CA1 pyramidal cell diversity is rooted in the time of neurogenesis
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Evaluation Summary:
This study uses the approach of labeling neurons with distinct birthdates so they can be differentiated in experiments performed later in development. The authors then test morphological, functional and circuit inputs/outputs patterns of these neurons by using immunohistochemistry, slice electrophysiology, retrograde labelling, morphological reconstructions and behavioral assays. The manuscript is likely to make a strong impact in the field of developmental neuroscience and a good impact related to more general cellular and molecular neuroscience.
(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 agreed to share their name with the authors.)
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Abstract
Cellular diversity supports the computational capacity and flexibility of cortical circuits. Accordingly, principal neurons at the CA1 output node of the murine hippocampus are increasingly recognized as a heterogeneous population. Their genes, molecular content, intrinsic morpho-physiology, connectivity, and function seem to segregate along the main anatomical axes of the hippocampus. Since these axes reflect the temporal order of principal cell neurogenesis, we directly examined the relationship between birthdate and CA1 pyramidal neuron diversity, focusing on the ventral hippocampus. We used a genetic fate-mapping approach that allowed tagging three groups of age-matched principal neurons: pioneer, early-, and late-born. Using a combination of neuroanatomy, slice physiology, connectivity tracing, and cFos staining in mice, we show that birthdate is a strong predictor of CA1 principal cell diversity. We unravel a subpopulation of pioneer neurons recruited in familiar environments with remarkable positioning, morpho-physiological features, and connectivity. Therefore, despite the expected plasticity of hippocampal circuits, given their role in learning and memory, the diversity of their main components is also partly determined at the earliest steps of development.
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Evaluation Summary:
This study uses the approach of labeling neurons with distinct birthdates so they can be differentiated in experiments performed later in development. The authors then test morphological, functional and circuit inputs/outputs patterns of these neurons by using immunohistochemistry, slice electrophysiology, retrograde labelling, morphological reconstructions and behavioral assays. The manuscript is likely to make a strong impact in the field of developmental neuroscience and a good impact related to more general cellular and molecular neuroscience.
(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 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
A strength of the manuscript is that it includes data obtained with a variety of complementary and integrated approaches, such as genetic fate-mapping, neuroanatomy, slice physiology, connectivity tracing and cFos staining. The main message that birthdate determines subsequent CA1 PN heterogeneity is persuasively supported by the experimental data. However, this claim should be a bit mitigated throughout the manuscript because other factors could contribute to adult CA1 PNs diversity.
The data submitted mostly remain at a descriptive/correlative level and should be integrated by attempts of describing the underlying mechanisms and by testing or at least discussing behavioral roles, e.g. anxiety, more specific for the ventral hippocampus.
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Reviewer #2 (Public Review):
Currently, glutamatergic neurons within the pyramidal cell layer of the CA1 hippocampus (CA1PNs) are largely classified into superficial or deep populations, based on their location relative to stratum radiatum and accompanying differences in many properties. In the current study, Cavalieri et al. set out to determine whether the embryonic birthdate of CA1PNs was correlated with these properties and whether any further unique CA1PN populations could be identified. While embryonic day (E) 14.5 birthdate neurons largely correspond to previously identified deep CA1PNs and E16.5 resemble superficial CA1PNs, the authors also describe a new E12.5 population of pioneer CA1PNs. The E12.5 CA1PNs show distinct morphological, intrinsic excitability, synaptic connectivity and behaviorally-associated properties that do …
Reviewer #2 (Public Review):
Currently, glutamatergic neurons within the pyramidal cell layer of the CA1 hippocampus (CA1PNs) are largely classified into superficial or deep populations, based on their location relative to stratum radiatum and accompanying differences in many properties. In the current study, Cavalieri et al. set out to determine whether the embryonic birthdate of CA1PNs was correlated with these properties and whether any further unique CA1PN populations could be identified. While embryonic day (E) 14.5 birthdate neurons largely correspond to previously identified deep CA1PNs and E16.5 resemble superficial CA1PNs, the authors also describe a new E12.5 population of pioneer CA1PNs. The E12.5 CA1PNs show distinct morphological, intrinsic excitability, synaptic connectivity and behaviorally-associated properties that do not fit into a simple linear gradient based on birthdate or laminar position with the other CA1PN populations.
This is an important, novel and interesting study that presents a useful approach of labeling neurons with distinct birthdates so they can be differentiated in experiments performed later in development. The authors then utilize a diverse array of approaches, including immunohistochemistry, slice electrophysiology, retrograde labelling, morphological reconstructions and behavioral assays to evaluate the heterogeneity of CA1PN populations.
While the main point of identifying a new pioneer population of CA1PNs is strongly supported, there remain areas of weakness that should be addressed, mostly related to statistics, rigor of analysis, methodological details, and sample sizes.
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Reviewer #3 (Public Review):
The study by Cavalieri et al. is a follow up of Marissal T. et al. 2012 and Save L. et al. 2018 published by the same group. In these articles the authors reported birth date-depended structural and functional features in excitatory cells of the hippocampal formation. They showed that certain cellular characteristics in the dentate gyrus granule cells and the CA3 pyramidal cells track with their date of birth. To label the cells born at E12.5, E14.5 and E16.5 cells the authors used the exact same fate mapping strategy (Ngn2CreER-Ai14 cross and tamoxifen administration) as in this manuscript.
Published work from other groups has utilized various anatomical and functional techniques to study the diversity within the CA1 pyramidal cell layer, which was for a long time considered as one big group of neurons …
Reviewer #3 (Public Review):
The study by Cavalieri et al. is a follow up of Marissal T. et al. 2012 and Save L. et al. 2018 published by the same group. In these articles the authors reported birth date-depended structural and functional features in excitatory cells of the hippocampal formation. They showed that certain cellular characteristics in the dentate gyrus granule cells and the CA3 pyramidal cells track with their date of birth. To label the cells born at E12.5, E14.5 and E16.5 cells the authors used the exact same fate mapping strategy (Ngn2CreER-Ai14 cross and tamoxifen administration) as in this manuscript.
Published work from other groups has utilized various anatomical and functional techniques to study the diversity within the CA1 pyramidal cell layer, which was for a long time considered as one big group of neurons performing the same role. This body of work is reference and described by the authors to suggest that the anatomical and in vitro and in vivo functional diversity previously observed can be better explained, and the CA1 pyramidal cells better segregated, by their embryonic birth day rather than position within the stratum pyramidale. The researchers provide evidence for this claim, by first of all showing that pyramidal cells born at E12.5 and E16.5 seem to have more similar E/I ratio of spontaneous synaptic inputs compared to E14.5. The latter receive more inhibitory synaptic inputs from PV-positive terminals on their cell soma and hence have a skewed distribution towards a reduced E/I ratio. The authors also report the intrinsic electrophysiological properties and apical dendrite extension and ramification of the three groups of cells and identify some differences in both domains.
Following the basic characterization of the properties of the cells, the authors also report a bias towards the projection specificity of the different groups, especially to the Nucleus Accumbens, where they report a projection enrichment of E14.5 fate mapped neurons. In a last set of experiments the authors put an effort to try to uncover the potential involvement of the three fate-mapped groups in a hippocampal-dependent exploration task. By placing the mice in a familiar versus novel environment they show that the E12.5 born cells are proportionally more active (based on cfos labeling) in the former.
Overall the study presents a set of differences between the three fate-mapped cohorts of neurons at different level of analysis, with some intriguing findings on their output connectivity and behavior-dependent activation. The results on the bias in output regions between the cohorts are interesting and provide a possible handle by which to target and manipulate specific populations of CA1 pyramidal cells. Equally interesting is the finding that the environment seems to differentially activate the different cohorts. It nevertheless remains to be determined how the electrophysiological and anatomical properties described in the manuscript assist in the particular function of the cells during exploration. The individual conclusions are largely supported by the data, but extra experiments and analysis would strengthen the claims made.
The message of the study that developmental events and cell trajectories can help us uncover the function of cell types and circuits in the adult brain is an important one for the field.
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