Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus.

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

Repeated fear-induced diurnal rhythm disruptions predict PTSD-like sensitized physiological acute stress responses in F344 rats.

AIM: To identify objective factors that can predict future sensitized stress responses, thus allowing for effective intervention prior to developing sensitization and subsequent stress-related disorders, including post-traumatic stress disorder (PTSD). METHODS: Adult male F344 rats implanted with biotelemetry devices were exposed to repeated conditioned fear or control conditions for 22 days followed by exposure to either no, mild or severe acute stress on day 23. Diurnal rhythms of locomotor activity (LA), heart rate (HR) and core body temperature (CBT) were biotelemetrically monitored throughout the study. In a subset of rat not implanted, corticosterone and indices of chronic stress were measured immediately following stress. RESULTS: Rats exposed to repeated fear had fear-evoked increases in behavioural freezing and HR/CBT during exposure to the fear environment and displayed indices of chronic stress. Repeated fear produced flattening of diurnal rhythms in LA, HR and CBT. Repeated fear did not sensitize the corticosterone response to acute stress, but produced sensitized HR/CBT responses following acute stress, relative to the effect of acute stress in the absence of a history of repeated fear. Greater diurnal rhythm disruptions during repeated fear predicted sensitized acute stress-induced physiological responses. Rats exposed to repeated fear also displayed flattened diurnal LA and basal increases in HR. CONCLUSIONS: Exposure to repeated fear produces outcomes consistent with those observed in PTSD. The results suggest that diurnal rhythm disruptions during chronic stressors may help predict sensitized physiological stress responses following traumatic events. Monitoring diurnal disruptions during repeated stress may thus help predict susceptibility to PTSD.

5-hydroxytryptamine 2C receptors in the dorsal striatum mediate stress-induced interference with negatively reinforced instrumental escape behavior.

Uncontrollable stress can interfere with instrumental learning and induce anxiety in humans and rodents. While evidence supports a role for serotonin (5-HT) and serotonin 2C receptors (5-HT(2C)R) in the behavioral consequences of uncontrollable stress, the specific sites of action are unknown. These experiments sought to delineate the role of 5-HT and 5-HT(2C)R in the dorsal striatum (DS) and the lateral/basolateral amygdala (BLA) in the expression of stress-induced instrumental escape deficits and exaggerated fear, as these structures are critical to instrumental learning and fear behaviors. Using in vivo microdialysis, we first demonstrated that prior uncontrollable, but not controllable, stress sensitizes extracellular 5-HT in the dorsal striatum, a result that parallels prior work in the BLA. Additionally, rats were implanted with bi-lateral cannula in either the DS or the BLA and exposed to uncontrollable tail shock stress. One day later, rats were injected with 5-HT(2C)R antagonist (SB242084) and fear and instrumental learning behaviors were assessed in a shuttle box. Separately, groups of non-stressed rats received an intra-DS or an intra-BLA injection of the 5-HT(2C)R agonist (CP809101) and behavior was observed. Intra-DS injections of the 5-HT(2C)R antagonist prior to fear/escape tests completely blocked the stress-induced interference with instrumental escape learning; a partial block was observed when injections were in the BLA. Antagonist administration in either region did not influence stress-induced fear behavior. In the absence of prior stress, intra-DS administration of the 5-HT(2C)R agonist was sufficient to interfere with escape behavior without enhancing fear, while intra-BLA administration of the 5-HT(2C)R agonist increased fear behavior but had no effect on escape learning. Results reveal a novel role of the 5-HT(2C)R in the DS in the expression of instrumental escape deficits produced by uncontrollable stress and demonstrate that the involvement of 5-HT(2C)R activation in stress-induced behaviors is regionally specific.