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The preoptic area (POA) is necessary for sleep, but the fundamental POA circuits have remained elusive. Previous studies showed that galanin (GAL)- and GABA-producing neurons in the ventrolateral preoptic nucleus (VLPO) express cFos after periods of increased sleep and innervate key wake-promoting regions. Although lesions in this region can produce insomnia, high frequency photostimulation of the POA GAL neurons was shown to paradoxically cause waking, not sleep. Here we report that photostimulation of VLPO GAL neurons in mice promotes sleep with low frequency stimulation (1–4 Hz), but causes conduction block and waking at frequencies above 8 Hz. Further, optogenetic inhibition reduces sleep. Chemogenetic activation of VLPO GAL neurons confirms the increase in sleep, and also reduces body temperature. In addition, chemogenetic activation of VLPO GAL neurons induces short-latency sleep in an animal model of insomnia. Collectively, these findings establish a causal role of VLPO GAL neurons in both sleep induction and heat loss. Anatomical lesions of the preoptic area (POA) can cause sleep loss while electrical, chemical, or thermal stimulation of POA can induce sleep. To better understand the exact neural function of the POA, this study shows that galanin and GABA+ inhibitory neurons in the ventrolateral POA that project to the wake-promoting tuberomammillary nucleus promote sleep in a stimulation frequency dependent manner.

Men and women sleep differently. While much is known about the mechanisms that drive sleep, the reason for these sex differences in sleep behaviour is unknown and understudied. Historically, women and female animals are underrepresented in studies of sleep and its disorders. Nevertheless, there is a growing recognition of sex disparities in sleep and rhythm disorders. Women typically report poorer quality and more disrupted sleep across various stages of life. Findings from clinical and basic research studies strongly implicate a role for sex steroids in sleep modulation. Understanding how neuroendocrine mediators and sex differences influence sleep is central to advancing our understanding of sleep-related disorders. The investigation into sex differences and sex steroid modulation of sleep is in its infancy. Identifying the mechanisms underlying sex and gender differences in sleep will provide valuable insights leading to tailored therapeutics that benefit each sex. The goal of this review is to discuss our current understanding of how biological sex and sex steroids influence sleep behaviour from both the clinical and pre-clinical perspective.

Humans and animals lacking orexin neurons exhibit daytime sleepiness, sleep attacks, and state instability. While the circuit basis by which orexin neurons contribute to consolidated wakefulness remains unclear, existing models posit that orexin neurons provide their wake-stabilizing influence by exerting excitatory tone on other brain arousal nodes. Here we show using in vivo optogenetics, in vitro optogenetic-based circuit mapping, and single-cell transcriptomics that orexin neurons also contribute to arousal maintenance through indirect inhibition of sleep-promoting neurons of the ventrolateral preoptic nucleus. Activation of this subcortical circuit rapidly drives wakefulness from sleep by differentially modulating the activity of ventrolateral preoptic neurons. We further identify and characterize a feedforward circuit through which orexin (and co-released glutamate) acts to indirectly target and inhibit sleep-promoting ventrolateral preoptic neurons to produce arousal. This revealed circuitry provides an alternate framework for understanding how orexin neurons contribute to the maintenance of consolidated wakefulness and stabilize behavioral state. Sleep and wakefulness is stabilized by a population of orexin-expressing neurons. In this study, the authors demonstrate how these neurons drive arousal by silencing sleep-promoting neurons in the ventrolateral preoptic nucleus.

Growing evidence has indicated that right ventrolateral prefrontal cortex (RVLPFC) is critical in down-regulating emotional responses to social exclusion, and that depression is accompanied by social emotional dysregulation associated with reduced lateral prefrontal engagement. This study used anodal transcranial direct current stimulation (tDCS) to examine whether stimulating RVLPFC could improve emotional down-regulation of social exclusion in individuals with high depressive mood (DM). A total of 96 high and 94 low DM individuals received active or sham tDCS while viewing social exclusion or individual negative pictures under no-reappraisal (passive viewing) and reappraisal conditions. Participants rate their negative emotional experience following the presentation of each image. Pupil diameter and visual fixation duration were also recorded during the task. It was found that tDCS-activated RVLPFC induced a stronger regulation effect on social exclusion than individual negative emotions. The effect of tDCS on regulation of social exclusion was more pronounced in low v. high DM individuals. These findings demonstrate the specific role of RVLPFC on social emotion regulation, which has implications for refining target areas for the treatment of social emotion dysregulation in depression. However the findings do not suggest that high DM individuals benefit from a single-tDCS session on the emotion regulation of social exclusion. Thus we suggest to use multiple tDCS sessions or transcranial magnetic stimulation to further explore the therapeutic proposal in the future.

Background Trigeminal neuropathic pain (TNP) is a chronic condition characterized by heightened nociceptive responses and neuroinflammatory changes. While astrocytes are recognized as critical players in pain modulation, their specific role in influencing descending trigeminal pain pathways via ventrolateral orbitofrontal cortex (vlOFC) activity modulation remains underexplored. Therefore, we investigated the impact of optogenetic modulation of astrocytes in the vlOFC on pain hypersensitivity in a rat model of chronic constriction injury of the infraorbital nerve (CCI-ION). Method Adult female Sprague Dawley rats underwent ION constriction to mimic TNP symptoms, with naive and sham animals serving as controls. AAV8-GFAP-hChR2-mCherry, AAV8-GFAP-eNpHR3.0-mCherry, or AAV8-GFAP-mCherry were delivered to the vlOFC for in vivo optogenetic manipulation. Pain behaviors were assessed using acetone, von Frey, and elevated plus maze tests, while electrophysiological recordings from the ventrolateral periaqueductal gray (vlPAG) and ventral posteromedial (VPM) thalamus were obtained. Results Orofacial hyperalgesia, reduced vlPAG activity, and thalamic hyperexcitability were associated with vlOFC astrocytic hyperactivity in the TNP animals. In contrast, optogenetic inhibition of vlOFC astrocytes restored vlOFC glutamatergic signaling, increased vlPAG glutamatergic neuronal activity, and reduced hyperactivity in the VPM thalamus. Behavioral assessments also revealed alleviation of hyperalgesia, allodynia, and anxiety-like behaviors during the stimulation-ON phase, alongside reduced neuroinflammatory markers, including P2 × 3 and Iba-1. However, astrocytic excitation and null virus controls did not alter TNP responses, underscoring the specificity of astrocytic inhibition. Conclusion These findings suggest that the astrocytic subpopulation in the vlOFC and its robust influence on vlPAG glutamatergic neurons play a crucial role in restoring descending pain processing pathways, potentially contributing to the development of novel therapeutic approaches for TNP management.

•Our work offer valuable insights into decompose the dynamic cognitive-neural mechanism processing of the interpersonal emotion regulation (IER).•Our findings reveal that the left middle temporal gyrus and ventrolateral prefrontal cortex serve as pivotal regions for enhancing one's tendency and efficiency in utilizing IER, while also augmenting its regulatory effects.•The findings hold significant clinical implications, providing a foundation for future clinicians to precisely target specific brain regions in individuals with impaired social context, encompassing those afflicted with social anxiety disorder, and depression disorder. Interpersonal emotion regulation (IER) is a crucial ability for effectively recovering from negative emotions through social interaction. It has been emphasized that the empathy network, cognitive control network, and affective generation network sustain the deployment of IER. However, the temporal dynamics of functional connectivity among these networks of IER remains unclear. This study utilized IER task-fMRI and sliding window approach to examine both the stationary and dynamic functional connectivity (dFC) of IER. Fifty-five healthy participants were recruited for the present study. Through clustering analysis, four distinct brain states were identified in dFC. State 1 demonstrated situation modification stage of IER, with strong connectivity between affective generation and visual networks. State 2 exhibited pronounced connectivity between empathy network and both cognitive control and affective generation networks, reflecting the empathy stage of IER. Next, a ‘top-down’ pattern is observed between the connectivity of cognitive control and affective generation networks during the cognitive control stage of state 3. The affective response modulation stage of state 4 mainly involved connections between empathy and affective generation networks. Specifically, the degree centrality of the left middle temporal gyrus (MTG) mediated the association between one's IER tendency and the regulatory effects in state 2. The betweenness centrality of the left ventrolateral prefrontal cortex (VLPFC) mediated the association between one's IER efficiency and the regulatory effects in state 3. Altogether, these findings revealed that dynamic connectivity transitions among empathy, cognitive control, and affective generation networks, with the left VLPFC and MTG playing dominant roles, evident across the IER processing.

The ventrolateral prefrontal cortices (VLPFC) are crucial regions involved in voluntary emotion regulation. However, the lateralization of the VLPFC in downregulating negative emotions remains unclear; and whether the causal role of the VLPFC is generalizable to upregulating positive emotions is unexplored. This study used transcranial magnetic stimulation (TMS) to examine the causal relationship between the left/right VLPFC and social emotion reappraisal. One hundred and twenty participants were randomly assigned to either active (left and right VLPFC groups, n = 40/40) or sham (vertex, n = 40) TMS groups. Participants were instructed to passively receive social feedback or use reappraisal strategies to positively regulate their emotions. While the subjective emotional rating showed that the bilateral VLPFC facilitated the reappraisal success, the electrophysiological measure of the late positive potential (LPP) demonstrated a more critical role of the right VLPFC on social pain relief (decreased LPP amplitudes) and social reward magnification (enhanced LPP amplitudes). In addition, the influence of emotion regulation on social evaluation was found to be mediated by the memory of social feedback, indicating the importance of memory in social behavioral shaping. These findings suggest clinical protocols for the rehabilitation of emotion‐regulatory function in patients with affective and social disorders. Previous studies of our lab have revealed that the ventrolateral prefrontal cortices (VLPFC) are crucial regions involved in voluntary emotion regulation. However, the lateralization of the VLPFC (left or right) as well as the generalizability of its critical role to upregulating positive emotions is largely unclear. To answer these questions, this study used transcranial magnetic stimulation (TMS) together with event‐related potential techniques to examine the causal relationship between the left/right VLPFC and emotion regulation. It was found that the right VLPFC, compared to its right counterpart, significantly facilitated downregulating negative and upregulating positive emotions.

The ability to voluntarily regulate our emotional response to threatening and highly arousing stimuli by using cognitive reappraisal strategies is essential for our mental and physical well-being. This might be achieved by prefrontal brain regions (e.g. inferior frontal gyrus, IFG) down-regulating activity in the amygdala. It is unknown, to which degree effective connectivity within the emotion-regulation network is linked to individual differences in reappraisal skills. Using psychophysiological interaction analyses of functional magnetic resonance imaging data, we examined changes in inter-regional connectivity between the amygdala and IFG with other brain regions during reappraisal of emotional responses and used emotion regulation success as an explicit regressor. During down-regulation of emotion, reappraisal success correlated with effective connectivity between IFG with dorsolateral, dorsomedial and ventromedial prefrontal cortex (PFC). During up-regulation of emotion, effective coupling between IFG with anterior cingulate cortex, dorsomedial and ventromedial PFC as well as the amygdala correlated with reappraisal success. Activity in the amygdala covaried with activity in lateral and medial prefrontal regions during the up-regulation of emotion and correlated with reappraisal success. These results suggest that successful reappraisal is linked to changes in effective connectivity between two systems, prefrontal cognitive control regions and regions crucially involved in emotional evaluation.

BackgroundMigraine is a common headache disorder, with cortical spreading depolarization (CSD) considered as the underlying electrophysiological event. CSD is a slowly propagating wave of neuronal and glial depolarization. Sleep disorders are well known risk factors for migraine chronification, and changes in wake-sleep pattern such as sleep deprivation are common migraine triggers. The underlying mechanisms are unknown. As a step towards developing an animal model to study this, we test whether sleep deprivation, a modifiable migraine trigger, enhances CSD susceptibility in rodent models.MethodsAcute sleep deprivation was achieved using the “gentle handling method”, chosen to minimize stress and avoid confounding bias. Sleep deprivation was started with onset of light (diurnal lighting conditions), and assessment of CSD was performed at the end of a 6 h or 12 h sleep deprivation period. The effect of chronic sleep deprivation on CSD was assessed 6 weeks or 12 weeks after lesioning of the hypothalamic ventrolateral preoptic nucleus. All experiments were done in a blinded fashion with respect to sleep status. During 60 min of continuous topical KCl application, we assessed the total number of CSDs, the direct current shift amplitude and duration of the first CSD, the average and cumulative duration of all CSDs, propagation speed, and electrical CSD threshold.ResultsAcute sleep deprivation of 6 h (n = 17) or 12 h (n = 11) duration significantly increased CSD frequency compared to controls (17 ± 4 and 18 ± 2, respectively, vs. 14 ± 2 CSDs/hour in controls; p = 0.003 for both), whereas other electrophysiological properties of CSD were unchanged. Acute total sleep deprivation over 12 h but not over 6 h reduced the electrical threshold of CSD compared to controls (p = 0.037 and p = 0.095, respectively). Chronic partial sleep deprivation in contrast did not affect CSD susceptibility in rats.ConclusionsAcute but not chronic sleep deprivation enhances CSD susceptibility in rodents, possibly underlying its negative impact as a migraine trigger and exacerbating factor. Our findings underscore the importance of CSD as a therapeutic target in migraine and suggest that headache management should identify and treat associated sleep disorders.

The unique sedative activities with rapid arousal of dexmedetomidine (Dex) are not fully understood. Growing evidence suggests the involvement of the ventrolateral preoptic area (VLPO) in sleep–wake cycle. The major type in the VLPO is sleep-active neurons, inhibited by noradrenaline (NA(−) neurons). The other type of neurons is activated by NA (NA(+) neurons), which are wake-active. Previous research showed that Dex-induced sedation and sleep homeostasis likely share common mechanisms. To explore the underlying mechanisms of Dex in the VLPO, in vivo polysomnography recording and in vitro electrophysiological recording were used in our study. Bath application of Dex (2 μM) increased the firing rate of both VLPO NA(−) and NA(+) neurons. Compared to the control group, there was no difference in the firing rate of both VLPO NA(−) and NA(+) neurons after Dex (2 μM) and RS79948 (1 mM) administration, an α2 receptor antagonist. No difference was detected regarding resting membrane potential (RMP) amplitude of both VLPO NA (−) and NA(+) neurons after application of Dex (2 μM). Moreover, Dex (2 μM) significantly reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in both VLPO NA(−) and NA(+) neurons. These electrophysiology results were consistent with behavioral sedation, with increased nonrapid eye movement sleep (NREM sleep) and increased expression of c-Fos in the VLPO during the dark phase after intraperitoneal injection with Dex (80 μg/kg). In conclusion, Dex activates NA(−) and NA(+) neurons in the VLPO via presynaptic α2 receptors. This mechanism may explain the unique sedative properties with rapid arousal. Summary Statement Dexmedetomidine is an important ICU sedative. The mechanism of dexmedetomidine is not fully understood. Activating NA(−) and NA(+) neurons in the VLPO by dexmedetomidine using polysomnography and electrophysiological recording, this may explain the unique sedative properties with rapid arousal.