Abstract
Cannabinoids are notorious and profound modulators of behavioral state. In the brain, endocannabinoids act via Type 1-cannabinoid receptors (CB1) to modulate synaptic transmission and mediate multiple forms of synaptic plasticity. CB1 knockout (CB1KO) mice display a range of behavioral phenotypes, in particular hypoactivity and various deficits in learning and memory, including cerebellum-dependent delay eyeblink conditioning. Here we find that the apparent effects of CB1 deletion on cerebellar learning are not due to direct effects on CB1-dependent plasticity, but rather, arise as a secondary consequence of altered behavioral state. Hypoactivity of CB1KO mice accounts for their impaired eyeblink conditioning across both animals and trials. Moreover, learning in these mutants is rescued by walking on a motorized treadmill during training. Finally, cerebellar granule-cell-specific CB1KOs exhibit normal eyeblink conditioning, and both global and granule-cell-specific CB1KOs display normal cerebellum-dependent locomotor coordination and learning. These findings highlight the modulation of behavioral state as a powerful independent means through which individual genes contribute to complex behaviors.
Highlights
Signals relating to ongoing behavior are widely represented in the brain (Musall et al, 2019; Stringer et al, 2019; Powell et al, 2015)
We recently demonstrated that engaging in locomotor activity enhances delay eyeblink conditioning within the cerebellum (Albergaria et al, 2018), raising the question of whether hypoactivity could indirectly contribute to the apparent impairments of CB1 knockout (CB1KO) mice in cerebellar learning
Consistent with a previous study that found impaired learning over seven acquisition sessions (Kishimoto and Kano, 2006), we found that CB1KOs displayed delayed learning, as measured by the percentage of trials that yielded learned conditioned responses (CRs; Figure 1C)
Summary
Signals relating to ongoing behavior are widely represented in the brain (Musall et al, 2019; Stringer et al, 2019; Powell et al, 2015). Sensorimotor signals can be used to monitor and refine ongoing movements, while generalized changes in behavioral state, including arousal and levels of locomotor activity, influence sensory processing and perception (Niell and Stryker, 2010; Ayaz et al, 2013; McGinley et al, 2015; Schneider and Mooney, 2015; Vinck et al, 2015; Pakan et al, 2016). Both locomotor activity and arousal modulate delay eyeblink conditioning, a form of cerebellum-dependent associative learning (Albergaria et al, 2018). Presynaptic CB1 receptors mediate short- and long-term forms of synaptic plasticity in a wide variety of brain regions and cell types, raising the possibility that they provide a direct substrate for learning and memory (Freund et al, 2003; Mackie, 2006; Chevaleyre et al, 2006; Regehr et al, 2009)
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