Control of parallel hippocampal output pathways by amygdalar long-range inhibition
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Evaluation Summary:
This manuscript suggests that the neuronal circuit from the basal amygdala (BA) to the ventral hippocampus (VH) consists of both excitatory and inhibitory projections to specific targeted areas. The main message is that excitatory input specifically targets VH neurons that in turn project to the BA and nucleus accumbens (NA). In contrast, BA inhibitory input preferentially targets VH neurons that project to the BA to gate place-value associations. The reviewers agree that the manuscript reports potentially interesting data. However, they all agree that the claim made is preliminary and only partially sustained by the submitted experimental evidence.
(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 #3 agreed to share their name with the authors.)
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Abstract
Projections from the basal amygdala (BA) to the ventral hippocampus (vH) are proposed to provide information about the rewarding or threatening nature of learned associations to support appropriate goal-directed and anxiety-like behaviour. Such behaviour occurs via the differential activity of multiple, parallel populations of pyramidal neurons in vH that project to distinct downstream targets, but the nature of BA input and how it connects with these populations is unclear. Using channelrhodopsin-2-assisted circuit mapping in mice, we show that BA input to vH consists of both excitatory and inhibitory projections. Excitatory input specifically targets BA- and nucleus accumbens-projecting vH neurons and avoids prefrontal cortex-projecting vH neurons, while inhibitory input preferentially targets BA-projecting neurons. Through this specific connectivity, BA inhibitory projections gate place-value associations by controlling the activity of nucleus accumbens-projecting vH neurons. Our results define a parallel excitatory and inhibitory projection from BA to vH that can support goal-directed behaviour.
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Evaluation Summary:
This manuscript suggests that the neuronal circuit from the basal amygdala (BA) to the ventral hippocampus (VH) consists of both excitatory and inhibitory projections to specific targeted areas. The main message is that excitatory input specifically targets VH neurons that in turn project to the BA and nucleus accumbens (NA). In contrast, BA inhibitory input preferentially targets VH neurons that project to the BA to gate place-value associations. The reviewers agree that the manuscript reports potentially interesting data. However, they all agree that the claim made is preliminary and only partially sustained by the submitted experimental evidence.
(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 …
Evaluation Summary:
This manuscript suggests that the neuronal circuit from the basal amygdala (BA) to the ventral hippocampus (VH) consists of both excitatory and inhibitory projections to specific targeted areas. The main message is that excitatory input specifically targets VH neurons that in turn project to the BA and nucleus accumbens (NA). In contrast, BA inhibitory input preferentially targets VH neurons that project to the BA to gate place-value associations. The reviewers agree that the manuscript reports potentially interesting data. However, they all agree that the claim made is preliminary and only partially sustained by the submitted experimental evidence.
(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 #3 agreed to share their name with the authors.)
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Reviewer #3 (Public Review):
This work provides a detailed map of mono-synaptic connections between the BA and the vH. Particularly valuable, they use CRACM to identify the inhibitory and excitatory mono-synaptic connections. They extend their investigation of mono-synaptic connections to the vH output neurons (BA, NAc, and mPFC projecting neurons). Then they build an integrate-and-fire network model, constrained by their experimental data. Finally, they test the model's prediction at the behavioral level.
Overall, this work is carefully designed and nicely executed. Although, I am not qualified in evaluating their modeling, I liked their approach. It is a well-rounded experimental design, where they use their own set of data to construct a model with predictive power that later put in test. That is, they bridged the gap between slice …
Reviewer #3 (Public Review):
This work provides a detailed map of mono-synaptic connections between the BA and the vH. Particularly valuable, they use CRACM to identify the inhibitory and excitatory mono-synaptic connections. They extend their investigation of mono-synaptic connections to the vH output neurons (BA, NAc, and mPFC projecting neurons). Then they build an integrate-and-fire network model, constrained by their experimental data. Finally, they test the model's prediction at the behavioral level.
Overall, this work is carefully designed and nicely executed. Although, I am not qualified in evaluating their modeling, I liked their approach. It is a well-rounded experimental design, where they use their own set of data to construct a model with predictive power that later put in test. That is, they bridged the gap between slice electrophysiology and behavior with circuit modeling.
However, some of the main claims require more experimental evidence. This includes increasing the power for the behavioral experiments, evaluating a potential contribution of topographical bias within the BA, verifying that high concentration of the calcium chelator is not having unintended consequences, and a more thorough validation of the effect of SalB on action potentials.
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Reviewer #2 (Public Review):
The work described in this manuscript very elegantly explores the functional connectivity of BA projections to vHPC neurons, using an original and skilful combination of optogenetics and retrograde tracing approaches, as well as the potential role of these projections in goal-directed behavior. Overall the manuscript benefits from extensive studies on the functional connectivity between BA and vHPC, and contributes important novel information to the field including solid evidence for the long postulated long-range inhibitory efferents from the BA.
My enthusiasm for the work is, however, diminished by the preliminary nature of the behavioural experiments and the lack of cogent experimental evidence for some of the claims, including the validity of the ratio used to compare the strength of the functional …
Reviewer #2 (Public Review):
The work described in this manuscript very elegantly explores the functional connectivity of BA projections to vHPC neurons, using an original and skilful combination of optogenetics and retrograde tracing approaches, as well as the potential role of these projections in goal-directed behavior. Overall the manuscript benefits from extensive studies on the functional connectivity between BA and vHPC, and contributes important novel information to the field including solid evidence for the long postulated long-range inhibitory efferents from the BA.
My enthusiasm for the work is, however, diminished by the preliminary nature of the behavioural experiments and the lack of cogent experimental evidence for some of the claims, including the validity of the ratio used to compare the strength of the functional BA-inputs to different populations of vHPC principal neurons shown in Fig 3 and Fig 4.
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Reviewer #1 (Public Review):
A strength of the manuscript is that it includes data obtained with a variety of complementary approaches, such as CRACM, electrophysiology, behavior and modeling that all contribute toward a comprehensive definition of BA-VH connectivity.
However, there are weaknesses that make the claims raised not as direct as they should. Furthermore, the data submitted does contains some important gaps. Specifically: CRACM should significantly improve, a better characterization of the "novel" BA long-range GABAergic neurons should be provided, the identification of the VH cellular targets (CA1, CA3 pyramidal cells?) should be provided too, VH pyramidal cells with multiple projection areas should be investigated.
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