Chronic stress biases behavioral strategies during decision-making: structural and physiological correlates The stress response is vital to maintain homeostasis. However, chronic stress can trigger maladaptive response and predispose to conditions ranging from neuropsychiatric disorders to everyday lapses of attention. Although previous reports have implicated chronic stress in executive function impairment, effects on decision-making processes remain to be clarified. Competing corticostriatal circuits are thought to control heterogeneous decision strategies. While the prelimbic (PL) cortex and the dorsomedial striatum (DMS, or associative striatum) have been implicated in goal-directed actions, the dorsolateral striatum (DLS, or sensorimotor striatum) has been implicated in automatic or habitual choices. We uncovered that in rats and mice chronic stress impairs the decision-making process, predisposing to habitual behavior in detriment to goal-directed strategies. We tested for action-outcome behavior in a lever pressing task and found that responses from rodents submitted to chronic stress became insensitive to both outcome devaluation and contingency degradation. Furthermore, we found that chronic stress causes opposing structural changes in associative and sensorimotor corticostriatal cricuits. Whereas chronic stress resulted in selective atrophy of pyramidal neurons in layer II/III of the PL and infralimbic (IL) sub-regions of medial prefrontal cortex (mPFC) and in medium spiny neurons (MSNs) of the DMS, it triggered an opposite effect in MSNs of the DLS. To determine if this structural reorganization of frontostriatal circuits has functional consequences, we recorded the simultaneous activity of neuronal ensembles in mPFC, DMS and DLS of control and stressed mice during behavioral training and testing. This approach will allow us to investigate if the changes in wiring observed in the associative and sensorimotor circuits underlies changes in neural activity in these circuits that could explain the bias from goal-directed towards habitual behavior observed in stressed subjects. Dynamic reorganization of striatal circuits via region and pathway-specific plasticity during the acquisition and consolidation of a skill Learning to execute and automatize certain actions is essential for survival. The learning of novel skills by trial and error, like riding a bicycle or playing a piano, is characterized by an initial stage of rapid improvement in performance, followed by a phase of more gradual improvements as the skills are consolidated and performance asymptotes (Kargo and Nitz, 2004;Karni et al., 1998;Miyachi et al., 2002;Miyachi et al., 1997). The different phases of skill learning have distinct behavioral and physiological hallmarks (Karni et al., 1998;Kleim et al., 2004;Muellbacher et al., 2002;Shiffrin and Schneider, 1977). For example, the early fast phase is susceptible to interference, while the later, more automatic phase is more resistant to interference (Shiffrin and Schneider, 1977). After the initial acquisitin phase, the memory of how to do things is gradually consolidated and for well-learned skills it can last a lifetime. Previous studies have shown changes in neural activity in the striatum, the major input nucleus of the basal ganglia, during motor and procedural learning (Barnes et al., 2005;Brasted and Wise, 2004;Carelli et al., 1997;Doyon et al., 1996;Jenkins et al., 1994;Ungerleider et al., 2002) . Some studies also suggested that the striatal circuits and processes engaged during the early and late phases of skill learning may differ (Costa et al., 2004;Miyachi et al., 2002;Miyachi et al., 1997). For example, the DMS, which receives input primarily from association cortices such as the prefrontal cortex (McGeorge and Faull, 1989;Voorn et al., 2004), seems to be preferentially involved in the initial stages of visuomotor learning annnd during the rapid acquisition of action-outcome contingencies (Miyachi et al., 2002;Miyachi et al., 1997;Yin et al., 2005). On the other hand, the DLS, which receives inputs from sensorimotor cortex (McGeorge and Faull, 1989;Voorn et al., 2004), is critical for the more gradual acquisition of habitual and automatic behavior (Miyachi et al., 2002;Miyachi et al., 1997;Yin et al., 2004). We have recently recorded neuronal activity in the DMS and DLS regions during the different stages of skill learning in vivo, and found that the task-related activity in these striatal regions differed during the acquisition and consolidation of a novel skill, with the DMS being engaged during the early phase, and the DLS during the late phase. We confirmed the differential involvement of these striatal regions in the different stages of skill learning using selective excitotoxic lesions of the dorsal striatum. We also investigated whether the changes in striatal neural activity observed during skill learning could be mediated by synaptic plasticity or excitability changes in medium spiny projection neurons in the dorsal striatum by using an ex vivo approach, and found that learning was accompanied by long-lasting changes in glutamatergic transmission. These changes evolved dynamically during the different phases of skill learning: changes in the DMS were predominant early in training, while changes in the DLS evolved only after extensive training. In summary, our previous studies indicated that during the automatization or consolidation of a skill, there is extensive potentiation of glutamatergic transmission in MSNs from the DLS, and that this region is necessary for the performance of automatized actions and skills. Neurons from the DLS do not all project to the same downstream basal ganglia structures. Medium spiny neurons projecting preferentially to the substantia nigra (striatonigral or direct pathway), and MSNs projecting to the external globus pallidus (striatopallidal or indirect pathway) have different dopamine receptor expression, different physiological properties, and different plasticity mechanisms (Gerfen et al., 1990;Kreitzer and Malenka, 2007;Shen et al., 2008;Shen et al., 2007). Until recently, LTP induction in the striatum was thought to always depend on D1-receptor activation (Kerr and Wickens, 2001), suggesting that it occurs preferentially in D1-expressing striatonigral neurons, and less in D2-expressing striatopalidal neurons. However, recent studies have shown that LTP can occur in both MSN types via different mechanisms (Shen et al., 2008). Thus, to understand the mechanisms underlying the consolidation and automatization of skills, it is crucial to determine whether the long-lasting potentiation observed in DLS after extended training occurs in striatonigral or striatopalidal MSNs, or in both. To this end we recorded from MSNs in the DLS of D2-EGFP mice and D1-EGFP mice that are naive or extensively trained on the rotarod. These mice allow the visualization of MSNs that express D1 receptors, which are almost exclusively striatonigral, and MSNs that express D2 receptors, which are almost exclusively striatopalidal, respectively. Using the D2-EGFP mice we obtained preliminary data indicating that extensive rotarod training resulted only in a slight potentiation in the non-D2 expressing neurons (putative striatonigral MSNs, direct pathway), but in a much greater potentiation in the D2-expressing MSNs (striatopallidal, indirect pathway) in the DLS of extensively trained animals. Concomitantly, the performance of the skill became less dependent on the activation of D1 receptors. These findings demonstrate that, as a skill becomes automatized, region- and pathway-specific plasticity sculpt the circuits involved in skill performance, and could elucidate why in Parkinsons disease voluntary movements are more affected than automatized movements.

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National Institute on Alcohol Abuse and Alcoholism
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