Social modulation of associative fear learning by pheromone communication

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned familiar mouse and by the putative stress-related anxiogenic pheromone β-phenylethylamine (β-PEA). Together, these findings suggest social modulation of higher-order cognitive processing through pheromone communication and support the concurrent excitor hypothesis of extinction learning.Social communication in mammals has evolved to facilitate reproductive behavior and for protection against environmental threat and predation. Mice communicate information about imminent danger through vocal (Seyfarth and Cheney 2003), visual (Kavaliers et al. 2001; Langford et al. 2006), and odor or pheromone cues (Rottman and Snowdon 1972), each with profound influences on defensive responding. There is also evidence of social empathy in mice (Langford et al. 2006). Mice will sensitize to pain-inducing stimuli simply by observing a conspecific that is currently experiencing pain. Importantly, sensitization occurs only when the conspecific is familiar with the observer (i.e., sibling or cage mate), a clear example of social modulation of an innate behavior. Müller-Velten (1966) provided the first evidence of a functional alarm chemosignal in mice by showing that animals would avoid a pathway in which the odor of a stressed mouse was present. Subsequent studies have shown effects of mammalian olfactory chemosignals on a variety of defensive behaviors such as analgesia, vigilance, and avoidance (Rottman and Snowdon 1972; Mackay-Sim and Laing 1981; Fanselow 1985; Zalaquett and Thiessen 1991). To date, research on social modulation of behavior has focused primarily on observational learning and innate or nonassociative processes. Two recent studies have demonstrated an influence of fear-related chemosignals on associative learning in humans (Chen et al. 2006; Prehn et al. 2006), evidence that supports the hypothesis that social modulation of behavior extends to higher-order cognitive processing.In the following experiments, we asked whether exposure to a familiar mouse recently fear conditioned or trained for fear extinction would influence associative fear learning in a conspecific. We find that exposure to a recently fear-conditioned mouse impairs acquisition of conditioned fear, while the same experience facilitates the extinction of conditioned fear; effects mimicked by exposure to an olfactory chemosignal emitted from fear-conditioned mice and by the putative anxiogenic pheromone, β-phenylethylamine (β-PEA). Interestingly, we find that exposure to a recently extinction-trained mouse results in an inhibition of fear extinction learning, an effect not related to an olfactory chemosignal emitted by a recently extinguished mouse or by exposure to β-PEA. These data suggest that mice communicate information about their experience, in part through pheromone communication, with different effects on associative learning depending on the valence of the task.     

The histone deacetylase inhibitor valproic acid enhances acquisition, extinction, and reconsolidation of conditioned fear

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its function as a histone deacetylase inhibitor (HDAC). Here we report that VPA enhances long-term memory for both acquisition and extinction of cued-fear. Interestingly, VPA enhances extinction, but also enhances renewal of the original conditioned fear when tested in a within-subjects design. This effect appears to be related to a reconsolidation-like process since a single CS reminder in the presence of VPA can enhance long-term memory for the original fear in the context in which fear conditioning takes place. We also show that by modifying the intertrial interval during extinction training, VPA can strengthen reconsolidation of the original fear memory or enhance long-term memory for extinction such that it becomes independent of context. These findings have important implications for the use of HDAC inhibitors as adjuncts to behavior therapy in the treatment of phobia and related anxiety disorders.     

Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear

Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.