Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit

The model network contained 338,740 cells, including 311,500 pyramidal cells and 27,240 interneurons.

“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).”

The network developed a stable, spontaneous theta rhythm (5-10 Hz) at certain tonic excitation levels.

“We varied the magnitude of arrhythmic, tonic excitation to the network (by systematically changing the mean spiking frequency of the artificial stimulating cells, see above) and identified excitation levels where the network developed a stable, spontaneous theta rhythm (5–10 Hz; Figure 3 and 4; Figure 3—source data 1–3 and Figure 4—source data 1–2).”

The model network contained a total of 5.19 billion synaptic connections.

“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.”

The theta oscillation was stable, maintaining a steady power level throughout the duration of the oscillation.

“The theta oscillation was stable, maintaining a steady power level throughout the duration of the oscillation (Figure 4A).”

The model network displayed gamma oscillations (25-80 Hz).

“In addition to theta rhythm, the model network displayed gamma oscillations (25–80 Hz; Figures 3B and 4D), as expected based on in vivo data (Soltesz and Deschênes, 1993; Tort et al., 2009; Colgin and Moser, 2010) and in vitro slice data showing 65–75 Hz gamma oscillations arising in response to theta rhythmic network stimulation (Butler et al., 2016).”

• cites Soltesz and Deschênes, 1993Not checked yet

  Not checked in the free run.

• cites Tort et al., 2009 sourceNot checked yet

  Not checked in the free run.

• cites Colgin and Moser, 2010Not checked yet

  Not checked in the free run.

Theta was apparent within one theta period of the simulation start in all measures of network activity.

“In all of these measures of network activity, theta was apparent within one theta period of the simulation start.”

The highest amplitude of the gamma oscillations in the model was observed at the theta trough (0°/360°) in the pyramidal layer LFP analog.

“The highest amplitude of the gamma oscillations in the model was observed at the theta trough (0°/360°) in the pyramidal layer LFP analog (Figure 4C).”

The amplitude envelope of the gamma oscillation was phase-locked to the theta rhythm.

“The amplitude envelope of the gamma oscillation was phase-locked to the theta rhythm (Figures 3A,B and 4C), as it is in the biological CA1, representing cross-frequency coupling (Soltesz and Deschênes, 1993; Bragin et al., 1995; Buzsáki et al., 2003; Jensen and Colgin, 2007; Belluscio et al., 2012).”

• cites Soltesz and Deschênes, 1993Not checked yet

  Not checked in the free run.

• cites Bragin et al., 1995 sourceNot checked yet

  Not checked in the free run.

• cites Buzsáki et al., 2003 sourceNot checked yet

  Not checked in the free run.

Pyramidal cell spikes exhibited peak power around the theta frequency of 7.8 Hz.

“The pyramidal cell spikes (Figures 3C and D) exhibited peak power around the theta frequency of 7.8 Hz (Figure 4 and Table 7).”

Pyramidal cells in the model tended to fire more than they typically do during theta oscillations in vivo.

“Indeed, the pyramidal cells in our model described above (Figures 3 and 4) tended to fire more than they typically do during theta oscillations in vivo (e.g., [Soltesz and Deschênes, 1993; Robbe et al., 2006]).”

• cites Soltesz and Deschênes, 1993Not checked yet

  Not checked in the free run.

• cites Robbe et al., 2006 sourceNot checked yet

  Not checked in the free run.

Every measure of network activity showed theta oscillations.

“Importantly, every measure of network activity showed theta oscillations, including the somatic intracellular membrane potential from individual cells (Figure 3D), the spike times of individual cells and all cells collectively (Figure 3C), and aggregate measures such as the spike density function (Szucs, 1998) per cell type and the LFP analog (Figure 3A and 4; see also Figure 4—figure supplement 1”

Interneuronal diversity itself is an important factor in theta generation.

“Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation.”

• Also stated in: § Introduction · plain

  “Perturbation experiments revealed that parvalbumin-expressing (PV+) interneurons, neurogliaform cells, connections between CA1 pyramidal cells, and interneuronal diversity were important for theta generation.”

Pyramidal cells preferentially discharged around the trough 0°/360° of the LFP analog theta rhythm.

“As expected, the numerically dominant pyramidal cells, whose intracellular membrane potential oscillations to a large extent generate and underlie the extracellular LFP signal during theta oscillations (Buzsáki et al., 2012), preferentially discharged around the trough 0o/360o of the LFP analog theta rhythm (Figure 5A).”

The phase preferences of model interneurons fell into two broad categories.

“Their phase preferences fell into two broad categories (Figure 5A).”

Parvalbumin-expressing interneurons are important factors in theta generation.

“Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation.”

• Also stated in: § Introduction · plain

  “Perturbation experiments revealed that parvalbumin-expressing (PV+) interneurons, neurogliaform cells, connections between CA1 pyramidal cells, and interneuronal diversity were important for theta generation.”

The ability to generate theta oscillations, phase-locked gamma oscillations, and theta-related phase-preferential firing of distinct interneuronal subtypes was not a universal property of the model.

“Importantly, the ability to generate theta oscillations, phase-locked gamma oscillations, and theta-related phase-preferential firing of distinct interneuronal subtypes was not a universal property of the model.”

The strongly constrained model only exhibited spontaneous theta oscillations at certain levels of afferent excitation.

“As shown in Figure 6A, our strongly constrained model only exhibited spontaneous theta oscillations at certain levels of afferent excitation.”

The largest differences between the model and the in vivo phase-preferential firing occurred for the PV+ basket cells and the ivy cells.

“The largest differences between the model and the in vivo phase-preferential firing occurred for the PV+ basket cells and the ivy cells”

The model's interneuronal phase preferences were in line with recent data from the isolated CA1 preparation in vitro, which showed that cells belonging to the broadly defined SOM+ and PV+ classes displayed phase preferences similar to the O-LM, PV+ basket and bistratified cells in the model.

“These results were in line with recent data from the isolated CA1 preparation in vitro (Ferguson et al., 2015) which showed that cells belonging to the broadly defined SOM+ and PV+ classes (identified using genetic drivers) displayed phase preferences similar to the O-LM, PV+ basket and bistratified cells in our model”

• cites Ferguson et al., 2015 sourceNot checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: The phase of LFP theta recorded in the stratum radiatum is approximately 180 degrees out of phase with the pyramidal cell layer theta used in this paper.

Neurogliaform cells are important factors in theta generation.

“Perturbation experiments identified parvalbumin-expressing interneurons and neurogliaform cells, as well as interneuronal diversity itself, as important factors in theta generation.”

• Also stated in: § Introduction · plain

  “Perturbation experiments revealed that parvalbumin-expressing (PV+) interneurons, neurogliaform cells, connections between CA1 pyramidal cells, and interneuronal diversity were important for theta generation.”

The second group of model interneurons, including ivy and neurogliaform cells, CCK+ basket cells and axo-axonic cells, fired least around the theta trough, leading to an inverted firing probability distribution relative to the first group.

“In contrast, the second group of cells, including the ivy and neurogliaform cells, the CCK+ basket cells and the axo-axonic cells, fired least around the theta trough, leading to an inverted firing probability distribution relative to the first group of interneurons (Figure 5A).”

Connections between CA1 pyramidal cells are important for theta generation.

“Perturbation experiments revealed that parvalbumin-expressing (PV+) interneurons, neurogliaform cells, connections between CA1 pyramidal cells, and interneuronal diversity were important for theta generation.”

The first group of model interneurons, including PV+ basket cells, bistratified cells and O-LM cells, were most likely to fire at the theta trough compared to other theta phases.

“The cells belonging to the first group, including the PV+ basket cells, bistratified cells and O-LM cells, were most likely to fire at the theta trough compared to other theta phases.”

The cell-type-specific preferred phases of firing emerged spontaneously from the full-scale model, without purposeful tuning of parameters except the mean spiking frequency and synaptic strength of the artificial stimulating cells.

“Importantly, this fundamental property emerged spontaneously from the full-scale model, without purposeful tuning of parameters except the mean spiking frequency and synaptic strength of the artificial stimulating cells to set the incoming excitation levels from afferents (see Materials and methods for details).”

Interneurons in the model preferentially fired at specific phases of theta oscillations, depending on the cell type.

“Interneurons in the model preferentially fired at specific phases of theta oscillations, depending on the cell type.”

The majority (71%; 5/7) of the interneuron types for which there were experimental data, including the CCK+ basket, axo-axonic, bistratified, O-LM and neurogliaform cells, showed similar preferential maxima in their firing probabilities in the model and in vivo.

“Specifically, the majority (71%; 5/7) of the interneuron types for which there were experimental data, including the CCK+ basket, axo-axonic, bistratified, O-LM and neurogliaform cells, showed similar preferential maxima in their firing probabilities in the model (Figure 5A) and in vivo (Figure 5B).”

• AssumptionRests on an assumption: The phase preferences of interneurons in anesthetized animals are comparable to those in the model's conditions for the purpose of validating the model.

The oscillation featured strong harmonics at multiples of the theta frequency of 7.8 Hz.

“The oscillation also featured strong harmonics at multiples of the theta frequency of 7.8 Hz.”

The differential effects of silencing PV+ versus SOM+ cells could also be obtained in a rationally simplified model called the Network Clamp.

“The differential effects of silencing PV+ versus SOM+ cells could also be obtained in a rationally simplified model called the Network Clamp, where a single pyramidal cell was virtually extracted from the full-scale CA1 network with all of its afferent synapses intact (for further details, see Bezaire et al., 2016a).”

• cites Bezaire et al., 2016aNot checked yet

  Not checked in the free run.

Silencing the output from any of the fast-spiking, PV family interneurons (PV+ basket, axo-axonic, or bistratified cells), CCK+ basket cells, or neurogliaform cells strongly reduced theta power in the network.

“Silencing the output from any of the fast-spiking, PV family interneurons (PV+ basket, axo-axonic, or bistratified cells), CCK+ basket cells, or neurogliaform cells also strongly reduced theta power in the network (Figure 6B).”

Muting other interneuronal types (S.C.-A cells, O-LM cells, or ivy cells) had no effect on this form of theta oscillations generated by the intra-CA1 network.

“In contrast, muting other interneuronal types (S.C.-A cells, O-LM cells, or ivy cells) had no effect on this form of theta oscillations generated by the intra-CA1 network (Figure 6B).”

These results were in overall agreement with experimental data from the isolated CA1 preparation indicating that optogenetic silencing of PV+ cells, but not SOM+ cells such as the O-LM cells, caused a marked reduction in theta oscillations.

“Reassuringly, these results were in overall agreement with experimental data from the isolated CA1 preparation indicating that optogenetic silencing of PV+ cells, but not SOM+ cells such as the O-LM cells, caused a marked reduction in theta oscillations (Amilhon et al., 2015).”

• cites Amilhon et al., 2015 sourceNot checked yet

  Not checked in the free run.

Removing the GABAB component from the neurogliaform synapses onto other neurogliaform cells and pyramidal cells showed a significant drop in theta power.

“Removing the GABAB component from the neurogliaform synapses onto other neurogliaform cells and pyramidal cells showed a significant drop in theta power.”

Massively increasing the weight of the GABAA component to produce a similar amount of charge transfer restored theta power.

“Massively increasing the weight of the GABAA component to produce a similar amount of charge transfer restored theta power”

Muting all the outputs from pyramidal cells caused the theta rhythm to disappear.

“When we muted all the outputs from pyramidal cells, theta rhythm disappeared (bar labeled ‘Pyr’ in Figure 6B)”

When the excitation level decreased below 0.65 Hz, the theta rhythm fell apart.

“When the excitation level decreased below 0.65 Hz, the theta rhythm fell apart”

Muting the relatively rare CA1 pyramidal cell to pyramidal cell excitatory connections alone was sufficient to collapse the theta rhythm.

“Interestingly, muting the relatively rare CA1 pyramidal cell to pyramidal cell excitatory connections alone (each pyramidal cell contacts 197 other pyramidal cells in the CA1; Bezaire and Soltesz, 2013) was sufficient to collapse the theta rhythm (bar labeled ‘None’ in Figure 6C)”

• cites Bezaire and Soltesz, 2013 sourceNot checked yet

  Not checked in the free run.

A wide range in excitation was unable to produce theta in the PV+ B. network.

“A wide range in excitation was unable to produce theta in the PV+ B. network.”

Theta power dramatically decreased when pyramidal cell to pyramidal cell connections were either increased (doubled) or decreased (halved) from the biologically observed 197.

“theta power dramatically decreased when these connections were either increased (doubled) or decreased (halved) from the biologically observed 197 (Figure 6C).”

Theta activity was restored when the neurogliaform cell output synapses had no slow GABAB component, only a scaled up fast GABAA IPSP with a charge transfer equivalent to the mixed GABAA,B synapses.

“As shown in Figure 6H (green bar), theta activity was restored when the neurogliaform cell output synapses had no slow GABAB component, only a scaled up fast GABAA IPSP with a charge transfer equivalent to the mixed GABAA,B synapses.”

When excited with arrhythmic inputs at physiologically relevant levels, the model displayed spontaneous theta (and gamma) oscillations with phase preferential firing across the nine model cell types (pyramidal cells and eight interneuron classes).

“When excited with arrhythmic inputs at physiologically relevant levels (see below), the model displayed spontaneous theta (and gamma) oscillations with phase preferential firing across the nine model cell types (pyramidal cells and eight interneuron classes).”

These oscillations emerged from the network model without explicit encoding, rhythmic inputs or purposeful tuning of intra-CA1 parameters.

“Consistent with experimental results (Goutagny et al., 2009; Amilhon et al., 2015), these oscillations emerged from the network model without explicit encoding, rhythmic inputs or purposeful tuning of intra-CA1 parameters (all anatomical connectivity parameters were exactly as previously published in Bezaire and Soltesz (2013)).”

• cites Goutagny et al., 2009 sourceNot checked yet

  Not checked in the free run.

• cites Amilhon et al., 2015 sourceNot checked yet

  Not checked in the free run.

• cites Bezaire and Soltesz (2013) sourceNot checked yet

  Not checked in the free run.

Theta was not apparent in any intermediate steps nor in the final network where all interneurons had become PV+ basket cells.

“Theta was not apparent in any intermediate steps nor in the final network where all interneurons had become PV+ basket cells (‘All PV+B’ in Figure 6F).”

Giving all interneurons a single electrophysiological profile appeared to create conditions that were not conducive for the appearance of spontaneous theta oscillations regardless of which interneuronal profile was used.

“Surprisingly, giving all interneurons a single electrophysiological profile appeared to create conditions that were not conducive for the appearance of spontaneous theta oscillations regardless of which interneuronal profile was used (Figure 6E; note that the cells still differed in the strengths, distribution, and identities of their incoming and outgoing connections after this manipulation).”

When the GABAB component of all neurogliaform cell outgoing synaptic connections was selectively removed, theta power was strongly reduced.

“Indeed, when we selectively removed the GABAB component of all neurogliaform cell outgoing synaptic connections, theta power was strongly reduced (Figure 6H).”

PV+ basket cells exhibited strong theta power in their spiking in the control network model.

“and exhibited strong theta power in their spiking in the control network model (Figure 4B).”

Theta rhythm did not appear at any of the wide range of incoming excitation levels tested in the 'All PV+ B' network.

“we subjected the ‘All PV+ B’ network to a wide range of incoming excitation levels (Figure 6G). Theta rhythm did not appear at any of these excitation levels.”

The phase preference of the axo-axonic cell in the model (163°) was closer to the anesthetized phase (185°) than to the awake phase (251°).

“the phase preference of the axo-axonic cell in the model (163°) was closer to the anesthetized phase (185°) than to the awake phase (251°)”

Our simulations showed that the relatively rare pyramidal cell to pyramidal cell local excitatory connections were also required for isolated theta generation.

“While it may be expected that isolated theta generation would require local pyramidal cells to provide rhythmic, recurrent excitation to interneurons, our simulations additionally showed that the relatively rare pyramidal cell to pyramidal cell local excitatory connections were also required.”

We had to increase the conductance of the GABAA synapse almost 300 times to achieve a similar charge transfer as that conveyed by the GABAB synapse.

“However, we had to increase the conductance of the GABAA synapse almost 300 times to achieve a similar charge transfer as that conveyed by the GABAB synapse.”

Bistratified and O-LM cells fired close to the trough in the model, under anesthesia and in awake animals.

“bistratified and O-LM cells fired close to the trough in the model, under anesthesia and in awake animals”

The PV+ basket cells in the model displayed phase preferential firing (357°) closer to data reported from awake (289°-310°) than anesthetized animals (234°-271°).

“the PV+ basket cells in the model displayed phase preferential firing (357°) closer to data reported from awake (289°–310°) than anesthetized animals (234°–271°)”

The CA1 model network exhibited phenomena that corresponded well with experimental results, for example, on the differential roles of PV+ basket cells and OLM cells.

“Our results obtained using the 0.65 Hz excitation indicated that the CA1 model network exhibited phenomena that corresponded well with experimental results, for example, on the differential roles of PV+ basket cells and OLM cells.”

Theta oscillations appeared only within certain levels of excitatory afferent activity, around 0.65 Hz for the average firing rate of the Poisson-distributed spike trains.

“Importantly, theta oscillations appeared only within certain levels of excitatory afferent activity, around 0.65 Hz for the average firing rate of the Poisson-distributed spike trains.”

When the 454,700 stimulating afferents in the model are active at a Poisson mean of 0.65 Hz, they generate approximately 37,900 incoming spikes per theta cycle, given a theta frequency of 7.8 Hz.

“When the 454,700 stimulating afferents in the model (representing the CA3 and entorhinal synapses; calculated in Bezaire and Soltesz (2013)) are active at a Poisson mean of 0.65 Hz, they generate approximately 37,900 incoming spikes / theta cycle, given a theta frequency of 7.8 Hz (Equation 1).”

• cites Bezaire and Soltesz (2013) sourceNot checked yet

  Not checked in the free run.

Emergent theta and gamma oscillations and theta phase preferential firing are possible even as additional interneuron types are incorporated and the network is scaled up to full size with realistic connectivity including 5 billion synapses between the 300,000-plus cells of the network model.

“we demonstrated that emergent theta and gamma oscillations and theta phase preferential firing are possible even as additional interneuron types are incorporated and the network is scaled up to full size with realistic connectivity including 5 billion synapses between the 300,000-plus cells of our network model”

Results from the strictly data-driven, full-scale CA1 model are consistent with earlier models that demonstrated the basic ingredients capable of producing emergent network oscillations at a range of frequencies in microcircuits and small networks.

“Our results from the strictly data-driven, full-scale CA1 model are consistent with those of earlier models that elegantly demonstrated the basic ingredients capable of producing emergent network oscillations at a range of frequencies in microcircuits and small networks”

• cites Rotstein et al., 2005 sourceNot checked yet

  Not checked in the free run.

• cites Siekmeier, 2009 sourceNot checked yet

  Not checked in the free run.

• cites Neymotin et al., 2011b; 2011aNot checked yet

  Not checked in the free run.

The current CA1 network model produces results in agreement with experimental data.

“The current CA1 network model produces results in agreement with experimental data”

CCK+ cells had a steep response to the weight of the incoming afferent synapses, remaining silent until the weight was increased significantly and then spiking at a high rate.

“CCK+ cells had a steep response to the weight of the incoming afferent synapses, remaining silent until the weight was increased significantly and then spiking at a high rate”

Spontaneous theta-frequency LFP oscillations are present in the isolated whole CA1 preparation in vitro.

“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).”

• cites Goutagny et al., 2009 sourceNot checked yet

  Not checked in the free run.

• cites Amilhon et al., 2015 sourceNot checked yet

  Not checked in the free run.

The intra-CA1 mechanisms that may contribute to the generation of the theta rhythm are not well understood.

“However, the intra-CA1 mechanisms that may contribute to the generation of the theta rhythm are not well understood (Colgin, 2013, 2016).”

• cites Colgin, 2013, 2016Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The eight model interneuron types collectively comprise the majority (~70%) of known CA1 interneurons.

“These cell types collectively comprise the majority (~70%) of known CA1 interneurons (Bezaire and Soltesz, 2013).”

• cites Bezaire and Soltesz, 2013 sourceNot checked yet

  Not checked in the free run.

Reduced-scale models of large networks with realistic single cell electrophysiological properties remain silent unless synaptic strengths or numbers are arbitrarily increased beyond biologically relevant levels.

“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”

• cites Dyhrfjeld-Johnsen et al., 2007 sourceNot checked yet

  Not checked in the free run.

• cites Sterratt et al., 2011 sourceNot checked yet

  Not checked in the free run.

The electrophysiology and other properties of individual cells and synapses were based on experimental data.

“An important set of constraints was the electrophysiology and other properties of individual cells and synapses (Figure 2; Figure 2—source data 3–27; Tables 3 and 4) that were based on experimental data (Lee et al., 2016; Quattrocolo and Maccaferri, 2016).”

• cites Lee et al., 2016 sourceNot checked yet

  Not checked in the free run.

• cites Quattrocolo and Maccaferri, 2016Not checked yet

  Not checked in the free run.

Synaptic kinetics, amplitudes, and locations on the postsynaptic cell were constrained using experimental data.

“We used experimental data to constrain the synaptic kinetics, amplitudes, and locations on the postsynaptic cell (Figure 1E, 2K and L).”

The afferent divergence and convergence onto the cells were anatomically patterned, maintaining the topographical arrangement seen experimentally.

“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.”

• cites Hongo et al., 2015 sourceNot checked yet

  Not checked in the free run.

The CA1 circuit has an intrinsic ability to generate some form of theta waves even without rhythmic external inputs.

“Therefore, the latter studies suggest an intrinsic ability of the CA1 circuit to generate some form of theta waves even without rhythmic external inputs.”

• cites Goutagny et al., 2009 sourceNot checked yet

  Not checked in the free run.

• cites Amilhon et al., 2015 sourceNot checked yet

  Not checked in the free run.

This is the first strictly data-driven, full-scale computational network model of the CA1 that exhibits spontaneous theta rhythm without rhythmic synaptic inputs.

“To our knowledge, this is the first strictly data-driven, full-scale computational network model of the CA1 that exhibits spontaneous theta rhythm without rhythmic synaptic inputs.”

The model was capable of reproducing the experimentally observed relatively low-firing frequencies for the principal cells during theta oscillations in vivo.

“Therefore, the model was capable of reproducing the experimentally observed relatively low-firing frequencies for the principal cells during theta oscillations in vivo.”

• AssumptionRests on an assumption: The missing 30% of interneurons do not qualitatively alter the generation of theta oscillations in the model.

The model was sufficiently well-constrained by experimental data to generate theta and gamma oscillations on its own, without extrinsic rhythmic inputs or deliberate tuning of intrinsic parameters.

“These results demonstrate that, in spite of gaps in our knowledge, our model was sufficiently well-constrained by experimental data that it generated theta and gamma oscillations on its own, without extrinsic rhythmic inputs or deliberate tuning of intrinsic parameters.”

• AssumptionRests on an assumption: The model parameters that could not be constrained by experimental data do not critically affect the model's conclusions.

Inhibition received by the pyramidal cells in the model was probably weaker than in the biological situation.

“Therefore, these lesser-known interneurons were not included in the model, which meant that inhibition received by the pyramidal cells was probably weaker than in the biological situation.”

• AssumptionRests on an assumption: The missing 30% of interneurons do not qualitatively alter the generation of theta oscillations in the model.

These cells received substantial excitatory inputs from local CA1 pyramidal cells both in the biological state and in the model.

“Since these cells received substantial excitatory inputs from local CA1 pyramidal cells both in the biological state and in the model (Bezaire and Soltesz, 2013)”

• cites Bezaire and Soltesz, 2013 sourceNot checked yet

  Not checked in the free run.

Theta-preferential discharges are to a large extent determined by the wiring properties of the CA1 circuit itself.

“A clear majority of the interneuronal types in the model showed phase preferences similar to the in vivo condition where rhythmically discharging afferent inputs are present, indicating that theta-preferential discharges are to a large extent determined by the wiring properties of the CA1 circuit itself.”

• AssumptionRests on an assumption: The phase preferences of interneurons in anesthetized animals are comparable to those in the model's conditions for the purpose of validating the model.

During theta oscillations in vivo, PV+ basket cells and ivy cells may be strongly driven by CA3 afferents active during the late falling phase of the theta cycle.

“suggesting that during theta oscillations in vivo these cells may be strongly driven by CA3 afferents active during the late falling phase of the theta cycle (Colgin and Moser, 2010)”

• cites Colgin and Moser, 2010Not checked yet

  Not checked in the free run.

The firing of the first group of interneurons in the isolated CA1 model was probably driven by the pyramidal cell discharges around the theta trough.

“their firing in the isolated CA1 model was probably driven by the pyramidal cell discharges around the theta trough.”

The differing phase preferences of the second group were most likely due to a combination of weak or non-existent excitatory inputs from local CA1 pyramidal cells and inhibition from the interneurons that prominently discharged around the theta trough.

“Their differing phase preferences were most likely due to a combination of weak or non-existent excitatory inputs from local CA1 pyramidal cells and inhibition from the interneurons that prominently discharged around the theta trough.”

Each pyramidal cell contacts 197 other pyramidal cells in the CA1.

“each pyramidal cell contacts 197 other pyramidal cells in the CA1; Bezaire and Soltesz, 2013”

• cites Bezaire and Soltesz, 2013 sourceNot checked yet

  Not checked in the free run.

The recurrent collaterals of pyramidal cells play a key role in theta oscillations.

“indicating that the recurrent collaterals of pyramidal cells play a key role in theta oscillations.”

While a hypothetical theta regime somewhere in the parameter space of low-diversity configurations could not be ruled out, any theta solution space would likely be smaller and more elusive than was able to be determined in the control configuration.

“While we could not rule out a hypothetical theta regime somewhere in the parameter space of such low-diversity configurations, any theta solution space would likely be smaller and more elusive than we were able to determine in the control configuration (Figure 6A).”

• AssumptionRests on an assumption: The parameter space explored for low-diversity configurations is sufficient to conclude that interneuronal diversity is necessary for spontaneous theta oscillations.

In agreement with previous predictions, the perturbation experiments suggested that neurogliaform cells were a necessary component for spontaneous theta to arise in the isolated CA1.

“In agreement with previous predictions (Capogna, 2011), the perturbation experiments described above suggested that neurogliaform cells were a necessary component for spontaneous theta to arise in the isolated CA1.”

• cites Capogna, 2011 sourceNot checked yet

  Not checked in the free run.

We produced a biologically detailed, full-scale CA1 network model constrained by extensive experimental data.

“We produced a biologically detailed, full-scale CA1 network model constrained by extensive experimental data (Bezaire and Soltesz, 2013).”

• cites Bezaire and Soltesz, 2013 sourceNot checked yet

  Not checked in the free run.

Taken together, these results indicated, for the first time, that interneuronal diversity itself is an important factor in the emergence of spontaneous theta oscillations from the CA1 network.

“Taken together, these results indicated, for the first time, that interneuronal diversity itself is an important factor in the emergence of spontaneous theta oscillations from the CA1 network.”

• AssumptionRests on an assumption: The parameter space explored for low-diversity configurations is sufficient to conclude that interneuronal diversity is necessary for spontaneous theta oscillations.

The model has the capacity to process a biologically realistic number of spike inputs per cycle while maintaining the theta rhythm.

“Thus, the model has the capacity to process a biologically realistic number of spike inputs per cycle while maintaining the theta rhythm.”

Our results also highlighted the importance of the recurrent excitatory collaterals from CA1 pyramidal cells in theta generation in the model of the isolated CA1 network.

“In addition to identifying key roles for certain inhibitory components (PV+ interneurons, neurogliaform cells, GABAB, and interneuron diversity), our results also highlighted the importance of the recurrent excitatory collaterals from CA1 pyramidal cells in theta generation in the model of the isolated CA1 network.”

Experimental data on the isolated CA1 preparation were obtained from both rat and mouse.

“the experimental data on the isolated CA1 preparation were obtained from both rat (Goutagny et al., 2009) and mouse (Amilhon et al., 2015)”

• cites Goutagny et al., 2009 sourceNot checked yet

  Not checked in the free run.

• cites Amilhon et al., 2015 sourceNot checked yet

  Not checked in the free run.

The modeling results provided the insight that GABAB receptors may play important roles in slow oscillations such as the theta rhythm not because their slow kinetics pace the oscillations, but because their slow kinetics enable a massive charge transfer.

“The modeling results also provided the interesting insight that GABAB receptors may play important roles in slow oscillations such as the theta rhythm not because their slow kinetics pace the oscillations, but because their slow kinetics enable a massive charge transfer.”

Some of the electrophysiology data used for constructing the single cell models came from the mouse.

“some of the electrophysiology data used for constructing the single cell models (Appendix) came from the mouse”

The model is fundamentally a model of the rat CA1 in terms of cell numbers and connectivity.

“our model is fundamentally a model of the rat CA1 (e.g., in terms of cell numbers and connectivity; see Table 3 in Bezaire and Soltesz [2013])”

• cites Bezaire and Soltesz [2013] sourceNot checked yet

  Not checked in the free run.

Slow GABAB synapses were not necessary for theta as long as their large charge was carried by the fast GABAA synapses.

“This insight was illuminated by the fact that slow GABAB synapses were not necessary for theta as long as their large charge was carried by the fast GABAA synapses.”

All the model configurations and simulation result data sets used in this work are available online.

“all the model configurations and simulation result data sets used in this work are available online”

• cites Bezaire et al., 2016bNot checked yet

  Not checked in the free run.

The theta that emerged from the model most closely resembled the atropine resistant form.

“it is likely that the theta that emerged from our model most closely resembled the atropine resistant form”

The cell number and connectivity parameters were exactly as reported previously in our in-depth quantitative assessment of anatomical data about the CA1.

“The cell number and connectivity parameters were exactly as we reported previously in our in-depth quantitative assessment of anatomical data about the CA1”

• cites Bezaire and Soltesz, 2013 sourceNot checked yet

  Not checked in the free run.