The neurochemical changes underlying human emotions and social behavior are largely unknown. Here we report on the changes in the levels of two hypothalamic neuropeptides, hypocretin-1 (Hcrt-1) and melanin concentrating hormone (MCH), measured in the human amygdala. We show that Hcrt-1 levels are maximal during positive emotion, social interaction, and anger, behaviors that induce cataplexy in human narcoleptics. In contrast, MCH levels are minimal during social interaction, but are increased after eating. Both peptides are at minimal levels during periods of postoperative pain despite high levels of arousal. MCH levels increase at sleep onset, consistent with a role in sleep induction, whereas Hcrt-1 levels increase at wake onset, consistent with a role in wake induction. Levels of these two peptides in humans are not simply linked to arousal, but rather to specific emotions and state transitions. Other arousal systems may be similarly emotionally specialized.

SUMMARY The fur seal (Callorhinus ursinus), a member of the Pinniped family, displays a highly expressed electroencephalogram (EEG) asymmetry during slow wave sleep (SWS), which is comparable with the unihemispheric sleep in cetaceans. In this study, we investigated the EEG asymmetry in the fur seal using spectral analysis. Four young (2-3 years old) seals were implanted with EEG electrodes for polygraphic sleep recording.In each animal, EEG spectral power in the frequency range of 1.2-16 Hz was computed in symmetrical cortical recordings over two consecutive nights. The degree of EEG asymmetry was measured by using thewhere L and R are the spectral powers in the left and right hemispheres, respectively]. In fur seals, EEG asymmetry, as measured by the percent of 20-s epochs with absolute AI > 0.3 and >0.6, was expressed in the entire frequency range (1.2-16 Hz). The asymmetry was significantly greater during SWS (25.6-44.2% of all SWS epochs had an absolute AI > 0.3 and 2.1-12.2% of all epochs had AI > 0.6) than during quiet waking (11.0-20.3% and 0-1.9% of all waking epochs, respectively) and REM sleep (4.2-8.9% of all REM sleep epochs and no epochs, respectively). EEG asymmetry was recorded during both low-and high-voltage SWS, and was maximal in the range of 1.2-4 and 12-16 Hz. As shown in this study, the degree of EEG asymmetry and the frequency range in which it is expressed during SWS in fur seals are profoundly different from those of terrestrial mammals and birds.

Fur seals are unique in that they display both bilateral slow-wave sleep (BSWS), as seen in all terrestrial mammals, and slow-wave sleep with interhemispheric electroencephalogram (EEG) asymmetry, resembling the unihemispheric slow waves of cetaceans. Little is known about the underlying mechanisms of this phenomenon, which is also termed asymmetrical slow wave sleep (ASWS). However, we may begin to understand the expression of ASWS by studying the neurotransmitter systems thought to be involved in the generation and maintenance of sleep-wake states in terrestrial mammals. We examined bilaterally the release of cortical acetylcholine (ACh), a neurotransmitter implicated in the regulation of cortical EEG and behavioral arousal, across the sleep-wake cycle in four juvenile northern fur seals (Callorhinus ursinus). In vivo microdialysis and high-performance liquid chromatography coupled with electrochemical detection were used to measure cortical ACh levels during polygraphically defined behavioral states. Cortical ACh release was state-dependent, showing maximal release during active waking (AW), similar levels during quiet waking (QW), and rapid eye movement (REM) sleep, and minimal release during BSWS. When compared with BSWS, cortical ACh levels increased ϳ300% during AW, and ϳ200% during QW and REM sleep. During these bilaterally symmetrical EEG states, ACh was synchronously released from both hemispheres. However, during ASWS, ACh release was lateralized with greater release in the hemisphere displaying lower voltage activity, at levels approximating those seen in QW. These findings demonstrate that cortical ACh release is tightly linked to hemispheric EEG activation.

We developed a rules‐based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co‐occurrence, segregation, and functional studies collected from internal and external sources. Scores were calculated by trained scientists using a quantitative framework that assigned differential weighting to these five types of data. We performed descriptive and comparative statistics on the dataset and tested interobserver concordance among the trained scientists. Private variants defined as variants found within single families (n = 5,182), were either VUS (80.5%; n = 4,169) or likely pathogenic (19.5%; n = 1,013). The remaining variants (n = 6,712) were VUS (38.4%; n = 2,577) or likely benign/benign (34.7%; n = 2,327) or likely pathogenic/pathogenic (26.9%, n = 1,808). Exact agreement between the trained scientists on the final variant score was 98.5% [95% confidence interval (CI) (98.0, 98.9)] with an interobserver consistency of 97% [95% CI (91.5, 99.4)]. Variant scores were stable and showed increasing odds of being in agreement with new data when re‐evaluated periodically. This carefully curated, standardized variant pathogenicity scoring system provides reliable pathogenicity scores for DNA variants encountered in a clinical laboratory setting.

Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a “designer” receptor into the HMN and selectively modulated it with a “designer” drug. We used cre-dependent viral vectors (AAV8-hSyn-DIO-hM3Dq-mCherry) to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq (activating) receptors. We measured sleep and breathing in three conditions: (i) sham, (ii) after systemic administration of clozapine-N-oxide (CNO; 1 mg/kg) or (iii) vehicle. CNO activates hM3Dq receptors but is otherwise biologically inert. Systemic administration of CNO caused significant and sustained increases in tongue muscle activity in non-REM (261 ± 33% for 10 hrs) and REM sleep (217 ± 21% for 8 hrs), both P < 0.01 versus controls. Responses were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states. These results support targeting a selective and restricted “druggable” target at the HMN (e.g., Kir2.4) to activate tongue motor activity during sleep.

No abstract

During the nursing period seals undergo several physiological and behavioural changes. A key component of development is increased cardiorespiratory control, fundamental for breath-holding and thus diving. This study focused on the ontogenetic changes in cardiac responses to respiration in quietly resting, pre-weaned harbour seal pups (Phoca vitulina). During periods of quiet rest, breathing became episodic, eupnoea interspersed with periods of apnoea. Little change was observed in respiration (~35·breaths·min -1 ) and eupnoeic heart rate (~160·beats·min -1 ) throughout the nursing period. However, apnoea duration increased (from ~20 to 40·s), while apnoeic heart rate decreased with age (from 150 to 90·beats·min -1 ). The observed decline in apnoeic heart rate resulted from an increase in cardiorespiratory control as pups approached weaning, evident by the ability to maintain a lower heart rate more consistently. Similar changes in cardiorespiratory patterns have been reported for elephant and Weddell seals. Due to the early onset of independent foraging, however, the rate of cardiorespiratory control development was more rapid in harbour seals. Our findings suggest that by 1 month of age, harbour seal pups possess the cardiorespiratory control necessary to sustain long-duration apnoeas, fundamental for proficient diving and successful foraging upon weaning.

Several behavioral and physiological adaptations have been developed in evolution of Pinnipeds allowing them to sleep both on land and in water. To date sleep has been examined in detail in eared and true seals (the families of Otariidae and Phocidae). The aim of this study was to examine sleep in another semiaquatic mammal - the walrus, which is the only extant representative of the family Odobenidae. Slow wave and paradoxical sleep (SWS and PS) in the examined walrus (2 year old female, weight 130 kg) averaged 19.4 ± 2.0 and 6.9 ± 1.1% of 24-h when on land, and 20.5 ± 0.8% of 24-h and 1.1 ± 0.6% when in water, respectively. The average duration of PS episode was 6.4 ± 0.6 min (maximum 23 min) when on land and 1.8 ± 0.1 min (maximum 3.3 min) when in water. In water, sleep occurred predominantly while the walrus submerged and lay on the bottom of the pool (89% of total sleep time). The walrus usually woke up while emerging to the surface for breathing. Most often EEG slow waves developed synchronously in both cortical hemispheres (90% of SWS time when on land and 97% when in water). Short episodes of interhemispheric EEG asymmetry usually coincided with brief opening of one eye. The pattern of sleep in the walrus was similar to the pattern of sleep in the Otariidae seals while on land (predominantly bilateral SWS, accompanied by regular breathing) and to the pattern of sleep in the Phocidae while in water (sleep during apneas both in depth and at the surface, interrupted by brief arousal when emerging for breathing).