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  1. Evaluation Summary:

    This paper will be of interest to neuroscientists, particularly those studying defensive behaviors. The authors provide novel insights into the mechanisms by which the brain computes contextual information associated with innate threats in mice. The experimental approach and data analysis are mostly adequate and the study provides the first causal evidence of a hippocampus-anterior hypothalamic pathway mediating spatial fear memory of ethological threats. The implementation of more robust statistical tests, as well as more detailed Methods and Discussion sections should serve to strengthen an already elegant study.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    In this study the authors use viral tracing and optogenetic manipulations to demonstrate the causal implication of a vHIP-AH circuit mediating both contextual fear memory retrieval and shelter-directed escape responses. The authors first show that photostimulation of AH neurons induces escape, aversion, and conditioned place avoidance and subsequently show that this effect is specifically mediated by a direct monosynaptic excitatory input derived from ventral hippocampal structures. By targeted optogenetic inhibition, they elegantly show that inhibition of a HPC to AH projection results in impaired shelter seeking similar to the one observed when an aversive stimulus (20 Hz sound) is delivered in the absence of a shelter. These findings are not unexpected as the AH has long been postulated to be the gateway structure within the medial hypothalamic defensive system for hippocampal inputs conveying contextual information. Here, the first causal evidence confirming this hypothesis is provided. The experiments are well designed, technically sound and methodological details well reported. Statistical analysis is mostly appropriate. However, in Fig. 6J and 8M TWO-WAY ANOVA should be performed instead of t-test. In particular, for Figure 8M, I don't believe that the obtained results support the conclusion and the results section should be changed accordingly. In conclusion, I believe that this manuscript, although not unexpected, substantially contributes to our understanding of how context encoding structures like the hippocampus contact the medial hypothalamic defensive system and guide innate and learned behavioral responses.

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  3. Reviewer #2 (Public Review):

    I read with great interest the manuscript of Bang and colleagues and I recognize the importance of the work on addressing missing points in the field. The questions of how the brain computes the contextual information produced by different aversive innate scenarios and the contextual memory induced by innate threats are addressed with several behavioral approaches. The authors combined multiple behavioral approaches with optogenetics, tracing and slice recordings to reveal a new hippocampus-hypothalamus circuit (HPC-AHN) that is involved in escape response and seems to play a role in contextual information.
    Although I recognized the hard work of the group, the importance of the questions raised as well as the quality of the experimental approach, there is a lack of clarity in the description of the methods, fundamental for interpretation of the data and reproducibility. Moreover, some interpretation of the data at the light of the results and the literature needs clarification.

    Major general suggestions:

    1. The study provides several interesting and innovative behavioral tasks that will definitely be of great interest to the behavioral neuroscience field. However, the description of the methodology for all experimental procedures requires an extensive revision. The way the methods are presented it is very unlikely other labs will be able to replicate with accuracy the procedures.

    1a) Information such as, total task time, number of trials; time difference among the escapability tasks (min, hours, days?) are missing. This is important for interpretation of whether the stimulation in one situation could affect the other.

    1b) It is not clear if the same animals were used among the different tasks and frequencies (6 or 20hz). I believe that clearly stating whether same or different animals were used is extremely important to the interpretation of the results. If the same animals were used for both frequencies and tasks, an extensive discussion about how the previous stimulation or tasks influences the effect of the second.

    1c) The way some of the behavioral quantification was done it is not clear or even not mentioned in the methods. For example, Fig 1 missing explanation of speed increase "fold", not sure what the fold means, how was the comparison made? Also lacking a clear explanation for the real-time indexes. The paper will benefit a lot if all behavioral measures are explicitly and clearly stated preferentially with the formulas used for the calculation, even if they are simple math operations. In igure 6, it is not clear what was defined as a "run".

    1. Another very important point that requires further clarification is the type of memory being tested. Sometimes the study has protocols that test for short-term memory whereas other protocols are testing long-term memory. It is not clear if the interpretation presented by the authors is related with memories that require consolidation or simply by spatial navigation.

    2. In addition, the role of the circuit HPC-AHN seems to be general for escape responses and does not depend on memory consolidation. The activation of the pathway produces escape responses even in absence of memory consolidation (Fig 4, Fig 7 and Fig 8). Authors need to clarify why their interpretation for the role of the circuit is experience-dependent, once the manipulation of the circuit also promotes escape behavior in a novel environment. It is interesting that the circuit can induce escape response in a novel environment, but when the memory is consolidated the escape response is more organized. The authors discussed the gap between the present study and previous ones that suggest PMd is fundamental for innate escape response and also contextual fear induced by innate threats. However, I do suggest for the authors to also review Wang and Schuette, et al (Neuron 2021 - PMID: 33861942) and try to reconcile their data with the Wang and Schuette study where they show the important role of PMd, but not other hypothalamic nuclei, on context-specific and panic-related escapes. In this paper the group discuss organized versus non-organized escape response. I believe the HPC-AHN circuit could be contributing to this kind of organized context-dependent space response, but also play a role in an unknown context inducing disorganized avoidance. This circuit might get potentiated with experience and therefore produce goal-directed (organized) escape behavior. However, it is not clear if the animals had a mental schema of the Fig 7 and 8 mazes. If animals were not exposed to the mazes, how do the authors reconcile the context-dependent experience interpretation with the fact the environment was new to the animals?

    3. Authors must include the individual data in all the plots (e.g. dots for each one of the animals), individual variability is extremely informative and can be explored further by the field, and brings more transparency for the data.

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