Fear extinction across development: the involvement of the medial prefrontal cortex as assessed by temporary inactivation and immunohistochemistry - PubMed (original) (raw)

Comparative Study

Fear extinction across development: the involvement of the medial prefrontal cortex as assessed by temporary inactivation and immunohistochemistry

Jee Hyun Kim et al. J Neurosci. 2009.

Abstract

Extinction in adult animals, including humans, appears to involve the medial prefrontal cortex (mPFC). However, the role of mPFC in extinction across development has not yet been studied. Given several recent demonstrations of developmental differences in extinction of conditioned fear at a behavioral level, different neural circuitries may mediate fear extinction across development. In all experiments, noise conditioned stimulus (CS) and shock unconditioned stimulus (US) were used. In experiment 1A, temporary unilateral inactivation of the mPFC during extinction training impaired long-term extinction the following day in postnatal day 24 (P24) rats but not in P17 rats. In experiment 1B, bilateral inactivation of the mPFC again failed to disrupt long-term extinction in P17 rats. In experiment 2, extinction training increased phosphorylated mitogen-activated protein kinase (pMAPK) in the mPFC for P24 rats but not for P17 rats, whereas rats of both ages displayed elevated pMAPK in the amygdala. Across both ages, "not trained," "reactivated," and "no extinction" control groups expressed very low numbers of pMAPK-immunoreactive (IR) neurons across both neural structures. This result indicates that the mere conditioning experience, the exposure to the CS, or the expression of CS-elicited fear in and of itself is not sufficient to explain the observed increase in pMAPK-IR neurons in the mPFC and/or the amygdala after extinction. Together, these findings show that extinction in P17 rats does not involve the mPFC, which has important theoretical and clinical implications for the treatment of anxiety disorders in humans.

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Figures

Figure 1.

Figure 1.

The effect of reversible unilateral inactivation of the mPFC in extinction in the developing rat. A, Histological reconstruction of coronal sections showing cannula placements in the mPFC. □, P17; ●, P24. B, Mean (±SEM) CS-elicited freezing at extinction and test. Unilateral inactivation of the mPFC during extinction disrupted long-term extinction in P24 rats but not in P17 rats. *Significant difference (p < 0.005) from the other groups.

Figure 2.

Figure 2.

The effect of reversible bilateral inactivation of the mPFC in extinction in the developing rat. P17 (●). A, Histological reconstruction of coronal sections showing cannula placements in the mPFC. B, Mean (±SEM) CS-elicited freezing at extinction and test. Bilateral inactivation of the mPFC during extinction had no effects on long-term extinction in P17 rats. *Significant difference (p < 0.05) from the other groups.

Figure 3.

Figure 3.

A, Mean (±SEM) CS-elicited freezing at extinction. Reactivated rats showed amounts of CS-elicited freezing equal to those of extinction rats during the first block of extinction. Only rats that were trained and extinguished showed significant extinction across trial; rats not trained did not show any CS-elicited freezing. B, Numbers of pMAPK-IR neurons in the PrL and IL after extinction training in P17 and P24 rats. Extinction of conditioned fear led to an elevated number of pMAPK-IR neurons in IL in P24 rats but not in P17 rats. *Significant difference (p < 0.005) from not trained and reactivated groups of the same age. **Significant difference (p < 0.005) from all other groups of the same age. C, D, Photomicrograph of pMAPK-IR neuronal staining in the medial prefrontal cortex (C) and pMAPK-IR neuronal staining in the IL in the trained–extinction group from a P17 rat (left) and a P24 rat (right) (D).

Figure 4.

Figure 4.

A, Numbers of pMAPK-IR neurons in the BLA after extinction training in P24 and P17 rats. *Significant effect of extinction across both ages (p < 0.05). B, Numbers of pMAPK-IR neurons in the BSTIA after extinction training in P24 and P17 rats. *Significant effect of extinction across both ages (p < 0.05). Extinction of conditioned fear led to an elevated number of pMAPK-IR neurons in the BLA and BSTIA at both ages. C, Photomicrograph of pMAPK-IR neuronal staining in the amygdala. D, E, pMAPK-IR neuronal staining in the BLA in the trained–extinction group from a P17 rat (left) and a P24 rat (right) (D) and pMAPK-IR neuronal staining in the BSTIA in trained–extinction group from a P17 rat (left) and a P24 rat (right) (E). CeA, Central amygdala.

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