A post-transcriptional regulatory landscape of aging in the female mouse hippocampus

Aging is associated with substantial physiological changes and constitutes a major risk factor for neurological disorders including dementia. Alterations in gene expression upon aging have been extensively studied; however, an in-depth characterization of post-transcriptional regulatory events remains elusive. Here, we profiled the age-related changes of the transcriptome and translatome in the female mouse hippocampus by RNA sequencing of total RNA and polysome preparations at four ages (3-, 6-, 12-, 20-month-old); and we implemented a variety of bioinformatics approaches to unravel alterations in transcript abundance, alternative splicing, and polyadenylation site selection. We observed mostly well-coordinated transcriptome and translatome expression signatures across age including upregulation of transcripts related to immune system processes and neuroinflammation, though transcripts encoding ribonucleoproteins or associated with mitochondrial functions, calcium signaling and the cell-cycle displayed substantial discordant profiles, suggesting translational control associated with age-related deficits in hippocampal-dependent behavior. By contrast, alternative splicing was less preserved, increased with age and was associated with distinct functionally-related transcripts encoding proteins acting at synapses/dendrites, RNA-binding proteins; thereby predicting regulatory roles for RBM3 and CIRBP. Only minor changes in polyadenylation site selection were identified, indicating pivotal 3′-end selection in young adults compared to older groups. Overall, our study provides a comprehensive resource of age-associated post-transcriptional regulatory events in the mouse hippocampus, enabling further examination of the molecular features underlying age-associated neurological diseases

Corrigendum: Circadian Chimeric Mice Reveal an Interplay Between the Suprachiasmatic Nucleus and Local Brain Clocks in the Control of Sleep and Memory.

[This corrects the article DOI: 10.3389/fnins.2021.639281.]

Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration.

Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 μl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use

Extrasynaptic GABAA receptors and the local regulation of sleep

GABA (γ-aminobutyric acid) is the main inhibitory transmitter in the mammalian brain. Recent studies emphasise the importance of extrasynaptic GABAA receptors (i.e., GABAA-Rs located outside the synapse) in controlling the excitability of local neuronal circuits. Extrasynaptic GABAA-Rs mediate a persistent tonic inhibitory transmission and the majority contain the δ-subunit. This novel type of transmission plays a key-role in maintaining the excitability of the thalamo-cortical circuits that generate sleep slow waves. Interestingly, drugs enhancing tonic inhibitory transmission induce slow waves. Traditionally, the regulation of the alternation between sleep and waking was considered to be a global brain process, regulated by the interaction of the circadian clock and a homeostatic process keeping track of how long we have been awake and asleep. However, several studies demonstrated that sleep is also regulated in a local, use-dependent manner. Thus, brain regions that are most activated during wakefulness show more slow waves during subsequent sleep. The aim of this project is to investigate the contribution of the δ-GABAA-Rs-mediated tonic transmission to the local, use-dependent regulation of slow wave sleep. We use an established model of local sleep regulation (i.e., unilateral whisker stimulation inducing changes selectively in the corresponding somatosensory cortex) in a mouse model deficient in the GABAA δ-subunit gene. We first investigate whether whisker stimulation during wakefulness alters the expression levels of δ-GABAA-Rs and other components underlying tonic inhibitory transmission in the controlateral somatosensory cortex and thalamus. We will also assess whether these changes are reversed during subsequent sleep and whether they are correlated with changes in sleep slow waves in the electroencephalogram. In addition, to uncover whether tonic inhibitory transmission contributes to the control of sleep regulation by the circadian clock, we will use an established protocol to separate use-dependent and circadian contributions to sleep regulation. Acknowledgements: Supported by BBSRC (BB/I008926/1

Modulation of Adult Hippocampal Neurogenesis by Sleep:Impact on Mental Health

The process of neurogenesis has been demonstrated to occur throughout life in the subgranular zone (SGZ) of the hippocampal dentate gyrus of several mammals, including humans. The basal rate of adult hippocampal neurogenesis can be altered by lifestyle and environmental factors. In this perspective review, the evidence for sleep as a modulator of adult hippocampal neurogenesis is first summarized. Following this, the impacts of sleep and sleep disturbances on hippocampal-dependent functions, including learning and memory, and depression are critically evaluated. Finally, we postulate that the effects of sleep on hippocampal-dependent functions may possibly be mediated by a change in adult hippocampal neurogenesis. This could provide a route to new treatments for cognitive impairments and psychiatric disorders

Characterisation of the Effects of Sleep Deprivation on the Electroencephalogram Using Permutation Lempel–Ziv Complexity, a Non-Linear Analysis Tool

Specific patterns of brain activity during sleep and waking are recorded in the electroencephalogram (EEG). Time-frequency analysis methods have been widely used to analyse the EEG and identified characteristic oscillations for each vigilance state (VS), i.e., wakefulness, rapid-eye movement (REM) and non-rapid-eye movement (NREM) sleep. However, other aspects such as change of patterns associated with brain dynamics may not be captured unless a non-linear-based analysis method is used. In this pilot study, Permutation Lempel–Ziv complexity (PLZC), a novel symbolic dynamics analysis method, was used to characterise the changes in the EEG in sleep and wakefulness during baseline and recovery from sleep deprivation (SD). The results obtained with PLZC were contrasted with a related non-linear method, Lempel–Ziv complexity (LZC). Both measure the emergence of new patterns. However, LZC is dependent on the absolute amplitude of the EEG, while PLZC is only dependent on the relative amplitude due to symbolisation procedure and thus, more resistant to noise. We showed that PLZC discriminates activated brain states associated with wakefulness and REM sleep, which both displayed higher complexity, compared to NREM sleep. Additionally, significantly lower PLZC values were measured in NREM sleep during the recovery period following SD compared to baseline, suggesting a reduced emergence of new activity patterns in the EEG. These findings were validated using PLZC on surrogate data. By contrast, LZC was merely reflecting changes in the spectral composition of the EEG. Overall, this study implies that PLZC is a robust non-linear complexity measure, which is not dependent on amplitude variations in the signal, and which may be useful to further assess EEG alterations induced by environmental or pharmacological manipulations

Effects of Ageing and Sex on Complexity in the Human Sleep EEG: A Comparison of Three Symbolic Dynamic Analysis Methods

Symbolic dynamic analysis (SDA) methods have been applied to biomedical signals and have been proven efficient in characterising differences in the electroencephalogram (EEG) in various conditions (e.g., epilepsy, Alzheimer’s, and Parkinson’s diseases). In this study, we investigated the use of SDA on EEGs recorded during sleep. Lempel-Ziv complexity (LZC), permutation entropy (PE), and permutation Lempel-Ziv complexity (PLZC), as well as power spectral analysis based on the fast Fourier transform (FFT), were applied to 8-h sleep EEG recordings in healthy men (n=31) and women (n=29), aged 20-74 years. The results of the SDA methods and FFT analysis were compared and the effects of age and sex were investigated. Surrogate data were used to determine whether the findings with SDA methods truly reflected changes in nonlinear dynamics of the EEG and not merely changes in the power spectrum. The surrogate data analysis showed that LZC merely reflected spectral changes in EEG activity, whereas PE and PLZC reflected genuine changes in the nonlinear dynamics of the EEG. All three SDA techniques distinguished the vigilance states (i.e., wakefulness, REM sleep, NREM sleep, and its sub-stages: stage 1, stage 2, and slow wave sleep). Complexity of the sleep EEG increased with ageing. Sex on the other hand did not affect the complexity values assessed with any of these three SDA methods, even though FFT detected sex differences. This study shows that SDA provides additional insights into the dynamics of sleep EEG and how it is affected by ageing

Food restriction induces functional resilience to sleep restriction in rats

Study Objectives. Sleep restriction leads to performance decrements across cognitive domains but underlying mechanisms remain largely unknown. The impact of sleep restriction on performance in rodents is often assessed using tasks in which food is the reward. Investigating how the drives of hunger and sleep interact to modulate performance may provide insights into mechanisms underlying sleep loss related performance decrements. Methods. Three experiments were conducted in male adult Wistar rats to assess: 1) Effects of food restriction on performance in the simple response latency task (SRLT) across the diurnal cycle (n=30); 2) Interaction of food restriction and sleep restriction (11-h) on SRLT performance, sleep EEG and event-related potentials (ERP) (n=10-13); 3) Effects of food restriction and sleep restriction on progressive ratio (PR) task performance to probe the reward value of food reinforcement (n=19). Results. Food restriction increased premature responding on the SRLT at the end of the light period of the diurnal cycle. Sleep restriction led to marked impairments in SRLT performance in the ad libitum-fed group, which were absent in the food-restricted group. After sleep restriction, food restricted rats displayed a higher amplitude of cue-evoked ERP components during the SRLT compared to the ad libitum group. Sleep restriction did not affect PR performance while food restriction improved performance. Conclusions. Hunger may induce a functional resilience to negative effects of sleep loss during subsequent task performance, possibly by maintaining attention to food-related cues.</p

Modulation of adult hippocampal neurogenesis by sleep: Impact on mental health

The process of neurogenesis has been demonstrated to occur throughout life in the subgranular zone (SGZ) of the hippocampal dentate gyrus of several mammals, including humans. The basal rate of adult hippocampal neurogenesis can be altered by lifestyle and environmental factors. In this perspective review, the evidence for sleep as a modulator of adult hippocampal neurogenesis is first summarized. Following this, the impacts of sleep and sleep disturbances on hippocampal-dependent functions, including learning and memory, and depression are critically evaluated. Finally, we postulate that the effects of sleep on hippocampal-dependent functions may possibly be mediated by a change in adult hippocampal neurogenesis. This could provide a route to new treatments for cognitive impairments and psychiatric disorders

Effects of ageing and sex on complexity in the human sleep EEG: a comparison of three symbolic dynamic analysis methods

Symbolic dynamic analysis (SDA) methods have been applied to biomedical signals and have been proven efficient in characterising differences in the electroencephalogram (EEG) in various conditions (e.g., epilepsy, Alzheimer’s and Parkinson’s diseases). In this study, we investigated the use of SDA on EEGs recorded during sleep. Lempel-Ziv Complexity (LZC), Permutation Entropy (PE), Permutation Lempel-Ziv Complexity (PLZC), as well as power spectral analysis based on the fast Fourier transform (FFT), were applied to 8-h sleep EEG recordings in healthy men (n=31) and women (n=29), aged 20-74 years. The results of the SDA methods and FFT analysis were compared and the effects of age and sex were investigated. Surrogate data were used to determine whether the findings with SDA methods truly reflected changes in non-linear dynamics of the EEG and not merely changes in the power spectrum. The surrogate data analysis showed that LZC merely reflected spectral changes in EEG activity, whereas PE and PLZC reflected genuine changes in the non-linear dynamics of the EEG. All three SDA techniques distinguished the vigilance states (i.e. wakefulness, REM sleep, NREM sleep and its sub stages: stage 1, stage 2 and slow wave sleep). Complexity of the sleep EEG increased with ageing. Sex on the other hand did not affect the complexity values assessed with any of these three SDA methods, even though FFT detected sex differences. This study shows that SDA provides additional insights into the dynamics of sleep EEG and how it is affected by ageing