Norepinephrine (NE) signalling via alpha- and beta-adrenergic receptors (ARs) plays a vital role in physiological functions. In cardiovascular function, NE modulates ion channels on cardiac cells, and AR agonists and antagonists are used treat cardiac diseases. In the central nervous system (CNS), NE signalling influences synaptic transmission by changing the excitatory and inhibitory balance in neural circuits. AR are present at high density in the cerebellum, a brain region known to be involved in motor learning, sensorimotor integration and prediction on short time scales. Recent work in the lab has shown that somatosensory input results in a brief well timed inhibition of Purkinje (Pkj) cells in the cerebellar cortex resulting in increased firing by cerebellar nuclear cells (CbN; the output of the cerebellum), which augments whisker movement. Preliminary results show that the beta-AR agonist isoproterenol greatly increases inhibitory postsynaptic currents (IPSCs) in Pkj cells. These results raise the possibility that NE signalling can modulate synaptic inhibition in Pkj cells and thereby affect sensorimotor integration and cerebellar prediction. To test this hypothesis, we will use TH-cre mice to express channelrhodopsin in NE neurons and will optogenetically activate NE axons in the cerebellum to release endogenous NE. To observe the effects of NE signalling on intrinsic firing and synaptic transmission, we will use in vitro slice electrophysiology. We will mimic sensory input to the cerebellar cortex by stimulating parallel fibers while recording from Pkj cells as well as their sources of inhibition, the molecular layer interneurons (MLIs). To distinguish which AR receptor is involved, experiments will be done with alpha- and beta- antagonists as appropriate. Finally, to understand how NE can affect signalling in vivo, we will record from Pkj and CbN cells from awake head-fixed mice during optogenetic activation and inhibition of TH-afferents and correlate firing patterns with to whisker movement with a sensory input to the whiskers. These experiments not only will help us understand effects of NE neuromodulation on synaptic plasticity in the cerebellar circuit during sensorimotor integration but will also provide further insight into effects of cardiovascular treatments on cerebellar function, especially lipophilic AR-antagonists that cross the blood brain barrier.
|Effective start/end date||4/1/21 → 3/31/23|
- American Heart Association (829841)
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