Learning-Related Translocation of δ-Opioid Receptors on Ventral Striatal Cholinergic Interneurons Mediates Choice between Goal-Directed Actions

Abstract

The ability of animals to extract predictive information from the environment to inform their future actions is a critical component of decision-making. This phenomenon is studied in the laboratory using the pavlovian-instrumental transfer protocol in which a stimulus predicting a specific pavlovian outcome biases choice toward those actions earning the predicted outcome. It is well established that this transfer effect is mediated by corticolimbic afferents on the nucleus accumbens shell (NAc-S), and recent evidence suggests that ␦-opioid receptors (DORs) play an essential role in this effect. In DOR-eGFP knock-in mice, we show a persistent, learning-related plasticity in the translocation of DORs to the somatic plasma membrane of cholinergic interneurons (CINs) in the NAc-S during the encoding of the specific stimulus-outcome associations essential for pavlovian-instrumental transfer. We found that increased membrane DOR expression reflected both stimulus-based predictions of reward and the degree to which these stimuli biased choice during the pavlovianinstrumental transfer test. Furthermore, this plasticity altered the firing pattern of CINs increasing the variance of action potential activity, an effect that was exaggerated by DOR stimulation. The relationship between the induction of membrane DOR expression in CINs and both pavlovian conditioning and pavlovian-instrumental transfer provides a highly specific function for DOR-related modulation in the NAc-S, and it is consistent with an emerging role for striatal CIN activity in the processing of predictive information. Therefore, our results reveal evidence of a long-term, experience-dependent plasticity in opioid receptor expression on striatal modulatory interneurons critical for the cognitive control of action.

Chronic Morphine Reduces Surface Expression of δ-Opioid Receptors in Subregions of Rostral Striatum

“…Somatic membrane DOPr-eGFP immunofluorescence was observed in CINs throughout the striatum of DOPr-eGFP knock-in mice, consistent with previous reports [17]. Fig.…”

“…In order to compare relative CIN somatic membrane DOPr levels, double immunofluorescence microscopy was conducted on striatal sections from morphine and vehicle mice as previously described [17]. This was performed with a sequential laserscanning confocal microscope (Olympus FV1000, Tokyo, Japan) and images were analysed 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 …”

“…Pavlovian training -i.e. the learning of cuereward associations -in mice induced a persistent upregulation of somatic membrane DOPr's in cholinergic interneurons (CINs) of the NAc shell subregion (NAc-S) [17]. That study exploited the ability to directly visualise DOPr using a transgenic mouse in which the DOPr is tagged at the C-terminal with eGFP, together with precise definition of the location of DOPr at the cell surface of CINs using immunohistochemistry of choline acetyltransferase (ChAT).…”

“…Pavlovian-to-instrumental transfer (PIT), while the administration of a DOPr antagonist directly into the NAc-S abolished this transfer effect [18]. Furthermore, this DOPr upregulation increased the variance in CIN firing, an effect enhanced by DOPr activation, and absent in mice not given Pavlovian training [17]. In vivo, this modulation of CIN firing activity is likely to have important consequences for the function of CINs as key modulators of local signalling within the striatum.…”

“…Given the upregulation of membrane DOPr's with chronic opioid exposure and the potential role of DOPr's in CINs in learning mechanisms related to drug addiction, the current study investigated the effects of chronic morphine and morphine sensitisation treatments on CIN membrane DOPr's in the striatum using the methods described in [17]. We are not aware of other published studies on the effects of chronic morphine exposure either on surface expression of DOPr in striatal CINs, or studies using DOPr-eGFP mice to examine the effects of chronic morphine on DOPr trafficking.…”