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The \u201ctwo hit\u201d hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these \u201ctwo hit\u201d effects is unclear. Our aim was to behaviorally characterize a \u201ctwo hit\u201d rat model of developmental stress accompanied by an in\u2010depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and\/or adolescent\/young\u2010adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon\u2010specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male \u201ctwo hit\u201d rats showed marked disruptions in short\u2010term spatial memory (Y\u2010maze) which were absent in females. However, female \u201ctwo hit\u201d rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two \u201chits\u201d. In the DHP, MS caused a male\u2010specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region\u2010specific and sex\u2010specific long\u2010term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex\u2010specific effects of developmental stress on anhedonic behaviors. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/hipo.22302","type":"journal-article","created":{"date-parts":[[2014,5,7]],"date-time":"2014-05-07T09:21:25Z","timestamp":1399454485000},"page":"1197-1211","source":"Crossref","is-referenced-by-count":93,"title":["Sex\u2010specific disruptions in spatial memory and anhedonia in a \u201ctwo hit\u201d rat model correspond with alterations in hippocampal brain\u2010derived neurotrophic factor expression and signaling"],"prefix":"10.1002","volume":"24","author":[{"given":"Rachel A.","family":"Hill","sequence":"first","affiliation":[{"name":"Florey Institute of Neuroscience and Mental Health, University of Melbourne Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Klug","sequence":"additional","affiliation":[{"name":"Florey Institute of Neuroscience 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