Norepinephrine controls the gain of the inhibitory circuit in the cerebellar input layer

Abstract

Golgi cells (GoCs) are the main inhibitory interneurons in the input layer of the cerebellar cortex and are electrically coupled together, forming syncytia. GoCs control the excitability of granule cells (GCs) through feedforward, feedback and spillovermediated inhibition. The GoC circuit therefore plays a central role in determining how sensory and motor information is transformed as it flows through the cerebellar input layer. Recent work has shown that GCs are activated when animals perform active behaviours, but the underlying mechanisms remain poorly understood. Norepinephrine (NE), also known as noradrenaline, is a powerful modulator of network function during active behavioral states and the axons of NE-releasing neurons in the locus coeruleus innervate the cerebellar cortex. Here we show that NE hyperpolarizes the GoC membrane potential, decreases spontaneous firing and reduces the gain of the spike frequency versus input-current relationship. The GoC membrane hyperpolarization can be mimicked with an α2-noradrenergic agonist, inhibited with a specific α2 antagonist and is abolished when G protein-coupled inwardly-rectifying potassium (GIRK) channels are blocked. Moreover, NE reduces the effective electrical coupling between GoCs through a persistent sodium current (INaP)-dependent mechanism. Our results suggest that NE controls the gain of the GoC inhibitory circuit by modulating membrane conductances that act to reduce membrane excitability and decrease electrical coupling. These mechanisms appear configured to reduce the level of GoC inhibition onto GCs during active behavioural states.

Multidimensional population activity in an electrically coupled inhibitory circuit in the cerebellar cortex

“…While our results provide evidence that electrical coupling between GoCs could quench independent input variability and generate the common population mode, other mechanisms could also contribute. These mechanisms include the slow neuromodulatory mechanisms that encode arousal ( Reimer et al., 2016 ), such as serotonin and norepinephrine, which depolarize and hyperpolarize GoCs, respectively ( Fleming and Hull, 2019 ; Lanore et al., 2019 ). The development of better tools for acute silencing of GJs beyond pharmacological approaches (which have non-specific effects) and improved fluorescent sensors for neuromodulators ( Sabatini and Tian, 2020 ) would enable experimental testing of these hypotheses.…”

“…Golgi cell ionic conductances were based on published models ( Solinas et al., 2007 ; Vervaeke et al., 2010 ), and active conductances were restricted to the somatic compartment ( Vervaeke et al., 2012 ). Heterogeneous populations of GoC were created by sampling from 25 sets of channel densities (5 per simulated network), each of which were optimized to have experimentally matched intrinsic firing frequencies (3-9 Hz) and slopes of firing rate-current relationships (14-25 Hz/nA) ( Lanore et al., 2019 ). GoCs were electrically coupled (except where specified) with ohmic gap junctional conductances (0.9 nS for each gap junction; Szoboszlay et al., 2016 ).…”

“…Neuron 109, 1-15, May 19, 2021 afterhyperpolarization (AHP) profiles (Figure 8B), spontaneous firing rate and firing rate-current relationships recorded from GoCs (Lanore et al, 2019). A total of 115 model GoCs were randomly placed within a 500 3 500 3 100 mm volume and connected via multiple linear GJ conductances, such that the coupling coefficient and connection probability between pairs of GoCs decayed with space constants of 70 and 40 mm, respectively, as measured in paired whole-cell recordings (Vervaeke et al, 2010).…”

Accounting for uncertainty: inhibition for neural inference in the cerebellum

“…From cerebellar nuclei instead, excitatory neurons give rise to MF collaterals innervating glomeruli [79], and inhibitory neurons selectively contact Golgi cells through long-range axons [80]. Moreover, Golgi cells are also sensitive to a variety of neuromodulators including serotonin [81] and noradrenaline [82], which exert opposing actions upon granular layer excitability. Clearly, these sources of input exert very different effects on information processing, and their specific role is still unresolved; nevertheless, this intricate circuit highlights the importance of properly tuning inhibition in the granular layer in order to contextualize incoming information.…”

Dopaminergic regulation of vestibulo-cerebellar circuits through unipolar brush cells

“…Differences in inputs and expression patterns of neuromodulatory receptors also distinguish cerebellar regions (Cerminara et al, 2015). While it is clear that norepinephrine (NE) regulates cerebellar output, the mechanistic details of neuromodulatory effects for other amines remain poorly understood (Basile and Dunwiddie, 1984; Carey and Regehr, 2009; Lanore et al, 2019; Lippiello et al, 2015). Several previous reports posit the expression of dopamine type 1 receptor (Drd1a) within the granular layer of the cerebellum (Locke et al, 2018; Panagopoulos et al, 1993).…”