Catecholaminergic Innervation of the Lateral Nucleus of the Cerebellum Modulates Cognitive Behaviors
Open Access
- 2 February 2021
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 41 (15), 3512-3530
- https://doi.org/10.1523/JNEUROSCI.2406-20.2021
Abstract
The cerebellum processes neural signals related to rewarding and aversive stimuli, suggesting that the cerebellum supports nonmotor 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 nonmotor functions is unknown. Using biochemical methods in male mice, we comprehensively mapped TH+ fibers throughout the entire cerebellum and known precerebellar nuclei. Using electrochemical (fast scan cyclic voltammetry), 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 rostrocaudal expression among the cerebellar nuclei. Norepinephrine is the major catecholamine measured in LCN. Distinct catecholaminergic projections to LCN arise only from locus coeruleus, and a subset of Purkinje cells 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 designer receptor exclusively activated by designer drugs 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.Funding Information
- HHS | NIH | National Institute of Mental Health (R01-MH116883, K08-MH104281, R01-MH0945, R21-MH098177)
This publication has 130 references indexed in Scilit:
- Sexually Dimorphic Effects of Catechol-O-Methyltransferase (COMT) Inhibition on Dopamine Metabolism in Multiple Brain RegionsPLOS ONE, 2013
- Consensus Paper: Pathological Role of the Cerebellum in AutismThe Cerebellum, 2012
- Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC NeuronsNeuron, 2011
- The basal ganglia communicate with the cerebellumProceedings of the National Academy of Sciences of the United States of America, 2010
- A robust and high-throughput Cre reporting and characterization system for the whole mouse brainNature Neuroscience, 2009
- Neurotransmitter release during delay eyeblink classical conditioning: Role of norepinephrine in consolidation and effect of ageNeurobiology of Learning and Memory, 2009
- Noradrenergic Control of Associative Synaptic Plasticity by Selective Modulation of Instructive SignalsNeuron, 2009
- The role of the cerebellar interpositus nucleus in short and long term memory for trace eyeblink conditioning.Behavioral Neuroscience, 2009
- Fronto-limbic functioning in children and adolescents with and without autismNeuropsychologia, 2008
- Learning-related long-term potentiation of inhibitory synapses in the cerebellar cortexProceedings of the National Academy of Sciences of the United States of America, 2008