Lassitude: That Sick Feeling May Actually Be An Emotion

That weary feeling that sets in with an illness is an emotion that helps you fight off infection, a University of Oregon research team reports.

Slack facial muscles and drooping eyelids appear early. Exhaustion, loss of appetite, and increased sensitivity to cold and pain come on. Those signs are among a long list of features that researchers have linked to the emotion of being sick, which the authors label lassitude, a now little-used term for weariness from 16th-century Latin.

The researchers argue[1] that the state of being sick qualifies as an emotion following a review of the literature on sickness behavior, most of which focused on behavioral and physiological changes in nonhuman animals.

Power Up The System

In the paper, the researchers merge the accrued knowledge from 130 published studies and proposed that lassitude is a complex adaptation, like the immune system, that evolved to help people fight infectious disease.

“The immune system clearly helps us fight off infections, but activating the immune system costs a lot of energy. This cost creates a series of predicaments for the body’s regulatory systems. Lassitude is the program that adjusts your body’s regulatory systems to set them up for fighting infection. These adjustments make you feel sadder, more fatigued, more easily nauseated, less hungry, and more sensitive to cold and pain,”

says lead author Joshua Schrock, a doctoral student at the University of Oregon.

Lassitude, the researchers write, persists until the immune response subsides. During that response, the body calls upon various mechanisms to coordinate the fight against infection, which, they note, can trigger symptoms resembling psychological depression.

The term lassitude is used to intentionally differentiate their concept from others such as fatigue, which typically goes away after a period of rest, unlike lassitude.

Costs Vs. Benefits

During the battle, lassitude coordinates adjustments to patterns of movement, risk avoidance, body temperature, body language, appetite, and even how a person elicits caregiving behavior from social networks.

Lassitude, the researchers write, “modifies the cost-benefit structure of a wide range of decisions.” Those who are ill place lower value on food and sex, for example, and often prefer to avoid social and physical risks.

“When threat levels are high, the system sends a signal to various motivational systems, configuring them in ways that facilitate effective immunity and pathogen clearance. We believe that investigating the information-processing structure of lassitude will contribute to a more complete understanding of sickness behavior, much like the information-processing structure of hunger helps us understand feeding behavior,”

the researchers conclude.

While the paper focused primarily on illnesses that bacteria, viruses, parasitic worms, and protozoans trigger, they also theorized that other situations — such as injuries, poisoning, and chronic degenerative diseases — may present similar adaptive problems.

[1] Joshua M. Schrock, J. Josh Snodgrass, Lawrence S.Sugiyama. Lassitude: The emotion of being sick. Evolution and Human Behavior. https://doi.org/10.1016/j.evolhumbehav.2019.09.002

During decision-making, neurons in the brain are capable of much more complex processing than previously thought, new research indicates.

The findings[1] show that during decision-making, there are a multitude of small sections of dendrite throughout each neuron that process information before it is sent to other neurons. This suggests that much more complex processing can occur in the brain through these many, tiny segments of dendrite.

“Now that we have these findings and approaches, we may gain a better understanding of what’s happening in diseases that affect synaptic function and why they affect information processing in the way they do,”

said first author Aaron Kerlin, Ph.D.

Dendrites And Spines

In the study, researchers, including Dr. Kerlin, who is an assistant professor in the Department of Neuroscience and member of the Medical Discovery Team on Optical Imaging and Brain Science at the University of Minnesota Medical School, were the first to develop a microscope that rapidly images large stretches of the dendrite where neurons receive thousands of inputs from other neurons.

Targeted high-speed imaging in behaving mice.

Targeted high-speed imaging in behaving mice. A) Optical layout for high-speed, high-resolution imaging in three dimensions. An x-axis mirror galvanometer, remote focusing arm, and prism-based GDD compensation unit were added to a high resolution (NA = 1.0) resonant two photon microscope. EOM, electro-optic modulator; GDD, group delay dispersion; Res., 8 kHz resonant scanner; PR, pupil relay; Gal., galvanometer; PBS, polarizing beam splitter; QWP, quarter wave plate; RFO, remote focusing objective; VC, voice coil; DM, dichroic mirror; IO, imaging objective; PMT, photomultiplier tube. (B) Maximum intensity projections (MIP) of anatomical stack collected from Syt17-Cre x Ai93 (pia to 306 um depth) mice. Traced dendrite (purple lines) and example targets (red lines) for an example imaging session. (C) Spatial and temporal distribution of the frames that compose the example functional imaging sequences in (B). (D) Average MIP of 30 min of the functional imaging sequence shown in (B, C). (E) Close-up of the dendritic branch outlined in (D) before and after motion correction. (F–I) same as (B–E) for a layer 5 cell (MIP in (F) is pia to 560 um depth). Credit: Aaron Kerlin, et al. CC-BY

Dr. Kerlin believes that future research may include investigating patterns of local processing in neurons within mouse models of autism to determine which dendritic computations are disrupted and over what scale the disruptions occur.

He has also created a web browser that allows the entire dataset to be publicly available to other researchers, which is part of his dedication to advancing the Open Science movement. He hopes that this will encourage theorists and other researchers to make new discoveries with this rich dataset and embark on further research within this field.

[1] Aaron Kerlin, Mohar Boaz, Daniel Flickinger, Bryan J MacLennan, Matthew B Dean, Courtney Davis, Nelson Spruston, Karel Svoboda. Functional clustering of dendritic activity during decision-making. eLife 2019;8:e46966 DOI: 10.7554/eLife.46966

Neuron Transplant May Avert Epilepsy Following Brain Injury

A new cell therapy enhanced memory and prevented seizures in mice after traumatic brain injury, researchers from the University of California, Irvine report[1].

The researchers transplanted embryonic progenitor cells capable of generating inhibitory interneurons, a specific type of nerve cell that controls the activity of brain circuits, into the brains of mice with traumatic brain injury. They targeted the hippocampus, a brain region responsible for learning and memory.

“Inhibitory neurons are critically involved in many aspects of memory, and they are extremely vulnerable to dying after a brain injury. While we cannot stop interneurons from dying, it was exciting to find that we can replace them and rebuild their circuits,”

says Robert Hunt, an assistant professor of anatomy and neurobiology at the School of Medicine at the University of California, Irvine, who led the study.

Neuron Migration

The researchers discovered that the transplanted neurons migrated into the injury where they formed new connections with the injured brain cells and thrived long term.

Within a month after treatment, the mice showed signs of memory improvement, such as being able to tell the difference between a box where they had an unpleasant experience from one where they did not. They were able to do this just as well as mice that never had a brain injury.

MGE transplantation

MGE transplantation does not alter glial responses to TBI.
(a) Coronal brain sections 125 DAT labeled for GFAP (orange), IBA1 (magenta) and transplanted MGE cells (green). In the ipsilateral hemisphere, there was prominent glial scar surrounding the impact site.
(b) Quantification of GFAP expression in neocortex and hippocampus in sections contralateral and ipsilateral to the injury. Ipsilateral neocortex: **P = 0.007, control vs TBI; **P = 0.009, control vs TBI-MGE; one-way ANOVA with Bonferroni post hoc test; Ipsilateral hippocampus: *P = 0.04, control vs TBI; **P = 0.008, control vs TBI-MGE; one-way ANOVA with Bonferroni post hoc test. n = 4 control mice, n = 3 TBI mice, n = 3 TBI-MGE mice.
(c) Quantification of IBA1 immunostaining in neocortex and hippocampus in sections contralateral and ipsilateral to the injury. Ipsilateral neocortex: *P = 0.03, control vs TBI; *P = 0.03, control vs TBI-MGE; one-way ANOVA with Bonferroni post hoc test.
(d) High resolution images of the boxed region in a labeled for GFAP (orange), IBA1 (magenta) and GFP (green). Transplanted MGE cells did not co-localize with glial markers (n = 3 mice per marker).
Credit: Bingyao Zhu, et al. CC-BY

The cell transplants also prevented the mice from developing epilepsy, which affected more than half of the mice not treated with new interneurons.

Traumatic brain injuries affect 2 million Americans each year and causes cell death and inflammation in the brain. People who experience a head injury often suffer from lifelong memory loss and can develop epilepsy.

Interneuron Transplantation Therapy

This is not the first time Hunt and his team has used interneuron transplantation therapy to restore memory in mice. In 2018, the team used a similar approach[2], delivered the same way but to newborn mice, to improve memory of mice with a genetic disorder.

Still, this was an exciting advance for the researchers.

“The idea to regrow neurons that die off after a brain injury is something that neuroscientists have been trying to do for a long time,” Hunt says. “But often, the transplanted cells don’t survive, or they aren’t able to migrate or develop into functional neurons.”

To further test their observations, Hunt and his team silenced the transplanted neurons with a drug, which caused the memory problems to return.

“It was exciting to see the animals’ memory problems come back after we silenced the transplanted cells, because it showed that the new neurons really were the reason for the memory improvement,”

says first author Bingyao Zhu, a junior specialist.

Currently, there are no treatments for people who experience a head injury. If the researchers can replicate the results in humans, it could have a tremendous impact for patients. The next step is to create interneurons from human stem cells.

[1] Bingyao Zhu, Jisu Eom & Robert F. Hunt. Transplanted interneurons improve memory precision after traumatic brain injury. Nat Commun 10, 5156 (2019) doi:10.1038/s41467-019-13170-w

[2] Young J. Kim, et al. Chd2 Is Necessary for Neural Circuit Development and Long-Term Memory. Neuron; Volume 100, Issue 5, p1180-1193.E6, December 05, 2018

General Intelligence Predicts Musical Skill Acquisition

Intelligence could play a role in learning music, according to a Michigan State University study that investigated the early stages of learning to play the piano[1]. The study may be the first to examine the relationship between intelligence, music aptitude, and growth mindset in beginner pianists.

A growth mindset refers to whether students believe they can improve necessary abilities, like piano ability.

“The strongest predictor of skill acquisition was intelligence, followed by music aptitude. By contrast, the correlation between growth mindset and piano performance was about as close to zero as possible,”

said Alexander Burgoyne, a doctoral candidate in cognition and cognitive neuroscience.

Skill Acquisition Trajectories

In the study, 161 undergraduates learned how to play “Happy Birthday” on the piano with the help of a video guide. After practice, the students performed the 25-note song multiple times.

Three MSU graduate students judged the performances based on their melodic and rhythmic accuracy. There were striking differences in the students’ skill acquisition trajectories.

Some learned quickly, earning perfect marks within six minutes of practice. Others performed poorly at first but improved substantially later.

By comparison, some seemed to fade as if they had lost their motivation, and others never figured it out, performing poorly throughout the study.

So why did some students fail while others succeeded?

Mindsets

To find out, the researchers gave the students tests of cognitive ability that measured things like problem-solving skills and processing speed, and tests of music aptitude that measured, for example, the ability to differentiate between similar rhythms. They also surveyed their growth mindset.

“The results were surprising because people have claimed that mindset plays an important role when students are confronted with challenges, like trying to learn a new musical instrument. And yet, it didn’t predict skill acquisition,”

Burgoyne said.

That said, results will likely differ for those with more skill.

“Our study examined one of the earliest stages of skill acquisition. Early experiences can be formative, but I would caution against drawing conclusions about skilled musicians based on our study of beginners,”

said Burgoyne.  The study’s findings may be helpful in education.

It follows a recent review of mindset research that found a weak relationship between a growth mindset and academic achievement. Perhaps more concerning, that study found interventions designed to boost performance by encouraging children to believe they can improve their necessary abilities may be fruitless.

That is, when those interventions successfully altered students’ mindsets, there wasn’t a significant effect on academic achievement.

[1] Alexander P. Burgoyne, Lauren Julius Harris, David Z. Hambrick. Predicting piano skill acquisition in beginners: The role of general intelligence, music aptitude, and mindset. Intelligence; Volume 76, September–October 2019, 101383

Lithium Can Reverse Radiation Damage After Brain Tumor Treatment

Children who have received radiotherapy for a brain tumor can develop cognitive problems later in life. In their studies on mice[1], researchers at Karolinska Institutet have now shown that the drug lithium can help to reverse the damage caused long after it has occurred.

Nowadays, four out of five children with a brain tumor survive. In the adult Swedish population, one in 600 people have been treated for childhood cancer, about one third of which were brain tumors.

Many of them live with damage caused by the radiotherapy, which can cause deficiencies in memory and learning.

Lithium Treatment

Researchers at Karolinska Institutet in Sweden now show that the memory capacity and learning capability of mice improve if lithium treatment is given after the irradiation of the brain. Mice that were irradiated early in life and then given lithium from adolescence until young adulthood performed just as well as mice who had not been given radiation.

The researchers observed an increase in the formation of new neurons in an area that is important to the memory (the hippocampus) during the period in which they received lithium, but their maturity into full nerve cells only occurred once the lithium treatment was discontinued.

“From this, we conclude that lithium, given along the lines of this model, can help to heal the damage caused by radiotherapy, even long after it was caused,”

says lead author Giulia Zanni, postdoctoral researcher at Columbia University and former Ph.D. student in Klas Blomgren’s group at Karolinska Institutet.

Pediatric Oncology Progress

The research group has previously shown that lithium protects against brain damage if given in connection with radiotherapy as it can prevent apoptosis (cell death). They now want to start clinical trials in the hope that they will be able to produce the first drug treatment for damage caused by the irradiation of the brain.

“In the past few years, pediatric oncology has become better at saving lives, but does so at a high cost. Virtually all children who have received radiation treatment for a brain tumor develop more or less serious cognitive problems. This can cause difficulties learning or socializing and even holding down a job later in life. We must be better at taking care of the damage we cause, and this is what this research is all about,”

says Klas Blomgren, consultant and professor of pediatric medicine at the Department of Women’s and Children’s Health at Karolinska Institutet.

Lithium is a drug that is already given to adults and children with bipolar disorder, but scientists are still uncertain about how it actually works. However, some new pieces of the puzzle have fallen into place with this study.

The researchers found that lithium affects Tppp, a protein that is important for the cytoskeleton and GAD65, a protein that affects the GABA system, which is central to neuronal maturity.

“We’re only just beginning to understand lithium’s effects on the brain’s ability to repair itself. In this study we observed that only irradiated cells are affected by lithium. Healthy cells were left relatively untouched. This is an interesting and promising result,”

says Ola Hermanson, researcher at the Department of Neuroscience at Karolinska Institutet.

[1] Giulia Zanni, Shinobu Goto, Adamantia F. Fragopoulou, Giulia Gaudenzi, Vinogran Naidoo, Elena Di Martino, Gabriel Levy, Cecilia A. Dominguez, Olga Dethlefsen, Angel Cedazo-Minguez, Paula Merino-Serrais, Antonios Stamatakis, Ola Hermanson & Klas Blomgren. Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition. Mol Psychiatry (2019) doi:10.1038/s41380-019-0584-0