Understanding how a few neurons in a tiny worm control eating under multiple conditions

or, technically,
Neural and genetic degeneracy underlies Caenorhabditis elegans feeding behavior. [See the original abstract on PubMed]

Authors: Nick F. Trojanowski, Olivia Padovan-Merhar, David M. Raizen, Chris Fang-Yen

Brief prepared by: Nick Trojanowski
Brief approved by: Alyse Thomas
Section Chief: Chris Palmer
Date posted: May 3, 2016

Brief in Brief (TL;DR)

What do we know: Only a few neurons control worm eating behavior. Even when you destroy most of them, the system still works properly. 

What don’t we know: The purpose and function of these neurons, since the system seems to work fine without most of them. 

What this study shows: Many of these neurons are capable of making the worm eat under some but not all conditions, ensuring that eating continues even when some parts of the system are changed. 

What we can do in the future because of this study:We can better understand how the worm decides which neurons to use during different conditions to ensure organism survival. 

Why you should care: We don’t really understand what causes most mental illnesses, but we think it has to do with systems of neurons malfunctioning. If we understand how a worm keeps working even when some parts of the nervous system break, we can better understand how to fix people’s brains when things go wrong during mental illness.

Brief for Non-Neuroscientists

For animals to survive and reproduce, it’s very important that they are able to ingest food. A microscopic worm, one that’s been studied by neuroscientists for 40 years, has a small system of neurons that controls feeding. When you individually destroy most of these neurons, the worm still eats properly. We wanted to define the purpose of the neurons that don’t seem to be critical for eating. To do this, we used a technique called optogenetics, which allows us to turn on neurons by shining a blue light on them. By turning on the neurons one by one, we found that many of the individual neurons initiate eating behavior. This result explains why previous studies found no change in eating after destroying individual neurons: some neurons can do the same job as other neurons, depending on the conditions. We also found that under certain conditions, destroying some of these neurons did affect eating, so these neurons don’t always have exactly the same functions. Understanding how systems of neurons in this small worm have evolved to maintain function when some neurons are destroyed will help researchers understand how systems of neurons in other animals, such as humans, respond to changes or injuries. We hope that this will eventually allow us to understand how neurons controlling behaviors associated with mental illness go wrong and why.

Brief for Neuroscientists

Degenerate networks, in which structurally distinct elements can perform the same function or yield the same output, are ubiquitous in biology and likely provide systems the ability to ensure organism survival under various conditions. Degeneracy contributes to the robustness and adaptability of networks in varied environmental and evolutionary contexts. However, how degenerate neural networks regulate behavior in vivo is poorly understood, especially at the genetic level. Here, we identify degenerate neural and genetic mechanisms that underlie excitation of the pharynx (feeding organ) in the nematode Caenorhabditis elegans using cell-specific optogenetic excitation and inhibition. We show that the pharyngeal neurons MC, M2, M4, and I1 form multiple direct and indirect excitatory pathways in a robust network for control of pharyngeal pumping. I1 excites pumping via MC and M2 in a state-dependent manner. We identify nicotinic and muscarinic receptors through which the pharyngeal network regulates feeding rate. These results identify two different mechanisms by which degeneracy is manifest in a neural circuit in vivo.

Activation of the brain's stress response in the 'mood center' of the brain produces sex-dependent changes

or, technically, 
Sex Differences in Corticotropin-Releasing Factor Receptor-1 Action Within the Dorsal Raphe Nucleus in Stress Responsivity [See the original abstract on PubMed]

Authors: Alexis R. Howerton, Alison V. Roland, Jessica M. Fluharty, Anikò Marshall, Alon Chen, Derek Daniels, Sheryl G. Beck, Tracy L. Bale

Brief prepared by: Felicia Davatolhagh
Brief approved by: Elaine Liu & Carolyn Keating
Section Chief: David Reiner
Date posted: August 10, 2017 

Brief in Brief (TL;DR)

What do we know: Women are twice as likely as men to suffer from stress-related disorders, such as depression and anxiety. A hormone called CRF is involved in the stress response and can act in in the 'mood center' of the brain, a region called the dorsal raphe. 

What don’t we know: Does CRF act differently within the dorsal raphe in males and females? 

What this study shows: CRF in the dorsal raphe does work differently in males and females. Females have a decreased response to CRF, compared to males. 

What we can do in the future because of this study:We can better understand sex differences that exist in stress-related disorders and improve how we treat men and women that have these disorders. 

Why you should care: CRF-targeting drugs, which are used to treat disorders such as depression, anxiety, and addiction, are sometimes unsuccessful in patients. Identifying and addressing sex differences in the brain's stress response might help fix this.

Brief for Non-Neuroscientists

In the United States, women are twice as likely as men to be afflicted by a stress-related affective disorder. Corticotropin-releasing factor (CRF) is a peptide hormone and neurotransmitter that mediates stress response through signaling in an area of the brain called the dorsal raphe (DR). CRF receptor-1 (CRFr1) inactivators have been extensively studied in the hope that they can alleviate symptoms of stress-related affective disorders; however, none has been successful in clinical trials. Differences in stress response circuitry between males and females might account for these unsatisfactory results. This study found that in males, infusions of a CRFr1 antagonist into the DR reduced production of the stress hormone corticosterone and alleviated anxiety-like behavior. On the other hand, the CRFr1 antagonist did not affect corticosterone levels or behavior in females. These results suggest sex-dependent differences in CRFr1 activity in the DR. Overall, these findings warrant further investigation into pharmacological therapies tailored toward sex-dependent differences in the brain's stress response system.

Brief for Neuroscientists

The prevalence of affective disorders is twice as high in women as it is in men. Corticotropin-releasing factor (CRF) has been shown to contribute to the development of affective disorders through excessive activation of its receptor CRFr1. The dorsal raphe (DR) is implicated in the central stress pathway response, through activation of CRFr1. This study aimed to elucidate the sex differences within the DR in response to stress, specifically examining CRF modulation in the DR circuits. Infusion of the CRFr1 antagonist NBI35965 (NBI) or CRF into the DR, resulted in robust bidirectional modulation of corticosterone production and behavioral stress response in males, while females were minimally responsive. Furthermore, male mice showed enhanced membrane excitability following CRF application, but the response in female mice was blunted. Therefore, these sex differences in stress circuitry might explain why CRFr1 antagonists have been unsuccessful in clinical trials. These studies warrant further investigation into pharmacological treatments directed at addressing sex differences in the CRF system.

Deep Brain Stimulation: A potential treatment for cocaine relapse

or, technically, 
Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats [See the original abstract on PubMed]

Authors: Leonardo A. Guercio, Heath D. Schmidt, R. Christopher Pierce

Brief prepared by: Leonardo Guercio
Brief approved by: Ari Kahn
Section Chief: David Reiner
Date posted: April 11, 2017 

Brief in Brief (TL;DR)

What do we know: Drug relapse in humans and animal models can be produced by three major factors: stress, drug-associated cues (environments and items), and re-exposure to the drug itself. The nucleus accumbens is a brain region that is critically involved in drug addiction and relapse. Deep brain stimulation (DBS), a Food and Drug Administration (FDA)-approved treatment for Parkinson's disease, of the nucleus accumbens can block cocaine relapse that is triggered by re-exposure to cocaine in animal models of addiction. 

What don’t we know: Can DBS of the nucleus accumbens also block cocaine relapse triggered by cocaine-associated cues, such as environments associated with drug use? 

What this study shows: We can effectively use DBS in the nucleus accumbens to block cocaine relapse triggered by cocaine-associated cues. However, DBS in this brain region may also affect the ability to seek naturally rewarding substances, such as sugar. 

What we can do in the future because of this study:We can figure out if DBS can become an FDA-approved treatment for drug addiction. Future findings may also help determine what other brain areas are involved in the different types of relapse, and whether DBS can be an effective treatment in all types of drug relapse. 

Why you should care: There are very few treatment options for drug addiction in general and there are no FDA-approved treatments for cocaine addiction. Existing FDA-approved treatments like DBS may be effective in treating relapse to cocaine and other drugs.

Brief for Non-Neuroscientists

A major problem facing cocaine addicts is the discouragingly high rate of relapse. Cocaine relapse in humans can be precipitated by three major factors: stress, drug-associated cues and contexts, and re-exposure to the drug itself. We can model cocaine relapse using these same factors in an animal behavior model called reinstatement. Briefly, animals are placed in an operant chamber where they can press a lever to self-administer cocaine. This is done daily for about 3 weeks, then the drug is removed and animals undergo a period of withdrawal. After approximately 1 week of withdrawal, the animals are placed back in the operant chamber, and cocaine seeking is reinstated either by an injection of cocaine, exposure to lights and tones previously paired with cocaine infusions, or a stressor. 

This reinstatement model is extremely useful for determining brain regions and neurotransmitters involved in cocaine relapse, with the hopes of developing a treatment for cocaine addiction and relapse. Currently, there are no FDA-approved therapies for cocaine addiction and relapse. Deep brain stimulation (DBS) is an FDA-approved treatment for Parkinson's disease. By applying DBS to the nucleus accumbens, a brain region critically involved in drug addiction and relapse, we were able to block cocaine reinstatement triggered by cocaine-associated cues. However, DBS in this brain region also blocked responding for sugar as well, so it may affect natural reward processing. Understanding how DBS can affect the brain regions and circuits involved in cocaine relapse may lead to repackaging DBS as a treatment for drug addiction.

Brief for Neuroscientists

Our lab has previously shown that deep brain stimulation (DBS) of the nucleus accumbens shell attenuates the priming-induced reinstatement of cocaine seeking, without perturbing sucrose reinstatement. In this study, we examined whether deep brain stimulation (DBS) can modulate cue-induced reinstatement of cocaine and sucrose seeking. We found that DBS of the accumbens shell attenuated cue-induced reinstatement of cocaine seeking. However, DBS in this region also attenuated cue-induced sucrose reinstatement, suggesting that the effects of DBS may not be drug-specific when suppressing cue-induced relapse. Further studies will examine the efficacy of DBS as a potential therapeutic avenue for cocaine reinstatement.

Chew on this: your daytime sleepiness depends on your diet, not your weight

or, technically, 
Diet/Energy Balance Affect Sleep and Wakefulness Independent of Body Weight [See the original abstract on PubMed]

Authors: Isaac J. Perron, Allan I. Pack, Sigrid Veasey

Brief prepared by: Isaac J. Perron
Brief approved by: Peter Dong
Section Chief: David Reiner
Date posted: March 17, 2017 

Brief in Brief (TL;DR)

What do we know: Obese people are more likely to be excessively tired during the day compared to their lean counterparts, but it is not clear why. This problem has been studied in mice, which are made obese by feeding them a high-fat diet, or HFD for short. Multiple reports have found HFD-fed obese mice have trouble staying awake and sleep much more than mice fed a low-calorie, regular diet (RD). 

What don’t we know: Are obese mice sleepy because they are eating the HFD or because they are obese? And how can you separate these effects anyway? 

What this study shows: The researchers made up a 'diet switch' food program, switching obese mice to a RD and skinny mice to a HFD, and studied the sleep patterns of the two mouse groups when they were of equal weights. The formerly-skinny mice switched to the HFD had the classic sleep problems observed in obese mice, while the formerly-obese mice switched to RD slept normally. Thus, when it comes to sleep and wakefulness, your diet is a more important factor than what your weight on the scale reads. 

What we can do in the future because of this study:Future work can investigate which types of food (e.g., fat vs carbohydrates vs protein) cause sleep problems, and whether other methods of weight loss (such as exercise) can also fix sleep issues. Also, researchers can use the 'diet switch' food program to figure out what else is affected by diet separate from body weight. 

Why you should care: Morbid obesity means that weight gain has become so severe that it is now considered a disease. One issue obese people face is excessive sleepiness. This research shows that beginning to lose weight by healthy eating can reverse this tiredness, even before all the weight is lost.

Brief for Non-Neuroscientists

Despite the high prevalence of obesity in the United States, many people are unaware of the strong association between obesity and excessive daytime sleepiness (EDS). Remarkably, obese patients who undergo bariatric surgery for weight loss report dramatic improvements in EDS before significant weight loss occurs, suggesting that other factors besides excess weight may contribute to daytime wake impairments. We hypothesize that the initiation of weight gain/loss due to changes in energy balance (calories ingested versus calories burned) can profoundly affect sleep and wakefulness, which may contribute to EDS in obese people. 

Our lab models human obesity by feeding normal mice a diet enriched with fat (a.k.a. 'high fat diet', or HFD). Similar to humans, obese mice are unable to stay awake for long periods of time and spend more time asleep when their non-obese counterparts are most active. However, no study to date has been able to separate the effects of energy balance (i.e., weight gain/loss) from body weight on sleep/wake impairments. 

To accomplish this, we designed an experiment that caused lean mice to gain weight and obese mice to lose weight; when body weight was similar between the two groups, we measured their sleep/wake behavior. We found that obese mice that had been switched to a normal diet lost weight and exhibited increased wake time and improved sleep/wake quality compared to lean mice gaining weight from HFD consumption, even though these two groups of mice had no differences in their body weight. Therefore, this study supports the hypothesis that modifying energy balance via dietary changes is sufficient to induce or reverse EDS in mice, independent of their body weight. These results are especially relevant to people, both obese and non-obese, who need to be alert, awake, and focused during the day (e.g., truck drivers, medical doctors, and airplane pilots).

Brief for Neuroscientists

Excessive daytime sleepiness commonly affects obese people, even in those without sleep apnea or other sleep disorders, yet its underlying mechanisms remain uncertain. Follow-up studies with obese patients who have undergone bariatric surgery for weight loss report significant improvements in daytime wakefulness, even though these patients are still obese. This suggests that obesity per se may not be the primary determinant in regulation of sleep and wakefulness. We implemented a novel feeding paradigm in mice that generates two groups with equal body weight but opposing energetic balance to test the relative importance of diet versus body weight. Two subsets of mice consuming either a normocaloric regular diet (RD) or hypercaloric high-fat diet (HFD) for 8 weeks were switched to the opposite diet for 1 week. One week later, these two groups of mice were of similar weight, although they were in diametrically opposed energetic statuses due to their respective diets. We found that animals switched to HFD (and thus gaining weight) had decreased wake time, increased NREM sleep time, and worsened sleep/wake fragmentation compared to mice switched to RC (which were in weight loss). These effects were driven by significant sleep/wake changes induced by acute dietary manipulations (during the week after the diet change). Sleep homeostasis, as measured by delta power increase following sleep deprivation, was unaffected by our feeding paradigm. Thus, acute dietary manipulations are sufficient to alter sleep and wakefulness independent of body weight and without effects on sleep homeostasis.

You are what you eat: discovery of a new process for how your brain controls how many calories you eat and how many calories you burn

or, technically, 
Protein-tyrosine Phosphatase 1B (PTP1B) Is a Novel Regulator of Central Brain-derived Neurotrophic Factor and Tropomyosin Receptor Kinase B (TrkB) Signaling [See the original abstract on PubMed]

Authors: Ceren Ozek, Scott E. Kanoski, Zhong-Yin Zhang, Harvey J. Grill, Kendra K. Bence

Brief prepared by: David Reiner & Isaac Perron
Brief approved by: Shachee Doshi
Section Chief: David Reiner
Date posted: March 13, 2017 

Brief in Brief (TL;DR)

What do we know: Your body weight is determined by the balance of how many calories you eat and how many calories you burn. Some parts of the brain control how many calories you eat and others control how many calories you burn. Activation of one protein called TrkB is well known to reduce the amount of calories eaten, but does not affect calories burned. A different protein called PTP1B is also important for maintaining normal body weight (e.g., obese people have too much PTP1B), but scientists are not sure if it affects the number of calories you eat or the number you burn. 

What don’t we know: How does PTP1B control the balance of calories eaten and calories burned? Do TrkB and PTP-1B work together, and if so, what happens when they do? 

What this study shows: The scientists found that TrkB activation can increase the number of calories burned, but only if the animals don't have any PTP1B. Therefore, PTP1B helps keep weight loss in check when TrkB is activated, preventing animals from losing weight too rapidly. 

What we can do in the future because of this study: This study identifies a new process in the brain that affects body weight. Decreasing PTP1B in the brain may be a potential way to treat obesity by increasing the number of calories burned. 

Why you should care: Roughly 1/3 of the US population is obese, increasing costs for patients and society as a whole. Currently treatments for obesity either involve surgery and are extremely expensive or do not work long term. By understanding how the brain promotes weight loss, we can begin to identify new targets for obesity treatment.

Brief for Non-Neuroscientists

Activation of the brain-specific receptor, TrkB, can decrease food intake. A different protein, protein-tyrosine phosphatase 1B (PTP1B), is increased in obesity and has some role in regulating body weight, but how it does this is unclear. This study explored whether TrkB and PTP1B interact to regulate calories consumed and calories burned. Here, the authors show that PTP1B binds and regulates TrkB, which ultimately affects body weight through changes in body temperature (i.e., calories burned). Specifically, TrkB activation reduces food intake in normal mice, but in mice lacking PTP1B, TrkB activation also increases body temperature with no effect on food intake. Thus, PTP1B reduces the effects of TrkB on weight loss by blocking body temperature increases. If we can block PTP1B in obese people, it may be a new way to accelerate weight loss in this population.

Brief for Neuroscientists

Protein-tyrosine phosphatase 1B (PTP1B) is elevated in obesity and negatively regulates leptin signaling. Therefore, it is assumed that PTP1B deficiency could stimulate negative energy balance by restoring leptin sensitivity. Here, the authors show that PTP1B also interacts with BDNF and its receptor, TrkB, to regulate energy balance. PTP1B overexpression suppresses BDNF/TrkB signaling, while PTP1B inhibition enhances BDNF/TrkB signaling. Mice administered BDNF show reductions in food intake, but no effects on core body temperature (i.e., energy expenditure). Importantly, mice lacking PTP1B have no caloric intake effects, but show increased core body temperature when administered BDNF. Therefore, BDNF-TrkB signaling is capable of reducing caloric intake on its own, but can also increase energy expenditure (and thus further weight loss) when PTP1B is absent. Thus, PTP1B could potentially be a drug target to accelerate weight loss in obese patients.

Controlling serotonin circuits in the brain with light manipulates mice into approaching or avoiding rodent bullies

or, technically, 
Optogenetic modulation of descending prefrontocortical inputs to the dorsal raphe bidirectionally bias socioaffective choices after social defeat. [See the original abstract on PubMed]

Authors: Collin Challis, Sheryl G. Beck, Olivier Berton

Brief prepared by: Collin Challis
Brief approved by: Isaac Perron and Yin Li
Section Chief: Shivon Robinson
Date posted: May 3, 2016 

Brief in Brief (TL;DR)

What do we know: Serotonin—a 'happiness' molecule in the brain—is important for making social decisions. The ventromedial prefrontal cortex is important for deciding what emotion we attach to things or people. 

What don’t we know: The specific way the brain is wired to control serotonin when we are deciding to approach or avoid a stranger. 

What this study shows: We can control whether a mouse approaches or avoids a new social partner by changing the activity of prefrontal cortical neurons that communicate with cells that inhibit serotonin neurons. 

What we can do in the future because of this study: We could find out if dysfunction in this brain wiring contributes to social symptoms of mood disorders and whether changing activity of this circuit can improve behavior. Future findings could also determine how changing the activity of this brain pathway affects serotonin actions in other brain regions, both long- and short-term. 

Why you should care: Current antidepressants, which broadly target serotonin in the brain, do not work well for many people. Instead of affecting all serotonin in the brain, new treatments that target specific parts of the brain (like the regions described here) may be more effective at treating patients with mood disorders.

Brief for Non-Neuroscientists

When we meet strangers, we make social decisions, including whether we want to approach or avoid them. These are based on social judgments made immediately and often unconsciously. People that are diagnosed with mood disorders, such as depression and anxiety disorders, often excessively avoid other people. Therefore, understanding how these social decisions are made can help us design new therapies to treat disorders involving skewed social decisions. Researchers have shown that altering levels of serotonin—a molecule in the brain thought to contribute to 'happiness'—can influence these decisions; however, scientists do not know which parts of the brain communicate to control this. In our study, we investigated how communication between a brain area important for processing social information (the prefrontal cortex) and a brain area that provides serotonin to the rest of the brain (the dorsal raphe) can affect social approach or avoidance decisions in mice. With a technique called optogenetics, which uses light from a laser to either increase or decrease communication between the prefrontal cortex and the dorsal raphe, we were able to change the social decisions made by mice. Understanding how brain wiring affects social behavior will improve our comprehension of mood disorders, such as depression, which may allow development of better therapies to treat those people affected.

Brief for Neuroscientists

Though it has long been known that serotonin can alter social perception, the underlying neural circuits that control serotonergic output during social interaction are complex. Previous mapping studies have shown that the ventromedial prefrontal cortex (vmPFC), an area of the brain believed to be important for encoding emotional value, sends excitatory projections to the serotonergic dorsal raphe nucleus (DRN). In this study, we first show that these vmPFC afferents actually synapse directly on GABA neurons in the DRN that then locally inhibit serotonin neurons. We then used optogenetics to manipulate this specific and direct pathway from the vmPFC to the DRN during social defeat, a paradigm that exposes mice to physical and sensory contact with a larger, more aggressive strain of mice and induces a long lasting form of social avoidance. We found that blocking vmPFC inputs to the DRN, thus disinhibiting serotonin neurons, prevented the social avoidance typically observed after defeat. Conversely, when we optogenetically activated the vmPFC terminals, these mice displayed strong social avoidance and a considerable delay in their decision to approach a social partner. Dissecting the role of the vmPFC-DRN in social decisions has implications for the social symptoms observed in mood disorders as well as the development of novel therapeutic treatments for these behaviors.