Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning

New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory

Targeted Use of Placebo Effects Decreases Experimental Itch in Atopic Dermatitis Patients: A Randomized Controlled Trial

Evidence from pain research shows that the effectiveness of active pharmacological treatments can be enhanced by placebo effects. The "open drug administration" is superior to "hidden drug administration." In a randomized controlled trial, we aimed to show that the targeted use of placebo effects increases the efficacy of an antihistamine (dimetindene) infusion in participants with atopic dermatitis. We openly infused dimetindene (drug) in full sight with information (intervention group 1: OPEN‐DRUG+INST), openly infused drug with an additional classical conditioning learning experience (intervention group 2: OPEN‐DRUG+INST+COND) or infused drug without any information or sight (i.e., hidden administration (control group 1: HIDDEN‐DRUG)). Control group 2 received a placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience (PLAC+INST+COND). Itch was experimentally induced with histamine via a skin prick test. Outcome was assessed at the subjective (primary end point: experimental itch intensity, numeric rating scale), and objective level (secondary end point: wheal size, mm2). Experimental‐induced itch intensity decreased in all groups but at different rates (P < 0.001). The groups with the open administration, whether it was dimetindene or placebo, had significantly stronger reductions in itch compared to the HIDDEN‐DRUG group (OPEN‐DRUG+INST+COND: P < 0.001; OPEN‐DRUG+INST: P = 0.009; and PLAC+INST+COND: P < 0.001). Additional drug conditioning mediated via expectation led to a stronger reduction of itching (P = 0.001). Results on wheal size were similar (P = 0.048), however, no significant difference between the HIDDEN‐DRUG group and the PLAC+INST+COND group (P = 0.967) was found. We conclude that specifically generated targeted placebo effects can significantly increase the action of a drug (dimetindene) and should be used in clinical practice