Neuromodulators are a class of signaling molecules that typically operate though second messenger signaling cascades, inducing long-lasting signals over potentially widespread areas. Some of the major ones may be familiar – dopamine, serotonin, acetylcholine, for example. However, there is a wide diversity of neuromodulators and their effects. One researcher attempting to de-mystify this class of molecules is Dr. Matthew Banghart, Assistant Professor in Neurobiology at UCSD studying neuromodulatory signaling pathways and their influence on neural circuit function, specifically in the mammalian basal ganglia. The basal ganglia are a group of brain nuclei critical that are implicated in a wide range of functions, including generation of purposeful movements, reinforcing behaviors that maximize reward, and motivational and habitual control. Several different neuromodulators are well known to act on this system. One important nucleus of the basal ganglia is the striatum, which is the principal input nucleus and integrates cortical and thalamic input to the basal ganglia. The striatum is anatomically and functionally complex with several levels of organization. One level is its division of neurons into patch and matrix compartments, where patches exist as interconnected tubes running through the matrix, much like the weaving of a textile. This organization is conserved across species and is therefore likely to play an important role in basal ganglia function.

Patch and matrix compartments are known to express different biochemical markers but the causes and consequences of this are not well understood. Furthermore, it is known that both compartments contribute to the direct and indirect output pathways of the striatum. Therefore, the functional consequences of patch-matrix compartmentalization are of interest in understanding local basal ganglia circuitry. In 2015 Dr. Banghart et al. published a paper titled “Enkephalin Disinhibits Mu Opioid Receptor-Rich Striatal Patches via Delta Opioid Receptors” which revealed the role of the neuromodulator enkephalin (enk) on patch output in dorsal striatum. Enkephalin is involved in the body’s response to harmful stimuli and is expressed in striatal neurons across species. In humans, enk-expressing striatal projection neurons (SPNs) are part of the indirect pathway of basal ganglia circuitry, while neurons of the direct pathway express other signaling molecules. Importantly, striatal patches are known have a high level of mu opioid receptor (MOR) which binds enk, whereas enk itself is expressed in indirect pathway SPNs (iSPNS) in the matrix. Given clear enk and MORs distribution, it was hypothesized that enk signaling may represent a means of communication between compartments.

In order to study enk signaling, the researchers used a transgenic mouse line allowing for the immunohistochemical identification of both direct and indirect striatal pathways as well as matrix and patch compartments, and performed histochemical and electrophysiological techniques on brain slices. The group recorded synaptic currents in patches while electrically stimulating in patch and then matrix compartments, finding that matrix stimulation did not elicit responses in patches. This observation suggests that patches are synaptically isolated. The most important finding was that enk was shown to modulate inhibitory activity of direct SPNs (dSPN) (see figure below). By expressing channelrhodopsin in both indirect and direct SPNs and examining the effect of enk on optogenetically-evoked inhibitory post-synaptic currents (IPSCs) in both striatal neuron classes, they were able to observe strong suppression by enk of synaptic inhibition originating from iSPNs and weaker suppression on inhibition from dSPNs. Contrary to their hypothesis, it was found that the majority of iSPN modulation on inhibitory activity was mediated by delta opioid receptors (DORs), not MORs. In sum, matrix neurons release enk, which binds predominantly to DORs on iSPN neurons in patches, and these provide collateral input to patch dSPN neurons. The implications of this work are that at least one type of neuromodulator, enkephalin, is a mechanism for patch-matrix communication, potentially gating information flow in the striatum by activating patch-specific DORs.

Screenshot from 2020-05-17 22-09-12
To hear about Dr. Banghart’s related projects, join us at his talk titled “Convergent neural pathways underlying pharmacological and cognitive pain modulation” this coming Tuesday May 19, 2020 at 4 pm via Zoom.

Written by Emma Boyd, a 1st year in the Neurosciences Graduate Program at UCSD.

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