Influência do cerebelo no processamento de funções não-motoras - revisão da literatura e estudo experimental

Abstract

The cerebellum is a structure widely recognized for its role in motor functions, such as movement control, motor learning, and balance. However, its participation in non-motor processes, such as emotions and cognitive functions, has been increasingly attracting interest. The functional network and connectivity of the cerebellum remain open areas of study, and both clinical and preclinical research have been dedicated to identifying these connections to gain a better understanding of cerebellar neurophysiology and its influence on other brain regions in various functions. STUDY 1 - OBJECTIVE: This study aimed to identify and synthesize the evidence in the literature regarding the activation and connectivity of the cerebellum with other brain structures involved in processing various functions. METHODS: A comprehensive literature search was conducted in the PubMed and Google Scholar databases using different search terms to identify clinical and preclinical studies related to cerebellar involvement in different functions, including sensory, motor, autonomic, cognitive, and emotional functions. The retrieved studies were summarized and presented in topics corresponding to the respective functions. RESULTS: It was demonstrated that regions of the anterior lobe of the cerebellum are more involved in motor control, proprioceptive and graviceptive signal integration, and reward anticipation. On the other hand, regions of the posterior lobe, including the cerebellar hemispheres, are more involved in processing eye movements, cognition, emotions, and auditory functions. It was also observed that similar cerebellar regions are activated in different functions, leading to the understanding that the same cerebellar region may simultaneously contribute to processing multiple functions. We hypothesize that microzones specialized in different functions may co-activate to support multimodal behaviors. CONCLUSION: The anterior cerebellar lobe plays a greater role in sensory-motor processing, whereas the posterior lobe is more involved in cognitive and emotional functions. Additionally, some cerebellar regions, such as lobules VI and VII, seem to act as integrative areas, as they are frequently described as participating in most of the investigated functions. STUDY 2 - OBJECTIVE: This study aimed to identify in the literature the main cerebellar activation regions in nociception and pain processing, as well as their connections with other nervous system regions involved in this process. METHODS: Searches were conducted in the PubMed and Google Scholar databases using specific search terms related to the study’s theme to obtain a comprehensive overview of factors associated with pain processing. Clinical and preclinical studies addressing the topic were selected. Cerebellar activation in response to nociceptive stimuli, the location of cerebellar activation, and its connections with other brain regions involved in nociception and pain processing were analyzed. RESULTS: The primary cerebellar regions involved in nociception and pain processing are lobules IV, V, VI, VII, Crus I, and Crus II. The cerebellum can communicate with brain structures involved in processing different dimensions of pain, as well as in pain modulation; however, studies investigating this hypothesis are still lacking. Research shows that cerebellar modulation reduces pain intensity by increasing the pain threshold and enhancing endogenous pain inhibition processes. CONCLUSION: The cerebellum may be involved in the multidimensional processing of pain and exert influence on pain modulation through its extensive connections with brain structures engaged in these processes. STUDY 3 - OBJECTIVE: This study aimed to analyze neuronal activation in the cerebellum in different spatiotemporal contexts involved in emotion and emotional memory processing, as well as its connections with other brain structures in animals. METHODS: A total of 43 naïve Swiss Albino mice were used. The animals were divided into four groups: Inhibitory Avoidance, Shock, No Shock, and Control Group. For behavioral assessment, the animals were exposed to the Inhibitory Avoidance apparatus, inferring emotion and emotional memory, for 1, 4, and 8 days in different exposure contexts. After the final exposure of each group to the assessment apparatus, euthanasia was performed, followed by transcardiac perfusion with 4% paraformaldehyde and brain extraction. The brains were sectioned at 40 μm for c-Fos immunofluorescence analysis in predefined structures. Microscopic images of brain structures were captured for the analysis of immunofluorescent cells. One-way ANOVA or the Kruskal-Wallis test was applied to the immunofluorescence analysis data, followed by the appropriate post-hoc test. Spearman’s correlation coefficient was used to analyze the correlation between the coefficients of brain structures. RESULTS: There was an increase in c-Fos expression in cerebellar lobules IV-V (p = 0.01). Dunn’s multiple comparisons test showed a significant difference in c-Fos expression between the Inhibitory Avoidance-4 days group and the Control Group (p = 0.01). An increase in c-Fos expression was also observed in cerebellar lobule VI (p = 0.01). Dunn’s multiple comparisons test indicated a significant difference in c-Fos expression between the Inhibitory Avoidance-4 days and Shock-4 days groups (p = 0.01). No significant difference was found in c-Fos expression in other regions of interest. Spearman’s correlation coefficient test did not show correlations between the coefficients of the regions of interest in the Inhibitory Avoidance-4 days Group. CONCLUSION: Lobules IV-V and VI were the cerebellar regions with the highest activity in animals that performed the Inhibitory Avoidance task for four days, suggesting involvement in emotion and emotional memory. GENERAL CONCLUSION: The cerebellum is involved in the processing of various functions performed by the nervous system. Once its anatomical and functional interaction with other brain structures also involved in this processing is clarified, the cerebellum could become a therapeutic target for the treatment of painful and psychiatric conditions.