Resection of colorectal carcinoma liver metastases: A population-based study in outcomes and factors associated with recurrent disease.

OBJECTIVE: To assess the hepatic disease-free survival (HDFS) and overall survival (OS) of patients who underwent resection of colorectal cancer liver metastases (CRCLM) in our population, and evaluate what factors are associated with these outcomes. METHODS: Patients with resected non-mucinous CRCLM between January 2013-February 2020 were retrospectively identified. Dates of diagnosis, surgery, and, if applicable, death were recorded. HDFS and OS were calculated using a census date of 24 September 2022. Separate Cox multivariate regression analyses were performed to evaluate for association between HDFS and OS and the following factors: pre-operative imaging interval (<4 weeks vs. ≥4 weeks); pre-operative imaging modality (CT only vs. MRI+CT); extrahepatic disease at time of hepatectomy (yes vs. no); tumor burden score (TBS, where TBS2 = (largest axial dimension of CRCLM)2 + (number of CRCLM)2); pT and pN; and neoadjuvant chemotherapy. RESULTS: 137 subjects (mean age, 61 ± 11 years, 86 males) were included. Associations with recurrent hepatic disease were found with chemotherapy (HR 2.11[95 % CI = 1.13-3.92]), TBS (HR 1.30[95 % CI = 1.17-1.45]), MRI+CT (HR 2.12[95 % CI = 1.29-3.48]), and extrahepatic disease at hepatectomy (HR 2.16[95 % CI = 1.08-4.35]). For mortality, associations were found with TBS (HR 1.22[95 % CI = 1.09-1.37]), pT (HR 1.45[95 % CI = 1.05-2.00]), and extrahepatic disease at hepatectomy (HR 2.10[95 % CI = 1.31-3.36]). CONCLUSION: In our population, non-imaging related factors TBS, neoadjuvant chemotherapy, pT and presence of extrahepatic disease at time of hepatectomy were associated with HDFS and/or OS. The preoperative imaging interval and use of preoperative MRI were not associated with improved patient outcomes.

Prostaglandin E2 activates melanin-concentrating hormone neurons to drive diet-induced obesity.

Hypothalamic inflammation reduces appetite and body weight during inflammatory diseases, while promoting weight gain when induced by high-fat diet (HFD). How hypothalamic inflammation can induce opposite energy balance outcomes remains unclear. We found that prostaglandin E2 (PGE2), a key hypothalamic inflammatory mediator of sickness, also mediates diet-induced obesity (DIO) by activating appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus in rats and mice. The effect of PGE2 on MCH neurons is excitatory at low concentrations while inhibitory at high concentrations, indicating that these neurons can bidirectionally respond to varying levels of inflammation. During prolonged HFD, endogenous PGE2 depolarizes MCH neurons through an EP2 receptor-mediated inhibition of the electrogenic Na+/K+-ATPase. Disrupting this mechanism by genetic deletion of EP2 receptors on MCH neurons is protective against DIO and liver steatosis in male and female mice. Thus, an inflammatory mediator can directly stimulate appetite-promoting neurons to exacerbate DIO and fatty liver.

Diagnostic Performance and Interreader Agreement of the MRI Clear Cell Likelihood Score for Characterization of cT1a and cT1b Solid Renal Masses: An External Validation Study.

BACKGROUND. The clear cell likelihood score (ccLS) has been proposed for the noninvasive differentiation of clear cell renal cell carcinoma (ccRCC) from other renal neoplasms on multiparametric MRI (mpMRI), though further external validation remains needed. OBJECTIVE. The purpose of our study was to evaluate the diagnostic performance and interreader agreement of the ccLS version 2.0 (v2.0) for characterizing solid renal masses as ccRCC. METHODS. This retrospective study included 102 patients (67 men, 35 women; mean age, 56.9 ± 12.8 [SD] years) who underwent mpMRI between January 2013 and February 2018, showing a total of 108 (≥ 25% enhancing tissue) solid renal masses measuring 7 cm or smaller (83 cT1a [≤ 4 cm] and 25 cT1b [> 4 cm and ≤ 7 cm]), all with a histologic diagnosis. Three abdominal radiologists independently reviewed the MRI examinations using ccLS v2.0. Median reader sensitivity, specificity, and accuracy were computed for predicting ccRCC by ccLS of 4 or greater, and individual reader AUCs were derived. The percentage of masses that were ccRCC was calculated, stratified by ccLS. Interobserver agreement was assessed by the Fleiss kappa statistic. RESULTS. The sample included 45 ccRCCs (34 cT1a, 11 cT1b), 30 papillary renal cell carcinomas (RCCs), 13 chromophobe RCCs, 14 oncocytomas, and six fat-poor angiomyolipomas. Median reader sensitivity, specificity, and accuracy for predicting ccRCC by ccLS of 4 or greater were 85%, 82%, and 83% among cT1a masses and 82%, 100%, and 92% among cT1b masses. The three readers' AUCs for predicting ccRCC by ccLS for cT1a masses were 0.90, 0.84, and 0.89 and for cT1b masses were 0.99, 0.97, and 0.92. Across readers, the percentage of masses that were ccRCC among cT1a masses was 0%, 0%, 20%, 68%, and 93% for ccLS of 1, 2, 3, 4, and 5, respectively; among cT1b masses, the percentage of masses that were ccRCC was 0%, 0%, 32%, 90%, and 100% for ccLS of 1, 2, 3, 4, and 5, respectively. Interobserver agreement among cT1a and cT1b masses for ccLS of 4 or greater was 0.82 and 0.83 and for ccLS of 1-5 overall was 0.65 and 0.62, respectively. CONCLUSION. This study provides external validation of the ccLS, finding overall high measures of diagnostic performance and interreader agreement. CLINICAL IMPACT. The ccLS provides a standardized approach to the noninvasive diagnosis of ccRCC by MRI.

Efficacy of Risk Prediction Models and Thresholds to Select Patients for Lung Cancer Screening.

PurposeScreening for lung cancer is recommended to reduce lung cancer mortality, but there is no consensus on patient selection for screening in Canada. Risk prediction models are more efficacious than the screening recommendations of the Canadian Task Force on Preventive Health Care (CTFPHC), but it remains to be determined which model and threshold are optimal. MethodsWe retrospectively applied the PLCOm2012, PLCOall2014 and LLPv2 risk prediction models to 120 lung cancer patients from a Canadian province, at risk thresholds of ≥ 1.51% and ≥ 2.00%, to determine screening eligibility at time of diagnosis. OncoSim modelling was used to compare these risk thresholds. ResultsSensitivities of the risk prediction models at a threshold of ≥ 1.51% were similar with 93 (77.5%), 96 (80.0%), and 97 (80.8%) patients selected for screening, respectively. The PLCOm2012 and PLCOall2014 models selected significantly more patients for screening at a ≥ 1.51% threshold. The OncoSim simulation model estimated that the ≥ 1.51% threshold would detect 4 more cancers per 100 000 people than the ≥ 2.00% threshold. All risk prediction models, at both thresholds, achieved greater sensitivity than CTFPHC recommendations, which selected 56 (46.7%) patients for screening. ConclusionCommonly considered lung cancer screening risk thresholds (≥1.51% and ≥2.00%) are more sensitive than the CTFPHC 30-pack-years criterion to detect lung cancer. A lower risk threshold would achieve a larger population impact of lung cancer screening but would require more resources. Patients with limited or no smoking history, young patients, and patients with no history of COPD may be missed regardless of the model chosen.

Short-term Fasting Induces Alternate Activation of Orexin and Melanin-concentrating Hormone Neurons in Rats.

Orexin and melanin-concentrating hormone (MCH) neurons constitute the energy balance circuitry that coordinates the fasting response. Orexin neurons mediate food foraging at the expense of energy storage, while MCH neurons promote energy storage by reducing energy expenditure and increasing food intake. It is unknown if these cell groups undergo plastic changes as hunger and metabolic changes escalate over time during fasting. To address this, we performed in vitro electrophysiological recording on orexin and MCH neurons in the lateral hypothalamus and perifornical area from rats fasted for 12 or 24 h or fed ad-libitum. Orexin neurons showed a transient decrease in presynaptic glutamate release at 12 h. This turned to an increase at 24 h of fasting, while membrane potential depolarized and AMPA receptor conductance increased. In contrast, MCH neurons were transiently depolarized at 12 h fasting along with increased presynaptic glutamate release. These changes reversed at 24 h, while the number of AMPA receptors decreased. Our results indicate that MCH neurons are preferentially activated during the early phase of fasting (12 h), which would protect against weight loss. With a longer fast, orexin neurons become activated, which would promote arousal and exploratory activity required for foraging behaviors. This alternating activation of these cell groups may reflect a dynamic balance of energy conservation and foraging behaviors to optimize energy balance during ongoing fasting.

A Single-Center Study on the Outcomes of Target Limb Revascularization in Femoropopliteal Lesions Treated With Drug Coated Balloons and Bare Metal Stents.

PURPOSE: Multiple randomized controlled trials have shown that both drug coated balloons (DCBs) and bare metal stents (BMSs) significantly reduce restenosis in femoropopliteal lesions compared with plain balloon angioplasty. However, few studies have directly compared DCB and BMS treatments. Therefore, the goal of our study was to determine if the rate of target lesion revascularization (TLR) differs between DCB and BMS treatment at our center. MATERIALS AND METHODS: We performed a retrospective chart review of femoropopliteal interventions at a single center from 2009 to 2017. The intervention, patient and lesion characteristics, and TLR events were recorded. Exclusion criteria were loss of follow-up, death, bail-out stenting, and amputation within 60 days of treatment. Freedom from TLR was analyzed over a 3 year period with Kaplan-Meier survival curves. Cox hazard ratios were calculated to account for patient and lesion characteristics. RESULTS: A total of 322 lesions (234 patients) treated with DCBs and 225 lesions (194 patients) treated with BMSs were included in this study. There were significant differences in baseline patient and lesion characteristics between groups-a greater proportion of women, patients with dyslipidemia, and lesions with popliteal involvement were treated with DCBs. There was no difference in the freedom from TLR between DCBs and BMSs. Accounting for patient and lesion characteristics, there was still no difference between DCBs and BMSs on the hazard of TLR. While our analysis did not detect a difference in the rate of TLR, there was a significant difference in the type of TLR. Compared with DCBs, a greater proportion of lesions initially treated with BMSs were retreated via surgical bypass rather than endovascular intervention, suggesting that lesions treated with DCBs may be more amenable to future endovascular intervention. CONCLUSION: Our retrospective analysis showed no difference in the rate of TLR between lesions treated with DCBs and BMSs. However, DCBs were more often used in complicated lesions involving popliteal arteries and may also allow for easier endovascular reintervention.

Successful Prophylactic Embolization of a Renal Artery Aneurysm During Pregnancy.

Renal artery aneurysms (RAA) have an increased risk of rupture during pregnancy with high mortality rates for the mother and fetus. There are many reports on the treatment of ruptured RAA during pregnancy and the Society for Vascular Surgery recommends to prophylactically treat unruptured RAA of any size in women of reproductive age to limit risk of rupture during pregnancy. However, to the best of our knowledge, there is no reported case of prophylactic treatment of unruptured RAA during pregnancy. Here we report the case of a 39-year-old G2P1 who had prophylactic endovascular coiling of an unruptured left RAA during her second trimester of pregnancy. Our case report is the first to demonstrate that unruptured RAA can be safely intervened endovascularly to prevent rupture without disrupting the pregnancy.

An Audit of Opportunistic Lung Cancer Screening in a Canadian Province.

OBJECTIVES: Lung cancer is a leading cause of cancer-related death in Canada. Early detection can improve outcomes and despite recommendations from the Canadian Task Force on Preventive Health Care to screen patients who are 55 to 74 years old and have a 30+ pack-year history, formal screening programs are rare in Canada. Our goal was to determine if screening is being performed in a representative Canadian population, if recommendations are being followed, and how screening impacts lung cancer stage at diagnosis and prognosis. METHODS: A retrospective chart review was performed to identify patients either screened for lung cancer or imaged due to lung cancer symptoms in Eastern Newfoundland between 2015 and 2018. Age, smoking history, screening modality, diagnosis, cancer stage, and mortality were recorded. RESULTS: Under 6.0% of the eligible population were screened for lung cancer with only 28.13% meeting age and smoking criteria and being screened appropriately with low-dose CT. However, 70% of patients that had lung cancers found by screening met age and smoking screening criteria. While lung cancer detection rates were similar, screening detected cancer in patients at an earlier stage (50% Stage 1) compared to patients who were not screened (20% Stage 1). Patients who were screened had an improved prognosis. CONCLUSIONS: Physicians are opportunistically screening for lung cancer, but not consistently following screening guidelines. As screening is sensitive, leads to earlier stage diagnosis, and has a mortality benefit, implementation of an organized screening program could increase quality assurance and prevent many lung-cancer related deaths.

The Online Cross-Country Tour: Evaluation of a Novel Online Series for Canadian Radiology Residency Programs and Future Implications for the Radiology CaRMS Process.

PURPOSE: The COVID-19 pandemic indefinitely cancelled visiting medical student radiology electives across Canada. In response, the Canadian Association of Radiologists Resident & Fellow Section (CAR RFS) and Medical Student Network (MSN) developed and evaluated an online series for medical students to learn about Canadian radiology residency programs. METHODS: Medical students from any year of training were recruited through the MSN, local radiology interest groups, and social media to attend a 2-week online series of interactive sessions via Zoom with program representatives from Canadian radiology residency programs. A survey evaluating the online series, in particular its impact on residency and career planning, was administered to program representatives and students. RESULTS: Fifteen of Canada's 16 radiology residency programs participated in the online series. A total of 212 students attended at least one session and nearly half were participating in the Canadian Resident Matching Service (CaRMS) this year. The postsurvey revealed that 77% of students agreed that the online series helped prepare them for CaRMS and ranking programs. The online series also benefited pre-CaRMS students as significantly more students were considering radiology as a specialty on the postsurvey compared to the presurvey. Students and program representatives agreed that this series should be held in future years, regardless of whether health and travel restrictions are lifted. CONCLUSION: The CAR RFS and MSN hosted an online series for medical students to learn about radiology residency programs outside their home institution. Feedback was highly positive with important implications for the future CaRMS iterations for any specialty.

Radiology Interest Groups: A Recipe for Success.

OBJECTIVES: Radiology Interest Groups (RIGs) are valuable for medical students and the radiology profession. The purpose of this study is to identify key components of a successful RIG and to discuss how to optimize available resources to increase student engagement in radiology. METHODS: Anonymous feedback forms (n = 478) completed by preclinical medical students attending 20 RIG events between September 2016 and May 2019 were analyzed. A five-point Likert-type scale was used to determine event effectiveness, and important themes reflecting student perspectives were identified using thematic analysis of freeform comments. RESULTS: Based on Likert feedback, 75% to 78% of students had a positive experience of RIG events and believed sessions were relevant to their studies. 31% to 42% of students believed these events increased their interest or insight into radiology and influenced their career choice. Four representative themes were identified by qualitative analysis of written feedback: engagement, professional development, mentorship, and suggestions for improvement. These themes provided insight into student perspectives of our RIG, and, along with experience from the RIG organizers, the authors present elements perceived to have contributed to these positive results. CONCLUSION: Thematic analysis of feedback reveals that students consider interactive events, contribution to professional development, and the opportunity for mentorship valuable elements of a RIG. From the perspective of the organizing committee, we embody these aspects through careful planning, innovative events, and consistent debriefing. In this way, our RIG promotes the future of the radiology profession and serves as a practical model for other similar organizations.

High-fat diet induces time-dependent synaptic plasticity of the lateral hypothalamus.

OBJECTIVE: Orexin (ORX) and melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus are critical regulators of energy homeostasis and are thought to differentially contribute to diet-induced obesity. However, it is unclear whether the synaptic properties of these cells are altered by obesogenic diets over time. METHODS: Rats and mice were fed a control chow or palatable high-fat diet (HFD) for various durations and then synaptic properties of ORX and MCH neurons were examined using exvivo whole-cell patch clamp recording. Confocal imaging was performed to assess the number of excitatory synaptic contacts to these neurons. RESULTS: ORX neurons exhibited a transient increase in spontaneous excitatory transmission as early as 1 day up to 1 week of HFD, which returned to control levels with prolonged feeding. Conversely, HFD induced a delayed increase in excitatory synaptic transmission to MCH neurons, which progressively increased as HFD became chronic. This increase occurred before the onset of significant weight gain. These synaptic changes appeared to be due to altered postsynaptic sensitivity or the number of active synaptic contacts depending on cell type and feeding duration. However, HFD induced no change in inhibitory transmission in either cell type at any time point. CONCLUSIONS: These results suggest that the effects of HFD on feeding-related neurons are cell type-specific and dynamic. This highlights the importance of considering the feeding duration for research and weight loss interventions. ORX neurons may contribute to early hyperphagia, whereas MCH neurons may play a role in the onset and long-term maintenance of diet-induced obesity.

A Single-Center Experience of Paclitaxel in the Treatment of Femoropopliteal Disease-No Evidence for an Association With Mortality.

PURPOSE: Paclitaxel-coated devices have been increasingly used in endovascular treatment of femoropopliteal disease as they limit recurrence of lesions and improve patient outcomes. However, a recent meta-analysis reported that these devices increase mortality risk at 2 years post-intervention but did not account for confounding variables. Therefore, our goal was to evaluate mortality after paclitaxel treatment of femoropopliteal disease using patient-level data. METHODS: We performed a retrospective review of all patients who received endovascular treatment for femoropopliteal lesions at our center between December 2009 and July 2017. There were 388 patients in the paclitaxel group and 314 control patients. RESULTS: Survival analysis with hazard ratios showed no difference between mortality in the paclitaxel and control groups. Age, renal insufficiency, and chronic limb-threatening ischemia were significant predictors of mortality. We also used logistic regression to evaluate mortality at 1, 2, and 5 years post-intervention and found no difference between the paclitaxel and control groups at any time point, while age, renal insufficiency, and chronic limb-threatening ischemia at the time of intervention were all associated with the risk of death. Finally, we tallied the causes of death in our cohort and found no difference in the distribution of causes between groups. CONCLUSION: Our single-center, retrospective study provides no evidence of increased risk of death with paclitaxel treatment in femoropopliteal disease. Contrastingly, age, renal insufficiency, and chronic limb-threatening ischemia were the most important factors contributing to mortality and therefore should be included as potential confounders in future studies assessing mortality in femoropopliteal disease.

Dopamine modulates excitatory transmission to orexin neurons in a receptor subtype-specific manner.

Dopamine (DA) can promote or inhibit consummatory and reward-related behaviors by activating different receptor subtypes in the lateral hypothalamus and perifornical area (LH/PF). Because orexin neurons are involved in reward and localized in the LH/PF, DA may modulate these neurons to influence reward-related behaviors. To determine the cellular mechanism underlying dopaminergic modulation of orexin neurons, the effect of DA on excitatory transmission to these neurons was investigated using in vitro electrophysiology on rat brain slices. We found that low concentrations (0.1-1 µM) of DA increased evoked excitatory postsynaptic current amplitude while decreasing paired-pulse ratio. In contrast, high concentrations (10-100 µM) of DA did the opposite. The excitatory effect of low DA was blocked by the D1 receptor antagonist SCH-23390, whereas the inhibitory effect of high DA was blocked by the D2 receptor antagonist sulpiride. These results indicate distinct roles of D1 and D2 receptors in bidirectional presynaptic modulation of excitatory transmission. DA had stronger effects on isolated synaptic activity than repetitive ones, suggesting that sensitivity to dopaminergic modulation depends on the level of network activity. In orexin neurons from high-fat diet-fed rats, a high concentration of DA was less effective in suppressing repetitive synaptic activity compared with chow controls. Therefore, in diet-induced obesity, intense synaptic inputs may preferentially reach orexin neurons while intermittent signals are inhibited by high DA levels. In summary, our study provides a cellular mechanism by which DA may exert opposite behavioral effects in the LH/PF through bidirectional modulation of orexin neurons via different DA receptors.

Electrophysiological Properties of Melanin-Concentrating Hormone and Orexin Neurons in Adolescent Rats.

Orexin and melanin-concentrating hormone (MCH) neurons have complementary roles in various physiological functions including energy balance and the sleep/wake cycle. in vitro electrophysiological studies investigating these cells typically use post-weaning rodents, corresponding to adolescence. However, it is unclear whether these neurons are functionally mature at this period and whether these studies can be generalized to adult cells. Therefore, we examined the electrophysiological properties of orexin and MCH neurons in brain slices from post-weaning rats and found that MCH neurons undergo an age-dependent reduction in excitability, but not orexin neurons. Specifically, MCH neurons displayed an age-dependent hyperpolarization of the resting membrane potential (RMP), depolarizing shift of the threshold, and decrease in excitatory transmission, which reach the adult level by 7 weeks of age. In contrast, basic properties of orexin neurons were stable from 4 weeks to 14 weeks of age. Furthermore, a robust short-term facilitation of excitatory synapses was found in MCH neurons, which showed age-dependent changes during the post-weaning period. On the other hand, a strong short-term depression was observed in orexin neurons, which was similar throughout the same period. These differences in synaptic responses and age dependence likely differentially affect the network activity within the lateral hypothalamus where these cells co-exist. In summary, our study suggests that orexin neurons are electrophysiologically mature before adolescence whereas MCH neurons continue to develop until late adolescence. These changes in MCH neurons may contribute to growth spurts or consolidation of adult sleep patterns associated with adolescence. Furthermore, these results highlight the importance of considering the age of animals in studies involving MCH neurons.

Short-term high-fat diet primes excitatory synapses for long-term depression in orexin neurons.

KEY POINTS: High-fat diet consumption is a major cause of obesity. Orexin neurons are known to be activated by a high-fat diet and in turn promote further consumption of a high-fat diet. Our study shows that excitatory synapses to orexin neurons become amenable to long-term depression (LTD) after 1 week of high-fat diet feeding. However, this effect reverses after 4 weeks of a high-fat diet. This LTD may be a homeostatic response to a high-fat diet to curb the activity of orexin neurons and hence caloric consumption. Adaptation seen after prolonged high-fat diet intake may contribute to the development of obesity. ABSTRACT: Overconsumption of high-fat diets is one of the strongest contributing factors to the rise of obesity rates. Orexin neurons are known to be activated by a palatable high-fat diet and mediate the activation of the mesolimbic reward pathway, resulting in further food intake. While short-term exposure to a high-fat diet is known to induce synaptic plasticity within the mesolimbic pathway, it is unknown if such changes occur in orexin neurons. To investigate this, 3-week-old male rats were fed a palatable high-fat western diet (WD) or control chow for 1 week and then in vitro patch clamp recording was performed. In the WD condition, an activity-dependent long-term depression (LTD) of excitatory synapses was observed in orexin neurons, but not in chow controls. This LTD was presynaptic and depended on postsynaptic metabotropic glutamate receptor 5 (mGluR5) and retrograde endocannabinoid signalling. WD also increased extracellular glutamate levels, suggesting that glutamate spillover and subsequent activation of perisynaptic mGluR5 may occur more readily in the WD condition. In support of this, pharmacological inhibition of glutamate uptake was sufficient to prime chow control synapses to undergo a presynaptic LTD. Interestingly, these WD effects are transient, as extracellular glutamate levels were similar to controls and LTD was no longer observed in orexin neurons after 4 weeks of WD. In summary, excitatory synapses to orexin neurons become amenable to LTD under a palatable high-fat diet, which may represent a homeostatic mechanism to prevent overactivation of these neurons and to curtail high-fat diet consumption.

Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons.

Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 µM) and high (100 µM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPßS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours.

Time-dependent effects of rapamycin on consolidation of predator stress-induced hyperarousal.

Previous studies have indicated that rapamycin, a potent inhibitor of the mammalian target of rapamycin (mTOR) pathway, blocks consolidation of shock-induced associative fear memories. Moreover, rapamycin's block of associative fear memories is time-dependent. It is unknown, however, if rapamycin blocks consolidation of predator stress-induced non-associative fear memories. Furthermore, the temporal pattern of mTOR activation following predator stress is unknown. Thus, the goal of the current studies was to determine if rapamycin blocks consolidation of predator stress-induced fear memories and if so, whether rapamycin's effect is time-dependent. Male rats were injected systemically with rapamycin at various time points following predator stress. Predator stress involves an acute, unprotected exposure of a rat to a cat, which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behaviour. We show that rapamycin injected immediately after predator stress blocked consolidation of stress-induced startle. However, rapamycin injected 9, 24 or 48h post predator stress potentiated stress-induced startle. Consistent with shock-induced associative fear memories, we show that mTOR signalling is essential for consolidation of predator stress-induced hyperarousal. However, unlike shock-induced fear memories, a second, persistent, late phase mTOR-dependent process following predator stress actually dampens startle. Consistent with previous findings, our data support the potential role for rapamycin in treatment of stress related disorders such as posttraumatic stress disorder. However, our data suggest timing of rapamycin administration is critical.

ATP-sensitive potassium channels mediate the thermosensory response of orexin neurons.

High body temperatures are generally associated with somnolence, lethargy, hypophagia and anhedonia. Orexin neurons have been suggested to play a role in such sickness behaviours due to their known functions in appetite, behavioural and autonomic activation. Furthermore, the activity of orexin neurons is inhibited by lipopolysaccharide that induces fever. However, the cellular mechanism(s) underlying this suppression of orexin neurons was unknown. We used patch-clamp recordings in acute rat brain slices to demonstrate that orexin neurons, including those projecting to the wake-promoting locus coeruleus, are inhibited by increasing the ambient temperature by a 2-4°C increment between 26 and 40°C. This effect was not mediated by conventional thermosensing mechanisms but instead involved the activation of ATP-sensitive potassium (KATP) channels. Since KATP channels can also sense energy substrate levels and cellular metabolism, our results suggest that orexin neurons can integrate the state of energy balance and body temperature, and adjust their output accordingly. Thus, the thermosensitivity of orexin neurons may be an important part of maintaining energy homeostasis during hyperthermia and fever.