Anxiety-related behavioral inhibition in rats: a model to examine mechanisms underlying the risk to develop stress-related psychopathology.

Behavioral inhibition (BI) is an adaptive defensive response to threat; however, children who display extreme BI as a stable trait are at risk for development of anxiety disorders and depression. The present study validates a rodent model of BI based on an ethologically relevant predator exposure paradigm. We show that individual differences in rat BI are stable and trait-like from adolescence into adulthood. Using in situ hybridization to quantify expression of the immediate early genes homer1a and fos as measures of neuronal activation, we show that individual differences in BI are correlated with the activation of various stress-responsive brain regions that include the paraventricular nucleus of the hypothalamus and CA3 region of the hippocampus. Further supporting the concept that threat-induced BI in rodents reflects levels of anxiety, we also show that BI is decreased by administration of the anxiolytic, diazepam. Finally, we developed criteria for identifying extreme BI animals that are stable in their expression of high levels of BI and also show that high BI (HBI) individuals exhibit maladaptive appetitive responses following stress exposure. These findings support the use of predator threat as a stimulus and HBI rats as a model to study mechanisms underlying extreme and stable BI in humans.

Predator stress induces behavioral inhibition and amygdala somatostatin receptor 2 gene expression.

Psychological stressors precipitate and maintain stress-induced psychopathology, and it is likely that altered amygdala function underlies some of the deleterious effects of psychological stress. To understand the mechanisms underlying the linkage between the response to psychological stressors and maladaptive or psychopathological responses, we have focused on amygdala responsivity in animal models employing species-specific psychological stressors. In the present study, we characterized the effects of a 15-min exposure to a natural predator, the ferret, on rat behavior and the expression of the somatostatin family of genes in the amygdala. We examined the somatostatin family of genes because substantial evidence shows that central somatostatin systems are altered in various neuropsychiatric illnesses. We report that rats respond to acute ferret exposure with a significant increase in fearful and anxious behaviors that is accompanied by robust amygdala activation and an increase in somatostatin receptor 2 (sst2) messenger RNA expression within the amygdala and anterior cingulate cortex. These studies are the first to show stress-induced changes in amygdala sst2 expression and may represent one mechanism by which psychological stress is linked to adaptive and maladaptive behavioral responses.

Invited review: Intermittent hypoxia and respiratory plasticity.

Intermittent hypoxia elicits long-term facilitation (LTF), a persistent augmentation (hours) of respiratory motor output. Considerable recent progress has been made toward an understanding of the mechanisms and manifestations of this potentially important model of respiratory plasticity. LTF is elicited by intermittent but not sustained hypoxia, indicating profound pattern sensitivity in its underlying mechanism. During intermittent hypoxia, episodic spinal serotonin receptor activation initiates cell signaling events, increasing spinal protein synthesis. One associated protein is brain-derived neurotrophic factor, a neurotrophin implicated in several forms of synaptic plasticity. Our working hypothesis is that increased brain-derived neurotrophic factor enhances glutamatergic synaptic currents in phrenic motoneurons, increasing their responsiveness to bulbospinal inspiratory inputs. LTF is heterogeneous among respiratory outputs, differs among experimental preparations, and is influenced by age, gender, and genetics. Furthermore, LTF is enhanced following chronic intermittent hypoxia, indicating a degree of metaplasticity. Although the physiological relevance of LTF remains unclear, it may reflect a general mechanism whereby intermittent serotonin receptor activation elicits respiratory plasticity, adapting system performance to the ever-changing requirements of life.

Seizures and sensory stimulation result in different patterns of brain derived neurotrophic factor protein expression in the barrel cortex and hippocampus.

Brain-derived neurotrophic factor (BDNF) is important for the development and trophic support of neurons, and may be involved in controlling axonal sprouting and synaptic plasticity. In order to investigate the activity-dependent regulation of the BDNF gene, BDNF expression was examined within the rat somatosensory cortex (SSC) and hippocampus following vibrissae stimulation, kainic acid induced seizure, and pentylenetetrazol (PTZ) induced seizure. The specific goals of this study were to determine the time course and magnitude of BDNF's activity-dependent expression, and to compare the expression patterns of three commonly used neuronal activation paradigms. Our results demonstrate three novel observations. First, the patterns of BDNF protein expression are dependent upon the neuronal stimulation model used. Both unilateral whisker stimulation (a model of experience dependent plasticity) and kainic acid induced seizure were able to increase the levels of BDNF protein within the SSC and hippocampus. In contrast, PTZ induced seizure did not increase BDNF protein levels in either tissue. Second, there is a dissociation between BDNF mRNA and protein levels following PTZ induced seizure. PTZ seizures resulted in strong increases of BDNF mRNA levels without corresponding increases of the protein. Finally, whisker stimulation resulted in an unexpected increase in BDNF mRNA and protein levels within the hippocampus. These results suggest specific types of neuronal activity can regulate gene expression differently. Furthermore, temporal and spatial differences between the expression of BDNF protein and mRNA levels suggest that the BDNF gene is regulated at the level of translation as well as transcription.