Model of theta frequency perturbations and contextual fear memory

Abstract

Theta oscillations in the hippocampal local field potential (LFP) appear during translational movement and arousal, modulate the activity of principal cells, and are associated with spatial cognition and episodic memory function. All known anxiolytics slightly but consistently reduce hippocampal theta frequency. However, whether this electrophysiological effect is mechanistically related to the decreased behavioral expression of anxiety is currently unclear. Here, we propose that a reduction in theta frequency affects synaptic plasticity and mnemonic function and that this can explain the reduction in anxiety behavior. We test this hypothesis in a biophysical model of contextual fear conditioning. First, we confirm that our model reproduces previous empirical results regarding the dependence of synaptic plasticity on presynaptic firing rate. Next, we investigate how theta frequency during contextual conditioning impacts learning. These simulations demonstrate that learned associations between threat and context are attenuated when learning takes place under reduced theta frequency. Additionally, our simulations demonstrate that learned associations result in increased theta activity in the amygdala, consistent with empirical data. In summary, we propose a mechanism that can account for the behavioral effect of anxiolytics by impairing the integration of threat attributes of an environment into the cognitive map due to reduced synaptic potentiation.

Keywords: anxiety; anxiolytic; contextual fear; fear recall; theta rhythm.

FIGURE 1

Schematic representation of the network configuration during conditioning and recall. Top—During conditioning, high levels of ACh inhibit EPSPs but support plasticity. Each fear cell receives location‐dependent inputs from the hippocampus, which activate NMDA receptors, and produce Poisson spike trains that reflect the absence or presence of noxious stimuli in the safe and threatening compartments, respectively. Bottom—During recall, low levels of ACh enhance EPSPs while inhibiting further synaptic plasticity. Noxious stimuli are no longer delivered, and the activity of fear cells is thus determined by place cell inputs and the synaptic weights induced by prior conditioning. As a result, place cells active in T⁺ elicit stronger activity in fear cells. In both panels, T_θ indicate the period of the theta rhythm

FIGURE 2

Dependence of synaptic strength on theta frequency during simulation of a presynaptic rate‐induced plasticity protocol

FIGURE 3

(a) Schematic of the simulated experimental protocol. Conditioning: High and low frequency sinusoids above the rodent's head represent conditioning at either high or low theta frequency, respectively, whereas the bolt symbol indicates the presence of noxious stimuli. Recall: The symbols above the rodent's head illustrate the behavior predicted by the model, with the three dots indicating no behavioral response and the exclamation mark a freezing response to the contextual cue. (b) Relative average synaptic strength obtained after simulating contextual conditioning during epochs of theta activity at 5.5 or 6 Hz in the threatening and safe compartment; error bars represent SEM. (c) Firing rate distribution of fear cells during recall at both theta frequencies in both compartments. (d) Percentage probability of freezing over 100 simulations

FIGURE 4

Power spectra of fear cell output spike trains in the safe (left) or threatening compartment (right). The solid cyan line and the blue dashed line indicate the spectrum before and after conditioning, respectively, with either low (5.5 Hz; top) or high (6.0 Hz; bottom) hippocampal theta frequency [Color figure can be viewed at wileyonlinelibrary.com]