Selective Survival and Maturation of Adult-Born Dentate Granule Cells Expressing the Immediate Early Gene Arc/Arg3.1

Progenitor cells in the adult dentate gyrus provide a constant supply of neuronal precursors, yet only a small fraction of these cells survive and develop into mature dentate granule cells (DGCs). A major challenge of current research is thus to understand the stringent selection process that governs the maturation and functional integration of adult-born DGCs. In mature DGCs, high-frequency stimulation (HFS) of the perforant path input elicits robust expression of the immediate early gene Arc/Arg3.1, trafficking of its mRNA to dendrites, and local synthesis of the protein necessary for consolidation of long-term potentiation (LTP). Given the synaptic commitment inherent in LTP consolidation, we considered that HFS-evoked expression of Arc could be used to timemap the functional integration of newborn DGCs. Dividing cells were birthmarked by BrdU-labeling at 1, 7, 14, 21, or 28 days prior to induction of LTP and expression of Arc was examined by confocal microscopy. Contrary to expectation, LTP did not induce Arc expression in newborn cells at any age, suggesting they might be refractory to synaptically-evoked Arc expression for at least one month. Importantly, however, spontaneous expression of Arc was detected in BrdU-labeled cells and strongly associated with the survival and maturation of NeuN-positive DGCs. Moreover, Arc expression at the earliest ages (1 and 7 days), clearly precedes the formation of glutamatergic synapses on new neurons. These results suggest an unexpected early role for Arc in adult-born DGCs, distinct from its functions in LTP, LTD, and homeostatic synaptic plasticity

Changes in hippocampal neurogenesis throughout early development

Adult hippocampal neurogenesis drastically diminishes with age but the underlying mechanisms remain unclear. Here, age-related influences on the hippocampal early neuroprogenitor cell (NPC) pool was examined by quantifying changes in Sox1-expressing cells in the dentate gyrus subgranular zone from early adulthood (3 months) to middle age (12 months). Proliferation of distinct NPC subpopulations (Sox1+, Nestin+, and Doublecortin+) and newborn cell survival were also investigated. Examination of total 5-bromodeoxyuridine (BrdU)+ and Doublecortin (DCX)± cells revealed an early and dramatic age-dependent decline of hippocampal neurogenesis. Increasing age from 3 to 12 months was primarily associated with reduced total proliferation, in vivo (−79% of BrdU+ cells) but not in vitro, and DCX+ cell numbers (−89%). When proliferative rates of individual NPC subpopulations were examined, a different picture emerged as proliferating Nestin+ neuroprogenitors (−95% at 9 months) and BrdU+/DCX+ neuroblasts and/or immature neurons (−83% at 12 months) declined the most, whereas proliferating Sox1+ NPCs only dropped by 53%. Remarkably, despite greatly reduced proliferative rates and recent reports of Nestin+ neuroprogenitor loss, total numbers of early Sox1+ NPCs were unaffected by age (at least up to middle age), and newborn cell survival within the dentate gyrus was increased. Neuronal differentiation was concomitantly reduced; however, thus suggesting age-associated changes in fate-choice determination

The Arc of synaptic memory

The immediate early gene Arc is emerging as a versatile, Wnely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modiWcation, localization, and degradation of Arc protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a “master regulator” of protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated

Chronic stress-induced changes in the rat brain:Role of sex differences and effects of long-term tianeptine treatment

Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatment of affective disorders. Abnormal expression and/or phosphorylation of numerous plasticity-related proteins have been observed in depression, while prolonged antidepressant treatment has been associated with the attenuation of stress-mediated effects on dendritic remodeling and adult hippocampal neurogenesis in experimental animals. This study explores the neurobiological adaptations induced by chronic stress and/or long-term tianeptine treatment. Male and female rats were studied to determine the potential contributory role of sex differences on stress-induced pathology and antidepressant-mediated actions. Our results confirm chronic stress-induced HPA axis disturbance and neuroplasticity impairment in both sexes (i.e. reduced CREB phosphorylation and hippocampal BrdU labeling). Commonly ensuing neurobiological alterations were accompanied by unique sex-specific adaptations. When the antidepressant tianeptine was administered, HPA axis hyperactivity was attenuated and specific neuronal defects were ameliorated in both sexes. These findings provide novel insight into sex-related influences on the neurobiological substrates mediating chronic stress-induced actions on neuroplasticity and the mechanisms underlying tianeptine-mediated therapeutic effects.

Antibiotic Resistance and the Risk of Recurrent Bacteremia

Background Direct health effects of antibiotic resistance are difficult to assess. We quantified the risk of recurrent bacteremia associated with resistance. Methods We extracted antimicrobial susceptibility testing data on blood isolates from the Dutch surveillance system for antimicrobial resistance between 2008 and 2017. First and first recurrent (4-30 days) bacteremia episodes were categorized as susceptible, single nonsusceptible, or co-nonsusceptible to third-generation cephalosporins without or with carbapenems (Enterobacteriaceae), ceftazidime without or with carbapenems (Pseudomonas species), aminopenicillins without or with vancomycin (Enterococcus species), or as methicillin-sensitive/-resistant S. aureus (MSSA/MRSA). We calculated risks of recurrent bacteremia after nonsusceptible vs susceptible first bacteremia, estimated the crude population attributable effect of resistance for the Netherlands, and calculated risks of nonsusceptible recurrent bacteremia after a susceptible first episode. Results Risk ratios for recurrent bacteremia after a single- and co-nonsusceptible first episode, respectively, vs susceptible first episode, were 1.7 (95% confidence interval [CI], 1.5-2.0) and 5.2 (95% CI, 2.1-12.4) for Enterobacteriaceae, 1.3 (95% CI, 0.5-3.1) and 5.0 (95% CI, 2.9-8.5) for Pseudomonas species, 1.4 (95% CI, 1.2-1.7) and 1.6 (95% CI, 0.6-4.2) for Enterococcus species, and 1.6 (95% CI, 1.1-2.4) for MRSA vs MSSA. The estimated population annual number of recurrent bacteremias associated with nonsusceptibility was 40. The risk of nonsusceptible recurrent bacteremia after a susceptible first episode was at most 0.4% (Pseudomonas species). Conclusions Although antibiotic nonsusceptibility was consistently associated with higher risks of recurrent bacteremia, the estimated annual number of additional recurrent episodes in the Netherlands (40) was rather limited