Author response: Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit
Year: 2016
Type: peer-review
Abstract: Full text Figures and data Side by side Abstract Introduction Results Discussion Materials and methods Appendix 1 Data availability References Decision letter Author response Article and author information Metrics Abstract The hippocampal theta rhythm plays important roles in information processing; however, the mechanisms of its generation are not well understood. We developed a data-driven, supercomputer-based, full-scale (1:1) model of the rodent CA1 area and studied its interneurons during theta oscillations. Theta rhythm with phase-locked gamma oscillations and phase-preferential discharges of distinct interneuronal types spontaneously emerged from the isolated CA1 circuit without rhythmic inputs. Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation. These simulations reveal new insights into the spatiotemporal organization of the CA1 circuit during theta oscillations. https://doi.org/10.7554/eLife.18566.001 Introduction The hippocampal CA1 area supports diverse cognitive tasks including learning, memory, and spatial processing (Squire, 1992; Remondes and Schuman, 2004; Manns et al., 2007; Moser et al., 2008). These cognitive tasks are thought to require coordination of neuronal activity provided by physiological network oscillations, including the theta rhythm (Buzsáki, 2002; Buzsáki and Moser, 2013). In rodents, hippocampal theta is a 5–10 Hz oscillation in the local field potential (LFP) and neuronal firing probabilities (Soltesz and Deschênes, 1993; Lee et al., 1994; Ylinen et al., 1995; Klausberger and Somogyi, 2008; Varga et al., 2012, 2014), occurring during locomotion and in REM sleep (Buzsáki, 2002). Though several major afferents provide theta-frequency rhythmic input to the CA1 in vivo (Soltesz and Deschênes, 1993; Buzsáki, 2002; Fuhrmann et al., 2015), recent reports indicate the presence of spontaneous theta-frequency LFP oscillations even in the isolated whole CA1 preparation in vitro (Goutagny et al., 2009; Amilhon et al., 2015). Therefore, the latter studies suggest an intrinsic ability of the CA1 circuit to generate some form of theta waves even without rhythmic external inputs. However, the intra-CA1 mechanisms that may contribute to the generation of the theta rhythm are not well understood (Colgin, 2013, 2016). Here we investigated the ability of the CA1 to generate intrinsic theta oscillations using a uniquely biological data-driven, full-scale computer model of the isolated CA1 network. Recent advances in supercomputing power and high-quality synaptic connectivity data present the intriguing opportunity to develop full-scale models where every biological synapse and neuron is explicitly represented. In principle, such full-scale models of mammalian circuits comprising hundreds of thousands of neurons of distinct types advantageously avoid the connectivity scaling tradeoff that besets reduced-scale models: smaller models of large networks with realistic single cell electrophysiological properties (e.g., input resistance and resting membrane potential) remain silent unless synaptic strengths or numbers are arbitrarily increased beyond the biologically relevant levels to compensate for fewer inputs to their model cells (e.g., [Dyhrfjeld-Johnsen et al., 2007; Sterratt et al., 2011]). Biological relevance may also increase as other network components are modeled in greater detail. However, full-scale models require considerable computational resources. Further, such detailed models have a large parameter space which risks being sub-optimally constrained by neurobiological properties that are only partially quantified (Sejnowski et al., 1988). Because the CA1 area is one of the most extensively studied brain regions, there are abundant anatomical and electrophysiological data about its organization, making it a logical choice for the development of a full-scale model. The CA1 area is also worth modeling at full-scale because of the diverse cognitive tasks it supports. These tasks likely require the simultaneous processing of thousands of incoming and outgoing signals, and full-scale network models, at least in principle, have the potential to match this in vivo processing capacity. In this paper, we describe the development of a full-scale CA1 computational network model of unprecedented biological detail and its application to gain insights into the roles and temporal organization of CA1 interneurons during theta rhythm. The simulated full-scale CA1 circuit was able to spontaneously generate theta waves as well as phase-locked gamma oscillations. Furthermore, distinct interneuron types discharged at particular phases of theta, demonstrating that phase-preferential firing (Klausberger et al., 2003, 2004, 2005; Ferraguti et al., 2005; Jinno et al., 2007; Fuentealba et al., 2008; Klausberger and Somogyi, 2008; Varga et al., 2012; Lapray et al., 2012; Katona et al., 2014; Varga et al., 2014) originates in part within the CA1 network. Perturbation experiments revealed that parvalbumin-expressing (PV+) interneurons, neurogliaform cells, connections between CA1 pyramidal cells, and interneuronal diversity were important for theta generation. These results provide new mechanistic insights into the emergence of the theta rhythm from within the CA1 circuitry and the role of interneurons in theta oscillations. Results Development of a data-driven, full-scale model of the isolated CA1 Details of the full-scale model are described in the Methods, and the most important features are illustrated in Figures 1 and 2 and summarized here. Briefly, CA1 model cells were evenly distributed within their respective layers in a 3-dimensional prism with realistic dimensions for the rodent hippocampal CA1 region (Figure 1A and B). The model network contained 338,740 cells (similar to the biological CA1 in rats, including 311,500 pyramidal cells and 27,240 interneurons) (Figure 1D–E and Figure 1—figure supplement 1). In addition, the network also incorporated 454,700 artificial stimulating cells (spiking units with random, Poisson-distributed interspike intervals) to simulate afferents to CA1; the cell type-specific distribution, dendritic position, amplitude and kinetics of the excitatory input synapses were all experimentally constrained by afferent CA3 and entorhinal cortical data. Cell type-specific connectivity data, including cell numbers (Figure 1D) and convergence and divergence values (Figure 1E; Figure 1—figure supplement 1 and Table 1) were taken without alteration from our previously published, in-depth, quantitative assessment of the CA1 circuit (Bezaire and Soltesz, 2013). Anatomical constraints of the connectivity were implemented in the model by accounting for the distribution of the axonal boutons as a function of longitudinal and transverse distance from the presynaptic cell soma (Figure 1—figure supplement 2). The afferent divergence and convergence onto the cells were also anatomically patterned, maintaining the topographical arrangement seen experimentally (Hongo et al., 2015), for a total of 5.19 billion synaptic connections in the model network. In addition, the remaining parameters that could not be constrained by experimental data were documented, with the assumptions used to arrive at them explicitly listed in Table 2 of Bezaire and Soltesz (2013) and additional parameter calculations described in the Appendix of the present paper, section 'Inhibitory connectivity'. To highlight the many constraints applied in the current work and address the unconstrained model parameters, we characterized all model components (constrained and unconstrained) in experimental terms, comparing with experimental data where possible (Figure 2; Appendix). For a four second simulation, the full-scale model required 3–4 terabytes (TB) of RAM and four hours of execution time on a supercomputer using ~3000 processors (or up to 12 hr for simulations calculating a high-accuracy local field potential (LFP) analog). Additional details and data about model performance are available in Table 2 and Bezaire et al. (2016a). Figure 1 with 2 supplements see all Download asset Open asset CA1 network connectivity. (A) The model network is arranged in a layered prism with the lengths of each dimension similar to the actual dimensions of the CA1 region and its layers. (B) The model cell somata within a small chunk of stratum pyramidale (as depicted in A) are plotted to show the regular distribution of model cells throughout the layer in which they are found. (C) Each pyramidal cell in the network has detailed morphology with realistic incoming synapse placement along the dendrites and soma. (D,E) Diagrams illustrate connectivity between types of cells. (D) The network includes one principal cell type (pyramidal cells) and eight interneuron types. Cell types that may connect are linked by a line colored according to the presynaptic cell type. Most cell types can connect to most other cell types. Total number of cells of each type are displayed, as are the number of local output synapses (boutons) from all cells of each type. (E) The number, position, and cell types of each connection are biologically constrained, as are the numbers and positions of the cells. See Figure 1—figure supplement 1) for details about the convergence onto each cell type. Also see Table 1 and Figure 1—figure supplement 2 for information about the cell-type combinations of the 5 billion connections and the axonal distributions followed by each cell type, as well as detailed connectivity results at http://doi.org/10.6080/K05H7D60. https://doi.org/10.7554/eLife.18566.002 Figure 2 Download asset Open asset Electrophysiology of the model network components. (A) Ion channel densities vary as a function of location (top) in the morphologically detailed pyramidal cell model (bottom; adapted from Poolos et al., 2002). Scale bar: 100 μm and 0.01 μF/cm2. (B–C) The sodium channel found in the pyramidal cell soma is characterized in terms of (B) the activation/inactivation curves and (C) the current-voltage relation at peak (transient) current and steady state. (D–G) Current sweeps are shown for four model cell types: (D) PV+ basket cell, (E) CCK+ basket cell, (F) O-LM cell, and (G) neurogliaform cell. Scale bar: 100 ms and 20 mV. (H–J) Electrophysiological properties for each cell type, including (H) input resistance, (I) membrane time constant, and (J) action potential threshold. (K–L) Pyramidal cell synaptic connections are characterized as post-synaptic currents with the postsynaptic cell voltage clamped at −50 mV; (K) synapses made onto the pyramidal cell from all other cell types and (L) synapses made by the pyramidal cell onto all network cell types. Cells represented by same colors as in Figure 1. Source Data available for electrophysiological characterizations shown here. Additional details available in the Methods, Table 3, and the Appendix. https://doi.org/10.7554/eLife.18566.005 Figure 2—source data 1 Model sodium channel activation. The ion channel characterized in this figure was an Nav channel, inserted into a single compartment cell of diameter and length 16.8 microns (a soma) with a density such that the maximum, macroscopic conductance was 0.001 μS/cm2. The reversal potential of the channel was + 55 mV and the settings during the characterization protocol were: temperature = 34 degrees Celsius, axial resistance = 210 ohm*cm, [Ca2+]internal=5.0000e-06 mM, specific membrane capacitance = 1 μF/cm2. For activation steps, the cell was held at −120 mV and then stepped to potential levels ranging from −90 mV to + 90 mV. For inactivation steps, the cell was held at various potential levels ranging from −90 mV to + 40 mV for 500 ms and then stepped to + 20 mV. Each current injection step is recorded in three columns, where t: time (ms), i: injection (nA), g: conductance (S/cm2). The column labels are followed by the voltage (hold or step, according to the file), with activation steps being recorded in the Na_Channel_Step.dat and inactivation steps being recorded in the Na_Channel_Hold.dat file. https://doi.org/10.7554/eLife.18566.006 Download elife-18566-fig2-data1-v2.dat Figure 2—source data 2 Model sodium channel inactivation. The ion channel characterized in this figure was an Nav channel, inserted into a single compartment cell of diameter and length 16.8 microns (a soma) with a density such that the maximum, macroscopic conductance was .001 μS/cm2. The reversal potential of the channel was + 55 mV and the settings during the characterization protocol were: temperature = 34 degrees Celsius, axial resistance = 210 ohm*cm, [Ca2+]internal=5.0000e-06 mM, specific membrane capacitance = 1 μF/cm2. For activation steps, the cell was held at −120 mV and then stepped to potential levels ranging from −90 mV to +90 mV. For inactivation steps, the cell was held at various potential levels ranging from −90 mV to +40 mV for 500 ms and then stepped to +20 mV. Each current injection step is recorded in three columns, where t: time (ms), i: injection (nA), g: conductance (S/cm2). The column labels are followed by the voltage (hold or step, according to the file), with activation steps being recorded in the Na_Channel_Step.dat and inactivation steps being recorded in the Na_Channel_Hold.dat file. https://doi.org/10.7554/eLife.18566.007 Download elife-18566-fig2-data2-v2.dat Figure 2—source data 3 Model axo-axonic cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.008 Download elife-18566-fig2-data3-v2.atf Figure 2—source data 4 Model bistratified cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.009 Download elife-18566-fig2-data4-v2.atf Figure 2—source data 5 Model CCK+ basket cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.010 Download elife-18566-fig2-data5-v2.atf Figure 2—source data 6 Model ivy cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.011 Download elife-18566-fig2-data6-v2.atf Figure 2—source data 7 Model neurogliaform cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.012 Download elife-18566-fig2-data7-v2.atf Figure 2—source data 8 Model O-LM cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.013 Download elife-18566-fig2-data8-v2.atf Figure 2—source data 9 Model PV+ basket cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.014 Download elife-18566-fig2-data9-v2.atf Figure 2—source data 10 Model pyramidal cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.015 Download elife-18566-fig2-data10-v2.atf Figure 2—source data 11 Model Schaffer Collateral-Associated cell current injection sweep. Simulated current injection sweep in AxoClamp ATF (tab-delimited) file format. https://doi.org/10.7554/eLife.18566.016 Download elife-18566-fig2-data11-v2.atf Figure 2—source data 12 Model paired recording of an Axo-axonic cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.017 Download elife-18566-fig2-data12-v2.dat Figure 2—source data 13 Model paired recording of a Bistratified cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.018 Download elife-18566-fig2-data13-v2.dat Figure 2—source data 14 Model paired recording of a CA3 cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.019 Download elife-18566-fig2-data14-v2.dat Figure 2—source data 15 Model paired recording of a CCK+ basket cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.020 Download elife-18566-fig2-data15-v2.dat Figure 2—source data 16 Model paired recording of an ECIII cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.021 Download elife-18566-fig2-data16-v2.dat Figure 2—source data 17 Model paired recording of an Ivy cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.022 Download elife-18566-fig2-data17-v2.dat Figure 2—source data 18 Model paired recording of a Pyramidal cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.023 Download elife-18566-fig2-data18-v2.dat Figure 2—source data 19 Model paired recording of a Neurogliaform cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.024 Download elife-18566-fig2-data19-v2.dat Figure 2—source data 20 Model paired recording of an O-LM cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.025 Download elife-18566-fig2-data20-v2.dat Figure 2—source data 21 Model paired recording of a PV+ basket cell to Pyramidal cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.026 Download elife-18566-fig2-data21-v2.dat Figure 2—source data 22 Model paired recording of a Pyramidal cell to Axo-axonic cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.027 Download elife-18566-fig2-data22-v2.dat Figure 2—source data 23 Model paired recording of a Pyramidal cell to Bistratified cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.028 Download elife-18566-fig2-data23-v2.dat Figure 2—source data 24 Model paired recording of a Pyramidal cell to Ivy cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.029 Download elife-18566-fig2-data24-v2.dat Figure 2—source data 25 Model paired recording of a Pyramidal cell to O-LM cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.030 Download elife-18566-fig2-data25-v2.dat Figure 2—source data 26 Model paired recording of a Pyramidal cell to PV+ basket cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.031 Download elife-18566-fig2-data26-v2.dat Figure 2—source data 27 Model paired recording of a Pyramidal cell to Schaffer Collateral-Associated cell connection. Simulated paired recordings where the postsynaptic cell was voltage-clamped at −50 mV and the reversal potential of the synapse was kept at its physiological potential, as defined in the network model code. Sodium channels in the postsynaptic cell were blocked to prevent a suprathreshold response. A spike was triggered in the presynaptic cell and the current response was measured in the postsynaptic cell at the soma. This recording was repeated 10 times, with a randomly chosen connection location (from anatomically likely locations) each time. Each of the 10 trials are included in this file. https://doi.org/10.7554/eLife.18566.032 Download elife-18566-fig2-data27-v2.dat Table 1 Number of synapses between each cell type. Connections between cells generally comprise 1–10 synapses each. Presynaptic cells are listed down the first column (corresponding to each row) and postsynaptic cells are listed along the first row (corresponding to each column). https://doi.org/10.7554/eLife.18566.033
Source: eLife
Institutions: University of California, Irvine, Stanford University
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W2982996326