An increase of inhibition drives the developmental decorrelation of neural activity
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Evaluation Summary:
This manuscript presents a combination of in vivo recording and optogenetic experiments that together with modeling brings a significant message: inhibition is functionally present in the newborn frontal cortex having major effects in EEG dynamics. The work challenges the view on the switch in GABAergic excitation to inhibition and extends phenomenological observations to human infant EEG data.
(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
Throughout development, the brain transits from early highly synchronous activity patterns to a mature state with sparse and decorrelated neural activity, yet the mechanisms underlying this process are poorly understood. The developmental transition has important functional consequences, as the latter state is thought to allow for more efficient storage, retrieval, and processing of information. Here, we show that, in the mouse medial prefrontal cortex (mPFC), neural activity during the first two postnatal weeks decorrelates following specific spatial patterns. This process is accompanied by a concomitant tilting of excitation-inhibition (E-I) ratio toward inhibition. Using optogenetic manipulations and neural network modeling, we show that the two phenomena are mechanistically linked, and that a relative increase of inhibition drives the decorrelation of neural activity. Accordingly, in mice mimicking the etiology of neurodevelopmental disorders, subtle alterations in E-I ratio are associated with specific impairments in the correlational structure of spike trains. Finally, capitalizing on EEG data from newborn babies, we show that an analogous developmental transition takes place also in the human brain. Thus, changes in E-I ratio control the (de)correlation of neural activity and, by these means, its developmental imbalance might contribute to the pathogenesis of neurodevelopmental disorders.
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Evaluation Summary:
This manuscript presents a combination of in vivo recording and optogenetic experiments that together with modeling brings a significant message: inhibition is functionally present in the newborn frontal cortex having major effects in EEG dynamics. The work challenges the view on the switch in GABAergic excitation to inhibition and extends phenomenological observations to human infant EEG data.
(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 #1 (Public Review):
This manuscript by Chini et al., investigates the role of local inhibition in the maturation of neural activity within the developing prefrontal cortex. They employ a range of methods to tackle this problem, including in vivo recordings, optogenetic manipulations and computational modeling. Their findings provide evidence that support recent studies that claim GABA may be inhibitory within the early brain (i.e. GABA reversal is below spike threshold), even though the GABA reversal potential may be more positive relative to the adult. This idea is not new, but there has been ongoing debate within the field for some time. The evidence they provide nicely supports their interpretation that GABA inhibits firing. One main advance of the study is that they perform these experiments in the prefrontal cortex, …
Reviewer #1 (Public Review):
This manuscript by Chini et al., investigates the role of local inhibition in the maturation of neural activity within the developing prefrontal cortex. They employ a range of methods to tackle this problem, including in vivo recordings, optogenetic manipulations and computational modeling. Their findings provide evidence that support recent studies that claim GABA may be inhibitory within the early brain (i.e. GABA reversal is below spike threshold), even though the GABA reversal potential may be more positive relative to the adult. This idea is not new, but there has been ongoing debate within the field for some time. The evidence they provide nicely supports their interpretation that GABA inhibits firing. One main advance of the study is that they perform these experiments in the prefrontal cortex, whereas previous studies have focused on sensory regions whose developmental timeline may differ. They also compare across mice and humans, showing that, at least at the level of neural activity, findings from mice mirror what is happening in the developing human brain. This suggests that the mechanisms they describe are shared across species. Finally, they extend their analysis to a recently published mouse model of neurodevelopmental disorder, observing that the changes occurring in the healthy brain are not present in these mice. Overall, their data support their claims and are consistent across a range of different forms of analysis. This work may help us look for early biomarkers for neurodevelopmental disorders linked to abnormal circuit maturation and interneuron dysfunction.
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Reviewer #2 (Public Review):
This manuscript addresses the link between the developmental change (increase) of excitatory-inhibitory (E/I) balance and the observed decorrelation of neural activity, measured by the decrease in spiking correlations between pairs of neurons). The authors perform in vivo electrophysiological recordings in the prefrontal cortex of mice and combine them with modeling, optogenetic experiments that target a specific neuronal population of interneurons to justify their claims and even consider a mouse disease model and human data from babies to ensure that their results go beyond the development of mice.
Strengths:
What is remarkable about this study is that it generates and explores data from multiple developmental ages providing a continuous glance into the developmental trajectory of the prefrontal cortex. …Reviewer #2 (Public Review):
This manuscript addresses the link between the developmental change (increase) of excitatory-inhibitory (E/I) balance and the observed decorrelation of neural activity, measured by the decrease in spiking correlations between pairs of neurons). The authors perform in vivo electrophysiological recordings in the prefrontal cortex of mice and combine them with modeling, optogenetic experiments that target a specific neuronal population of interneurons to justify their claims and even consider a mouse disease model and human data from babies to ensure that their results go beyond the development of mice.
Strengths:
What is remarkable about this study is that it generates and explores data from multiple developmental ages providing a continuous glance into the developmental trajectory of the prefrontal cortex. The authors consider the ages of P2-12 and investigate the properties of spontaneous activity of over 100 mice, including the evolution of activity from being discrete and very infrequent to completely continuous, as in adulthood. The model is a great addition to the paper and is used very well in testing new hypothesis that are then explored back in the data. The authors also nicely use a measure for correlations, the spike time tiling coefficient, that was explicitly proposed for developmental data that has wildly varying firing rates. With this measure, they demonstrate that correlations decrease as a function of age, suggesting activity decorrelation. With the use of optogenetics they can increase the activity of interneurons and demonstrate one of the long-standing questions in the field about whether GABA is excitatory or inhibitory early in development. Similarly, optogenetic inactivation of interneurons increased overall levels of activity in the network. These optogenetic manipulations are then nicely linked to the change in spiking pairwise correlations. The authors also provide an interesting connection to a disease mouse model (GE) which have an altered E/I ratio and consequently different activity decorrelation compared to wildtype.Weaknesses:
While the paper explores large data sets from many points of view, it can do a better job of connecting the observed activity patterns to existing literature on spontaneous activity (work of M. Colonese, C. Lohmann, R. Khazipov, N. Rochefort & A. Konnerth). There are some references in the introduction but they should be expanded to put the paper in a broader context.
Though the model is very useful, it is not clear what assumptions went into it and why. For example, why lognormal synaptic connection strengths, what happens if this assumption is relaxed?
The effects on the firing rates in the population are not very clear upon optogenetic manipulation. The authors hint at the "paradoxical effect" in their Discussion, but a more extensive discussion of this would be good, also possibly in the results, to properly be able to interpret the observed results.
The authors present the decorrelation of neural activity as the ultimate goal of the cortical network, but why it's not clear why that is so. In the abstract it is mentioned "for the efficient retrieval and processing of information" but this is very loose and imprecise. How does this link (does it?) to the emergence of sensory processing and the transition to sensory driven activity? -
Reviewer #3 (Public Review):
This manuscript presents a series of experiments that together carry a significant message: inhibition is functionally present in the newborn frontal areas. The work challenges the simplistic view on the switch in GABAergic excitation to inhibition. Showing the phenomenological comparison between experimental work to human infant EEG brings a nice translational bridge that may turn out to have significant impact on clinical studies as well.
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