Single Prolonged Stress Reduces Intrinsic Excitability and Excitatory Synaptic Drive Onto Pyramidal Neurons in the Infralimbic Prefrontal Cortex of Adult Male Rats.

Mark L Baccei,Nawshaba Nawreen,James P Herman

doi:10.3389/fncel.2021.705660

Abstract

Post-traumatic stress disorder (PTSD) is a chronic, debilitating mental illness marked by abnormal fear responses and deficits in extinction of fear memories. The pathophysiology of PTSD is linked to decreased activation of the ventromedial prefrontal cortex (vmPFC). This study aims to investigate underlying functional changes in synaptic drive and intrinsic excitability of pyramidal neurons in the rodent homolog of the vmPFC, the infralimbic cortex (IL), following exposure to single prolonged stress (SPS), a paradigm that mimics core symptoms of PTSD in rats. Rats were exposed to SPS and allowed 1 week of recovery, following which brain slices containing the PFC were prepared for whole-cell patch clamp recordings from layer V pyramidal neurons in the IL. Our results indicate that SPS reduces spontaneous excitatory synaptic drive to pyramidal neurons. In addition, SPS decreases the intrinsic membrane excitability of IL PFC pyramidal cells, as indicated by an increase in rheobase, decrease in input resistance, hyperpolarization of resting membrane potential, and a reduction in repetitive firing rate. Our results suggest that SPS causes a lasting reduction in PFC activity, supporting a body of evidence linking traumatic stress with prefrontal hypoactivity.

Highlights

Post-traumatic stress disorder (PTSD) is among the most prevalent and debilitating neuropsychiatric disorders in the world
Our results indicate that single prolonged stress (SPS) causes physiological changes in infralimbic cortex (IL) medial prefrontal cortex (mPFC) glutamatergic pyramidal neurons and their associated synaptic inputs (Figure 4)
We demonstrate that SPS reduces the intrinsic membrane excitability of IL pyramidal neurons, as indicated by an increased rheobase, decreased input resistance, hyperpolarized resting membrane potential (RMP), and a reduction in repetitive firing rate

Summary

Introduction

Post-traumatic stress disorder (PTSD) is among the most prevalent and debilitating neuropsychiatric disorders in the world. To date no universally efficacious treatment exists for PTSD, underscoring the importance of the development of effective therapeutic strategies for this disorder. Symptoms of PTSD can be modeled in rodents using the single prolonged stress (SPS) paradigm (Liberzon et al, 1997; Eagle et al, 2013). Multiple studies indicate that SPS disrupts the extinction of SPS Effects on IL Physiology fear memories in male rats (Yamamoto et al, 2008; Knox et al, 2012; Souza et al, 2017). Studies in our group indicate that SPS disrupts extinction learning in male (but not female) rats, indicative of a sex-specific impact on fear regulation (Cotella et al, 2021)

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