Recent Advances in the Understanding of Specific Efferent Pathways Emerging From the Cerebellum

Abstract

The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.

Novel cerebello-amygdala connections provide missing link between cerebellum and limbic system

“…The BLA is not the sole nucleus in the amygdala complex that receives cerebellar signals 95 . Similarly, it is unlikely that the CM and PF are the only nuclei to serve cerebello-amygdala communication (our findings; and 96 ). Further studies are warranted to delineate the complete neuroanatomical and functional landscape of cerebello-amygdala connectivity.…”

Cerebro-Cerebellar Networks in Migraine Symptoms and Headache

“…Each group was controlled by a specific set of PCs in the vermis and IO neurons in the brainstem and sends topographically organized axonal projections to motor and non-motor areas in the brainstem, midbrain, and diencephalon. Interestingly, diencephalic thalamic projections were not limited to motor VL and VMl, but terminal labeling was also seen within other thalamic intralaminar areas, such as parafascicular (Pf), zona incerta (ZI), centrolateral (CL), and mediodorsal (MD) nuclei ( 156 , 175 ). This pattern of projection suggests actions contributing to control of motor functions (i.e., axial and proximal parts of the body and ocular motion), and regulation of autonomic and affective reactions (i.e., cardiovascular, respiratory, and emotional responses) ( 171 ).…”

“…In animals, FN and DN projections to glutamatergic, GABA, and dopamine neurons in the ventrolateral PAG are thought to participate in freezing behavior and fear memory formation ( 81 , 163 , 214 – 217 ). Similarly, cerebellar projections to the DRN, a major source of serotonin, may cooperate with the DN-VTA pathway to regulate mood-, reward-, and stress-associated behaviors, as evidenced by recovery from depressive symptoms due to increased firing of DRN serotonergic neurons in rodents ( 156 , 218 ). Lastly, DCN and Purkinje projections to the LC, the main source of NA, may participate in functions related to arousal, attention, motivation, and stress responses ( 219 – 221 ).…”

“…Purkinje projections aim at inhibiting the mostly excitatory (glutamatergic) neurons in DCN, which will, in turn, influence its extra-cerebellar targets. Inhibitory influence of DCN has also been described, in which IPN and DN neurons targeting brainstem and midbrain structures are GABAergic and glycinergic (151)(152)(153)(154)(155)(156). For example, there is GABAergic input to the IO through the nucleoolivary circuit (DCN-IO); there is another important inhibitory input to the PN (DCN-PN)-a major source of mossy fiber inputs to the cerebellum, suggesting that cerebellar inhibition of PN is a parallel regulatory feedback pathway similar to that looping through the IO (94,138,151).…”

“…For example, there is GABAergic input to the IO through the nucleoolivary circuit (DCN-IO); there is another important inhibitory input to the PN (DCN-PN)-a major source of mossy fiber inputs to the cerebellum, suggesting that cerebellar inhibition of PN is a parallel regulatory feedback pathway similar to that looping through the IO (94,138,151). Concerning cerebellar output to VN, areas of the DCN under control of the flocculonodular cerebellar PCs connect to VN for oculomotor control during voluntary eye movements, as well as for optokinetic reflex (156)(157)(158).…”