Jeanneteau asks the question of whether synapses essential for learning and memory, which are lost during Alzheimer’s Disease, can be functionally reinstated. As a rationale for this question, the reversible effect of chronic stress on brain plasticity is proposed. However, as stated by the author: chronic stress and glucocorticoids do not cause Alzheimer’s disease, but rather may affect its progression. After first giving background information, several questions are posed which subsequently are addressed on various levels of the brain’s complexity.
The author demonstrates impressive scholarship and the paper presents an important resource of facts on a timely and important topic. The narrative is however complex and occasionally unhinged and some editing is therefore required.

Comments
1. A definition of engram is needed. Is it restricted to the hippocampus, or does this engram also extend over several brain regions as a network of sparsely distributed neurons? How is an engram identified? Can the engram be identified with stress-induced cfos staining as some investigators suggest?

1. Last sentence page 3: “neurocentric from vascular signaling effects of glucocorticoids”. Vascular means systemic effects? Please note that glucocorticoids have profound effects on energy metabolism. Anyway, it is perhaps good to point out that glucocorticoid hormones have different effects on various cells and tissues to coordinate their function during adaptation. Please rewrite.

2. Section 2: Outstanding question: this section reads like a catalog. My suggestion is to reduce the list to 4 questions that match the 4 next sections (ligand, receptors, signaling cascades, and cells/networks).

3. Page 7, the very long sentence at the bottom is incomprehensible. Please rewrite with the appropriate citations if the goal is to convey the message that glucocorticoid action in the limbic brain, notably the hippocampus, is mediated by MR and GR. Aldosterone-selective MR depends on colocalization 11HSD-2, for instance in the kidney or N. tractus solitarii. Good citations would be de Kloet et al. 1999, to distinguish the ‘good and bad’ actions of GCs, Daskalakis, Meijer et al. Neurobiology of Stress 2022 for MR-GR update, and Gasparini, Geerling et al Brain Struct Funct 2019, for aldosterone actions in the NTS on salt appetite and blood pressure regulation.

4. Figure 1:
   • gene X and Z are not indicated on the left but on the right-hand figure.
   • Chronic stress not necessarily is accompanied by hypercorticism, can also be by hypocortisolism. See Agorastos and Chrousos, Endocrine Reviews 2021
   • Which brain area is shown here?

5. Figure 2:
   • The right-hand figure requires a matching explanation in the legend.

6. Figure 3:
   • left-hand figure: what do the colors mean?
   • Citations to reviews that focus on the role of glucocorticoids and stress in neuronal networks are required, e.g. EJ Hermans et al. TINS 2014; L Schwabe et al Neuron 2022
   • Middle figure: where are engram cells localized? Hippocampus?
   • Right-hand figure: where are these cells localized? Please provide a reference to the green-white-blue bar of MR vs GR expression in neurons of this synaptic network (see also page 9, sentence after Figure 3). Note that the Allen Brain Atlas is not a reference, their n is too low and receptor expression needs to be verified under the indicated conditions.

7. Conclusions should match the four questions to be posed in section 2, and the text in the Abstract

Minor Comments: Please, carefully edit the text; below are only a few examples given that need to be corrected.

1. Page 2: “It is believed that such risk factors that are stress-sensitive only become pathogenic when organismal physiology is compromised beyond the range of adaptive capacity also coined allostasis (15).” In my reading of the McEwen papers, allostasis is defined as the process of adaptation to change for better or worse rather than capacity (See Agorastos and Chrousos, 2021).

2. Page 3, line 3. “Too much awakening levels of glucocorticoids” – please correct language;

3. Page 3, section receptors- par 2, line 13: “post-traductional” = post-translational

4. Page 3: section receptors- par 2, line 16: “The expression of both types opposes” – what is meant here?

5. Page 10, para 2, line 17, etc. “In rodents, excess inhibition….. etc. These sentences are incomprehensible without further explanation. Moreover, see Ulrich-Lai and Herman 2009 and Radley and Johnson, 2018 show that the PVN is surrounded by a GABA-ergic network on which the excitatory prefrontal afferents impinge. Please correct.

6. CReDiT, before References: As stated, SDG and HK were responsible for the ‘Writing-review & editing’, but are not listed as Authors on the Title page.