde tracing reveals distinct targeting of individual serotonin cell groups (B5-B9) to the forebrain and brainstem, Brain Struct. Funct, 221, 535, 10.1007/s00429-014-0924-4 · DOI · Paper page
  34. 10.1038/s41583-019-0151-3 · DOI · Paper page
  35. 2022, Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors, Neuron, 110, 2664, 10.1016/j.neuron.2022.05.015 · DOI
  36. 2019, Serotonin Regulation of the Prefrontal Cortex: Cognitive Relevance and the Impact of Developmental Perturbation, ACS Chem. Neurosci, 10, 3078, 10.1021/acschemneuro.9b00073 · DOI · Paper page
  37. 10.1152/jn.00507.2009 · DOI
  38. 10.1016/j.cell.2018.07.043 · DOI · Paper page
  39. 10.1038/ncomms10503 · DOI
  40. 10.1016/j.neuron.2014.02.010 · DOI · Paper page
  41. 10.1126/science.aau8722 · DOI
  42. 2022, Early life adversity shapes neural circuit function during sensitive postnatal developmental periods, Transl. Psychiatry, 12, 1
  43. 10.1080/10253890.2017.1343296 · DOI
  44. 2021, Floating Rodents and Stress-Coping Neurobiology, Biol. Psychiatry, 90, e19, 10.1016/j.biopsych.2021.04.003 · DOI
  45. 2016, Alterations in amygdala-prefrontal circuits in infants exposed to prenatal maternal depression, Transl. Psychiatry, 6, e935, 10.1038/tp.2016.146 · DOI · Paper page
  46. 10.1017/S0954579417001456 · DOI
  47. 2013, Permanent genetic access to transiently active neurons via TRAP: Targeted recombination in active populations, Neuron, 79, 1257, 10.1016/j.neuron.2013.08.031 · DOI
  48. 10.1073/pnas.0504510102 · DOI
  49. Terstege, D. J. , Oboh, D. O. & Epp, J. R. FASTMAP: Open-Source Flexible Atlas Segmentation Tool for Multi-Area Processing of Biological Images. eNeuro 9, (2022). · DOI
  50. 10.2139/ssrn.3498571 · DOI
  51. 10.1196/annals.1401.026 · DOI
  52. 10.1038/npp.2009.83 · DOI · Paper page
  53. 1999, Regional cerebral blood flow during script-driven imagery in childhood sexual abuse-related PTSD: A PET investigation, Am. J. Psychiatry, 156, 575, 10.1176/ajp.156.4.575 · DOI · Paper page
  54. 10.1097/00001756-200112210-00020 · DOI
  55. 10.1016/j.biopsych.2007.04.004 · DOI
  56. 10.1016/S0006-3223(98)00026-2 · DOI
  57. 1998, Neuroimaging and the Neuroanatomy of Posttraumatic Stress Disorder, CNS Spectr, 3, 30, 10.1017/S1092852900007306 · DOI
  58. 2023, Early Social Adversity, Altered Brain Functional Connectivity, and Mental Health, Biol. Psychiatry, 93, 430, 10.1016/j.biopsych.2022.10.019 · DOI
  59. 2019, Abnormal Prefrontal Development in Pediatric Posttraumatic Stress Disorder: A Longitudinal Structural and Functional Magnetic Resonance Imaging Study, Biol Psychiatry Cogn Neurosci Neuroimaging, 4, 171
  60. 10.1016/j.biopsych.2010.12.037 · DOI
  61. 10.1126/sciadv.abc7246 · DOI
  62. 10.1523/JNEUROSCI.0859-10.2010 · DOI · Paper page
  63. 10.1038/npp.2014.277 · DOI
  64. 2020, The Long-Term Impact of Early Life Stress on Orbitofrontal Cortical Thickness, Cereb. Cortex, 30, 1307, 10.1093/cercor/bhz167 · DOI
  65. 2015, Markers of serotonergic function in the orbitofrontal cortex and dorsal raphé nucleus predict individual variation in spatial-discrimination serial reversal learning, Neuropsychopharmacology, 40, 1619, 10.1038/npp.2014.335 · DOI · Paper page
  66. 2020, Serotonergic Innervations of the Orbitofrontal and Medial-prefrontal Cortices are Differentially Involved in Visual Discrimination and Reversal Learning in Rats, Cereb. Cortex, 31, 1090
  67. 10.1523/JNEUROSCI.2355-19.2020 · DOI
  68. 10.1093/cercor/bht279 · DOI · Paper page
  69. 10.1196/annals.1401.006 · DOI
  70. 10.1016/j.neuroimage.2011.02.064 · DOI · Paper page
  71. vol., 2019, Orbitofrontal Cortex: A “Non-rewarding” New Treatment Target in Depression?, Current biology: CB, 29, R59, 10.1016/j.cub.2018.11.057 · DOI · Paper page

Metadata

Authors
Ramkumar, R., Edge-Partington, M., Adigun, K., Ren, Y., Terstege, D. J., Khan, N. S., Rouhi, N., Jamani, N. F., Tsutsui, M., Epp, J. R., & Sargin, D.
Affiliations
University of Calgary (CA)
Corresponding author
Sargin, Derya
ORCID
Venue
Biological Psychiatry
Publisher
openRxiv
Published
2023-08-02
Volume
96
Issue
4
Pages
287-299
ISSN
0006-3223 (ISSN-L)
DOI
10.1101/2023.08.01.551573
OpenAlex
W4391508905
Cited by
30
References
1
Citations by year
2026: 10 · 2025: 11 · 2024: 9
FWCI
5.25
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Biological Psychiatry (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Alberta Children's Hospital Research Institute
  • Canadian Institutes of Health Research
  • Natural Sciences and Engineering Research Council of Canada
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
early life stress, serotonin, raphe nuclei, brain connectivity, anxiety-like behavior, orbitofrontal cortex, sex differences, mood disorders, c-fos
MeSH terms
Animals, Anxiety, Behavior, Animal, Disease Models, Animal, Female, Male, Mice, Inbred C57BL, Neural Pathways, Raphe Nuclei, Serotonin, Stress, Psychological, Proto-Oncogene Proteins c-fos, Prefrontal Cortex, Mice, Optogenetics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review