Catecholaminergic Innervation of the Lateral Nucleus of the Cerebellum Modulates Cognitive Behaviors.

The cerebellum processes neural signals related to rewarding and aversive stimuli, suggesting that the cerebellum supports non-motor functions in cognitive and emotional domains. Catecholamines are a class of neuromodulatory neurotransmitters well known for encoding such salient stimuli. Catecholaminergic modulation of classical cerebellar functions have been demonstrated. However, a role for cerebellar catecholamines in modulating cerebellar non-motor functions is unknown. Using biochemical methods in male mice, we comprehensively mapped tyrosine hydroxylase (TH)+ fibers throughout the entire cerebellum and known precerebellar nuclei. Using electrochemical (fast scan cyclic voltammetry, FSCV), and viral/genetic methods to selectively delete Th in fibers innervating the lateral cerebellar nucleus (LCN), we interrogated sources and functional roles of catecholamines innervating the LCN, which is known for its role in supporting cognition. The LCN has the most TH+ fibers in cerebellum, as well as the most change in rostro-caudal expression among the cerebellar nuclei (CN). Norepinephrine is the major catecholamine measured in LCN. Distinct catecholaminergic projections to LCN arise only from locus coeruleus (LC), and a subset of Purkinje cells (PCs) that are positive for staining of TH. LC stimulation was sufficient to produce catecholamine release in LCN. Deletion of Th in fibers innervating LCN (LCN-Th-cKO) resulted in impaired sensorimotor integration, associative fear learning, response inhibition, and working memory in LCN-Th-cKO mice. Strikingly, selective inhibition of excitatory LCN output neurons with inhibitory DREADDs led to facilitation of learning on the same working memory task impaired in LCN-Th-cKO mice. Collectively, these data demonstrate a role for LCN catecholamines in cognitive behaviors. SIGNIFICANCE STATEMENT: Here, we report on interrogating sources and functional roles of catecholamines innervating the lateral nucleus of the cerebellum (LCN). We map and quantify expression of tyrosine hydroxylase (TH), the rate limiting enzyme in catecholamine synthesis, in the entire cerebellar system, including several precerebellar nuclei. We utilized cyclic voltammetry and pharmacology to demonstrate sufficiency of LC stimulation to produce catecholamine release in LCN. We used advanced viral techniques to map and selectively knockout catecholaminergic neurotransmission to the LCN, and characterized significant cognitive deficits related to this manipulation. Finally, we show that inhibition of excitatory LCN neurons with DREADDs, designed to mimic Gi-coupled catecholamine GPCR signaling, results in facilitation of a working memory task impaired in LCN-specific TH knockout mice.