Tag Archives: #rhythms

How Behavioral Rhythms Are Fine-tuned in the Brain? (Neuroscience)

Researchers led by a team at Kanazawa University report that vasopressin neurons in the brain’s circadian rhythm control center are critical for regulating the timing of output from the molecular clock of the center, and thus circadian behaviors

Our bodies and behaviors often seem to have rhythms of their own. Why do we go to the bathroom at the same time every day? Why do we feel off if we can’t go to sleep at the right time? Circadian rhythms are a behind-the-scenes force that shape many of our behaviors and our health. Michihiro Mieda and his team at Kanazawa University in Japan are researching how the brain’s circadian rhythm control center regulates behavior.

Termed the superchiasmatic nucleus, or SCN, the control center contains many types of neurons that transmit signals using the molecule GABA, but little is known about how each type contributes to our bodily rhythms. In their newest study, the researchers focused on GABA neurons that produce arginine vasopressin, a hormone that regulates kidney function and blood pressure in the body, and which the team recently showed is also involved in regulating the period of rhythms produced by the SCN in the brain.

To examine the function of these neurons, and only these neurons, the researchers first created mice in which a gene needed for GABA signaling between neurons was deleted only in vasopressin-producing SCN neurons. “We removed a gene that codes for a protein that allows GABA to be packaged before it is sent to other neurons,” explains Mieda. “Without packaging, none of the vasopressin neurons could send out any GABA signals.”

This means that these neurons could no longer communicate with the rest of the rhythm control center using GABA. On the surface, the results were simple. The mice showed longer periods of activity, beginning activity earlier and ending activity later than control mice. So, lack of the packaging gene in the neurons disrupted the molecular clock signal, right? In fact, the reality was not so simple. Closer examination showed that the molecular clock progresses correctly. So, what was happening?

The researchers used calcium imaging to examine the clock rhythms within the vasopressin neurons. They found that while the rhythm of activity matched the timing of behavior in control mice, this relationship was disturbed in the mice whose GABA transmission from the vasopressin neurons was missing. In contrast, the rhythm of SCN output, i.e. SCN neuronal electrical activity, in the modified mice had the same irregular rhythm as their behavior. “Our study shows that GABA signaling from vasopressin neurons in the suprachiasmatic nucleus help fix behavioral timing within the constraints of the molecular clock,” says Mieda.

Featured image: A schema summarizing the effects caused by the deficiency of GABAergic transmission from vasopressin neurons on circadian rhythms at multiple levels. Without GABA release from vasopressin neurons, the spatiotemporal pattern of GABAergic transmission alters within the SCN. Such an alteration does not significantly disturb the spatiotemporal organization of molecular clocks measured with clock gene expression and intracellular calcium, but it does cause an aberrant bimodal pattern of the SCN firing (electrical activity) rhythm that may lead to the increased interval between the morning and evening locomotor activities. Thus, GABAergic transmission of vasopressin neurons regulates the SCN neuronal activity rhythm to modulate the time at which SCN molecular clocks enable circadian behavior. © Kanazawa University

Reference: Takashi Maejima, Yusuke Tsuno, Shota Miyazaki, Yousuke Tsuneoka, Emi Hasegawa, Md Tarikul Islam, Ryosuke Enoki, Takahiro J. Nakamura, Michihiro Mieda, “GABA from vasopressin neurons regulates the time at which suprachiasmatic nucleus molecular clocks enable circadian behavior”, PNAS February 9, 2021 118 (6) e2010168118; https://doi.org/10.1073/pnas.2010168118

Provided by Kanazawa University

Anesthesia Doesn’t Simply Turn Off the Brain, It Changes its Rhythms (Neuroscience)

Simultaneous measurement of neural rhythms and spikes across five brain areas in animals reveals how propofol induces unconsciousness

In a uniquely deep and detailed look at how the commonly used anesthetic propofol causes unconsciousness, a collaboration of labs at The Picower Institute for Learning and Memory at MIT shows that as the drug takes hold in the brain, a wide swath of regions become coordinated by very slow rhythms that maintain a commensurately languid pace of neural activity. Electrically stimulating a deeper region, the thalamus, restores synchrony of the brain’s normal higher frequency rhythms and activity levels, waking the brain back up and restoring arousal.

“There’s a folk psychology or tacit assumption that what anesthesia does is simply ‘turn off’ the brain,” said Earl Miller, Picower Professor of Neuroscience and co-senior author of the study in eLife. “What we show is that propofol dramatically changes and controls the dynamics of the brain’s rhythms.”

Conscious functions, such as perception and cognition, depend on coordinated brain communication, in particular between the thalamus and the brain’s surface regions, or cortex, in a variety of frequency bands ranging from 4 to 100 Hz. Propofol, the study shows, seems to bring coordination among the thalamus and cortical regions down to frequencies around just 1 Hz.

Miller’s lab, led by postdoc Andre Bastos and former graduate student Jacob Donoghue, collaborated with that of co-senior author Emery N. Brown, who is Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience and an anesthesiologist at Massachusetts General Hospital. The collaboration therefore powerfully unified the Miller lab’s expertise on how neural rhythms coordinate the cortex to produce conscious brain function with the Brown lab’s expertise in the neuroscience of anesthesia and statistical analysis of neural signals.

Brown said studies that show how anesthetics change brain rhythms can directly improve patient safety because these rhythms are readily visible on the EEG in the operating room. The study’s main finding of a signature of very slow rhythms across the cortex offers a model for directly measuring when subjects have entered unconsciousness after propofol administration, how deeply they are being maintained in that state, and how quickly they may wake up once propofol dosing ends.

“Anesthesiologists can use this as a way to better take care of patients,” Brown said.

Data from the research shows strong increases in synchrony only in very slow frequencies (deep red color) between the thalamus and four cortical regions. © Picower Institute

Brown has long studied how brain rhythms are affected in humans under general anesthesia by making and analyzing measurements of rhythms using scalp EEG electrodes and to a limited extent, cortical electrodes in epilepsy patients. Because the new study was conducted in animal models of those dynamics, the team was able to implant electrodes that could directly measure the activity or “spiking” of many individual neurons and rhythms in the cortex and thalamus. Brown said the results therefore significantly deepen and extend his findings in people.

For instance, the same neurons that they measured chattering away with spikes of voltage 7-10 times a second during wakefulness routinely fired only once a second or less  during propofol-induced unconsciousnesss, a notable slowing called a “down state.” In all, the scientists made detailed simultaneous measurements of rhythms and spikes in five regions: two in the front of the cortex, two toward the back, and the thalamus.

“What’s so compelling is we are getting data down to the level of spikes,” Brown said. “The slow oscillations modulate the spiking activity across large parts of the cortex.”

As much as the study explains how propofol generates unconsciousness, it also helps to explain the unified experience of consciousness, Miller said.

“All the cortex has to be on the same page to produce consciousness,” Miller said. “One theory about how this works is through thalamo-cortical loops that allow the cortex to synchronize. Propofol may be breaking the normal operation of those loops by hyper synchronizing them in prolonged down states. It disrupts the ability of the cortex to communicate.”

For instance, by making measurements in distinct layers of the cortex, the team found that higher frequency “gamma” rhythms, which are normally associated with new sensory information like sights and sounds, were especially reduced in superficial layers. Lower frequency “alpha” and “beta” waves, which Miller has shown tend to regulate the processing of the information carried by gamma rhythms, were especially reduced in deeper layers.

In addition to the prevailing synchrony at very slow frequencies, the team noted other signatures of unconsciousness in the data. As Brown and others have observed in humans before, alpha and beta rhythm power was notably higher in posterior regions of the cortex during wakefulness, but after loss of consciousness power at those rhythms flipped to being much higher in anterior regions.

The team further showed that stimulating the thalamus with a high frequency pulse of current (180Hz) undid propofol’s effects.

“Stimulation produced an awake-like cortical state by increasing spiking rates and decreasing slow-frequency power,” the authors wrote in the study. “In all areas, there was a significant increase in spiking during the stimulation interval compared to pre-stimulation baseline.”

In addition to Miller, Brown, Bastos and Donoghue, the paper’s other authors are  Scott Brincat, Meredith Mahnke, Jorge Yanar, Josefina Correa, Ayan Waite, Mikael Lundqvist, and Jefferson Roy.

The National Institutes of Health and the JPB Foundation provided funding for the study.

Reference: André M Bastos et al., “Neural effects of propofol-induced unconsciousness and its reversal using thalamic stimulation”, Neuroscience, 2021. DOI: 10.7554/eLife.60824

Provided by Picower Institute