Efeitos da estimulação encefálica profunda do estriado e do núcleo subtalâmico sobre o desempenho de ratos em tarefas de flexibilidade comportamental

Abstract

Behavioral flexibility, the ability to modify behavior in response to changes in environmental contingencies, may be impaired in conditions such as obsessive-compulsive disorder and depression. In refractory cases, deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) and of the subthalamic nucleus (STN) has been used as a therapeutic alternative, but its effects on flexibility and the neural circuits involved remain poorly understood. Given that flexibility involves distinct processes, this work investigated whether the effects of DBS generalize across different forms of adaptation or depend on the stimulated target and on behavioral demands. First, two systematic reviews identified patterns and gaps in the preclinical literature on striatal (73 studies) and STN (29 studies) neuromodulation in rodents, indicating that the effects depend on the target, the animal model, the task, and the parameters used, with a predominance of studies in males. In the experimental stage, bilateral DBS (bipolar electrodes; 130 Hz, 50 μs, 300 μA) was evaluated in three operant tasks standardized in this work. In reversal learning, which assesses the updating of contingencies, the medial striatum, the ventral striatum, and the STN were stimulated; in set-shifting, which assesses the replacement of learned rules, the medial striatum and the STN; and in the two-armed spatial restless Bandit, which assesses feedback-guided choices under uncertainty, the medial striatum. In the first two tasks, male Wistar rats received DBS or sham stimulation for 1 h before and during testing; in the Bandit, Long-Evans rats of both sexes were evaluated in a within-subject design, without stimulation and under continuous or pseudorandom stimulation, only during testing. In reversal learning, ventral striatal DBS favored slower and more accurate responses after the contingency change, whereas medial striatal and STN DBS produced no consistent changes. In set-shifting, medial striatal DBS reduced reaction time and omissions without altering accuracy, replicating previous findings, whereas STN DBS increased reaction time. In the Bandit, medial striatal DBS reduced accuracy and altered the use of feedback without changing the proportion of exploration; only continuous stimulation reduced above-chance reward, whereas pseudorandom stimulation increased reaction time. In sum, the effects of DBS were specific to the target, the stimulation pattern, and the task, with no indication of a general improvement in behavioral flexibility. The replication of the set-shifting effect supports the use of medial striatal stimulation as a preclinical model of the modulation of cognitive control by VC/VS DBS.