Anxiety- and depressive-like responses and c-fos activity in preproenkephalin knockout mice: Oversensitivity hypothesis of enkephalin deficit-induced posttraumatic stress disorder

Abstract

The present study used the preproenkephalin knockout (ppENK) mice to test whether the endogenous enkephalins deficit could facilitate the anxiety- and depressive-like symptoms of posttraumatic stress disorder (PTSD). On Day 1, sixteen wildtype (WT) and sixteen ppENK male mice were given a 3 mA or no footshock treatment for 10 seconds in the footshock apparatus, respectively. On Days 2, 7, and 13, all mice were given situational reminders for 1 min per trial, and the freezing response was assessed. On Day 14, all mice were tested in the open field test, elevated plus maze, light/dark avoidance test, and forced swim test. Two hours after the last test, brain tissues were stained to examine c-fos expression in specific brain areas. The present results showed that the conditioned freezing response was significant for different genotypes (ppENK vs WT). The conditioned freezing effect of the ppENK mice was stronger than those of the WT mice. On Day 14, the ppENK mice showed more anxiety- and depressive-like responses than WT mice. The magnitude of Fos immunolabeling was also significantly greater in the primary motor cortex, bed nucleus of the stria terminalis-lateral division, bed nucleus of the stria terminalis-supracapsular division, paraventricular hypothalamic nucleus-lateral magnocellular part, central nucleus of the amygdala, and basolateral nucleus of the amygdala in ppENK mice compared with WT mice. In summary, animals with an endogenous deficit in enkephalins might be more sensitive to PTSD-like aversive stimuli and elicit stronger anxiety and depressive PTSD symptoms, suggesting an oversensitivity hypothesis of enkephalin deficit-induced PTSD.

Genetic and experimental evidence supports the continuum of the central extended amygdala and a mutiple embryonic origin of its principal neurons

“…On the other hand, it appears that ENK þ neurons of the central amygdala do not project directly to the brainstem (Moga and Gray, 1985;Gray andMagnuson, 1987, 1992) but appear to be involved in projections to the lateral BST, being responsible of part of the enkephalinergic innervation in this center (Rao et al, 1987). Central amygdalar ENK þ projections may modulate directly or indirectly the role of BSTL in stress and anxiety-like behaviors (Walker et al, 2009;Kung et al, 2010), although they also appear to play a role in the context-specific behavioral effects of psychostimulants (Day et al, 2001). Moreover, because ENK þ cells are so abundant in the capsular subnucleus of the central amygdala (Poulin et al, 2008, present results), it is likely that these cells are involved in other known projections of this subdivision, such as the intranuclear projections to the medial subdivision of the central amygdala (Petrovich and Swanson, 1997;Jolkkonen and Pitkänen, 1998) and the projections to the lateral hypothalamus (Petrovich et al, 2001).…”

Extinction after retrieval: Effects on the associative and nonassociative components of remote contextual fear memory

“…Furthermore, the long-lasting outcomes of the procedure were evaluated 1 mo later by testing animals for spontaneous recovery, fear incubation, anxiety levels, social interaction, and spatial learning. These tests have been chosen on the basis of recent advances showing increased anxiety, social withdrawal, and visuo-spatial memory deficits in both animal models of PTSD and human patients (Uddo et al 1993;Gilbertson et al 2001;Cohen et al 2003Cohen et al , 2006Cohen et al , 2011Louvart et al 2005;Morgan et al 2006;Wessa et al 2006;Kohda et al 2007;Siegmund and Wotjak 2007a;Kung et al 2010;Arbisi et al 2011). Recent studies show the ineffectiveness of the extinction procedure in attenuating fear sensitization (Golub et al 2009) and suggest that the associative and the nonassociative component of fear memory might be independent of each other, with a key role for the nonassociative component in the onset of PTSD-like symptoms (Siegmund and Wotjak 2007b).…”

Temporal association of elevated cholecystokininergic tone and adolescent trauma is critical for posttraumatic stress disorder-like behavior in adult mice

“…Thus, the deficit in fear extinction in our dtg mice indicates that the enhanced fear response in the fearconditioning test is more relevant to an anxiety-related phenotype. The use of the elevated-plus maze and open-field tests apparently strengthens the phenotypical validation, in which a higher avoidance level or a lower exploratory motivation could be considered as a homolog of avoidance/numbing in PTSD patients (22). Similarly, fear to a conditioned cue in the mouse is frequently used to model the hyperarousal observed in PTSD patients (19,20).…”