Chronic inhibition of GABA synthesis in the infralimbic cortex facilitates conditioned safety memory and reduces contextual fear

Abstract

Accurate discrimination between danger and safety cues is essential for survival. Recent findings in humans indicate that patients suffering from anxiety disorders cannot reliably use safety cues in order to inhibit fear responses. However, the neuroanatomical pathways of conditioned safety are still unclear. Aim of the present study was to investigate whether chronic inhibition of GABA synthesis in the infralimbic (IL) cortex, a critical region for fear inhibition, would lead to enhanced conditioned safety memory. Male Sprague Dawley rats were equipped with osmotic mini-pumps attached to an infusion cannula aimed at the IL. Mini-pumps were either filled with the glutamate decarboxylase (GAD) inhibitor L-allylglycine (L-AG) or the inactive enantiomer D-allylglycine (D-AG). Previous studies demonstrated that chronic infusions of LAG lead to lower GABA levels and overall enhanced neural activity. The effect of IL disinhibition on conditioned safety was investigated utilizing the acoustic startle response. Chronic disinhibition of the IL facilitated conditioned safety memory, along with reduced contextual fear and lower corticosterone levels. The present findings suggest that the IL is a key brain region for conditioned safety memory. Because anxiety disorder patients are often not capable to use safety cues to inhibit unnecessary fear responses, the present findings are of clinical relevance and could potentially contribute to therapy optimization.

Intranasal oxytocin compensates for estrus cycle-specific reduction of conditioned safety memory in rats: Implications for psychiatric disorders

“…While the prospective safety cue had no effects on the startle magnitude pre-conditioning, it significantly attenuated the startle magnitude after single-cued safety conditioning in male and female rats. This, as well as data from other studies applying the same type of training indicate that a positive associative memory to the safety cue was formed ( Kong et al, 2014 ; Kreutzmann et al, 2020a , 2020b , 2021 ; Rogan et al, 2005 ; Camp et al, 2012 ; Ostroff et al, 2010 ; Kreutzmann and Fendt, 2020 ). We further observed that vehicle-treated rats, regardless of sex, expressed potentiated context startle magnitudes following safety conditioning.…”

“…We further observed that vehicle-treated rats, regardless of sex, expressed potentiated context startle magnitudes following safety conditioning. This suggests that rats were fear conditioned to the context in which electric stimuli had previously been received ( Kreutzmann and Fendt, 2020 ; Kreutzmann et al, 2021 ). Of note, the pre-conditioning IN application procedures seem to generally attenuate contextual fear conditioning in both treatment groups.…”

Infralimbic cortex activity is required for the expression but not the acquisition of conditioned safety

“…Our results demonstrate a robust protocol for safety conditioning and underscore that the ASR is a useful tool to measure the effects of conditioned safety in rats. Of note, other studies have also applied this type of conditioning (explicit unpairing) as safety protocol (Rogan et al 2005;Pollak et al 2008;Pollak et al 2010;Ostroff et al 2010;Kreutzmann et al 2019;Kreutzmann and Fendt 2020). In contrast to these studies, we added a pseudo-conditioning group in order to assess non-associative effects of the light cue and to control for potential unspecific effects of the IL/ PL manipulations.…”

Impact of clinical pharmacist services on anticoagulation management of total joint arthroplasty: A retrospective observational study

“…Assuming that statistical power was 95%, significance level was 0.05 and effect size was 0.5 (Cohen's standard medium), it was estimated that at least 210 participants (105 participants per group) would be required to show a statistically significant difference in medication use or rationality between two groups. 15 Statistical analyses were performed with SPSS 22.0 (IBM Inc.).…”