Dataset Information

NPY controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors.

ABSTRACT:

Background and purpose

Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown.

Experimental approach

Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice.

Key results

NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y₁ receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y₂ receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y₁ and Y₂ receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y₁ and Y₂ receptors. In Y₁ receptor single KO mice, fear extinction was delayed and was unchanged in Y₂ receptor KO mice. Deletion of NPY and particularly Y₂ receptors resulted in a generalization of conditioned fear.

Conclusions and implications

Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y₁ receptors, the pronounced phenotype of Y₁Y₂ receptor double KO mice suggests a synergistic role of Y₂ receptors in fear acquisition and in fear extinction.

SUBMITTER: Verma D

PROVIDER: S-EPMC3401902 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The extinction of contextual fear is commonly an essential requirement for successful exposure therapy for fear disorders. However, experimental work on extinction of contextual fear is limited, and there little or no directly relevant theoretical work. Here, we extend BACON, a neurocomputational model of context fear conditioning that provides plausible explanations for a number of aspects of context fear conditioning, to deal with extinction (calling the model BaconX). In this model, contextual representations are formed in the hippocampus and association of fear to them occurs in the amygdala. Representation creation, conditionability, and development of between-session extinction are controlled by degree of confidence (assessed by the Bayesian weight of evidence) that an active contextual representation is in fact that of the current context (i.e., is "valid"). The model predicts that: (1) extinction which persists between sessions will occur only if at a sessions end there is high confidence that the active representation is valid. It follows that the shorter the context placement-to-US (shock) interval ("PSI") and the less is therefore learned about context, the longer extinction sessions must be for enduring extinction to occur, while too short PSIs will preclude successful extinction. (2) Short-PSI deficits can be rescued by contextual exposure even after conditioning has occurred. (3) Learning to discriminate well between a conditioned and similar safe context requires representations of each to form, which may not occur if PSI was too short. (4) Extinction-causing inhibition must be applied downstream of the conditioning locus for reasonable generalization properties to be generated. (5) Context change tends to cause return of extinguished contextual fear. (6). Extinction carried out in the conditioning context generalizes better than extinction executed in contexts to which fear has generalized (as done in exposure therapy). (7) BaconX suggests novel approaches to exposure therapy.