Showing papers by "Jacob Raber published in 2012"

Anaplastic lymphoma kinase and leukocyte tyrosine kinase: functions and genetic interactions in learning, memory and adult neurogenesis.

Abstract: Anaplastic Lymphoma Kinase (Alk) is a receptor tyrosine kinase expressed throughout the adult mammalian hippocampus. Recent studies in Drosophila and prior studies in Caenorhabditis elegans have implicated Alk signaling in learning and neurogenesis. We have studied the roles of Alk and the closely related receptor Leukocyte Tyrosine Kinase (Ltk) in learning, behavior and neurogenesis. In the hippocampus, both receptors are expressed throughout the dentate gyrus, CA1 and CA3. To assess the functional roles of Alk and Ltk in the mammalian brain, we analyzed phenotypes in Alk mutant, Ltk mutant and Alk/Ltk double-mutant mice compared to wild-type littermates. Similar to Drosophila, we found enhanced performance in spatial memory in Alk mutant mice. Also similar to Drosophila, we observed reduced neurogenesis associated with loss of Alk function. We also report genetic interactions between Alk and Ltk with respect to neurogenesis and behavioral measures such as activity, anxiety levels, and retention of spatial memory.

Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of 56Fe Irradiation on the Brain

Abstract: Purpose In humans, apolipoprotein E (apoE) is encoded by three major alleles (e2, e3, and e4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of 56 Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk. Methods and Materials We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after 56 Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis. Results In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice. Conclusions The short-term effects of 56 Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.

Trauma‐induced alterations in cognition and Arc expression are reduced by previous exposure to 56Fe irradiation

Abstract: Exposure to ionizing irradiation may affect brain functions directly, but may also change tissue sensitivity to a secondary insult such as trauma, stroke, or degenerative disease. To determine if a low dose of particulate irradiation sensitizes the brain to a subsequent injury, C56BL6 mice were exposed to brain only irradiation with 0.5 Gy of 56 Fe ions. Two months later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Three weeks after trauma, animals received multiple BrdU injections and 30 days later were tested for cognitive performance in the Morris water maze. All animals were able to locate the visible and hidden platform during training; however, treat- ment effects were seen when spatial memory retention was assessed in the probe trial (no platform). Although sham and irradiated animals showed spatial memory retention, mice that received trauma alone did not. When trauma was preceded by irradiation, performance in the water maze was not different from sham-treated animals, suggesting that low- dose irradiation had a protective effect in the context of a subsequent traumatic injury. Measures of hippocampal neurogenesis showed that combined injury did not induce any changes greater that those seen after trauma or radiation alone. After trauma, there was a significant decrease in the percentage of neurons expressing the behaviorally induced imme- diate early gene Arc in both hemispheres, without associated neuronal loss. After combined injury there were no differences relative to sham- treated mice. Our results suggest that combined injury resulted in decreased alterations of our endpoints compared to trauma alone. Although the underlying mechanisms are not yet known, these results resemble a preconditioning, adaptive, or inducible-like protective response, where a sublethal or potentially injurious stimulus (i.e., irradia- tion) induces tolerance to a subsequent and potentially more damaging insult (trauma). V C 2010 Wiley-Liss, Inc.

Object recognition testing tools and techniques for measuring cognitive ability and cognitive impairment

Abstract: Techniques and tools for measuring cognitive ability and/or detecting cognitive impairment or decline For example, techniques and tools are described that can be used to diagnose or test susceptibility to cognitive impairments in children or in elderly people (such as cognitive impairments associated with Alzheimer's Disease) Techniques and tools are described that can be used to evaluate treatment effects and/or measure cognitive decline over time

Astrocyte-Specific Disruption of SynCAM1 Signaling Results in ADHD-Like Behavioral Manifestations

Abstract: SynCAM1 is an adhesion molecule involved in synaptic differentiation and organization. SynCAM1 is also expressed in astroglial cells where it mediates astrocyte-to astrocyte and glial-neuronal adhesive communication. In astrocytes, SynCAM1 is functionally linked to erbB4 receptors, which are involved in the control of both neuronal/glial development and mature neuronal and glial function. Here we report that mice carrying a dominant-negative form of SynCAM1 specifically targeted to astrocytes (termed GFAP-DNSynCAM1 mice) exhibit disrupted diurnal locomotor activity with enhanced and more frequent episodes of activity than control littermates during the day (when the animals are normally sleeping) accompanied by shorter periods of rest. GFAP-DNSynCAM1 mice also display high levels of basal activity in the dark period (the rodent's awake/active time) that are attenuated by the psychostimulant D,L-amphetamine, and reduced anxiety levels in response to both avoidable and unavoidable provoking stimuli. These results indicate that disruption of SynCAM1-dependent astroglial function results in behavioral abnormalities similar to those described in animals model of attention-deficit hyperactive disorder (ADHD), and suggest a hitherto unappreciated contribution of glial cells to the pathophysiology of this disorder.

ApoE isoform-dependent deficits in extinction of contextual fear conditioning.

Abstract: The three major human apoE isoforms (apoE2, apoE3 and apoE4) are encoded by distinct alleles (ϵ2, ϵ3 and ϵ4) Compared with ϵ3, ϵ4 is associated with increased risk to develop Alzheimer's disease (AD), cognitive impairments in Parkinson's disease (PD), and other conditions In contrast, a recent study indicated an increased susceptibility to the recurring and re-experiencing symptom cluster of Post-Traumatic Stress Disorder (PTSD), as well as related memory impairments, in patients carrying at least one ϵ2 allele Contextual fear conditioning and extinction are used in human and animal models to study this symptom cluster In this study, acquisition (day 1, training), consolidation (day 2, first day of re-exposure) and extinction (days 2-5) of conditioned contextual fear in human apoE2, apoE3 and apoE4 targeted replacement and C57BL/6J wild-type (WT) mice was investigated Male and female apoE2 showed acquisition and retrieval of conditioned fear, but failed to exhibit extinction In contrast, WT, apoE3 and apoE4 mice showed extinction While apoE2 mice exhibited lower freezing in response to the context on day 2 than apoE3 and apoE4 mice, this cannot explain their extinction deficit as WT mice exhibited similar freezing levels as apoE2 mice on day 2 but still exhibited extinction Elevating freezing through extended training preserved extinction in controls, but failed to ameliorate extinction deficits in apoE2 animals These data along with clinical data showing an association of apoE2 with susceptibility to specific symptom clusters in PTSD supports an important role for apoE isoform in the extinction of conditioned fear

The Polyamine Inhibitor Alpha-Difluoromethylornithine Modulates Hippocampus-Dependent Function after Single and Combined Injuries

Abstract: Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.

Novel image–novel location object recognition task sensitive to age-related cognitive decline in nondemented elderly

Abstract: Traditional tests used in the clinic to identify dementia, such as the mini-mental state examination (MMSE), are useful to identify severe cognitive impairments but might be less sensitive to detect more subtle age-related cognitive changes. Previously, the novel image–novel location (NINL) object recognition test was shown to be sensitive to detect effects of apolipoprotein E4, a risk factor for developing age-related cognitive decline and Alzheimer’s disease, in nondemented elderly. In the present longitudinal study, performance on the MMSE and the NINL tests were compared over a 4-year period. Individual NINL scores over this period were highly correlated. In addition, while MMSE scores did not change over the 4-year period, NINL scores did. In a final testing session of a subset of the participants, NINL scores correlated with logical memory and word recall lists, cognitive tasks used to detect dementia in the clinic, as well as clinical dementia rating scales. These results support that the NINL might be a valuable tool to assess age-related cognitive decline.

Neuroscience-based Tests for Assessing Cognitive Changes in Normal Aging and in the Prodromal Phase of Alzheimer’s Disease

Abstract: Slow decline in cognition is key to the clinical diagnosis of Alzheimer’s disease (AD). This diagnosis relies on screening tests insensitive to detection of prodromal AD, which occurs years before the appearance of clinical symptoms. Neuroscience-based tests of eyeblink classical conditioning, spatial navigation, and object recognition are associated with synaptic-level function. They show promise in detecting early changes in AD-impacted memory circuits. Eyeblink conditioning engages synapses dependent upon nicotinic acetylcholine receptors and medial septal cholinergic input to the hippocampus. Spatial navigation and object recognition engage perforant pathway entorhinal cortical input to the hippocampus. Synapses in these circuits are among the earliest impacted by beta amyloid. These three translational tests are well characterized in normal aging and AD in humans and pertinent animal models, including organisms expressing the AD risk factor apolipoprotein E4. They may detect cognitive decline in prodromal AD and prove useful for population screening and evaluation of therapeutic interventions.