Phenotyping of light-activated neurons in the mouse SCN based on the expression of FOS and EGR1

Light-sensitive neurons are located in the ventral and central core of the suprachiasmatic nucleus (SCN), whereas stably oscillating clock neurons are found mainly in the dorsal shell. Signals between the SCN core and shell are believed to play an important role in light entrainment. Core neurons express vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), and Neuroglobin (Ngb), whereas the shell neurons express vasopressin (AVP), prokineticin 2, and the VIP type 2 (VPAC2) receptor. In rodents, light has a phase-shifting capacity at night, which induces rapid and transient expression of the EGR1 and FOS in the SCN.Methods: The present study used immunohistochemical staining of FOS, EGR1, and phenotypical markers of SCN neurons (VIP, AVP, Ngb) to identify subtypes/populations of light-responsive neurons at early night.Results: Double immunohistochemistry and cell counting were used to evaluate the number of SCN neurons expressing FOS and EGR1 in the SCN. The number of neurons expressing either EGR1 or FOS was higher than the total number of neurons co-storing EGR1 and FOS. Of the total number of light-responsive cells, 42% expressed only EGR1, 43% expressed only FOS, and 15% expressed both EGR1 and FOS. Light-responsive VIP neurons represented only 31% of all VIP neurons, and EGR1 represents the largest group of light-responsive VIP neurons (18%). VIP neurons expressing only FOS represented 1% of the total light-responsive VIP neurons. 81% of the Ngb neurons in the mouse SCN were light-responsive, and of these neurons expressing only EGR1 after light stimulation represented 44%, whereas 24% expressed FOS. Although most light-responsive neurons are found in the core of the SCN, 29% of the AVP neurons in the shell were light-responsive, of which 8% expressed EGR1, 10% expressed FOS, and 11% co-expressed both EGR1 and FOS after light stimulation.Discussion: Our analysis revealed cell-specific differences in light responsiveness between different peptidergic and Ngb-expressing neurons in different compartments of the mouse SCN, indicating that light activates diverse neuronal networks in the SCN, some of which participate in photoentrainment

Reference values for intracranial pressure and lumbar cerebrospinal fluid pressure: a systematic review.

Funder: Rigshospitalet; doi: http://dx.doi.org/10.13039/501100005111Funder: The DMSK FoundationBACKGROUND: Although widely used in the evaluation of the diseased, normal intracranial pressure and lumbar cerebrospinal fluid pressure remain sparsely documented. Intracranial pressure is different from lumbar cerebrospinal fluid pressure. In addition, intracranial pressure differs considerably according to the body position of the patient. Despite this, the current reference values do not distinguish between intracranial and lumbar cerebrospinal fluid pressures, and body position-dependent reference values do not exist. In this study, we aim to establish these reference values. METHOD: A systematic search was conducted in MEDLINE, EMBASE, CENTRAL, and Web of Sciences. Methodological quality was assessed using an amended version of the Joanna Briggs Quality Appraisal Checklist. Intracranial pressure and lumbar cerebrospinal fluid pressure were independently evaluated and subdivided into body positions. Quantitative data were presented with mean ± SD, and 90% reference intervals. RESULTS: Thirty-six studies were included. Nine studies reported values for intracranial pressure, while 27 reported values for the lumbar cerebrospinal fluid pressure. Reference values for intracranial pressure were -  5.9 to 8.3 mmHg in the upright position and 0.9 to 16.3 mmHg in the supine position. Reference values for lumbar cerebrospinal fluid pressure were 7.2 to 16.8 mmHg and 5.7 to 15.5 mmHg in the lateral recumbent position and supine position, respectively. CONCLUSIONS: This systematic review is the first to provide position-dependent reference values for intracranial pressure and lumbar cerebrospinal fluid pressure. Clinically applicable reference values for normal lumbar cerebrospinal fluid pressure were established, and are in accordance with previously used reference values. For intracranial pressure, this study strongly emphasizes the scarcity of normal pressure measures, and highlights the need for further research on the matter

Altered light induced EGR1 expression in the SCN of PACAP deficient mice.

The brain's biological clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus and generates circadian rhythms in physiology and behavior. The circadian clock needs daily adjustment by light to stay synchronized (entrained) with the astronomical 24 h light/dark cycle. Light entrainment occurs via melanopsin expressing retinal ganglion cells (mRGCs) and two neurotransmitters of the retinohypothalamic tract (RHT), PACAP and glutamate, which transmit light information to the SCN neurons. In SCN neurons, light signaling involves the immediate-early genes Fos, Egr1 and the clock genes Per1 and Per2. In this study, we used PACAP deficient mice to evaluate PACAP's role in light induced gene expression of EGR1 in SCN neurons during early (ZT17) and late (ZT23) subjective night at high (300 lux) and low (10 lux) white light exposure. We found significantly lower levels of both EGR1 mRNA and protein in the SCN in PACAP deficient mice compared to wild type mice at early subjective night (ZT17) exposed to low but not high light intensity. No difference was found between the two genotypes at late night (ZT23) at neither light intensities. In conclusion, light mediated EGR1 induction in SCN neurons at early night at low light intensities is dependent of PACAP signaling. A role of PACAP in shaping synaptic plasticity during light stimulation at night is discussed

k-Shape clustering for extracting macro-patterns in intracranial pressure signals

BACKGROUND: Intracranial pressure (ICP) monitoring is a core component of neurosurgical diagnostics. With the introduction of telemetric monitoring devices in the last years, ICP monitoring has become feasible in a broader clinical setting including monitoring during full mobilization and at home, where a greater diversity of ICP waveforms are present. The need for identification of these variations, the so-called macro-patterns lasting seconds to minutes—emerges as a potential tool for better understanding the physiological underpinnings of patient symptoms. METHODS: We introduce a new methodology that serves as a foundation for future automatic macro-pattern identification in the ICP signal to comprehensively understand the appearance and distribution of these macro-patterns in the ICP signal and their clinical significance. Specifically, we describe an algorithm based on k-Shape clustering to build a standard library of such macro-patterns. RESULTS: In total, seven macro-patterns were extracted from the ICP signals. This macro-pattern library may be used as a basis for the classification of new ICP variation distributions based on clinical disease entities. CONCLUSIONS: We provide the starting point for future researchers to use a computational approach to characterize ICP recordings from a wide cohort of disorders

Transient intracranial pressure elevations (B waves) are associated with sleep apnea

Background: Repetitive transient intracranial pressure waveform elevations up to 50 mmHg (ICP B-waves) are often used to define pathological conditions and determine indications for ICP-reducing treatment. We recently showed that nocturnal transient ICP elevations are present in patients without structural brain lesions or hydrocephalus in whom they are associated with sleep apnea. However, whether this signifies a general association between ICP macropatterns and sleep apnea remains unknown. Methods: We included 34 patients with hydrocephalus, or idiopathic intracranial hypertension (IIH), who were referred to the Neurosurgical Department, Copenhagen, Denmark, from 2017 to 2021. Every patient underwent diagnostic overnight ICP monitoring for clinical indications, with simultaneous polysomnography (PSG) sleep studies. All transient ICP elevations were objectively quantified in all patients. Three patients were monitored with continuous positive airway pressure (CPAP) treatment for an additional night. Results: All patients had transient ICP elevations associated with sleep apnea. The mean temporal delay from sleep apnea to transient ICP elevations for all patients was 3.6 s (SEM 0.2 s). Ramp-type transient ICP elevations with a large increase in ICP were associated with rapid eye movement (REM) sleep and sinusoidal-type elevations with non-REM (NREM) sleep. In three patients treated with CPAP, the treatment reduced the number of transient ICP elevations with a mean of 37%. CPAP treatment resulted in insignificant changes in the average ICP in two patients but elevated the average ICP during sleep in one patient by 5.6 mmHg. Conclusion: The findings suggest that sleep apnea causes a significant proportion of transient ICP elevations, such as B-waves, and sleep apnea should be considered in ICP evaluation. Treatment of sleep apnea with CPAP can reduce the occurrence of transient ICP elevations. More research is needed on the impact of slow oscillating mechanisms on transient ICP elevations during high ICP and REM sleep.</p

Intracranial pressure following surgery of an unruptured intracranial aneurysm—a model for normal intracranial pressure in humans

Abstract Objective Optimizing the treatment of several neurosurgical and neurological disorders relies on knowledge of the intracranial pressure (ICP). However, exploration of normal ICP and intracranial pressure pulse wave amplitude (PWA) values in healthy individuals poses ethical challenges, and thus the current documentation remains scarce. This study explores ICP and PWA values for healthy adults without intracranial pathology expected to influence ICP. Methods Adult patients (age > 18 years) undergoing surgery for an unruptured intracranial aneurysm without any other neurological co-morbidities were included. Patients had a telemetric ICP sensor inserted, and ICP was measured in four different positions: supine, lateral recumbent, standing upright, and 45-degree sitting, at day 1, 14, 30, and 90 following the surgery. Results ICP in each position did not change with time after surgery. Median ICP was 6.7 mmHg and median PWA 2.1 mmHg in the supine position, while in the upright standing position median ICP was − 3.4 mmHg and median PWA was 1.9 mmHg. After standardization of the measurements from the transducer site to the external acoustic meatus, the median ICPmidbrain was 8.3 mmHg in the supine position and 1.2 mmHg in the upright standing position. Conclusion Our study provides insights into normal ICP dynamics in healthy adults following a uncomplicated surgery for an unruptured aneurysm. These results suggest a slightly wider normal reference range for invasive intracranial pressure than previously suggested, and present the first normal values for PWA in different positions. Further studies are, however, essential to enhance our understanding of normal ICP. Trial registration The study was preregistered at www.clinicaltrials.gov (NCT03594136) (11 July 2018