Post-trauma behavioral phenotype predicts the degree of vulnerability to fear relapse after extinction in male rats.

Current treatments for trauma-related disorders remain ineffective for many patients.1,2 Fear extinction deficiency is a prominent feature of these diseases,3 and many behavioral treatments rely on extinction training.4,5 However, in many patients, therapy is followed by a relapse of symptoms, and the underpinnings of such interindividual variations in vulnerability to relapse remain unknown.6-8 Here, we modeled interindividual differences in post-therapy fear relapse with an ethologically relevant trauma recovery paradigm. After fear conditioning, male rats underwent fear extinction while foraging in a large enriched arena, permitting the expression of a wide spectrum of behaviors. An automated multidimensional behavioral assessment revealed that post-conditioning fear response profiles clustered into two groups: some animals expressed fear by freezing more, whereas others darted more, as if fleeing from danger. Remarkably, the tendency of an animal to dart or to freeze after CS presentation during the first extinction session was, respectively, associated with stronger or weaker fear renewal. Moreover, genome-wide transcriptional profiling revealed that these groups differentially regulated specific sets of genes, some of which were previously implicated in anxiety and trauma-related disorders. Our results suggest that post-trauma behavioral phenotypes and the associated gene expression landscapes can serve as markers of fear relapse susceptibility and thus may be instrumental for future development of more effective treatments for psychiatric patients.

Selective activation of D1 dopamine receptors exerts antidepressant-like activity in rats.

BACKGROUND: Major depressive disorder is a common illness that severely decreases psychosocial functioning. Due to the major limitations of current treatments including response failure, it is crucial to develop better therapy strategies. Evidence suggests that dopamine dysregulation might play a major role in major depressive disorder physiopathology. AIMS: This study investigates whether the dopamine D1 receptor agonist A77636 modulates antidepressant-like activity in rats. METHODS: Rats were injected with an acute single dose of A77636 (0.75, 1.5 or 3 mg/kg), a potent and selective dopamine D1-like receptor agonist. Their locomotor activity, social interactions and behavioural response to the forced swim test were analysed 30 min after the injection. RESULTS: During the forced swim test, the D1 agonist dose dependently reduced the immobility while the time of bursting was increased. Social interactions were significantly increased in the animals exposed to 3 mg/kg of A77636 whereas no significant changes were measured in general motor activity. CONCLUSIONS: The present results provide evidence that pharmacological modulation of D1 receptor by the selective agonist A77636 induces antidepressant-like effects in rats, which encourages further studies regarding D1-specific modulation in major depressive disorder treatment.

Dysregulation of peripheral expression of the YWHA genes during conversion to psychosis.

The seven human 14-3-3 proteins are encoded by the YWHA-gene family. They are expressed in the brain where they play multiple roles including the modulation of synaptic plasticity and neuronal development. Previous studies have provided arguments for their involvement in schizophrenia, but their role during disease onset is unknown. We explored the peripheral-blood expression level of the seven YWHA genes in 92 young individuals at ultra-high risk for psychosis (UHR). During the study, 36 participants converted to psychosis (converters) while 56 did not (non-converters). YWHA genes expression was evaluated at baseline and after a mean follow-up of 10.3 months using multiplex quantitative PCR. Compared with non-converters, the converters had a significantly higher baseline expression levels for 5 YWHA family genes, and significantly different longitudinal changes in the expression of YWHAE, YWHAG, YWHAH, YWHAS and YWAHZ. A principal-component analysis also indicated that the YWHA expression was significantly different between converters and non-converters suggesting a dysregulation of the YWHA co-expression network. Although these results were obtained from peripheral blood which indirectly reflects brain chemistry, they indicate that this gene family may play a role in psychosis onset, opening the way to the identification of prognostic biomarkers or new drug targets.

A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice.

Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long-term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study's in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1-11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA-treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice.