Ontogeny and neural substrates of the context preexposure facilitation effect

Abstract

Contextual fear conditioning emerges around post-natal day (PD) 23 in the rat. This is thought to reflect hippocampus-dependent conjunctive learning, which binds the individual features of the context into a unified representation (Rudy, 1993). However, context conditioning can also be supported by hippocampus-independent, feature-based simple associations (Rudy, 2009) and these may operate at PD23–24 (Pugh & Rudy, 1996). To address this issue, we studied the ontogeny of a variant of contextual fear conditioning, termed the context-preexposure-facilitation-effect (CPFE), in which exposure to context and (immediate) foot shock occur on successive occasions. This variant requires conjunctive as opposed to feature-based simple associations (Rudy, 2009). We tested PD17, 24, and 31 rats on the CPFE vs. conventional context conditioning (Exp. 1) and on the CPFE with stronger reinforcement (Exp. 2). The CPFE emerged on PD24 regardless of reinforcer strength and in parallel with context conditioning. Infusions of the NMDA antagonist, MK-801, into the dorsal hippocampus just before preexposure on PD24 eliminated the CPFE, whereas infusions occurring after preexposure had no effect (Exp. 3). These findings demonstrate a role of hippocampal NMDA receptors in the CPFE as early as PD24 and implicate conjunctive learning mechanisms in the ontogeny of contextual fear conditioning.

Ontogeny of contextual fear memory formation, specificity, and persistence in mice

“…Although some studies report that rats fail to associate a shock with a context until 23-24 d of age (Spear 1979;Rudy 1993;Rudy and Morledge 1994;Raineki et al 2010;Schiffino et al 2011), others demonstrate that this type of learning can occur at 17-18 d of age under some training conditions (Brasser and Spear 2004;Esmoris-Arranz et al 2008;Pisano et al 2012) or following certain neonatal manipulations (i.e., injection of fibroblast growth factor-2, sensory stimulation) (Woodcock and Richardson 2000;Graham and Richardson 2010;Callaghan and Richardson 2011). Our finding that mice are able to associate a shock with a context as early as 13-14 d of age, however, suggests that brain and behavioral development is accelerated in mice compared to rats, consistent with previous proposals (Pellis and Iwaniuk 2000;Whishaw et al 2001).…”

“…Although it is possible that young rodents could condition to independent elements of the training context through nonhippocampus-dependent processes (Rudy 2009), accumulating evidence suggests that the hippocampus is involved in the formation of contextual fear memories during infancy. Specifically, the developmental onset of contextual fear learning coincides with the onset of training-induced hippocampal immediate early gene expression (Raineki et al 2010), and lesion or inactivation of the hippocampus blocks the formation of context and contextual fear memories in infant rats (Foster and Burman 2010;Raineki et al 2010;Schiffino et al 2011). Therefore, the emerging ability of mice to form context-shock associations at 13-14 d of age may reflect the functional maturation of the hippocampus, which continues to undergo changes in neuron number (Altman and Bayer 1975), dendritic arborization (Rahimi and Claiborne 2007), signaling mechanisms (Paylor et al 1996), synaptic plasticity (Harris and Teyler 1984), and spatial firing (Langston et al 2010;Wills et al 2010;Scott et al 2011) during the postnatal period.…”

“…During infancy and adolescence, the progressive growth and refinement of neural circuitry supporting sensation and perception (Bourne 2010;Froemke and Jones 2011), cognition (Benes et al 2000;Dumas 2005), and emotion (Braun 2011) gradually enables young rodents to begin learning about their surroundings. For example, around 17 d of age, rats start to form memories of contexts they encounter (Brasser and Spear 2004;Yap and Richardson 2005;Foster and Burman 2010), and by 23 d of age, they can associate those contexts with the occurrence of aversive events (Rudy 1993;Rudy and Morledge 1994;Raineki et al 2010;Schiffino et al 2011). …”

Relearning a context-shock association after forgetting is an NMDAr-independent process

“…In this procedure, animals are placed into the context and immediately given a foot shock. When subsequently tested, these animals exhibit very low levels of freezing in the context [34,35], which has been attributed to animals in this condition having insufficient time to form a context representation to associate with the shock US.…”

Differences in Stress-Induced Changes in Extinction and Prefrontal Plasticity in Postweanling and Adult Animals

“…However, developmental differences among different brain regions determine the age at which different subtypes of learned fear associations can be acquired. For example, whereas amygdala-dependent auditory fear conditioning emerges by postnatal day (PND) 16 to 18, hippocampal-dependent contextual fear conditioning was reported around PND 23 and has been attributed to the ongoing maturation of the hippocampus (7)(8)(9)(10)(11)(12).…”