Biomedical subjects

Jacob Raber

Publications and source records attributed to Jacob Raber.

At least 19 recordsLinked to original sources

PubMed2007

A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory.

The scaffolding protein WAVE-1 (Wiskott-Aldrich syndrome protein family member 1) directs signals from the GTPase Rac through the Arp2/3 complex to facilitate neuronal actin remodeling. The WAVE-associated GTPase activating protein called WRP is implicated in human mental retardation, and WAVE-1 knock-out mice have altered behavior. Neuronal time-lapse imaging, behavioral analyses, and electrophysiological recordings from genetically modified mice were used to show that WAVE-1 signaling complexes control aspects of neuronal morphogenesis and synaptic plasticity. Gene targeting experiments in mice demonstrate that WRP anchoring to WAVE-1 is a homeostatic mechanism that contributes to neuronal development and the fidelity of synaptic connectivity. This implies that signaling through WAVE-1 complexes is essential for neural plasticity and cognitive behavior.

Amino Acid Sequence↗

PubMed2006

Deletion of the Ttf1 gene in differentiated neurons disrupts female reproduction without impairing basal ganglia function.

Thyroid transcription factor 1 (TTF1) [also known as Nkx2.1 (related to the NK-2 class of homeobox genes) and T/ebp (thyroid-specific enhancer-binding protein)], a homeodomain gene required for basal forebrain morphogenesis, remains expressed in the hypothalamus after birth, suggesting a role in neuroendocrine function. Here, we show an involvement of TTF1 in the control of mammalian puberty and adult reproductive function. Gene expression profiling of the nonhuman primate hypothalamus revealed that TTF1 expression increases at puberty. Mice in which the Ttf1 gene was ablated from differentiated neurons grew normally and had normal basal ganglia/hypothalamic morphology but exhibited delayed puberty, reduced reproductive capacity, and a short reproductive span. These defects were associated with reduced hypothalamic expression of genes required for sexual development and deregulation of a gene involved in restraining puberty. No extrapyramidal impairments associated with basal ganglia dysfunction were apparent. Thus, although TTF1 appears to fulfill only a morphogenic function in the ventral telencephalon, once this function is satisfied in the hypothalamus, TTF1 remains active as part of the transcriptional machinery controlling female sexual development.

Animals↗

PubMed2006

Impairments in spatial memory retention of GFAP-apoE4 female mice.

The human apolipoprotein E isoforms, apoE2, apoE3, and apoE4, have differential effects on brain function. Compared to apoE3, apoE4 increases the risk of age-related cognitive decline in humans and female mice expressing apoE in neurons. Here, we show impaired spatial memory retention in female mice expressing apoE4 in astrocytes compared to those expressing apoE3 in astrocytes or lacking apoE. Thus, apoE4 impairs cognition whether expressed in neurons or astrocytes.

Analysis of Variance↗

PubMed2006

Effects of sex on object recognition and spatial navigation in humans.

Human tests designed to mirror rodent tests of object recognition and spatial navigation were administered to adult cognitively healthy humans. Facial recognition was also assessed. There was no sex difference in facial recognition, consistent with earlier studies. In the object recognition test, the test-retest NINL total scores during the same visit were highly correlated, comparable to the test-retest correlations obtained in the established facial recognition test. There were no effects of sex on object recognition. However, in the spatial navigation test, there were effects of sex on spatial learning and memory during the session with the hidden, but not visible, target. These tests might be useful to compare assessments of object recognition and spatial learning and memory in humans and animal models.

Adult↗

PubMed2006

Novel object recognition in Apoe(-/-) mice improved by neonatal implantation of wild-type multipotential stromal cells.

Multipotential bone marrow stromal cells (MSCs) from wild-type (Wt) or apolipoprotein E deficient (Apoe(-/-)) mice were implanted into the cerebral ventricles of Apoe(-/-) mice. MSCs from Wt mice continued expressing apoE up to 6 months after implantation and were associated with enhanced novel object recognition and increased microtubule-associated protein 2 (MAP2) immunoreactivity in the dentate gyrus. These data show that MSCs can be used to distinguish developmental from post-developmental effects of a gene knockout and support their therapeutic potential for neurodegenerative diseases.

Animals↗

PubMed2006

Sex- and histamine-dependent long-term cognitive effects of methamphetamine exposure.

As prenatal methamphetamine (MA) exposure results in long-term hippocampus-dependent cognitive deficits, the increased MA use in women of childbearing age is of great concern. As mice are most commonly used in genetic models, we started to study the potential effects of neonatal MA exposure in female and male mice on brain function 3 months later. As histamine (HA) might mediate some effects of MA in adulthood, we also tested whether in neonates HA might mediate the long-term effects of MA using HA H(3) receptor agonists and antagonists. Stimulation of HA H(3) receptors by H(3) agonists inhibits HA synthesis and release, whereas inhibition of H(3) receptors by H(3) receptor antagonists increases HA release. MA (5 mg/kg), the H(3) receptor antagonist thioperamide (5 mg/kg), and the H(3) receptor agonist immepip (5 mg/kg) alone or in the presence of MA (5 mg/kg) were administered once daily from postnatal days 11 to 20 and the mice were tested at 3 months of age. Here we show that in mice exposure to MA early in life causes sex-dependent impairments in object recognition, spatial learning, and memory in the water maze, and pre-pulse inhibition in adulthood. HA mediates these impairments. Increasing HA release mimicked, whereas inhibiting HA release blocked the long-term detrimental MA effects. This model could be used to determine the role of genetic and environmental factors in MA-dependent cognitive impairments and to develop therapeutic strategies to inhibit them.

Analysis of Variance↗

PubMed2006

Reduction in mitochondrial superoxide dismutase modulates Alzheimer's disease-like pathology and accelerates the onset of behavioral changes in human amyloid precursor protein transgenic mice.

Alzheimer's disease (AD) is associated with accumulations of amyloid-beta (Abeta) peptides, oxidative damage, mitochondrial dysfunction, neurodegeneration, and dementia. The mitochondrial antioxidant manganese superoxide dismutase-2 (Sod2) might protect against these alterations. To test this hypothesis, we inactivated one Sod2 allele (Sod2(+/-)) in human amyloid precursor protein (hAPP) transgenic mice, reducing Sod2 activity to approximately 50% of that in Sod2 wild-type (Sod2(+/+)) mice. A reduction in Sod2 activity did not obviously impair mice without hAPP/Abeta expression. In hAPP mice, however, it accelerated the onset of behavioral alterations and of deficits in prepulse inhibition of acoustic startle, a measure of sensorimotor gating. In these mice, it also worsened hAPP/Abeta-dependent depletion of microtubule-associated protein 2, a marker of neuronal dendrites. Sod2 reduction decreased amyloid plaques in the brain parenchyma but promoted the development of cerebrovascular amyloidosis, gliosis, and plaque-independent neuritic dystrophy. Sod2 reduction also increased the DNA binding activity of the transcription factor nuclear factor kappaB. These results suggest that Sod2 protects the aging brain against hAPP/Abeta-induced impairments. Whereas reductions in Sod2 would be expected to trigger or exacerbate neuronal and vascular pathology in AD, increasing Sod2 activity might be of therapeutic benefit.

Alzheimer Disease↗

PubMed2006

Age-dependent measures of anxiety and cognition in male histidine decarboxylase knockout (Hdc-/-) mice.

Histidine decarboxylase deficient (Hdc(-/-)) and wild-type male mice on the C57Bl6/J background were used to determine the role of histamine in brain function. 3-5 (Y) and 12-14 (MA) month-old Hdc(-/-) mice showed hypoactivity and increased measures of anxiety in the open field, light-dark, elevated plus-maze, and elevated zero maze tests. Y Hdc(-/-) mice showed superior performance in the hidden sessions of the water maze and passive avoidance memory retention. In contrast, Y Hdc(-/-) mice were impaired in novel location recognition, spent less time searching in the target quadrant and more time searching in the outer zone of the water maze during the probe trials. These behaviors are likely due to increased measures of anxiety and are not found in MA Hdc(-/-) mice. These data support a role for histamine in anxiety and cognition and underline the importance of considering age and potential effects on measures of anxiety in the interpretation of the role of histaminergic neurotransmission in cognitive function.

Age Factors↗

PubMed2006

NF-kappaB/Rel regulates inhibitory and excitatory neuronal function and synaptic plasticity.

Changes in synaptic plasticity required for memory formation are dynamically regulated through opposing excitatory and inhibitory neurotransmissions. To explore the potential contribution of NF-kappaB/Rel to these processes, we generated transgenic mice conditionally expressing a potent NF-kappaB/Rel inhibitor termed IkappaBalpha superrepressor (IkappaBalpha-SR). Using the prion promoter-enhancer, IkappaBalpha-SR is robustly expressed in inhibitory GABAergic interneurons and, at lower levels, in excitatory neurons but not in glia. This neuronal pattern of IkappaBalpha-SR expression leads to decreased expression of glutamate decarboxylase 65 (GAD65), the enzyme required for synthesis of the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) in GABAergic interneurons. IkappaBalpha-SR expression also results in diminished basal GluR1 levels and impaired synaptic strength (input/output function), both of which are fully restored following activity-based task learning. Consistent with diminished GAD65-derived inhibitory tone and enhanced excitatory firing, IkappaBalpha-SR+ mice exhibit increased late-phase long-term potentiation, hyperactivity, seizures, increased exploratory activity, and enhanced spatial learning and memory. IkappaBalpha-SR+ neurons also express higher levels of the activity-regulated, cytoskeleton-associated (Arc) protein, consistent with neuronal hyperexcitability. These findings suggest that NF-kappaB/Rel transcription factors act as pivotal regulators of activity-dependent inhibitory and excitatory neuronal function regulating synaptic plasticity and memory.

Animals↗

PubMed2006

Traumatic injury to the immature brain results in progressive neuronal loss, hyperactivity and delayed cognitive impairments.

The immature brain may be particularly vulnerable to injury during critical periods of development. To address the biologic basis for this vulnerability, mice were subjected to traumatic brain injury at postnatal day 21, a time point that approximates that of the toddler-aged child. After motor and cognitive testing at either 2 weeks (juveniles) or 3 months (adults) after injury, animals were euthanized and the brains prepared for quantitative histologic assessment. Brain-injured mice exhibited hyperactivity and age-dependent anxiolysis. Cortical lesion volume and subcortical neuronal loss were greater in brain-injured adults than in juveniles. Importantly, cognitive decline was delayed in onset and coincided with loss of neurons in the hippocampus. Our findings demonstrate that trauma to the developing brain results in a prolonged period of pathogenesis in both cortical and subcortical structures. Behavioral changes are a likely consequence of regional-specific neuronal degeneration.

Aging↗

PubMed2006

Sex- and APOE isoform-dependent effects of radiation on cognitive function.

Clinical irradiation of the brain induces hippocampus-dependent cognitive impairments in some but not all individuals, suggesting the involvement of genetic risk factors. Deficiency of apolipoprotein E (APOE), which is important for the metabolism and redistribution of lipoproteins and cholesterol, increases behavioral impairments after irradiation, supporting a protective role for APOE against radiation-induced cognitive injury. Compared to APOE3, APOE4 increases while APOE2 decreases the risk of developing age-related cognitive decline and Alzheimer's disease, particularly in women. To determine the potential effects of APOE isoform and sex on radiation-induced cognitive impairments, we irradiated 2-month-old male and female APOE2, APOE3 and APOE4 mice and assessed their cognitive performance 3 months later. When hippocampus-dependent spatial learning and memory were assessed in the water maze, sham-irradiated female APOE2, APOE3 and APOE4 and irradiated female APOE2 mice showed spatial memory retention, but irradiated female APOE3 and APOE4 mice did not. Compared to sham-irradiated female APOE4 mice, irradiated female APOE4 mice also required more trials to reach criterion in the hippocampus-dependent passive avoidance test. Radiation had no effects on water maze or passive avoidance learning and memory of male APOE2, APOE3 or APOE4 mice, indicating that the effects of radiation on cognitive performance are dependent on sex- and APOE isoform.

Animals↗

PubMed2005

Anxiety and cognition in female histidine decarboxylase knockout (Hdc(-/-)) mice.

The role of histamine in brain function has been studied using histidine decarboxylase (HDC) deficient male mice. As the effects of HDC deficiency on brain function might be sex-dependent, we behaviorally analyzed Hdc(-/-) and control female mice. Compared to female control mice, Hdc(-/-) female mice showed hypoactivity, increased measures of anxiety, impairments in water-maze performance, but enhanced passive avoidance memory retention. Following behavioral testing, arginine vasopression (AVP) immunoreactivity was higher in the dorsal hypothalamus and central and basolateral nuclei of the amygdala of Hdc(-/-) than Hdc(+/+) mice. Finally, MAP2 immunoreactivity in the hippocampal CA1 region correlated positively with measures of anxiety in the open-field and light-dark tests and negatively with performance during the hidden sessions of the water-maze. As the effects of HDC deficiency on object recognition, water-maze, and rotorod performance, were sex-dependent, it is important to consider potential effects of sex in the interpretation of the role of histaminergic neurotransmission in brain function.

Animals↗

PubMed2005

Role of circulating androgen levels in effects of apoE4 on cognitive function.

Compared with apoE2 and E3, apoE4 increases the risk of cognitive impairments and of developing Alzheimer's disease (AD). ApoE4 interacts with female sex, further increasing AD risk. Previously, we showed that female Apoe-/- mice are more susceptible to apoE4-induced cognitive deficits than male mice. Androgens protect against these deficits and apoE4 male mice are more sensitive to acute blockade of androgen receptors than apoE3 male mice. To determine the chronic effects of reduced circulating androgen levels on susceptibility to the effects of apoE4 on cognitive function in males, we castrated and sham-castrated apoE4, apoE3, and Apoe-/- male mice and behaviorally compared them 3 months later. Castration impaired novel location recognition in apoE4, but not apoE3 or Apoe-/-, mice. In contrast, castration impaired novel object recognition and spatial memory retention in the water maze in Apoe-/-, but not apoE3 or apoE4, mice. On the contrary, castrated, but not sham-castrated, apoE4 mice showed improved acquisition over the first two hidden platform sessions and spatial memory retention in the first probe trial. While apoE3 and Apoe-/- mice increased their exploratory times with the objects in the trial with the novel object, apoE4 mice did not. ApoE4 mice required more trials than apoE3 or Apoe-/- mice to reach criterion during passive avoidance training, but castration did not modulate passive avoidance learning or memory. Thus, androgens have differential roles in object recognition and spatial learning and memory in the water maze, depending on whether or not apoE4 is present.

Analysis of Variance↗

PubMed2005

Mouse behavioural analysis in systems biology.

Molecular techniques allowing in vivo modulation of gene expression have provided unique opportunities and challenges for behavioural studies aimed at understanding the function of particular genes or biological systems under physiological or pathological conditions. Although various animal models are available, the laboratory mouse (Mus musculus) has unique features and is therefore a preferred animal model. The mouse shares a remarkable genetic resemblance and aspects of behaviour with humans. In this review, first we describe common mouse models for behavioural analyses. As both genetic and environmental factors influence behavioural performance and need to be carefully evaluated in behavioural experiments, considerations for designing and interpretations of these experiments are subsequently discussed. Finally, common behavioural tests used to assess brain function are reviewed, and it is illustrated how behavioural tests are used to increase our understanding of the role of histaminergic neurotransmission in brain function.

Animals↗

PubMed2005

Behavioral performance of tfm mice supports the beneficial role of androgen receptors in spatial learning and memory.

In adulthood, androgens and androgen receptors might contribute to the sexually dimorphic performance in spatial learning and memory, but their roles seem complex. To study the potential role of androgen receptors in spatial learning and memory, we tested adult 6-8-month-old mutant mice with a naturally occurring defect in the androgen receptor gene (testicular feminization mutant or tfm) and C57Bl/6J wild-type mice. Because the trait is X-linked, only tfm males are completely androgen insensitive while female tfm mice are heterozygous, carrying one wild-type and one tfm copy of the androgen receptor. Here we show that female tfm carrier mice outperform tfm male mice in the water maze, while there are no gender differences in water maze performance in wild-type mice. In tfm mice, there were no gender differences in measures of anxiety in the open field or plus maze or sensorimotor function, indicating that potential differences in these measures did not contribute to the differences observed in the water maze. There were no differences in tfm and wild-type female and male mice in emotional learning and memory in the passive avoidance test. These findings support a beneficial role for androgen receptors in spatial learning and memory.

Androgen-Insensitivity Syndrome↗

PubMed2005

apoE isoforms and measures of anxiety in probable AD patients and Apoe-/- mice.

Increased anxiety may occur in up to 70% of AD patients during the course of their illness. Here we show that human apoE isoforms, which differ in AD risk, have differential effects on measures of anxiety in adult Apoe-/- male mice expressing human apoE3 or apoE4 in their brains and male probable AD (PRAD) patients. Compared with wild-type mice, Apoe-/- mice without human apoE or with apoE4, but not apoE3, showed increased measures of anxiety. These behavioral alterations were associated with reduced microtubule-associated protein 2-positive neuronal dendrites in the central nucleus of the amygdala. Consistent with the mouse data, male and female PRAD patients with epsilon4/epsilon4 showed higher anxiety scores than those with epsilon3/epsilon3. We conclude that human apoE isoforms have differential effects on measures of anxiety.

Aged↗

PubMed2005

Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8.

To study the role of the metabotropic glutamate receptor 8 (mGluR8), mice lacking this receptor were generated by homologous recombination. Homozygous mGluR8-deficient mice are about 8% heavier than their wild-type age-matched controls after reaching 4 weeks of age. This weight difference is not caused by an altered food intake and is not exacerbated by feeding the animals a high-fat diet. Moreover, mGluR8-/- mice are mildly insulin resistant, possibly as a result of being overweight. Behavioral testing revealed a reduced locomotor activity of mGluR8-/- mice compared with wild-type mice during the first 3 days in a novel enclosed environment. However after 3 days, the locomotor activities of wild-type and mGluR8-/- mice were similar, suggesting a reduced exploratory behavior of mGluR8-/- mice in a novel enclosed environment. By contrast, there were no genotype differences in locomotor activity in the open field, plus maze, or in total time spent exploring objects during object recognition tests, indicating that there is a dissociation between effects of mGluR8 deficiency in exploratory activity in a novel safe enclosed environment vs. a more anxiogenic novel open environment. The absence of mGluR8 also leads to increased measures of anxiety in the open field and elevated plus maze. Whether the diverse phenotypic differences observed in mGluR8-/- mice result from the misregulation of a unique neural pathway, possibly in the thalamus or hypothalamus, or whether they are the consequence of multiple developmental and functional alterations in synaptic transmission, remains to be determined.

Absorptiometry, Photon↗

PubMed2004

Androgens, apoE, and Alzheimer's disease.

Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.

Alzheimer Disease↗