Lateralization of behavioral control in the striatum

These findings suggest that in the early phase of the training, the behavior is controlled by the mediodorsal striatum. With extended training, the dorsolateral striatum takes over the control of the behavior. The mechanism of the lateralization is yet to be fully understood. One attractive idea is that a spiraling pattern of connectivity between the striatum and midbrain controls the lateralization (Keiflin and Janak, 2015; Lüscher et al., 2020; Volkow et al., 2019). DA neurons in the VTA project to the NAc, and then NAc D1-MSNs project back to GABAergic neurons in the midbrain. Some D1-D1-MSNs project to the same region of the VTA, forming closed reciprocal loop, while others project to more lateral part of the midbrain, organizing open non-reciprocal loop. These DA neurons project to more dorsal and lateral part of the striatum. In the end, this loop reaches lateral part of the dorsal striatum and substantia nigra pars compacta (SNc). The existence of this spiral loop has been shown in an anatomically study (Haber et al., 2000). There are several other studies supporting this hypothesis. In a classical Pavlovian conditioning experiment, in untrained rats, unpredicted food reward delivery induces a DA transient in the NAc core but not mediodorsal or dorsolateral striatum. Only after training, reward cues and unpredicted food rewards evokes DA transients in the dorsomedial striatum (Brown

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et al., 2011). In the case of cocaine self-administration, reward cues which signals the delivery of cocaine evokes DA transients in the NAc but not in the DLS in rats with limited training (Willuhn et al., 2012). However, the same cues triggers DA transients in the DLS of well-trained rats. Interestingly, this transition is abolished with the lesion of the NAc core (Willuhn et al., 2012). This spiraling loop hypothesis is also consistent with habit formation.

It has been demonstrated that animals display habitual behavior only after extended training and that this behavior depends on the activity of the DLS (Zapata et al., 2010).

Several studies imply that abnormal habit formation underlies compulsive drug seeking.

Some rats become compulsive only after extended training, while with limited training, almost all rats become non-compulsive (Pelloux et al., 2012, 2015). This is consistent with the finding that only after extended training, rats show habitual cocaine seeking (Zapata et al., 2010). However, because in the latter study, individual vulnerability to addiction is not taken into consideration, it is unclear if compulsive rats have stronger habit formation or not. In a different study, silencing of the DLS attenuates compulsivity (Jonkman et al., 2012). As we have seen, the same procedure blocks habitual cocaine seeking (Zapata et al., 2010). However, this study does not assess the correlation between habitual behavior and compulsivity. In conclusion, direct evidence showing that abnormal habit underlies compulsion is still lacking. The idea that habit formation is necessary for compulsion has been questioned (Singer et al., 2017). In one study, rats need to solve a puzzle to get access to cocaine. Since the puzzle changes every session, the behavior is supposed to be goal-directed. Actually, the cocaine seeking is controlled by ventral striatum even after prolonged training. Surprisingly, some rats show addiction like behavior even though their cocaine seeking behavior is goal-directed (Singer et al., 2017). Clinical observations indicate that addicted patients can create elaborated plans to get drugs, demonstrating that their behavior is goal-directed at least when it is necessary. Another possibility is that an extreme form of directed behavior leads to compulsivity. The behavior is goal-directed but the estimated value for the drug reward is extremely high, and so addicted patients do whatever it takes to procure the drug. Recently, it has been demonstrated that the potentiation at OFC-DS pathway promotes compulsive reward taking (Pascoli et al., 2018)s. In physiological conditions, this pathway is crucial to calculate integrated value (Hirokawa et al., 2019) to make a decision. Another study showed the potentiation of this

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pathway induces goal-directed behavior (Gremel et al., 2016). Based on these findings, one could argue that OFC-DS pathway is crucial for goal-directed, model-based behavior.

The potentiation of this synapse could increase the estimated outcome. In the context of addiction, persistent potentiation at this pathway might lead to the overestimation of the value of the drug reward, resulting in the compulsive drug seeking.

Figure 1.7 Diagram of the organization of striatonigrostriatal projections. (Haber et al., 2000).

The colored gradient in the rostral and caudal striatal schematics show the organization of functional connectivity of cortico-striatal projections (red=limbic, green=associative, blue=motor). Midbrain projections from the nucleus accumbens (NAc) shell target both the ventral tegmental area (VTA) and medial substantia nigra pars compacta (SNc). Dopaminergic projections from the VTA to NAc shell form a closed, reciprocal loop (red), while projections from the medial SNc form an open, spiral loop (orange). The spiral continues through striatonigrostriatal projections with pathways originating in more dorsal and lateral part of the striatum (blue). Magnified oval region shows a hypothetical model of the synaptic interactions of striatonigrostriatal projections in reciprocal versus feedforward loops. The reciprocal component (red arrows) of each limb of the SNS projection terminates directly (a) on a dopamine cell, resulting in inhibition. The non-reciprocal, or feedforward, component (orange arrow) terminates indirectly (b) on a dopamine cell via a GABAergic interneuron (brown cell), resulting in disinhibition and facilitation of dopaminergic cell burst firing. Note that after this paper was published, it has been shown that striatal medium spiny neurons (MSNs) mainly project to GABAergic interneurons in the midbrain (Bocklisch et al., 2013). There are some direct projections from MSNs to midbrain dopamine neurons but those synapses express only GABA-B receptors, lacking GABA-A receptors (Edwards et al., 2017). The organization proposed here remains to be shown.

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