Individual behavioral profiling as a translational approach to assess treatment efficacy in an animal model of post-traumatic stress disorder.

A major challenge in treating post-traumatic stress disorder (PTSD) continues to be the large variability in responsiveness to pharmacotherapy. Only 20-30% of patients experience total remission to a specific treatment, while others demonstrate either partial remission or no response. However, this heterogeneity in response to pharmacotherapy has not been adequately addressed in animal models, since these analyze the averaged group effects, ignoring the individual variability to treatment response, which seriously compromises the translation power of such models. Here we examined the possibility of employing an "individual behavioral profiling" approach, originally developed to differentiate between "affected" and "exposed-unaffected" individuals in an animal model of PTSD, to also enable dissociating "responders" or "non-responders" after SSRI (fluoxetine) treatment. Importantly, this approach does not rely on a group averaged response to a single behavioral parameter, but considers a cluster of behavioral parameters, to individually characterize an animal as either "responder" or "non-responder" to the treatment. The main variable to assess drug efficacy thus being the proportion of "responders" following treatment. Alteration in excitatory/inhibitory (E/I) balance has been proposed as being associated with stress-related psychopathology. Toward a functional proof of concept for our behaviorally-based characterization approach, we examined the expression patterns of α1 and α2 subunits of GABAA receptor, and GluN1 and GluN2A subunits of the NMDAR receptor in the ventral hippocampus, as well as electrophysiologically local circuit activity in the dorsal dentate gyrus (DG). We demonstrate that with both parameters, treatment "responders" differed from treatment "non-responders," confirming the functional validity of the behavior-based categorization. The results suggest that the ability to respond to fluoxetine treatment may be linked to the ability to modulate excitation-inhibition balance in the hippocampus. We propose that employing the "individual behavioral profiling" approach, and the resultant novel variable of the proportion of "recovered" individuals following treatment, offers an effective translational tool to assess pharmacotherapy treatment efficacy in animal models of stress and trauma-related psychopathology.

Chemogenetic activation of the mPFC alleviates impaired fear memory extinction in an animal model of PTSD.

BACKGROUND AND AIM: Although impaired extinction of fear memory (EFM) is a hallmark symptom of posttraumatic stress disorder (PTSD), the mechanisms underlying the impairment are unknown. Activation of the infralimbic cortex (IL) in the medial prefrontal cortex (mPFC) has been reported to predict successful fear extinction, whereas functionally disrupting this region impairs extinction. We examined whether chemogenetic activation of the IL could alleviate impaired EFM in a single prolonged stress (SPS) rat model of PTSD. METHODS: Chemogenetic activation of IL and prelimbic (PL) excitatory neurons was undertaken to evaluate EFM using a contextual fear conditioning paradigm. Neuronal activity in the IL was recorded using a 32-multichannel silicon electrode. To examine histological changes in the mPFC, apoptosis was measured by TUNEL staining. RESULTS: Chemogenetic activation of excitatory neurons in the IL, but not the PL, enhanced EFM in sham rats and resulted in alleviation of EFM impairment in SPS rats. The alleviation of impaired EFM in SPS rats was observed during the extinction test session. Neuronal activity in the IL of SPS rats was lower than that of sham rats after clozapine-n-oxide administration. Increased apoptosis was found in the IL of SPS rats. CONCLUSIONS: These findings suggest that a decreased excitatory response in the IL due, at least in part, to an increase in apoptosis in SPS rats leads to impaired EFM, and that neuronal activation during extinction training could be useful for the treatment of impaired EFM in PTSD patients.

Effects of paroxetine on PTSD-like symptoms in mice.

RATIONALE: After exposure to a severe traumatic event, avoidance, fear sensitization, and increased anxiety are among features that can persist over time in people developing posttraumatic stress disorder (PTSD). Basic research on treatment interfering with these symptoms can provide insights to improve PTSD treatment. OBJECTIVES: The purposes of the present study were to induce these behavioral changes in mice and examine whether paroxetine would interfere with their expression. METHODS: Mice were submitted to avoidance training with a low (0.4 mA) or high (1.5 mA) foot-shock intensity, as mild and severe stressors, respectively, and posttraining avoidance was evaluated 1 and 12 days later. Fear sensitization, measured as increased freezing to a neutral tone, and enhanced contextual fear, measured as increased freezing to a conditioned context (wherein all mice received a 0.4-mA foot-shock), were assessed during this time window. An elevated plus maze test was also used to assess mouse anxiety-like behavior. RESULTS: Persistent avoidance, persistent fear sensitization, and long-term enhancement of contextual fear and increased anxiety-like behavior were established only in mice that received the 1.5-mA foot-shock during avoidance training. Paroxetine (at 8 mg/kg/day), injected from day 5 to day 11 after avoidance training, suppressed all of these behavioral changes. CONCLUSIONS: These data provide additional evidence for the role of paroxetine against expression of PTSD-like behaviors in mice.

The Neurological Ecology of Fear: Insights Neuroscientists and Ecologists Have to Offer one Another.

That the fear and stress of life-threatening experiences can leave an indelible trace on the brain is most clearly exemplified by post-traumatic stress disorder (PTSD). Many researchers studying the animal model of PTSD have adopted utilizing exposure to a predator as a life-threatening psychological stressor, to emulate the experience in humans, and the resulting body of literature has demonstrated numerous long-lasting neurological effects paralleling those in PTSD patients. Even though much more extreme, predator-induced fear and stress in animals in the wild was, until the 1990s, not thought to have any lasting effects, whereas recent experiments have demonstrated that the effects on free-living animals are sufficiently long-lasting to even affect reproduction, though the lasting neurological effects remain unexplored. We suggest neuroscientists and ecologists both have much to gain from collaborating in studying the neurological effects of predator-induced fear and stress in animals in the wild. We outline the approaches taken in the lab that appear most readily translatable to the field, and detail the advantages that studying animals in the wild can offer researchers investigating the "predator model of PTSD."