Kurzfassung

Projekt B01: Finding the good in the bad: fear extinction reconceptualized as an appetitive learning process

Positive appraisal style theory of resilience (Kalisch et al., 2015) considers extinction a critical case of adaptive, flexible stress response regulation (see Starting Point 5 in section 1.2.2.3 of the CRC’s Academic profile). As a result of a positive reappraisal of threat-associated stimuli (conditioned stimuli, CSs) that have ceased to predict threat (the unconditioned stimulus,...Projekt B01: Finding the good in the bad: fear extinction reconceptualized as an appetitive learning process

Positive appraisal style theory of resilience (Kalisch et al., 2015) considers extinction a critical case of adaptive, flexible stress response regulation (see Starting Point 5 in section 1.2.2.3 of the CRC’s Academic profile). As a result of a positive reappraisal of threat-associated stimuli (conditioned stimuli, CSs) that have ceased to predict threat (the unconditioned stimulus, UCS), unnecessary, costly fear responses (CRs) are attenuated or abolished. This reduces allostatic load. Good extinction ability may therefore constitute a resilience-conducive trait (cf. Starting Point 3) that benefits mental health by facilitating the activation of an important resilience mechanism (here, extinction learning) during re-exposure to once-dangerous situations. Indeed, extinction ability has recently been shown to predict resilience to the deteriorating effects of military trauma (Lommen et al., 2013).
Extinction learning occurs when a CS is no longer followed by the UCS. Classical models of associative learning state that unexpected UCS omission induces a prediction error signal, PE, that leads to an update (reduction) of the UCS prediction, that is, a decrease of the aversive value associated with the CS. This positive re-valuation or reappraisal process in turn leads to a decay of CRs. Because not getting a predicted UCS may be subjectively experienced as a pleasant surprise and induce feelings of relief and safety, it has also been proposed more recently that PE during extinction should be conceptualized specifically as an appetitive or reward-like prediction error, PEapp (e.g., Raczka et al., 2011). The reduction of CRs during extinction would then not result from a reduced UCS prediction but instead from the generation of a new, appetitive prediction of safety from the UCS, which functions to inhibit fear reactions. Thus, this alternative account of extinction states that extinction learning is not mediated by the brain’s aversive system that also mediates fear conditioning, but by an opponent appetitive learning system. Activation of the appetitive system in turn competes with the aversive system for control over behavior, thereby reducing CRs (see also opponent systems theory in 1.2.2.3, theory section). Identifying such a contribution of the appetitive system to the functioning of a key resilience mechanism would place the appetitive system in a central position for resilience theory.
One of the strongest findings in the reward learning literature is that PEapp is encoded by a phasic increase at the time of UCS omission in the firing of dopaminergic VTA neurons terminating in the ventral striatum (VS) (Schultz, 2006; Steinberg et al., 2013). Therefore, showing that extinction is mediated by a dopamine-dependent PEapp signal in the VS is a necessary (though not sufficient) test criterion for the appetitive learning theory of extinction and a natural first step to take in its evaluation. On the basis of initial evidence from a computational fMRI study by the Kalisch lab (Raczka et al., 2011), we will here use computational modeling of trial-by-trial behavioral data in combination with fMRI to firmly establish encoding of PEapp in VS in humans (Aim 1). These experiments will then be performed under systemic L-DOPA administration, supposed to amplify dopamine transients. We predict that extinction learning will be accelerated and ventral striatal PEapp signals will be amplified in the L-DOPA relative to placebo subjects (Aim 2). In mice, we will perform optogenetic activation and inhibition of VTA dopamine neuron firing precisely at the time of UCS omission, expecting acceleration and deceleration, respectively, of extinction (Aim 3). To confirm that these effects are mediated by dopamine, the experiments will also be performed after local dopamine D1 receptor antagonist infusion (Aim 4). The mouse experiments will thus allow us to test the causal role of phasic VTA dopamine neuron firing in extinction.
More generally, by using two different species and a range of different, complementary methods, these proposed neurophysiological studies will permit definitive conclusions on the role of dopaminergic PEapp signals in extinction. They will thereby inform future experiments on the appetitive nature of extinction. Furthermore, they will provide a ground for examining the role of extinction-related PEapp signals in resilience. To start to address this issue and to prepare more extended work in future funding periods, we will retrospectively test an association with resilience outcomes R (cf. Fig. 5 in 1.2.2.4) in humans (Aim 5) and mice (Aim 6).» weiterlesen» einklappen