Balancing the brain’s energy supply: neurovascular coupling in the cortex and hippocampus
Dr Kira Shaw, University of Sussex
Neurovascular coupling has been predominantly studied in primary sensory cortices, where neuronal activation leads to increased cerebral blood flow and a large influx of oxygenated blood. However, neural activity may be less well-coupled to increased blood flow in other brain areas. For example, local field potentials are highly correlated with fMRI/BOLD signals in sensory cortex, but not in the hippocampus (Ekstrom, 2010), suggesting neurovascular coupling may differ between sensory cortex and hippocampus. To investigate this directly, Dr Hall and her team used 2-photon imaging to record fluctuations in neuronal activity and microvascular diameter in primary visual cortex (V1) and the hippocampus of awake, behaving mice, as well as combined laser doppler flowmetry and haemoglobin spectroscopy to record baseline and stimulus-induced alterations in macroscopic haemodynamics. Compared to V1, the hippocampus had lower resting blood flow and blood oxygen saturation, despite similar rates of oxygen consumption. Furthermore, individual blood vessels dilated significantly less frequently and to a smaller extent in the hippocampus compared to V1, despite equivalent-sized calcium responses. Finally, increases in regional oxygen consumption led to smaller macroscopic increases in blood flow in the hippocampus compared to V1. These data suggest that not only is the hippocampus under-supplied with oxygen compared to primary sensory cortex at rest, but it is also less able to increase local blood flow in response to increased neuronal activity. These deficits in neurovascular coupling could contribute to the vulnerability of the hippocampus to hypoxia by reducing the ability of hippocampal neurons to match energy supply with demand.
Building a mathematical model of brain energy metabolism
Professor Renaud Jolivet, University of Geneva and CERN, Switzerland
The brain consumes an inordinate amount of energy with respect to its weight. Understanding brain energy metabolism is crucial as numerous studies point to a metabolic component in various neurodegenerative disorders and because energetic considerations might have played an important role during evolution, constraining behaviour and providing a powerful explanation of certain cellular features as trade-offs between performance in information processing and energy savings. Professor Jolivet will briefly discuss these points before describing how to design models of brain energy metabolism and neurovascular coupling, the importance of calibration due to the multicellular complexity of the brain and algorithmic tools to analyse the behaviour of such models. The brain consumes an inordinate amount of energy with respect to its weight. Understanding brain energy metabolism is crucial as numerous studies point to a metabolic component in various neurodegenerative disorders and because energetic considerations might have played an important role during evolution, constraining behaviour and providing a powerful explanation of certain cellular features as trade-offs between performance in information processing and energy savings. Professor Jolivet will briefly discuss these points before describing how to design models of brain energy metabolism and neurovascular coupling, the importance of calibration due to the multicellular complexity of the brain and algorithmic tools to analyse the behaviour of such models.
Neuronal activity and neuroenergetics with and without CBF
Dr Anna Devor, University of California, San Diego, USA
Neurons in the brain rely on blood vessels for supply of oxygen and glucose. An increase in neuronal activity normally leads to vasodilation increasing cerebral blood flow (CBF), so that supply meets demand. Dilation is driven by multiple mechanisms emphasising its importance for healthy brain function. Vasoactive messengers are released by different types of neurons and possibly glia. In addition, blood vessels are endowed with an array of ion channels that propagate the signal along their walls ensuring “upstream” dilation magnifying the CBF response. But what happens to the oxygen and glucose? According to standard textbooks, brain’s energy is produced mostly by the oxidation of glucose to carbon dioxide and water. This notion is based on observations that cortical neuronal activity is lost within ~15 seconds of CBF interruption. A paradox that challenges this paradigm comes from Positron Emission Tomography studies, where glucose consumption was shown to exceed the oxygen consumption predicted by the stoichiometry of complete aerobic oxidation. Most of the brain’s grey matter energy is used to restore neuronal membrane potential that involves moving ions across against their concentration gradients. Therefore, Dr Devor and her team asked whether the ability of neurons to repolarise was lost within seconds of CBF interruption. Cortical neurons in the mouse brain, when repeatedly depolarised via light-controlled ion channels, continued to restore their membrane potential for over 20 minutes after a cardiac arrest. This observation suggests that neurons can utilise oxygen-independent mechanisms such as glycolysis, possibly not only upon asphyxia but also under normal physiological conditions.
The neurovascular unit in health and disease: lessons from animal models
Professor Costantino Iadecola, Weill Cornell Medicine, USA
The concept of neurovascular unit (NVU) emerged from the first Stroke Progress Review Group meeting of the National Institutes of Health in the year 2000, to highlight the close developmental, structural and functional interactions between neurons, glia and the cerebral vasculature.The NVU concept emphasised the symbiotic relationship between brain cells and cerebral blood vessels in health and disease. Over the past 18 years, the NVU construct has evolved considerably. In addition to astrocytes, neurons, smooth muscle cells, and endothelium, new cell types have emerged as critical components of the NVU, such as pericytes and perivascular macrophages, etc. The extracellular matrix, matrix proteases and basement membranes (matrisome) constitute an integral part of the NVU. The NVU has also emerged as a guardian of innate and adaptive immune homeostasis and as a key regulator of the trafficking of immune cells in and out of the brain. New trophic interactions have been discovered between vascular cells and brain cells (neurons, astrocytes and oligodendrocytes), which are essential for brain survival and repair. Furthermore, the NVU is involved in the clearance of unwanted molecules from the brain and in proteostasis through the blood–brain barrier (transvascular pathway) or the perivascular space (peri- and para-vascular pathways). These critical functions of the NVU are impaired by vascular risk factors, eg, hypertension, by ageing and by pathological changes associated with Alzheimer’s disease. Consequently the NVU has taken centerstage in a wide variety of brain diseases, but particularly in conditions associated with cognitive impairment. This presentation will provide a brief overview of the structure and function of the NVU and of its critical role in brain function and cognitive health.