Inhibition of mTOR kinase via rapamycin blocks persistent predator stress-induced hyperarousal

Abstract

Si. Johns Newfound land Abstr actTraumatic. stressful lif e events arc thought to trigger acquired anxie ty disorders such as post-t raumatic stress disorder (PTSD). PTSD is characteri sed by several symptoms including both associative and non-associative tear memories, It has been previously established that the mamm alian target of rapamycin (mTO R) pathw ay plays a key role in associa tive fear memories: howev er, it is unknown whether this pathway attenuates non-associative fear memories (or fear sensitization). Thus. the goal of these ex periments was to exam ine the role ofmIO k in non-associative fear memories, In thc current set of experi ments. non-associative fear memories were produced by predator stress. Predator stress invo lves an acute. unprotected ex posure of a rat to a cat which causes long-lasting non-associative fear memor ies ex pressed as genera lized hypcra rousal (ma ni fested as increased startle response and anxiety-like behavior and measured in the eleva ted plus maze. hole board and light/dark box). l lcrc. we show that rapamyci n. when given before (Experiment I) or after (Experiment 2) stress. attenuated predat or stressinduced hypcrarou sal. lasting at least three weeks. In addition. rapamyc in blocked a subset ofanxiety-like behaviors. Furthermore. when rc-cxposcd to the predator stress context. rapamyci n-trca rcd predator stressed rats showed increased activity compared to vehicle controls. These data suggest that rapamyciu blocks conso lidatio n of pI' cd'ItOI' stress-induced non-associa tive and associative fear memor ies. In a seco nd set of experiments, we examined the eff ects ofra pamycin fo llowin g reactivation (Experiment 3) and without reactivation ( Ex pcri mcnr -l ) of predator stress-induced fear memories on nonassociative lear memorie s, A single. 10 minute rc-cx posurc to the predator strcss context was sulficicnt to extingui sh predator stress -ind uced hypcrarousa l (Experiments 3. 4 ).Ra pam yc in blocked this exti ncti on (Ex pe riment 3). We al so show that . con sistent w ith previous data . rap am ycin si gnificantl y reduced wei ght ga in lasting at least lour week s (Ex periments 1-4). Tak e n to ge ther with past research. our result s indicate that m'l'Ok regul ati on o r protein tran s lation is requ ired for con so lidat ion or bot h ass ocia tive and nonasso ciati ve rear me mories. Overa ll. these data sugg es t that rap amycin. a dru g already in c lin ica l trial s. may be a no vel treatm ent tor pa tient s suff eri ng lrom ac q uired anx ie ty di sorders suc h as I'T S D.

Inhibition of mTOR signaling by genetic removal of p70 S6 Kinase 1 leads to anxiety-like disorders

“…In line with previous reports highlighting a role for mTORC1 signaling in both associative and non-associative fear memories 43 , our data also show that constitutive deletion of S6K1 causes a deficit in shock-induced contextual associative fear memory, while spatial navigation is spared. This dataset is consistent with reports that S6K1 is required for acquisition and consolidation of normal contextual fear memory but not necessary for spatial navigation 38 .…”

“…Thus, we propose that an enhanced emotional reactivity linked to an anxious phenotype be at the origin of the associative fear deficits. Supporting this view, rapamycin administration blocks predator stress-induced associative fear memory 43 as well as shock-induced inhibitory avoidance 3 .…”

Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

“…administration, rats received either vehicle (VEH: 5% ethanol in 5% Tween 80 and 5% PEG 400 in distilled water) or RAP (LC Laboratories, Woburn, MA, USA) in vehicle at 0.1, 1, or 10 mg/kg, similar to [12], [13].…”

Predator-based psychosocial stress animal model of PTSD: Preclinical assessment of traumatic stress at cognitive, hormonal, pharmacological, cardiovascular and epigenetic levels of analysis

“…More recent work by Blundell and her co-workers has focused on mechanistic and behavioral approaches toward improving our understanding of the formation and persistence of a "traumatic" memory, enhancing its extinction in cat-exposed rodents and preventing the development of PTSD-like behavioral changes (Clay et al, 2011;Fifield et al, 2013;Fifield et al, 2015;Mac Callum et al, 2014).…”