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Cited by 2Neurotransmitter Receptor Influence on BehaviorStress Responses and CortisolTreatment of Major Depression

Social isolation and predator scent tests alter brain BDNF levels differentially according to gender, in rats and effects of fluoxetine

Open access
Aykaç, Aslı, Öncül, Şule, Onur, Rüştü·2018·Marmara Pharmaceutical Journal
DOI 10.12991/mpj.2018.56
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Abstract

We compared different stress conditions on brain BDNF levels, in rats exposed to social isolation test (SIT) and predator scent tests (PST).BDNF expression in the frontal cortex, hippocampus, and amygdala was compared, and effects of chronic fluoxetine (FLU) treatment were evaluated.Rats were exposed to SIT and PST for one month.FLU was given (5 mg/kg/day, ip) throughout stress procedures.Controls, stress, and treatment groups were evaluated in elevated plus maze, anxiety scores were calculated.BDNF expression was determined by Western blot.SIT and PST induced anxiety in both sexes, females had greater anxiety scores than males (p<0.05).FLU restored anxiety scores in both sexes (p<0.01) in both tests.Male and female rats exhibited reduced cortical BDNF levels in SIT (p<0.001).PST reduced cortical BDNF in females, but increased in males.Hippocampal BDNF expression was lowered in SIT (p<0.01) and PST (p<0.001) in both sexes.Female rats had 40% lower BDNF expression than males in the amygdala in SIT.FLU did not restore cortical BDNF in females in both tests, but reduced increased BDNF levels in males in PST (p<0.001).FLU did not restore reduced brain BDNF in males in the hippocampus and amygdala, but restored in hippocampus, in females.Our findings indicate that sex differences must be considered in studies related to mood disorders of animal models, and suggest that BDNF expression in different brain regions are altered differentially in a gender-dependent manner in rats.Antianxiety effect of FLU is not mediated through increasing BDNF activity in cortex in both genders.Increased BDNF in hippocampus and amygdala may reflect antidepressant effect of FLU in female rats, but not in males.

AI snapshot

Written from the paper’s full text.

TL;DR

In rats, one-month social isolation and predator scent stress induced anxiety and altered BDNF in frontal cortex, hippocampus, and amygdala in sex- and stressor-dependent ways. Chronic fluoxetine restored anxiety scores in both sexes but did not uniformly restore BDNF, suggesting its anxiolytic effect is not mediated simply by increasing cortical BDNF.

Key findings

  • Social isolation test (SIT) and predator scent test (PST) induced anxiety in both sexes; females had greater anxiety scores than males (p<0.05), and chronic fluoxetine (FLU, 5 mg/kg/day, i.p.) restored anxiety scores in both sexes in both tests (p<0.01).
  • In frontal cortex, SIT reduced BDNF in both sexes (p<0.001); PST reduced cortical BDNF in females but increased it in males (p<0.05). FLU did not restore cortical BDNF in females in either test, but reduced the increased cortical BDNF in males in PST (p<0.001).
  • Hippocampal BDNF was lowered by SIT (p<0.01) and PST (p<0.001) in both sexes. FLU restored hippocampal BDNF in females in both tests (p<0.05 and p<0.01, respectively) but not in males.
  • In amygdala, females had about 40% lower BDNF than males after SIT; SIT reduced amygdala BDNF in females (p<0.001) but not males, while PST reduced it in males (p<0.05) but not females. FLU restored the SIT-induced reduction in females (p<0.05) but did not influence male amygdala BDNF.

Methods

  • Sprague-Dawley rats of both sexes (180–200 g), total 128 rats, eight per group; groups were control, FLU alone, stress, and stress+FLU for each stress test, after a 10-day acclimation period.
  • Stress procedures: social isolation (one rat per cage for one month) or predator scent test (10 min on dirty cat litter, with a clean-litter reminder one month after onset). Fluoxetine was given at 5 mg/kg/day i.p. for one month; anxiety was assessed by elevated plus maze.
  • BDNF protein in frontal cortex, hippocampus, and amygdala was measured by Western blot (n=4 rats per group for immunoblotting, duplicate analyses; β-actin normalization). Statistics used two-way ANOVA with Bonferroni for anxiety indices and one-way ANOVA with Tukey for immunoblotting; p<0.05 was significant.

Limitations

  • Stated: the paper notes that the human disorder is not identically mimicked in animals, and that examination of BDNF expression in the amygdala in PST may not be suitable for evaluation in rat models of depression.
  • Evident from the text: immunoblotting used n=4 rats per group, limiting statistical power; only one fluoxetine dose (5 mg/kg/day) was tested; and the text does not report controlling for estrous cycle phase in female rats.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.12991/mpj.2018.56

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Female rats had significantly greater basal BDNF density in frontal cortex than male rats exposed to SIT (p<0.01).

    “Female rats had significantly greater basal BDNF density in the frontal cortex than male rats that were exposed to SIT (Figure 2a, p<0.01).”
    Quote in the paperSubstantial claim
  • Findingown data

    This difference in basal BDNF density in frontal cortex was not observed in animals exposed to PST.

    “However, this difference was not observed in the animals that were exposed to PST.”
    Quote in the paperSubstantial claim
  • Findingown data

    FLU alone (5 mg/kg) did not appreciably alter anxiety indexes in both stress tests and both genders.

    “Administration of FLU alone (5 mg/kg) did not appreciably alter anxiety indexes in both stress tests and both genders.”
    Quote in the paperNot a substantial claim
  • Findingown data

    SIT and PST induced anxiety in both male and female rats.

    “We observed that SIT and PSTs effectively induced anxiety in both male and female rats.”
    Quote in the paperSubstantial claim
  • Findingown data

    In PST, female rats exhibited significant reduction in cortical BDNF levels (p<0.001).

    “PST reduced cortical BDNF in females, but increased in males.”
    • Also stated in: § 2. RESULTS · plain
      “Female rats exhibited a significant reduction in BDNF levels when they are exposed to both SIT (p<0.001) and PST (Figure 2a and 2b, p<0.001).”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 20

  • May combine two claims.

    Findingown data

    Chronic FLU treatment restored anxiety scores of rats towards control values, significantly lower than stressor groups, in both female (p<0.01) and male (p<0.001) rats in both SIT and PST.

    “Chronic FLU treatment restored anxiety scores of rats towards control values and the anxiety indexes were found to be significantly lower from that observed in the presence of stressors for both female (p<0.01)and male (p<0.001)rats in two settings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In PST, male rats did not show reduced cortical BDNF levels; an increase was noted (p<0.05).

    “However, PST did not reduce cortical BDNF levels, but an increase was noted in the male rats (Figure 2b, p<0.05).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    SIT reduced BDNF expression in amygdala in female rats (p<0.001).

    “SIT reduced BDNF expression in the female rats (p<0.001) but did not reduce it when the PST was applied.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Anxiety-reducing effect of FLU is not mediated through cortical BDNF activity, but may be due to other mechanisms such as inhibition of serotonin reuptake.

    “This finding may suggest that anxiety-reducing effect of FLU is not mediated through cortical BDNF activity, but it may be due to other mechanisms, such as inhibition of serotonin reuptake which is the crucial mechanism of action of SSRIs in the treatment of depression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Hormonal and structural differences between female and male rats may contribute to discrepancy.

    “Hormonal and structural differences between female and male rats may also contribute to this discrepancy.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The reason for discrepancy in male rats may be due to anxiety reducing effect of FLU not solely mediated through hippocampal BDNF activity, but may be due to other mechanisms shared by other SSRIs.

    “The reason for this discrepancy in the male rats may be due to an anxiety reducing effect of FLU is not solely mediated through hippocampal BDNF activity, but may be due to other mechanisms shared by other SSRIs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    In SIT, female rats displayed reduced BDNF levels markedly in amygdala when compared with other brain regions, and FLU treatment normalized this reduction concomitantly with its antidepressant effect.

    “In the SIT, female rats displayed reduced BDNF levels markedly in the amygdala when compared with other brain regions, and FLU treatment normalized this reduction concomitantly with its antidepressant effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Increased BDNF in hippocampus and amygdala may reflect antidepressant effect of FLU in female rats, but not in males.

    “Increased BDNF in hippocampus and amygdala may reflect antidepressant effect of FLU in female rats, but not in males.”
    • Also stated in: § 4. CONCLUSION · hedged
      “Increased BDNF expression in hippocampus and amygdala may reflect an antidepressant effect of FLU in the female rats, but not in the males.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Increased cortical BDNF expression in male rats may be genetically encoded, rather than in females, since males are more prone to natural predators.

    “This increased cortical BDNF expression may be genetically encoded in the male rats, rather than in the females, since the males are more prone to be exposed to natural predators and this mechanism may initiate effective protective neuronal or humoral responses concomitant with increased anxiety.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Our results indicate that there is a definite response to FLU treatment for both social isolation and predator stress groups regarding hippocampal BDNF levels.

    “Our results indicate that there is a definite response to FLU treatment for both social isolation and predator stress groups regarding hippocampal BDNF levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    Sex differences must be considered in studies related to mood disorders of animal models.

    “Our findings indicate that sex differences must be considered in studies related to mood disorders of animal models”
    • Also stated in: § 4. CONCLUSION · hedged
      “Our findings indicate that sex differences must be considered in studies related to mood disorders of animal models”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In some experimental models, BDNF provides protection against stress-induced neuronal damage.

    “In some experimental models, BDNF is reported to provide protection against stress-induced neuronal damage [10,11]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Stress affects BDNF levels in various brain regions and thus an increased stress response in females could be responsible for increased incidence of depression in females.

    “Stress affects BDNF levels in various brain regions and thus an increased stress response in females could be responsible for the increased incidence of depression in females [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    In rats exposed to chronic psychosocial isolation stress, BDNF mRNA levels were depressed to a similar extent in hippocampus and chronic FLU treatment increased BDNF mRNA in females but not in males.

    “In rats who were exposed to chronic psychosocial isolation stress, BDNF mRNA levels were depressed to a similar extent in hippocampus and the chronic FLU treatment increased BDNF mRNA in females but not in males [23].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Institutional Ethical Committee approval was obtained.

    “After the approval from the Institutional Ethical Committee of Marmara University was obtained for this study, all experiments and treatment procedures were initiated (MÜHDEK approval no: 86.2013.mar).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hippocampus has connections with frontal cortex and amygdala, both contribute to regulation of cognition and emotional states.

    “Moreover, hippocampus has connections with frontal cortex and amygdala, both are contributed to regulation of cognition and emotional states [2,27,28].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    For immunoblotting analysis n=4 rats per group and analyses performed in duplicate.

    “For the immunoblotting analysis n=4 rats were used for each group and the analyses were performed in duplicate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    SIT and PST are well-documented methods for inducing depression-like syndrome and PTSD, respectively, in rodents.

    “SIT and PSTs are well-documented methods for inducing depression-like syndrome, and PTSD, respectively, in rodents [24,25].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [25]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Depression occurs twice as frequently in women.

    “and depression occur twice as frequently in women [19][20][21].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Random selection was performed to construct control, FLU alone, stress, stress+FLU groups for each stress test.

    “For experimental design random selection was performed to construct control, FLU alone, stress, stress+FLU treatment groups for each stress tests after 10 days of acclimation period.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Antidepressant treatments increased expression of BDNF, especially in hippocampus.

    “Animal experiments also showed that antidepressant treatments increased the expression of BDNF, especially in the hippocampus [2,14,15].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Total 128 rats were used including eight rats per group.

    “Total 128 rats were used including eight rats per group.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Neurotrophin hypothesis: stress and depression associated with decreased BDNF, antidepressants reduce depressive behavior by increasing BDNF levels in brain.

    “The neurotrophin hypothesis suggests that since stress and depression are associated with decreased expression of BDNF, antidepressants reduce depressive behavior by increasing BDNF levels in the brain [1,2,16].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [16]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    β-actin was used to normalize amount of protein loaded in each lane.

    “β-actin was used to normalize the amount of protein loaded in each lane.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Acute immobilization in rats leads to stress causing a decrease in BDNF levels.

    “In literature, acute immobilization in rats leads to stress causing a decrease in BDNF levels [5,27].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [27]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SSRIs increase expression of BDNF in brain and this effect is related to duration of antidepressant drug therapy.

    “It is known that SSRIs increase the expression of BDNF in the brain and this effect is related to the duration of antidepressant drug therapy [2,15].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Infusion of BDNF into midbrain showed an antidepressant-like effect.

    “and infusion of BDNF into the midbrain showed an antidepressant-like effect [12,13].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Types of stress such as social isolation, immobilization, restraint, and footshock decrease expression of BDNF in hippocampus and FLU increases hippocampal BDNF levels in some studies.

    “Types of stress such as social isolation, immobilization, restraint, and footshock decrease the expression of BDNF in the hippocampus and FLU increases hippocampal BDNF levels in some studies [2,14,15].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Imaging studies have shown hippocampal volume is decreased in patients with mood disorders.

    “Imaging studies have shown that hippocampal volume is decreased in those patients with mood disorders [29,30].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

29 of 29

  • The paper relies on this without support.

    Stress gives rise to anxiety and anxiety may lead to depression.

    “Stress gives rise to anxiety and anxiety in turn, may lead to (precipitate) depression.”

  • The paper relies on this without support.

    Exposure of animals to emotional or physical stress causes depression-like behavior.

    “Exposure of the animals to emotional or physical stress causes depression-like behavior.”

  • The paper relies on this without support.

    Antidepressants have been effective in alleviating depressive mood but have been less effective in decreasing symptoms of re-experiencing fear conditions.

    “Antidepressants have been effective in alleviating depressive mood but have been less effective in decreasing the symptoms of re-experiencing the fear conditions.”
3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Smith MA, Makino S, Kvetnansky R, Post RM. Stress alters the express brain derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995; 15: 1768-1777.
  2. McEwen B. Stress and hippocampus plasticity. Curr Opin Neurobiol. 1999; 5:205-216.
  3. Sapolsky R. Glucocorticoids and atrophy of the human hippocampus. Sci. 1999; 273: 749-750.
  4. Sapolsky R. Depression, antidepressant, and the shrinking hippocampus. Proc Natl Acad Sci USA. 2001; 98: 12320- 12322.

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Related

Authors
Aykaç, A., Öncül, Ş., & Onur, R.
Affiliations
Near East University (CY)
Corresponding author
Aykaç, Aslı
ORCID
Aykaç, Aslı
Venue
Marmara Pharmaceutical Journal
Publisher
Marmara University
Published
2018-04-06
Volume
22
Issue
2
Pages
190-198
ISSN
1309-0801 (ISSN-L)
DOI
10.12991/mpj.2018.56
OpenAlex
W2796015420
Semantic Scholar
9d8f29da9ac307a61fe14d772eb2f08487ddcd96
Cited by
2
References
28
Citations by year
2023: 1 · 2018: 1
FWCI
0.10
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • MARMARA PHARMACEUTCAL JOURNAL (publishedVersion, other-oa)
  • DergiPark (Istanbul University) (submittedVersion)
Funders
İstanbul Medeniyet Üniversitesi
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
brain-derived neurotrophic factor, social isolation, fluoxetine, sex differences, anxiety, chronic stress, hippocampus, amygdala, frontal cortex, antidepressant mechanism, mood disorders, rats

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