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Generalized anxiety disorder (GAD) is highly prevalent and incapacitating. Here we used the Carioca High-Conditioned Freezing (CHF) rats, a previously validated animal model for GAD, to identify biomarkers and structural changes in the hippocampus that could be part of the underlying mechanisms of their high-anxiety profile. Spatial and fear memory was assessed in the Morris water maze and passive avoidance test. Serum corticosterone levels, immunofluorescence for glucocorticoid receptors (GR) in the dentate gyrus (DG), and western blotting for hippocampal brain derived neurotrophic factor (BDNF) were performed. Immunohistochemistry for markers of cell proliferation (bromodeoxiuridine/Ki-67), neuroblasts (doublecortin), and cell survival were undertaken in the DG, along with spine staining (Golgi) and dendritic arborization tracing. Hippocampal GABA release was assessed by neurochemical assay. Fear memory was higher among CHF rats whilst spatial learning was preserved. Serum corticosterone levels were increased, with decreased GR expression. No differences were observed in hippocampal cell proliferation/survival, but the number of newborn neurons was decreased, along with their number and length of tertiary dendrites. Increased expression of proBDNF and dendritic spines was observed; lower ratio of GABA release in the hippocampus was also verified. These findings suggest that generalized anxiety/fear could be associated with different hippocampal biomarkers, such as increased spine density, possibly as a compensatory mechanism for the decreased hippocampal number of neuroblasts and dendritic arborization triggered by high corticosterone. Disruption of GABAergic signaling and BDNF impairment are also proposed as part of the hippocampal mechanisms possibly underlying the anxious phenotype of this model.

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evaluation of eight rat lines selected for high and low anxiety-related responses" (2013 • Genetic models are powerful tools to help understand anxiety disorders.• In order to determine the extent to which multiple anxiety traits generalize we compared eight genetic lines of rats selected for single high or low emotional responses.• We find many behavioral traits generalize across different animal lines selected for a single trait. a b s t r a c t Anxiety traits can be stable and permanent characteristics of an individual across time that is less susceptible of influences by a particular situation. One way to study trait anxiety in an experimental context is through the use of rat lines, selected according to contrasting phenotypes of fear and anxiety. It is not clear whether the behavioral differences between two contrasting rat lines in one given anxiety test are also present in others paradigms of state anxiety. Here, we examine the extent to which multiple anxiety traits generalize across selected animal lines originally selected for a single anxiety trait. We review the behavioral results available in the literature of eight rat genetic models of trait anxiety -namely Maudsley Reactive and Non-reactive rats, Floripa H and L rats, Tsukuba High and Low Emotional rats, High and Low Anxiety-related rats, High and Low Ultrasonic Vocalization rats, Roman High and Low Avoidance rats, Syracuse High and Low Avoidance rats, and Carioca High and Low Conditioned Freezing rats -across 11 behavioral paradigms of innate anxiety or aversive learning frequently used in the experimental setting. We observed both convergence and divergence of behavioral responses in these selected lines across the 11 paradigms. We find that predisposition for specific anxiety traits will usually be generalized to other anxiety provoking stimuli. However this generalization is not observed across all genetic models indicating some unique trait and state interactions. Genetic models of enhanced-anxiety related responses are beginning to help define how anxiety can manifest differently depending on the underlying traits and the current environmentally induced state. a r t i c l e i n f o

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Panic disorder involves both recurrent unexpected panic attacks and persistent concern about having additional attacks. Electrical stimulation of the dorsal periaqueductal gray (dPAG) is an animal model of both panic attack and panic disorder, whereas contextual fear conditioning represents a model of anticipatory anxiety. Previous research indicated that anxiety has an inhibitory effect on panic attack-like behavior. However, still unclear is the role that anticipatory anxiety plays in panic disorder-like behaviors. This issue was investigated with two lines of animals selectively bred for high (Carioca High-Freezing) and low (Carioca Low-Freezing) freezing in response to contextual cues associated with footshock. The results suggest that although anticipatory anxiety might exert an inhibitory effect on the expression of panic attack, it might also facilitate the pathogenesis of panic disorder.

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We recently reported two novel breeding lines of rats known as Carioca High-and Low-conditioned Freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric footshock. The present study used animals of the 8 th generation of our selective breeding program to investigate both contextual fear extinction and re-extinction. The results consistently showed that CHF animals froze more than CLF animals. Long extinction training was able to extinguish phenotypic differences between lines, but the divergence was restored after just one fear reacquisition training session. These differences disappeared again during re-extinction training. The possible neural mechanisms involved in these two types of learning are discussed.