Cholecystokinin-expressing (CCK+) basket cells are key controllers of theta-gamma coupled rhythms in the hippocampus

Abstract

It has been shown that different inhibitory cell types underlie brain rhythmic and cross-frequency coupling output, but exactly how inhibitory cell types manifest their contributions to these outputs is far from clear. Brain rhythms and their couplings are functionally important in cognition and behaviour, and thus it is essential that we determine and understand these contributions. To do this, one needs simultaneous access to multiple cell types and population brain output in functionally relevant states. This is extremely challenging to do with experiments alone, and here we use mathematical models of different types to gain insight into the contributions of the different inhibitory cell types. We focus on theta and gamma rhythms in the hippocampus and use a previously developed detailed model to develop precise hypotheses of how these rhythms are generated and coupled. We find critical contributions by four different cell types - pyramidal cells, parvalbumin expressing (PV+) basket cells (BCs), cholecystokinin-expressing (CCK+) BCs and bistratified cells. We develop a reduced population rate model (PRM) based on these hypotheses and do extensive explorations and visualizations of the PRM to obtain testable predictions. We find that CCK+BCs exhibit a much higher degree of control relative to PV+BCs for theta or gamma rhythm dominance and thus their coupling, and that coupling from PV+BCs to CCK+BCs more strongly affects theta frequencies relative to coupling from CCK+BCs to PV+BCs. As it is now possible to target these specific inhibitory cell types in the behaving animal, experimentally testing these hypotheses and predictions would be possible. Moreover, our work shows that a variety of mathematical model types creates new insights that would not be revealed with a single model type.

Cell-type specific contributions to theta-gamma coupled rhythms in the hippocampus

“…This model combines connections and cell types that were identified as critical for the existence of theta-gamma rhythms based on previous work using more detailed circuit models with nine different cell types (pyramidal cells, bistratified cells, PV-expressing basket cells, CCK-expressing basket cells, axo-axonic cells, Schaeffer collateral-associated cells, ivy cells, neurogliaform cells and oriens-lacunosum-moleculare cells) (Bezaire et al, 2016;Chatzikalymniou et al, 2021Chatzikalymniou et al, , 2022. Specifically, we have previously shown that the initiation of theta rhythms requires the presence of excitatory coupling between pyramidal cells (Chatzikalymniou et al, 2021), and that theta rhythms are lost with the removal of certain connections (Chatzikalymniou et al, 2022). In summary, we rationalize the use of a four cell-type microcircuit based on the more elaborate nine cell-type microcircuit (Bezaire et al, 2016;Chatzikalymniou et al, 2022) to examine theta-gamma coupled rhythms in CA1 hippocampus.…”

“…Specifically, we have previously shown that the initiation of theta rhythms requires the presence of excitatory coupling between pyramidal cells ( Chatzikalymniou et al, 2021 ), and that theta rhythms are lost with the removal of certain connections ( Chatzikalymniou et al, 2022 ). In summary, we rationalize the use of a four cell-type microcircuit based on the more elaborate nine cell-type microcircuit ( Bezaire et al, 2016; Chatzikalymniou et al, 2022 ) to examine theta-gamma coupled rhythms in CA1 hippocampus. The four cell types are pyramidal cells, bistratified cells and PV-expressing and CCK-expressing basket cells.…”

“…In order to disambiguate the respective role of cell types and their mutual connectivity motifs in the generation and control of theta-gamma coupled rhythms in the CA1 hippocampus, we developed a reduced, system-level mean field population rate model (PRM). This model combines connections and cell types that were identified as critical for the existence of theta-gamma rhythms based on previous work using more detailed circuit models with nine different cell types (pyramidal cells, bistratified cells, PV-expressing basket cells, CCK-expressing basket cells, axo-axonic cells, Schaeffer collateral-associated cells, ivy cells, neurogliaform cells and oriens-lacunosum-moleculare cells) (Bezaire et al, 2016;Chatzikalymniou et al, 2021Chatzikalymniou et al, , 2022. Specifically, we have previously shown that the initiation of theta rhythms requires the presence of excitatory coupling between pyramidal cells (Chatzikalymniou et al, 2021), and that theta rhythms are lost with the removal of certain connections (Chatzikalymniou et al, 2022).…”

“…One such important constraint is the manifest loss of theta activity following connection removal. Based on previous simulation studies using detailed network models (Chatzikalymniou et al, 2021(Chatzikalymniou et al, , 2022, theta oscillations should no longer be present whenever connections between PYR and PYR, from CCK to PV, from PV to PYR, and from BiC to PYR, are removed. This constraint guided our parameter search: from an initial set of parameter values, we used a genetic algorithm search in the parameter space of the synaptic weights (𝑤) and obtained 200 sets of synaptic weights satisfying the above criterion.…”

“…However, in general, high dimensional spiking network model systems challenge our capacity to extract explicit mechanisms. To circumvent this, we here build and analyze a cell-type specific mean field model that combines pyramidal cells and three distinct inhibitory cell types (bistratified cells, PV-and CCK-expressing basket cells) that were found to be essential for theta-gamma coupled rhythms from cell-type and cell-type interaction perspectives (Bezaire, Raikov, Burk, Vyas, & Soltesz, 2016; Chatzikalymniou, Sengupta, Lefebvre, & Skinner, 2022). This model leverages population-scale description of neural activity with experimentally constrained parameters to gather insight about theta-gamma coupling and theta frequency control in the hippocampus, while providing testable predictions.…”