The quality and quantity of social relationships in the modern era are rapidly changing, with increasing social isolation, and many individuals no longer living in extended families or missing close confidants. Restricted social relationships can endanger public health and increase mortality rate (Mikosz et al., 2016). Males and females, both human and animal, respond differently to social interactions. Differences may range from changes in neurobiological processes (Mikosz et al., 2016; Stack et al., 2010; Ngun et al., 2011; Cherif et al., 2003) to displaying distinctive gender-specific behaviours (Szell and Thurner, 2013; Jukka-Pekka Onnela et al., 2014; Palchykov et al., 2012; Trainor et al., 2011). Genetic and hormonal determinants regulate social behaviours (Choleris et al., 2018) and dictate morphological and behavioural variations in males and females. Robust sexual dimorphism was found in the neuropeptide oxytocin (OT) receptor density throughout the rat brain (Smith et al., 2017) and in OT receptor signaling in the medial prefrontal cortex (mPFC), which may modulate social interactions in females in response to OT (Nakajima et al., 2014). Primarily synthesized in the paraventricular nucleus (PVN) and supraoptic nucleus of the hypothalamus (Jurek and Neumann, 2018), OT is a key hormonal correlate of social behaviours in mammals (Anacker and Beery, 2013; Knobloch and Grinevich, 2014). OT exposure promotes social behaviours (Gamer et al., 2010; Guastella et al., 2008; Andari et al., 2010; Lim and Young, 2006; Bernaerts et al., 2017; McGraw and Young, 2010) and facilitates adaptive responses to stressors and stress resiliency (Olff et al., 2013). OT has also been shown to prevent premature aging of muscle tissue and facilitates muscle regeneration (Elabd et al., 2014). Hence, it can be hypothesized that OT exposure influences the chances of healthy aging.

A specific cellular index which differs according to age and sex indicates changes in telomere length (TL). Telomeres are DNA-repetitive nucleotide segments at the ends of each chromosome in mammals that protect genetic material from degradation during somatic cell division. Telomeric DNA in humans naturally shortens with age, and therefore TL represents a sensitive indicator of tissue-specific cellular aging (Puterman et al., 2016). As TL decreases along with proliferation in each cell division, telomere shortening can be considered a measure of biological aging (Sahin and DePinho, 2010; Blackburn, 2005). A variety of influences such as distress (Epel et al., 2004; Epel et al., 2010), childhood adversity (Puterman et al., 2016), interpersonal instability (Drury et al., 2014), social disadvantages and deprivation (Theall et al., 2013), and social isolation (Aydinonat et al., 2014) have been shown to be correlated with TL erosion. TL has also been shown to be positively associated with psychosocial factors, such as conscientiousness (Edmonds et al., 2015), optimism (Schutte et al., 2016), social support (Uchino et al., 2012), and social-pair mate choice (Johnsen et al., 2017).

It appears that females generally have longer telomeres than males (Gardner et al., 2014; Barrett and Richardson, 2011), and shorter telomeres in males are correlated with reduced social support (Zalli et al., 2014). This has led to the speculation that social experiences possibly make females more susceptible to telomere elongation than males, a lifestyle-dependent process that, in concert with sex-specific hormonal correlates results in longevity gender gaps (Merrill et al., 2017). Also, females show facilitated social learning compared to males (Ervin et al., 2015), along with estrogenic control of OT and OT receptor activity (Anacker and Beery, 2013). Accordingly, we have recently shown that prolonged social experiences change brain structure and behaviours in a sexually dimorphic manner in rats (Faraji et al., 2018).

Here, we investigated whether social experiences modulate genetic and behavioural repertoires through OT in male and female rats. Whereas OT facilitates novelty-seeking behaviour and TL, the OT antagonist (OT ANT) L-366,509 in socially raised male and female rats intermittently reduced OT secretion. The results suggest that extended social experiences modulate novelty seeking and TL through OT in a sex-dependent manner, with females being more susceptible than males.

The present rodent study indicates that persistent social experience is causally associated with increased OT level, elevated exploratory behaviour, and telomere elongation. These changes occurred in a sex-dependent manner to support three main conclusions: (i) social experience increases plasma OT levels, (ii) enhanced novelty-seeking behaviour and TL in socially housed females is mediated by higher OT levels, and (iii) social females respond to interrupted endogenous OT secretion with TL erosion and novelty-seeking deficit. Thus, OT is arguably involved in mediating beneficial effects of social experience on behaviour and TL. The findings reveal a dynamic interplay between social interactions and OT hormone to promote genetic and behavioural resiliency in female rats (Figure 5).

Figure 5

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All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.

1. 1. Alburges ME
   2. Ramos BP
   3. Bush L
   4. Hanson GR

   (2000) Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments

   European Journal of Pharmacology 390:119–126.

   https://doi.org/10.1016/S0014-2999(99)00919-X

   • Google Scholar
2. 1. Anacker AMJ
   2. Beery AK

   (2013) Life in groups: the roles of oxytocin in mammalian sociality

   Frontiers in Behavioral Neuroscience 7:185.

   https://doi.org/10.3389/fnbeh.2013.00185

   • Google Scholar
3. 1. Andari E
   2. Duhamel J-R
   3. Zalla T
   4. Herbrecht E
   5. Leboyer M
   6. Sirigu A

   (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders

   PNAS 107:4389–4394.

   https://doi.org/10.1073/pnas.0910249107

   • Google Scholar
4. 1. Auyeung B
   2. Lombardo MV
   3. Heinrichs M
   4. Chakrabarti B
   5. Sule A
   6. Deakin JB
   7. Bethlehem RAI
   8. Dickens L
   9. Mooney N
   10. Sipple JAN
   11. Thiemann P
   12. Baron-Cohen S

   (2015) Oxytocin increases eye contact during a real-time, naturalistic social interaction in males with and without autism

   Translational Psychiatry 5:e507.

   https://doi.org/10.1038/tp.2014.146

   • Google Scholar
5. 1. Averbeck BB

   (2010) Oxytocin and the salience of social cues

   PNAS 107:9033–9034.

   https://doi.org/10.1073/pnas.1004892107

   • Google Scholar
6. 1. Aydinonat D
   2. Penn DJ
   3. Smith S
   4. Moodley Y
   5. Hoelzl F
   6. Knauer F
   7. Schwarzenberger F

   (2014) Social isolation shortens telomeres in African Grey parrots (Psittacus erithacus erithacus)

   PLoS ONE 9:e93839.

   https://doi.org/10.1371/journal.pone.0093839

   • PubMed
   • Google Scholar
7. 1. Ayers LW
   2. Missig G
   3. Schulkin J
   4. Rosen JB

   (2011) Oxytocin reduces background anxiety in a fear-potentiated startle paradigm: peripheral vs central administration

   Neuropsychopharmacology 36:2488–2497.

   https://doi.org/10.1038/npp.2011.138

   • PubMed
   • Google Scholar
8. 1. Bardo MT
   2. Donohew RL
   3. Harrington NG

   (1996) Psychobiology of novelty seeking and drug seeking behavior

   Behavioural Brain Research 77:23–43.

   https://doi.org/10.1016/0166-4328(95)00203-0

   • Google Scholar
9. 1. Barraza JA
   2. Zak PJ

   (2009) Empathy toward strangers triggers oxytocin release and subsequent generosity

   Annals of the New York Academy of Sciences 1167:182–189.

   https://doi.org/10.1111/j.1749-6632.2009.04504.x

   • PubMed
   • Google Scholar
10. 1. Barrett ELB
    2. Richardson DS

    (2011) Sex differences in telomeres and lifespan

    Aging Cell 10:913–921.

    https://doi.org/10.1111/j.1474-9726.2011.00741.x

    • Google Scholar
11. 1. Bartz JA
    2. Zaki J
    3. Bolger N
    4. Ochsner KN

    (2011) Social effects of oxytocin in humans: context and person matter

    Trends in Cognitive Sciences 15:301–309.

    https://doi.org/10.1016/j.tics.2011.05.002

    • Google Scholar
12. 1. Baumgartner T
    2. Heinrichs M
    3. Vonlanthen A
    4. Fischbacher U
    5. Fehr E

    (2008) Oxytocin shapes the neural circuitry of trust and trust adaptation in humans

    Neuron 58:639–650.

    https://doi.org/10.1016/j.neuron.2008.04.009

    • PubMed
    • Google Scholar
13. 1. Beery AK
    2. Kaufer D

    (2015) Stress, social behavior, and resilience: Insights from rodents

    Neurobiology of Stress 1:116–127.

    https://doi.org/10.1016/j.ynstr.2014.10.004

    • Google Scholar
14. 1. Bernaerts S
    2. Prinsen J
    3. Berra E
    4. Bosmans G
    5. Steyaert J
    6. Alaerts K

    (2017) Long-term oxytocin administration enhances the experience of attachment

    Psychoneuroendocrinology 78:1–9.

    https://doi.org/10.1016/j.psyneuen.2017.01.010

    • Google Scholar
15. 1. Blackburn EH

    (2005) Telomeres and telomerase: their mechanisms of action and the effects of altering their functions

    FEBS Letters 579:859–862.

    https://doi.org/10.1016/j.febslet.2004.11.036

    • Google Scholar
16. 1. Cawthon RM

    (2002) Telomere measurement by quantitative PCR

    Nucleic Acids Research 30:e47.

    https://doi.org/10.1093/nar/30.10.e47

    • PubMed
    • Google Scholar
17. 1. Cerulo KA

    (2009) Nonhumans in Social Interaction

    Annual Review of Sociology 35:531–552.

    https://doi.org/10.1146/annurev-soc-070308-120008

    • Google Scholar
18. 1. Charney DS

    (2004) Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress

    American Journal of Psychiatry 161:195–216.

    https://doi.org/10.1176/appi.ajp.161.2.195

    • PubMed
    • Google Scholar
19. 1. Cherif H
    2. Tarry JL
    3. Ozanne SE
    4. Hales CN

    (2003) Ageing and telomeres: a study into organ- and gender-specific telomere shortening

    Nucleic Acids Research 31:1576–1583.

    https://doi.org/10.1093/nar/gkg208

    • Google Scholar
20. 1. Choleris E
    2. Galea LAM
    3. Sohrabji F
    4. Frick KM

    (2018) Sex differences in the brain: Implications for behavioral and biomedical research

    Neuroscience & Biobehavioral Reviews 85:126–145.

    https://doi.org/10.1016/j.neubiorev.2017.07.005

    • Google Scholar
21. 1. Churchland PS
    2. Winkielman P

    (2012) Modulating social behavior with oxytocin: How does it work? What does it mean?

    Hormones and Behavior 61:392–399.

    https://doi.org/10.1016/j.yhbeh.2011.12.003

    • Google Scholar
22. 1. Cohen S
    2. Wills TA

    (1985) Stress, social support, and the buffering hypothesis

    Psychological Bulletin 98:310–357.

    https://doi.org/10.1037/0033-2909.98.2.310

    • Google Scholar
23. 1. Deing V
    2. Roggenkamp D
    3. Kühnl J
    4. Gruschka A
    5. Stäb F
    6. Wenck H
    7. Bürkle A
    8. Neufang G

    (2013) Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis

    Experimental Dermatology 22:399–405.

    https://doi.org/10.1111/exd.12155

    • Google Scholar
24. 1. Ditzen B
    2. Schaer M
    3. Gabriel B
    4. Bodenmann G
    5. Ehlert U
    6. Heinrichs M

    (2009) Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict

    Biological Psychiatry 65:728–731.

    https://doi.org/10.1016/j.biopsych.2008.10.011

    • PubMed
    • Google Scholar
25. 1. Drury SS
    2. Theall K
    3. Gleason MM
    4. Smyke AT
    5. De Vivo I
    6. Wong JYY
    7. Fox NA
    8. Zeanah CH
    9. Nelson CA

    (2012) Telomere length and early severe social deprivation: linking early adversity and cellular aging

    Molecular Psychiatry 17:719–727.

    https://doi.org/10.1038/mp.2011.53

    • Google Scholar
26. 1. Drury SS
    2. Mabile E
    3. Brett ZH
    4. Esteves K
    5. Jones E
    6. Shirtcliff EA
    7. Theall KP

    (2014) The association of telomere length with family violence and disruption

    Pediatrics 134:e128–e137.

    https://doi.org/10.1542/peds.2013-3415

    • PubMed
    • Google Scholar
27. 1. Edmonds GW
    2. Côté HC
    3. Hampson SE

    (2015) Childhood Conscientiousness and Leukocyte Telomere Length 40 Years Later in Adult Women--Preliminary Findings of a Prospective Association

    Plos One 10:e0134077.

    https://doi.org/10.1371/journal.pone.0134077

    • PubMed
    • Google Scholar
28. 1. Elabd C
    2. Cousin W
    3. Upadhyayula P
    4. Chen RY
    5. Chooljian MS
    6. Li J
    7. Kung S
    8. Jiang KP
    9. Conboy IM

    (2014) Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration

    Nature Communications 5:4082.

    https://doi.org/10.1038/ncomms5082

    • Google Scholar
29. 1. Epel ES
    2. Blackburn EH
    3. Lin J
    4. Dhabhar FS
    5. Adler NE
    6. Morrow JD
    7. Cawthon RM

    (2004) Accelerated telomere shortening in response to life stress

    PNAS 101:17312–17315.

    https://doi.org/10.1073/pnas.0407162101

    • Google Scholar
30. 1. Epel ES
    2. Lin J
    3. Dhabhar FS
    4. Wolkowitz OM
    5. Puterman E
    6. Karan L
    7. Blackburn EH

    (2010) Dynamics of telomerase activity in response to acute psychological stress

    Brain, Behavior, and Immunity 24:531–539.

    https://doi.org/10.1016/j.bbi.2009.11.018

    • Google Scholar
31. 1. Ervin KSJ
    2. Lymer JM
    3. Matta R
    4. Clipperton-Allen AE
    5. Kavaliers M
    6. Choleris E

    (2015) Estrogen involvement in social behavior in rodents: Rapid and long-term actions

    Hormones and Behavior 74:53–76.

    https://doi.org/10.1016/j.yhbeh.2015.05.023

    • Google Scholar
32. 1. Evans BE
    2. Leighton JL
    3. Rittle KE
    4. Gilbert KF
    5. Lundell GF
    6. Gould NP
    7. Hobbs DW
    8. DiPardo RM
    9. Veber DF
    10. Pettibone DJ
    11. Clineschmidt BV
    12. Anderson PS
    13. Freidinger RM

    (1992) Orally active, nonpeptide oxytocin antagonists

    Journal of Medicinal Chemistry 35:3919–3927.

    https://doi.org/10.1021/jm00099a020

    • Google Scholar
33. 1. Fagan E
    2. Sun F
    3. Bae H
    4. Elo I
    5. Andersen SL
    6. Lee J
    7. Christensen K
    8. Thyagarajan B
    9. Sebastiani P
    10. Perls T
    11. Honig LS
    12. Schupf N
    13. Long Life Family Study

    (2017) Telomere length is longer in women with late maternal age

    Menopause 24:497–501.

    https://doi.org/10.1097/GME.0000000000000795

    • PubMed
    • Google Scholar
34. 1. Faraji J
    2. Soltanpour N
    3. Jafari SY
    4. Moeeini R
    5. Pakdel S
    6. Moharreri A
    7. Metz GAS

    (2014) Stress inhibits psychomotor performance differently in simple and complex open field environments

    Hormones and Behavior 65:66–75.

    https://doi.org/10.1016/j.yhbeh.2013.11.007

    • Google Scholar
35. 1. Faraji J
    2. Karimi M
    3. Soltanpour N
    4. Rouhzadeh Z
    5. Roudaki S
    6. Hosseini SA
    7. Jafari SY
    8. Abdollahi A-A
    9. Soltanpour N
    10. Moeeini R
    11. Metz GAS

    (2018) Intergenerational Sex-Specific Transmission of Maternal Social Experience

    Scientific Reports 8:10529.

    https://doi.org/10.1038/s41598-018-28729-8

    • Google Scholar
36. 1. Gamer M
    2. Zurowski B
    3. Büchel C

    (2010) Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans

    PNAS 107:9400–9405.

    https://doi.org/10.1073/pnas.1000985107

    • PubMed
    • Google Scholar
37. 1. Gardner M
    2. Bann D
    3. Wiley L
    4. Cooper R
    5. Hardy R
    6. Nitsch D
    7. Martin-Ruiz C
    8. Shiels P
    9. Sayer AA
    10. Barbieri M
    11. Bekaert S
    12. Bischoff C
    13. Brooks-Wilson A
    14. Chen W
    15. Cooper C
    16. Christensen K
    17. De Meyer T
    18. Deary I
    19. Der G
    20. Diez Roux A
    21. Fitzpatrick A
    22. Hajat A
    23. Halaschek-Wiener J
    24. Harris S
    25. Hunt SC
    26. Jagger C
    27. Jeon HS
    28. Kaplan R
    29. Kimura M
    30. Lansdorp P
    31. Li C
    32. Maeda T
    33. Mangino M
    34. Nawrot TS
    35. Nilsson P
    36. Nordfjall K
    37. Paolisso G
    38. Ren F
    39. Riabowol K
    40. Robertson T
    41. Roos G
    42. Staessen JA
    43. Spector T
    44. Tang N
    45. Unryn B
    46. van der Harst P
    47. Woo J
    48. Xing C
    49. Yadegarfar ME
    50. Park JY
    51. Young N
    52. Kuh D
    53. von Zglinicki T
    54. Ben-Shlomo Y
    55. Halcyon study team

    (2014) Gender and telomere length: systematic review and meta-analysis

    Experimental Gerontology 51:15–27.

    https://doi.org/10.1016/j.exger.2013.12.004

    • PubMed
    • Google Scholar
38. 1. Guastella AJ
    2. Mitchell PB
    3. Dadds MR

    (2008) Oxytocin increases gaze to the eye region of human faces

    Biological Psychiatry 63:3–5.

    https://doi.org/10.1016/j.biopsych.2007.06.026

    • PubMed
    • Google Scholar
39. 1. Gur RC
    2. Richard J
    3. Calkins ME
    4. Chiavacci R
    5. Hansen JA
    6. Bilker WB
    7. Loughead J
    8. Connolly JJ
    9. Qiu H
    10. Mentch FD
    11. Abou-Sleiman PM
    12. Hakonarson H
    13. Gur RE

    (2012) Age group and sex differences in performance on a computerized neurocognitive battery in children age 8−21

    Neuropsychology 26:251–265.

    https://doi.org/10.1037/a0026712

    • Google Scholar
40. 1. Hari R
    2. Henriksson L
    3. Malinen S
    4. Parkkonen L

    (2015) Centrality of Social Interaction in Human Brain Function

    Neuron 88:181–193.

    https://doi.org/10.1016/j.neuron.2015.09.022

    • Google Scholar
41. 1. Hehar H
    2. Mychasiuk R

    (2016) The use of telomere length as a predictive biomarker for injury prognosis in juvenile rats following a concussion/mild traumatic brain injury

    Neurobiology of Disease 87:11–18.

    https://doi.org/10.1016/j.nbd.2015.12.007

    • Google Scholar
42. 1. Hillerer KM
    2. Jacobs VR
    3. Fischer T
    4. Aigner L

    (2014) The Maternal Brain: An Organ with Peripartal Plasticity

    Neural Plasticity 2014:1–20.

    https://doi.org/10.1155/2014/574159

    • Google Scholar
43. 1. Holt-Lunstad J
    2. Smith TB
    3. Layton JB

    (2010) Social relationships and mortality risk: a meta-analytic review

    PLoS Medicine 7:e1000316.

    https://doi.org/10.1371/journal.pmed.1000316

    • PubMed
    • Google Scholar
44. 1. House JS
    2. Umberson D
    3. Landis KR
    4. House James S
    5. Landis Karl UD

    (1988) Structures and Processes of Social Support

    Annual Review of Sociology 14:293–318.

    https://doi.org/10.1146/annurev.so.14.080188.001453

    • Google Scholar
45. 1. Hughes RN

    (1968) Behaviour of male and female rats with free choice of two environments differing in novelty

    Animal Behaviour 16:92–96.

    https://doi.org/10.1016/0003-3472(68)90116-4

    • Google Scholar
46. 1. Joel D
    2. Berman Z
    3. Tavor I
    4. Wexler N
    5. Gaber O
    6. Stein Y
    7. Shefi N
    8. Pool J
    9. Urchs S
    10. Margulies DS
    11. Liem F
    12. Hänggi J
    13. Jäncke L
    14. Assaf Y

    (2015) Sex beyond the genitalia: The human brain mosaic

    PNAS 112:15468–15473.

    https://doi.org/10.1073/pnas.1509654112

    • Google Scholar
47. 1. Johnsen A
    2. Pauliny A
    3. Lifjeld JT
    4. Blomqvist D

    (2017) Is telomere length associated with mate choice in a songbird with a high rate of extra-pair paternity?

    PLoS One 12:e0182446.

    https://doi.org/10.1371/journal.pone.0182446

    • Google Scholar
48. 1. Jukka-Pekka Onnela BNW
    2. Pentland A
    3. Schnorf S
    4. Lazer D

    (2014) Using sociometers to quantify social interaction patterns

    Scientific Reports 4:.

    https://doi.org/10.1038/srep05604

    • Google Scholar
49. 1. Jurek B
    2. Neumann ID

    (2018) The Oxytocin Receptor: From Intracellular Signaling to Behavior

    Physiological Reviews 98:1805–1908.

    https://doi.org/10.1152/physrev.00031.2017

    • Google Scholar
50. 1. Kazlauckas V
    2. Schuh J
    3. Dall’Igna OP
    4. Pereira GS
    5. Bonan CD
    6. Lara DR

    (2005) Behavioral and cognitive profile of mice with high and low exploratory phenotypes

    Behavioural Brain Research 162:272–278.

    https://doi.org/10.1016/j.bbr.2005.03.021

    • Google Scholar
51. 1. Kirsch P
    2. Esslinger C
    3. Chen Q
    4. Mier D
    5. Lis S
    6. Siddhanti S
    7. Gruppe H
    8. Mattay VS
    9. Gallhofer B
    10. Meyer-Lindenberg A

    (2005) Oxytocin modulates neural circuitry for social cognition and fear in humans

    Journal of Neuroscience 25:11489–11493.

    https://doi.org/10.1523/JNEUROSCI.3984-05.2005

    • PubMed
    • Google Scholar
52. 1. Kitano H
    2. Takeda T
    3. Suzuki M
    4. Kitanishi T
    5. Yazawa Y
    6. Kitajima K
    7. Kimura H
    8. Tooyama I

    (1997) Vasopressin and oxytocin receptor mRNAs are expressed in the rat inner ear

    NeuroReport 8:2289–2291.

    https://doi.org/10.1097/00001756-199707070-00038

    • Google Scholar
53. 1. Knobloch HS
    2. Grinevich V

    (2014) Evolution of oxytocin pathways in the brain of vertebrates

    Frontiers in Behavioral Neuroscience 8:31.

    https://doi.org/10.3389/fnbeh.2014.00031

    • Google Scholar
54. 1. Kobayashi M
    2. Akahane M
    3. Minami K
    4. Moro M
    5. Ajisawa Y
    6. Inoue Y
    7. Kawarabayashi T

    (1999) Role of oxytocin in the initiation of term and preterm labor in rats: Changes in oxytocin receptor density and plasma oxytocin concentration and the effect of an oxytocin antagonist, L-366,509

    American Journal of Obstetrics and Gynecology 180:621–627.

    https://doi.org/10.1016/S0002-9378(99)70264-4

    • Google Scholar
55. 1. Kosfeld M
    2. Heinrichs M
    3. Zak PJ
    4. Fischbacher U
    5. Fehr E

    (2005) Oxytocin increases trust in humans

    Nature 435:673–676.

    https://doi.org/10.1038/nature03701

    • Google Scholar
56. 1. Kring AM
    2. Gordon AH

    (1998) Sex differences in emotion: Expression, experience, and physiology

    Journal of Personality and Social Psychology 74:686–703.

    https://doi.org/10.1037/0022-3514.74.3.686

    • Google Scholar
57. 1. Lefevre A
    2. Mottolese R
    3. Dirheimer M
    4. Mottolese C
    5. Duhamel J-R
    6. Sirigu A

    (2017) A comparison of methods to measure central and peripheral oxytocin concentrations in human and non-human primates

    Scientific Reports 7:17222.

    https://doi.org/10.1038/s41598-017-17674-7

    • Google Scholar
58. 1. Lim MM
    2. Young LJ

    (2006) Neuropeptidergic regulation of affiliative behavior and social bonding in animals

    Hormones and Behavior 50:506–517.

    https://doi.org/10.1016/j.yhbeh.2006.06.028

    • Google Scholar
59. 1. Lincoln KD
    2. Support S
    3. Interactions NS
    4. Well-Being P

    (2000) Social Support, Negative Social Interactions, and Psychological Well‐Being

    Social Service Review 74:231–252.

    https://doi.org/10.1086/514478

    • Google Scholar
60. 1. Mather KA
    2. Jorm AF
    3. Parslow RA
    4. Christensen H

    (2011) Is telomere length a biomarker of aging? A review

    The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 66:202–213.

    https://doi.org/10.1093/gerona/glq180

    • PubMed
    • Google Scholar
61. 1. McGraw LA
    2. Young LJ

    (2010) The prairie vole: an emerging model organism for understanding the social brain

    Trends in Neurosciences 33:103–109.

    https://doi.org/10.1016/j.tins.2009.11.006

    • Google Scholar
62. 1. Merrill LC
    2. Jones CW
    3. Drury SS
    4. Theall KP

    (2017) The differential impact of oxytocin receptor gene in violence-exposed boys and girls

    International Journal of Developmental Neuroscience 59:60–67.

    https://doi.org/10.1016/j.ijdevneu.2017.03.009

    • Google Scholar
63. 1. Mikosz M
    2. Nowak A
    3. Werka T
    4. Knapska E

    (2016) Sex differences in social modulation of learning in rats

    Scientific Reports 5:18114.

    https://doi.org/10.1038/srep18114

    • Google Scholar
64. 1. Mitchell C
    2. McLanahan S
    3. Schneper L
    4. Garfinkel I
    5. Brooks-Gunn J
    6. Notterman D

    (2017) Father Loss and Child Telomere Length

    Pediatrics 140:e20163245.

    https://doi.org/10.1542/peds.2016-3245

    • Google Scholar
65. 1. Nakajima M
    2. Görlich A
    3. Heintz N

    (2014) Oxytocin modulates female sociosexual behavior through a specific class of prefrontal cortical interneurons

    Cell 159:295–305.

    https://doi.org/10.1016/j.cell.2014.09.020

    • PubMed
    • Google Scholar
66. 1. Ngun TC
    2. Ghahramani N
    3. Sánchez FJ
    4. Bocklandt S
    5. Vilain E

    (2011) The genetics of sex differences in brain and behavior

    Frontiers in Neuroendocrinology 32:227–246.

    https://doi.org/10.1016/j.yfrne.2010.10.001

    • Google Scholar
67. 1. Olff M
    2. Frijling JL
    3. Kubzansky LD
    4. Bradley B
    5. Ellenbogen MA
    6. Cardoso C
    7. Bartz JA
    8. Yee JR
    9. van Zuiden M

    (2013) The role of oxytocin in social bonding, stress regulation and mental health: An update on the moderating effects of context and interindividual differences

    Psychoneuroendocrinology 38:1883–1894.

    https://doi.org/10.1016/j.psyneuen.2013.06.019

    • Google Scholar
68. 1. Ozbay F
    2. Johnson DC
    3. Dimoulas E
    4. Morgan CA
    5. Charney D
    6. Southwick S

    (2007)

    Social support and resilience to stress: from neurobiology to clinical practice

    Psychiatry (Edgmont 4:35–40.

    • PubMed
    • Google Scholar
69. 1. Palchykov V
    2. Kaski K
    3. Kertész J
    4. Barabási A-L
    5. Dunbar RIM

    (2012) Sex differences in intimate relationships

    Scientific Reports 2:370.

    https://doi.org/10.1038/srep00370

    • Google Scholar
70. 1. Pettibone DJ
    2. Clineschmidt BV
    3. Kishel MT
    4. Lis EV
    5. Reiss DR
    6. Woyden CJ
    7. Evans BE
    8. Freidinger RM
    9. Veber DF
    10. Cook MJ

    (1993)

    Identification of an orally active, nonpeptidyl oxytocin antagonist

    The Journal of Pharmacology and Experimental Therapeutics 264:308–314.

    • PubMed
    • Google Scholar
71. 1. Puterman E
    2. Gemmill A
    3. Karasek D
    4. Weir D
    5. Adler NE
    6. Prather AA
    7. Epel ES

    (2016) Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

    PNAS 113:E6335–E6342.

    https://doi.org/10.1073/pnas.1525602113

    • Google Scholar
72. 1. Rilling J
    2. Gutman D
    3. Zeh T
    4. Pagnoni G
    5. Berns G
    6. Kilts C

    (2002) A neural basis for social cooperation

    Neuron 35:395–405.

    https://doi.org/10.1016/S0896-6273(02)00755-9

    • PubMed
    • Google Scholar
73. 1. Sahin E
    2. DePinho RA

    (2010) Linking functional decline of telomeres, mitochondria and stem cells during ageing

    Nature 464:520–528.

    https://doi.org/10.1038/nature08982

    • Google Scholar
74. 1. Schilbach L
    2. Timmermans B
    3. Reddy V
    4. Costall A
    5. Bente G
    6. Schlicht T
    7. Vogeley K

    (2013) Toward a second-person neuroscience

    Behavioral and Brain Sciences 36:393–414.

    https://doi.org/10.1017/S0140525X12000660

    • Google Scholar
75. 1. Schutte NS
    2. Palanisamy SKA
    3. McFarlane JR

    (2016) The relationship between positive psychological characteristics and longer telomeres

    Psychology & Health 31:1466–1480.

    https://doi.org/10.1080/08870446.2016.1226308

    • Google Scholar
76. 1. Sippel LM
    2. Pietrzak RH
    3. Charney Dennis S,
    4. Mayes LC
    5. Southwick SM

    (2015) How does social support enhance resilience in the trauma-exposed individual?

    Ecology and Society 20:.

    https://doi.org/10.5751/ES-07832-200410

    • Google Scholar
77. 1. Smith AS
    2. Ågmo A
    3. Birnie AK
    4. French JA

    (2010) Manipulation of the oxytocin system alters social behavior and attraction in pair-bonding primates, Callithrix penicillata

    Hormones and Behavior 57:255–262.

    https://doi.org/10.1016/j.yhbeh.2009.12.004

    • Google Scholar
78. 1. Smith CJW
    2. Poehlmann ML
    3. Li S
    4. Ratnaseelan AM
    5. Bredewold R
    6. Veenema AH

    (2017) Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network

    Brain Structure and Function 222:981–1006.

    https://doi.org/10.1007/s00429-016-1260-7

    • Google Scholar
79. 1. Stack A
    2. Carrier N
    3. Dietz D
    4. Hollis F
    5. Sorenson J
    6. Kabbaj M

    (2010) Sex differences in social interaction in rats: role of the immediate-early gene zif268

    Neuropsychopharmacology 35:570–580.

    https://doi.org/10.1038/npp.2009.163

    • PubMed
    • Google Scholar
80. 1. Swain JE
    2. Kim P
    3. Spicer J
    4. Ho SS
    5. Dayton CJ
    6. Elmadih A
    7. Abel KM

    (2014) Approaching the biology of human parental attachment: Brain imaging, oxytocin and coordinated assessments of mothers and fathers

    Brain Research 1580:78–101.

    https://doi.org/10.1016/j.brainres.2014.03.007

    • Google Scholar
81. 1. Szell M
    2. Thurner S

    (2013) How women organize social networks different from men

    Scientific Reports 3:1214.

    https://doi.org/10.1038/srep01214

    • Google Scholar
82. 1. Theall KP
    2. Brett ZH
    3. Shirtcliff EA
    4. Dunn EC
    5. Drury SS

    (2013) Neighborhood disorder and telomeres: Connecting children's exposure to community level stress and cellular response

    Social Science & Medicine 85:50–58.

    https://doi.org/10.1016/j.socscimed.2013.02.030

    • PubMed
    • Google Scholar
83. 1. Trainor BC
    2. Pride MC
    3. Villalon Landeros R
    4. Knoblauch NW
    5. Takahashi EY
    6. Silva AL
    7. Crean KK

    (2011) Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus)

    PLoS ONE 6:e17405.

    https://doi.org/10.1371/journal.pone.0017405

    • PubMed
    • Google Scholar
84. 1. Uchino BN

    (2006) Social support and health: a review of physiological processes potentially underlying links to disease outcomes

    Journal of Behavioral Medicine 29:377–387.

    https://doi.org/10.1007/s10865-006-9056-5

    • PubMed
    • Google Scholar
85. 1. Uchino BN
    2. Cawthon RM
    3. Smith TW
    4. Light KC
    5. McKenzie J
    6. Carlisle M
    7. Gunn H
    8. Birmingham W
    9. Bowen K

    (2012) Social relationships and health: Is feeling positive, negative, or both (ambivalent) about your social ties related to telomeres?

    Health Psychology 31:789–796.

    https://doi.org/10.1037/a0026836

    • Google Scholar
86. 1. Umberson D
    2. Montez JK

    (2010) Social relationships and health: a flashpoint for health policy

    Journal of Health and Social Behavior 51 Suppl:S54–S66.

    https://doi.org/10.1177/0022146510383501

    • PubMed
    • Google Scholar
87. 1. Williams PD
    2. Anderson PS
    3. Ball RG
    4. Bock MG
    5. Carroll L
    6. Chiu SH
    7. Clineschmidt BV
    8. Culberson JC
    9. Erb JM
    10. Evans BE

    (1994) 1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor

    Journal of Medicinal Chemistry 37:565–571.

    https://doi.org/10.1021/jm00031a004

    • PubMed
    • Google Scholar
88. 1. Wotjak CT
    2. Ganster J
    3. Kohl G
    4. Holsboer F
    5. Landgraf R
    6. Engelmann M

    (1998) Dissociated central and peripheral release of vasopressin, but not oxytocin, in response to repeated swim stress: New insights into the secretory capacities of peptidergic neurons

    Neuroscience 85:1209–1222.

    https://doi.org/10.1016/S0306-4522(97)00683-0

    • Google Scholar
89. 1. Yang YC
    2. Boen C
    3. Gerken K
    4. Li T
    5. Schorpp K
    6. Harris KM

    (2016) Social relationships and physiological determinants of longevity across the human life span

    PNAS 113:578–583.

    https://doi.org/10.1073/pnas.1511085112

    • Google Scholar
90. 1. Yee JR
    2. Cavigelli SA
    3. Delgado B
    4. McClintock MK

    (2008) Reciprocal affiliation among adolescent rats during a mild group stressor predicts mammary tumors and lifespan

    Psychosomatic Medicine 70:1050–1059.

    https://doi.org/10.1097/PSY.0b013e31818425fb

    • PubMed
    • Google Scholar
91. 1. Zalli A
    2. Carvalho LA
    3. Lin J
    4. Hamer M
    5. Erusalimsky JD
    6. Blackburn EH
    7. Steptoe A

    (2014) Shorter telomeres with high telomerase activity are associated with raised allostatic load and impoverished psychosocial resources

    PNAS 111:4519–4524.

    https://doi.org/10.1073/pnas.1322145111

    • Google Scholar
92. 1. Zheng J-J
    2. Li S-J
    3. Zhang X-D
    4. Miao W-Y
    5. Zhang D
    6. Yao H
    7. Yu X

    (2014) Oxytocin mediates early experience–dependent cross-modal plasticity in the sensory cortices

    Nature Neuroscience 17:391–399.

    https://doi.org/10.1038/nn.3634

    • Google Scholar
93. 1. Zucchi FC
    2. Yao Y
    3. Ilnytskyy Y
    4. Robbins JC
    5. Soltanpour N
    6. Kovalchuk I
    7. Kovalchuk O
    8. Metz GA

    (2014) Lifetime stress cumulatively programs brain transcriptome and impedes stroke recovery: benefit of sensory stimulation

    PLoS ONE 9:e92130.

    https://doi.org/10.1371/journal.pone.0092130

    • PubMed
    • Google Scholar

[Editors’ note: this article was originally rejected after discussions between the reviewers, but the authors were invited to resubmit after an appeal against the decision.]

Thank you for submitting your work entitled "Oxytocin-mediated Social Enrichment Promotes Longevity and Novelty Seeking" for consideration by eLife. Your article has been reviewed by four peer reviewers, including Peggy Mason as the Reviewing Editor and Reviewer #1, and the evaluation has been overseen by a Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Takefumi Kikusui (Reviewer #3).

Our decision has been reached after consultation between the reviewers. Based on these discussions and the individual reviews below, we regret to inform you that your work will not be considered further for publication in eLife.

The reviewers' chief concern is the lack of an OXT antag control. It is plausible that the stress of the non-trivial number of injections was the active agent here rather than the pharmaceutical compound. If the authors came back with such a control, we would be interested in such a (new) submission. The authors may also benefit from a number of other comments from the reviewers including walking back some of the conclusions to acknowledge the correlational nature of the data as well as the lack of a compelling direct path from housing to telomere length regulation.

Reviewer #1:

There is a lot to like and a fair amount to easily worry about in this study. The big positives are the large groups compared to normal social housing. Comparing normal (yet deprived in the natural scheme of things) to enriched (probably close to true normal for rats) is a strong design, far better than comparing 2-4 rodent groups (deprived) to social isolation (a ridiculous condition with no ecological correlate). The investigation of brave behavior (going in to the OF center with or without an object there) across the sexes and housing conditions is an interesting design aimed at important questions regarding early social development and sexual dimorphisms. The biggest issue with this paper is the lack of an injection control for the OXT antag injections. The results obtained – less exploration of the center after the antag – could easily result from a differential effect of stress (the stress of 28 injections!!) on females compared to males, Is this issue surmountable with the data in hand? I fear no but look forward to seeing what the other reviewers think.

At the outset of the results it is necessary to state how many rats are in social (n=10-11) and standard (n=2-3) groups. It would also be useful to state how the rats from different litters were assigned to the groups. The no difference reported across litter is not interpretable without this information.

Then the authors need to be far more careful about the use of the word "group." They state "…across different groups (n=21-23/group)" which appears to say that there are 21-23 in the group housed cages but in point of fact this appears to be the number of animals in the social or standard conditions. Which would imply that two Social groups (n=20-22 rats), one for each sex, were compared to 8-10 Standard groups, half for each sex? This should be explicitly stated. Then the number of rats in Figure 1A Social as 44 and in 1B as 54. Please make sense of these various numbers.

A significant effect of Housing Condition (F1,86=24.85, p{less than or equal to}0.001) and Group (F3,84=13.69, p{less than or equal to}0.001). By Group do the authors mean sex? I thought the conditions were the groups. This is very confusingly written. I think the authors are saying there are 4 groups whereas it should be a 2x2 factor design with housing – 2 conditions – and sex – 2 groups.

It appears that the groups are mixed males and females. Are some of the females then pregnant? If this is the case, then some of the females must be pregnant which would obviously change their behavior. Please explain.

There is no saline control for the OT antag injections. This is an experimental choice that must be justified and is possibly a deal-killer. The injections were "every other day (between 11:00-12:00 am) for 13 days (in total, 28 doses/rat)…" Clearly every other day for 13 days does not yield 28 doses per rat. So, this needs to be rewritten into careful English so that the reader is told what was done.

Reviewer #2:

This is a terrific paper that should be published as soon as possible. I believe it stands to make a substantive contribution to the field and will be heavily cited. It explains the interactions among social relationships, Oxytocin, telomeres and longevity convincingly. Links to HPA axis function are also very interesting. The implications for human relationships are very intriguing. The background and discussion are soundly presented. The analytic methods are sound, and the results are compelling.

I am less able to review the data collection methods, as I am not an animal scientist, so I trust other reviewers to do so.

There were no grammatical or typos to note.

Again, I recommend publication as soon as possible.

Reviewer #3:

This paper demonstrated that long-term social housing in the juvenile period enhanced peripheral OT secretion, together with longer TL. Novelty-seeking behavior was also increased by social housing. These housing effects were more robust in females. The data are interesting because the authors examined causality between OT secretion, TL and behavior. Even though there is no neuron/ brain region analysis conducted, the findings would reveal a new function of OT.

Here are my concerns,

1) Ear notch samples were used to assess TL, but is there any evidence showing that these cells express oxytocin receptor? If so, please add the reference in the Materials and methods section. If not, the authors need to include the discussion how blood OT can affect TL in these OTR-lacking cells.

2) OT antagonist L-366,509 was used to inhibit OT system in the CNS. Please add the information about penetration of this chemical through blood brain barrier in the Materials and methods section.

3) The authors mentioned the function of OT on the HPA axis, but this paper did not include the data of corticosterone. If the blood samples remain, please measure corticosterone, to make the conclusion more convincing.

4) Related to #2 and #3, higher corticosterone exposure will shorten the TL in peripheral cells. Please add the corticosterone data if possible.

5) Were the changes observed in social-housing rats caused by social interactions? If the rats were housed in a large area, the locomotor activity can increase. In this experimental setting, the authors cannot conclude that the changes were caused by social interactions. There might be an appropriate control group needed, such as similar locomotor activity without social interaction. If the authors cannot exclude the effect of activity (physical exercise can facilitate OT secretion, TL etc.), the discussion should be modified.

6) The social housing was conducted just after the weaning, so the effects of social housing would be robust (still in the developmental period). If the social housing were to be conducted in the adulthood or aged rats, could the same positive affects be observed? In humans, social loneliness in elderly is one of the important social issues related to the health problems.

Reviewer #4:

In manuscript by Faraji et al., the authors reported correlations between circulating oxytocin concentration and prolonged social housing, in both male and female rats. They further showed that prolonged social housing correlated with elongated telomere length in only in female rats, an effect blocked by the oxytocin antagonist L-366,509. While the correlation between oxytocin and telomere length is potentially interesting, I believe that there are some gaps of logic in the author's interpretation of the results.

1) The title states that "oxytocin-mediated social enrichment promotes longevity and novelty seeking". The authors did not measure life span of their experimental animals, only telomere length. To my understanding, telomere length is not equivalent to longevity and thus I find the title misleading.

2) This is my main concern: the authors showed that social housing increased oxytocin (OT) level in both male and female rats, but only increased telomere length in female rats. Administration of the OT antagonist blocked the effect of social housing in both males and females, but only blocked TL increase in social females. Based on these results, the authors concluded that "…extended social experiences modulate TL and novelty seeking through the OT system in a sex-dependent manner…" (Abstract). These is extensive literature reporting oxytocin as a "social hormone", thus the correlation between oxytocin level and social housing is consistent with other published results. To my knowledge, the link between oxytocin level and telomere length has not been previously reported and certainly there are no proposed mechanisms. Under these circumstances, I would be more willing to accept the authors' correlative results as potentially interesting and significant, if the correlations between oxytocin level and telomere length were similar to those of social housing, i.e. either both correlations held for males and females, or both held for only females.

3) I do not know the telomere field, but is telomere length in the ear representative of the entire body? Would telomere length in multiple cell types need to be measured to reach a conclusion?

4) I do not agree with the authors' interpretation of their results, in statements such as: "The present study demonstrates a key role of OT in socially mediated behavioral fitness and telomere length as an indicator of overall health and longevity" (Discussion section); "…Thus OT is causally involved in mediating beneficial effects of social experience on behavior and TL…" (Discussion section), and "The present data causally associates social stimulation with genetic and behavioral improvements as a function of endogenous OT" (subsection “Conclusion”). The authors did not measure behavior fitness, health or longevity. Based on arguments presented in point 2 above, I don't think the results provided sufficient evidence to demonstrate a causal link between OT and TL. In order to demonstrate a causal link, at a minimum, the authors would need to demonstrate that in vivo OT administration can promote telomere length, and that the effect of social housing on telomere length are abolished in oxytocin knockout mice. Telomere length needs to be measuring in multiple tissues and not just ear punches. Also, no statements can be made regarding behavior fitness, health or longevity unless data is provided.

5) Related to points 2 and 4 and given the discussion regarding how accurately oxytocin level in the plasma measured using RIA or ELISA reflects oxytocin level in the brain, the authors could measure oxytocin mRNA level or immunostain for oxytocin in brain sections, to further establish the correlation between oxytocin level and telomere length.

6) Results presented in Figure 2A-D are very similar to that presented in a previous publication from the same lab (Faraji et al., 2018). The authors should reference their previous results in the Results section, and not just the Materials and methods section.

7) Statements such as "…Thus, social females' exploration in the corridor zone decreased -1.84 for each pM of OT concentration" (subsection “Novelty-Seeking Behaviour in Females was Significantly Influenced by Social Experiences”), and "…TL, therefore, only in social females increased 8.53 bp for each pM of OT level" (subsection “Novelty-Seeking Behaviour in Females was Significantly Influenced by Social Experiences”), do not make sense to me, as the data points for TL range from 4000 to 5700 bp, and that for OT range from around 40 to 125 pM. In light of huge differences in the levels of OT and TL, these precise interpretations do not make much sense to me.

[Editors’ note: what now follows is the decision letter after the authors submitted for further consideration.]

It is great that you did saline controls. Of course, it is a problem that none of the reviewers realized that. Please address this by making it far more evident in the manuscript. Also make sure that the saline groups make their way into the figures. Finally, please respond to the other issues raised by the reviewers. We look forward to your resubmission.

[Editors’ note: the author responses to the first round of peer review follow.]

Our decision has been reached after consultation between the reviewers. Based on these discussions and the individual reviews below, we regret to inform you that your work will not be considered further for publication in eLife.

The reviewers' chief concern is the lack of an OXT antag control. It is plausible that the stress of the non-trivial number of injections was the active agent here rather than the pharmaceutical compound. If the authors came back with such a control, we would be interested in such a (new) submission. The authors may also benefit from a number of other comments from the reviewers including walking back some of the conclusions to acknowledge the correlational nature of the data as well as the lack of a compelling direct path from housing to telomere length regulation.

Reviewer #1:

There is a lot to like and a fair amount to easily worry about in this study. The big positives are the large groups compared to normal social housing. Comparing normal (yet deprived in the natural scheme of things) to enriched (probably close to true normal for rats) is a strong design, far better than comparing 2-4 rodent groups (deprived) to social isolation (a ridiculous condition with no ecological correlate). The investigation of brave behavior (going in to the OF center with or without an object there) across the sexes and housing conditions is an interesting design aimed at important questions regarding early social development and sexual dimorphisms. The biggest issue with this paper is the lack of an injection control for the OT antag injections. The results obtained – less exploration of the center after the antag – could easily result from a differential effect of stress (the stress of 28 injections!!) on females compared to males, Is this issue surmountable with the data in hand? I fear no but look forward to seeing what the other reviewers think.

As stated in the manuscript (Materials and methods section), physiologic saline solution was injected in control groups. The new paragraph now reads:

“…Physiologic saline solution was injected subcutaneously in control groups (42-43 doses/rat) to avoid the confounding differential effect of stress resulted by repeated OT ANT injections.”

We also included the word “saline” in control group terminology in Figures 3 and 4 in order to highlight the saline injections in all control animals in Experiment 2 (please see Figure 3A-D, and Figure 4A-D, F and H).

At the outset of the results it is necessary to state how many rats are in social (n=10-11) and standard (n=2-3) groups. It would also be useful to state how the rats from different litters were assigned to the groups. The no difference reported across litter is not interpretable without this information.

We appreciate this comment and haveaddressed this concern by re-writing the first sentence of the Results section in the manuscript as the reviewer suggested. The new sentence now reads:

“…Figure 1A shows the changes in plasma OT concentrations across different groups as a function of housing condition (Standard, males: n=23, females: n=21; Social, males: n=22, females: n=22)…”.

Also:

“…Examination of TL in ear notch skin cells showed that socially-raised rats (males: n=31, females: n=23) had greater telomere length than standard animals (males: n=28, females: n=27;…” (Results section).

Moreover, to further address the reviewer’s concerns we have re-written the sampling method for different litters in the manuscript that now reads:

“…Pups and their mothers were left undisturbed from postnatal day (PND) 1–21. After weaning at PND 21, 48 pups (5-6 rats per litter) gathered from 9 different litters were randomly assigned to four experimental groups in two housing conditions:…”(Materials and methods section).

Then the authors need to be far more careful about the use of the word "group." They state "…across different groups (n=21-23/group)" which appears to say that there are 21-23 in the group housed cages but in point of fact this appears to be the number of animals in the social or standard conditions. Which would imply that two Social groups (n=20-22 rats), one for each sex, were compared to 8-10 Standard groups, half for each sex? This should be explicitly stated. Then the number of rats in Figure 1A Social as 44 and in 1B as 54. Please make sense of these various numbers.

We have re-written this part of the Results section to address the reviewer’s concerns that now reads:

“Figure 1A shows the changes in plasma OT concentrations across different groups as a function of housing condition (Standard, males: n=23, females: n=21; Social, males: n=22, females: n=22). A significant effect of Housing Condition was observed in terms of circulating OT concentration (Social vs. Standard; F_1,86=24.85, p≤0.001) and Group (social males and females vs. standard males and females; F_3,84=13.69, p≤0.001), suggesting…”..

A significant effect of Housing Condition (F1,86=24.85, p{less than or equal to}0.001) and Group (F3,84=13.69, p{less than or equal to}0.001). By Group do the authors mean sex? I thought the conditions were the groups. This is very confusingly written. I think the authors are saying there are 4 groups whereas it should be a 2x2 factor design with housing – 2 conditions – and sex – 2 groups.

Please, refer to the previous comments. Also, we have included further information into the Statistical Analysis about how we defined and analyzed variables in order to address this major concern. The new inclusion now reads:

“…Effects of main factors (Housing Condition; 2 levels, Group; 4 & 8 levels, Sex; 2 levels, Zone; 3 levels, Litter; 9 & 11 levels) were analyzed separately for the time spent in CFT, with and without …” (Materials and methods section).

It appears that the groups are mixed males and females. Are some of the females then pregnant? If this is the case, then some of the females must be pregnant which would obviously change their behavior. Please explain.

The authors apologize for not making this clear enough in the manuscript. Males and females were raised separately either in social or standard housing conditions. This is mentioned in the revised manuscript in the Materials and methods section for further explanation.

There is no saline control for the OT antag injections. This is an experimental choice that must be justified and is possibly a deal-killer.

We have addressed these concerns by including a new paragraph. The new paragraph now reads:

“…Physiologic saline solution was injected subcutaneously in control groups (42-43 doses/rat) to avoid the confounding differential effect of stress resulted by repeated OT ANT injections.” (Materials and methods section).

We also included the word “saline” in control group terminology in Figures 3 and 4 in order to highlight the saline injections in all control animals in Experiment 2 (please see Figure 3A-D, and Figure 4A-D, F and H).

The injections were "every other day (between 11:00-12:00 am) for 13 days (in total, 28 doses/rat)…" Clearly every other day for 13 days does not yield 28 doses per rat. So, this needs to be rewritten into careful English so that the reader is told what was done.

Many thanks for the comment, and we apologize for this mistake. We rephrased the sentence that now reads:

“…was administered (50 mg/kg) subcutaneously into the scruff of the neck in the OT ANT groups in Experiment 2. Administration occurred every other day (between 11:00-12:00 am) for 42-43 days (in total, 42-43 doses/rat) to intermittently inhibit or reduce OT secretion.…” (Materials and methods section).

Reviewer #3:

This paper demonstrated that long-term social housing in the juvenile period enhanced peripheral OT secretion, together with longer TL. Novelty-seeking behavior was also increased by social housing. These housing effects were more robust in females. The data are interesting because the authors examined causality between OT secretion, TL and behavior. Even though there is no neuron/ brain region analysis conducted, the findings would reveal a new function of OT.

Here are my concerns,

1) Ear notch samples were used to assess TL, but is there any evidence showing that these cells express oxytocin receptor? If so, please add the reference in the Materials and methods section. If not, the authors need to include the discussion how blood OT can affect TL in these OTR-lacking cells.

This is a wonderful suggestion which we take very seriously. Indeed, we found out that at least in three previously published papers by Kitano et al., (1997), Bolan and Goren, (1987) and Deing et al., (2013), OT receptors were found to be expressed in the rat inner ear and epididymal adipocytes, and human skin. Two of them are cited now in the manuscript (please see Materials and methods section) to address the reviewer’s concerns. Moreover, the authors hypothesize that one possible mechanism in bridging increased plasma OT concentration to telomere elongation in the present experiments likely relies upon axo-vasal contacts for endocrine neurosecretion (please see Knobloch and Grinevich, 2014). By its traditional definition, endocrine neurosecretion refers to release and delivery of OT, VP and their homologues to systemic blood circulation. It is traditionally assumed that blood stream carries these molecules (e.g. OT) to their receptors which are abundantly expressed in peripheral organs such as uterus, mammary glands, intestinal tracts, heart, and more specifically in this case, even in the skin. Thus, we anticipate that a major part of the observed changes in TL induced by prolonged social experiences and the following OT enhancement is influenced by the axo-vasal contacts, which reveals an alternative explanation of the dynamic dialogue between the central capacities and peripheral repertoires in response to social experiences.

Also, to further address the reviewer’s concerns, we included a new paragraph in the discussion that now reads:

“…The pathways through which telomere elongation is influenced by peripheral OT enhancement or inhibition are not yet fully understood. For the present results, axo-vasal contacts for endocrine neurosecretion¹⁴, a prominent central-peripheral axis which releases OT, vasopressin (VP) and their homologues into systemic blood circulation, may explain how alterations in peripheral OT can influence TL measured in the samples collected from ear…” (please see subsection “Social Experiences Increase TL in Females via OT Enhancement”).

2) OT antagonist L-366,509 was used to inhibit OT system in the CNS. Please add the information about penetration of this chemical through blood brain barrier in the Materials and methods section.

We appreciate this thoughtful comment. To our best knowledge, there is no detailed proof available in the literature for the penetration of antagonist L-366,509 through the blood-brain barrier. However, based on experimental evidence, we assumed that L-366,509 crosses the blood-brain barrier. First, all lipophilic molecules readily cross the blood-brain barrier, even though hydrophilic molecules including OT itself do not (please see McEwen, 2004; Churchland and Winkielman, 2012). Because camphor-based non-peptide OT antagonists such as L-366,509 belong to bulky, lipophilic groups (see Evans et al., 1992) that have a high tolerance and considerably improved solubility in aqueous media, we anticipate that antagonist L-366,509 crosses the blood-brain barrier. Second and more importantly, the non-peptide OT antagonist L-368,899 is a newer member of structural classes of spiroindenes that is structurally derived from L-366,509 (see Williams et al., 1994). The most prominent difference between these two antagonists, however, refers to the higher affinity of L-368,899 rather than L-366,509 for OT receptors. Hence, as L-368,899 is reported to cross the blood-brain barrier with selective accumulation in specific areas of the limbic system where it might inhibit OT-induced social behaviours (see Smith et al., 2010), it allowed the authors to predict that antagonist L-366,509 can also cross the blood-brain barrier.

We fully agree that this issue has to be reported in the manuscript, and we apologize for this shortcoming. Therefore, we addressed the reviewer’s concern in the manuscript in a new paragraph that reads:

“…Although there is no information available on the penetration of L-366,509 into the blood-brain barrier (BBB) in the literature, a new generation of spiroindenylpiperidine camphor-sulfinamide OT antagonist (Williams et al., 1994) which readily crosses the BBB (Smith et al., 2010) was developed from L-366,509 with the same structural and lipophilic molecular characteristics. Thus, it is likely that antagonist L-366,509 crossed the BBB.” (please see Materials and methods section).

3) The authors mentioned the function of OT on the HPA axis, but this paper did not include the data of corticosterone. If the blood samples remain, please measure corticosterone, to make the conclusion more convincing.

The reviewer is absolutely right that CORT data could potentially provide support for the current results. Unfortunately, due to economic instabilities in Iran and other practical constraints we were unable to do these analyses. We deeply regret this issue as we indeed had initially planned on these analyses. Instead, to compensate for the lack of information of CORT changes, we now discuss our results in the light of previous relevant work by others and by our team in the Discussion section. The considerable amount of existing evidence provides solid support for our current findings. Again, we very much apologize for this shortcoming.

4) Related to #2 and #3, higher corticosterone exposure will shorten the TL in peripheral cells. Please add the corticosterone data if possible.

Please, see comment #3.

5) Were the changes observed in social-housing rats caused by social interactions?

This is an excellent point for consideration, thank you. We agree with the reviewer that both experiments in the present study could be conducted with more controls to better control for potentially confounding variables, even though we have done our best to have most of the confounding variables controlled. Also, it is very difficult to mention that changes observed in the present experiments were only the results of social interactions, because other uncontrolled external factors simultaneously may confound and/or overshadow our results. However, we strongly believe that social interactions as the most prominent component of social-housing condition designed here played a key role in the changes reported in the present study. Please refer to our logics in the next part of our answer to this comment.

If the rats were housed in a large area, the locomotor activity can increase. In this experimental setting, the authors cannot conclude that the changes were caused by social interactions. There might be an appropriate control group needed, such as similar locomotor activity without social interaction. If the authors cannot exclude the effect of activity (physical exercise can facilitate OT secretion, TL etc.), the discussion should be modified.

As stated in the manuscript (please see Materials and methods section), the same size of cage (86 cm × 86 cm × 41 cm) was used for the social and standard housing conditions, thus varying only the number of cage mates (standard, n = 2–3 vs. social, n =10- 11) while keeping the size of the environments constant (please see Faraji et al., 2018 for further details on the housing conditions). For two reasons, therefore, we do not agree with the reviewer that the observed changes are influenced by the enhanced level of physical activities in social-housing condition. First, if physical activity could determine the incidence or the extent of changes, all of these changes should be normally observed in the standard animals (here, controls) who were raised in the large but less crowded units. Second, changes in OT levels in response to physical activity induced by voluntary wheel running in rats are not entirely evident, yet (for instance, please see Broderick et al., 2014 and Bakos et al., 2007). Moreover, physical activity, to our knowledge, has been shown to impact OT levels in humans only if associated with a more strenuous type of physical exercise (see also Frisen et al., 2017 and Landgraf et al., 1982, for example). No additional enrichment stimulus such as a running wheel was provided for rats in neither standard nor social housing conditions. Further follow-up studies that address these issues would make a timely contribution to the literature.

6) The social housing was conducted just after the weaning, so the effects of social housing would be robust (still in the developmental period). If the social housing were to be conducted in the adulthood or aged rats, could the same positive affects be observed? In humans, social loneliness in elderly is one of the important social issues related to the health problems.

This is a very interesting question and worthy a follow-up study. Unfortunately, the present data do not allow a conclusion on social enrichment effects in older age, although previous data suggest that this assumption is very reasonable and worthy of further consideration (For example, please see Okabayashi’s report about social interactions and their effects on subjective well-being among Japanese elders; Okabayashi and Houghman, 2014).

Reviewer #4:

In manuscript by Faraji et al., the authors reported correlations between circulating oxytocin concentration and prolonged social housing, in both male and female rats. They further showed that prolonged social housing correlated with elongated telomere length in only in female rats, an effect blocked by the oxytocin antagonist L-366,509. While the correlation between oxytocin and telomere length is potentially interesting, I believe that there are some gaps of logic in the author's interpretation of the results.

1) The title states that "oxytocin-mediated social enrichment promotes longevity and novelty seeking". The authors did not measure life span of their experimental animals, only telomere length. To my understanding, telomere length is not equivalent to longevity and thus I find the title misleading.

We appreciate this comment and changed the title. The revised title now reads:

Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking

2) This is my main concern: the authors showed that social housing increased oxytocin (OT) level in both male and female rats, but only increased telomere length in female rats. Administration of the OT antagonist blocked the effect of social housing in both males and females, but only blocked TL increase in social females. Based on these results, the authors concluded that "…extended social experiences modulate TL and novelty seeking through the OT system in a sex-dependent manner…" (Abstract). These is extensive literature reporting oxytocin as a "social hormone", thus the correlation between oxytocin level and social housing is consistent with other published results. To my knowledge, the link between oxytocin level and telomere length has not been previously reported and certainly there are no proposed mechanisms. Under these circumstances, I would be more willing to accept the authors' correlative results as potentially interesting and significant, if the correlations between oxytocin level and telomere length were similar to those of social housing, i.e. either both correlations held for males and females, or both held for only females.

We would like to address this thoughtful and challenging comment by discussing several main arguments. First and most importantly, we believe that the experimental design of the present study enables us to make causal conclusions for the most parts of the results. Therefore, although for some experimental constraints we did not identify and/or offer a causal mechanism to connect variations in dependent variables such as peripheral OT levels to the TL, our data are still able to profile a clear “causal effect” for the independent and dependent variables, beyond the mere correlational conclusion. Indeed, the presence of control group(s) in both experiments assures empirical correlation along with temporal priority of the independent variable, thus providing a solid causal effect. Like the reviewer, the authors are also concerned about spurious data interpretation. Moreover, heavily standardized conditions by which we raised the groups of animals in standard units and aged-matched groups in a social environment helped us to interpret most variations in dependent variables (behavioural, hormonal and genetic) in the light of a causal conclusion. We believe that if we could (1) provide evidence of empirical association between at least one independent variable and one dependent variable, (2) confirm temporal priority of the independent variable (here, housing condition) using control groups, and also (3) tried to have nonspurious changes which were not influenced by irrelevant variable(s), the minimum criteria for making an experimental casual effect are met. Therefore, we believe that as long as we are able to manipulate the independent variable in a systematic manner and address internal and external control variables using careful implementation and analysis, the causal conclusion (if A [where A is social experience], then B [where B is OT enhancement and/or telomere elongation) can be possible and suggested.

Second, we agree with the reviewer that “…these is extensive literature reporting oxytocin as a "social hormone", thus the correlation between oxytocin level and social housing is consistent with other published results…”. However, to our knowledge, most of these correlational reports are depicting a hormone-to-behaviour approach (as stated in the manuscript) through which subjects are exposed to OT first, and then they are monitored for possible behavioural impacts of OT. In the present experiment, by contrast, we have chosen an alternative, behaviour-to-hormone approach by which we examined the impact of prolonged social experience on OT levels. This approach provides a new argument of causality to our results and conclusions as opposed to most literature about the experimental administration of OT and its consequences.

Third, we regard our data as considerably valid to causally link social lifestyle in early development (the major independent variable) among females to behavioural, endocrine and genetic outcomes (dependent variables). This seems more important when such changes are questioned in response to interruptions in social relationships among females and their health consequences, or when factors that in general determine telomere length in early life are investigated. Also, simultaneous responses (enhanced novelty seeking, increased levels of OT and telomere elongation) of females to persistent social experiences have implications in future investigations to causally hypothesize these changes. Examples include sex hormones that were previously shown to play a key role in telomere length (see Calado et al., 2006, for example) or for neurotrophins (e.g. BDNF) that are confirmed to influence telomere function (see Niu and Yip, 2011) and OT receptors in women (see Chagnon et al., 2015).

3) I do not know the telomere field, but is telomere length in the ear representative of the entire body? Would telomere length in multiple cell types need to be measured to reach a conclusion?

These are very exciting questions. The answer to both questions is “not necessarily”, even though the TL in lifespan is gender-related and follows a tissue-specific regulation during development. Indeed, the TL within individual tissues is regulated independently. In humans, TL seems highly variable between tissues and individuals. However, samples taken from peripheral organs such as kidney, liver, lung, etc. for inter-tissue comparison in intact rats are showing the same profile of changes in the TL (please, see Cherif et al.,’s work, such as Cherif et al., 2003). Also, studies with various strains of mice did not detect any differences in TL between tissues such as liver, testes or kidney (for instance, please see Coviello-McLaughlin and Prowse, 1997), although the TL generally differs between species. Moreover, TL in hearts and lungs in rats are equally affected by physical stress (please, see Wang et al., 2018) meaning that peripheral organs are possibly showing similar telomeric responses to experimental manipulations. Therefore, because different tissue types may represent different deterioration processes along with variable mortality, inter-tissue analysis in humans can potentially create more valid assessment of TL alterations in response to developmental influences or environmental manipulations. However, this does not seem to be necessarily required in rats as mentioned above. The only exception is for the TL in the brain tissues in rats and mice that were shown to depict different rates of TL alterations when compared with, for instance, spleen or other peripheral organs. Importantly, the reasons by which we have chosen the ear notch samples in the present study, in addition to the ease of collection, was that samples from ear are emerged from ectoderm, the same lineage as brain tissue. Like brain tissue, skin samples also contain a mixture of collagenous proteins, reticulin, vasculature, and connective tissues such as fibroblasts and adipocytes. Therefore, changes in rat peripheral TL in general, and skin cells in particular not only may represent TL changes in other organs influenced by experimental interventions, but also arguably predict TL alterations in the brain tissue (please see Hehar and Mychasiuk, 2016). To address this concern, we have included a new statement in the Discussion section that now reads:

“…It is also important to consider that, as they share a common ontogenetic origin from ectoderm, both brain and skin tissues contain similar collagenous proteins, reticulin, vasculature, and connective tissues such as fibroblasts and adipocytes. Therefore, changes in peripheral TL in general, and skin cells in particular, predict TL alterations found in brain tissue (Hehar and Mychasiuk, 2016).

4) I do not agree with the authors' interpretation of their results, in statements such as: "The present study demonstrates a key role of OT in socially mediated behavioral fitness and telomere length as an indicator of overall health and longevity" (Discussion section); "…Thus OT is causally involved in mediating beneficial effects of social experience on behavior and TL…" (Discussion section), and "The present data causally associates social stimulation with genetic and behavioral improvements as a function of endogenous OT" (subsection “Conclusion”). The authors did not measure behavior fitness, health or longevity.

Thanks to the reviewer for these comments. We have made some changes in the sentences in the manuscript as the reviewer requested. We hope that these changes address the reviewer’s concerns:

- Old sentence: “…The present rodent study demonstrates a key role of OT in socially mediated behavioral fitness and telomere length as an indicator of overall health and longevity…”.

New sentence: “…The present rodent study indicates that persistent social experience is causally associated with increased OT level, elevated exploratory behaviour, and telomere elongation….” (please see Discussion section).

- Old sentence: “…Thus OT is causally involved in mediating beneficial effects of social experience on behaviour and TL…".

New sentence: “…Thus OT is arguably involved in mediating beneficial effects of social experience on behaviour and TL…” (please see Discussion section).

- Old sentence: “…The present data causally associates social stimulation with genetic and behavioural improvements as a function of endogenous OT…".

New sentence: “…The present data causally associates social stimulation with genetic and behavioural improvements possibly as a function of endogenous OT…” (please see Discussion section).

Based on arguments presented in point 2 above, I don't think the results provided sufficient evidence to demonstrate a causal link between OT and TL. In order to demonstrate a causal link, at a minimum, the authors would need to demonstrate that in vivo OT administration can promote telomere length, and that the effect of social housing on telomere length are abolished in oxytocin knockout mice. Telomere length needs to be measuring in multiple tissues and not just ear punches. Also, no statements can be made regarding behavior fitness, health or longevity unless data is provided.

We agree with the reviewer that data in the present experiments cannot draw a direct line to connect changes in OT levels to TL, as the study was not originally designed for such questions. However, we still believe that the present data can make causal conclusion(s) for bridging the independent variable (i.e. social life) and dependent variables (i.e. enhanced novelty-seeking, increased levels of OT and/or telomere elongation). Please see our rationales in response to comment 2. Moreover, even though longevity was not measured in the present study, TL itself has been proposed as a potential biomarker for longevity in humans, mice, and other organisms in many studies (please, see Calado and Dumetrio, 2013, for example). More importantly, as shown by Monaghan’s team, TL in early life predicts lifespan (see Heidinger et al., 2012). From our viewpoint, results in our experiments significantly advance the understanding factors that may causally determine early life influences on TL.

5) Related to points 2 and 4 and given the discussion regarding how accurately oxytocin level in the plasma measured using RIA or ELISA reflects oxytocin level in the brain, the authors could measure oxytocin mRNA level or immunostain for oxytocin in brain sections, to further establish the correlation between oxytocin level and telomere length.

We appreciate this comment and apologize for our mistake. The authors confirm that 7 standard animals (4 males and 3 females) and 6 social animals (3 males and 3 females) from our previous experiment were included into the analysis of novelty-seeking behaviour in Experiment 1 in the present study. The inclusion of these animals has been conducted to increase sample size and to reduce within-group variation, thus achieving more precise estimates of average. To address the reviewer’s concern, we included a new sentence into the Material and Methods section which seemed more relevant that now reads:

“…Novelty-seeking behaviour analysis included 7 standard animals (4 males, 3 females) and 6 social animals (3 males, 3 females) from a previous experiment (Faraji et al., 2018) to increase sample size…”.

6) Results presented in Figure 2A-D are very similar to that presented in a previous publication from the same lab (Faraji et al., 2018). The authors should reference their previous results in the Results section, and not just the Materials and methods section.

Thank you for the great suggestion. Some of us (SR and RM) are analysing brain tissues for OT responses in the PVN and SON in the hypothalamus in response to social life, but unfortunately the results might not be reported in the present manuscript due to the extended amount of time required for such analyses. For the present study, based on previous findings in the literature we assumed that peripheral levels of OT can properly reflect central releases of OT in rats (for example, please see Wotjak et al., 1998). Furthermore, it seems that there is a coordinated axonal release of OT in the brain and in the circulatory system, and central OT and peripheral OT in animals can be released simultaneously. In humans, a correlation was shown between plasma and brain OT indicating that (at least under specific testing conditions) peripheral OT represents a suitable proxy of central OT (please see Lefvre and others 2017). Therefore, the authors believe that plasma OT concentration in the present study can be considered as a marker of its action in the brain. To address this concern, we have included a new statement in the Discussion section that now reads:

“…Axonal release of OT in the brain and in the circulatory system seem to be coordinated as central OT and peripheral OT in rats can be released simultaneously (Wotjak et al., 1998). In humans, a correlation was shown between plasma and brain OT indicating that peripheral OT represents a suitable proxy of central OT (Lefvre et al., 2017).

7) Statements such as "…Thus, social females' exploration in the corridor zone decreased -1.84 for each pM of OT concentration" (subsection “Novelty-Seeking Behaviour in Females was Significantly Influenced by Social Experiences”), and "…TL, therefore, only in social females increased 8.53 bp for each pM of OT level" (subsection “Novelty-Seeking Behaviour in Females was Significantly Influenced by Social Experiences”), do not make sense to me, as the data points for TL range from 4000 to 5700 bp, and that for OT range from around 40 to 125 pM. In light of huge differences in the levels of OT and TL, these precise interpretations do not make much sense to me.

We agree and are now convinced that the reviewer is absolutely right. Therefore, we omitted both sentences from the manuscript to address the reviewer’s concerns.

[Editors’ note: the author responses to the re-review follow.]

It is great that you did saline controls. Of course, it is a problem that none of the reviewers realized that. Please address this by making it far more evident in the manuscript. Also make sure that the saline groups make their way into the figures. Finally, please respond to the other issues raised by the reviewers. We look forward to your resubmission.

We appreciate this comment and have addressed these concerns by re-writing the corresponding sentence in the manuscript as the reviewer suggested. The new paragraph now reads:

“…Physiologic saline solution was injected subcutaneously in control groups (42-43 doses/rat) to avoid the confounding differential effect of stress resulted by repeated OT ANT injections.” (please, see Materials and methods section).

We also included the word “saline” in control group terminology in Figures 3 and 4 in order to highlight the saline injections in all control animals in Experiment 2 (please, see Figure 3A-D, and Figure 4A-D, F and H).

Author details

1. Jamshid Faraji

   1. Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Canada
   2. Faculty of Nursing & Midwifery, Golestan University of Medical Sciences, Gorgan, Iran

   Contribution

   Conceptualization, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1726-5836

2. Mitra Karimi

   Inclusive-Integrated Education Program for Children with Special Needs, Exceptional Education Organization, Tehran, Iran

   Contribution

   Supervision, Investigation, Visualization, Project administration

   Competing interests

   No competing interests declared

3. Nabiollah Soltanpour

   Department of Anatomical Sciences, Babol University of Medical Sciences, Babol, Iran

   Contribution

   Conceptualization, Data curation, Supervision, Investigation, Methodology, Project administration

   Competing interests

   No competing interests declared

4. Alireza Moharrerie

   Department of Anatomy, Golestan University of Medical Sciences, Gorgan, Iran

   Contribution

   Formal analysis, Supervision, Investigation, Project administration

   Competing interests

   No competing interests declared

5. Zahra Rouhzadeh

   Department of Psychology, Islamic Azad University, Sari, Iran

   Contribution

   Investigation, Project administration

   Competing interests

   No competing interests declared

6. Hamid lotfi

   Department of Psychology, Islamic Azad University, Tonekabon, Iran

   Contribution

   Supervision, Investigation, Project administration

   Competing interests

   No competing interests declared

7. S Abedin Hosseini

   Faculty of Nursing & Midwifery, Golestan University of Medical Sciences, Gorgan, Iran

   Contribution

   Investigation, Project administration

   Competing interests

   No competing interests declared

8. S Yaghoob Jafari

   Faculty of Nursing & Midwifery, Golestan University of Medical Sciences, Gorgan, Iran

   Contribution

   Investigation, Project administration

   Competing interests

   No competing interests declared

9. Shabnam Roudaki

   Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd, Iran

   Contribution

   Formal analysis, Supervision, Investigation, Methodology, Project administration

   Competing interests

   No competing interests declared

10. Reza Moeeini

    Department of Behavioural Studies, Avicenna Institute of Neuroscience, Yazd, Iran

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Validation, Methodology, Project administration, Writing—review and editing

    For correspondence

    reza.moeeni123@gmail.com

    Competing interests

    No competing interests declared

11. Gerlinde AS Metz

    Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Canada

    Contribution

    Conceptualization, Resources, Supervision, Methodology, Writing—review and editing

    For correspondence

    gerlinde.metz@uleth.ca

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-5801-7716

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