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Reply to: Multiple Comparisons and Inappropriate Statistical Testing Lead to Spurious Sex Differences in Gene Expression

      In our recent publication (
      • Walker D.M.
      • Zhou X.
      • Cunningham A.M.
      • Lipschultz A.P.
      • Ramakrishnan A.
      • Cates H.M.
      • et al.
      Sex-specific transcriptional changes in response to adolescent social stress in the brain’s reward circuitry.
      ), we used RNA sequencing of several limbic brain regions to identify sex-specific transcriptional profiles in response to cocaine that are disrupted by adolescent experience. RNA sequencing provides a powerful approach to investigate transcription on a global scale and has been instrumental in contributing to an improved understanding of brain function in recent years. For example, our laboratories have successfully employed transcriptomic analyses to identify novel key drivers important for regulating behavioral and neural abnormalities associated with stress- and addiction-related disorders [e.g., (
      • Bagot R.C.
      • Cates H.M.
      • Purushothaman I.
      • Lorsch Z.S.
      • Walker D.M.
      • Wang J.
      • et al.
      Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility.
      ,
      • Issler O.
      • van der Zee Y.Y.
      • Ramakrishnan A.
      • Wang J.
      • Tan C.
      • Loh Y.E.
      • et al.
      Sex-Specific role for the long non-coding RNA LINC00473 in depression.
      ,
      • Labonte B.
      • Engmann O.
      • Purushothaman I.
      • Menard C.
      • Wang J.
      • Tan C.
      • et al.
      Sex-specific transcriptional signatures in human depression.
      ,
      • Lorsch Z.S.
      • Hamilton P.J.
      • Ramakrishnan A.
      • Parise E.M.
      • Salery M.
      • Wright W.J.
      • et al.
      Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.
      ,
      • Pena C.J.
      • Kronman H.G.
      • Walker D.M.
      • Cates H.M.
      • Bagot R.C.
      • Purushothaman I.
      • et al.
      Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.
      ,
      • Walker D.M.
      • Zhou X.
      • Ramakrishnan A.
      • Cates H.M.
      • Cunningham A.M.
      • Peña C.J.
      • et al.
      Adolescent social isolation reprograms the medial amygdala: Transcriptome and sex differences in reward.
      )].
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      References

        • Walker D.M.
        • Zhou X.
        • Cunningham A.M.
        • Lipschultz A.P.
        • Ramakrishnan A.
        • Cates H.M.
        • et al.
        Sex-specific transcriptional changes in response to adolescent social stress in the brain’s reward circuitry.
        Biol Psychiatry. 2022; 91: 118-128
        • Bagot R.C.
        • Cates H.M.
        • Purushothaman I.
        • Lorsch Z.S.
        • Walker D.M.
        • Wang J.
        • et al.
        Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility.
        Neuron. 2016; 90: 969-983
        • Issler O.
        • van der Zee Y.Y.
        • Ramakrishnan A.
        • Wang J.
        • Tan C.
        • Loh Y.E.
        • et al.
        Sex-Specific role for the long non-coding RNA LINC00473 in depression.
        Neuron. 2020; 106: 912-926.e5
        • Labonte B.
        • Engmann O.
        • Purushothaman I.
        • Menard C.
        • Wang J.
        • Tan C.
        • et al.
        Sex-specific transcriptional signatures in human depression.
        Nat Med. 2017; 23: 1102-1111
        • Lorsch Z.S.
        • Hamilton P.J.
        • Ramakrishnan A.
        • Parise E.M.
        • Salery M.
        • Wright W.J.
        • et al.
        Stress resilience is promoted by a Zfp189-driven transcriptional network in prefrontal cortex.
        Nat Neurosci. 2019; 22: 1413-1423
        • Pena C.J.
        • Kronman H.G.
        • Walker D.M.
        • Cates H.M.
        • Bagot R.C.
        • Purushothaman I.
        • et al.
        Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2.
        Science. 2017; 356: 1185-1188
        • Walker D.M.
        • Zhou X.
        • Ramakrishnan A.
        • Cates H.M.
        • Cunningham A.M.
        • Peña C.J.
        • et al.
        Adolescent social isolation reprograms the medial amygdala: Transcriptome and sex differences in reward.
        bioRxiv. 2020; https://doi.org/10.1101/2020.2002.2018.955187
        • Mukamel E.A.
        Multiple comparisons and inappropriate statistical testing lead to spurious sex differences in gene expression.
        Biol Psychiatry. 2022; 91: e1-e2
        • Cates H.M.
        • Li X.
        • Purushothaman I.
        • Kennedy P.J.
        • Shen L.
        • Shaham Y.
        • et al.
        Genome-wide transcriptional profiling of central amygdala and orbitofrontal cortex during incubation of methamphetamine craving.
        Neuropsychopharmacology. 2018; 43: 2426-2434
        • Walker D.M.
        • Cates H.M.
        • Loh Y.E.
        • Purushothaman I.
        • Ramakrishnan A.
        • Cahill K.M.
        • et al.
        Cocaine self-administration alters transcriptome-wide responses in the brain's reward circuitry.
        Biol Psychiatry. 2018; 84: 867-880
        • Wiersielis K.R.
        • Ceretti A.
        • Hall A.
        • Famularo S.T.
        • Salvatore M.
        • Ellis A.S.
        • et al.
        Sex differences in corticotropin releasing factor regulation of medial septum-mediated memory formation.
        Neurobiol Stress. 2019; 10: 100150

      Linked Article

      • Multiple Comparisons and Inappropriate Statistical Testing Lead to Spurious Sex Differences in Gene Expression
        Biological PsychiatryVol. 91Issue 1
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          The substantial differences in the incidence and symptoms of stress, depression, and addiction between males and females have motivated studies of sex differences in the brain’s molecular responses to environmental stimuli. In a study of three mouse brain regions from the Nestler laboratory, Walker et al. (1) reported sex-specific transcriptional responses to cocaine and baseline sex differences. They further examined the impact of social isolation on these brain gene expression patterns. However, the transcriptome data (RNA sequencing) and analysis in this study do not support the authors’ conclusions.
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