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Some inhibitory neurons always active, study suggests

Researchers observe ‘rhythmic marching of neurons’ even at rest

Even during rest, the brain is always actively balancing its cycles of activation and deactivation, a new study by University researchers suggests. A team of neuroscientists explored how multiple inhibitory cells remain active to offset excitatory cells, even when the brain is in a calm and sedated state in order to maintain balanced up and down cycles of activity, according to the study, published in this month’s issue of the Journal of Neuroscience.


The ways these up and down states are regulated also vary in different areas of the brain, according to the article.


The two-year study sought to uncover why there are so many different types of inhibitory cells in the mouse brain and what their functions are, said Barry Connors, professor of neuroscience, chair of the department and senior author on the paper. The project also aimed to determine how the alternating brain cycles correlate with behavior on a cellular level, Connors added.


“The mammalian brain can initiate and sustain its own activity,” and studying this spontaneous network activation can reveal how the cortex changes the way it routes information, said Garrett Neske GS, lead author of the article. The study focused on the barrel cortex in mice, an area associated with touch and sensation, similar to the somatosensory cortex in humans, Neske added. The mouse area is almost entirely made up of four subtypes of inhibitory cells: PV, SOM, VIP and NPY cells. Of these cells — which are also known as interneurons — the “fast-spiking PV cell was by far the most active interneuron subtype and provided the majority of activity in the up state” to counteract the excitatory pyramidal cells, Neske said.


By genetically engineering PV cells in mice to produce fluorescent protein under the microscope — a procedure known as optogenetics — Neske and his team monitored the levels of activity in these cell types over time. These network activities happened spontaneously in the slices, which were less than half a millimeter thick and were kept “alive” in a chemical solution containing essential nutrients such as glucose, sodium and potassium, which mimics the composition of the human cerebral spinal fluid, Neske said.


A comparable study conducted by Yale researchers examined the up and down brain states in a different mouse brain area: the entorhinal cortex, which is associated with reason and navigation. This “rhythmic marching of the neurons” during its up and down cycles allows the brain to regulate normal activities even when asleep, said David McCormick, professor of neurobiology and psychology at Yale and coauthor of the Yale paper.


A disturbance of this delicate balance could cause the brain to enter a seizure or a coma, he added.


The study from the Yale lab also used these “sleeping slices” of brain tissue kept in artificial cerebral spinal fluid and found that the PV cells in the entorhinal cortex were almost all inactive. These findings were contrary to those of Neske, who found that all inhibitory neurons in the barrel cortex were active. Neske replicated the Yale study and concluded that the roles of inhibitory interneurons can vary substantially in different cortical areas, Neske said.


The combined findings of the two studies not only reveal much about the role of inhibitory cells in maintaining brain activity on a spontaneous level but also call for “more comparative work among cortical areas,” Neske said.


McCormick’s lab at Yale will extend its research to examine the up and down states in the auditory cortex. Specifically, the Yale researchers intend to study the relationship between pupil dilation and cortical activity to analyze how the mouse brain processes auditory information.


Other follow-up studies could use more advanced techniques to control the interneurons for a deeper exploration of the roles different cells play in up states, Connors said. “We can shut one of the cell types off, remove them and do further study,” he added.



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