Palatal tremor and myorhythmia in Hashimoto's encephalopathy.
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Adult↗
Biomedical subjects
J C Erickson
Publications and source records attributed to J C Erickson.
Effect of peripheral axotomy on dorsal root ganglion neuron phenotype and autonomy behaviour in neuropeptide Y-deficient mice.
The lumbar 5 (L5) dorsal root ganglia (DRGs) were studied in neuropeptide tyrosine (NPY)-deficient (-/-) and wild type (+/+) mice after unilateral sciatic nerve transection using in situ hybridization and immunohistochemistry. NPY, galanin and two NPY receptors (Y-Rs) were analyzed as well as self-mutilation behaviour (autotomy) and nociceptive thresholds. No difference between wild type and NPY-deficient mice was seen in the tail-flick or hot plate test. However, -/- mice showed a much stronger autotomy behaviour than wild type mice. NPY was not found in L5 DRGs in -/- mice, not even after axotomy. Galanin was upregulated to the same extent after axotomy in NPY-deficient and wild type mice. Y1- and Y2-R mRNAs were found mainly in small DRG neuron profiles. Both receptor mRNAs were downregulated after axotomy, to about the same extent in NPY-deficient as in wild type mice. In control and contralateral ganglia the mRNA levels of both receptors were lower in NPY-deficient mice than in wild type mice. The contralateral Y2-R mRNA levels did not reach control values in the NPY-deficient mice, as they did in the wild type mice. In both strains the Y1-R protein was decorating the somatic plasmalemma. The present results suggest that lack of NPY may cause exaggerated autotomy, a self-mutilation behaviour possibly related to pain sensation, in agreement with the described analgesic effect of NPY. Although significant differences in levels of Y1- and especially Y2-R mRNAs were observed between wild type and NPY-deficient mice, they were only moderate. These findings suggest that expression, regulation, localization and possible function of Y1- and Y2-Rs are not dependent on presence of the endogenous ligand. Also, deletion of NPY does not seem to influence the expression of the partly coexisting peptide galanin.
Animals↗
Response of neuropeptide Y-deficient mice to feeding effectors.
Neuropeptide Y (NPY) is thought to be an important central regulator of feeding behavior and body weight. However, mice lacking NPY due to targeted genetic deletion do not display abnormalities in food intake or body weight with ad libitum access to food or in response to fasting. In this study, we investigate the response of NPY-deficient (NPY-/-) mice to anorexic and orexigenic treatments. The dose-dependent stimulation of food intake by central NPY administration was unaltered in NPY-/- mice. Peripheral administration of various doses of leptin for 2 days elicited a two-fold greater inhibition of food intake in NPY-/- mice than in wildtype (NPY+/+) mice. In addition, lateral ventricular administration of leptin (1 microg) suppressed refeeding in NPY-/- mice after a 24 h fast, but had little effect in NPY+/+ mice. However, the response to other feeding inhibitors such as corticotrophin releasing factor (CRF), dexfenfluramine, and a melanocortin 4 receptor (MC4R) agonist, MTII, was unaltered in NPY-/- mice. These results indicate that the appetite-suppressant action of exogenous leptin is uniquely amplified in NPY-/- mice, and suggest that NPY may tonically antagonize leptin action.
Animals↗
Role of neuropeptide Y in diet-, chemical- and genetic-induced obesity of mice.
OBJECTIVE: The goal of this study was to ascertain whether neuropeptide Y (NPY) is required in mice for the development of obesity induced by a high-fat diet (HFD), chemical lesions of the hypothalamus caused by monosodium glutamate (MSG) or gold thioglucose (GTG), impaired brown adipose tissue (BAT) due to a diphtheria toxin transgene driven by the uncoupling protein 1 promoter (UCP-DTA) or the lethal yellow agouti mutation (Ay). BACKGROUND: The obesity syndrome of the leptin-deficient (ob/ob) mouse can be partially reversed by the genetic removal of NPY. In the murine models of obesity examined in this study, the animals become obese despite increased serum leptin levels, indicating that they are resistant to the weight-limiting actions of leptin. The role of NPY in these obesity models with elevated leptin levels is unknown. EXPERIMENTAL DESIGN: Mice lacking NPY due to genetic disruption of the gene and wildtype littermates were made obese by allowing them access to a highly palatable HFD, by treatment with MSG, or GTG, or by inheriting the dominant UCP-DTA or Ay alleles. Food consumption, body weight and dissectable fat pad weights were measured and compared to values obtained from non-obese littermates. RESULTS: In each model of obesity tested, NPY-deficient mice achieved the same food intake, body weight and fat content as wildtype littermates. CONCLUSION: NPY is not necessary for the progressive development of obesity exhibited by multiple murine models with leptin resistance.
Adipose Tissue, Brown↗
Effect of fasting and leptin deficiency on hypothalamic neuropeptide Y gene transcription in vivo revealed by expression of a lacZ reporter gene.
Neuropeptide Y (NPY), a peptide synthesized in the hypothalamic arcuate nucleus, is implicated in the physiologic control of food intake and body weight. Because both genetic (e.g. in obese ob/ob mice) and acquired leptin deficiency (e.g. fasting in normal mice) increase hypothalamic NPY accumulation, and as leptin administration reverses this effect, we hypothesized that leptin inhibits transcription of the NPY gene by arcuate nucleus neurons. To test this hypothesis, we studied mice with a targeted mutation of the NPY gene (NPY knockout mice), in which the lacZ reporter gene was inserted into the first exon of the NPY gene. As a result, these mice express beta-galactosidase (beta gal; the enzyme encoded by lacZ) in neurons that normally express the NPY gene. To determine whether beta gal staining provides a valid measure of lacZ expression, we used a histochemical method to count the number of beta gal+ neurons in coronal sections of brain tissue from mice bearing either one (NPY+/-) or two (NPY-/-) mutant alleles. In both the arcuate nucleus and the thalamic reticular nucleus, beta gal+ cell number was 260% higher in NPY-/- than in NPY+/- mice (P < 0.05). Fasting for 48 h also increased the mean beta gal+ cell number in the arcuate nucleus of NPY+/- mice by 260% (P < 0.001), but had no effect in the thalamic reticular nucleus. Similarly, obese leptin-deficient ob/ob, NPY+/- mice had a 67.3% increase in arcuate nucleus beta gal+ cell number compared with lean ob/+, NPY+/- littermates (P < 0.05), and this effect was attenuated 36.6% (P < 0.05) by leptin administration (70 microg/day, i.p., for 4 days). Based on the results of this novel method for measuring NPY gene transcription in vivo, we conclude that both fasting and genetic leptin deficiency increase NPY gene transcription in the arcuate nucleus and that this transcriptional response is attenuated by leptin administration in ob/ob, NPY+/- mice.
Animals↗
Increased expression of mRNA for the long form of the leptin receptor in the hypothalamus is associated with leptin hypersensitivity and fasting.
The responsiveness of the hypothalamus to the inhibitory effects of leptin on food intake and body weight is influenced by multiple factors, including deficiency of either leptin or leptin receptors (Ob-R). To investigate whether altered expression of Ob-R in the hypothalamus could potentially contribute to altered leptin sensitivity, we performed in situ hybridization with riboprobes that detected either mRNAs encoding both the long (Ob-Rb) and short (Ob-Ra) splice variants or mRNA encoding only Ob-Rb. In the arcuate nucleus, mRNA encoding Ob-Rb, the predominant signaling form of the receptor, was 2.3 times greater in obese db/db and ob/ob mice than in lean +/ob controls (P < 0.01). In ob/ob mice, systemic administration of leptin reduced Ob-Rb mRNA content of the arcuate nucleus by 30% compared with saline-treated, pair-fed controls (P < 0.05). A 48-h fast increased Ob-Rb mRNA levels in the arcuate nucleus of normal and neuropeptide Y (NPY)-knockout mice (P < 0.01), although the effect was greater in the NPY-knockout mice (400 vs. 247%, P < 0.05). In addition, Ob-Rb mRNA hybridization was elevated by 40% in the arcuate nucleus (P < 0.05) and by 75% in the ventromedial nucleus (P < 0.05) of rats fasted 48 h. The results suggest that expression of Ob-Rb mRNA in the hypothalamus is sensitive to genetic and physiological interventions that alter circulating leptin levels, and that overexpression of Ob-Rb in the hypothalamus may contribute to increased leptin sensitivity.
Animals↗
Life without neuropeptide Y.
Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
Animals↗
Knock-out mice reveal a critical antiepileptic role for neuropeptide Y.
Neuropeptide Y (NPY) inhibits excitatory synaptic transmission in the hippocampus and is implicated in control of limbic seizures. In the present study, we examined hippocampal function and the response to pharmacologically induced seizures in mutant mice lacking this peptide. In slice electrophysiology studies, no change in normal hippocampal function was observed in NPY-deficient mice compared with normal wild-type littermates. Kainic acid (KA) produced limbic seizures at a comparable latency and concentration in NPY-deficient mice compared with littermates. However, KA-induced seizures progressed uncontrollably and ultimately produced death in 93% of NPY-deficient mice, whereas death was rarely observed in wild-type littermates. Intracerebroventricular NPY infusion, before KA administration, prevented death in NPY-deficient mice. These results suggest a critical role for endogenous NPY in seizure control.
Action Potentials↗
Endocrine function of neuropeptide Y knockout mice.
Among its many proposed functions, neuropeptide Y (NPY) is thought to modulate the hypothalamic-pituitary axis. Specifically, increased hypothalamic NPY signaling may be critical in mediating the neuroendocrine response to fasting. To determine the consequences of NPY deficiency on endocrine physiology, multiple hormones were quantitated in wildtype and NPY-knockout mice under fed and fasted conditions. Serum concentrations of leptin, corticosterone, thyroxine, and testosterone were normal in NPY-knockout males fed ad libitum. A 48-hour fast resulted in a 50% reduction in leptin, a 60% reduction in thyroxine, a 75% reduction in testosterone, and a 12-fold increase in corticosterone in both wildtype and NPY-knockout mice. Fasting also increased the estrous cycle length by 3 days in both wildtype and NPY-deficient female mice. We conclude that NPY is not essential for appropriate function of the gonadotropic, thyrotropic, or corticotropic axes under ad lib fed conditions or in response to acute fasting.
Animals↗
Disruption of the metallothionein-III gene in mice: analysis of brain zinc, behavior, and neuron vulnerability to metals, aging, and seizures.
Metallothionein-III (MT-III), a brain-specific member of the metallothionein family of metal-binding proteins, is abundant in glutamatergic neurons that release zinc from their synaptic terminals, such as hippocampal pyramidal neurons and dentate granule cells. MT-III may be an important regulator of zinc in the nervous system, and its absence has been implicated in the development of Alzheimer's disease. However, the roles of MT-III in brain physiology and pathophysiology have not been elucidated. Mice lacking MT-III because of targeted gene inactivation were generated to evaluate the neurobiological significance of MT-III. MT-III-deficient mice had decreased concentrations of zinc in several brain regions, including hippocampus, but the pool of histochemically reactive zinc was not disturbed. Mutant mice exhibited normal spatial learning in the Morris water maze and were not sensitive to systemic zinc or cadmium exposure. No neuropathology or behavioral deficits were detected in 2-year-old MT-III-deficient mice, but the age-related increase in glial fibrillary acidic protein expression was more pronounced in mutant brain. MT-III-deficient mice were more susceptible to seizures induced by kainic acid and subsequently exhibited greater neuron injury in the CA3 field of hippocampus. Conversely, transgenic mice containing elevated levels of MT-III were more resistant to CA3 neuron injury induced by seizures. These observations suggest a potential role for MT-III in zinc regulation during neural stimulation.
Aging↗
Metallothioneins in brain--the role in physiology and pathology.
A symposium on the role of brain metallothioneins (MTs) in physiology and pathology was held at the 1996 Annual Society of Toxicology Meeting in Anaheim, California. The objectives of this symposium were to: (1) review the physiologic function of MTs, (2) examine the distribution of brain MTs with particular emphasis on cell-specific localization (neurons vs neuroglia), (3) discuss MT gene responsiveness upon toxic insult with metals, and (4) discuss the potential role of MTs in the etiology of neurodegenerative disorders. Dr. Cherian discussed the biochemical properties of the MTs, emphasizing structural similarities and differences between the MTs. Dr. Klaassen addressed the expression and distribution of the MTs in brains with special reference to the cell-specific localization of MTs. Dr. Aschner provided data illustrating a potential role for MTs in attenuating the cytotoxicity caused by methylmercury (MeHg) in cultured neonatal astrocytes. Dr. Palmiter discussed the properties of MT-III and the increased sensitivity of MT-III knockout mice to kainate-induced seizures. Cerebral zinc metabolism, its relationship to MT homeostasis, and its pathogenic potential in Alzheimer's disease was addressed by Dr. Bush.
Animals↗
EMG analysis of lower extremity muscle recruitment patterns during an unloaded squat.
During an unloaded squat, hamstring and quadriceps co-contraction has been documented and explained via a co-contraction hypothesis. This hypothesis suggests that the hamstrings provide a stabilizing force at the knee by producing a posteriorly-directed force on the tibia to counteract the anterior tibial force imparted by the quadriceps. Research support for this hypothesis, however, is equivocal. Therefore, the purposes of this study were 1) to determine muscle recruitment patterns of the gluteus maximus, hamstrings, quadriceps, and gastrocnemius during an unloaded squat exercise via EMG and 2) to describe the amount of hamstring-quadriceps co-contraction during an unloaded squat. Surface electrodes were used to monitor the EMG activity of six muscles of 41 healthy subjects during an unloaded squat. Each subject performed three 4-s maximal voluntary isometric contractions (MVIC) for each of the six muscles. Electrogoniometers were applied to the knee and hip to monitor joint angles, and each subject performed three series of four complete squats in cadence with a metronome (50 beats.min-1). Each squat consisted of a 1.2-s eccentric, hold, and concentric phase. A two-way repeated measures ANOVA (6 muscles x 7 arcs) was used to compare normalized EMG (percent MVIC) values during each arc of motion (0-30 degrees, 30-60 degrees, 60-90 degrees, hold, 90-60 degrees, 60-30 degrees, 30-0 degrees) of the squat. Tukey post-hoc analyses were used to quantify and interpret the significant two-way interactions. Results revealed minimal hamstring activity (4-12% MVIC) as compared with quadriceps activity (VMO: 22-68%, VL: 21-63% of MVIC) during an unloaded squat in healthy subjects. This low level of hamstring EMG activity was interpreted to reflect the low demand placed on the hamstring muscles to counter anterior shear forces acting at the proximal tibia.
Adult↗
Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y.
The obesity syndrome of ob/ob mice results from lack of leptin, a hormone released by fat cells that acts in the brain to suppress feeding and stimulate metabolism. Neuropeptide Y (NPY) is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin deficiency, ob/ob mice deficient for NPY were generated. In the absence of NPY, ob/ob mice are less obese because of reduced food intake and increased energy expenditure, and are less severely affected by diabetes, sterility, and somatotropic defects. These results suggest that NPY is a central effector of leptin deficiency.
Adipose Tissue↗
Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.
Neuropeptide Y (NPY), a 36-amino-acid transmitter distributed throughout the nervous system, is thought to function as a central stimulator of feeding behaviour. NPY has also been implicated in the modulation of mood, cerebrocortical excitability, hypothalamic-pituitary signalling, cardiovascular physiology and sympathetic function. However, the biological significance of NPY has been difficult to establish owing to a lack of pharmacological antagonists. We report here that mice deficient for NPY have normal food intake and body weight, and become hyperphagic following food deprivation. Mutant mice decrease their food intake and lose weight, initially to a greater extent than controls, when treated with recombinant leptin. Occasional, mild seizures occur in NPY-deficient mice and mutants are more susceptible to seizures induced by a GABA (gamma-aminobutyric acid) antagonist. These results indicate that NPY is not essential for certain feeding responses or leptin actions but is an important modulator of excitability in the central nervous system.
Animals↗
Bioactivity of metallothionein-3 correlates with its novel beta domain sequence rather than metal binding properties.
Human and mouse metallothionein-3 (MT-3) molecules exhibit the same metal binding stoichiometry with Zn(II), Cd(II), or Cu(I) as MT-1 or MT-2 molecules, suggesting that MT-3 consists of two domains enfolding separate polymetallic clusters. The kinetic reactivities of Zn(II) complexes of MT-3 with the chelator ethylenediaminetetraacetic acid (EDTA) or the thiol reagent dithiobis(2-nitrobenzoic acid) (DTNB) resembles the reactivity of ZnMT-1. Furthermore, the candidate alpha and beta domain peptides of human MT-3 are very similar to MT-1 domain peptides in the reactivity of Zn(II) complexes. Zn(II) complexes of human and mouse MT-3 inhibit the survival of rat cortical neurons cultured in the presence of an Alzheimer's disease brain extract. Inhibitory activity is unique to the MT-3 isoform and is a property of the N-terminal beta domain. The inhibitory activity of the 32-residue MT-3 beta domain is abolished by a double mutation within the beta domain resulting in the conversion of the C-P-C-P sequence to either C-S-C-A or C-T-C-T. Thus, the bioactivity arises from a novel structure of the N-terminal beta domain of MT-3 and not any unusual metal-binding properties.
Amino Acid Sequence↗
Expression of human metallothionein-III in transgenic mice.
Transgenic mice that express human metallothionein-III (hMT-III) were generated. Human MT-III mRNA expression was prominent in brain, resulting in a 9-fold elevation of MT-III mRNA in cortex, a 3-5-fold elevation in hippocampus, thalamus, brainstem, and olfactory bulb, and a 1.4-fold elevation in cerebellum. Human MT-III protein was detected biochemically and accounted for a 3.4-fold increase in total brain MT. The concentration of zinc (but not copper) was elevated in those brain regions that expressed the most hMT-III mRNA. The histochemically reactive pool of zinc, as measured by Timm's stain or TS-Q histofluorescence, was not appreciably altered. No changes in brain weight, morphology or histology have been noted; the mice breed normally and appear to have normal behavior.
Animals↗
Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF).
Alzheimer's disease (AD) is a chronic neurodegenerative disorder for which the pathogenic mechanisms are not well understood. Previous studies demonstrated that extracts prepared from AD brains could increase the survival of rat cortical neurons in vitro. Additional studies indicated that this enhanced neurotrophic activity of AD brain was due to a reduction of a growth inhibitory factor (GIF) that was subsequently shown to be a new member of the metallothionein (MT) gene family, and designated MT-III. The study presented here examined the association between neurotrophic activity and MT-III expression in frontal cortices from eight AD and five control brains, and further characterized the inhibitory activity of MT-III. On average, AD extracts stimulated the survival of approximately 2-fold more rat cortical neurons than control extracts, demonstrating that AD brain possesses elevated neurotrophic activity. When recombinant MTs were added to cultures grown in the presence of brain extract, MT-III but not MT-I had an inhibitory effect on neuron survival, confirming that MT-III is a specific inhibitory factor in this assay. However, in contrast to previous reports, neither MT-III mRNA nor MT-III protein levels were significantly decreased in the AD group. Therefore, the difference in neurotrophic activity between the AD and control brain samples examined in this study is probably not directly mediated by MT-III. These results suggest that MT-III down-regulation is not an important pathogenic event in some cases of AD.
Alzheimer Disease↗
Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia.
A new member of the metallothionein (MT) gene family was discovered that lies about 20 kb 5' of the MT-III gene in both mouse and human. The MT-IV proteins are highly conserved in both species and have a glutamate insertion at position 5 relative to the classical MT-I and MT-II proteins. Murine MT-IV mRNA appears to be expressed exclusively in stratified squamous epithelia associated with oral epithelia, esophagus, upper stomach, tail, footpads, and neonatal skin. The MT derived from tongue epithelium contains both zinc and copper. Many of these epithelia develop parakeratosis during zinc deficiency in the rat. In situ hybridization reveals intense labeling of MT-IV mRNA in the differentiating spinous layer of cornified epithelia, whereas MT-I is expressed predominantly in the basal, proliferative layer; thus, there is a switch in MT isoform synthesis during differentiation of these epithelia. We suggest that MT-IV plays a special role in regulating zinc metabolism during the differentiation of stratified epithelia.
Amino Acid Sequence↗