Human urocortin II, a selective agonist for the type 2 corticotropinreleasing factor receptor, decreases feeding and drinking in the rat

ABSTRACT Corticotropin-releasing factor (CRF) has been hypothesized to modulate consummatory behavior through the Type 2 CRF (CRF 2 ) receptor. However, behavioral functions subserved by the CRF 2 receptor remain poorly understood. Recently, human urocortin II (hUcn II), a selective CRF 2 receptor agonist, was identified. To study the effects of this neuropeptide on ingestive behavior, we examined the effects of centrally infused hUcn II (i.c.v. 0, 0.01, 0.1, 1.0, 10.0 g) on the microstructure of nosepoke responding for food and water in nondeprived, male rats. Malaise-inducing properties of the peptide were monitored using conditioned taste aversion (CTA) testing. To identify potential sites of action, central induction of Fos protein expression was examined. hUcn II dose dependently reduced the quantity and duration of responding for food and water at doses lower (0.01-1.0 g) than that forming a CTA (10 g). Effects were most evident during hours 4 to 6 of the dark cycle. Meal pattern analysis showed that hUcn II potently (0.1 g) increased the satiating value of food. Rats ate and drank smaller and shorter meals without changing meal frequency. Rats also ate more slowly. hUcn II induced Fos in regions involved in visceral sensory processing and autonomic/neuroendocrine regulation and resembling those activated by appetite suppressants. hUcn II is a promising neuropeptide for investigating the role of the CRF 2 receptor in ingestive behavior. Corticotropin-releasing factor (CRF) is hypothesized to mediate behavioral, autonomic, endocrine, and immunological responses to stres

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Further Evidence of Emotional Allodynia in Unmedicated Young Adults with Major Depressive Disorder

<div><p>Background</p><p>Recent evidence suggests that sensitivity to the emotional sequela of experimental thermal pain(measured by emotional unpleasantness) is heightened in individuals with major depressive disorder(MDD), a phenomenon we termed “emotional allodynia”. The aim of this study was to examine whether acute happy and sad mood induction alters emotional allodynia in MDD. We hypothesized that emotional allodynia will be a robust characteristic of individuals with MDD compared to healthy controls. Thus, it would remain following acute mood induction, independent of valence.</p><p>Methods</p><p>Twenty-one subjects with current MDD and 21 well-matched healthy subjects(HC) received graded brief temperature stimuli following happy and sad mood inductions procedures(MIP). All subjects rated the intensity and affect(pleasantness/unpleasantness) of each stimulus. Sensory(pain intensity) and affective(pain unpleasantness) thresholds were determined by methods of constant stimuli.</p><p>Results</p><p>The MIPs reliably induced happy and sad mood and the resulting induced mood and subjective arousal were not different between the groups at the time of temperature stimulation. Compared to HC, MDD individuals demonstrated emotional allodynia. We found significantly decreased affective pain thresholds whereby significantly lower temperatures became unpleasant in the MDD compared to the HC group. This was not observed for the sensory pain thresholds. Within the MDD, the affective pain thresholds were significantly lower than the corresponding pain intensity thresholds, whereby non-painful temperatures were already unpleasant for the MDD irrespective of the induced mood. This was not observed for the HC groups where the affective and pain intensity thresholds were comparable.</p><p>Conclusions</p><p>These findings suggest that emotional allodynia may be a chronic characteristic of current MDD. Future studies should determine if emotional allodynia persists after psychological or pharmacological interventions. Finally, longitudinal work should examine whether emotional allodynia is a result of or vulnerability for depression and the role it plays in the increased susceptibility for pain complaints in this disorder.</p></div

Experimental Design.

<p>Upon arrival subjects rated their mood and arousal (Rating 1). Subjects were then seated quietly in front of the laptop computer while listening to 7 min of previously chosen and individualized for each participant sad/happy music (see Appendix) and reading and re-experiencing the autobiographical event displayed on the computer screen. Mood and arousal ratings were taken immediately after (Rating 2a). This was followed by a series of brief temperature stimuli of six different intensities (T1–T6: 36, 38, 40, 42, 44, 46°C) delivered every 60 sec in random and counterbalanced order to subjects’ left forearm. After 12 temperature stimulations, mood induction was repeated with the new sad/happy music and autobiographical script, after which subjects again rated their mood and arousal (Rating 2b). A total of 24 temperature stimuli were delivered for a total duration of ∼40 min. After mood neutralization for ∼35 min (see Methods) subjects are asked to rate their mood and arousal (Rating 3). The procedure is repeated with the opposite valence.</p

Mood Ratings.

<p>Subjects rated their mood prior to mood induction (M1), immediately after mood induction (M2) when temperature stimulations were applied and at the end of sad/happy experimental blocks (M3) (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080507#pone-0080507-g001" target="_blank"><b>Figure 1</b></a> and text for more details). Significant within-subjects effects of mood induction on subjects’ rating of mood in both manipulations (happy: F(2,38) = 6.113, p<0.01; sad: F(2,38) = 12.306, p<0.001) with mood ratings being significantly lower during sad than happy MIP. (<b>A</b>) <b>Happy MIP</b>: MDD subjects showed significantly lower M1 (F(1,39) = 5.199, p<0.05) and M3 ratings (F(1,39) = 13.970, p<0.01) but not M2 rating (F(1,39) = 0.894, p>0.05); (<b>B</b>) <b>Sad MIP:</b> MDD subjects showed significantly lower M1 (F(1,39) = 11.584, p<0.01) and M3 (F(1,39) = 11.133, p<0.01) rating but not M2 rating (F(1,39) = 3.720, p>0.05).</p

Demographic, Clinical and Psychological Variables.

<p>MDD/(E) – Major Depressive Disorder/(Episode); HC – Healthy Control; BDI – Beck Depression Inventory 2;</p

Arousal Ratings.

<p>Subjects rated their arousal prior to the mood induction (A1), immediately after mood induction (A2) when temperature stimulations were applied and at the end of sad/happy experimental blocks (A3) (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0080507#pone-0080507-g001" target="_blank"><b>Figure 1</b></a> and text for more details). ) <b>(a)</b><b>Happy MIP</b>: MDD compared to controls had higher A1 rating (F(1,39) = 9.242, p<0.01) but not A2 (F(1,39) = 2.263, p>0.05) or A3 (F(1,39) = 1.981, p>0.05) rating. <b>(b)</b><b>Sad MIP:</b> MDD compared to control group did not differ in their A1 (F(1,39) = 2.321, p>0.05) or A2 (F(1,39) = 0.972, p>0.05) rating and had higher A3 rating (F(1,39) = 6.735, p<0.05).</p

Pain Intensity and Affective Thresholds.

<p><b>a)</b> Highly significant group effect on the affective thresholds was observed following happy and sad mood inductions whereby significantly lower affective thresholds were found in the MDD compared to the HC group (F(1,39) = 7.473, p<0.01); <b>b</b>) No significant group effect was observed for the intensity thresholds following mood induction (F(1,39) = 0.33, p>0.05).</p