Inhibiting Ca channels in Alzheimer's disease model mice relaxes pericytes, improves cerebral blood flow and reduces immune cell stalling and hypoxia.

Early in Alzheimer's disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of pericytes.

Glia in Neurodegenerative Disease.

It is becoming increasingly clear that the dominant, century-old neurocentric view of neurodegeneration is insufficient to explain why certain neurons degenerate, in particular with aging. Genetic studies in patient populations as well as mechanistic and functional studies in animal models altogether implicate nonneuronal cells, especially glia, to play more than bystander roles in neurodegeneration. Throughout the life span, neuronal function and homeostasis are modulated by glia, the functions of which become even more critical with aging.

Developmental shaping of node of Ranvier geometry contributes to spike timing maturation in primary auditory afferents.

Sound is encoded by action potentials in spiral ganglion neurons (SGNs), the auditory afferents from the cochlea. Rapid action potential transmission along SGNs is crucial for quick reactions to sounds, and binaural differences in action potential arrival time at the SGN output synapses enable sound localization based on interaural time or phase differences. SGN myelination increases conduction speed but other cellular changes may contribute.

Pericytes in the brain and heart: functional roles and response to ischemia and reperfusion.

In the last 20 years there has been a revolution in our understanding of how blood flow is regulated in many tissues. Whereas it used to be thought that essentially all blood flow control occurred at the arteriole level, it is now recognised that control of capillary blood flow by contractile pericytes plays a key role both in regulating blood flow physiologically and in reducing it in clinically-relevant pathological conditions. In this article we compare and contrast how brain and cardiac pericytes regulate cerebral and coronary blood flow, focusing mainly on the pathological events of cerebral and cardiac ischemia.

Amyloid plaques and normal ageing have differential effects on microglial Ca activity in the mouse brain.

In microglia, changes in intracellular calcium concentration ([Ca]) may regulate process motility, inflammasome activation, and phagocytosis. However, while neurons and astrocytes exhibit frequent spontaneous Ca activity, microglial Ca signals are much rarer and poorly understood. Here, we studied [Ca] changes of microglia in acute brain slices using Fluo-4-loaded cells and mice expressing GCaMP5g in microglia.

Heart failure causes sleepless nights.

Cardiac dysfunction triggers immune-mediated loss of pineal gland melatonin release.

A tight squeeze: how do we make sense of small changes in microvascular diameter?

The brain is an energetically demanding tissue which, to function adequately, requires constant fine tuning of its supporting blood flow, and hence energy supply. Whilst blood flow was traditionally believed to be regulated only by vascular smooth muscle cells on arteries and arterioles supplying the brain, recent work has suggested a critical role for capillary pericytes, which are also contractile. This concept has evoked some controversy, especially over the relative contributions of arterioles and capillaries to the control of cerebral blood flow.

Noradrenaline released from locus coeruleus axons contracts cerebral capillary pericytes via adrenergic receptors.

Noradrenaline (NA) release from locus coeruleus axons generates vascular contractile tone in arteriolar smooth muscle and contractile capillary pericytes. This tone allows neuronal activity to evoke vasodilation that increases local cerebral blood flow (CBF). Much of the vascular resistance within the brain is located in capillaries and locus coeruleus axons have NA release sites closer to pericytes than to arterioles.

SARS-CoV-2 triggers pericyte-mediated cerebral capillary constriction.

The SARS-CoV-2 receptor, ACE2, is found on pericytes, contractile cells enwrapping capillaries that regulate brain, heart and kidney blood flow. ACE2 converts vasoconstricting angiotensin II into vasodilating angiotensin-(1-7). In brain slices from hamster, which has an ACE2 sequence similar to human ACE2, angiotensin II evoked a small pericyte-mediated capillary constriction via AT1 receptors, but evoked a large constriction when the SARS-CoV-2 receptor binding domain (RBD, original Wuhan variant) was present.

Hyperoxia evokes pericyte-mediated capillary constriction.

Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF.

Neuronal energy use and brain evolution.

Consider how advantageous it might be to have eyes on our hands, rather than on our faces: depth perception would be improved by the greater distance between the eyes, and it would be easy to look into relatively inaccessible spaces by appropriate movement of the hands. The absence of mammals that use this visual strategy draws attention to constraints on how evolution is able to 'design' the nervous system. Energy use in particular, in this case the large amount of energy that would be needed to send visual information along the ∼10 optic nerve axons over the length of the arms to the brain (instead of along the much shorter optic nerve), imposes significant design constraints on the nervous system.

Immune-vascular mural cell interactions: consequences for immune cell trafficking, cerebral blood flow, and the blood-brain barrier.

Brain barriers are crucial sites for cerebral energy supply, waste removal, immune cell migration, and solute exchange, all of which maintain an appropriate environment for neuronal activity. At the capillary level, where the largest area of brain-vascular interface occurs, pericytes adjust cerebral blood flow (CBF) by regulating capillary diameter and maintain the blood-brain barrier (BBB) by suppressing endothelial cell (EC) transcytosis and inducing tight junction expression between ECs. Pericytes also limit the infiltration of circulating leukocytes into the brain where resident microglia confine brain injury and provide the first line of defence against invading pathogens.

The non-adrenergic imidazoline-1 receptor protein nischarin is a key regulator of astrocyte glutamate uptake.

Astrocytic GLT-1 is the main glutamate transporter involved in glutamate buffering in the brain, pivotal for glutamate removal at excitatory synapses to terminate neurotransmission and for preventing excitotoxicity. We show here that the surface expression and function of GLT-1 can be rapidly modulated through the interaction of its N-terminus with the nonadrenergic imidazoline-1 receptor protein, Nischarin. The phox domain of Nischarin is critical for interaction and internalization of surface GLT-1.

The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia.

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activated chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels.

Pericyte-mediated constriction of renal capillaries evokes no-reflow and kidney injury following ischaemia.

Acute kidney injury is common, with ~13 million cases and 1.7 million deaths/year worldwide. A major cause is renal ischaemia, typically following cardiac surgery, renal transplant or severe haemorrhage.

The Effect of Hyperoxemia on Neurological Outcomes of Adult Patients: A Systematic Review and Meta-Analysis.

Hyperoxemia commonly occurs in clinical practice and is often left untreated. Many studies have shown increased mortality in patients with hyperoxemia, but data on neurological outcome in these patients are conflicting, despite worsened neurological outcome found in preclinical studies. To investigate the association between hyperoxemia and neurological outcome in adult patients, we performed a systematic review and meta-analysis of observational studies.

Astrocyte Ca-evoked ATP release regulates myelinated axon excitability and conduction speed.

In the brain’s gray matter, astrocytes regulate synapse properties, but their role is unclear for the white matter, where myelinated axons rapidly transmit information between gray matter areas. We found that in rodents, neuronal activity raised the intracellular calcium concentration ([Ca]) in astrocyte processes located near action potential–generating sites in the axon initial segment (AIS) and nodes of Ranvier of myelinated axons. This released adenosine triphosphate, which was converted extracellularly to adenosine and thus, through A receptors, activated HCN2-containing cation channels that regulate two aspects of myelinated axon function: excitability of the AIS and speed of action potential propagation.

Monitoring phagocytic uptake of amyloid β into glial cell lysosomes in real time.

Phagocytosis by glial cells is essential to regulate brain function during health and disease. Therapies for Alzheimer's disease (AD) have primarily focused on targeting antibodies to amyloid β (Aβ) or inhibitng enzymes that make it, and while removal of Aβ by phagocytosis is protective early in AD it remains poorly understood. Impaired phagocytic function of glial cells during later stages of AD likely contributes to worsened disease outcome, but the underlying mechanisms of how this occurs remain unknown.

Diverse mechanisms regulating brain energy supply at the capillary level.

Neural information processing depends critically on the brain's energy supply, which is provided in the form of glucose and oxygen in the blood. Regulation of this supply occurs by smooth muscle and contractile pericytes adjusting the diameter of arterioles and capillaries, respectively. Controversies exist over the relative importance of capillary and arteriolar level control, whether enzymatically generated signals or K ions are the dominant controller of cerebral blood flow, and the involvement of capillary endothelial cells.