The NAc integrates reward-related information conveyed by dopamine and GABAergic inputs from the midbrain with glutamatergic inputs from regions throughout the brain. There is a fairly consistent cellular architecture throughout the dorsal and ventral striatum, including the NAc (79
). Striatal projection neurons, also known as medium spiny neurons (MSNs), make up more than 90% of the local neurons in the NAc and are GABAergic (81
). Striatal interneurons are a mix of both cholinergic and GABAergic neurons (82
). MSNs are typically classified into two main groups based on the type of opioid peptides they release (dynorphin or enkephalin) and the dopamine receptors they express (D1 or D2), as well as their projection targets (direct or indirect to the midbrain; see ; 79
). However, this strict division between the two types of MSNs may be less true in the NAc than in the dorsal striatum (84
). It is also unclear if this division is as steadfast in species other than mice, where transgenic animals have provided strong evidence for discrete populations of projection neurons (86
Intrinsic and extrinic circuitry of the Nucleus Accumbens
Optogenetic investigations utilizing ChR2 in acute brain slices have demonstrated that direct pathway MSNs in the NAc specifically target GABAergic neurons in the VTA (74
; see above). This target specificity has also been observed in direct pathway MSNs of the dorsal striatum, which only innervate GABAergic neurons of the substantia nigra pars reticulata (87
). Neither of these optogenetic investigations found evidence for direct innervation of midbrain DA neurons by MSNs. Indirect pathway MSNs from the dorsal and ventral striatum target the external segment of the globus pallidus and the ventral pallidum, respectively (88
). As with the direct pathway MSNs, the projections from indirect pathway MSNs may selectively target specific GABAergic neurons (87
). In addition, striatal MSNs form inhibitory synapses onto each other, as well as local cholinergic, but not fast-spiking GABAergic interneurons (87
). The intricate connectivity within the NAc suggests that multiple genetically distinct neuronal subtypes cooperate to orchestrate motivated behavior.
The distinct projection targets of the two main types of MSNs suggest that the activity of these pathways oppose each other and can produce a bidirectional regulation of behavior (79
). Recent optogenetic investigations have provided additional support for this hypothesis. When ChR2 was expressed selectively in either D1R or D2R expressing MSNs in the dorsomedial striatum by viral delivery, basal locomotion could be increased or decreased, respectively (90
). While these results support the idea that the dorsal striatum has a critical role in the bidirectional control of motor behavior, selective activation of these distinct neural circuit elements on a physiologically relevant timescale was not possible without optogenetic manipulations.
Optogenetic investigations specifically in the NAc have explored whether the activation or inhibition of specific cell types alters either basal locomotion or cocaine-induced behaviors. In one study in which ChR2 was expressed in D1R- or D2R-expressing MSNs in naïve mice, optogenetic activation of these two neuronal subtypes in the NAc did not influence basal locomotor activity (91
). However, when the mice were treated with multiple injections of cocaine that could reliably produce behavioral sensitization, optogenetic activation of NAc D1R-expressing MSNs became sufficient to enhance locomotion (91
). This demonstrates that repeated exposure to cocaine might alter the functional activity of NAc D1R-expressing MSNs so that effects on locomotion become evident upon activation of this pathway. This emergent effect may account for the increased locomotion observed in behavioral sensitization, although this idea remains to be tested.
The optical activation of D1R- or D2R-expressing NAc MSNs on its own was ineffective in eliciting a place preference when optically stimulated at 10 Hz (91
). However, activation of D1R-expressing NAc MSNs during cocaine exposure enabled a sub-threshold dose of cocaine to produce a conditioned place preference (91
). Similar effects were observed with an indiscriminate ChR2-mediated activation of all NAc neurons during cocaine exposure (91
). Conversely, activation of D2R-expressing MSNs in the NAc during cocaine exposure diminished the development of a conditioned place preference (91
). These opposing effects are another example of how the two types of MSNs can exert bidirectional control over behavior, specifically on the ability of cocaine to induce a conditioned place preference.
The influence of interneuron populations on behavior has been explored by optogenetically silencing or augmenting their activity. Both the light-activated chloride pump halorhodopsin 3.0 and ChR2 have been introduced into NAc cholinergic interneurons by viral methods. Neither activating nor inhibiting these neurons with light produced gross behavioral effects (92
). These manipulations in their own right were also ineffective in eliciting a place preference (92
). Inhibiting these neurons during cocaine exposure, however, decreased CPP, which is similar in effect to that observed from activating NAc D2R-expressing MSNs during cocaine exposure (91
). Interestingly, the inhibition of NAc cholinergic interneurons increased the firing rate in the majority of neighboring cells (92
). This observation is inconsistent with the finding that indiscriminate activation of all NAc neurons with ChR2 augments cocaine reward (91
), but perhaps cholinergic interneuron inhibition preferentially activates D2R-expressing MSNs.
Taken together, these experiments confirm that the two main populations of MSNs exert opposing effects on behavior. In the NAc, optogenetic manipulations to specific cell types affect the development of cocaine-induced conditioned place preference. While no publications to date have examined the behavioral effects of optogenetic manipulations to NAc GABAergic interneurons, it is likely that they also influence cocaine-related behaviors. Overall, the behaviors examined with optogenetic techniques to date (locomotion, behavioral sensitization, and conditioned place preference) are indirect metrics of reward-seeking. As optogenetic techniques become more widely adopted, it will be interesting to see how specific neural circuit perturbation directly alters reward-seeking behaviors such as drug self-administration.