OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency.

Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD.

[Influence of the autonomic nervous system on the initial response of heart rate to active and passive orthostatism]. / Influencia del sistema nervioso autónomo en la respuesta inicial de la frecuencia cardíaca al ortostatismo activo y pasivo.

Influence of the autonomic nervous system on the heart rate response to active and passive orthostatism. The purposes of this study were twofold. First, to compare heart rate responses as measured by R-R interval under two conditions of orthostatic stress, i.e. a change from supine to an active free standing-up position (active orthostatism, AO), and from supine to a passive 70 head-up tilt posture (passive orthostatism, PO) second, to utilize a standard pharmacological model to study the participation of the autonomic nervous system upon heart rate responses evoked by AO. In the first part of the research, eight healthy subjects (seven men, one woman) were evaluated for AO and PO. In both occasions, subjects were supine for 5 minutes and then adopted an upright or a tilted position in 3-5 seconds and remained motionless during 5 minutes. In the second part, eight men participated twice in the pharmacological studies. In day one, they stood up for control (AOC), after IV administration of atropine sulfate (0.04 mg/kg) (AO+atro) and after IV administration of propranolol hydrochloride (0.16 mg/kg) (AO+ATRO+PROPRA). In day two, subjects repeated the control AO (AOCII) and after the administration for propranolol hydrochloride alone. In the first study, AO was characterized by a fast shortening of R-R interval, which was maximal at beat 15th (relative tachycardia), followed by a rebound lengthening of R-R interval, reaching a plateau at beat 30 (relative bradycardia), demonstrating a biphasic response. PO was characterized by a small and gradual shortening of R-R interval without the biphasic responses of AO.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of body posture on serum concentration of lipids]. / "Efecto de la postura corporal sobre la concentración de los lipidos séricos".

The purpose of this study was to evaluate the effects of body postural changes (supine-upright), upon the serum concentration of cholesterol (CT), triglycerides (TG), high density lipoproteins (HDL), low density (LDL) and very low density lipoproteins (VLDL) and hemoglobin, hematocrit, and plasma proteins (to calculate delta% change in plasma y volume). Nine healthy men participated as subjects. Their age ranged from 32 +/- 3 years old, and 16 +/- 4% body fat (X +/- SD). After 10-12 hours post absorptive and appropriate rest, they performed a standard orthostatic maneuver: subjects remained supine for 30 minutes, then assumed the standing position (unsupported and with minimal movement) for additional 30 minutes. Blood samples were obtained after 30 minutes supine and at 10, 20 and 30 minutes of standing. At 10 minutes of orthostatism, CT, TG, HDL and VLDL had a significant increase as compared to supine values; these changes were associated with a reduction of 8.9% on plasma volume (PV) (p less than 0.05). After 30 minutes of orthostatism CT, TG, HDL and VLDL showed increments of 8.5%, 33.3%, 20.1% and 32% respectively, in relation to the supine values (p less than 0.05). Changes on serum lipids were associated with PV reductions until 20 minutes of orthostatism. However, there was not a significant association between these variables at 30 minutes of standing. These data indicated that the body position and the time in which blood samples are obtained significantly influence lipid and lipoprotein serum level. Therefore, in any study related to lipids, such variables should be considered and properly controlled.