Dual Regulation of Spine-Specific and Synapse-to-Nucleus Signaling by PKCδ during Plasticity.

The activity-dependent plasticity of synapses is believed to be the cellular basis of learning. These synaptic changes are mediated through the coordination of local biochemical reactions in synapses and changes in gene transcription in the nucleus to modulate neuronal circuits and behavior. The protein kinase C (PKC) family of isozymes has long been established as critical for synaptic plasticity. However, because of a lack of suitable isozyme-specific tools, the role of the novel subfamily of PKC isozymes is largely unknown. Here, through the development of fluorescence lifetime imaging-fluorescence resonance energy transfer activity sensors, we investigate novel PKC isozymes in synaptic plasticity in CA1 pyramidal neurons of mice of either sex. We find that PKCδ is activated downstream of TrkB and DAG production, and that the spatiotemporal nature of its activation depends on the plasticity stimulation. In response to single-spine plasticity, PKCδ is activated primarily in the stimulated spine and is required for local expression of plasticity. However, in response to multispine stimulation, a long-lasting and spreading activation of PKCδ scales with the number of spines stimulated and, by regulating cAMP response-element binding protein activity, couples spine plasticity to transcription in the nucleus. Thus, PKCδ plays a dual functional role in facilitating synaptic plasticity.SIGNIFICANCE STATEMENT Synaptic plasticity, or the ability to change the strength of the connections between neurons, underlies learning and memory and is critical for brain health. The protein kinase C (PKC) family is central to this process. However, understanding how these kinases work to mediate plasticity has been limited by a lack of tools to visualize and perturb their activity. Here, we introduce and use new tools to reveal a dual role for PKCδ in facilitating local synaptic plasticity and stabilizing this plasticity through spine-to-nucleus signaling to regulate transcription. This work provides new tools to overcome limitations in studying isozyme-specific PKC function and provides insight into molecular mechanisms of synaptic plasticity.

A single-center, nonblinded, clinical trial comparing blood pressures before and after tourniquet application in healthy humans: A study protocol.

INTRODUCTION: Cardiac arrest is the leading cause of natural death in the United States, and most surviving patients suffer from neurological dysfunction. Although this is recognized as a problem, there have been very few changes to the cardiopulmonary resuscitation (CPR) procedure. Tourniquets have been recognized for their ability to increase truncal blood pressure and have been shown to improve CPR outcomes in animal models. However, the relationship between tourniquet application and blood pressure elevation has not been adequately explored in healthy human adults. OBJECTIVES: The objective of this study is to demonstrate that bilateral, non-invasive, peripheral vascular occlusion in the thighs results in an increased proximal systolic blood pressure ≥ 10 mmHg. METHODS: This is a single-center, non-blinded clinical trial. Volunteers will be screened for eligibility at least 24 hours before the day of the trial. On the day of the trial, volunteers will undergo an informed consent process. If they choose to participate in the trial after informed consent, their baseline blood pressure will be measured. Volunteers will then have a Combat Application Tourniquet (CAT) applied to each thigh, and the windlasses will be tightened by IRB-approved personnel. Once no pulse can be felt in the lower extremity, blood pressure will be measured in the arm. This will be replicated three times, and the tourniquets will be loosened between trials to allow the volunteers to rest. Any complications that arise during the trial will be handled by the physician that is present. ANALYSIS: Changes in systolic blood pressure and diastolic blood pressure will be analyzed using a Shapiro-Wilk test. Then, a one-way repeated measures analysis of variance (ANOVA) will be performed with a Holm-Sidak post-hoc test to determine the mean differences. The significance level will be set to 5% for statistical significance. REGISTRY AND REGISTRATION NUMBER: Clinicaltrials.gov, NCT05324306.

Peripheral Arterial Compression as a New Adjunct Technique to Cardiopulmonary Resuscitation.

The success of cardiopulmonary resuscitation (CPR) is critically dependent on the maintenance of myocardial and cerebral perfusion; therefore, preferential perfusion of these vital organs over non-vital vascular beds, such as the extremities, is desirable. We propose that compression of the femoral and/or brachial arteries during CPR improves resuscitation outcomes.