ABSTRACT
Anorexia nervosa (AN) is a debilitating eating disorder characterized by severely restricted eating and significant body weight loss. In addition, many individuals also report engaging in excessive exercise. Previous research using the activity-based anorexia (ABA) model has implicated the hypothalamic proopiomelanocortin (POMC) system. Using the ABA model, Pomc mRNA has been shown to be transiently elevated in both male and female rodents undergoing ABA. In addition, the POMC peptide ß-endorphin appears to contribute to food anticipatory activity (FAA), a characteristic of ABA, as both deletion and antagonism of the µ opioid receptor (MOR) that ß-endorphin targets, results in decreased FAA. The role of ß-endorphin in reduced food intake in ABA is unknown and POMC neurons release multiple transmitters in addition to ß-endorphin. In the current study, we set out to determine whether targeted inhibition of POMC neurons themselves rather than their peptide products would lessen the severity of ABA. Inhibition of POMC neurons during ABA via chemogenetic Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology resulted in reduced FAA in both male and female mice with no significant changes in body weight or food intake. The selective reduction in FAA persisted even in the face of concurrent chemogenetic inhibition of additional cell types in the hypothalamic arcuate nucleus. The results suggest that POMC neurons could be contributing preferentially to excessive exercise habits in patients with AN. Furthermore, the results also suggest that metabolic control during ABA appears to take place via a POMC neuron-independent mechanism.
Subject(s)
Anorexia/metabolism , Body Weight/physiology , Food , Neurons/metabolism , Pro-Opiomelanocortin/metabolism , Animals , Arcuate Nucleus of Hypothalamus/metabolism , Hypothalamus/metabolism , Mice , beta-Endorphin/metabolism , beta-Endorphin/pharmacologyABSTRACT
Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) are a diverse group of neurons that project widely to different brain regions. It is unknown how this small population of neurons organizes its efferent projections. In this study, we hypothesized that individual ARH POMC neurons exclusively innervate select target regions. To investigate this hypothesis, we first verified that only a fraction of ARH POMC neurons innervate the lateral hypothalamus (LH), the paraventricular nucleus of the hypothalamus (PVN), the periaqueductal gray (PAG), or the ventral tegmental area (VTA) using the retrograde tracer cholera toxin B (CTB). Next, two versions of CTB conjugated to distinct fluorophores were injected bilaterally into two of the regions such that PVN and VTA, PAG and VTA, or LH and PVN received tracers simultaneously. These pairs of target sites were chosen based on function and location. Few individual ARH POMC neurons projected to two brain regions at once, suggesting that there are ARH POMC neuron subpopulations organized by their efferent projections. We also investigated whether increasing the activity of POMC neurons could increase the number of ARH POMC neurons labeled with CTB, implying an increase in new synaptic connections to downstream regions. However, chemogenetic enhancement of POMC neuron activity did not increase retrograde tracing of CTB back to ARH POMC neurons from either the LH, PVN, or VTA. Overall, subpopulations of ARH POMC neurons with distinct efferent projections may serve as a way for the POMC population to organize its many functions.
Subject(s)
Arcuate Nucleus of Hypothalamus/metabolism , Neuroanatomical Tract-Tracing Techniques , Neurons/metabolism , Pro-Opiomelanocortin/metabolism , Animals , Arcuate Nucleus of Hypothalamus/cytology , Calcium Signaling , Efferent Pathways/metabolism , Female , Genes, Reporter , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Pro-Opiomelanocortin/geneticsABSTRACT
The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor involved in sweet-taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions regulated by the sweet-taste perception system, we hypothesized that a disruption of the sweet-taste perception in the brain could have a key role in the development of cognitive dysfunction. To assess the importance of the sweet-taste receptors in the brain, we conducted transcriptomic and proteomic analyses of cortical and hippocampal tissues isolated from T1R3 knock-out (T1R3KO) mice. The effect of an impaired sweet-taste perception system on cognition functions were examined by analyzing synaptic integrity and performing animal behavior on T1R3KO mice. Although T1R3KO mice did not present a metabolically disrupted phenotype, bioinformatic interpretation of the high-dimensionality data indicated a strong neurodegenerative signature associated with significant alterations in pathways involved in neuritogenesis, dendritic growth, and synaptogenesis. Furthermore, a significantly reduced dendritic spine density was observed in T1R3KO mice together with alterations in learning and memory functions as well as sociability deficits. Taken together our data suggest that the sweet-taste receptor system plays an important neurotrophic role in the extralingual central nervous tissue that underpins synaptic function, memory acquisition, and social behavior.
Subject(s)
Behavior, Animal , Dendritic Spines/metabolism , Learning , Memory , Neurites/metabolism , Receptors, G-Protein-Coupled/deficiency , Social Behavior , Animals , Dendritic Spines/pathology , Mice , Mice, Knockout , Neurites/pathologyABSTRACT
Huntington disease (HD) is a neurodegenerative disorder characterized by progressive motor impairment and cognitive alterations. Hereditary HD is primarily caused by the expansion of a CAG trinucleotide repeat in the huntingtin (Htt) gene, which results in the production of mutant huntingtin protein (mHTT) with an expanded amino-terminal polyglutamine (poly(Q)) stretch. Besides pathological mHTT aggregation, reduced brain-derived neurotrophic factor (BDNF) levels, impaired neurotrophin signaling, and compromised mitochondrial functions also contribute to the deleterious progressive etiology of HD. As a well tolerated Food and Drug Administration-approved antidepressant, amitriptyline (AMI) has shown efficacy in treating neurodegenerative murine models via potentiation of BDNF levels and amelioration of alterations in neurotrophin signaling pathways. In this study, we observed profound improvements in the motor coordination of AMI-treated N171-82Q HD model mice. The beneficial effects of AMI treatment were associated with its ability to reduce mHTT aggregation, potentiation of the BDNF-TrkB signaling system, and support of mitochondrial integrity and functionality. Our study not only provides preclinical evidence for the therapeutic potency of AMI in treating HD, but it also represents an important example of the usefulness of additional pharmacogenomic profiling of pre-existing drugs for novel therapeutic effects with often intractable pathological scenarios.
Subject(s)
Amitriptyline/therapeutic use , Huntington Disease/drug therapy , Huntington Disease/physiopathology , Mitochondria/metabolism , Nerve Growth Factors/metabolism , Animals , Brain-Derived Neurotrophic Factor , Computational Biology , Disease Models, Animal , Female , Huntington Disease/metabolism , Male , Mice , Mitochondria/drug effectsABSTRACT
Recent studies on the effect of stress on modulation of fear memory in our laboratory have uncovered endogenous opioid and adrenergic based modulation systems, working in concert, that limit the strengthening or weakening of newly acquired fear memory during consolidation under conditions of mild or intense stress, respectively. The present study sought to determine if similar stress-dependent modulation, mediated by endogenous opioid and adrenergic systems, occurs during reconsolidation of newly retrieved fear memory. Rats underwent contextual fear conditioning followed 24h later by reactivation of fear memory; a retention test was administered the next day. Stress was manipulated by varying duration of recall of fear memory during reactivation. In the first experiment, vehicle or the opioid-receptor blocker naloxone was administered immediately after varied durations (30 or 120 s) of reactivation. The results indicate that (1) reactivation, in the absence of drug, has a marked effect on freezing behavior-as duration of reactivation increases from 30 to 120 s, freezing behavior and presumably fear-induced stress increases and (2) naloxone, administered immediately after 30 s (mild stress) or 120 s (intense stress) of reactivation, enhances or impairs retention, respectively, the next day. In the second experiment, naloxone and the ß-adrenergic blocker propranolol were administered either separately or in combination immediately after 120 s (intense stress) reactivation. The results indicate that separate administration of propranolol and naloxone impairs retention, while the combined administration fails to do so. Taken together the results of the two experiments are consistent with a protective mechanism, mediated by endogenous opioid and adrenergic systems working in concert, that limits enhancement and impairment of newly retrieved fear memory during reactivation in a stress-dependent manner.
Subject(s)
Fear/physiology , Mental Recall/physiology , Receptors, Adrenergic, beta/physiology , Receptors, Opioid/physiology , Stress, Psychological/physiopathology , Adrenergic beta-Antagonists/pharmacology , Animals , Conditioning, Psychological/drug effects , Fear/drug effects , Male , Mental Recall/drug effects , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Propranolol/pharmacology , Rats , Rats, Long-EvansABSTRACT
Our aim was to employ novel analytical methods to investigate the therapeutic treatment of the energy regulation dysfunction occurring in a Huntington disease (HD) mouse model. HD is a neurodegenerative disorder that is characterized by progressive motor impairment and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. We determined the effects of three different euglycemic agents on HD progression using standard physiological and transcriptomic signature analyses. N171-82Q HD mice were treated with insulin, Exendin-4, and the newly developed GLP-1-Tf to determine whether these agents could improve energy regulation and delay disease progression. Blood glucose, insulin, metabolic hormone levels, and pancreatic morphology were assessed. Hypothalamic gene transcription, motor coordination, and life span were also determined. The N171-82Q mice exhibited significant alterations in hypothalamic gene transcription signatures and energy metabolism that were ameliorated, to varying degrees, by the different euglycemic agents. Exendin-4 or GLP-1-Tf (but not insulin) treatment also improved pancreatic morphology, motor coordination, and increased life span. Using hypothalamic transcription signature analyses, we found that the physiological efficacy variation of the drugs was evident in the degree of reversal of the hypothalamic HD pathological signature. Euglycemic agents targeting hypothalamic and energy regulation dysfunction in HD could potentially alter disease progression and improve quality of life in HD.
Subject(s)
Blood Glucose/metabolism , Huntington Disease/genetics , Hypothalamus/metabolism , Serotonin Plasma Membrane Transport Proteins/genetics , Transcription, Genetic , Animals , Diabetes Mellitus/metabolism , Drug Design , Exenatide , Glucagon-Like Peptide 1/metabolism , Huntington Disease/blood , Insulin/metabolism , Male , Mice , Mice, Transgenic , Models, Animal , Models, Neurological , Oligonucleotide Array Sequence Analysis , Pancreas/metabolism , Peptides/metabolism , Venoms/metabolismABSTRACT
Anorexia nervosa (AN) has a lifetime prevalence of up to 4% and a high mortality rate (~5-10%), yet little is known regarding the etiology of this disease. In an attempt to fill the gaps in knowledge, activity-based anorexia (ABA) in rodents has been a widely used model as it mimics several key features of AN including severely restricted food intake and excessive exercise. Using this model, a role for the hypothalamic proopiomelanocortin (POMC) system has been implicated in the development of ABA as Pomc mRNA is elevated in female rats undergoing the ABA paradigm. Since the Pomc gene product α-MSH potently inhibits food intake, it could be that elevated α-MSH might promote ABA. However, the α-MSH receptor antagonist SHU9119 does not protect against the development of ABA. Interestingly, it has also been shown that female mice lacking the mu opioid receptor (MOR), the primary receptor activated by the Pomc-gene-derived opioid ß-endorphin, display blunted food anticipatory behavior (FAA), a key feature of ABA. Thus, we hypothesized that the elevation in Pomc mRNA observed during ABA may lead to increased ß-endorphin concentrations and MOR activation to promote ABA. Further, given the known sex differences in AN and ABA, we hypothesized that MORs may contribute differentially in male and female mice. Using wild-type and MOR knockout mice of both sexes, a MOR antagonist and careful analysis of food anticipatory behavior and ß-endorphin levels, we found 1) increased Pomc mRNA levels in both female and male mice that underwent ABA, 2) increased ß-endorphin in female mice that underwent ABA, and 3) blunted FAA in both sexes in response to MOR genetic deletion yet blunted FAA only in males in response to MOR antagonism. The results presented provide support for both hypotheses and suggest that it may be the ß-endorphin resulting from increased Pomc transcription that supports the development of some features of ABA.
Subject(s)
Anorexia/drug therapy , Hypothalamus/drug effects , Physical Conditioning, Animal/physiology , beta-Endorphin/pharmacology , Animals , Anorexia/metabolism , Female , Hypothalamus/metabolism , Male , Mice , Pro-Opiomelanocortin/metabolism , Receptors, Opioid, mu/genetics , Receptors, Opioid, mu/metabolismABSTRACT
Naltrexone is an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorders at doses of 50-150 mg/d. Naltrexone has also been prescribed at much lower doses (3-6 mg/d) for the off-label treatment of inflammation and pain. Currently, a compelling mechanistic explanation for the reported efficacy of low-dose naltrexone (LDN) is lacking and none of the proposed mechanisms can explain patient reports of improved mood and sense of well-being. Here, we examined the possibility that LDN might alter the activity of the endogenous opioid system involving proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) in male and female mice. Known actions of POMC neurons could account for changes in pain perception and mood. However, using electrophysiologic, imaging and peptide measurement approaches, we found no evidence for such a mechanism. LDN did not change the sensitivity of opioid receptors regulating POMC neurons, the production of the ß-endorphin precursor Pomc mRNA, nor the release of ß-endorphin into plasma. Spontaneous postsynaptic currents (sPSCs) onto POMC neurons were slightly decreased after LDN treatment and GCaMP fluorescent signal, a proxy for intracellular calcium levels, was slightly increased. However, LDN treatment did not appear to change POMC neuron firing rate, resting membrane potential, nor action potential threshold. Therefore, LDN appears to have only slight effects on POMC neurons that do not translate to changes in intrinsic excitability or baseline electrical activity and mechanisms beyond POMC neurons and altered opioid receptor sensitivity should continue to be explored.
Subject(s)
Naltrexone , Pro-Opiomelanocortin , Analgesics, Opioid , Animals , Female , Humans , Male , Mice , Naltrexone/pharmacology , Neurons , Pro-Opiomelanocortin/genetics , beta-EndorphinABSTRACT
Recent research has proposed that GIT2 (G protein-coupled receptor kinase interacting protein 2) acts as an integrator of the aging process through regulation of 'neurometabolic' integrity. One of the commonly accepted hallmarks of the aging process is thymic involution. At a relatively young age, 12 months old, GIT2-/- mice present a prematurely distorted thymic structure and dysfunction compared to age-matched 12 month-old wild-type control (C57BL/6) mice. Disruption of thymic structure in GIT2-/- (GIT2KO) mice was associated with a significant reduction in the expression of the cortical thymic marker, Troma-I (cytokeratin 8). Double positive (CD4+CD8+) and single positive CD4+ T cells were also markedly reduced in 12 month-old GIT2KO mice compared to age-matched control wild-type mice. Coincident with this premature thymic disruption in GIT2KO mice was the unique generation of a novel cervical 'organ', i.e. 'parathymic lobes'. These novel organs did not exhibit classical peripheral lymph node-like characteristics but expressed high levels of T cell progenitors that were reflexively reduced in GIT2KO thymi. Using signaling pathway analysis of GIT2KO thymus and parathymic lobe transcriptomic data we found that the molecular signaling functions lost in the dysfunctional GIT2KO thymus were selectively reinstated in the novel parathymic lobe - suggestive of a compensatory effect for the premature thymic disruption. Broader inspection of high-dimensionality transcriptomic data from GIT2KO lymph nodes, spleen, thymus and parathymic lobes revealed a systemic alteration of multiple proteins (Dbp, Tef, Per1, Per2, Fbxl3, Ddit4, Sin3a) involved in the multidimensional control of cell cycle clock regulation, cell senescence, cellular metabolism and DNA damage. Altered cell clock regulation across both immune and non-immune tissues therefore may be responsible for the premature 'aging' phenotype of GIT2KO mice.
Subject(s)
Aging, Premature/genetics , Aging/genetics , Cell Cycle Proteins/genetics , Cellular Senescence/genetics , Immune System/physiopathology , Phosphoproteins/genetics , Thymus Gland/physiopathology , Aging/immunology , Aging/physiology , Aging, Premature/immunology , Aging, Premature/physiopathology , Animals , GTPase-Activating Proteins , Intercellular Signaling Peptides and Proteins , Keratin-8/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/genetics , Thymus Gland/immunology , TranscriptomeABSTRACT
Autism spectrum disorders (ASD) are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR) T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR) display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6) control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including "axon guidance" and "regulation of actin cytoskeleton." In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.
ABSTRACT
Insults to nuclear DNA induce multiple response pathways to mitigate the deleterious effects of damage and mediate effective DNA repair. G-protein-coupled receptor kinase-interacting protein 2 (GIT2) regulates receptor internalization, focal adhesion dynamics, cell migration, and responses to oxidative stress. Here we demonstrate that GIT2 coordinates the levels of proteins in the DNA damage response (DDR). Cellular sensitivity to irradiation-induced DNA damage was highly associated with GIT2 expression levels. GIT2 is phosphorylated by ATM kinase and forms complexes with multiple DDR-associated factors in response to DNA damage. The targeting of GIT2 to DNA double-strand breaks was rapid and, in part, dependent upon the presence of H2AX, ATM, and MRE11 but was independent of MDC1 and RNF8. GIT2 likely promotes DNA repair through multiple mechanisms, including stabilization of BRCA1 in repair complexes; upregulation of repair proteins, including HMGN1 and RFC1; and regulation of poly(ADP-ribose) polymerase activity. Furthermore, GIT2-knockout mice demonstrated a greater susceptibility to DNA damage than their wild-type littermates. These results suggest that GIT2 plays an important role in MRE11/ATM/H2AX-mediated DNA damage responses.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/metabolism , Cell Cycle Proteins/metabolism , DNA Damage , DNA Repair , GTPase-Activating Proteins/metabolism , Phosphoproteins/metabolism , Animals , Cell Cycle Proteins/analysis , Cell Cycle Proteins/genetics , Cell Line , Cell Line, Tumor , Cell Nucleus/genetics , Cell Nucleus/metabolism , GTPase-Activating Proteins/analysis , GTPase-Activating Proteins/genetics , Intercellular Signaling Peptides and Proteins , Mice , Mice, Knockout , Mutagenesis, Site-Directed , Phosphoproteins/analysis , Phosphoproteins/geneticsABSTRACT
Aging represents one of the most complicated and highly integrated somatic processes. Healthy aging is suggested to rely upon the coherent regulation of hormonal and neuronal communication between the central nervous system and peripheral tissues. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity and therefore likely coordinates multiple systems in the aging process. We previously identified, in hypothalamic and peripheral tissues, the G protein-coupled receptor kinase interacting protein 2 (GIT2) as a stress response and aging regulator. As metabolic status profoundly affects aging trajectories, we investigated the role of GIT2 in regulating metabolic activity. We found that genomic deletion of GIT2 alters hypothalamic transcriptomic signatures related to diabetes and metabolic pathways. Deletion of GIT2 reduced whole animal respiratory exchange ratios away from those related to primary glucose usage for energy homeostasis. GIT2 knockout (GIT2KO) mice demonstrated lower insulin secretion levels, disruption of pancreatic islet beta cell mass, elevated plasma glucose, and insulin resistance. High-dimensionality transcriptomic signatures from islets isolated from GIT2KO mice indicated a disruption of beta cell development. Additionally, GIT2 expression was prematurely elevated in pancreatic and hypothalamic tissues from diabetic-state mice (db/db), compared to age-matched wild type (WT) controls, further supporting the role of GIT2 in metabolic regulation and aging. We also found that the physical interaction of pancreatic GIT2 with the insulin receptor and insulin receptor substrate 2 was diminished in db/db mice compared to WT mice. Therefore, GIT2 appears to exert a multidimensional "keystone" role in regulating the aging process by coordinating somatic responses to energy deficits.
ABSTRACT
Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder characterized by alterations in social functioning, communicative abilities, and engagement in repetitive or restrictive behaviors. The process of aging in individuals with autism and related neurodevelopmental disorders is not well understood, despite the fact that the number of individuals with ASD aged 65 and older is projected to increase by over half a million individuals in the next 20 years. To elucidate the effects of aging in the context of a modified central nervous system, we investigated the effects of age on the BTBR T + tf/j mouse, a well characterized and widely used mouse model that displays an ASD-like phenotype. We found that a reduction in social behavior persists into old age in male BTBR T + tf/j mice. We employed quantitative proteomics to discover potential alterations in signaling systems that could regulate aging in the BTBR mice. Unbiased proteomic analysis of hippocampal and cortical tissue of BTBR mice compared to age-matched wild-type controls revealed a significant decrease in brain derived neurotrophic factor and significant increases in multiple synaptic markers (spinophilin, Synapsin I, PSD 95, NeuN), as well as distinct changes in functional pathways related to these proteins, including "Neural synaptic plasticity regulation" and "Neurotransmitter secretion regulation." Taken together, these results contribute to our understanding of the effects of aging on an ASD-like mouse model in regards to both behavior and protein alterations, though additional studies are needed to fully understand the complex interplay underlying aging in mouse models displaying an ASD-like phenotype.
ABSTRACT
Huntington's disease (HD) is an inherited neurodegenerative disorder typified by involuntary body movements, and psychiatric and cognitive abnormalities. Many HD patients also exhibit metabolic changes including progressive weight loss and appetite dysfunction. Here we have investigated metabolic function in pre-manifest and manifest HD subjects to establish an HD subject metabolic hormonal plasma signature. Individuals at risk for HD who have had predictive genetic testing showing the cytosine-adenine-guanine (CAG) expansion causative of HD, but who do not yet present signs and symptoms sufficient for the diagnosis of manifest HD are said to be "pre-manifest." Pre-manifest and manifest HD patients, as well as both familial and non-familial controls, were evaluated for multiple peripheral metabolism signals including circulating levels of hormones, growth factors, lipids, and cytokines. Both pre-manifest and manifest HD subjects exhibited significantly reduced levels of circulating growth factors, including growth hormone and prolactin. HD-related changes in the levels of metabolic hormones such as ghrelin, glucagon, and amylin were also observed. Total cholesterol, HDL-C, and LDL-C were significantly decreased in HD subjects. C-reactive protein was significantly elevated in pre-manifest HD subjects. The observation of metabolic alterations, even in subjects considered to be in the pre-manifest stage of HD, suggests that in addition, and prior, to overt neuronal damage, HD affects metabolic hormone secretion and energy regulation, which may shed light on pathogenesis, and provide opportunities for biomarker development.
ABSTRACT
Calorie restriction (CR) is a lifestyle intervention employed to reduce body weight and improve metabolic functions primarily via reduction of ingested carbohydrates and fats. Taste perception is highly related to functional metabolic status and body adiposity. We have previously shown that sweet taste perception diminishes with age; however, relatively little is known about the effects of various lengths of CR upon taste cell morphology and function. We investigated the effects of CR on taste bud morphology and expression of sweet taste-related modulators in 5-, 17-, and 30-month-old rats. In ad libitum (AL) and CR rats, we consistently found the following parameters altered significantly with advancing age: reduction of taste bud size and taste cell numbers per taste bud and reduced expression of sonic hedgehog, type 1 taste receptor 3 (T1r3), α-gustducin, and glucagon-like peptide-1 (GLP-1). In the oldest rats, CR affected a significant reduction of tongue T1r3, GLP-1, and α-gustducin expression compared with age-matched AL rats. Leptin receptor immunopositive cells were elevated in 17- and 30-month-old CR rats compared with age-matched AL rats. These alterations of sweet taste-related modulators, specifically during advanced aging, suggest that sweet taste perception may be altered in response to different lengths of CR.
Subject(s)
Aging/physiology , Caloric Restriction , Taste Buds/pathology , Taste Buds/physiopathology , Taste/physiology , Animals , Glucagon-Like Peptide 1/metabolism , Hedgehog Proteins/metabolism , Male , Rats , Receptors, G-Protein-Coupled/metabolism , Transducin/metabolismABSTRACT
Thyrotropin releasing hormone (TRH) is primarily known as the central regulator of the hypothalamic-pituitary-thyroid (HPT) axis. However, TRH also exerts a variety of central nervous system effects independent from its activity in the HPT axis. With advancing age, decreases in TRH synthesis, expression, and activity have been demonstrated. Associated with this emerging evidence suggests that TRH is implicated in neurodegenerative diseases of aging, including Alzheimer's disease and Parkinson's disease. TRH and its synthetic analogs have been recognized as trophic factors in neurons of the diencephalon and spinal cord, and as neuroprotectants against oxidative stress, glutamate toxicity, caspase-induced cell death, DNA fragmentation, and inflammation. In this review, we will provide an overview of some of the roles of TRH, outside of the HPT axis, associated with pathological aging and neurodegeneration and we shall discuss the potential of TRH and TRH analogs for the treatment of neurodegenerative diseases.
ABSTRACT
Text mining is rapidly becoming an essential technique for the annotation and analysis of large biological data sets. Biomedical literature currently increases at a rate of several thousand papers per week, making automated information retrieval methods the only feasible method of managing this expanding corpus. With the increasing prevalence of open-access journals and constant growth of publicly-available repositories of biomedical literature, literature mining has become much more effective with respect to the extraction of biomedically-relevant data. In recent years, text mining of popular databases such as MEDLINE has evolved from basic term-searches to more sophisticated natural language processing techniques, indexing and retrieval methods, structural analysis and integration of literature with associated metadata. In this review, we will focus on Latent Semantic Indexing (LSI), a computational linguistics technique increasingly used for a variety of biological purposes. It is noted for its ability to consistently outperform benchmark Boolean text searches and co-occurrence models at information retrieval and its power to extract indirect relationships within a data set. LSI has been used successfully to formulate new hypotheses, generate novel connections from existing data, and validate empirical data.
ABSTRACT
High-dimensionality data is rapidly becoming the norm for biomedical sciences and many other analytical disciplines. Not only is the collection and processing time for such data becoming problematic, but it has become increasingly difficult to form a comprehensive appreciation of high-dimensionality data. Though data analysis methods for coping with multivariate data are well-documented in technical fields such as computer science, little effort is currently being expended to condense data vectors that exist beyond the realm of physical space into an easily interpretable and aesthetic form. To address this important need, we have developed Plurigon, a data visualization and classification tool for the integration of high-dimensionality visualization algorithms with a user-friendly, interactive graphical interface. Unlike existing data visualization methods, which are focused on an ensemble of data points, Plurigon places a strong emphasis upon the visualization of a single data point and its determining characteristics. Multivariate data vectors are represented in the form of a deformed sphere with a distinct topology of hills, valleys, plateaus, peaks, and crevices. The gestalt structure of the resultant Plurigon object generates an easily-appreciable model. User interaction with the Plurigon is extensive; zoom, rotation, axial and vector display, feature extraction, and anaglyph stereoscopy are currently supported. With Plurigon and its ability to analyze high-complexity data, we hope to see a unification of biomedical and computational sciences as well as practical applications in a wide array of scientific disciplines. Increased accessibility to the analysis of high-dimensionality data may increase the number of new discoveries and breakthroughs, ranging from drug screening to disease diagnosis to medical literature mining.
ABSTRACT
Bioluminescence resonance energy transfer (BRET) is an improved version of earlier resonance energy transfer technologies used for the analysis of biomolecular protein interaction. BRET analysis can be applied to many transmembrane receptor classes, however the majority of the early published literature on BRET has focused on G protein-coupled receptor (GPCR) research. In contrast, there is limited scientific literature using BRET to investigate receptor tyrosine kinase (RTK) activity. This limited investigation is surprising as RTKs often employ dimerization as a key factor in their activation, as well as being important therapeutic targets in medicine, especially in the cases of cancer, diabetes, neurodegenerative, and respiratory conditions. In this review, we consider an array of studies pertinent to RTKs and other non-GPCR receptor protein-protein signaling interactions; more specifically we discuss receptor-protein interactions involved in the transmission of signaling communication. We have provided an overview of functional BRET studies associated with the RTK superfamily involving: neurotrophic receptors [e.g., tropomyosin-related kinase (Trk) and p75 neurotrophin receptor (p75NTR)]; insulinotropic receptors [e.g., insulin receptor (IR) and insulin-like growth factor receptor (IGFR)] and growth factor receptors [e.g., ErbB receptors including the EGFR, the fibroblast growth factor receptor (FGFR), the vascular endothelial growth factor receptor (VEGFR) and the c-kit and platelet-derived growth factor receptor (PDGFR)]. In addition, we review BRET-mediated studies of other tyrosine kinase-associated receptors including cytokine receptors, i.e., leptin receptor (OB-R) and the growth hormone receptor (GHR). It is clear even from the relatively sparse experimental RTK BRET evidence that there is tremendous potential for this technological application for the functional investigation of RTK biology.
ABSTRACT
The un-biased and reproducible interpretation of high-content gene sets from large-scale genomic experiments is crucial to the understanding of biological themes, validation of experimental data, and the eventual development of plans for future experimentation. To derive biomedically-relevant information from simple gene lists, a mathematical association to scientific language and meaningful words or sentences is crucial. Unfortunately, existing software for deriving meaningful and easily-appreciable scientific textual 'tokens' from large gene sets either rely on controlled vocabularies (Medical Subject Headings, Gene Ontology, BioCarta) or employ Boolean text searching and co-occurrence models that are incapable of detecting indirect links in the literature. As an improvement to existing web-based informatic tools, we have developed Textrous!, a web-based framework for the extraction of biomedical semantic meaning from a given input gene set of arbitrary length. Textrous! employs natural language processing techniques, including latent semantic indexing (LSI), sentence splitting, word tokenization, parts-of-speech tagging, and noun-phrase chunking, to mine MEDLINE abstracts, PubMed Central articles, articles from the Online Mendelian Inheritance in Man (OMIM), and Mammalian Phenotype annotation obtained from Jackson Laboratories. Textrous! has the ability to generate meaningful output data with even very small input datasets, using two different text extraction methodologies (collective and individual) for the selecting, ranking, clustering, and visualization of English words obtained from the user data. Textrous!, therefore, is able to facilitate the output of quantitatively significant and easily appreciable semantic words and phrases linked to both individual gene and batch genomic data.