Kathryn D. Baker

Memory retrieval before or after extinction reduces recovery of fear in adolescent rats.

Adolescent rats exhibit impaired extinction retention compared to pre-adolescent and adult rats. A single nonreinforced exposure to the conditioned stimulus (CS; a retrieval trial) given shortly before extinction has been shown in some circumstances to reduce the recovery of fear after extinction in adult animals. This study investigated whether a retrieval-extinction procedure would reduce the recovery of extinguished fear in adolescent rats. Furthermore, the effect of the retrieval-extinction sequence on fear recovery was examined by presenting the retrieval trial following extinction to some animals. In Experiment 1 adolescent rats received one nonreinforced CS presentation (a retrieval trial) or equivalent context exposure (no retrieval) 10 min before fear extinction. A retrieval trial shortly before extinction reduced overall levels of fear in both test contexts (i.e., it improved extinction retention and reduced renewal). In Experiment 2 a weakening of renewal was observed with a retrieval-extinction manipulation, regardless of whether the retrieval trial occurred in the training or extinction context. A key result was that a retrieval trial 10 min, but not 6 h, after extinction led to reduced overall levels of fear similar to that observed if the retrieval trial was given before extinction (Experiments 3 and 4), inconsistent with the current interpretation of the reduction in relapse being due to a disruption of reconsolidation. Together, these findings show that the impaired extinction retention observed in adolescents can be ameliorated by a very simple behavioral manipulation, but also raise some questions about the mechanisms underlying the retrieval-extinction effect.

The role of intracellular calcium stores in synaptic plasticity and memory consolidation.

Memory processing requires tightly controlled signalling cascades, many of which are dependent upon intracellular calcium (Ca(2+)). Despite this, most work investigating calcium signalling in memory formation has focused on plasma membrane channels and extracellular sources of Ca(2+). The intracellular Ca(2+) release channels, ryanodine receptors (RyRs) and inositol (1,4,5)-trisphosphate receptors (IP3Rs) have a significant capacity to regulate intracellular Ca(2+) signalling. Evidence at both cellular and behavioural levels implicates both RyRs and IP3Rs in synaptic plasticity and memory formation. Pharmacobehavioural experiments using young chicks trained on a single-trial discrimination avoidance task have been particularly useful by demonstrating that RyRs and IP3Rs have distinct roles in memory formation. RyR-dependent Ca(2+) release appears to aid the consolidation of labile memory into a persistent long-term memory trace. In contrast, IP3Rs are required during long-term memory. This review discusses various functions for RyRs and IP3Rs in memory processing, including neuro- and glio-transmitter release, dendritic spine remodelling, facilitating vasodilation, and the regulation of gene transcription and dendritic excitability. Altered Ca(2+) release from intracellular stores also has significant implications for neurodegenerative conditions.

A window of vulnerability: impaired fear extinction in adolescence.

There have been significant advances made towards understanding the processes mediating extinction of learned fear. However, despite being of clear theoretical and clinical significance, very few studies have examined fear extinction in adolescence, which is often described as a developmental window of vulnerability to psychological disorders. This paper reviews the relatively small body of research examining fear extinction in adolescence. A prominent finding of this work is that adolescents, both humans and rodents, exhibit a marked impairment in extinction relative to both younger (e.g., juvenile) and older (e.g., adult) groups. We then review some potential mechanisms that could produce the striking extinction deficit observed in adolescence. For example, one neurobiological candidate mechanism for impaired extinction in adolescence involves changes in the functional connectivity within the fear extinction circuit, particularly between prefrontal cortical regions and the amygdala. In addition, we review research on emotion regulation and attention processes that suggests that developmental changes in attention bias to threatening cues may be a cognitive mechanism that mediates age-related differences in extinction learning. We also examine how a differential reaction to chronic stress in adolescence impacts upon extinction retention during adolescence as well as in later life. Finally, we consider the findings of several studies illustrating promising approaches that overcome the typically-observed extinction impairments in adolescent rodents and that could be translated to human adolescents.

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animals age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages. We examined neural correlates of impaired extinction retention by detection of phosphorylated mitogen-activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions. Unexpectedly, adolescent rats exhibited good extinction retention if fear was acquired before adolescence. Further, fear acquired in adolescence could be successfully extinguished in adulthood but not within adolescence. Adolescent rats did not show extinction-induced increases in pMAPK-IR in the medial prefrontal cortex or the basolateral amygdala, or a pattern of reduced caudal central amygdala pMAPK-IR, as was observed in juveniles. This dampened prefrontal and basolateral amygdala MAPK activation following extinction in adolescence occurred even when there was no impairment in extinction retention. In contrast, only adolescent animals that exhibited impaired extinction retention showed elevated pMAPK-IR in the posterior paraventricular thalamus. These data suggest that neither the animals age at the time of fear acquisition or extinction determines whether impaired extinction retention is exhibited. Rather, it appears that forming competing fear conditioning and extinction memories in adolescence renders this a vulnerable developmental period in which fear is difficult to inhibit. Furthermore, even under conditions that promote good extinction, the neural correlates of extinction in adolescence are different than those recruited in animals of other ages.

D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues.

The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

Impaired fear extinction in adolescent rodents: Behavioural and neural analyses.

Despite adolescence being a developmental window of vulnerability, up until very recently there were surprisingly few studies on fear extinction during this period. Here we summarise the recent work in this area, focusing on the unique behavioural and neural characteristics of fear extinction in adolescent rodents, and humans where relevant. A prominent hypothesis posits that anxiety disorders peak during late childhood/adolescence due to the non-linear maturation of the fear inhibition neural circuitry. We discuss evidence that impaired extinction retention in adolescence is due to subregions of the medial prefrontal cortex and amygdala mediating fear inhibition being underactive while other subregions that mediate fear expression are overactive. We also review work on various interventions and surprising circumstances which enhance fear extinction in adolescence. This latter work revealed that the neural correlates of extinction in adolescence are different to that in younger and older animals even when extinction retention is not impaired. This growing body of work highlights that adolescence is a unique period of development for fear inhibition.

Inhibition of mGluR1 and IP3Rs impairs long-term memory formation in young chicks

Calcium (Ca(2+)) is involved in a myriad of cellular functions in the brain including synaptic plasticity. However, the role of intracellular Ca(2+) stores in memory processing remains poorly defined. The current study explored a role for glutamate-dependent intracellular Ca(2+) release in memory processing via blockade of metabotropic glutamate receptor subtype 1 (mGluR1) and inositol (1,4,5)-trisphosphate receptors (IP(3)Rs). Using a single-trial discrimination avoidance task developed for the young chick, administration of the specific and potent mGluR1 antagonist JNJ16259685 (500nM, immediately post-training, ic), or the IP(3)R antagonist Xestospongin C (5microM, immediately post-training, ic), impaired retention from 90min post-training. These findings are consistent with mGluR1 activating IP(3)Rs to release intracellular Ca(2+) required for long-term memory formation and have been interpreted within an LTP2 model. The consequences of different patterns of retention loss following ryanodine receptor (RyR) and IP(3)R inhibition are discussed.

A ryanodine receptor agonist promotes the consolidation of long-term memory in young chicks.

Young chicks were trained on a weakly reinforced variant of a single-trial discrimination avoidance task which typically fails to consolidate the long-term memory stage. The ryanodine receptor (RyR) agonist 4-chloro-m-cresol (500 microM, i.c.) persistently promoted high retention until at least 24 h post-training when administered between the time of training and 20 min post-training. The consolidation of the long-term memory stage by RyR activation implicates intracellular calcium release in triggering long-term memory.

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

Infantile amnesia (i.e., the rapid rate of forgetting in young animals) is at least partially due to a memory retrieval, rather than a storage, failure as studies have shown that these engrams can continue to influence later behavior. For example, prior conditioning affects the neural mechanisms underlying future learning. In adult animals, the initial learning of a context-shock association depends upon N-Methyl-D-Aspartate (NMDA) receptors, but this conditioning renders subsequent learning to a similar context NMDAr-independent. In the present study, we examined whether this transition from NMDAr-dependent to NMDAr-independent context conditioning occurs even after infantile amnesia. Experiment 1 demonstrated that infant (i.e., postnatal day 17) rats acquire a context-shock association when trained with multiple shocks, as assessed by context freezing one day later. However, they exhibit significant forgetting of this association 10days later. Experiments 2 and 3 showed that even when animals had forgotten the initial learning experience, future conditioning to the same context was NMDAr-independent. There was evidence of a transition to NMDAr-independent context fear learning in animals exposed only to the foot shock in infancy (Experiment 3) or only to the context in infancy (Experiment 3 but not Experiment 2). These latter results suggest that animals do not have to be exposed to the entire conditioning procedure at postnatal day 17 to show a transition to NMDAr-independent context learning. These experiments add to a growing body of evidence that forgotten infant memories can continue to affect later behavior by demonstrating that prior experience alters the mechanisms of future learning.

D-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick.

L-Lactate is a metabolite possibly able to meet some neuronal energy demands. However, a clear role for L-lactate in behaviour remains elusive. Administration of the inactive isomer D-lactate (1.75 mM; ic), immediately post-training, resulted in a persistent retention loss from 40 min post-training when used in conjuction with a single trial discrimination avoidance task designed for the young chick. Furthermore, 1mM noradrenaline (ic) administered 20 min post-training overcame the retention loss induced by D-lactate. Although not directly demonstrated in the current study, it is plausible that D-lactate inhibited memory processing by competing with L-lactate for uptake into neurons. The time of onset of the retention loss induced by D-lactate is in accord with findings where the action of noradrenaline is inhibited. The successful challenge of D-lactate inhibition by a high concentration of noradrenaline may suggest a relationship by some unidentified mechanism.