A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits.

Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons

A Conditional Random Field for Multiple-Instance Learning

We present MI-CRF, a conditional random field (CRF) model for multiple instance learning (MIL). MI-CRF models bags as nodes in a CRF with instances as their states. It combines discriminative unary instance classifiers and pairwise dissimilarity measures. We show that both forces improve the classification performance. Unlike other approaches, MI-CRF considers all bags jointly during training as well as during testing. This makes it possible to classify test bags in an imputation setup. The parameters of MI-CRF are learned using constraint generation. Furthermore, we show that MI-CRF can incorporate previous MIL algorithms to improve on their results. MI-CRF obtains competitive results on five standard MIL datasets. 1

Clinical Perspectives on Incorporating Cardiorespiratory Fitness in Clinical Practice

Cardiorespiratory fitness (CRF) has been documented as a strong, independent predictor of non-communicable disease and mortality in both clinical and apparently healthy populations. This well-established relationship has impelled organizations, including the American Heart Association, to release scientific statements highlighting the importance of accurate quantification of CRF. Current knowledge of the relationship between CRF and mortality is predominantly based on estimated CRF obtained from varying indirect methods. Cardiopulmonary exercise testing (CPX), the gold standard method of CRF measurement, provides a more accurate and reliable quantification of CRF compared to estimated methods. This review provides support for the diagnostic and prognostic use of CRF based on the current literature and makes a case for the use of CPX when available, as well as the need for standardization of normative values defining CRF levels to increase the efficacy of the risk assessment. Further, clinical applications of CPX-derived CRF are discussed, providing clinicians with recommendations on how to use and interpret this measure in practice to guide clinical decisions and improve patient outcomes

Augmented Cocaine Seeking in Response to Stress or CRF Delivered into the Ventral Tegmental Area Following Long-Access Self-Administration Is Mediated by CRF Receptor Type 1 But Not CRF Receptor Type 2

Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress-induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 μg/side) or antisauvagine-30(ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1-dependent regulation of addiction-related neurocircuitry in the VTA

The Association Between the Long-Term Change in Directly Measured Cardiorespiratory Fitness and Mortality Risk

Introduction: There is a strong inverse association between cardiorespiratory fitness (CRF) and mortality outcomes. This relationship has predominantly been assessed cross-sectionally, however low CRF is a modifiable risk factor, thus assessing this association using a single baseline measure may be sub-optimal. Purpose: To examine the association of the long-term change in CRF, measured using cardiopulmonary exercise testing (CPX) with all-cause and disease-specific mortality. Methods: Participants included 833 apparently healthy men and women (42.9±10.8 years) who underwent two maximal CPXs, the second CPX being ≥ 1 year following the baseline assessment. Participants were followed for 17.7 ± 11.8 years for allcause, cardiovascular disease (CVD), and cancer mortality. Cox-proportional hazard models were performed to determine the association between the change in CRF, computed as visit 1 (V1) peak oxygen consumption (VO2peak (ml·kg-1·min-1)) – visit 2 (V2) VO2peak, and mortality outcomes. Results: During follow-up, 172 participants died. Overall, the change in CPX-derived CRF was inversely related to all-cause, CVD, and cancer mortality (p\u3c0.05). Each 1 ml·kg-1·min-1 increase was associated with a 10.8, 14.7, and 15.9% reductions in allcause, CVD, and cancer mortality, respectively. The inverse relationship between CRF and all-cause mortality remained significant (p\u3c0.05) when men and women were examined independently, after adjusting for years since first CPX, baseline VO2peak, and age. Conclusion: Long-term changes in CRF were inversely related to mortality outcomes, and mortality was better predicted by CRF measured at subsequent examination than baseline CRF. These findings support the recent American Heart Association scientific statement advocating CRF as a clinical vital sign that should be assessed routinely in clinical practice, as well as support regular participation in physical activity to maintain adequate CRF levels across the lifespan

Linking cardiorespiratory fitness classification criteria to early subclinical atherosclerosis in children

It is unclear if cardiorespiratory fitness (CRF) can be used as a screening tool for premature changes in carotid intima-media thickness (cIMT) in paediatric populations. The purpose of this cross-sectional study was 3-fold: (i) to determine if CRF can be used to screen increased cIMT; (ii) to determine an optimal CRF cut-off to predict increased cIMT; and (iii) to evaluate its ability to predict increased cIMT among children in comparison with existent CRF cut-offs. cIMT was assessed with high-resolution ultrasonography and CRF was determined using a maximal cycle test. Receiver operating characteristic analyses were conducted in boys (n = 211) and girls (n = 202) aged 11-12 years to define the optimal sex-specific CRF cut-off to classify increased cIMT (≥75th percentile). Logistic regression was used to examine the association between the CRF cut-offs with the risk of having an increased cIMT. The optimal CRF cut-offs to predict increased cIMT were 45.81 and 34.46 mL·kg(-1)·min(-1) for boys and girls, respectively. The odds-ratios for having increased cIMT among children who were unfit was up to 2.8 times the odds among those who were fit (95% confidence interval: 1.40-5.53). Considering current CRF cut-offs, only those suggested by Adegboye et al. 2011. (Br. J. Sports Med. 45(9): 722-728) and Boddy et al. 2012 (PLoS One, 7(9): e45755) were significant in predicting increased cIMT. In conclusion, CRF cut-offs (boys: ≤ 45.8; girls: ≤ 34.5 mL·kg(-1)·min(-1)) are associated with thickening of the arterial wall in 11- to 12-year-old children. Low CRF is an important cardiovascular risk factor in children and our data highlight the importance of obtaining an adequate CRF.info:eu-repo/semantics/publishedVersio