Medial Septal Glutamatergic Neurons Modulate States of Consciousness during Sevoflurane Anesthesia in Mice.

BACKGROUND: Multiple neural structures involved in maintaining wakefulness have been found to promote arousal from general anesthesia. The medial septum is a critical region that modulates arousal behavior. This study hypothesized that glutamatergic neurons in the medial septum play a crucial role in regulating states of consciousness during sevoflurane general anesthesia. METHODS: Adult male mice were used in this study. The effects of sevoflurane anesthesia on neuronal activity were determined by fiber photometry. Lesions and chemogenetic manipulations were used to study the effects of the altered activity of medial septal glutamatergic neurons on anesthesia induction, emergence, and sensitivity to sevoflurane. Optogenetic stimulation was used to observe the role of acute activation of medial septal glutamatergic neurons on cortical activity and behavioral changes during sevoflurane-induced continuous steady state of general anesthesia and burst suppression state. RESULTS: The authors found that medial septal glutamatergic neuronal activity decreased during sevoflurane anesthesia induction and recovered in the early period of emergence. Chemogenetic activation of medial septal glutamatergic neurons prolonged the induction time (mean ± SD, hM3Dq-clozapine N-oxide vs. hM3Dq-saline, 297.5 ± 60.1 s vs. 229.4 ± 29.9 s, P < 0.001, n = 11) and decreased the emergence time (53.2 ± 11.8 s vs. 77.5 ± 33.5 s, P = 0.025, n = 11). Lesions or chemogenetic inhibition of these neurons produced the opposite effects. During steady state of general anesthesia and deep anesthesia-induced burst suppression state, acute optogenetic activation of medial septal glutamatergic neurons induced cortical activation and behavioral emergence. CONCLUSIONS: The study findings reveal that activation of medial septal glutamatergic neurons has arousal-promoting effects during sevoflurane anesthesia in male mice. The activation of these neurons prolongs the induction and accelerates the emergence of anesthesia.

Medial septum glutamatergic neurons modulate nociception in chronic neuropathic pain via projections to lateral hypothalamus.

The medial septum (MS) contributes in pain processing and regulation, especially concerning persistent nociception. However, the role of MS glutamatergic neurons in pain and the underlying neural circuit mechanisms in pain remain poorly understood. In this study, chronic constrictive injury of the sciatic nerve (CCI) surgery was performed to induce thermal and mechanical hyperalgesia in mice. The chemogenetic activation of MS glutamatergic neurons decreased pain thresholds in naïve mice. In contrast, inhibition or ablation of these neurons has improved nociception thresholds in naïve mice and relieved thermal and mechanical hyperalgesia in CCI mice. Anterograde viral tracing revealed that MS glutamatergic neurons had projections to the lateral hypothalamus (LH) and supramammillary nucleus (SuM). We further demonstrated that MS glutamatergic neurons regulate pain thresholds by projecting to LH but not SuM, because the inhibition of MS-LH glutamatergic projections suppressed pain thresholds in CCI and naïve mice, yet, optogenetic activation or inhibition of MS-SuM glutamatergic projections had no effect on pain thresholds in naïve mice. In conclusion, our results reveal that MS glutamatergic neurons play a significant role in regulating pain perception and decipher that MS glutamatergic neurons modulate nociception via projections to LH.

Alteration of neural activity and neuroinflammatory factors in the insular cortex of mice with corneal neuropathic pain.

Dry eye disease (DED) affects nearly 55% of people worldwide; several studies have proposed that central sensitization and neuroinflammation may contribute to the developing corneal neuropathic pain of DED, while the underlying mechanisms of this contribution remain to be investigated. Excision of extra orbital lacrimal glands established the dry eye model. Corneal hypersensitivity was examined through chemical and mechanical stimulation, and open field test measured the anxiety levels. Restingstate fMRI is a method of functional magnetic resonance imaging (rs-fMRI) was performed for anatomical involvement of the brain regions. The amplitude of low-frequency fluctuation (ALFF) determined brain activity. Immunofluorescence testing and Quantitative real-time polymerase chain reaction were also performed to further validate the findings. Compared with the Sham group, ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were increased in the dry eye group. This change of ALFF in the insular cortex was linked with the increment in corneal hypersensitivity (p < 0.01), c-Fos (p < 0.001), brain-derived neurotrophic factor (p < 0.01), TNF-α, IL-6, and IL-1ß (p < 0.05). In contrast, IL-10 levels (p < 0.05) decreased in the dry eye group. DED-induced corneal hypersensitivity and upregulation of inflammatory cytokines could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin-B (p < 0.01) without affecting anxiety levels. Our study reveals that the functional activity of the brain associated with corneal neuropathic pain and neuroinflammation in the insular cortex might contribute to dry eye-related corneal neuropathic pain.

The piRNA response to BmNPV infection in the silkworm fat body and midgut.

Bombyx mori nucleopolyhedrovirus (BmNPV) is a DNA virus that causes huge losses to the silkworm industry but the piRNA responses during BmNPV infection in the silkworm remain uninvestigated. Here, silkworm piRNA profiles of uninfected and BmNPV-infected fat body and midgut were determined by high-through sequencing in the early stages of BmNPV infection. A total of 2675 and 3396 genome-derived piRNAs were identified from fat body and midgut, respectively. These genome-derived piRNAs mainly originated from unannotated instead of transposon regions in the silkworm genome. In total, 572 piRNAs were associated with 280 putative target genes in fat body and 805 piRNAs with 380 target genes in midgut. Compared to uninfected tissues, 322 and 129 piRNAs were significantly upregulated in BmNPV-infected fat body and midgut, respectively. In addition, 276 and 117 piRNAs were significantly downregulated. Moreover, differentially expressed (DE) piRNAs during BmNPV infection differed significantly between fat body and midgut. Putative DE piRNA-targeted genes were associated with "response to stimulus" and "environmental information processing" in fat body after infection with BmNPV, which may indicate an active piRNA response to BmNPV infection in fat body. This study may lay the foundation for future research of the potential roles of the piRNA pathway and specific piRNAs in BmNPV pathogenesis.