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

Abstract

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.

The nature of individual differences in inhibited temperament and risk for psychiatric disease: A review and meta-analysis

“…Individual differences in rodent inhibited temperament can be elicited by exposing rats to a novel environment (Cavigelli and McClintock, 2003) or to a natural predator (i.e., ferret; Qi et al, 2010). Inhibited temperament in rodent models is stable over time and has been associated with increased anxiety-like behavior throughout development and increased corticosterone response to novelty (Cavigelli and McClintock, 2003; Clinton et al, 2011; Jiao et al, 2011b; Qi et al, 2010). Similar to findings in humans with anxiety disorders, inhibited rats exhibit alterations in avoidance learning.…”

“…During avoidance learning, more inhibited rats had less activation of the medial prefrontal cortex, but no differences in amygdala activation (Perrotti et al, 2013). Inhibited behaviors in rats can be reduced by diazepam administration, a common treatment for anxiety in humans, (Qi et al, 2010). In rats, inhibited temperament was associated with increased immediate early gene expression in the hippocampus and hypothalamus in response to a predator threat, but not in the amygdala (Qi et al, 2010).…”

Amygdala–cingulate intrinsic connectivity is associated with degree of social inhibition

“…Social inhibition is assumed to have a biological basis; inhibited children display a pattern of physiological hyperarousal including a high and stable heart rate (Kagan, Reznick, & Snidman, 1998a) and elevated cortisol levels (Kagan et al, 1998a). Consistent with the amygdala's influence on the sympathetic nervous system (Davis, 1992), studies in rodents, non-human primates, and humans point to the amygdala as a key brain region mediating individual differences in social inhibition (Blackford, Avery, Shelton, &Zald, 2009; Kalin, Shelton, & Davidson, 2004; Qi et al, 2010; Schwartz, Wright, Shin, Kagan, & Rauch, 2003a). For example, in adults who are inhibited, or were inhibited as children, the amygdala shows heightened responsivity to novel (Beaton et al, 2008; Schwartz et al, 2003a) or threatening (Pérez-Edgar et al, 2007) faces and fails to show the normal habituation to repeated presentations of faces (Blackford, Avery, Cowan, Shelton, & Zald, 2011; Schwartz et al, 2012).…”

“…Social inhibition also reflects an underlying trait that exists along a continuum, ranging from low to high social inhibition (Schneier, Blanco, Antia, & Liebowitz, 2002; Stein, Walker, & Forde, 1994). Social inhibition is a fundamental behavior that is heritable (Eley et al, 2003; Emde et al, 1992; Robinson, Reznick, Kagan, & Corley, 1992; Schwartz et al, 2003b), present early in development (Kagan, Snidman, & Arcus, 1998b), and observable across species (Clinton, Stead, Miller, Watson, & Akil, 2011; Fox, Shelton, Oakes, Davidson, &Kalin, 2008; Gosling, 2001; Qi et al, 2010). Social inhibition is assumed to have a biological basis; inhibited children display a pattern of physiological hyperarousal including a high and stable heart rate (Kagan, Reznick, & Snidman, 1998a) and elevated cortisol levels (Kagan et al, 1998a).…”

Temperament moderates the influence of periadolescent social experience on behavior and adrenocortical activity in adult male rats

“…Neophobic or inhibited males also had greater plasma CORT responses to novelty and stress compared with neophilic or non-inhibited males (Takahashi, 1992; Cavigelli & McClintock, 2003; Veenema, Sijtsma, Koolhaas, & de Kloet, 2005; Cavigelli et al, 2007; Qi et al, 2010; Díaz-Morán et al 2013; c.f. Dellu et al 1996).…”