Prefrontal Cortex Deep Brain Stimulation Improves Fear and Anxiety-Like Behavior and Reduces Basolateral Amygdala Activity in a Preclinical Model of Posttraumatic Stress Disorder

Abstract

Deep brain stimulation (DBS) is being investigated for a number of psychiatric indications, including posttraumatic stress disorder (PTSD). Preclinical studies continue to be a cornerstone for the development of new DBS applications. We investigate whether DBS delivered to the infralimbic cortex (IL), a region involved in mechanisms of stress resiliency, may counter behavioral abnormalities in rats that present persistent extinction deficits and long-term anxiety after exposure to fear conditioning. Rats undergoing fear conditioning/extinction were segregated into weak and strong extinction groups (WE >70% or SE <30% of freezing during extinction). Following 2 weeks of DBS, animals were exposed to novel recall sessions and tested in the open field, novelty-suppressed feeding, and elevated plus maze. zif268 expression was measured in structures involved in mechanisms of fear and stress. In vivo electrophysiology was used to record activity from the basolateral amygdala (BLA). We found that DBS improved extinction deficits and anxiety-like behavior in WE animals, having no significant effects in SE rats. No major differences in absolute zif268 levels were recorded across groups. However, correlation between zif268 expression in the IL and BLA was disrupted in WE animals, a deficit that was countered by DBS treatment. Electrophysiology experiments have shown that DBS reduced BLA firing of both putative principal cells and interneurons in WE rats, with no significant differences being detected between SE and SE DBS animals. In summary, IL DBS mitigated fear, partially improved anxiety-like behavior, reversed neurocircuitry abnormalities, and reduced BLA cell firing in a preclinical model of PTSD.

Prefrontal excitatory/inhibitory balance in stress and emotional disorders: Evidence for over-inhibition

“…Future molecular and cellular analyses will also be conducted to verify the behavioral results are related to activity in the PFC. The observation of stress resilience in Kv3.1 KO mice is also in line with previous work showing that increased activity of the PFC is associated with anxiolytic behavior (Fuchikami et al, 2015;Pati et al, 2018;Reznikov et al, 2018). Reducing prefrontal inhibition may therefore be a therapeutic strategy for increasing activity in the PFC and preventing or treating anxiety disorders.…”

“…One possible explanation is that SSRIs reduce markers of inhibitory transmission in the PFC (Sung et al, 2008;Ohira et al, 2013;Guirado et al, 2014;Lee et al, 2018). These interventions would elevate activity levels in the PFC, which has been shown to be therapeutic for anxiety and depression (Covington et al, 2010;Kumar et al, 2013;Fuchikami et al, 2015;Reznikov et al, 2018). By contrast, chronic benzodiazepine treatment may be exacerbating prefrontal hypoactivity, as shown by elevations in GAD1 expression that correlated with increased anxiety-like behavior.…”

“…Stimulation of the PFC has also been shown to reduce anxiety-and depression-related behaviors in rodents (Covington et al, 2010;Kumar et al, 2013;Fuchikami et al, 2015;Pati et al, 2018;Reznikov et al, 2018). PFC activation is also necessary for the extinction of learned fear (Fucich et al, 2018;Ramanathan et al, 2018) via decreasing activity in the amygdala (Quirk et al, 2003).…”

Altered emotional recognition and expression in patients with Parkinson&rsquo;s disease

“…Studies have found that the amygdala and orbitofrontal cortex are associated with fear conditioning. 23 – 25 In addition, diminished motor function may further contribute to impaired emotional expression processing. Delayed onset and reduced amplitude of facial muscles has been recorded during facial expressions.…”

An Associated Research for Genetic Polymorphism of 5-HTTLPR with Post-Traumatic Stress Disorder

“…The S genotype restricts the transcriptional activity producing low functional expression of the 5-HTT and thus decreasing serotonin reuptake, while the L genotype does not results in this changes [11]. While current evidence does not fully support a direct effect of the polymorphism 5-HTTLPR on PTSD [12], the present study further aims at exploring the correlation of genotype and allele frequencies of 5-HTTLPR with PTSD in a Chinese population of earthquakes survivors. The study further explores a scientific basis for the clinical diagnosis of PTSD patients based on genetic research of the condition.…”