Abstract
Extinction of Pavlovian conditioning is a complex process that involves brain regions such as the medial prefrontal cortex (mPFC), the amygdala and the locus coeruleus. In particular, noradrenaline (NA) coming from the locus coeruleus has been recently shown to play a different role in two subregions of the mPFC, the prelimbic (PL) and the infralimbic (IL) regions. How these regions interact in conditioning and subsequent extinction is an open issue. We studied these processes using two approaches: computational modelling and NA manipulation in a conditioned place preference paradigm (CPP) in mice. In the computational model, NA in PL and IL causes inputs arriving to these regions to be amplified, thus allowing them to modulate learning processes in amygdala. The model reproduces results from studies involving depletion of NA from PL, IL, or both in CPP. In addition, we simulated new experiments of NA manipulations in mPFC, making predictions on the possible results. We searched the parameters of the model and tested the robustness of the predictions by performing a sensitivity analysis. We also present an empirical experiment where, in accord with the model, a double depletion of NA from both PL and IL in CPP with amphetamine impairs extinction. Overall the proposed model, supported by anatomical, physiological, and behavioural data, explains the differential role of NA in PL and IL and opens up the possibility to understand extinction mechanisms more in depth and hence to aid the development of treatments for disorders such as addiction.
Highlights
In the last decade, extinction of Pavlovian conditioning has gained interest as a possible means to treat disorders such as anxiety disorders, addiction, and eating disorders (Delamater and Westbrook 2014)
Our model proposes that the behaviour observed in medial prefrontal cortex (mPFC) NA depletion experiments is caused by enhanced or impaired plasticity events triggered by mPFC in the Amg
BAe-ITCv connections only grow during the extinction phase and allow the ITCv to inhibit the conditioned response triggered by central amygdala nucleus (CEA)
Summary
Extinction of Pavlovian conditioning has gained interest as a possible means to treat disorders such as anxiety disorders, addiction, and eating disorders (Delamater and Westbrook 2014). Extinction is modelled in preclinical studies by non-reinforced exposure to previously conditioned stimuli in behavioural paradigms (Bernardi and Lattal 2010; McNally 2014). In a conditioned place preference paradigm (CPP), a mouse learns to associate a drug with a particular environment, exhibiting a preference for such environment with respect to one not associated with the drug. Subsequent exposures to the same environment without the presence of the drug cause the extinction of the association measured as same preference for the two environments. Neural substrates of extinction are still elusive but there is increasing evidence that brain regions such as the medial prefrontal cortex (mPFC), amygdala (Amg) and locus coeruleus (LC) play a crucial role in this process (Dunsmoor et al 2015). NA causes an early extinction when depleted from the prelimbic (PL) region but impairs
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