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.
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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.
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- Award ID(s):
- 1652060
- NSF-PAR ID:
- 10191203
- Date Published:
- Journal Name:
- Sleep
- Volume:
- 43
- Issue:
- 5
- ISSN:
- 0161-8105
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract ANK3 is a leading bipolar disorder (BD) candidate gene in humans and provides a unique opportunity for studying epilepsy-BD comorbidity. Previous studies showed that deletion ofAnk3-1b , a BD-associated variant ofAnk3 in mice leads to increased firing threshold and diminished action potential dynamic range of parvalbumin (PV) interneurons and absence epilepsy, thus providing a biological mechanism linking epilepsy and BD. To explore the behavioral overlap of these disorders, we characterized behavioral patterns ofAnk3-1b KO mice during overnight home-cage activity and examined network activity during these behaviors using paired video and EEG recordings. Since PV interneurons contribute to the generation of high-frequency gamma oscillations, we anticipated changes in the power of neocortical EEG signals in the gamma frequency range (> 25 Hz) during behavioral states related to human BD symptoms, including abnormal sleep, hyperactivity, and repetitive behaviors.Ank3-1b KO mice exhibited an overall increase in slow gamma (~25-45 Hz) power compared to controls, and slow gamma power correlated with seizure phenotype severity across behaviors. During sleep, increased slow gamma power correlated with decreased time spent in the rapid eye movement (REM) stage of sleep. Seizures were more common during REM sleep compared to non-REM (NREM) sleep. We also found thatAnk3-1b KO mice were hyperactive and exhibited a repetitive behavior phenotype that co-occurred with increased slow gamma power. Our results identify a novel EEG biomarker associatingAnk3 genetic variation with BD and epilepsy and suggest modulation of gamma oscillations as a potential therapeutic target. -
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Abstract Study Objectives To use relatively noisy routinely collected clinical data (brain magnetic resonance imaging (MRI) data, clinical polysomnography (PSG) recordings, and neuropsychological testing), to investigate hypothesis-driven and data-driven relationships between brain physiology, structure, and cognition.
Methods We analyzed data from patients with clinical PSG, brain MRI, and neuropsychological evaluations. SynthSeg, a neural network-based tool, provided high-quality segmentations despite noise. A priori hypotheses explored associations between brain function (measured by PSG) and brain structure (measured by MRI). Associations with cognitive scores and dementia status were studied. An exploratory data-driven approach investigated age-structure-physiology-cognition links.
Results Six hundred and twenty-three patients with sleep PSG and brain MRI data were included in this study; 160 with cognitive evaluations. Three hundred and forty-two participants (55%) were female, and age interquartile range was 52 to 69 years. Thirty-six individuals were diagnosed with dementia, 71 with mild cognitive impairment, and 326 with major depression. One hundred and fifteen individuals were evaluated for insomnia and 138 participants had an apnea–hypopnea index equal to or greater than 15. Total PSG delta power correlated positively with frontal lobe/thalamic volumes, and sleep spindle density with thalamic volume. rapid eye movement (REM) duration and amygdala volume were positively associated with cognition. Patients with dementia showed significant differences in five brain structure volumes. REM duration, spindle, and slow-oscillation features had strong associations with cognition and brain structure volumes. PSG and MRI features in combination predicted chronological age (R2 = 0.67) and cognition (R2 = 0.40).
Conclusions Routine clinical data holds extended value in understanding and even clinically using brain-sleep-cognition relationships.
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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
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1093/sleep/zsz296
