Polychlorinated biphenyl and polybrominated diphenyl ether profiles vary with feeding ecology and marine rearing distribution among 10 Chinook salmon (Oncorhynchus tshawytscha) stocks in the North Pacific Ocean.

Chinook salmon (Oncorhynchus tshawytscha) along the west coast of North America have experienced significant declines in abundance and body size over recent decades due to several anthropogenic stressors. Understanding the reasons underlying the relatively high levels of persistent organic pollutants (POPs) in Chinook stocks is an important need, as it informs recovery planning for this foundation species, as well for the Chinook-dependent Resident killer whales (Orcinus orca, RKW) of British Columbia (Canada) and Washington State (USA). We evaluated the influence of stock-related differences in feeding ecology, using stable isotopes, and marine rearing ground on the concentrations and patterns of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in Chinook salmon. A principal components analysis (PCA) revealed a clear divergence of PCB and PBDE congener patterns between Chinook with a nearshore rearing distribution ('shelf resident') versus a more offshore distribution. Shelf resident Chinook had 12-fold higher PCB concentrations and 46-fold higher PBDE concentrations relative to offshore stocks. Shelf resident Chinook had PCB and PBDE profiles that were heavier and dominated by more bioaccumulative congeners, respectively. The higher δ13C and δ15N in shelf resident Chinook compared to the offshore rearing stocks, and their different marine distributions explain the large divergence in contaminant levels and profiles, with shelf resident stocks being heavily influenced by land-based sources of industrial contamination. Results provide compelling new insight into the drivers of contaminant accumulation in Chinook salmon, raise important questions about the consequences for their health, and explain a major pathway to the heavily POP-contaminated Resident killer whales that consume them.

Regulation of mouse exploratory behaviour by irradiance and cone-opponent signals.

BACKGROUND: Animal survival depends on the ability to adjust behaviour according to environmental conditions. The circadian system plays a key role in this capability, with diel changes in the quantity (irradiance) and spectral content ('colour') of ambient illumination providing signals of time-of-day that regulate the timing of rest and activity. Light also exerts much more immediate effects on behaviour, however, that are equally important in shaping daily activity patterns. Hence, nocturnal mammals will actively avoid light and dramatically reduce their activity when light cannot be avoided. The sensory mechanisms underlying these acute effects of light are incompletely understood, particularly the importance of colour. RESULTS: To define sensory mechanisms controlling mouse behaviour, we used photoreceptor-isolating stimuli and mice with altered cone spectral sensitivity (Opn1mwR), lacking melanopsin (Opn1mwR; Opn4-/-) or cone phototransduction (Cnga3-/-) in assays of light-avoidance and activity suppression. In addition to roles for melanopsin-dependent irradiance signals, we find a major influence of spectral content in both cases. Hence, remarkably, selective increases in S-cone irradiance (producing a blue-shift in spectrum replicating twilight) drive light-seeking behaviour and promote activity. These effects are opposed by signals from longer-wavelength sensitive cones, indicating a true spectrally-opponent mechanism. Using c-Fos-mapping and multielectrode electrophysiology, we further show these effects are associated with a selective cone-opponent modulation of neural activity in the key brain site implicated in acute effects of light on behaviour, the subparaventricular zone. CONCLUSIONS: Collectively, these data reveal a mechanism whereby blue-shifts in the spectrum of environmental illumination, such as during twilight, promote mouse exploratory behaviour.

Colour opponency is widespread across the mouse subcortical visual system and differentially targets GABAergic and non-GABAergic neurons.

Colour vision plays many important roles in animal behaviour but the brain pathways processing colour remain surprisingly poorly understood, including in the most commonly used laboratory mammal, mice. Indeed, particular features of mouse retinal organisation present challenges in defining the mechanisms underlying colour vision in mice and have led to suggestions that this may substantially rely on 'non-classical' rod-cone opponency. By contrast, studies using mice with altered cone spectral sensitivity, to facilitate application of photoreceptor-selective stimuli, have revealed widespread cone-opponency across the subcortical visual system. To determine the extent to which such findings are truly reflective of wildtype mouse colour vision, and facilitate neural circuit mapping of colour-processing pathways using intersectional genetic approaches, we here establish and validate stimuli for selectively manipulating excitation of the native mouse S- and M-cone opsin classes. We then use these to confirm the widespread appearance of cone-opponency (> 25% of neurons) across the mouse visual thalamus and pretectum. We further extend these approaches to map the occurrence of colour-opponency across optogenetically identified GABAergic (GAD2-expressing) cells in key non-image forming visual centres (pretectum and intergeniculate leaflet/ventral lateral geniculate; IGL/vLGN). Strikingly, throughout, we find S-ON/M-OFF opponency is specifically enriched in non-GABAergic cells, with identified GABAergic cells in the IGL/VLGN entirely lacking this property. Collectively, therefore, we establish an important new approach for studying cone function in mice, confirming a surprisingly extensive appearance of cone-opponent processing in the mouse visual system and providing new insight into functional specialisation of the pathways processing such signals.

Factors associated with time to initiation of a PCSK9 inhibitor after hospital discharge for acute myocardial infarction.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) lower atherosclerotic cardiovascular disease (ASCVD) event risk. OBJECTIVE: Analyze patient characteristics associated with time to PCSK9i initiation following an acute myocardial infarction (AMI). METHODS: We analyzed characteristics of patients ≥21 years of age in the Marketscan or Medicare databases who initiated a PCSK9i 0-89 days, 90-179 days, or 180-365 days after an AMI between July 2015 and December 2018 (n=1,705). We estimated the cumulative incidence of recurrent ASCVD events before PCSK9i initiation. RESULTS: Overall, 42%, 25%, and 33% of patients who initiated a PCSK9i did so 0-89 days, 90-179 days, and 180-365 days following AMI hospital discharge, respectively. Taking ezetimibe prior to AMI hospitalization and initiating ezetimibe within 30 days after AMI hospital discharge were each associated with a higher likelihood of PCSK9i initiation in the 0-89 days versus 180-365 days post-discharge (adjusted odds ratio [OR] 1.83, 95% confidence interval [95%CI] 1.35-2.49 and 1.76, 95%CI 1.11-2.80, respectively). Statin use before and statin initiation within 30 days after AMI hospitalization were associated with a lower likelihood of PCSK9i initiation 0-89 days versus 180-365 days post-discharge (adjusted OR 0.64, 95%CI 0.49-0.84 and 0.39, 95%CI 0.28-0.54, respectively). Overall, 8.0%, 10.5%, and 12.5% of patients had an ASCVD event at 90, 180, and 365 days following AMI hospital discharge and before initiating a PCSK9i, respectively. CONCLUSION: Among patients initiating a PCSK9i after AMI, a low proportion did so within 89 days of hospital discharge. Many patients had a recurrent ASCVD event before treatment initiation.

Commissural communication allows mouse intergeniculate leaflet and ventral lateral geniculate neurons to encode interocular differences in irradiance.

KEY POINTS: Unlike other visual thalamic regions, the intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/vLGN) possess extensive reciprocal commissural connections, the functions of which are unknown. Using electrophysiological approaches, it is shown that commissural projecting IGL/vLGN cells are primarily activated by light increments to the contralateral eye while cells receiving commissural input typically exhibit antagonistic binocular responses. Across antagonistic cells, the nature of the commissural input (excitatory or inhibitory) corresponds to the presence of ipsilateral ON or OFF visual responses and in both cases antagonistic responses disappear following inactivation of the contralateral thalamus. The steady state firing rates of antagonistic cells uniquely encode interocular differences in irradiance. There is a pivotal role for IGL/vLGN commissural signalling in generating new sensory properties that are potentially useful for the proposed contributions of these nuclei to visuomotor/vestibular and circadian control. ABSTRACT: The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/vLGN) are portions of the visual thalamus implicated in circadian and visuomotor/vestibular control. A defining feature of IGL/vLGN organisation is the presence of extensive reciprocal commissural connections, the functions of which are at present unknown. Here we use a combination of multielectrode recording, electrical microstimulation, thalamic inactivation and a range of visual stimuli in mice to address this deficit. Our data indicate that, like most IGL/vLGN cells, those that project commissurally primarily convey contralateral ON visual signals while most IGL/vLGN neurons that receive this input exhibit antagonistic binocular responses (i.e. excitatory responses driven by one eye and inhibitory responses driven by the other), enabling them to encode interocular differences in irradiance. We also confirm that this property derives from commissural input since, following inactivation of the contralateral visual thalamus, these cells instead display monocular contralateral-driven ON responses. Our data thereby reveal a fundamental role for commissural signalling in generating new visual response properties at the level of the visual thalamus.

Spatial and temporal trends of alternative flame retardants and polybrominated diphenyl ethers in ringed seals (Phoca hispida) across the Canadian Arctic.

Concentrations of alternative flame retardants and polybrominated diphenyl ethers (PBDEs) were analyzed in ringed seal (Phoca hispida) blubber collected across the Canadian Arctic during subsistence hunts between 1998 and 2013. More than 80% of sampled animals were females and juvenile males. The highest mean ΣPBDE concentrations (sum of 13 congeners) were found in seals from Nain (Nunatsiavut) as well as Inukjuaq and Arviat (Hudson Bay) and the lowest mean levels were found in seals from Lancaster Sound. BDE-47 and -99 were the predominant PBDE congeners quantified in ringed seals. The most frequently detected non-PBDE flame retardants were polybrominated biphenyl 101 (BB-101, 57% of samples analyzed for this chemical), hexabromocyclododecane (HBCDD; 38%), hexabromobenzene (HBB, 30%), and 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EHTeBB, 23%). The relative trophic position of seals, estimated using stable isotopes, did not vary over time and did not influence flame retardant blubber concentrations. The relative carbon source increased over time at Arviat and Resolute Bay and weak relationships were observed with ΣPBDEs in blubber of seals. ΣPBDEs increased significantly from 1998 to 2008 in ringed seals from East Baffin and subsequently decreased in recent years. PBDE levels at other sites fluctuated slightly over time. HBCDD concentrations increased at several sites over the past decade. The presence of flame retardants in ringed seals suggests their persistence and their continuous inputs in the Canadian Arctic environment. Monitoring and research on the effects of these contaminants in seals are warranted given the importance of this species in Arctic marine food webs and for local communities.

Return to sender: the need to re-address patient antibiotic allergy labels in Australia and New Zealand.

BACKGROUND/AIM: Antibiotic allergies are frequently reported and have significant impacts upon appropriate prescribing and clinical outcomes. We surveyed infectious diseases physicians, allergists, clinical immunologists and hospital pharmacists to evaluate antibiotic allergy knowledge and service delivery in Australia and New Zealand. METHODS: An online multi-choice questionnaire was developed and endorsed by representatives of the Australasian Society of Clinical Immunology and Allergy (ASCIA) and the Australasian Society of Infectious Diseases (ASID). The 37-item survey was distributed in April 2015 to members of ASCIA, ASID, the Society of Hospital Pharmacists of Australia and the Royal Australasian College of Physicians. RESULTS: Of 277 respondents, 94% currently use or would utilise antibiotic allergy testing (AAT) and reported seeing up to 10 patients/week labelled as antibiotic-allergic. Forty-two per cent were not aware of or did not have AAT available. Most felt that AAT would aid antibiotic selection, antibiotic appropriateness and antimicrobial stewardship (79, 69 and 61% respectively). Patients with the histories of immediate hypersensitivity were more likely to be referred than those with delayed hypersensitivities (76 vs 41%, P = 0.0001). Lack of specialist physicians (20%) and personal experience (17%) were barriers to service delivery. A multidisciplinary approach was a preferred AAT model (53%). Knowledge gaps were identified, with the majority overestimating rates of penicillin/cephalosporin (78%), penicillin/carbapenem (57%) and penicillin/monobactam (39%) cross-reactivity. CONCLUSIONS: A high burden of antibiotic allergy labelling and demand for AAT is complicated by a relative lack availability or awareness of AAT services in Australia and New Zealand. Antibiotic allergy education and deployment of AAT, accessible to community and hospital-based clinicians, may improve clinical decisions and reduce antibiotic allergy impacts. A collaborative approach involving infectious diseases physicians, pharmacists and allergists/immunologists is required.

Transplacental Transfer of Polychlorinated Biphenyls, Polybrominated Diphenylethers, and Organochlorine Pesticides in Ringed Seals (Pusa hispida).

The transplacental transfer of persistent organic pollutants in marine mammals takes place at a formative developmental period, thereby exposing the fetus to endocrine-disrupting compounds. We evaluated the transplacental transfer of polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs), and organochlorine pesticides (OCPs) in five pregnant ringed seals in Northern Labrador, Canada. PCBs, PBDEs, and OCPs were transferred from the mother to the fetus with average concentrations in the fetuses ranging from 0.3 ng/g lipid weight (lw) of mirex to 94 ng/g lw of PCBs. The average percent transferred to the blubber in the fetus was very low with <0.02 % for each of the compounds studied. Based on relationships observed, transfer for full-term fetuses is estimated to range from 0.03 to 0.27 %. Log K(ow) explained the transfer of PCBs (r (2) = 0.67, p < 0.001) and OCPs (r (2) = 0.62, p < 0.001) with those PCB congeners and OCP compounds having a log K(ow) of <6.0 and 4.6, respectively, because they are preferentially transferred to the fetus. Adult females transferred a contaminant mixture to their fetuses, which correlated with estimated fetal age (p < 0.001; r (2) = 0.697), with younger fetuses showing a greater proportion of compounds with low K(ow) compared with later-term fetuses. The implications for the prenatal exposure to these developmental toxicants remains unknown because current toxicity thresholds in marine mammals have only been derived from juveniles or adults.

Distinguishing between mechanisms of cell aggregation using pair-correlation functions.

Many cell types form clumps or aggregates when cultured in vitro through a variety of mechanisms including rapid cell proliferation, chemotaxis, or direct cell-to-cell contact. In this paper we develop an agent-based model to explore the formation of aggregates in cultures where cells are initially distributed uniformly, at random, on a two-dimensional substrate. Our model includes unbiased random cell motion, together with two mechanisms which can produce cell aggregates: (i) rapid cell proliferation and (ii) a biased cell motility mechanism where cells can sense other cells within a finite range, and will tend to move towards areas with higher numbers of cells. We then introduce a pair-correlation function which allows us to quantify aspects of the spatial patterns produced by our agent-based model. In particular, these pair-correlation functions are able to detect differences between domains populated uniformly at random (i.e. at the exclusion complete spatial randomness (ECSR) state) and those where the proliferation and biased motion rules have been employed - even when such differences are not obvious to the naked eye. The pair-correlation function can also detect the emergence of a characteristic inter-aggregate distance which occurs when the biased motion mechanism is dominant, and is not observed when cell proliferation is the main mechanism of aggregate formation. This suggests that applying the pair-correlation function to experimental images of cell aggregates may provide information about the mechanism associated with observed aggregates. As a proof of concept, we perform such analysis for images of cancer cell aggregates, which are known to be associated with rapid proliferation. The results of our analysis are consistent with the predictions of the proliferation-based simulations, which supports the potential usefulness of pair correlation functions for providing insight into the mechanisms of aggregate formation.

Solid-state solar modules based on mesoscopic organometal halide perovskite: a route towards the up-scaling process.

We fabricated the first solid state modules based on organometal halide perovskite CH3NH3PbI3-xClx using Spiro-OMeTAD and poly(3-hexylthiophene) as hole transport materials. Device up-scaling was performed using innovative procedures to realize large-area cells and the integrated series-interconnections. The perovskite-based modules show a maximum conversion efficiency of 5.1% using both poly(3-hexylthiophene) and Spiro-OMeTAD. A long-term stability test was performed (in air, under AM1.5G, 1 Sun illumination conditions) using both materials showing different behaviour under continuous light stress. Whilst the poly(3-hexylthiophene)-based module efficiency drops by about 80% with respect to the initial value after 170 hours, the Spiro-based module shows a promising long-term stability maintaining more than 60% of its initial efficiency after 335 hours.

Evaluation of a modified pH-shift process to reduce 2-methylisoborneol and geosmin in spiked catfish and produce a consumer acceptable fried catfish nugget-like product.

UNLABELLED: Muddy and/or musty off-flavors in farmed-raised catfish occur as a result of the absorption of geosmin (GEO) and 2-methylisoborneol (MIB), compounds produced by algae. Previous research suggests the acid pH-shift method may be able to reduce off-flavors to produce a consumer acceptable product. The objective of this research was to evaluate application of the acid pH-shift method using a shaker sieve for protein recovery and to evaluate consumer acceptability of a resultant batter-coated fried nugget-like catfish product. Farm-raised catfish were either allowed to depurate (control) or treated with 1 ppb GEO or MIB. Fillets from each replicate were collected and ground and treated by the acid pH-shift process. Samples from all treatments and replicates were evaluated for residual GEO and MIB. In addition, batter-coated fried catfish samples were prepared for a consumer sensory evaluation. Results demonstrated that the pH-shift process decreased moisture, ash, and collagen content of catfish fillet tissue (P < 0.05). Flavor of control samples was preferred (P < 0.05). Texture of catfish samples treated by the pH-shift process was preferred (P < 0.05). Results demonstrate the pH-shift process can be utilized to reduce off-flavors and increase the acceptability of a processed catfish product. PRACTICAL APPLICATION: Use of a sieve as an economic alternative for the pH-shift process was evaluated for removing off-flavors from catfish. Difficulties were encountered with regard to protein recovery using the sieve and suggestions are made to, perhaps, make the process more applicable for a sieve-based recovery step. The process as described reduced off-flavors, but only 2-fold suggesting the process would work best on catfish near or just over off-flavor thresholds. Results also indicated the pH-shift process could be used to improve texture of a fried catfish product designed to be similar to chicken nuggets.

Kepler detected gravity-mode period spacings in a red giant star.

Stellar interiors are inaccessible through direct observations. For this reason, helioseismologists made use of the Sun's acoustic oscillation modes to tune models of its structure. The quest to detect modes that probe the solar core has been ongoing for decades. We report the detection of mixed modes penetrating all the way to the core of an evolved star from 320 days of observations with the Kepler satellite. The period spacings of these mixed modes are directly dependent on the density gradient between the core region and the convective envelope.

Neuropsychiatric Outcome of an Adolescent Who Received Deep Brain Stimulation for Tourette's Syndrome.

This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf) for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow-up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation.

The perspective of patients with haemophilia with inhibitors and their care givers: preferences for treatment characteristics.

Treatment preferences of haemophilia patients with inhibitors have not been well documented. This study sought to identify treatment attributes that patients/caregivers consider most important in the USA, inasmuch as those preferences may affect patient adherence to treatment plans. A discrete choice experiment was conducted to elicit treatment preferences. Haemophilia patients with inhibitors, or their caregivers on their behalf, completed a written survey that elicited preferences for treatment features and levels synthesized from the medical literature including: risk of viral transmission, rise in inhibitor titre, reduction in thromboembolic events, number of infusions, preparation time, infusion time/volume, time required to stop bleeding/alleviate pain, use of prophylaxis, use of major surgery and medication cost. Relative importance (RI) of preferences was modelled using a multinomial logit function. Most respondents were male (49 of 51, 96.1%); mean age, 20.7 years (SD = 18.8) and 88.5% of patients had haemophilia type A. The three most important patient-identified treatment attributes were as follows: time required to stop bleeding (RI = 19.3), possibility that the level of inhibitor may rise (RI = 14.3) and risk of contracting a virus from the product (RI = 13.5). Haemophilia patients with inhibitors and their caregivers appear to be willing to accept treatments that may be more inconvenient and painful as long as the treatments are effective in quickly controlling bleeds, do not increase inhibitor levels and do not pose a risk for viral contraction. Study findings provide meaningful input to the clinical community from patients and caregivers and support the importance of physicians understanding their patients' treatment preferences.

Thermal activation of mass transport and charge transfer at Pt in the I(3)(-)/I(-) electrolyte of a dye-sensitized solar cell.

The electrochemical properties of the I(3)(-)/I(-) reaction mediator as a function of temperature in the range from 30 degrees C to 80 degrees C were investigated by means of symmetric Pt electrodes thin-layer cells (TLC), using three electro-analytical techniques: Electrochemical Impedance Spectroscopy (EIS), Slow Scan Cyclic Voltammetry (SSCV) and Chronoamperometry (CA). Our study pointed out that raising the cell temperature has a beneficial effect both on charge transfer and on mass transport, with an activation energy for the electron transfer process at equilibrium of 24 kJ mol(-1), and of 12 kJ mol(-1) for the mass transfer process at equilibrium. Viscosity and conductivity measurements have demonstrated that most of the ionic mass transport in the solvent (methoxypropionitrile) follows the Stokes' law and that the Walden product is constant, in the temperature range investigated. The diffusion of I(3)(-), however, was found to be partly "non-Stokesian" at lower temperature where the viscosity of the electrolyte is higher. We have shown that EIS and chronoamperometry are both valid methods to derive diffusion coefficients of redox ions in TLC, even if their exact concentration in the electrolyte is not known.

Health-related quality of life and productivity impact in haemophilia patients with inhibitors.

To measure health-related quality of life (HRQL), its determinants, and its association with patient and caregiver productivity among a sample of haemophilia patients with inhibitors in the United States (US). Data on demographical and clinical characteristics, treatment patterns, HRQL (SF-12v2), and productivity outcomes were reported for 53 patients. Mean SF-12v2 domain and mental (MCS) and physical (PCS) component summary scores were assessed and compared with US norms. Regression analyses explored the association of patient and treatment factors with HRQL and productivity. Patients' mean age was 20.7 years (SD = 18.8), 88.5% were type A, and 39.6% received on-demand therapy as their only mode of treatment. Mean PCS was significantly lower than the US norm (PCS, 39.9, P < 0.01) and mean MCS showed no significant difference (MCS, 49.9, P = ns). On-demand treatment (B = -0.336, P < 0.05) and number of haemorrhages (B = -0.366, P < 0.05) were negatively associated with PCS; and PCS was associated with patients' missed work or school days [incidence rate ratio (IRR) = 0.93, P < 0.001] and perceived impact on daily activities (OR = 0.72, P < 0.05). Younger age (IRR = 0.91, P < 0.01), lower PCS (IRR = 0.94, P < 0.01), more haemorrhages (IRR = 1.05, P < 0.05), and surgery (IRR = 2.74, P < 0.05) were associated with fewer patients' productive days. Physical functioning among inhibitor patients in the US is compromised and is negatively associated with their daily activities and productivity. These data suggest a positive association of prophylactic and immunotolerance therapy with HRQL, specifically physical impairment.

Spatiotemporal heterogeneity in the electrical activity of suprachiasmatic nuclei neurons and their response to photoperiod.

The coordinated activity of thousands of cellular oscillators in the suprachiasmatic nuclei (SCN) temporally regulates mammalian physiology to anticipate daily environmental changes across the seasons. The phasing of clock gene expression varies according to anatomical location in the SCN and is thought to encode photoperiodic information. However, it is unclear whether similar variations in phase occur in the electrical activity of SCN neurons, a measure of both intraSCN signaling and clock output. To address this, we recorded single-unit and multiunit activity (SUA/MUA) from dorsal and ventral subregions of the middle level of the rostrocaudal axis of the SCN in coronal brain slices prepared from mice housed under different photoperiods. We demonstrate that under a symmetrical (12 h light:12 h dark) photoperiod, cells in the dorsal SCN are less tightly synchronized than those in the ventral SCN. Comparison of recordings made from mice under short (8 h light:16 h dark) or long (16 h light:8 h dark) photoperiods shows that the phase distribution of ventral, but not dorsal, SCN neurons expands with increasing day length. Conversely, the duration that individual neurons are active increases in dorsal, but not ventral, SCN under long days. These data indicate that in the ventral SCN photoperiod is encoded at the network level, while this coding occurs at the level of individual cells in the dorsal SCN.

Electrophysiological actions of orexins on rat suprachiasmatic neurons in vitro.

The study of neural arousal mechanisms has been greatly aided by the discovery of the orexin peptides (orexin A and orexin B), the subsequent identification of the neurons that synthesize these peptides, their projections in the brain, and the distribution of orexin receptors in the central nervous system. Orexin neuron activation is partly controlled by circadian signals generated in the brain's main circadian pacemaker, the suprachiasmatic nuclei (SCN). The SCN clock is in turn reset by arousal-promoting stimuli and, intriguingly, orexin fibers and receptor expression are detected in the SCN region. It is unclear, however, if orexin can alter SCN neuronal activity. Here using a coronal brain slice preparation, we found that orexin A and orexin B (0.1-1 microM) elicited significant changes in the extracellularly recorded firing rate and firing pattern in approximately 80% of rat SCN cells tested; the most common response was suppression of firing rate. Co-application of orexin A with a cocktail of ionotropic GABA and glutamate receptor antagonists did not alter the actions of this peptide on firing rate, but did change some its effects on firing pattern. We conclude that orexins can alter SCN neurophysiology and may influence the transmission of information through the SCN to other CNS regions.