Cellular and MolecularReviewInvestigating striatal function through cell-type-specific manipulations
Highlights
▶Cell-type-specific manipulations enable insight into striatal function. ▶Several techniques have been used to knockout, ablate, or inactivate striatal neurons. ▶Optogenetic methods have enabled selective stimulation of striatal neurons. ▶A remarkable convergence of results indicates unique functions for D1 MSNs, D2 MSNs, and striatal interneurons.
Section snippets
Organization of striatal circuits
Different striatal subregions receive inputs from distinct cortical areas, and correspondingly participate in distinct aspects of behavioral control. Very roughly, putamen in primates (dorsal/lateral/posterior striatum in rodents) is a component of “sensorimotor” circuits, caudate (dorsal/medial striatum in rodents) participates in “associative” circuits, and nucleus accumbens (NAc core and shell; ventral/anterior striatum) is part of “limbic” circuitry (McGeorge and Faull, 1989, Brog et al.,
Manipulations of striatal projection neurons
In normal animals, D1 MSNs and D2 MSNs are difficult to distinguish. In brain slices, they have a similar appearance under the light microscope. In vivo, MSNs have generally similar waveforms, and are typically quiescent outside of a specific combination of context, cues, and action (Hollerman et al., 2000). The development and application of BAC transgenic mice have been instrumental in distinguishing these subtypes, using either D1 or M4 lines to identify direct-pathway MSNs, and D2 or A2A
Striatal interneurons
In comparison to MSNs, far less is known about the function of striatal interneurons. A focus of much early research was the cholinergic cells, known anatomically as large aspiny interneurons and electrophysiologically as tonically active neurons (TANs). One early tool developed to selectively inactivate cholinergic neurons was ethylcholine mustard aziridinium ion (AF64A) (Mantione et al., 1981). Although the specificity of putative cholinergic neurotoxins is a major problem, injections of
Conclusions
Results using a variety of methods to selectively target D1 or D2 MSNs in behaving animals have yielded remarkably consistent results. Activation of D1 MSNs enhances locomotion and CPP. Activation of D2 MSNs induces parkinsonian motor deficits and decreases CPP. In contrast, lesions or inactivations of D1 MSNs lead to slowed movements, reduced sensitization to psychostimulants, and reduced CPP, whereas loss of D2 MSN function yielded hyperactivity, enhanced sensitization, and CPP, as well as a
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2014, NeuroscienceCitation Excerpt :Researchers must be careful to consider these properties when drawing conclusions. It has been shown using a variety of techniques including optogenetic stimulation that activation of the D1 pathways results in enhanced locomotion and conditioned place preference, whereas activation of the D2-pathways results in Parkinsonian-like deficits with reduced CPP (Kreitzer and Berke, 2011). We would argue that this is because gross activation of the D2 pathways results in large inter-pathway competition, holding the system in a state of deliberation.