Understanding ethanol's acute effects on medial prefrontal cortex neural activity using state-space approaches

Abstract

Acute ethanol (EtOH) intoxication results in several maladaptive behaviors that may be attributable, in part, to the effects of EtOH on neural activity in medial prefrontal cortex (mPFC). The acute effects of EtOH on mPFC function have been largely described as inhibitory. However, translating these observations on function into a mechanism capable of delineating acute EtOH's effects on behavior has proven difficult. This review highlights the role of acute EtOH on electrophysiological measurements of mPFC function and proposes that interpreting these changes through the lens of dynamical systems theory is critical to understand the mechanisms that mediate the effects of EtOH intoxication on behavior. Specifically, the present review posits that the effects of EtOH on mPFC N-methyl-d-aspartate (NMDA) receptors are critical for the expression of impaired behavior following EtOH consumption. This hypothesis is based on the observation that recurrent activity in cortical networks is supported by NMDA receptors, and, when disrupted, may lead to impairments in cognitive function. To evaluate this hypothesis, we discuss the representation of mPFC neural activity in low-dimensional, dynamic state spaces. This approach has proven useful for identifying the underlying computations necessary for the production of behavior. Ultimately, we hypothesize that EtOH-related alterations to NMDA receptor function produces alterations that can be effectively conceptualized as impairments in attractor dynamics and provides insight into how acute EtOH disrupts forms of cognition that rely on mPFC function. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.

Keywords: Alcohol; Attractor; Cognition; Dynamics systems theory; Intoxication; Prefrontal cortex; Up-states.

Figure 1.. Reproduction of the model and results of EtOH-relevant manipulation on non-noised conditions without noise.

A. The response of the excitatory and inhibitory units is shown as a function of excitatory input. A non-linearity in the model leads to input values below the threshold θ_X to be output as 0. After the input surpasses the threshold θ_X, the output is a steady state firing rate of each respective population according to the gain term g_E or g_I. B. The phase plane of rates demonstrates three possible fixed points in the fast subsystem. The down-state is the stable fixed point where both the excitatory and inhibitory rates are at 0, which is denoted by the circle D. The up-state is the stable fixed point where both excitatory and inhibitory rates are non-zero, which is denoted by the circle U. The dashed circle at the 2^nd intersection indicates an unstable fixed point. C. Adjusting the EtOH parameter produces longer decay times for the adaptation current of this model. D. In the absence of noise and with EtOH equal to 1, up-down states proceed at regular intervals. E. With EtOH equal to 5, down-states are significantly prolonged due to the longer decay times of the adaptation current. F. In the absence of noise, down-state durations linearly increase as a function of our EtOH parameter. Up-state durations are only minorly affected.

Figure 2.. Model results during noised conditions with noise.

A. With noise added to the system, up-down states proceed irregularly for variable periods of time. B. With EtOH equal to 20, noise is sufficient to drive up-states that did not occur in the non-noise condition, however, down-states are on average considerably lengthened. C. Down-states increase as a function of EtOH in the noise condition. Additionally, down-state durations are considerably shorter compared to comparable EtOH values in the non-noise condition. Values depicted are median ± SEM. D and E are adaptations from Morningstar (2020). These are empirical results during a urethane anesthetized recording before and after a 1.0 g/kg EtOH injection. D shows a small, significant decrease in up-state duration following EtOH (Median Saline: 0.524 ± 0.664; Median EtOH: 0.515 ± 0.240; Wilcoxon’s rank-sum: z = −6.55, p < 0.001, Effect Size = −0.04) and E shows a larger, significant increase in down-state duration following EtOH (Median Saline: 0.676 ± 1.456; Median EtOH: 0.972 ± 2.007; Wilcoxon’s rank-sum: z = 14.69, p < 0.001, Effect Size = 0.08). Median values are followed by STD. Effect size was calculated by dividing the z-score by the square root of the total number of up or down-states tested.