Evidence for hippocampus-dependent contextual learning at postnatal day 17 in the rat

Abstract

Long-term memory for fear of an environment (contextual fear conditioning) emerges later in development (postnatal day; PD 23) than long-term memory for fear of discrete stimuli (PD 17). As contextual, but not explicit cue, fear conditioning relies on the hippocampus; this has been interpreted as evidence that the hippocampus is not fully developed until PD 23. Alternatively, the hippocampus may be functional prior to PD 23, but unable to cooperate with the amygdala for fearful learning. The current experiments investigate this by separating the phases of conditioning across developmental stages. Rats were allowed to learn about the context on one day and to form the fearful association on another. Rats exposed to the context on PD 17 exhibited significant fear only when trained and tested a week later (PD 23, 24), but not on consecutive days (PD 18, 19), demonstrating that rats can learn about a context as early as PD 17. Further experiments clarify that it is associative mechanisms that are developing between PD 18 and 23. Finally, the hippocampus was lesioned prior to training to ensure the task is being solved in a hippocampus-dependent manner. These data provide compelling evidence that the hippocampus is functional for contextual learning as early as PD 17, however, its connection to the amygdala or other relevant brain structures may not yet be fully developed.Research in recent decades has yielded a great deal of information regarding the neural substrates of cognitive processes, such as emotional expression and learning and memory in adult organisms, but relatively little regarding the neural substrates underlying these processes in developing organisms. Pavlovian fear conditioning has proven a useful tool for studying cognition in adult organisms (Malenka and Nicoll 1997;Anagnostaras et al. 2001;Maren 2001) and ought to be an especially powerful tool to help uncover the neural substrates of various cognitive processes in adolescent organisms due to its reliance on relatively basic sensory, motor, and affective systems (Campbell and Spear 1972). Indeed, several behavioral and toxicological studies have already adapted methods pioneered in the adult for use in developing animals with great success (Rudy

Extinction of fear memory during development: lesson for a better exposure therapy?

“…In contrast, rats extinguished at P24 exhibited a return of fear in both situations (Kim and Richardson, 2010b). Our group has observed elevated activity in the HPC during extinction retrieval in the juvenile mice, which suggested that HPC is likely to be functioning at this age [32]. This context-independent in cued fear memory extinction retrieval in the juvenile is consistent with previous findings [16,[33][34][35].…”

Postnatal development of the amygdala: A stereological study in rats

“…Both the amygdala and the hippocampus are involved in contextual conditioning (Anagnostaras et al, 2001;LeDoux, 2000b;Matus-Amat et al, 2007;Wiltgen et al, 2006). It has been shown that conditioning to a context emerges between 17 and 24 days of age in rats (Foster and Burman, 2010;Raineki et al, 2010;Rudy, 1993). Interestingly, however, whereas the hippocampus is not activated during such context conditioning in 21-day-old rats, it is activated in 24-dayolds (Raineki et al, 2010).…”

“…Individual components of the fear response are thought to incorporate sequentially as animals mature, eventually giving rise to what are identified as mature fear behaviors (Wiedenmayer, 2009). Indeed, several studies have revealed that distinct fear behaviors emerge at different times during early postnatal life and continue to mature during late postnatal development (Blozovski and Cudennec, 1980;Bronstein and Hirsch, 1976;Chen et al, 2006;Collier et al, 1979;Foster and Burman, 2010;Hefner and Holmes, 2007;Hubbard et al, 2004;Ito et al, 2009;Kim and Richardson, 2007;Moriceau et al, 2004;Raineki et al, 2010;Rudy, 1993;Takahashi, 1992;Wiedenmayer andBarr, 1998, 2001a,b).…”

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

“…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). …”