PMC

Ratio of the test response to the conditioning response (T/C ratio) as a function of interstimulus interval when a presynaptic mechanism is included in the model. The test response is sufficiently suppressed for all interstimulus intervals tested, including 0.5 s

Schematic representation of presynaptic mechanisms of GABA_B. Presynaptic GABA_B acted at cortical (EC) and recurrent excitatory synapses (P) in the model by reducing the synaptic strength of the synapse. The GABA_B was released from the interneurons (I) when the cells were stimulated by septal nicotinic input

A–C. The response of a model pyramidal cell to synaptic input. Each trace shows the time course of somatic voltage, ES. A The response of the model pyramidal cell to excitatory and inhibitory synaptic input. The inputs were onto both the somatic and dendritic compartment and resulted in low-frequency bursting. B Strong current injection into the soma resulted in high-frequency somatic spiking. C Strong current injection into the dendrites produced a combination of somatic spikes and weak dendritic bursts

Model of CA3 pyramidal cell. The model of the CA3 pyramidal cell had two compartments. There were nine synaptic inputs: recurrent excitation, local GABA_A and local GABA_B, excitatory input from the dentate gyrus (DG) and the entorhinal cortex (EC), and muscarinic and nicotinic cholinergic input from the septum. Inputs to the cell were distributed as shown. In addition, there was a voltage-dependent potassium conductance in the soma (GK) and a calcium-dependent potassium current in the dendrite (GKD). Finally, there was a voltage-dependent calcium current in the dendrite (GCA)

A–C. Effect of modulating GABA_B presynaptic receptors and nicotinic cholinergic activity in the model. A Normal P50 auditory sensory gating, described in , is reproduced here for convenience. B The effect of blocking nicotinic receptors, described in , is reproduced here for comparison. C Simulating a presynaptic GABA_B agonist improved gating by decreasing the amplitude of the test response (T) but had no effect on the conditioning response (C). This decreased the T/C ratio to 36.0%. Calibration bars are the same for each evoked potential: vertical calibration bar is 0.5 mV, horizontal calibration bar is 50 ms

A–C. Effect of modulating nicotinic cholinergic activity in the model. A Normal P50 auditory sensory gating, described in is reproduced here for convenience. B Blocking nicotinic receptors in the model reduced sensory gating by producing a large decrease in the conditioning amplitude as compared to the normal case (A). Therefore, when nicotine was blocked, the T/C ratio was increased to 92.5%. C Simulating a nicotinic agonist restored gating. This decreased the T/C ratio to 12.0%, which was similar to the normal gating T/C ratio of 16.9%. Calibration bars are the same for each evoked potential: vertical calibration bar is 0.5 mV, horizontal calibration bar is 50 ms

A,B. Computer simulations of the P50 auditory-evoked potential to two paired-click stimuli. A Normal gating was simulated by increasing cholinergic activity from the septum and stimulating one of the four patterns embedded in the network via the EC input. The amplitude of the conditioning respones (C) was greater than the amplitude of the test response (T) by 83.1% (T/C ratio was 16.9%). T was modeled by reducing the cholinergic input to half of the input during the C and decreasing the EPSP by half to simulate presynaptic GABA_B activity. B When presynaptic GABA_B receptors were blocked, the amplitude of C was unchanged. However, the amplitude of T increased, reducing sensory gating. The T/C ratio was 81.8%. Calibration bars are the same for each evoked potential: vertical calibration bar is 0.5 mV, horizontal calibration bar is 50 ms

Ratio of the test response to the conditioning response (T/C ratio) as a function of interstimulus interval. When the interstimulus interval is 175 ms, local postsynaptic GABA_b activity is sufficient to suppress the response to the test click. However, as the interstimulus interval is increased, the response to the test response also increases. Insets show the total GABA_b current generated. The large arrow marks time of the first click. Inset 1: GABA_B current generated when interstimulus interval is 175 ms. Inset 2: GABA_B current generated when interstimulus interval is 250 ms. Inset 3: GABA_B current generated when interstimulus interval is 500 ms. At 175 ms and 250 ms, the postsynaptic GABA_B-receptor-mediated inhibitory current did not completely decay away before the second or test stimulus was activated (refer to dotted lines below second, smaller arrow). Therefore, postsynaptic GABA_B currents contributed to the suppression of the test response when the interstimulus interval was 250 ms or less. When the interstimulus interval was 500 ms, the GABA_B postsynaptic current was completely decayed away before the onset of the second stimulus. pS is picosiemens. Vertical calibration bar: 100 pS. Horizontal calibration bar: 200 ms

A,B. A. Poststimulus time histograms for pyramidal cells in the model when information was represented as average firing rate A and when information was represented as cell assemblies B. The stimulus is a single, simulated auditory click stimulus. A Response of four cells representing the population. These responses were representative of all cells in the network. All cells showed a small response to the stimulus. B Poststimulus time histograms for four pyramidal cells in the model when information was represented as cell assemblies. The top two responses were cells that were part of the pattern being recalled. There was a large response approximately 20 ms after the simulated input. The bottom two responses were from two cells not part of the pattern. These cells did not response to the stimulus. Bin sizes were 1 ms. The arrow points to the simulated stimulus input. The results were the sums for 80 trials

A,B. Schematic representation of the CA3 region of the hippocampus modeled in this study. The model included 600 individually modeled pyramidal cells (P) and 60 interneuron cells (I). A Recurrent activity between these two cell populations included excitatory activity between pyramidal cells and onto the interneurons and inhibitory activity between interneurons and pyramidal cells. Connections were made based on patterns embedded in the network (see text for details). Each interneuron had both GABA_A and GABA_B terminals. B Afferent inputs modeled in this study. Inputs from the entorhinal cortex (EC) and dentate gyrus (DG) were excitatory onto both the pyramidal cells and the interneuron cells. Inputs from the medial septum-diagonal band complex (MSDB) were of two types. MSDB cholinergic input was onto both pyramidal cells and interneuron cells at nicotinic and muscarinic receptors. MSDB GABAergic input was onto both pyramidal cells and interneurons, but this input was constant throughout the simulations (see text for details). Each of these inputs to the CA3 network was modeled using biologically relevant postsynaptic conductance changes

A,B. Four averaged auditory-evoked potentials recorded from the hippocampus of an awake, freely moving rat in response to two sets of paired auditory click stimuli spaced 0.5 s apart. Gating was quantitatively expressed as the amplitude of the evoked potential recorded in response to the second (test) click divided by the amplitude of the response to the first (conditioning) click, or T/C ratio. A Two N40 auditory-evoked potentials recorded in response to the paired-click stimuli. The first waveform, or conditioning response, has a greater amplitude than the second waveform or test response. These data are from a session during which the animal markedly suppressed or gated the hippocampal response to the second click. In this case, a T/C ratio of 0.28 indicated that the response to the test click was 72% smaller than the response to the conditioning click. B Data recorded from a session during which the animals did not gate or suppress their response to the test stimuli. In this case, a T/C ratio of 0.72 indicated that the amplitude of the response to the test click was only 28% smaller than the amplitude of the conditioning response. For both A and B these data represented responses to 80 pairs of clicks that were averaged. Presentation of pairs occurred every 15 s. Computer-generated marks below each tracing indicate the peak of the N40 wave. The auditory stimulus occurs at the beginning of each trace. The horizontal calibration is 20 ms; vertical is 1.0 mV

A,B. Diagram of the cell assemblies in the model. A Representation of a single pattern embedded in the network. Cells 1–10 constitute one link, while cells 11–20 are the second link, cells 21–30 the third link, 31–40 the fourth link, and cells 41–50 the final link. The cells in the first link (cells 1–10) are synaptically connected to each of the other links. The value of the synaptic strengths are modified according to . For example, the magnitude of the synaptic-strength modification for cells between the first and second link is 1.0. The magnitude of the synaptic-strength modification between the first and third link is 0.605, and that between the first and fourth link is 0.368. Cells in the second link are synaptically connected to the third and fourth links (cells 21–40), while cells in the third link are synaptically connected to the fourth link. The pattern can be recalled by stimulating the first link of the pattern. For example, if the network is stimulated with the first link (i.e., all cells in the first link fire simultaneously), each of the cells in the first link will project synaptic activation to cells 11–40 according to . This synaptic activation is sufficient to cause the cells in the second link to fire at the next time step. These cells then provide synaptic input to the third link, which fires at the next time step. If only one pattern is embedded in the network, the pattern will respond with no noise and the cells will fire as defined by the pattern. B Effect of sharing synapses among patterns embedded in the network. When three more patterns were embedded in the network, several synapses were shared among the patterns, and therefore cross-talk activity caused the recall of the pattern to be noisy. Cells may fire earlier or later then their appointed time or they may not fire at all. In addition, cells not in the pattern (e.g., cells 56, 72, 73, etc.) received enough excitation to fire action potentials