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John H Morrison

Publications and source records attributed to John H Morrison.

At least 19 recordsLinked to original sources
PubMed2007

Distribution of NMDA and AMPA receptor subunits at thalamo-amygdaloid dendritic spines.

Synapses onto dendritic spines in the lateral amygdala formed by afferents from the auditory thalamus represent a site of plasticity in Pavlovian fear conditioning. Previous work has demonstrated that thalamic afferents synapse onto LA spines expressing glutamate receptor (GluR) subunits, but the GluR subunit distribution at the synapse and within the cytoplasm has not been characterized. Therefore, we performed a quantitative analysis for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits GluR2 and GluR3 and N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2B by combining anterograde labeling of thalamo-amygdaloid afferents with postembedding immunoelectron microscopy for the GluRs in adult rats. A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%), while a smaller proportion of spines expressed NR2B (59%). To compare across the various subunits, the cytoplasmic to synaptic ratios of GluRs were measured within thalamo-amygdaloid spines. Analyses revealed that the cytoplasmic pool of GluR2 receptors was twice as large compared to the GluR3, NR1, and NR2B subunits. Our data also show that in the adult brain, the NR2B subunit is expressed in the majority of in thalamo-amygdaloid spines and that within these spines, the various GluRs are differentially distributed between synaptic and non-synaptic sites. The prevalence of the NR2B subunit in thalamo-amygdaloid spines provides morphological evidence supporting its role in the fear conditioning circuit while the differential distribution of the GluR subtypes may reflect distinct roles for their involvement in this circuitry and synaptic plasticity.

Amygdala↗
PubMed2006

Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting.

Stressful life events have been implicated clinically in the pathogenesis of mental illness, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of these psychiatric conditions are associated with structural and functional abnormalities in a network of prefrontal cortical structures. Here, we examine whether chronic stress-induced dendritic alterations in the medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) underlie impairments in the behaviors that they subserve. After 21 d of repeated restraint stress, rats were tested on a perceptual attentional set-shifting task, which yields dissociable measures of reversal learning and attentional set-shifting, functions that are mediated by the OFC and mPFC, respectively. Intracellular iontophoretic injections of Lucifer yellow were performed in a subset of these rats to examine dendritic morphology in layer II/III pyramidal cells of the mPFC and lateral OFC. Chronic stress induced a selective impairment in attentional set-shifting and a corresponding retraction (20%) of apical dendritic arbors in the mPFC. In stressed rats, but not in controls, decreased dendritic arborization in the mPFC predicted impaired attentional set-shifting performance. In contrast, stress was not found to adversely affect reversal learning or dendritic morphology in the lateral OFC. Instead, apical dendritic arborization in the OFC was increased by 43%. This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.

Animals↗
PubMed2006

Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of beta-amyloid (Abeta)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the Abeta42/Abeta40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximately 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.

Aging↗
PubMed2006

Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys.

Long-term cyclic treatment with 17beta-estradiol reverses age-related impairment in ovariectomized rhesus monkeys on a test of cognitive function mediated by the prefrontal cortex (PFC). Here, we examined potential neurobiological substrates of this effect using intracellular loading and morphometric analyses to test the possibility that the cognitive benefits of hormone treatment are associated with structural plasticity in layer III pyramidal cells in PFC area 46. 17beta-Estradiol did not affect several parameters such as total dendritic length and branching. In contrast, 17beta-estradiol administration increased apical and basal dendritic spine density, and induced a shift toward smaller spines, a response linked to increased spine motility, NMDA receptor-mediated activity, and learning. These results document that, although the aged primate PFC is vulnerable in the absence of factors such as circulating estrogens, it remains responsive to long-term cyclic 17beta-estradiol treatment, and that increased dendritic spine density and altered spine morphology may contribute to the cognitive benefits of such treatment.

Aging↗
PubMed2006

Neuroinformatics: a new tool for studying the brain.

BACKGROUND: Central nervous system diseases constitute a major target for drug development. Genes expressed by the nervous system may represent half or more of the mammalian genome, with literally tens of thousands of gene products. METHODS: Better methods are therefore required to accelerate the pace of mapping gene expression patterns in the mouse brain and to evaluate the progressive phenotypic changes in genetic models of human brain diseases. CONCLUSIONS: Recent studies of mouse models of Amyotrophic Lateral Sclerosis and Alzheimer's disease illustrate how such data could be used for drug development. Since these two diseases-- especially Alzheimer's Disease-- entail disordered behavior, cognition and emotions, the framework and the methodology described in this article might in the future find applications in research on affective disorders.

Alzheimer Disease↗
PubMed2006

Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats.

BACKGROUND: Intrathecal (IT) gene transfer is an attractive approach for targeting spinal mechanisms of nociception but the duration of gene expression achieved by reported methods is short (up to two weeks) impairing their utility in the chronic pain setting. The overall goal of this study was to develop IT gene transfer yielding true long-term transgene expression defined as > or = 3 mo following a single vector administration. We defined "IT" administration as atraumatic injection into the lumbar cerebrospinal fluid (CSF) modeling a lumbar puncture. Our studies focused on recombinant adeno-associated virus (rAAV), one of the most promising vector types for clinical use. RESULTS: Conventional single stranded rAAV2 vectors performed poorly after IT delivery in rats. Pseudotyping of rAAV with capsids of serotypes 1, 3, and 5 was tested alone or in combination with a modification of the inverted terminal repeat. The former alters vector tropism and the latter allows packaging of self-complementary rAAV (sc-rAAV) vectors. Combining both types of modification led to the identification of sc-rAAV2/l as a vector that performed superiorly in the IT space. IT delivery of 3 x 10e9 sc-rAAV2/l particles per animal led to stable expression of enhanced green fluorescent protein (EGFP) for > or = 3 mo detectable by Western blotting, quantitative PCR, and in a blinded study by confocal microscopy. Expression was strongest in the cauda equina and the lower sections of the spinal cord and only minimal in the forebrain. Microscopic examination of the SC fixed in situ with intact nerve roots and meninges revealed strong EGFP fluorescence in the nerve roots. CONCLUSION: sc-rAAVl mediates stable IT transgene expression for > or = 3 mo. Our findings support the underlying hypothesis that IT target cells for gene transfer lack the machinery for efficient conversion of the single-stranded rAAV genome into double-stranded DNA and favor uptake of serotype 1 vectors over 2. Experiments presented here will provide a rational basis for utilizing IT rAAV gene transfer in basic and translational studies on chronic pain.

Animals↗
PubMed2006

Associative Pavlovian conditioning leads to an increase in spinophilin-immunoreactive dendritic spines in the lateral amygdala.

Changes in dendritic spine number and shape are believed to reflect structural plasticity consequent to learning. Previous studies have strongly suggested that the dorsal subnucleus of the lateral amygdala is an important site of physiological plasticity in Pavlovian fear conditioning. In the present study, we examined the effect of auditory fear conditioning on dendritic spine numbers in the dorsal subnucleus of the lateral amygdala using an immunolabelling procedure to visualize the spine-associated protein spinophilin. Associatively conditioned rats that received paired tone and shock presentations had 35% more total spinophilin-immunoreactive spines than animals that had unpaired stimulation, consistent with the idea that changes in the number of dendritic spines occur during learning and account in part for memory.

Acoustic Stimulation↗
PubMed2005

Estrogen induces rapid decrease in dendritic thorns of CA3 pyramidal neurons in adult male rat hippocampus.

Modulation of hippocampal synaptic plasticity by estrogen has been attracting much attention. Thorns of thorny excrescences of CA3 hippocampal neurons are post-synaptic regions whose presynaptic partners are mossy fiber terminals. Here we demonstrated the rapid effect of estradiol on the density of thorns of thorny excrescences, by imaging Lucifer Yellow-injected CA3 neurons in adult male rat hippocampal slices. The application of 1nM estradiol induced rapid decrease in the density of thorns on pyramidal neurons within 2h. The estradiol-mediated decrease in the density of thorns was blocked by CNQX (AMPA receptor antagonist) and PD98059 (MAP kinase inhibitor), but not by MK-801 (NMDA receptor antagonist). ERalpha agonist PPT induced the same suppressive effect as that induced by estradiol on the density of thorns, but ERbeta agonist DPN did not affect the density of thorns. Note that a 1nM estradiol treatment did not affect the density of spines in the stratum radiatum and stratum oriens. A search for synaptic ERalpha was performed using purified RC-19 antibody. The localization of ERalpha (67kDa) in the CA3 mossy fiber terminals and thorns was demonstrated using immunogold electron microscopy. These results imply that estradiol drives the signaling pathway including ERalpha and MAP kinase.

Aging↗
PubMed2005

Reversibility of apical dendritic retraction in the rat medial prefrontal cortex following repeated stress.

Apical dendritic retraction and axospinous synapse loss in the medial prefrontal cortex (PFC) are structural alterations that result from repeated restraint stress. Such changes in this brain region may be associated with impaired working memory, altered emotionality, and inability to regulate hypothalamic-pituitary adrenal activity, which in turn may underlie stress-related mental illnesses. In the present study, we examined the persistence of these stress-induced dendritic alterations in the medial PFC following the cessation of stress. Animals received either daily restraint stress for a 3-week period and were then allowed to recover for another 3 weeks, restraint stress for 3 or 6 weeks, or no restraint. Following perfusion and fixation, intracellular iontophoretic injections of Lucifer Yellow were performed in layer II/III pyramidal neurons in slices from the medial PFC, and apical and basal dendritic arbors were reconstructed in three dimensions. We observed a significant reduction in apical dendritic length and branch number following 3 or 6 weeks of repeated stress compared to 3-week stress/3-week recovery. These results suggest that stress-induced dendritic plasticity in the medial PFC is reversible and may have implications for the functional recovery of medial PFC function following prolonged psychological stress.

Animals↗
PubMed2005

Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex.

The prefrontal cortex (PFC) plays an important role in higher cognitive processes, and in the regulation of stress-induced hypothalamic-pituitary-adrenal (HPA) activity. Here we examined the effect of repeated restraint stress on dendritic spine number in the medial PFC. Rats were perfused after receiving 21 days of daily restraint stress, and intracellular iontophoretic injections of Lucifer Yellow were carried out in layer II/III pyramidal neurons in the anterior cingulate and prelimbic cortices. We found that stress results in a significant (16%) decrease in apical dendritic spine density in medial PFC pyramidal neurons, and confirmed a previous observation that total apical dendritic length is reduced by 20% in the same neurons. We estimate that nearly one-third of all axospinous synapses on apical dendrites of pyramidal neurons in medial PFC are lost following repeated stress. A decrease in medial PFC dendritic spines may not only be indicative of a decrease in the total population of axospinous synapses, but may impair these neurons' capacity for biochemical compartmentalization and plasticity in which dendritic spines play a major role. Dendritic atrophy and spine loss may be important cellular features of stress-related psychiatric disorders where the PFC is functionally impaired.

Animals↗
PubMed2005

Mouse models of human neurodegenerative disorders: requirements for medication development.

Central nervous system diseases constitute a major target for drug development. Transgenic mouse models, in which genes identified in familial forms of human brain diseases are expressed in mouse neurons and glia, offer opportunities to detect and follow pathologic progression and provide potential biomarkers by which to assess therapeutic interventions. Evidence for Alzheimer disease suggests some starting requirements for the experimental data that could enhance the likelihood of developing medications in these mouse models that would also be effective in humans.

Alzheimer Disease↗
PubMed2005

Repeated stress and structural plasticity in the brain.

Although adrenal steroid receptors are distributed widely throughout the central nervous system, specific limbic and cortical regions targeted by stress hormones play a key role in integrating behavioral and physiological responses during stress and adaptation to subsequent stressors. When the stressor is of a sufficient magnitude or prolonged, it may result in abnormal changes in brain plasticity that, paradoxically, may impair the ability of the brain to appropriately regulate and respond to subsequent stressors. Here we review how repeated stress produces alterations in brain plasticity in animal models, and discuss its relevance to behavioral changes associated with these regions. Interestingly, prolonged stress produces opposing effects on structural plasticity, notably dendritic atrophy and excitatory synapse loss in the hippocampus and prefrontal cortex, and growth of dendrites and spines in the amygdala. The granule cells of the dentate gyrus are also significantly affected through a decrease in the rate neurogenesis following prolonged stress. How functional impairments in these brain regions play a role in stress-related mental illnesses is discussed in this context. Finally, we discuss the cumulative impact of stress-induced structural plasticity in aging.

Aging↗
PubMed2005

Cellular and synaptic distribution of NR2A and NR2B in macaque monkey and rat hippocampus as visualized with subunit-specific monoclonal antibodies.

The functional and pharmacological attributes of the N-methyl-D-aspartate (NMDA) receptor are related to its subunit composition, thus resolving the subunit composition of NMDA receptors in specific classes of synapses is an important step in characterizing excitatory circuits. Toward this end, mouse monoclonal antibodies were raised against fusion protein antigens corresponding to the putative amino acid sequences of human NMDA receptor subunits NR2A and NR2B. The subunit specificity of these monoclonal antibodies was demonstrated with transfected human and rat NMDA receptor cDNAs, and their immunoreactivity was established in rat, macaque monkey, and human brain tissue. At the light microscopic level, both NR2A and NR2B exhibit a distribution in monkey and rat hippocampus very similar to NMDA receptor subunit NR1, and both are highly colocalized with NR1. Electron microscopic immunogold studies demonstrated that both NR2A and NR2B are often present in asymmetric synapses in CA1, commonly colocalized with NR1, and often colocalized with each other in the same asymmetric synapses. Both assembly and synthetic pools are present within spines and spine necks, respectively, particularly for NR2A. The confocal and ultrastructural data suggest that whereas NR1, NR2A, and NR2B are essentially uniformly colocalized in hippocampal projection neurons, there is extensive heterogeneity at the synaptic level that would lead to multiple functional classes of NMDA receptor-mediated synapses, and extensive capacity for plasticity at the synapse. Thus, the subunit profile of a given synapse may be dynamic, with regulation of local synthesis and insertion of different subunits into the synapse leading to a complex, heterogeneous, and shifting set of functional attributes of the NMDA receptor.

Animals↗
PubMed2005

New prospects and strategies for drug target discovery in neurodegenerative disorders.

The future of neurodegenerative therapeutics development depends upon effective disease modification strategies centered on carefully investigated targets. Pharmaceutical research endeavors that probe for a much deeper understanding of disease pathogenesis, and explain how adaptive or compensatory mechanisms might be engaged to delay disease onset or progression, will produce the needed breakthroughs. Below, we discuss the prospects for new targets emerging out of the study of brain disease genes and their associated pathogenic pathways. We describe a general experimental paradigm that we are employing across several mouse models of neurodegenerative disease to elucidate molecular determinants of selective neuronal vulnerability. We outline key elements of our target discovery program and provide examples of how we integrate genomic technologies, neuroanatomical methods, and mouse genetics in the search for neurodegenerative disease targets.

Animals↗
PubMed2004

Genetically decreased spinal cord copper concentration prolongs life in a transgenic mouse model of amyotrophic lateral sclerosis.

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (FALS) by gain of an aberrant function that is not yet well understood. The role of Cu(2+) in mediating the toxicity of mutant SOD1 has been earnestly contested. We tested the in vivo effects of genetically induced copper deprivation on the ALS phenotype of transgenic mice expressing G86R mutant mouse SOD1, a protein that fails to incorporate Cu(2+) in its active site. Genetically copper-deficient SOD1(G86R) transgenic mice were produced by mating SOD1(G86R) males to female carriers of the X-linked mottled/brindled (Mobr) mutation. We found that the Mobr allele causes a severe ( approximately 60%) depletion of spinal cord copper levels; however, despite the burden of double genetic lesions, it lengthens the lives of SOD1(G86R) transgenic mice by 9%. These findings provide evidence supporting a role for copper in the pathogenesis of FALS linked to SOD1 mutations.

Adenosine Triphosphatases↗
PubMed2004

Estrogen modulates synaptic N-methyl-D-aspartate receptor subunit distribution in the aged hippocampus.

Estrogen interacts with N-methyl-D-aspartate (NMDA) receptors to regulate multiple aspects of morphological and functional plasticity. In hippocampus, estrogen increases both dendritic spine density and synapse number, and NMDA antagonists block these effects. Thus, estrogen-mediated hippocampal plasticity may be of particular importance in the context of age-related changes in endocrine status and cognitive performance. NR1 levels per synapse are increased in CA1 by estrogen in aged rats but not young rats, although no information is available on estrogen-induced synaptic alterations in other NMDA receptor subunits that might impact function. Therefore, the present study was designed to investigate the effect of estrogen on the synaptic and subsynaptic distributions of the NMDA receptor subunits, NR2A and NR2B in CA1 pyramidal cells, within the context of aging. Our results demonstrated that the overall synaptic levels of NR2A and NR2B are similar in young and aged female rats, regardless of estrogen treatment. However, in the aged CA1, estrogen restores NR2B levels back to young levels in the lateral portions of the active synaptic zone. Thus, estrogen may impact the mobility of NMDA receptors across the synapse and, in the process, restore a more youthful synaptic profile. These findings have important implications for the mechanism of estrogen-induced alterations in NMDA receptor-mediated processes, particularly in the context of aging.

Aging↗
PubMed2004

Effects of estrogen replacement therapy on cholinergic basal forebrain neurons and cortical cholinergic innervation in young and aged ovariectomized rhesus monkeys.

Estrogen modulates the function of cholinergic basal forebrain neurons in aged female rats. The present study tested the hypothesis that estrogen enhances the phenotype of cholinergic basal forebrain neurons and their cortical cholinergic innervation in young adult and aged ovariectomized rhesus monkeys. Sixteen monkeys (9 young and 7 aged) received two injections of estradiol cypionate or vehicle separated by 3 weeks. All monkeys were killed 1 day after the last injection. Quantitative immunofluorescence in the vertical limb of the diagonal band (VLDB) revealed enhanced optical density for choline acetyltransferase (ChAT) in both young and aged monkeys treated with estrogen. In contrast, optical density for low-affinity p75 neurotrophin receptor immunoreactivity in the VLDB did not change after estrogen treatment in either aged or young animals. Quantitative immunofluorescence for either ChAT or the low-affinity p75 neurotrophin receptor in the nucleus basalis Meynert failed to reveal differences between vehicle and estrogen treatment in either age group. Quantitative estimates of acetylcholinesterase (AChE) fiber density revealed that estrogen-treated aged monkeys but not their younger counterparts had decreased numbers of AChE-positive fibers in layer II of frontal, insular, and cingulate cortices. These data indicate that estrogen administered in a manner simulating natural hormonal cyclicity produces modest age-specific chemical phenotypic and regional changes in select neuronal subfields of the cholinergic basal forebrain and their cortical projection sites in nonhuman primates.

Aging↗