Attachment Theory: Novel Clinical and Molecular Insights

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for inviting me to review this review of potential animal models for secure and insecure attachment.  Beyond the easy transfer of paradigms between studies, I am curious about the authors' choice to limit their review to mice. For example, because they are evoking ELA, one article that came to mind was this one (particularly its discussion of the mediating effects of alcohol in aggression, a good proxy for parental substance involvement as a well-documented ACE): Miczek KA, Takahashi A, Gobrogge KL, Hwa LS, de Almeida RM. Escalated Aggression in Animal Models: Shedding New Light on Mesocorticolimbic Circuits. Curr Opin Behav Sci. 2015;3:90-95. doi:10.1016/j.cobeha.2015.02.007

I was also hoping that the authors could say more about variability in response to, e.g., low bedding. Abuse of offspring is well-documented but not the only response, especially when one is trying to account for the myriad effects of ELA.  Overall, I would ask the authors to highlight the nuances around their otherwise solid review of the existing research and its leading paradigms.  

Author Response

Please see attachment. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review is fairly competently executed, but some changes are still recommended:

1. The use of “clinical” in the subtitle gives the impression that the study is human-centered, when its main focus is on rodent studies. I recommend excising the word “clinical” and perhaps giving some indication that the primary focus is on non-human animals.

2. Terms such as “parent–child” are arguably used inappropriately at times, in that a substitute such as “offspring” is preferable when discussing non-humans.

3. The authors are either overstating or misstating matters when making assertions such as the following: “Randomized controlled trials provide compelling evidence that attachment-based interventions strengthen caregiver–child relationships and confer lasting mental and physical health benefits following early life adversity.”

*On the one hand, the use of “caregiver–child” suggests that the authors are implying that rodent studies are strongly applicable to humans. Of course, such work is relevant, but I would not want to overstate this, given cultural differences in humans that include divergent drug responses and different biomarkers for alleged disorders, to the point that it is sometimes unclear whether researchers are even examining the same disorder across different cultural contexts (for review, see "Selective Permeability in Global Cultures: Normative Shadings of Self-Illness Ambiguity and Psychiatry," 2025).  Matters like this should be briefly mentioned, with a few citations advised (e.g., from the above).

*On the other hand, if the authors’ focus is solely on rodents, then the “caregiver–child” phrasing is a misstatement.

4. This suggestions is somewhat dated, but there is a relevant line of work (in multiple studies) that the authors could incorporate into their discussion, namely a reframing of neo-analytic attachment theory examining father-absent families under two conditions. In the first, the father had died, but the mother kept photos, reminded the children that their father loved them and would have been there for them, and so on. In the second, the father had effectively abandoned the family.

Although there are many possible confounding variables, researchers found that individuals in the abandonment condition became sexually mature earlier (e.g., earlier menarche in girls), showed more precocious sexual interest, and had more children with multiple partners, did so at younger ages etc. Boys also showed higher verbal skills, with researchers speculating about a possible role in seduction. The researchers speculated that there was slight within-species shift from K-selection to J-selection. This was combined with insecure attachment styles.

In any case, given that some of these effects involve the endocrine system, there is relevance to the authors’ work. I suspect there has also been follow-up research on the original study over the past two or three decades. I do not recall the authors, but the present authors could likely locate worthwhile work in this area.

Author Response

Please see attachment. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is well structured and the topic is timely, but the conceptual narrative is too “emotionalized” and not sufficiently grounded in pathophysiology. In multiple places attachment is treated almost as “emotions → health”, while stress-biology and inflammation are only mentioned fragmentarily. Please add a short mechanistic bridge (text or a simple scheme) linking ELA/caregiving to altered stress reactivity (HPA axis and sympathetic tone), immune tone/low-grade inflammation (including glucocorticoid sensitivity), neuroimmune programming (microglial priming/synaptic pruning) and only then to clinical outcomes. Without this bridge, several conclusions read overconfident. As one possible conceptual backbone for such integration, you may consider recent synthesis of neuroimmune interactions in stress and depression within the neuroinflammation–depression nexus / NIIS framework (Sarapultsev et al., Curr Med Chem, 2024; PMID: 39350557), together with recent mechanistic reviews integrating early-life stress, HPA–immune interactions and downstream affective and somatic outcomes (Phillips et al., Brain Behav Immun Health, 2024; Bonaz et al., Front Neurosci, 2024).
A second important issue is terminology in animal models. The text uses “disorganized/avoidant attachment”, “emotional dysregulation”, “fear/anhedonia” in rodents as if these are equivalent to human constructs. In animals you measure operationalized behavioral proxies, not subjective emotions. Please use consistent “-like phenotype / attachment-relevant behavior” wording and add an explicit paragraph on limits of translation (construct/predictive validity, risk of anthropomorphization), and soften direct animal→human extrapolations.
Finally, causal wording should be more cautious when relying on mediation in cohorts and on attachment-oriented RCTs, because both are sensitive to confounding and interventions modify multiple environmental factors, not only “attachment”. Please separate clearly RCT evidence, longitudinal associations, and animal mechanistic suggestions, especially for broad somatic outcomes.
•    Sarapultsev A, Gusev E, Chereshnev V, Komelkova M, Hu D. Neuroimmune Interactions in Stress and Depression: Exploring the Molecular and Cellular Mechanisms within the Neuroinflammation-depression Nexus. Curr Med Chem. 2024 Sep 30. doi: 10.2174/0109298673320710240920055041. PMID: 39350557.
•    Bonaz B, Sinniger V, Pellissier S. Role of stress and early-life stress in the pathogeny of inflammatory bowel disease. Front Neurosci. 2024 Sep 10;18:1458918. doi: 10.3389/fnins.2024.1458918. PMID: 39319312
•    Phillips RD. Neural and immune interactions linking early life stress and anhedonia. Brain Behav Immun Health. 2024 Sep 30;42:100881. doi: 10.1016/j.bbih.2024.100881. PMID: 39415844; PMCID: PMC11480252.

Author Response

Please see attachment. 

Author Response File: Author Response.pdf