Daily Optogenetic Stimulation of the Left Infralimbic Cortex Reverses Extinction Impairments in Male Rats Exposed to Single Prolonged Stress.

Lucas Canto-De-Souza,Christa K Mcintyre,Samantha Plas,Peyton G Demetrovich,Rimenez R Souza,Cleopatra Silva Planeta,Ricardo Luiz Nunes-De-Souza,Joseph Epperson,Ryan T Lalumiere,Krista L Wahlstrom

doi:10.3389/fnbeh.2021.780326

Abstract

Post-traumatic stress disorder (PTSD) is associated with decreased activity in the prefrontal cortex. PTSD-like pathophysiology and behaviors have been observed in rodents exposed to a single prolonged stress (SPS) procedure. When animals are left alone for 7 days after SPS treatment, they show increased anxiety-like behavior and impaired extinction of conditioned fear, and reduced activity in the prefrontal cortex. Here, we tested the hypothesis that daily optogenetic stimulation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) during the 7 days after SPS would reverse SPS effects on anxiety and fear extinction. Male Sprague-Dawley rats underwent SPS and then received daily optogenetic stimulation (20 Hz, 2 s trains, every 10 s for 15 min/day) of glutamatergic neurons of the left or right IL for seven days. After this incubation period, rats were tested in the elevated plus-maze (EPM). Twenty-four hours after the EPM test, rats underwent auditory fear conditioning (AFC), extinction training and a retention test. SPS increased anxiety-like behavior in the EPM task and produced a profound impairment in extinction of AFC. Optogenetic stimulation of the left IL, but not right, during the 7-day incubation period reversed the extinction impairment. Optogenetic stimulation did not reverse the increased anxiety-like behavior, suggesting that the extinction effects are not due to a treatment-induced reduction in anxiety. Results indicate that increased activity of the left IL after traumatic experiences can prevent development of extinction impairments. These findings suggest that non-invasive brain stimulation may be a useful tool for preventing maladaptive responses to trauma.

Highlights

The medial prefrontal cortex maintains vast connections with both cortical and subcortical structures (McKlveen et al, 2015; Porter and Sepulveda-Orengo, 2020) and contributes to the regulation of emotions (Kesner and Churchwell, 2011) and stress-related responses (Cerqueira et al, 2008)
These findings suggest that the number of enclosed arm entries was not an influential factor in the anxiogenic-like behavior induced by the single prolonged stress (SPS)
Enhanced anxiety-like behavior and impaired extinction memory are symptoms observed in male rodents subjected to the SPS procedure (Liberzon and Young, 1997; Kohda et al, 2007; Knox et al, 2012a, 2016; Noble et al, 2017; FerlandBeckham et al, 2021)

Summary

Introduction

The medial prefrontal cortex (mPFC) maintains vast connections with both cortical and subcortical structures (McKlveen et al, 2015; Porter and Sepulveda-Orengo, 2020) and contributes to the regulation of emotions (Kesner and Churchwell, 2011) and stress-related responses (Cerqueira et al, 2008). The SPS procedure involves a series of successive stressors in a single day followed by a 7-day quiescent period, and it leads to many PTSD-like behavioral and physiological symptoms (Liberzon and Young, 1997; Kohda et al, 2007; Milad et al, 2009; Glover et al, 2011; Norrholm et al, 2011; Knox et al, 2012a, 2016; Noble et al, 2017). After a 7-day incubation period in which animals are left undisturbed following SPS exposure, rats show increased anxiety-like behavior and impaired extinction learning, along with reduced glutamate levels in the infralimbic (IL) portion of the mPFC (Knox et al, 2010, 2016; Lim et al, 2017; Piggott et al, 2019; Nawreen et al, 2021)

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Results

Conclusion