Impaired Extinction Retention in Adolescent Rats: Effects of D-Cycloserine

McCallum, Jessica; Kim, Jee Hyun; Richardson, Rick

doi:10.1038/npp.2010.92

Cited by 186 publications

(245 citation statements)

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“…These findings demonstrate that neither the animal's age at the time of fear learning or extinction determines whether fear extinction is impaired. Rather, it appears that the impairment in extinction retention previously reported in adolescence (McCallum et al 2010;Kim et al 2011;Pattwell et al 2012;Baker et al 2013) requires both fear conditioning and extinction occur in adolescence (Fig. 5).…”

Section: Discussionmentioning

confidence: 88%

“…Impaired extinction retention in adolescents is a robust, reliable finding that has been replicated across species (i.e., mice, rats, and humans) (McCallum et al 2010;Kim et al 2011;Pattwell et al 2012). It has generally been assumed that adolescents show impaired fear inhibition because of their age at extinction.…”

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confidence: 93%

“…Although extinction of learned fear is widely accepted as a valid model for exposure-based therapy (Graham and Milad 2011), there is a relatively small body of research on fear extinction in adolescent rodents and humans (Baker et al 2014;Casey et al 2015). A prominent finding of these studies is that retention of fear extinction is impaired in this stage of development, relative to both younger and older age groups (McCallum et al 2010;Kim et al 2011;Pattwell et al 2012). This impaired fear inhibition could be caused by inefficient recruitment of the medial prefrontal cortex (mPFC) during extinction in adolescents.…”

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confidence: 99%

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

Baker

Richardson

2015

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Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n ¼ 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 animal's 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.

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Section: Discussionmentioning

confidence: 88%

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confidence: 93%

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confidence: 99%

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

Baker

Richardson

2015

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“…Specifically, BLA-specific CB1 receptors and fluoxetine-induced increases in AEA mediated the effects of fluoxetine (but not citalopram) on fear extinction (39). Given the high incidence of anxiety disorders during adolescence (1) and prior evidence of diminished fear extinction during adolescence across species (40)(41)(42), these findings in the context of recent work on treatment mechanisms related to the endocannabinoid system have significant potential to optimize treatment for anxiety during this sensitive window of development.…”

Section: Discussionmentioning

confidence: 98%

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

Gee

Fetcho

Jing

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3-to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxietyrelated behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.A nxiety disorders typically emerge during adolescence, when the incidence of mental illness peaks (1, 2). The developmental phase of adolescence is characterized by dynamic changes in gene expression, frontolimbic circuitry (3, 4), and overall tone of the endocannabinoid system, which are implicated in anxiety (5-7).The corticolimbic endocannabinoid system undergoes dynamic changes across development. The onset of adolescence is marked by the highest expression of type 1 cannabinoid receptor (CB1) in both cortical and subcortical brain regions, with CB1 expression declining to adult levels throughout adolescence (8, 9). Across the amygdala and prefrontal cortex, fatty acid amide hydrolase (FAAH) expression shows a transient increase from postnatal day 35 (P35) to P45 during adolescence in mice (10). Consistent with the regulatory role of FAAH, anandamide (AEA) levels show an inverse pattern of a peak at P35 and subsequent decrease during adolescence (10, 11). AEA is an endogenous ligand for the CB1 receptor, suggesting that the concurrent changes in AEA and CB1 expression reflect decreasing endocannabinoid signaling during adolescence (12), which may be associated with increasing risk for anxiety (Fig. 1).A common human polymorphism in the gene encoding FAAH (C385A; rs324420), the primary catabolic enzyme of the prototypical endocannabinoid AEA, regulates FAAH activity. The variant FAAH A385 allele destabilizes the FAAH protein, causing lower levels of FAAH enzymatic activity and/or increased levels of AEA in T lymphocytes and brain (13,14). Phenotypic expression of common polymorphism...

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“…Paralleling the influence of stress on the maturation of fear learning, separation from the mother advances the onset of adult-like extinction learning, from which fears reemerge (Callaghan and Richardson, 2011). In contrast to the ease with which fears are diminished in these younger animals, both fear extinction learning and retention are attenuated during adolescence (Kim et al, 2011;McCallum et al, 2010;Pattwell et al, 2012). Relative to pre-and post-adolescent animals, adolescents exhibit diminished fear extinction learning that is paralleled by an absence of fear-learning-induced synaptic plasticity within the PL and extinction-learning-induced plasticity within the IL .…”

Section: Developmental Changes In Fear-learning Circuitsmentioning

confidence: 99%

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

Hartley

Lee

2014

Neuropsychopharmacol

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At specific maturational stages, neural circuits enter sensitive periods of heightened plasticity, during which the development of both brain and behavior are highly receptive to particular experiential information. A relatively advanced understanding of the regulatory mechanisms governing the initiation, closure, and reinstatement of sensitive period plasticity has emerged from extensive research examining the development of the visual system. In this article, we discuss a large body of work characterizing the pronounced nonlinear changes in fear learning and extinction that occur from childhood through adulthood, and their underlying neural substrates. We draw upon the model of sensitive period regulation within the visual system, and present burgeoning evidence suggesting that parallel mechanisms may regulate the qualitative changes in fear learning across development.

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Impaired Extinction Retention in Adolescent Rats: Effects of D-Cycloserine

Cited by 186 publications

References 49 publications

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

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

Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species

Sensitive Periods in Affective Development: Nonlinear Maturation of Fear Learning

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