7.4 A Model of Cortico-Hippocampal Connectivity
7.4.4 PFC-to-CA1: Entorhinal Cortex Temporoammonic Input
Although a topographic organization of the EC3 connections to the distal dendrites in the stratum lacunosum moleculare in CA1 has been described [8], the exact details of this circuit are not well understood. For example, an estimate of how many CA1 pyramidal cells or interneurons are contacted by a single EC3 axon is unknown. It has been shown though, that the TA input has little effect on the firing of postsynaptic pyramidal cells, but exerts a powerful inhibitory effect in CA1 activity [45, 69]. The interneurons implemented in our model are perisomatic, lying in the stratum pyramidale, for which limited connections are expected to arise via the TA pathway. But since the fixed pyramidal cell EPSP, in the model, is much weaker than the interneuronal one (Table 7.1), inhibition can easily dominate and prevent pyramidal spikes. Therefore a large number of connections from cortical cells to CA1 pyramidal cells is needed in order for them to overcome the strong feedforward inhibition.
We implemented various values for the numbers of pyramidal and interneuronal cells that each cortical cell targets (kEC−P Y and kEC−IN respectively), in order to test their effect on the resulting CA1 responses. Firstly, we removed the CA3 input to isolate the effect of the TA input on CA1. Figure 7.11 contains spike raster plots with different sets of kEC−P Y and kEC−IN (shown on top of each panel) from simulations where the
CA3 network was omitted. Note that an interneuron receives on average 10×kEC−IN
connections. In all cases, cortical DOWN states are accompanied by sparse spontaneous firing of CA1 pyramidal cells, depolarising neighbouring interneurons. When kEC−P Y
= 50 and kEC−IN = 1, the pyramidal activity is practically the same during UP and
DOWN states. Doubling kEC−P Y leads to more pyramidal spikes in the UP states and
consequently more interneuronal spikes as well. Increasing kEC−IN promotes interneu- ronal spiking and the suppression of pyramidal spikes. A further increase of kEC−P Y and kEC−IN, while keeping their ratio constant, appears to favour interneuronal activity over pyramidal. Thus, in the last case, only few pyramidal cells fire during UP states, with multiple spikes. The majority are suppressed by feedforward inhibition.
Chapter 7: A Model of Cortico-Hippocampal Interactions 0 500 1000 CA1 0 500 1000 CA1 0 500 1000 Cortex 0 500 1000 CA1 0 500 1000 CA1 0.5 sec 50, 1 100, 1 100, 2 200, 4
Figure 7.11: Spike raster plot of the cortical slow oscillation (top) and the CA1 response through only the TA input. Pyramidal cell spikes are shown in black and interneuronal ones in grey. The number of CA1 pyramidal and interneuronal cells each cortical cell targets, on average, is given on top of each panel.
can influence CA1 in producing ripple-frequency responses; namely whether TA can shift the spectral peak of the interneuronal average membrane potential back to 150 − 200 Hz. The corresponding spectral densities from simulations with various combinations
of kEC−P Y and kEC−IN (not shown) are similar to Figure 7.10A, indicating that the
TA input alone cannot drive CA1 interneurons to oscillate at higher frequencies during CA3 population bursts.
Since the TA input affects CA1 spiking, we next examined how pyramidal cell firing rates depend on it. In Figure 7.12, the Z-score normalised firing rates of pyramidal cells are plotted, same as in Figure7.8, for various combinations of kEC−P Y and kEC−IN. Similar to CA3, most cells fire preferentially either in the UP or the DOWN states. As expected, increasing only the pyramidal cell drive results in more UP-state active cells. Increasing the interneuronal drive, even modestly, has the opposite effect. Moreover, an increase
Chapter 7: A Model of Cortico-Hippocampal Interactions
in the TA drive to pyramidal cells does not significantly improve the phase locking of their spiking with ripple troughs (not shown). So the pyramidal spike histogram aligned with the average ripple remains similar to Figure7.10.
CellNumber 100, 1 900 800 700 600 500 400 300 200 100 0 200, 1 900 800 700 600 500 400 300 200 100 0 200, 2 900 800 700 600 500 400 300 200 100 0 200, 4 900 800 700 600 500 400 300 200 100 0 -0.5 0 0.5 1 1.5 2 Cortical Firing Rate(a.u.) lags (msec) -20 -15 -10 -5 0 5 -20 -15 -10 -5 0 5 -20 -15 -10 -5 0 5 -20 -15 -10 -5 0 5 CA1FiringRate(Z-score)
Figure 7.12: Colour coded Z-score normalised firing rates of CA1 pyramidal cells, for various TA inputs. The rates are averaged over all SO cycles (shown on top) and arranged by their peak in descending order. The values of kEC−P Y and kEC−IN are shown on top of each panel. Note how the increase in the TA-induced excitation-to- inhibition ratio favours UP state pyramidal spiking and vice versa.
It thus becomes clear that, although the TA input does not particularly affect the fre- quency of the interneuronal responses to CA3 bursts, it does determine, to a large extent, the fraction of pyramidal cells that will overcome the UP state-elevated inhibition. The model suggests that a strong TA-depolarisation of CA1 pyramidal cells, compared to interneurons, aids in reproducing the CA1 spiking behavior described in [104]. We thus
fix the TA input to kEC−P Y = 200 and kEC−IN = 2. Moreover, since the Schaffer
collateral input affects the ripple-frequency responses in CA1, we further increase the average number and SD of synapses per Schaffer connection to 18.
Chapter 7: A Model of Cortico-Hippocampal Interactions
parameter values. We calculated the firing histogram of all pyramidal cells belonging either to the strongly-driven subset, or the moderately-driven one, in correlation with the average SO cycle (Figure 7.13B). This time, the additional excitation from the TA drives many more cells above spiking thresholds, hence spiking activity increases during UP states in both groups. As expected, interneurons also increase their firing during UP states. 0 500 1000 Cortex 0 500 1000 CA1 0 500 1000 CA3 0.5 sec
A
C
0 500 1000 1500 2000 Pyramidal S p. Histogram -10000 -800 -600 -400 -200 0 200 1000 2000 3000 InterneuronS p. Histogram lags (msec )B
0 100 200 300 400 500 1 1.4 1.8 InterneuronalMemb.Potential PowerS pectrum Frequency (Hz)Figure 7.13: A: Spike raster plot of the cortical, CA3 and CA1 networks, when each cortical cell excites 1 CA3 pyramidal cell and 1 CA3 interneuron through the dentate gyrus input and 200 pyramidal cells and 2 interneurons through the TA pathway. B: Spike histogram of the strongly-driven CA1 pyramidal cells (top grey), the moderately- driven ones (top black) and the interneurons (bottom), correlated with the average SO cycle. C: Power spectral density of the average membrane potential of CA1 interneurons after increasing the CA3-to-CA1 input.
The power spectral density of the average membrane potential of CA1 interneurons is shown in Figure 7.13C. The additional drive the interneurons receive, through the increased Schaffer input, has shifted the peak of their oscillation back to 150-200 Hz, bringing the CA1 oscillatory responses again within the ripple frequency range.
Chapter 7: A Model of Cortico-Hippocampal Interactions
cycle. Approximately 12% of CA3 pyramidal cells fire on the average population burst. The same percentage of CA1 cells fires in the corresponding ripples. This is in close agreement with the recorded percentage (10%) in naturally sleeping rats [241]. There- fore, it is again only a minority of cells firing in each ripple episode. Figures 7.14A,B display a segment of the cortical synaptic activity and the corresponding CA1 activity bandpass filtered at 150-200 Hz. Detected SO cycles and ripples are also displayed. The ripple histogram over the average SO cycle (Figures7.14C,D) indicates again that more ripples appear during the UP states. Moreover, the firing histogram of CA1 pyramidal cells in correlation with the average ripple (Figures7.14E), reveals that the phase lock- ing of spikes from the strongly-driven subset to the ripple troughs is now restored to a large extent. The fact that histogram peaks do not completely overlap with the ripple troughs is due to the ripples in DOWN states where the CA3 drive is weaker. In fact, after subtracting DOWN state ripples by increasing the ripple detection threshold, the prominent phase locking is restored (not shown).
Finally, to examine the SO effect on the spiking of individual CA1 pyramidal cells, we repeated the Z-score normalised firing rate calculation for each cell, and arranged them according to either the time of the firing rate peak (Figure 7.15A), or the number of synapses per Schaffer input each cell receives (Figure 7.15B). The number of synapses per Schaffer-connection that each cell receives is plotted next to each panel. Figure
7.15A indicates that, with the implemented combination of TA- and CA3-drive, roughly half of the CA1 pyramidal cells fire preferentially during UP states. The corresponding Schaffer-input is, on average, stronger for these cells. In fact, Figure7.15B suggests that the stronger the CA3 drive, the higher the probability that the cell will fire mostly in the UP states. Therefore, both plots indicate that generally the strongly-driven cells fire preferentially during UP states, where they receive higher depolarising input. Note however, that some cells with strong CA3-drive get too inhibited in UP states and tend to fire more in DOWN states. In contrast, many of the cells that receive average or weak CA3 input, and are silent during DOWN states, get strongly depolarised from the TA input, and thus fire in UP states. In conclusion, the correlation of a cell’s firing rate with the SO appears to depend on a combination of both the CA3 and the TA drive.