Cannabinoids modulate associative cerebellar learning via alterations in behavioral state

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.

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

“…They utilised a similar PKG-neo recombination strategy, only replacing the coding region of the Cnr1 gene between amino acids 32 and 448. These chimeric mice were subsequently bred with C57BL/6J animals for more than 10 generations, resulting in mutants with a congenic C57BL/6J background [159][160][161][162]. Marsicano et al later generated a new CB1R-null mutant line using the Cre-lox system for site-directed recombination [163].…”

“…Despite differences in mutation techniques and genetic backgrounds, these investigations have yielded similar and congruent results (Table 10). Overall, these mutant mice exhibited increased mortality and more severe seizures [142,164], anxietylike behaviours [153,155], reduced locomotor activity [142,162], accelerated cognitive decline [159][160][161][162], and impaired memory extinction processes [163,165,166]. Interestingly, CB1R was proven to be dispensable for memory extinction in appetite-motivated learning tasks, whereas it presumably plays a crucial role in fear extinction, primarily via habituation-like processes [166].…”

Delay eyeblink conditioning performance and brain-wide c-Fos expression in male and female mice

“…Sex and strain are not the only variables that can potentially influence mice performance during delay eyeblink conditioning. This task is most commonly performed in head-fixed mice freely running on a wheel and studies have shown that locomotion speed on the wheel positively correlates with a higher percentage of CRs [ 27 , 28 ]. However, it is still unknown if locomotion strategy during delay eyeblink conditioning is sex dependent.…”

Tracking motion kinematics and tremor with intrinsic oscillatory property of instrumental mechanics

“…For example, the cerebellum engages different functions for walking when two legs in human (or two sides of limbs in mice) move in the same versus different cycling speed. [1][2][3][4] This has been the foundation of cerebellar-based motor learning and rehabilitation after cerebral insults. 3,4 Adding to the complexity, most of the movement disorders behave very differently when volitional movement is involved.…”

“…However, many motor phenomena, such as reaching movement, walking, or balancing, involved complex coordinated movement beyond the limb being studied. For example, the cerebellum engages different functions for walking when two legs in human (or two sides of limbs in mice) move in the same versus different cycling speed 1–4 . This has been the foundation of cerebellar‐based motor learning and rehabilitation after cerebral insults 3,4 .…”