MicroRNAs (miRNAs) are short noncoding RNAs that act as negative regulators of mRNA translation and stability (Bartel, 2018). Over the last decade, a large body of evidence shows that miRNAs control excitatory neuron development, function, and plasticity (McNeill and Van Vactor, 2012; Schratt, 2009). Specific miRNAs, for example, miR-132, -134, and -138, have been identified which control dendritic spines, the major sites of excitatory synaptic contact (Schratt et al., 2006; Siegel et al., 2009). The complete lack of miRNAs from excitatory forebrain neurons in Dicer-deficient mice enhances learning and memory (Konopka et al., 2010), and specific miRNAs have been linked to both short-term and long-term memory regulation (Cheng et al., 2018; Gao et al., 2010; Walgrave et al., 2021). Although miRNAs are likewise substantially expressed in inhibitory γ-aminobutyric acid (GABA)ergic interneurons (He et al., 2012), relatively little is known about miRNA function in this cell type. The complete lack of miRNAs reduces the number of cortical interneurons (Tuncdemir et al., 2015) while the absence of miRNAs in interneurons expressing vasoactive intestinal peptide (VIP) leads to cortical circuit dysfunction (Qiu et al., 2020). miR-128 knockout in Drd1a-positive GABAergic medium spiny neurons of the striatum results in increased motor activity and fatal epilepsy (Tan et al., 2013).

In the rodent hippocampus, microcircuits of excitatory pyramidal neurons and local inhibitory interneurons provide an extensively studied model in the context of information processing, with specific implications for the control of spatial short-term and long-term memory (Booker and Vida, 2018; Markram et al., 2004; Pelkey et al., 2017). Among the different interneuron classes, fast-spiking parvalbumin (PV)-expressing interneurons play a particularly prominent role in controlling pyramidal neuron output to drive appropriate behavioral responses (Murray et al., 2011; Rico and Marín, 2011). For example, CA1 PV interneurons are required for spatial working memory, but neither for reference memory nor for memory acquisition in contextual fear conditioning (CFC) (Fuchs et al., 2007; Lovett-Barron et al., 2014; Murray et al., 2011). PV interneuron dysfunction has been implicated in neuropsychiatric disorders, most notably schizophrenia (SCZ), but also epilepsy and autism-spectrum disorders (ASD) (Del Pino et al., 2018; Sohal and Rubenstein, 2019). However, the role of specific miRNAs in PV interneurons in the context of higher cognitive function is completely elusive.

We previously identified the brain-enriched miR138-5p as an important regulator of excitatory synapse function in hippocampal pyramidal neurons (Siegel et al., 2009). To study the role of miR138-5p on a behavioral level, we generated mice with a conditional ROSA26 transgene (138-floxed) which allows expression of a miR138-5p inactivating sponge transcript harboring a lacZ coding sequence and six imperfect miR138-5p binding sites (6x-miR-138sponge) upon Cre-recombinase expression. Sponge transcripts sequester endogenous miRNA, thereby leading to miRNA inactivation and the derepression of cognate target genes (Ebert and Sharp, 2010). 138-floxed mice without Cre transgene served as a control throughout the experiments. Since these control mice completely lack expression of any sponge-related transcript in vivo, we first carefully validated the specificity and efficiency of the 138-sponge transcript in primary rat hippocampal neurons. Therefore, we compared the 138-sponge transcript to an identical control sponge, except that the six imperfect miR-138 binding sites were replaced with a shuffled sequence not supposed to sequester any miRNA expressed in neurons (cf. Materials and methods). This analysis revealed a robust and specific inactivation of miR138-5p by 138-sponge in vitro (Figure 1—figure supplement 1a-c).

We then activated 138-sponge expression at embryonic stage in vivo by crossing 138-floxed mice to the ubiquitous Cre-driver line CMV-Cre (138-sponge^ub, Figure 1a). lacZ staining revealed highly penetrant expression of 6x-miR-138 sponge in the hippocampus of 138-floxed mice upon CMV-Cre expression (Figure 1—figure supplement 1d). To test for the degree of miR138-5p inhibition in vivo, we made use of a dual fluorescence miR-138 sensor virus which we injected into the hippocampus of 138-sponge^ub mice. Briefly, the sensor consists of a GFP coding sequence (cds) followed by two perfect miR-138 binding sites and a mCherry cds (Figure 1—figure supplement 1e). Thus, the lower the ratio of GFP/mCherry, the higher the cellular miR-138 activity. Quantifying GFP/mCherry ratios over many infected neurons revealed that in neurons with 6x-miR-138-sponge expression, GFP/mCherry ratios were significantly higher compared to controls, indicative of an efficient sequestering of endogenous miR138-5p by our sponge construct (Figure 1b).

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We next assessed the cognitive abilities of 138-sponge^ub mice using behavioral testing. Locomotion in the home cage was similar between 138-sponge^ub and control mice, ruling out severe developmental motor impairments as a potential confound (Figure 1—figure supplement 1f). In the Y-maze test, no genotype-dependent differences in spontaneous alternations were observed, suggesting that exploratory behavior was not affected by miR138-5p inactivation (Figure 1—figure supplement 1g). In contrast, 138-sponge^ub mice displayed a significant impairment in novelty preference (Figure 1c), indicating a loss of spatial short-term memory. In the novel object recognition (NOR) task, 138-sponge^ub mice were unable to discriminate the novel from the familiar object (Figure 1d), thereby corroborating the observed short-term memory deficit. In contrast, associative long-term memory, as assessed by classical fear conditioning (Figure 1e), as well as anxiety-related behavior (open field, elevated plus maze [EPM]), was not affected by miR138-5p inhibition (Figure 1—figure supplement 1h-j). Thus, ubiquitous miR138-5p inhibition leads to a short-term memory deficit.

We went on to test whether short-term memory impairments in 138-sponge^ub mice were associated with alterations in synaptic transmission in hippocampal area CA1 and recorded miniature excitatory postsynaptic currents (mEPSCs) in CA1 pyramidal neurons. Amplitude and frequency of mEPSCs were indistinguishable between 138-sponge^ub and control slices (Figure 1f, Figure 1—figure supplement 1k, i). Likewise, we did not detect any significant alterations in dendritic spine morphology in these neurons using Golgi staining (Figure 1g). Finally, we did not observe differences in paired-pulse ratio (PPR), which negatively correlates with presynaptic release probability (Figure 1—figure supplement 1m), suggesting that excitatory synaptic transmission at the Schaffer collateral CA1 pyramidal cell synapse was not affected by miR138-5p inhibition.

To identify miR138-5p target mRNAs and to obtain further insight into the biological function of miR138-5p regulated genes, we performed polyA-RNA sequencing with total RNA isolated from hippocampal tissue. Differential gene expression analysis recovered a total of 338 differentially expressed genes (DEGs; 265 upregulated, 73 downregulated) (FDR <0.05; Figure 2a). The presence of miR138-5p binding sites correlated with increased transcript levels compared with 138-floxed mice (Figure 2b). miR138-5p 7-mer 1a, and to a lesser extent 7mer-m8 and 8mer sites, predicted significant derepression (Figure 2—figure supplement 1a). In total, 56 (21%) of the upregulated, but only 6 (8%) of the downregulated genes harbor miR138-5p binding sites within their 3′UTR. Taken together, this data demonstrates that many of the observed upregulated genes are a direct consequence of miR138-5p inhibition and further confirms the specificity of the miR138-5p sponge transgene.

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Gene ontology (GO) term analysis on DEGs from the RNA-seq analysis (Figure 2c; Figure 2—figure supplement 1b) revealed that many GO terms associated with synaptic function are strongly overrepresented in genes upregulated in the hippocampus of 138-sponge^ub mice. In order to specify the origin for the observed gene expression changes, we compared DEGs to single-cell RNA-seq data from different cell types present in the hippocampus (Zeisel et al., 2018; Figure 2d, Figure 2—figure supplement 1c). Surprisingly, we found that those genes which were significantly upregulated in 138-sponge^ub mice are strongly enriched in inhibitory GABAergic interneurons. This finding is in line with the observation that excitatory synaptic transmission in hippocampal CA1 was not affected by miR138-5p inactivation (Figure 1f and g, Figure 2—figure supplement 1j-l). Accordingly, many of the upregulated miR138-5p targets showed a strong expression signal in different classes of inhibitory interneurons (Figure 2—figure supplement 1d). In contrast, known validated targets of miR138-5p which are not enriched in inhibitory interneurons (e.g., Lypla1, Sirt1, and Reln) were not differentially expressed between 138-sponge^ub and control mice (Figure 2—figure supplement 1e).

Next, we performed single-molecule miRNA FISH in cultured rat hippocampal neurons to visualize miR138-5p expression at subcellular resolution. This analysis revealed strong expression of miR138-5p in both Camk2a-positive excitatory and Erbb4-positive inhibitory hippocampal neurons (Figure 3a). Erbb4-positive cells express Gad65, but not Camk2a, confirming their GABAergic phenotype (Figure 3a). Quantification of the FISH signal did not reveal any significant differences in the average cellular miR138-5p expression between excitatory and inhibitory neurons (Figure 3—figure supplement 1a), in agreement with an analysis of published miRNA-seq data from the mouse cortex (Figure 3—figure supplement 1b; He et al., 2012). In contrast, miR138-5p expression was undetectable in GFAP-positive glial cells (Figure 3—figure supplement 1c). Thus, miR138-5p is robustly expressed in inhibitory interneurons, consistent with a previously unrecognized function in these cells.

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We went on to validate miR138-5p dependent regulation of predicted interneuron-enriched target genes, focusing on Erbb4 (Erb-B2 receptor tyrosine kinase 4). Erbb4 is an SCZ risk gene that has been linked to the regulation of GABAergic synaptic transmission and short-term memory (Fazzari et al., 2010; Wang et al., 2018). Using qPCR and Western blot, we observed a significant upregulation of both Erbb4 mRNA (Figure 3b) and protein (Figure 3c) levels in the hippocampus of 138-sponge^ub compared to 138-floxed mice, thereby validating our results from RNA-seq. On the other hand, transfection of primary rat hippocampal neurons with a synthetic miR138-5p mimic reduced Erbb4 protein levels (Figure 3d), demonstrating that miR138-5p is necessary and sufficient for the inhibition of Erbb4 expression. In luciferase reporter gene assays, transfection of miR138-5p significantly reduced the expression of an Erbb4 3′UTR construct containing a wild-type, but not mutant miR138-5p binding site (Figure 3e), rendering Erbb4 as direct miR138-5p target. Furthermore, we were able to validate the presynaptic vesicle-associated Rims3 as an interneuron-enriched miR138-5p target (Figure 3—figure supplement 1d-f).

To study the regulation of Erbb4 by miR138-5p specifically in interneurons, we designed a viral construct in which expression of an inhibitory miR-138 sponge or a respective control sponge is under the control of the interneuron-specific Dlx5/6 promoter (Dlx-138 sponge and Dlx-control sponge). rAAV expressing Dlx-138 sponge or DLX-control sponge co-localizes with Gad65/67 in primary rat hippocampal neurons, confirming interneuron-specific expression (Figure 3—figure supplement 1g). Erbb4 RNA based on single-molecule fluorescence in situ hybridization (smFISH) was significantly elevated in Dlx-138 sponge compared to Dlx-control sponge infected interneurons (Figure 3f), demonstrating that miR138-5p cell-autonomously inhibits Erbb4 expression in hippocampal interneurons.

Our experiments so far suggest that impairments in interneurons are causally involved in short-term memory deficits upon miR-138 inhibition. To address the hypothesis that the observed short-term deficits are hippocampus-dependent, we stereotactically injected Dlx-138 sponge or Dlx-control sponge into the dorsal hippocampus of young adult mice and assessed short-term memory 4 weeks later, as described. Specific expression of 138- and control sponge in hippocampal interneurons was confirmed by immunostaining (Figure 4a). The previously observed 138 sponge mediated impairments in Y-maze novel preference and NOR were fully recapitulated by this approach (Figure 4b and c), strongly suggesting that miR138-5p function in hippocampal interneurons is required for intact short-term memory. Importantly, short-term memory was fully preserved upon hippocampal interneuron-specific expression of the control sponge (Figure 4b and c), providing an independent confirmation of the specificity of our approach for miR138-5p inactivation.

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Next, we investigated electrophysiological alterations that might underlie the observed short-term memory deficits. In hippocampal CA1 pyramidal neurons, which are the main targets of PV-positive (PV+) interneurons in the hippocampal circuit, frequency of miniature inhibitory postsynaptic current (mIPSC) was significantly increased in mice injected with the Dlx-138 sponge as compared to control sponge injected mice (Figure 4d). In contrast, amplitude (Figure 4e, Figure 4—figure supplement 1a) as well as rise and decay time (Figure 4—figure supplement 1) of mIPSCs was unaltered.

Based on this observation, we speculated that miR138-5p inactivation might be more robust in PV+ interneurons compared to other cell types. Thus, we again injected a miR-138 pbds sensor construct into the hippocampus of control or miR-138 sponge^Ub mice (Figure 1b), but now counterstained for PV to quantify miR-138 activity in PV+ and PV− cells (Figure 4—figure supplement 1c). Analysis of GFP/mCherry ratios revealed that expression of a miR-138 sponge significantly inactivated miR138-5p in PV+ neurons but had only a marginal effect in PV− cells (which predominantly consist of excitatory pyramidal neurons). Thus, the observed lack of regulation of miR138-5p targets in excitatory pyramidal neurons of 138-sponge^Ub mice is likely a result of inefficient sponge-mediated miR138-5p inhibition in this cell type. Since miR138-5p and alterations in PV+ interneuron function had recently been linked to SCZ (Pelkey et al., 2017; Watanabe et al., 2014), we performed a comparison between DEGs from 138-sponge^ub mouse hippocampus and cortical tissue of SCZ patients (Gandal et al., 2018). We found a significant overlap between genes upregulated in the 138-sponge^ub hippocampus and SCZ patients (p=0.00884; Figure 4—figure supplement 1d). Taken together, our results suggest that miR138-5p inactivation due to expression of a miR-138 sponge predominantly affects PV+ interneurons leading to an upregulation of synaptic genes which are deregulated in SCZ.

To elaborate on the functional role of miR138-5p in PV+ interneurons, we generated 138-sponge^PV mice by crossing 138-floxed mice to PV-Cre mice (Figure 5a). In 138-sponge^PV mice, the 6x-miR-138-sponge transcript is selectively expressed in the majority (about 90%) of PV-expressing inhibitory interneurons (PV-positive cells) (Figure 5b). On a behavioral level, we found that locomotion and anxiety-related behavior, as measured in the open field and EPM tests, was unaltered in 138-sponge^PV mice compared to their littermate controls (Figure 5—figure supplement 1a-c). However, similar as 138-sponge^ub mice (Figure 1c and d) and mice injected with rAAV-Dlx5/6-138-sponge into the hippocampus (Figure 4b and c), 138-sponge^PV mice showed impairments in behavioral tasks addressing short-term memory, such as the Y-maze novelty preference (Figure 5c) and NOR (Figure 5d) tests. No genotype-dependent differences in spontaneous alternations in the Y-maze were observed (Figure 5e). Similar to 138-sponge^ub mice, associative long-term memory as assessed by conditional fear conditioning was not affected in 138-sponge^PV mice (Figure 5—figure supplement 1d). These results demonstrate that miR138-5p activity in PV-positive interneurons is required to sustain proper short-term memory. Next, we investigated electrophysiological alterations that might underlie the observed short-term memory deficits. In hippocampal CA1 pyramidal neurons of 138-sponge^PV mice, similar to rAAV-Dlx5/6-138-sponge injected mice, frequency of mIPSC was significantly increased in 138-sponge^PV as compared to control slices (Figure 6a, Figure 6—figure supplement 1a), while neither amplitude, nor rise or decay time were changed (Figure 6—figure supplement 1b-d). The total number of PV-positive interneurons in the hippocampus was similar between 138-sponge^PV and 138-floxed mice (Figure 6—figure supplement 1e), suggesting that mIPSC frequency changes either result from an increased number of inhibitory presynaptic boutons synapsing onto pyramidal cells or an enhanced neurotransmitter release. To distinguish between these possibilities, we first analyzed presynaptic boutons contacting CA1 pyramidal cells by staining slices obtained from 138-floxed and 138-sponge^PV mice with antibodies against PV and the vesicular GABA transporter (VGAT). Our analysis revealed no significant difference in the number and intensity of PV-positive presynaptic boutons impinging onto the somata of CA1 pyramidal cells between 138-sponge^PV mice and their littermate controls (Figure 6b). To probe for changes in presynaptic release probability, we first recorded extracellularly stimulated inhibitory PPRs (iPPRs) in CA1 pyramidal cells but did not observe differences between the two groups (Figure 6c). Finally, we performed paired whole-cell recordings between presynaptic putative fast-spiking PV-positive interneurons in stratum pyramidale and postsynaptic CA1 pyramidal cells (Figure 6d–f; Figure 6—figure supplement 1f). The analysis of unitary connections revealed increased, albeit not significant, unitary inhibitory postsynaptic current (uIPSC) amplitudes (including failures of transmission) and success rates (i.e., an action potential elicits an IPSC) in 138-sponge^PV mice as compared to their control littermates (Figure 6d). However, we did not observe significant changes in PPR (Figure 6e). Our further analysis though revealed a significant decrease of the coefficient of variation (CV), indicative of more reliable unitary synaptic connections between PV-positive interneurons and CA1 pyramidal neurons in 138-sponge^PV mice (Figure 6f). These findings may also explain why mIPSC frequency was found to be altered as these inhibitory currents reflect inputs of many GABAergic neurons onto a single excitatory pyramidal neuron. In conclusion, CA1 pyramidal neurons in 138-sponge^PV mice receive increased inhibitory GABAergic synaptic input from putative fast-spiking PV-positive interneurons without detectable changes in perisomatic inhibitory bouton density or size.

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Here, we describe a central role for the brain-enriched miRNA miR138-5p in the regulation of inhibitory GABAergic transmission in the hippocampus. Particularly, we find that cell type-specific inhibition of miR138-5p in PV-positive interneurons enhances the reliability of unitary synaptic connections from putative fast-spiking PV-positive interneurons onto CA1 pyramidal neurons. The resulting increase in neurotransmitter release at this synapse is possibly due to an increase in the number of presynaptic release sites within individual boutons (Sakamoto et al., 2018), as we observed a decrease in CV, but did not detect significant changes in release probability. PV-positive interneurons are the main source of feedforward inhibition onto pyramidal neurons (Pouille and Scanziani, 2001) and have been functionally linked to working memory (Murray et al., 2011), possibly via controlling gamma oscillations (Hájos et al., 2004). We therefore propose a model whereby miR138-5p activity in PV+ interneurons is regulating neurotransmitter release, thereby keeping pyramidal cell output in a range required for proper information processing. Since miR138-5p controls dendritic spine morphogenesis in cultured hippocampal pyramidal neurons (Siegel et al., 2009), it might further regulate E-I balance in the hippocampal circuitry by controlling pyramidal neuron excitatory input. The absence of changes in excitatory synaptic transmission in the hippocampus of 138-sponge^ub mice might be due to ineffective silencing of the highly abundant miR138-5p in pyramidal neurons via our approach. This view is supported by our observation that a miR138-5p sensor plasmid is effectively unsilenced in PV+, but not PV− hippocampal neurons of 138-sponge^ub mice (Figure 4—figure supplement 1d) and by the lack of upregulation of miR138-5p targets preferentially expressed in pyramidal neurons (Figure 2—figure supplement 1c). The molecular explanation for this PV-specific miR138-5p inactivation is currently unknown.

Sponge-mediated inactivation of miRNAs is routinely used in cell culture, but studies employing this approach in transgenic mice are still scarce (Giusti et al., 2014), possibly in part because a stringent control would require the generation of an independent transgenic line. Here, we addressed this issue by comparing the effects of miR-138-sponge to a highly similar, but ineffective control sponge, in primary neurons in vitro and in the hippocampus in vivo using multiple assays. Thereby, we reproducibly observed 138-sponge specific effects on reporter gene expression (Figure 1—figure supplement 1b), dendritic spine size (Figure 1—figure supplement 1c), miniature inhibitory postsynaptic currents (Figure 4d and e), and short-term memory (Figure 4b and c), strongly arguing that the effects seen in miR-138-sponge mice are due to miR138-5p inactivation.

The molecular mechanisms downstream of miR138-5p inactivation leading to enhanced inhibition remain to be elucidated, but likely involve upregulation of proteins organizing inhibitory synapse function. An interesting candidate in this regard represents Erbb4, which has been shown to control GABAergic transmission (Fazzari et al., 2010; Wang et al., 2018) and working memory (Tian et al., 2017; Wen et al., 2010). In particular, release probability of GABAergic synapses onto pyramidal neurons was diminished in Erbb4 KO mice (Wang et al., 2018), which is in agreement with our finding that elevated Erbb4 levels in miR-138 sponge mice are paralleled by higher mIPSC frequencies. However, additional presynaptic genes might function downstream of miR138-5p, for example, Rims3, which physically and functionally interacts with presynaptic voltage-dependent Ca²⁺ channels (VDCCs) and increases neurotransmitter release (Takada et al., 2015). In the future, restoring the expression of specific inhibitory presynaptic genes in miR-138 sponge mice will be needed to assess their contribution to cellular and behavioral phenotypes caused by miR-138 inhibition.

Intriguingly, interfering with miR138-5p in inhibitory neurons of the adult hippocampus fully recapitulates deficits in inhibitory synaptic transmission and short-term memory observed in 138-sponge^Ub and 138-sponge^PV mice (Figure 4). Although this finding does not rule out a role for miR138-5p at early stages of development, it stresses the importance of miR138-5p for the homeostasis of the fully developed circuitry. A similar critical role at adulthood in the regulation of GABAergic transmission and behavior was recently shown for the miR138-5p target Erbb4 (Wang et al., 2018).

Our model of miR138-5p being a positive regulator of memory is consistent with results obtained from previous studies performed in mice (Boscher et al., 2020; Tatro et al., 2013; Tian et al., 2018). Moreover, GWAS analysis identified miR138-5p as a putative regulator of human memory performance (Schröder et al., 2014). A rare miR-138-2 gene variation is furthermore associated with SCZ in a Japanese population (Watanabe et al., 2014), and miR138-5p levels are altered in the superior temporal gyrus and dorsolateral prefrontal cortex of SCZ patients (Beveridge et al., 2010; Moreau et al., 2011). Finally, several miR138-5p targets have been genetically linked to SCZ (e.g., Erbb4, Drd2, and Igsf9b) (Kumar et al., 2010; Nicodemus et al., 2006) or are deregulated in the cortex of SCZ patients (e.g., Gabra3, Fxyd6, Tmem132c, and Baiap3, Gandal et al., 2018). Thus, miR138-5p might be involved in the control of cognitive function in humans and represent a promising target for the treatment of cognitive deficits associated with SCZ and other neurodevelopmental disorders.

RNA-seq data has been deposited to GEO (accession no. GSE173982).

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Author details

1. Reetu Daswani

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Investigation, Methodology, Visualization, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

2. Carlotta Gilardi

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Investigation

   Competing interests

   No competing interests declared

3. Michael Soutschek

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Formal analysis, Software

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8472-8124

4. Prakruti Nanda

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Investigation

   Competing interests

   No competing interests declared

5. Kerstin Weiss

   Institute for Physiological Chemistry, Biochemical-Pharmacological Center Marburg, Philipps-University of Marburg, Marburg, Germany

   Contribution

   Investigation

   Competing interests

   No competing interests declared

6. Silvia Bicker

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6276-5653

7. Roberto Fiore

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Investigation, Supervision

   Competing interests

   No competing interests declared

8. Christoph Dieterich

   Section of Bioinformatics and Systems Cardiology, Department of Internal Medicine III and Klaus Tschira Institute for Integrative Computational Cardiology, University of Heidelberg, Heidelberg, Germany

   Contribution

   Formal analysis, Funding acquisition, Software, Supervision

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9468-6311

9. Pierre-Luc Germain

   Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

   Contribution

   Formal analysis, Software, Supervision

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3418-4218

10. Jochen Winterer

    Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

    Contribution

    Conceptualization, Investigation, Supervision, Visualization, Writing - review and editing

    For correspondence

    jochen.winterer@hest.ethz.ch

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-6800-6594

11. Gerhard Schratt

    Lab of Systems Neuroscience, Institute for Neuroscience, Department of Health Science and Technology, Swiss Federal Institute of Technology ETH, Zurich, Switzerland

    Contribution

    Conceptualization, Funding acquisition, Supervision, Visualization, Writing - original draft, Writing - review and editing

    For correspondence

    gerhard.schratt@hest.ethz.ch

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-7527-2025

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