An Explicit Strategy Prevails When the Cerebellum Fails to Compute Movement Errors

In sensorimotor adaptation, explicit cognitive strategies are thought to be unnecessary because the motor system implicitly corrects performance throughout training. This seemingly automatic process involves computing an error between the planned movement and actual feedback of the movement. When explicitly provided with an effective strategy to overcome an experimentally induced visual perturbation, people are immediately successful and regain good task performance. However, as training continues, their accuracy gets worse over time. This counterintuitive result has been attributed to the independence of implicit motor processes and explicit cognitive strategies. The cerebellum has been hypothesized to be critical for the computation of the motor error signals that are necessary for implicit adaptation. We explored this hypothesis by testing patients with cerebellar degeneration on a motor learning task that puts the explicit and implicit systems in conflict. Given this, we predicted that the patients would be better than controls in maintaining an effective strategy assuming strategic and adaptive processes are functionally and neurally independent. Consistent with this prediction, the patients were easily able to implement an explicit cognitive strategy and showed minimal interference from undesirable motor adaptation throughout training. These results further reveal the critical role of the cerebellum in an implicit adaptive process based on movement errors and suggest an asymmetrical interaction of implicit and explicit processes

Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork

Lithium salt has been widely used in treatment of Bipolar Disorder, a mental disturbance associated with circadian rhythm disruptions. Lithium mildly but consistently lengthens circadian period of behavioural rhythms in multiple organisms. To systematically address the impacts of lithium on circadian pacemaking and the underlying mechanisms, we measured locomotor activity in mice in vivo following chronic lithium treatment, and also tracked clock protein dynamics (PER2::Luciferase) in vitro in lithium-treated tissue slices/cells. Lithium lengthens period of both the locomotor activity rhythms, as well as the molecular oscillations in the suprachiasmatic nucleus, lung tissues and fibroblast cells. In addition, we also identified significantly elevated PER2::LUC expression and oscillation amplitude in both central and peripheral pacemakers. Elevation of PER2::LUC by lithium was not associated with changes in protein stabilities of PER2, but instead with increased transcription of Per2 gene. Although lithium and GSK3 inhibition showed opposing effects on clock period, they acted in a similar fashion to up-regulate PER2 expression and oscillation amplitude. Collectively, our data have identified a novel amplitude-enhancing effect of lithium on the PER2 protein rhythms in the central and peripheral circadian clockwork, which may involve a GSK3-mediated signalling pathway. These findings may advance our understanding of the therapeutic actions of lithium in Bipolar Disorder or other psychiatric diseases that involve circadian rhythm disruptions

Autonomic function in mice lacking α5 neuronal nicotinic acetylcholine receptor subunit

Neuronal acetylcholine nicotinic receptors (nAChR) are composed of 12 subunits (α2-10, β2-4), of which α3, α5, α7,β2 and β4 subunits are known to exist in the autonomic nervous system (ANS). α5 subunits possess unique biophysical and pharmacological properties. The present study was undertaken to examine the functional role and pharmacological properties of the nAChR α5 subunits in the ANS using mice lacking α5 nAChR subunits (α5–/–). These mice grew to normal size showing no obvious physical or neurological deficit. They also showed normality in thermo- regulation, pupil size and resting heart rate under physiological conditions. The heart rate and rectal temperature did not differ between α5–/– and wild-type mice during exposure to cold stress. An impairment of cardiac parasympathetic ganglionic transmission was observed during high frequency vagal stimulation, which caused cardiac arrest in all wild-type animals while α5–/– mice were more resistant. Deficiency of α5 subunits strikingly increased the sensitivity to a low concentration of hexamethonium, leading to a nearly complete blockade of bradycardia in response to vagal stimulation. Such a concentration of hexamethonium only slightly depressed the effects of vagal stimulation in control mice. Deficiency of α5 subunits significantly increased ileal contractile responses to cytisine and epibatidine. These results suggest that α5 subunits may affect the affinity and sensitivity of agonists and antagonists in the native receptors. Previous studies revealed that α5 subunits form functional receptors only in combination with other α and β subunits. Thus, the data presented here imply that α5 subunits modulate the activity of nAChR in autonomic ganglia in vivo