Impaired extinction of learned fear in rats selectively bred for high anxiety – evidence of altered neuronal processing in prefrontal‐amygdala pathways

Abstract

The impaired extinction of acquired fear is a core symptom of anxiety disorders, such as post-traumatic stress disorder, phobias or panic disorder, and is known to be particularly resistant to existing pharmacotherapy. We provide here evidence that a similar relationship between trait anxiety and resistance to extinction of fear memory can be mimicked in a psychopathologic animal model. Wistar rat lines selectively bred for high (HAB) or low (LAB) anxiety-related behaviour were tested in a classical cued fear conditioning task utilizing freezing responses as a measure of fear. Fear acquisition was similar in both lines. In the extinction trial, however, HAB rats showed a marked deficit in the attenuation of freezing responses to repeated auditory conditioned stimulus presentations as compared with LAB rats, which exhibited rapid extinction. To gain information concerning the putatively altered neuronal processing associated with the differential behavioural response between HAB and LAB rats, c-Fos expression was investigated in the main prefrontal-amygdala pathways important for cued fear extinction. HAB compared to LAB rats showed an attenuated c-Fos response to repeated conditioned stimulus presentations in infralimbic and cingulate cortices, as well as in the lateral amygdala, but facilitated the c-Fos response in the medial part of the central amygdala. In conclusion, the present results support the notion that impaired extinction in high anxiety rats is accompanied by an aberrant activation profile in extinction-relevant prefrontal-amygdala circuits. Thus, HAB rats may represent a clinically relevant model to study the mechanisms and potential targets to accelerate delayed extinction processes in subjects with enhanced trait anxiety.

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex

“…The use of male and female rats in our study enabled us to investigate whether the effects of peri-pubertal stress were sex-specific. Our study replicates the lower activation of the infralimbic cortex in non-stressed males with impaired AFC extinction (Barrett, Shumake, Jones, & Gonzalez-Lima, 2003;Hefner et al, 2008;Herry & Garcia, 2002;Muigg et al, 2008). Yet we expand that knowledge by showing that the correlation between infralimbic cortex activation & extinction is not found in control females or in animals of both sexes previously exposed to stress.…”

“…Recent studies indicate that close interactions between these brain regions contribute to distinct extinction processes, with learning mediated by cellular networks centered on the basal amygdala and consolidation recruiting subregions of the PFC and hippocampus (Quirk & Mueller, 2008). For example, inactivation of the basal amygdala completely blocks acquisition of extinction (Herry et al, 2008) and c-fos induction in the basal amygdala is strongly reduced in animal models of impaired extinction learning (Muigg et al, 2008). Likewise higher amygdala activation during extinction learning has been described in a recent human imaging study investigating PTSD patients (Milad et al, 2009).…”

“…The majority of previous rodent studies of metabolic activation during extinction focused on males (Bruchey et al, 2007;Hefner et al, 2008;Herry & Mons, 2004;Muigg et al, 2008). The use of male and female rats in our study enabled us to investigate whether the effects of peri-pubertal stress were sex-specific.…”

“…This is possible because, during glycolysis, 2DG is trapped within active brain cells when it is phosphorylated by hexokinase (Sokoloff et al, 1977). So far, the majority of studies imaging metabolic activation during extinction in rodents have focused on males (mainly adults) (Bruchey, Shumake, & Gonzalez-Lima, 2007;Hefner et al, 2008;Herry & Mons, 2004;Muigg et al, 2008). Yet it is becoming increasingly clear that females differ from males in their morphological and behavioral responses to stress and brain response to various stimuli (Garrett & Wellman, 2009;Maeng, Waddell, & Shors, 2010).…”

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

“…For example, there are a number of rodent models in which a specific rat or mouse strain (Cohen et al, 2008), sub-population (Duvarci et al, 2009), or selectively bred line (Muigg et al, 2008) exhibits features consistent with inherent susceptibility to excessive fear after an experimental trauma such as Pavlovian fear conditioning. Along these lines, we recently identified an inbred mouse strain, 129S1/SvImJ (S1), which displays a profound deficit in cued fear extinction, coupled with functional abnormalities in corticoamygdala circuitry mediating extinction (Camp et al, 2009;Hefner et al, 2008;Whittle et al, 2010).…”