Why heat makes us sleepy

On the hottest summer days, you may find yourself dozing off in the middle of the day. In some parts of the world, it's a cultural norm to schedule "siestas" and shutter businesses during the warmest hours of the day. As it turns out, biology, not just culture, may be behind this.

Temperature affects the span of human behavior, from eating and activity levels to sleep-wake cycles. We may have a harder time sleeping in the summer and be slow to get out of bed on colder mornings. But the link between sensory neurons and neurons that control this cycle are not understood completely.

Northwestern University neurobiologists have found a few clues about what's happening. In a new study, published today (Aug. 17) in the journal Current Biology, researchers found that fruit flies are pre-programmed to take a nap in the middle of the day. A follow-up to their 2020 Biology paper that identified a brain thermometer only active in cold weather, the new paper explores a similar "thermometer" circuit for hot temperatures.

"Changes in temperature have a strong effect on behavior in both humans and animals, and offer animals a cue that is time to adapt to the changing seasons," said Marco Gallio, associate professor of neurobiology in the Weinberg College of Arts and Sciences. "The effect of temperature on sleep can be quite extreme, with some animals deciding to sleep off an entire season -- think of a hibernating bear -- but the specific brain circuits that mediate the interaction between temperature and sleep centers remain largely unmapped."

Gallio led the study and said fruit flies are a particularly good model to study big questions like "why do we sleep," and "what does sleep do for the brain" because they don't attempt to disrupt instinct in the same way humans do when we pull all-nighters, for example. They also allow researchers to study the influence of external cues like light and temperature on cellular pathways.

Cells that stay on longer

The paper is the first to identify "absolute heat" receptors in fly head, which respond to temperatures above about 77 degrees Fahrenheit -- the fly's favorite temperature. As it turns out, the common laboratory fruit fly (Drosophila) has colonized nearly the entire planet by forming a close association with humans. Not surprisingly, its favorite temperature also matches that of many humans.

Just as they expected based on the results of their previous paper on cold temperature, researchers found that brain neurons receiving information about heat are part of the broader system that regulates sleep. When the hot circuit, which runs parallel to the cold circuit, is active, the target cells that promote midday sleep stay on longer. This results in an increase in midday sleep that keeps flies away from the hottest part of the day.

The study was enabled by a 10-year initiative that produced the first completed map of neural connections in an animal (a fly), called the connectome. With the connectome, researchers have access to a computer system that tells them all possible brain connections for each of the fly's ~100,000 brain cells. However, even with this extremely detailed road map, researchers still need to figure out how information in the brain goes from point A to B. This paper helps fill that gap.

The different circuits for hot versus cold temperatures make sense to Gallio because "hot and cold temperatures can have quite different effects on physiology and behavior," he said. This separation may also reflect evolutionary processes based on heat and cold cycles of the Earth. For example, the possibility that brain centers for sleep may be directly targeted in humans by a specific sensory circuit is now open to be investigated based on this work.

Next steps

Next, Gallio's team hopes to figure out the common targets of the cold and hot circuit, to discover how each can influence sleep.

"We identified one neuron that could be a site of integration for the effects of hot and cold temperatures on sleep and activity in Drosophila," said Michael Alpert, the paper's first author and a post-doctoral researcher in the Gallio lab. "This would be the start of interesting follow-up studies."

Gallio added that the team is interested in looking at the long-term effects of temperature on behavior and physiology to understand the impact of global warming, looking at how adaptable species are to change.

"People may choose to take an afternoon nap on a hot day, and in some parts of the world this is a cultural norm, but what do you choose and what is programmed into you?" Gallio said. "Of course, it's not culture in flies, so there actually might be a very strong underlying biological mechanism that is overlooked in humans."

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Neuroscientists find multiple brain regions control speech, challenging common assumption

Neurobiologists at the University of Pittsburgh School of Medicine give new meaning to the term "motor mouth" in a study published today in the Proceedings of the National Academy of Sciences. By carefully mapping neural networks in marmoset and macaque monkeys, they determined that multiple areas in the brain's frontal lobe control the muscles of vocalization and could provide a foundation for complex speech.

The findings -- which could lead to a better understanding of speech disorders -- refute a long-existing presumption that only the primary motor cortex, nicknamed M1, directly influences the larynx or voice box, said principal investigator Peter L. Strick, Ph.D., Thomas Detre Professor and chair of neurobiology at Pitt. Instead, several cortical regions send signals to laryngeal muscles to create greater vocal finesse in some nonhuman primates.

"This kind of parallel processing in our neural wiring might explain why humans are capable of highly sophisticated language that allows us to share information, express and perceive emotion, and tell memorable stories," said Strick, who also is scientific director of Pitt's Brain Institute. "Our remarkable speech skills are due to more evolved brains, not better muscles."

Led by Christina M. Cerkevich, Ph.D., research assistant professor of neurobiology, the investigators compared in marmosets and macaques neural networks that are the origin of descending command signals to control monkey vocalizations.

"We selected these two monkey species because of the striking differences in their vocal behavior," Cerkevich explained. "Marmosets readily vocalize in ways that are akin to humans by taking turns to speak and altering the volume, timing and pitch of their calls to each other. Macaques, on the other hand, make mostly simple, spontaneous calls."

The researchers injected a transneuronal tracer made from rabies virus into the cricothyroid muscle of the monkeys' larynxes. The tracer infects nerve cells and has the unique property of moving from one neuron to another only at synapses, which are the special sites where neurons interact with each other. This makes it possible to track neuronal circuits from the muscle back to the areas of the cerebral cortex that control it.

In addition to M1, both kinds of monkeys had multiple premotor areas in the frontal lobe that send descending command signals to the cricothyroid muscle. But two of the premotor areas provided a substantially larger source of descending output in marmosets, leading the researchers to propose that the enhanced vocal motor skills of marmosets are due, in part, to the expansion of neural signaling from these premotor areas.

"This result challenges the long-held view that improvements in motor skills of vocalization are due largely to changes in the output from M1, the primary motor cortex," Strick said. "It appears there is no single control center, but rather parallel processing sites that enable complex vocalization and, ultimately, speech."

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How long-known genes continue to surprise researchers

Alternative splicing can lead to the formation of numerous protein variants. For the first time, alternative splicing has now been systematically analysed for the family of glutamate receptors.

Proteins are encoded by genes -- however, this information is divided into small coding sections, which are only assembled during a process called splicing. Various combinations are possible, some of which are still unknown. Dr. Robin Herbrechter and Professor Andreas Reiner from the junior research group Cellular Neurobiology at Ruhr-Universität Bochum (RUB) now systematically analysed alternative splicing in the family of ionotropic glutamate receptors (iGluRs), which is essential for signal processing in the brain. These findings were published in the journal Cellular and Molecular Life Sciences on 8 June 2021.

Huge splicing diversity in the brain

The human genome was sequenced around 20 years ago. Since then, the sequence information encoding our proteins is known -- at least in principle. However, this information is not continuously stored in the individual genes, but is divided into smaller coding sections. These coding sections, also known as exons, are assembled in a process called splicing. Depending on the gene, different exon combinations are possible, which is why they are referred to as different or alternative splicing combinations.

Almost all 20,000 human genes can be alternatively spliced. A particularly huge variety of different splice variants is found in the brain, which allows for creating a huge diversity and allows to adapt the proteins to specific requirements. "However, it is not easy to determine, which protein variants are actually present," says Andreas Reiner. "Sequencing of already-spliced messenger RNAs (mRNAs), so-called RNA-Seq data, which are now increasingly being obtained with high-throughput approaches, offers a way out." Robin Herbrechter and Andreas Reiner now used such data to obtain an overview of all ionotropic glutamate receptor splice variants.

New glutamate receptor variants detected

Using bioinformatic methods, the researchers aligned billions of mRNA sequence snippets to the genome to reconstruct the frequency of individual splice events. This method also enabled them to detect new, previously unknown splice variants. There were quite a few surprises: the systematic analysis showed that some variants found in the previously studied model organisms mouse and rat do not occur in humans at all, or are much less abundant than previously assumed.

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Grasping an object: Model describes complete movement planning in the brain

 Every day we effortlessly make countless grasping movements. We take a key in our hand, open the front door by operating the door handle, then pull it closed from the outside and lock it with the key. What is a natural matter for us is based on a complex interaction of our eyes, different regions of the brain and ultimately our muscles in the arm and hand. Neuroscientists at the German Primate Center (DPZ) -- Leibniz Institute for Primate Research in Göttingen have succeeded for the first time in developing a model that can seamlessly represent the entire planning of movement from seeing an object to grasping it. Comprehensive neural and motor data from grasping experiments with two rhesus monkeys provided decisive results for the development of the model, which is an artificial neural network that, by feeding it with images showing certain objects, is able to simulate processes and interactions in the brain for the processing of this information. The neuronal data from the artificial network model were able to explain the complex biological data from the animal experiments and thus prove the validity of the functional model. This could be used in the long term for the development of better neuroprostheses, for example, to bridge the damaged nerve connection between brain and extremities in paraplegia and thus restore the transmission of movement commands from the brain to arms and legs (PNAS).

Rhesus monkeys, like humans, have a highly developed nervous and visual system as well as dexterous hand motor control. For this reason, they are particularly well suited for research into grasping movements. From previous studies in rhesus monkeys it is known that the interaction of three brain areas is responsible for grasping a targeted object. Until now, however, there has been no detailed model at the neural level to represent the entire process from the processing of visual information to the control of arm and hand muscles for grasping that object.

In order to develop such a model, two male rhesus monkeys were trained to grasp 42 objects of different shapes and sizes, presented to them in random order. The monkeys wore a data glove that continuously recorded the movements of arm, hand and fingers. The experiment was performed by first briefly illuminating the object to be grasped while the monkeys looked at a red dot below the respective object and performed the grasping movement with a short delay after a blinking signal. These conditions provide information about the time at which the different brain areas are active in order to generate the grasping movement and the associated muscle activations based on the visual signals.

In the next step, images of the 42 objects, taken from the perspective of the monkeys, were fed into an artificial neural network in the computer, whose functionality was mimicking the biological processes in the brain. The network model consisted of three interconnected stages, corresponding to the three cortical brain areas of the monkeys, and provided meaningful insights into the dynamics of the brain networks. After appropriate training with the behavioral data of the monkeys, the network was able to precisely reflect the grasping movements of the rhesus monkeys. It was able to process images of recognizable objects and could reproduce the muscle dynamics required to grasp the objects accurately.

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A clue as to why it's so hard to wake up on a cold winter's morning

Winter may be behind us, but do you remember the challenge of waking up on those cold, dark days? Temperature affects the behavior of nearly all living creatures, but there is still much to learn about the link between sensory neurons and neurons controlling the sleep-wake cycle.

Northwestern University neurobiologists have uncovered a clue to what's behind this behavior. In a study of the fruit fly, the researchers have identified a "thermometer" circuit that relays information about external cold temperature from the fly antenna to the higher brain. They show how, through this circuit, seasonally cold and dark conditions can inhibit neurons within the fly brain that promote activity and wakefulness, particularly in the morning.

"This helps explains why -- for both flies and humans -- it is so hard to wake up in the morning in winter," said Marco Gallio, associate professor of neurobiology in the Weinberg College of Arts and Sciences. "By studying behaviors in a fruit fly, we can better understand how and why temperature is so critical to regulating sleep."

The study, led by Gallio and conducted in Drosophila melanogaster, was published today (May 21) in the journal Current Biology.

The paper describes for the first time "absolute cold" receptors residing in the fly antenna, which respond to temperature only below the fly's "comfort zone" of approximately 77 degrees Fahrenheit. Having identified those neurons, the researchers followed them all the way to their targets within the brain. They found the main recipients of this information are a small group of brain neurons that are part of a larger network that controls rhythms of activity and sleep. When the cold circuit they discovered is active, the target cells, which normally are activated by morning light, are shut down.

Drosophila is a classic model system for circadian biology, the area in which researchers study the mechanisms controlling our 24-hour cycle of rest and activity. The focus of much current work is on how changes in external cues such as light and temperature impact rhythms of activity and sleep and how the cues reach the specific brain circuits that control these responses.

While detection of environmental temperature is critical for small "cold-blooded" fruit flies, humans are still creatures of comfort and are continually seeking ideal temperatures. Part of the reason humans seek optimal temperatures is that core and brain temperatures are intimately tied to the induction and maintenance of sleep. Seasonal changes in daylight and temperature are also tied to changes in sleep.

"Temperature sensing is one of the most fundamental sensory modalities," said Gallio, whose group is one of only a few in the world that is systematically studying temperature sensing in fruit flies. "The principles we are finding in the fly brain -- the logic and organization -- may be the same all the way to humans. Whether fly or human, the sensory systems have to solve the same problems, so they often do it in the same ways."

Gallio is the corresponding author of the paper. Michael H. Alpert, a postdoctoral fellow in Gallio's lab, and Dominic D. Frank, a former Ph.D. student in Gallio's lab, are the paper's co-first authors.

"The ramifications of impaired sleep are numerous -- fatigue, reduced concentration, poor learning and alteration of a myriad of health parameters -- yet we still do not fully understand how sleep is produced and regulated within the brain and how changes in external conditions may impact sleep drive and quality," Alpert said.

The study, a collaborative effort many years in the making, was performed in the Gallio lab by a range of scientists at different stages of their careers, ranging from undergraduate students to the principal investigator.

"It is crucial to study the brain in action," Frank said. "Our findings demonstrate the importance of functional studies for understanding how the brain governs behavior."

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