Role of M4 -receptor cholinergic signaling in direct pathway striatal projection neurons during dopamine depletion.

Direct pathway striatal projection neurons (dSPNs) are characterized by the expression of dopamine (DA) class 1 receptors (D1 R), as well as cholinergic muscarinic M1 and M4 receptors (M1 R, M4 R). D1 R enhances neuronal firing through phosphorylation of voltage-gate calcium channels (CaV 1 Ca2+ channels) activating Gs proteins and protein kinase A (PKA). Concurrently, PKA suppresses phosphatase PP-1 through DARPP-32, thus extending this facilitatory modulation. M1 R also influences Ca2+ channels in SPNs through Gq proteins and protein kinase C. However, the signaling mechanisms of M4 R in dSPNs are less understood. Two pathways are attributed to M4 R: an inhibitory one through Gi/o proteins, and a facilitatory one via the cyclin Cdk5. Our study reveals that a previously observed facilitatory modulation via CaV 1 Ca2+ channels is linked to the Cdk5 pathway in dSPNs. This result could be significant in treating parkinsonism. Therefore, we questioned whether this effect persists post DA-depletion in experimental parkinsonism. Our findings indicate that in such conditions, M4 R activation leads to a decrease in Ca2+ current and an increased M4 R protein level, contrasting with the control response. Nevertheless, parkinsonian and control actions are inhibited by the Cdk5 inhibitor roscovitine, suggesting Cdk5's role in both conditions. Cdk5 may activate PP-1 via PKA inhibition in DA depletion. Indeed, we found that inhibiting PP-1 restores control M4 R actions, implying that PP-1 is overly active via M4 Rs in DA-depleted condition. These insights contribute to understanding how DA-depletion alters modulatory signaling in striatal neurons. Additional working hypotheses are discussed.

Effects of Varying Approaches to Lifting COVID-19 Pandemic Restrictions in the United States

BackgroundPolicy approaches to lifting COVID-19 restrictions have varied significantly across the United States. An evaluation of the effects of state reopening policies on population health outcomes can inform ongoing and future pandemic responses. This study evaluates the approaches to lifting social distancing restrictions based on adherence to the Centers for Disease Control and Prevention (CDC) guidance established during the first wave of the COVID-19 pandemic. MethodsWe performed a retrospective study using difference-in-differences analyses to examine the effects of reopening policies on COVID-19 outcomes with risk-adjustment for population density, temporal changes, and concurrent mask policy implementation. We examined the effects of reopening policies on per capita case rates and rates of severe COVID-19 outcomes, including hospitalizations and deaths. ResultsAdherence to the CDCs reopening gating metrics and phased social distancing guidelines resulted in fewer COVID-19 cases, hospitalizations, and deaths. Phase one adherent states exhibited a 50-fold reduction in daily new cases and a 3-fold reduction in daily new deaths after reopening. Phase two adherent states experienced improvements in COVID-19 outcomes after reopening, while non-adherent states had a resurgence of worsening outcomes after lifting restrictions. ConclusionsOur study findings indicate that adherence to the CDCs reopening guidance after implementing social distancing restrictions during the COVID-19 pandemic substantially prevents new cases, hospitalizations, and deaths. Following a stepwise reopening strategy and ensuring a sustained decline in case rates and test positivity rates before lifting restrictions can mitigate on a large scale the negative effects of a pandemic on population health outcomes.