RETRACTED ARTICLE: Predator odor increases avoidance and glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling

Abstract

Acute exposure to a salient stressor, such as in post-traumatic stress disorder, can have lasting impacts upon an individual and society. To study stress in rodents, some naturalistic methods have included acute exposure to a predator odor, such as the synthetic fox odor 2,4,5, trimethyl-3-thiazoline (TMT). These experiments explore the stress-related behaviors and cortical activity induced by TMT exposure in adult male C57BL/6J mice and the influence of the stress neuropeptide corticotropin-releasing factor (CRF) on these responses. Compared to H 2 O and a novel odorant, vanilla, mice exposed to TMT in the home cage showed increased avoidance and defensive burying indicative of evident stress responses. Consistent with stress-induced activation of the medial prefrontal cortex (mPFC), we found that the prelimbic (PL) and infralimbic (IL) subregions of the mPFC had elevated c-Fos immunolabeling after TMT and vanilla compared to H 2 O. Slice physiology recordings were performed in layers 2/3 and 5 of the PL and IL, following TMT, vanilla, or H 2 O exposure. In TMT mice, but not vanilla or H 2 O mice, PL layers 2/3 showed heightened spontaneous excitatory post-synaptic currents and synaptic drive, suggesting TMT enhanced excitatory transmission. Synaptic drive in PL was increased in both TMT and H 2 O mice following bath application of 300 nM CRF, but only H 2 O mice increased excitatory currents with 100 nM CRF, suggesting dose-effect curve shifts in TMT mice. Further, systemic pretreatment with the CRF-R1 antagonist CP154526 and bath application with the CRF-R1 antagonist NBI27914 reduced excitatory transmission in TMT mice, but not H 2 O mice. CP154526 also reduced stress-reactive behaviors induced by TMT. Taken together, these findings suggest that exposure to TMT leads to CRF-R1 driven changes in behavior and changes in synaptic function in layer 2/3 neurons in the PL, which are consistent with previous findings that CRF-R1 in the mPFC plays an important role in predator odor-related behaviors.Neuropsychopharmacology (2019) 44:766-775; https://doi.

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats

“…Finally, control rats spent significantly more time grooming than the TMT group, presumably because the TMT group was engaging in digging and freezing behaviors. Increased digging, immobility, avoidance, and decreased grooming during the TMT exposure are consistent with previous findings using TMT stress 26,40,30,41 . Together, these data reflect a shift from an early, active approach behavior (digging) to a passive immobility/freezing and avoidance behavior.…”

“…Rats engaged in digging behavior during the first 6 mins of exposure, which ultimately resulted in a pile of bedding under the TMT source. Digging behavior appears similar to defensive burying behavior, which rodents display in response to predator odors 40 . However, because hanging the predator odor from a basket makes burying impossible, digging may reflect a failed attempt at defensive burying behavior.…”

The synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline increases alcohol self-administration and alters basolateral amygdala response to alcohol in rats

“…To begin to understand the neurobiological basis of increased alcohol self-administration, Experiment 2 examined whether TMT-exposed rats showed differential expression of c-Fos, a marker of neuronal activity, in response to alcohol 1 week after the final TMT exposure. We examined subregions of the mPFC and amygdala, which are implicated in both PTSD, AUD, and activated by predator odor (Asok et al, 2013, Edwards et al, 2013, Hwa et al, 2019). Acute administration of alcohol (2 g/kg, i.g.)…”

Alcohol Drinking Alters Stress Coping via Extended Amygdala Kappa Opioid Receptor Signaling in Male Mice

“…TMT Predator Odor Exposure. Exposure to fox-derived synthetic predator odor, trimethylthiazoline (TMT), was performed in the home cage as previously described to elicit stress reactions in mice (6). For a baseline pre-trial period, mice habituated to a cotton tip 5 applicator held vertically in place for 10 min in the home cage.…”

“…Slice Electrophysiology. Ninety minutes following TMT, which was also 24 hr after the last EtOH access, mice were sacrificed via deep isoflurane anesthesia, and coronal brain slices containing the BNST were collected according to standard laboratory protocols (6,8,10 . oEPSC amplitude (pA) was the first peak of the paired pulse ratio with a 50 ms interstimulus interval.…”