Hippocampus
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In the context of Alzheimer's disease (AD), hippocampal alterations have been well described in advanced stages of the pathology, when amyloid deposition, inflammation and glial activation occur, but less attention has been directed to studying early brain and behavioral changes. Using an animal model of AD, the transgenic PDAPP-J20 mouse at 5 months of age, when no amyloid plaques are present and low cerebral levels of amyloid peptides are detectable, we found structural, morphological, and cellular alterations in the hippocampus. Young transgenic mice showed a reduced hippocampal volume with less number of pyramidal and granular neurons, which additionally exhibited cell atrophy. ⋯ Moreover, multivariate statistical analysis of the behavioral outcome in the open-field test evidenced an elevated anxiety score in Tg mice compared with age-matched control mice. In line with this, the transgenic group showed a higher number of c-Fos+ nuclei in central and basolateral amygdala, a result that supports the early involvement of the emotionality factor in AD pathology. Applying an integrative approach, this work focuses on early structural, morphological and functional changes and provides new and compelling evidence of behavioral alterations that precede manifest AD.
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Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behavior, cognition, and reward sensitivity in adult rats. We investigated whether escalating doses of the cannabinoid receptor 1 (CB1 R) agonist, HU-210, in adolescence would affect adult hippocampal neurogenesis and behavioral processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague-Dawley rats. Escalating doses of HU-210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. ⋯ However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB1 R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB1 R activation during adolescence results in sex-dependent, long-term, changes to hippocampal structure and function, an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex.
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The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover,the function of neurogenesis in this brain region differs in adolescent and adult mice. ⋯ In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts.