Even while we are sleeping, the brain does not rest completely. Surprisingly, the blood flow in a sleeping brain can be greater than when it is in a wakeful state. This allows the brain to remove waste metabolites, which is important to prevent the development and progression of neurological dysfunctions such as dementia. However, the exact mechanism of how the sleeping brain increases blood flow has not been known.

Researchers led by director Seong-Gi Kim, PhD, of the Center for Neuroscience Imaging Research within the Institute for Basic Science, South Korea, recently discovered the secrets behind this phenomenon. The study is published in the Proceedings of the National Academy of Sciences.

It was discovered that a type of inhibitory neuron called parvalbumin neuron secretes material called “substance P” that is responsible for vasodilation and control of blood flow to the brain.

Role of parvalbumin neuron activity in the awake and anesthetized brain. When the inhibitory parvalbumin neuron is activated in the awake brain, excitatory neurons are inhibited and vasoconstriction is observed (left). In the anesthetized brain, substance P is secreted by the parvalbumin neurons, which activates nitric oxide synthase neurons and causes slow vasodilation (right). Optical imaging was used to measure total hemoglobin, which is used to infer the level of blood flow.
Photo credit: Institute for Basic Science

Unlike other inhibitory subtype neurons, it was previously thought that GABAergic parvalbumin neurons do not release vasoactive substances, hence their role in blood flow regulation has been controversial. To investigate the role of parvalbumin neurons on blood flow regulation, the researchers expressed an opsin protein called channelrhodopsin-2 in mouse parvalbumin neurons and selectively activated parvalbumin neurons by light stimulation. 

Vascular responses to the activation of parvalbumin neurons were measured by wide-field optical imaging and functional magnetic resonance imaging. In addition, to identify the role of the parvalbumin neurons on blood flow under anesthesia, the researchers used ketamine/xylazine to put the animals to sleep.

The results showed that in lightly anesthetized animals, stimulation of parvalbumin neurons induced vasoconstriction and a decline in blood flow. This was followed by a slow vasodilation and an increase in blood flow from 20 seconds up to a minute after cessation of stimulation. On the other hand, in active animals, the parvalbumin neuron activity only resulted in a reduction of blood flow. This means that the parvalbumin neurons have two different mechanisms for the control of cerebral blood flow, depending on whether the brain is awake or asleep.

Furthermore, the researchers also discovered the mechanism behind the observed slow vasodilation after optogenetic stimulation. When the parvalbumin neurons are activated, it inhibits the nearby excitatory neurons, which causes vasoconstriction and reduced blood flow. At the same time, it was found that these parvalbumin neurons release a peptide called substance P, which is responsible for the observed slow vasodilation. Substance P activates cells called nitric oxide synthase GABAergic neurons secreting nitrous oxide, a known vasodilator.

The present research finally unveiled the factors that control blood flow to the brain during sleep and the previously unknown role of parvalbumin neurons in this process. “Our research suggested a new direction of research on cerebral blood flow control mechanisms, with possible implications in insomnia and sleep disorder treatment,” says Kim in a press release.

Photo 16415942 © Boazyiftach | Dreamstime.com