Dual Circuitry for Odor-Shock Conditioning during Infancy: Corticosterone Switches between Fear and Attraction via Amygdala

Abstract

Rat pups must learn maternal odor to support attachment behaviors, including nursing and orientation toward the mother. Neonates have a sensitive period for rapid, robust odor learning characterized by increased ability to learn odor preferences and decreased ability to learn odor aversions. Specifically, odor-0.5 mA shock association paradoxically causes an odor preference and coincident failure of amygdala activation in pups until postnatal day 10 (P10). Because sensitive-period termination coincides with a declining "stress hyporesponsive period" when corticosterone release is attenuated, we explored the role of corticosterone in sensitive-period termination. Odor was paired with 0.5 mA shock in either sensitive-period (P8) or postsensitive-period (P12) pups while manipulating corticosterone. We then assessed preference/aversion learning and the olfactory neural circuitry underlying its acquisition. Although sensitive-period control paired odor-shock pups learned an odor preference without amygdala participation, systemic (3 mg/kg, i.p.; 24 h and 30 min before training) or intra-amygdala corticosterone (50 or 100 ng; during training) permitted precocious odor-aversion learning and evoked amygdala neural activity similar to that expressed by older pups. In postsensitive-period (P12) pups, control paired odor-shock pups showed an odor aversion and amygdala activation, whereas corticosterone-depleted (adrenalectomized) paired odor-shock pups showed odor-preference learning and activation of an odor learning circuit characteristic of the sensitive period. Intra-amygdala corticosterone receptor antagonist (0.3 ng; during training) infused into postsensitive-period (P12) paired odor-shock pups also showed odor-preference learning. These results suggest corticosterone is important in sensitive-period termination and developmental emergence of olfactory fear conditioning, acting via the amygdala as a switch between fear and attraction. Because maternal stimulation of pups modulates the pups' endogenous corticosterone, this suggests maternal care quality may alter sensitive-period duration.

Early developmental emergence of human amygdala–prefrontal connectivity after maternal deprivation

“…Prior research suggests that developmental changes in cortisol (40,41) contribute to brain development through interactions with receptors that regulate genes involved in neuromaturational processes (42,43). Some of these maturational changes are specific to amygdala-mPFC circuitry, instantiated either through direct administration of glucocorticoids or via maternal absence (which elevates glucocorticoid levels) (5,8,15). We observed higher levels of cortisol, the primary glucocorticoid in humans, in the PI group, consistent with past findings in similar samples (44).…”

“…Our interpretation that the observed mature-like negative amygdala-mPFC connectivity in PI children evidences accelerated development is supported by rodent models that have demonstrated causal relationships between maternal absence and acceleration of amygdala-mPFC phenotypes (5,15,17). Research in normative human development has shown that regulatory connections between the amygdala and mPFC manifest as positive coupling in childhood and shift to a mature pattern of negative coupling during adolescence (28).…”

“…Early life caregiving adversity in rodents alters amygdala-medial prefrontal cortex (mPFC) circuits that in adulthood serve to regulate the activity of the amygdala (13,14), perhaps through accelerating development of the circuitry. For example, maternal deprivation results in the early emergence of adult-like fear learning based in frontoamygdala circuitry (5) and earlier emergence of amygdala function (8,15) and structural maturation (16). Maternal separation has also been associated with increased development of neurons in mPFC (17).…”

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

“…Our previous work has shown that FKBP5 'risk' polymorphisms that manifest with enhanced induction of FKBP5, altered cortisol release, and impaired negative feedback are associated with an increased risk to develop PTSD or related symptoms. Consistent with the ultra-short negative feedback between the FKBP5 protein and GR activation, genotype-mediated increases in FKBP5 transcription have been shown to be associated with GR resistance (Moriceau et al, 2006;Binder et al, 2008) and with a decreased efficiency of negative feedback of the stress hormone axes accompanied by prolonged cortisol release (Ising et al, 2008). The SNPs, rs3800373 and rs1360780, have been associated with increased peri-traumatic dissociation in children after medical trauma (Koenen et al, 2005) and higher levels of peri-traumatic dissociation have been shown to be predictors of PTSD in adults (Ozer et al, 2003).…”

Attachment Figure's Regulation of Infant Brain and Behavior

“…The infant rodent amygdala is uniquely dependent upon stress hormones for engaging mechanisms for plasticity within the amygdala: the infant amygdala can be switched on and off simply based on the level of stress hormones with stress hormones being robustly controlled by the caregiver in early development (Barr et al, 2009;Moriceau, Wilson, Levine, & Sullivan, 2006;Shionoya et al, 2007;Thompson, Sullivan, & Wilson, 2008). Specifically, in rat pups, amygdala-dependent threat (fear) conditioning can be precociously induced by increasing systemic stress hormone corticosterone (analogous to cortisol in humans) by injecting pups, or through naturalistic means such as increasing pups' early life stress or by exposing pups to a mother releasing an alarm pheromone (Barr et al, 2009;Debiec & Sullivan, 2014;Moriceau et al, 2009).…”