Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors

Abstract

SUMMARY Opioid neuropeptides and their receptors are evolutionarily conserved neuromodulatory systems that profoundly influence behavior. In dorsal striatum, which expresses the endogenous opioid enkephalin, patches (or striosomes) are limbic-associated subcompartments enriched in mu opioid receptors. The functional implications of opioid signaling in dorsal striatum and the circuit elements in patches regulated by enkephalin are unclear. Here, we examined how patch output is modulated by enkephalin and identified the underlying circuit mechanisms. We found that patches are relatively devoid of parvalbumin-expressing interneurons and exist as self-contained inhibitory microcircuits. Enkephalin suppresses inhibition onto striatal projection neurons selectively in patches, thereby disinhibiting their firing in response to cortical input. The majority of this neuromodulation is mediated by delta, not mu opioid receptors, acting specifically on intra-striatal collateral axons of striatopallidal neurons. These results suggest that enkephalin gates limbic information flow in dorsal striatum, acting via a patch-specific function for delta opioid receptors.

Genetic-Based Dissection Unveils the Inputs and Outputs of Striatal Patch and Matrix Compartments

“…Matrix-Cre mice contained both direct (53.4 ± 3.9%) and indirect pathway (39.9 ± 3.9 %) neurons. In contrast, patch-Cre mice were predominantly D1 expressing (83.2 ± 1.9 %; t 3 = 9.36, p = 0.0026), matching previous reports (Gerfen and Young, 1988; Besson et al, 1990; Fujiyama et al, 2011; Banghart et al, 2015). Patch and exo-patch SPNs were found to have similar distributions of D1 (Figure S2; patch: 80.3 ± 1.8%; exo-patch: 80.7 ± 2.1%; paired sample t-test; t 1 = 0.94, p = 0.52) and D2 SPNs (patch: 14.7 ± 7.1%; exo-patch: 10.1 ± 2.4%; paired sample t-test; t 2 = 0.91, p = 0.46).…”

“…We have broadened the definition of patches to include “exo-patch” SPNs, which are located in the matrix but are characteristically more similar to patch SPNs. Specifically, patch and exo-patch groups are D1-receptor dominant, as previously shown for patches (Banghart et al, 2015), compared to matrix SPNs. Additionally, exo-patch SPNs appear in the expression profile of multiple patch-enriched genes (see Table 1 in Crittenden and Graybiel, 2011 for list of genes).…”

“…High levels of Oprm1, the transcript encoding MORs, were found to colocalize with Pdyn-cells (Banghart et al, 2015), supporting the neurochemical relationship of MOR with patch and exo-patch SPNs (Figure S1). Furthermore, our patch clamp recordings confirm that inhibitory transmission in patch and exo-patch SPNs is sensitive to enkephalin, whereas matrix SPNs are not.…”

“…Patch and exo-patch cells show increased staining for MORs (Figure S1), suggesting that enkephalin, the endogenous ligand for MORs (and delta opioid receptors, DOR), could modulate synaptic transmission on exo-patch SPNs. MOR (and DOR) agonists suppress excitatory synaptic transmission on patch and matrix SPNs (Atwood et al 2014, Blomeley et al 2011; Jiang and North, 1992; Miura et al 2007), but MOR (and DOR) agonists selectively suppress IPSCs in patch SPNs (Miura et al 2007, Banghart et al 2015). The source of these enkephalin-sensitive inhibitory afferents is believed to be from local D2- SPNs (Banghart et al, 2015), but may arise from as yet unknown extrastriatal sources as well.…”

Striatal Local Circuitry: A New Framework for Lateral Inhibition

“…First identified by the expression patterns of proteins such as mu-opioid receptors and acetylcholinesterase, there are now over 60 genes known to be differentially expressed in patch vs. matrix compartments (Crittenden and Graybiel, 2011). Though patches only represent a small proportion of the striatum by volume, many of the differentially expressed genes are neuromodulators and their receptors suggesting that the patch and matrix have distinct pharmacological properties (Banghart et al, 2015; Brimblecombe and Cragg, 2016). Afferents to patch and matrix are also thought to arise from different sources with patches receiving limbic inputs and matrix neurons receiving sensorimotor inputs (Gerfen, 1984).…”