skip to main content


Title: A circuit perspective on narcolepsy
Abstract The sleep disorder narcolepsy is associated with symptoms related to either boundary state control that include excessive daytime sleepiness and sleep fragmentation, or rapid eye movement (REM) sleep features including cataplexy, sleep paralysis, hallucinations, and sleep-onset REM sleep events (SOREMs). Although the loss of Hypocretin/Orexin (Hcrt/Ox) peptides or their receptors have been associated with the disease, here we propose a circuit perspective of the pathophysiological mechanisms of these narcolepsy symptoms that encompasses brain regions, neuronal circuits, cell types, and transmitters beyond the Hcrt/Ox system. We further discuss future experimental strategies to investigate brain-wide mechanisms of narcolepsy that will be essential for a better understanding and treatment of the disease.  more » « less
Award ID(s):
1652060
NSF-PAR ID:
10191203
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
Sleep
Volume:
43
Issue:
5
ISSN:
0161-8105
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. REM sleep is important for the processing of emotional memories, including fear memories. Rhythmic interactions, especially in the theta band, between the medial prefrontal cortex (mPFC) and limbic structures are thought to play an important role, but the ways in which memory processing occurs at a mechanistic and circuits level are largely unknown. To investigate how rhythmic interactions lead to fear extinction during REM sleep, we used a biophysically based model that included the infralimbic cortex (IL), a part of the mPFC with a critical role in suppressing fear memories. Theta frequency (4–12 Hz) inputs to a given cell assembly in IL, representing an emotional memory, resulted in the strengthening of connections from the IL to the amygdala and the weakening of connections from the amygdala to the IL, resulting in the suppression of the activity of fear expression cells for the associated memory. Lower frequency (4 Hz) theta inputs effected these changes over a wider range of input strengths. In contrast, inputs at other frequencies were ineffective at causing these synaptic changes and did not suppress fear memories. Under post-traumatic stress disorder (PTSD) REM sleep conditions, rhythmic activity dissipated, and 4 Hz theta inputs to IL were ineffective, but higher-frequency (10 Hz) theta inputs to IL induced changes similar to those seen with 4 Hz inputs under normal REM sleep conditions, resulting in the suppression of fear expression cells. These results suggest why PTSD patients may repeatedly experience the same emotionally charged dreams and suggest potential neuromodulatory therapies for the amelioration of PTSD symptoms. SIGNIFICANCE STATEMENT Rhythmic interactions in the theta band between the mPFC and limbic structures are thought to play an important role in processing emotional memories, including fear memories, during REM sleep. The infralimbic cortex (IL) in the mPFC is thought to play a critical role in suppressing fear memories. We show that theta inputs to the IL, unlike other frequency inputs, are effective in producing synaptic changes that suppress the activity of fear expression cells associated with a given memory. Under PTSD REM sleep conditions, lower-frequency (4 Hz) theta inputs to the IL do not suppress the activity of fear expression cells associated with the given memory but, surprisingly, 10 Hz inputs do. These results suggest potential neuromodulatory therapies for PTSD. 
    more » « less
  2. Abstract Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them. 
    more » « less
  3. null (Ed.)
    Sleep has many roles, from strengthening new memories to regulating mood and appetite. While we might instinctively think of sleep as a uniform state of reduced brain activity, the reality is more complex. First, over the course of the night, we cycle between a number of different sleep stages, which reflect different levels of sleep depth. Second, the amount of sleep depth is not necessarily even across the brain but can vary between regions. These sleep stages consist of either rapid eye movement (REM) sleep or non-REM (NREM) sleep. REM sleep is when most dreaming occurs, whereas NREM sleep is particularly important for learning and memory and can vary in duration and depth. During NREM sleep, large groups of neurons synchronize their firing to create rhythmic waves of activity known as slow waves. The more synchronous the activity, the deeper the sleep. Vaidyanathan et al. now show that brain cells called astrocytes help regulate NREM sleep. Astrocytes are not neurons but belong to a group of specialized cells called glia. They are the largest glia cell type in the brain and display an array of proteins on their surfaces called G-protein-coupled receptors (GPCRs). These enable them to sense sleep-wake signals from other parts of the brain and to generate their own signals. In fact, each astrocyte can communicate with thousands of neurons at once. They are therefore well-poised to coordinate brain activity during NREM sleep. Using innovative tools, Vaidyanathan et al. visualized astrocyte activity in mice as the animals woke up or fell asleep. The results showed that astrocytes change their activity just before each sleep–wake transition. They also revealed that astrocytes control both the depth and duration of NREM sleep via two different types of GPCR signals. Increasing one of these signals (Gi-GPCR) made the mice sleep more deeply but did not change sleep duration. Decreasing the other (Gq-GPCR) made the mice sleep for longer but did not affect sleep depth. Sleep problems affect many people at some point in their lives, and often co-exist with other conditions such as mental health disorders. Understanding how the brain regulates different features of sleep could help us develop better – and perhaps more specific – treatments for sleep disorders. The current study suggests that manipulating GPCRs on astrocytes might increase sleep depth, for example. But before work to test this idea can begin, we must first determine whether findings from sleeping mice also apply to people. 
    more » « less
  4. Abstract

    Irritable bowel syndrome (IBS) is the most prevalent disorder of brain-gut interactions that affects between 5 and 10% of the general population worldwide. The current symptom criteria restrict the diagnosis to recurrent abdominal pain associated with altered bowel habits, but the majority of patients also report non-painful abdominal discomfort, associated psychiatric conditions (anxiety and depression), as well as other visceral and somatic pain-related symptoms. For decades, IBS was considered an intestinal motility disorder, and more recently a gut disorder. However, based on an extensive body of reported information about central, peripheral mechanisms and genetic factors involved in the pathophysiology of IBS symptoms, a comprehensive disease model of brain-gut-microbiome interactions has emerged, which can explain altered bowel habits, chronic abdominal pain, and psychiatric comorbidities. In this review, we will first describe novel insights into several key components of brain-gut microbiome interactions, starting with reported alterations in the gut connectome and enteric nervous system, and a list of distinct functional and structural brain signatures, and comparing them to the proposed brain alterations in anxiety disorders. We will then point out the emerging correlations between the brain networks with the genomic, gastrointestinal, immune, and gut microbiome-related parameters. We will incorporate this new information into a systems-based disease model of IBS. Finally, we will discuss the implications of such a model for the improved understanding of the disorder and the development of more effective treatment approaches in the future.

     
    more » « less
  5. Abstract Background and Objectives

    Sleep disorders often predict or co-occur with cognitive decline. Yet, little is known about how the relationship unfolds among older adults at risk for cognitive decline. To examine the associations of sleep disorders with cognitive decline in older adults with unimpaired cognition or impaired cognition (mild cognitive impairment and dementia).

    Research Design and Methods

    A total of 5,822 participants (Mage = 70) of the National Alzheimer’s Coordinating Center database with unimpaired or impaired cognition were followed for 3 subsequent waves. Four types of clinician-diagnosed sleep disorders were reported: sleep apnea, hyposomnia/insomnia, REM sleep behavior disorder, or “other.” Cognition over time was measured by the Montreal Cognitive Assessment (MoCA) or an estimate of general cognitive ability (GCA) derived from scores based on 12 neuropsychological tests. Growth curve models were estimated adjusting for covariates.

    Results

    In participants with impaired cognition, baseline sleep apnea was related to better baseline MoCA performance (b = 0.65, 95% confidence interval [95% CI] = [0.07, 1.23]) and less decline in GCA over time (b = 0.06, 95% CI = [0.001, 0.12]). Baseline insomnia was related to better baseline MoCA (b = 1.54, 95% CI = [0.88, 2.21]) and less decline in MoCA over time (b = 0.56, 95% CI = [0.20, 0.92]). Furthermore, having more sleep disorders (across the 4 types) at baseline predicted better baseline MoCA and GCA, and less decline in MoCA and GCA over time. These results were only found in those with impaired cognition and generally consistent when using self-reported symptoms of sleep apnea or insomnia.

    Discussion and Implications

    Participants with sleep disorder diagnoses may have better access to healthcare, which may help maintain cognition through improved sleep.

     
    more » « less