Overlapping Striatal Circuits and Molecular Mechanisms in Rodent Models of Addiction and Depression

Overview of Striatal Circuits

The striatum is a major brain nuclei in the basal ganglia (BG) system. The BG consists of set of corticobasal ganglia-cortical loops, which are a series of parallel projection loops that convey limbic, associative, and sensorimotor information. In this circuit, cortical neurons send input to striatum, which conveys output through various BG nuclei, relaying information to thalamus and then ultimately back to cortex. The striatum consists of the dorsal striatum (dStr, caudate and putamen in humans), which regulates actions and habits, and the ventral striatum (a.k.a. nucleus accumbens [NAc]), which is involved in motivation and reinforcement. These striatal areas have distinct projections through the BG output nuclei, consisting of two distinct pathways (often referred to as the direct and indirect pathways) and they were originally proposed to play antagonistic but balancing roles on BG output and behavior. The two pathways can be resolved at a cellular level in the main projection neurons of the striatum. The projection neurons, which comprise 90%–95% of all neurons in the striatum, are medium spiny neurons (MSNs), which are divided into two morphologically identical and heterogeneously distributed cell types. The MSNs in striatum are subdivided into two subtypes based on their axonal targets. MSNs that are considered part of the direct pathway project to globus pallidus internal (GPi), ventral pallidum (VP), and midbrain regions including substantia nigra (SN) and ventral tegmental area (VTA); whereas the indirect pathway MSNs project to the globus pallidus external (GPe) and VP ( Fig. 9.1 ). However, it is important to note that MSN projections from dStr appear more segregated from those in NAc. The dStr MSN subtypes have distinct projections with minimal overlap to BG nuclei, whereas the NAc MSN subtypes both send input to VP. Thus this ventral BG circuit does not quite represent the classical direct and indirect pathways (see Fig. 9.1 ). Due to this overlap in NAc MSN subtype projections, we refer to these two neuron subtypes based on their enrichment of dopamine receptors 1 versus 2, with D1-MSNs being part of the classical direct pathway and D2-MSNs part of the indirect pathway. Although both D1-MSNs and D2-MSNs in NAc project to VP, the NAc D1-MSNs also send projections to classical direct pathway nuclei including GPi, SN, and VTA (see Fig. 9.1 ).

Fig. 9.1, D1-tdTomato/D2-GFP mouse demonstrates D1-MSNs (red) versus D2-MSNs (green) in dorsal striatum (dStr) or ventral striatum (nucleus accumbens [NAc] ). These MSNs have distinct projections to BG output nuclei: globus pallidus external (GPe) , globus pallidus internal GPi), ventral pallidum (VP) , and substantia nigra (SN) . Scale bar 200 μm. Right inlay image shows little overlap in D1-MSNs (red) versus D2-MSNs (green). Scale bar 20 μm.

Along with their enrichment of D1 versus D2 receptors, the two MSN subtypes are further distinguished by their differential expression of several other genes, most notably G-protein–coupled receptors and neuropeptides. D1-MSNs express muscarinic receptor 4, substance P, and dynorphin, whereas D2-MSNs express adenosine receptor 2a, G-protein–coupled receptor 6, and enkephalin ( Fig. 9.2 ). Through the two BG pathways the D1-MSNs versus D2-MSNs have been demonstrated to display differential behavioral output. Activity in the D1-MSNs is implicated in movement initiation, reinforcement, and reward seeking, whereas activity in the D2-MSNs antagonizes the D1-MSN pathway, thus inhibiting movement, promoting punishment or avoidance, and inhibiting reward seeking. ^a

a References 23, 25, 39, 46, 48, 52, 55.

However, there are some studies that support a role for coordinated activity in these two neurons in actions and natural reward behaviors. Studies on animal models of addiction and depression have demonstrated distinct roles of these MSN subtypes in striatal circuits in these motivational diseases. This chapter discusses these current findings and the overlap between these striatal circuits in addiction and depression.

Fig. 9.2, Images of a D1-MSN (green) and D2-MSN (purple) and their respective enriched genes. D1-MSNs are enriched in dopamine 1 receptor (D1) , acetylcholine muscarinic receptor 4 (M4) , dynorphin (Dyn) , and substance P (SubstP) . D2-MSNs are enriched in dopamine 2 receptor (D2) , adenosine 2A receptor (A2A) , G-protein–coupled receptor 6 (Gpr6), and enkephalin (Enk) .

Striatal Circuit Activity in Animal Models of Addiction and Depression

Striatal MSN Subtype Activity in Addictive Drug Exposure and Behavior

Much of the evidence for the differential roles of D1-MSNs and D2-MSNs in addiction is based on studies examining cocaine-induced behaviors in rodents, using neuron-subtype–specific techniques to activate or inhibit these MSN subtypes. Enhanced activity in D1-MSNs underlies the reinforcing and sensitizing effects of cocaine. Likewise, blocking activity in D2-MSNs results in similar outcomes. ^b

b References 8, 11, 23, 39, 52, 70.

The first insight into MSN-subtype participation in psychostimulant-mediated behavior involved NAc D2-MSN ablation. Ablating these MSNs increased psychostimulant-induced conditioned place preference without altering normal locomotion. Subsequent studies demonstrated an opposite role for D1-MSNs versus D2-MSNs in psychostimulant-mediated behavior. Optogenetic stimulation, using the blue light–activated channelrhodopsin-2 (ChR2) of NAc D1-MSNs enhances the rewarding properties of cocaine, and NAc D2-MSN optogenetic stimulation reduces this outcome. In addition, after repeated exposure to cocaine the optogenetic activation of NAc D1-MSNs resulted in enhanced locomotor activity. This implicates that cocaine primes these MSN subtypes to display a sensitized response to other stimuli, in this case artificial activation. The selective blockade of neurotransmission in D1-MSNs reduces cocaine-induced locomotor sensitization and conditioned place preference. Conversely, using optogenetics or chemogenetics, the latter using designer receptor activated by designer drugs (DREADDs), inhibition of D1-MSNs or activation of D2-MSNs reduces psychostimulant-induced locomotor sensitization, while the inhibition of D2-MSNs increases this behavior. Furthermore, chemogenetic inhibition of D2-MSNs, in cocaine self-administration, enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. Finally, a recent study using in vivo fiber photometry with the calcium indicator, gCamp6f, confirmed the MSN subtype activity manipulation studies described above. This study showed that acute cocaine exposure enhanced D1-MSN and suppressed D2-MSN activity, and that cocaine-induced D1-MSN activity is required for formation of cocaine–context associations. In addition, MSN subtype–specific signaling encodes contextual information about the cocaine environment such that increased D1-MSN activity precedes entry into a cocaine-paired environment, while decreased D2-MSN activity occurred after entering the cocaine-paired environment. Finally, inhibiting this D1-MSN calcium signal by DREADD inhibition blocked the cocaine-conditioned preference. Altogether, these findings show that a circuit imbalance of these D1-MSN versus D2-MSN pathways occurs upon cocaine exposure, leading to an enhanced D1-MSN pathway, thus promoting cocaine-seeking, intake, and sensitization behaviors ( Fig. 9.3 ).

Fig. 9.3, Predicted model of MSN-subtype activity within the basal ganglia in addiction and depression. In a nondiseased brain the two MSN subtypes display balanced activity to produce normal behavioral output. In addiction, the D1-MSN pathway is overactive, while the D2-MSN pathway is suppressed, leading to excessive motivation for a drug of abuse. In depression the D1-MSN pathway is reduced, while the D2-MSN pathway is enhanced, leading to reduced motivation. MSN , Medium spiny neuron.

Electrophysiology studies examining psychostimulant-induced plasticity in the MSN subtypes corroborate with the activity studies described earlier. Excitatory synaptic potentiation occurs at D1-MSNs after repeated cocaine exposure or cocaine self-administration. Of interest, mice that display poor cocaine intake display enhanced excitatory synaptic input at D2-MSNs. Consistent with this, increased dendritic spine remodeling occurs in D1-MSNs after repeated injections (i.p) of cocaine. Evidence demonstrates that the increased spines in D1-MSNs are thin or immature spines, characterized as silent synapses, since they consist of N -methyl- d -aspartate (NMDAR) receptors but lack α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) receptors. The silent synapses, which are typical throughout the immature brain, can either retract or develop into fully functional synapses to induce new neural circuits, after periods of cocaine withdrawal. It is likely that these new neural circuits mediate enduring behaviors in response to cocaine, such as relapse behavior. Future studies examining MSN subtypes in relapse behavior will be important for understanding their role in the long-term effects of cocaine and the transition from early drug taking to the addictive state. Finally, examination into MSN subtype output in the VP, the one region receiving dense innervation from both MSN subtypes, demonstrates potentiated output of D1-MSNs but weakened output of D2-MSNs after repeated cocaine exposure. This study further showed that optogenetic depotentiation of D1-MSN output to the VP abolished cocaine locomotor sensitization; however, restoring D2-MSN transmission to VP did not alter this behavior.

As described in the preceding text, much of the data examining the striatal MSN circuits in drug abuse are from studies performed with cocaine. However, a small number of studies examine striatal circuits in morphine-mediated behaviors. Similar to the cocaine studies, optogenetic activation of NAc D1-MSNs enhanced morphine-conditioned place preference, whereas optogenetic activation of NAc D2-MSNs blunted this behavior. Of interest, examination of plasticity in these MSNs reveals a different outcome compared to cocaine, since silent synapses are induced in D2-MSNs after repeated morphine exposure. Finally, examination of analgesic tolerance demonstrated that optogenetic activation of D1-MSNs facilitates the development of morphine tolerance, whereas activation of D2-MSNs did not affect the development of tolerance. Additional studies examining these MSN subtypes in opiate-mediated behaviors are needed to uncover the mechanisms accounting for differences between cocaine and morphine.

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