Memory Deficits and Transcription Factor Activity Following Traumatic Brain Injury

Traumatic brain injury (TBI) is a serious condition and a leading cause of death and disability [1]. No two head injuries are alike and multiple complications are common in TBI. The most serious aspect of TBI is that of cognitive impairment as evidenced by animal and clinical studies focusing on synaptic plasticity and memory [2-5]. However, post trauma effects also includ

Zinc deficiency and neurodevelopment: the case of neurons

Zinc is essential for normal brain development. Gestational severe zinc deficiency can lead to overt fetal brain malformations. Although not teratogenic, suboptimal zinc nutrition during gestation can have long-term effects on the offspring's nervous system. This article will review current knowledge on the role of zinc in modulating neurogenesis and neuronal apoptosis as well as the proposed underlying mechanisms. A decrease in neuronal zinc causes cell cycle arrest, which in part involves a deregulation of select signals (ERK1/2, p53, and NF-κB). Zinc deficiency also induces apoptotic neuronal death through the intrinsic (mitochondrial) pathway, which can be triggered by the activation of the zinc-regulated enzyme caspase-3, and as a consequence of abnormal regulation of prosurvival signals (ERK1/2 and NF-κB). Alterations in the finely tuned processes of neurogenesis, neuronal migration, differentiation, and apoptosis, which involve the developmental shaping of the nervous system, could have a long-term impact on brain health. Zinc deficiency during gestation, even at the marginal levels observed in human populations, could increase the risk for behavioral/neurological disorders in infancy, adolescence, and adulthood.Fil: Adamo, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Oteiza, Patricia Isabel. University of California at Davis; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition

Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 hours, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory

Intracortical injection of endothelin-1 induces cortical infarcts in mice: effect of neuronal expression of an adenosine transporter

Abstract Background Activation of adenosine A1 receptors has neuroprotective effects in animal stroke models. Adenosine levels are regulated by nucleoside transporters. In vitro studies showed that neuron-specific expression of human equilibrative nucleoside transporter 1 (hENT1) decreases extracellular adenosine levels and adenosine A1 receptor activity. In this study, we tested the effect of hENT1 expression on cortical infarct size following intracerebral injection of the vasoconstrictor endothelin-1 (ET-1) or saline. Methods Mice underwent stereotaxic intracortical injection of ET-1 (1 μl; 400 pmol) or saline (1 μl). Some mice received the adenosine receptor antagonist caffeine (25 mg/kg, intraperitoneal) 30 minutes prior to ET-1. Perfusion and T2-weighted magnetic resonance imaging (MRI) were used to measure cerebral blood flow (CBF) and subsequent infarct size, respectively. Results ET-1 reduced CBF at the injection site to 7.3 ± 1.3% (n = 12) in hENT1 transgenic (Tg) and 12.5 ± 2.0% (n = 13) in wild type (Wt) mice. At 48 hours following ET-1 injection, CBF was partially restored to 35.8 ± 4.5% in Tg and to 45.2 ± 6.3% in Wt mice; infarct sizes were significantly greater in Tg (9 ± 1.1 mm3) than Wt (5.4 ± 0.8 mm3) mice. Saline-treated Tg and Wt mice had modest decreases in CBF and infarcts were less than 1 mm3. For mice treated with caffeine, CBF values and infarct sizes were not significantly different between Tg and Wt mice. Conclusions ET-1 produced greater ischemic injury in hENT1 Tg than in Wt mice. This genotype difference was not observed in mice that had received caffeine. These data indicate that hENT1 Tg mice have reduced ischemia-evoked increases in adenosine receptor activity compared to Wt mice.Peer Reviewe

Healthy skin wins: A glowing pressure ulcer prevention program

Session presented on Monday, November 9, 2015 and Tuesday, November 10, 2015: Pressure ulcers (PUs) are one indicator of the quality of health care. The prevalence of PUs in acute care hospitals in Canada is estimated at 25.1% with half of PUs assessed as Stage 1. In 2013, an observational survey using a modified Braden Scale was conducted among 272 patients in an acute care hospital located in a Western Canadian city. The prevalence rate of PUs was 34.9% with only one third of the PUs at Stage 1. In this poster presentation, we describe how a multidisciplinary research team implemented and evaluated a PU prevention program (PUPP). The multi-disciplinary research team was comprised of a physiotherapist, an occupational therapist, a dietician, wound care specialists, and several nurses. The team used the Iowa Model of Evidence-Based Practice to Promote Quality Care in conjunction with Rogers\u27 Diffusion of Innovations Model as guiding frameworks. The PUPP included the establishment of specialized mattresses hospital-wide, new products for patients with incontinence, use of sliders, and discontinued use of soaker pads. A staff awareness campaign was launched; it was entitled, Healthy Skin Wins with posters and weekly newsletters about changes in practice, nutritional support for at-risk patients, and a 20-minute online tutorial about PUs and PU prevention. A mixed methods study, funded by the Manitoba Centre for Nursing and Health Research, was employed to determine the effectiveness of the PUPP with a pre-test/post-test design, a repeat observational PU prevalence survey, and three focus group interviews. Health care aides, licensed practical nurses, registered nurses, and allied health care professionals were invited to complete an anonymous 18-item knowledge assessment tool before and after an online tutorial about PU prevention using FluidSurveys.com. Eighty staff members volunteered to participate in the pre-test/post-test with a statistically significant increase in their knowledge about PUs and PU prevention. A repeat PU prevalence observational survey was conducted after the launch of the PUPP in 2014 with 240 in-hospital patients, and a statistically significant reduction in the prevalence rate (7.5%). Following analysis of the quantitative data, health care aides, nurses, and allied health professionals were invited to participate in three semi-structured, audio-recorded focus group interviews to share their perceptions of the PUPP. The audio-recordings of the interviews were transcribed verbatim. Transcripts were read and reread to facilitate a process of thematic analysis to describe hospital staff\u27s experiences of the PUPP. In this poster presentation, we share the results of the mixed methods study that determined the effectiveness of the PUPP. This mixed methods study can be used as a template to incorporate and evaluate evidence-based practice changes in various health care facilities around the world

NF-κB p50 subunit knockout impairs late LTP and alters long term memory in the mouse hippocampus

Abstract Background Nuclear factor kappa B (NF-κB) is a transcription factor typically expressed with two specific subunits (p50, p65). Investigators have reported that NF-κB is activated during the induction of in vitro long term potentiation (LTP), a paradigm of synaptic plasticity and correlate of memory, suggesting that NF-κB may be necessary for some aspects of memory encoding. Furthermore, NF-κB has been implicated as a potential requirement in behavioral tests of memory. Unfortunately, very little work has been done to explore the effects of deleting specific NF-κB subunits on memory. Studies have shown that NF-κB p50 subunit deletion (p50−/−) leads to memory deficits, however some recent studies suggest the contrary where p50−/− mice show enhanced memory in the Morris water maze (MWM). To more critically explore the role of the NF-κB p50 subunit in synaptic plasticity and memory, we assessed long term spatial memory in vivo using the MWM, and synaptic plasticity in vitro utilizing high frequency stimuli capable of eliciting LTP in slices from the hippocampus of NF-κB p50−/− versus their controls (p50+/+). Results We found that the lack of the NF-κB p50 subunit led to significant decreases in late LTP and in selective but significant alterations in MWM tests (i.e., some improvements during acquisition, but deficits during retention). Conclusions These results support the hypothesis that the NF-κ p50 subunit is required in long term spatial memory in the hippocampus. </jats:sec