RESUMEN
The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α1, α2, and other receptor subtypes. Correlation and slope of unity were found for the α2A-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC50) and relative efficacy (RE) were determined. Compared with NE (pEC50, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC50, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC50, 7.94; RE, 37.9%), exhibited the highest potency (pEC50). In contrast, the catecholamines, EPI (pEC50, 6.95; RE, 120%) and α-methyl-NE (pEC50, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α2A-AR agonists that can cross the blood-brain barrier.
Asunto(s)
Agonistas alfa-Adrenérgicos , Región CA3 Hipocampal , Norepinefrina , Convulsiones , Animales , Ratas , Agonistas alfa-Adrenérgicos/farmacología , Epinefrina/farmacología , Ligandos , Norepinefrina/farmacología , Receptores Adrenérgicos , Región CA3 Hipocampal/fisiopatología , Convulsiones/tratamiento farmacológico , Técnicas In VitroRESUMEN
This study analyzed terminal degree and career choices of students who performed undergraduate research. In one analysis, the study compared terminal degree and career choices between a course-based undergraduate research experience (CURE) and traditional non-course-based undergraduate research experiences at one primarily undergraduate institution (PUI). Students who pursued postbaccalaureate programs chose terminal degrees at levels exceeding 75%, with no significant difference between a CURE experience and a traditional research experience. Analysis of terminal degree and career choices at four PUIs providing traditional research experiences showed a marked difference in the number of students pursuing terminal degrees. Two PUIs showed rates > 75%, whereas students at the other two PUIs pursued terminal degrees <50% of the time. The majority of students not pursuing terminal degrees chose M.S. degrees in education and healthcare. An analysis was also performed among students participating in traditional summer undergraduate research on a research-intensive university (RIU) campus with a medical school. Students were accepted from two programs, an NIH IDeA Network of Biomedical Research Excellence (INBRE) program recruiting students from the RIU and an NSF Research Experiences for Undergraduates (REU) program recruiting undergraduates from rural PUIs and minority-serving institutions, particularly tribal colleges. Analysis showed that >70% of the students who pursued postbaccalaureate programs chose terminal degrees. INBRE undergraduates displayed a marked preference for the M.D. degree (73.9% vs. 17.4%), whereas the REU students chose the Ph.D. degree (75.0% vs. 22.9%). American Indian students were also analyzed separately for career choice and showed an equal preference for the M.D. and Ph.D. degrees when pursuing postbaccalaureate education. Overall, the results provide evidence that undergraduate student research stimulates student careers in areas needed by the nation's citizen stakeholders.
Asunto(s)
Investigación Biomédica , Selección de Profesión , Humanos , Grupos Minoritarios , Estudiantes , UniversidadesRESUMEN
This study documents the efforts of the North Dakota (ND) IDeA Networks of Biomedical Research Excellence (INBRE) program to assist in the development of undergraduate research programs at four state-supported primarily undergraduate institutions (PUIs) in ND. The study was initiated in the 2004-2005 academic year and continues to the present. The study shows that gaining initial institutional support for undergraduate research was assisted by providing salary support for faculty involved in undergraduate research. Once research was ongoing, each institution evolved their own unique plan for the use of support from the ND INBRE. Undergraduate student researchers have prepared, presented, and defended their research results on 188 unique posters since initiation of the program, with many posters being presented at more than one meeting. PUI faculty have authored 35 peer-reviewed manuscripts. Evaluation has shown that over 95% of the undergraduate students performing research matriculated with their bachelor's degree. Career choices of 77.2% of these graduates was determined, and 37% pursued a career in the health professions. Of the students not pursuing a post-baccalaureate degree, 81.2% chose careers directly linked to science. The study reinforces the concept that undergraduate research can be performed directly on the PUI campus and be of value in preparing the next generation of health professionals in research, service, and teaching.
Asunto(s)
Investigación Biomédica/normas , Ciencia/educación , Investigación Biomédica/educación , Selección de Profesión , Docentes/estadística & datos numéricos , Humanos , North Dakota , Población Rural , Ciencia/estadística & datos numéricos , Ciencia/tendencias , Estudiantes/estadística & datos numéricosRESUMEN
The importance of adult neurogenesis has only recently been accepted, resulting in a completely new field of investigation within stem cell biology. The regulation and functional significance of adult neurogenesis is currently an area of highly active research. G-protein-coupled receptors (GPCRs) have emerged as potential modulators of adult neurogenesis. GPCRs represent a class of proteins with significant clinical importance, because approximately 30% of all modern therapeutic treatments target these receptors. GPCRs bind to a large class of neurotransmitters and neuromodulators such as norepinephrine, dopamine, and serotonin. Besides their typical role in cellular communication, GPCRs are expressed on adult neural stem cells and their progenitors that relay specific signals to regulate the neurogenic process. This review summarizes the field of adult neurogenesis and its methods and specifies the roles of various GPCRs and their signal transduction pathways that are involved in the regulation of adult neural stem cells and their progenitors. Current evidence supporting adult neurogenesis as a model for self-repair in neuropathologic conditions, adult neural stem cell therapeutic strategies, and potential avenues for GPCR-based therapeutics are also discussed.
Asunto(s)
Células Madre Adultas/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/fisiología , Receptores Acoplados a Proteínas G/fisiología , Adulto , Células Madre Adultas/efectos de los fármacos , Células Madre Adultas/patología , Animales , Senescencia Celular/fisiología , Humanos , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/patología , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/terapia , Neurogénesis/efectos de los fármacos , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Trasplante de Células MadreRESUMEN
In-person undergraduate research experiences (UREs) promote students' integration into careers in life science research. In 2020, the COVID-19 pandemic prompted institutions hosting summer URE programs to offer them remotely, raising questions about whether undergraduates who participate in remote research can experience scientific integration and whether they might perceive doing research less favorably (i.e., not beneficial or too costly). To address these questions, we examined indicators of scientific integration and perceptions of the benefits and costs of doing research among students who participated in remote life science URE programs in Summer 2020. We found that students experienced gains in scientific self-efficacy pre- to post-URE, similar to results reported for in-person UREs. We also found that students experienced gains in scientific identity, graduate and career intentions, and perceptions of the benefits of doing research only if they started their remote UREs at lower levels on these variables. Collectively, students did not change in their perceptions of the costs of doing research despite the challenges of working remotely. Yet students who started with low cost perceptions increased in these perceptions. These findings indicate that remote UREs can support students' self-efficacy development, but may otherwise be limited in their potential to promote scientific integration.
Asunto(s)
COVID-19 , Estudiantes , Humanos , PandemiasRESUMEN
The COVID-19 pandemic shut down undergraduate research programs across the United States. A group of 23 colleges, universities, and research institutes hosted remote undergraduate research programs in the life sciences during Summer 2020. Given the unprecedented offering of remote programs, we carried out a study to describe and evaluate them. Using structured templates, we documented how programs were designed and implemented, including who participated. Through focus groups and surveys, we identified programmatic strengths and shortcomings as well as recommendations for improvements from students' perspectives. Strengths included the quality of mentorship, opportunities for learning and professional development, and a feeling of connection with a larger community. Weaknesses included limited cohort building, challenges with insufficient structure, and issues with technology. Although all programs had one or more activities related to diversity, equity, inclusion, and justice, these topics were largely absent from student reports even though programs coincided with a peak in national consciousness about racial inequities and structural racism. Our results provide evidence for designing remote Research Experiences for Undergraduates (REUs) that are experienced favorably by students. Our results also indicate that remote REUs are sufficiently positive to further investigate their affordances and constraints, including the potential to scale up offerings, with minimal concern about disenfranchising students.
Asunto(s)
COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Estudiantes , Racismo Sistemático , Estados UnidosRESUMEN
The role of α(1)-adrenergic receptors (α(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. α(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term α(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α(1A)AR. CAM-α(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the α(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term α(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Afecto/fisiología , Cognición/fisiología , Longevidad/fisiología , Plasticidad Neuronal/fisiología , Receptores Adrenérgicos alfa 1/metabolismo , Afecto/efectos de los fármacos , Animales , Cognición/efectos de los fármacos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Longevidad/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Ratones Transgénicos , Plasticidad Neuronal/efectos de los fármacos , Técnicas de Cultivo de Órganos , Receptores Adrenérgicos alfa 1/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/fisiologíaRESUMEN
Sympathetic nervous system regulation by the α(1)-adrenergic receptor (AR) subtypes (α(1A), α(1B), α(1D)) is complex, whereby chronic activity can be either detrimental or protective for both heart and brain function. This review will summarize the evidence that this dual regulation can be mediated through the different α(1)-AR subtypes in the context of cardiac hypertrophy, heart failure, apoptosis, ischemic preconditioning, neurogenesis, locomotion, neurodegeneration, cognition, neuroplasticity, depression, anxiety, epilepsy, and mental illness.
Asunto(s)
Citoprotección , Miocardio/citología , Neuronas/citología , Sustancias Protectoras/metabolismo , Receptores Adrenérgicos alfa 1/clasificación , Receptores Adrenérgicos alfa 1/metabolismo , Animales , Humanos , Sustancias Protectoras/clasificación , Receptores Adrenérgicos alfa 1/genéticaRESUMEN
The understanding of the function of alpha(1)-adrenergic receptors in the brain has been limited due to a lack of specific ligands and antibodies. We circumvented this problem by using transgenic mice engineered to overexpress either wild-type receptor tagged with enhanced green fluorescent protein or constitutively active mutant alpha(1)-adrenergic receptor subtypes in tissues in which they are normally expressed. We identified intriguing alpha(1A)-adrenergic receptor subtype-expressing cells with a migratory morphology in the adult subventricular zone that coexpressed markers of neural stem cell and/or progenitors. Incorporation of 5-bromo-2-deoxyuridine in vivo increased in neurogenic areas in adult alpha(1A)-adrenergic receptor transgenic mice or normal mice given the alpha(1A)-adrenergic receptor-selective agonist, cirazoline. Neonatal neurospheres isolated from normal mice expressed a mixture of alpha(1)-adrenergic receptor subtypes, and stimulation of these receptors resulted in increased expression of the alpha(1B)-adrenergic receptor subtype, proneural basic helix-loop-helix transcription factors, and the differentiation and migration of neuronal progenitors for catecholaminergic neurons and interneurons. alpha(1)-Adrenergic receptor stimulation increased the apoptosis of astrocytes and regulated survival of neonatal neurons through phosphatidylinositol 3-kinase signaling. However, in adult normal neurospheres, alpha(1)-adrenergic receptor stimulation increased the expression of glial markers at the expense of neuronal differentiation. In vivo, S100-positive glial and betaIII tubulin neuronal progenitors colocalized with either alpha(1)-adrenergic receptor subtype in the olfactory bulb. Our results indicate that alpha(1)-adrenergic receptors can regulate both neurogenesis and gliogenesis that may be developmentally dependent. Our findings may lead to new therapies to treat neurodegenerative diseases.
Asunto(s)
Neurogénesis , Neuroglía/metabolismo , Neuronas/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Agonistas de Receptores Adrenérgicos alfa 1 , Animales , Animales Recién Nacidos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Biomarcadores/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Movimiento Celular/genética , Movimiento Celular/fisiología , Proteínas Fluorescentes Verdes/metabolismo , Imidazoles/farmacología , Inmunohistoquímica , Interneuronas/citología , Interneuronas/metabolismo , Ratones , Ratones Transgénicos , Neuronas/citología , Neuronas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores Adrenérgicos alfa 1/genética , Esferoides Celulares/metabolismoRESUMEN
Activation of G protein-coupled alpha(2) adrenergic receptors (ARs) inhibits epileptiform activity in the hippocampal CA3 region. The specific mechanism underlying this action is unclear. This study investigated which subtype(s) of alpha(2)ARs and G proteins (Galpha(o) or Galpha(i)) are involved in this response using recordings of mouse hippocampal CA3 epileptiform bursts. Application of epinephrine (EPI) or norepinephrine (NE) reduced the frequency of bursts in a concentration-dependent manner: (-)EPI > (-)NE >>> (+)NE. To identify the alpha(2)AR subtype involved, equilibrium dissociation constants (pK(b)) were determined for the selective alphaAR antagonists atipamezole (8.79), rauwolscine (7.75), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride (WB-4101; 6.87), and prazosin (5.71). Calculated pK(b) values correlated best with affinities determined previously for the mouse alpha(2A)AR subtype (r = 0.98, slope = 1.07). Furthermore, the inhibitory effects of EPI were lost in hippocampal slices from alpha(2A)AR-but not alpha(2C)AR-knockout mice. Pretreatment with pertussis toxin also reduced the EPI-mediated inhibition of epileptiform bursts. Finally, using knock-in mice with point mutations that disrupt regulator of G protein signaling (RGS) binding to Galpha subunits to enhance signaling by that G protein, the EPI-mediated inhibition of bursts was significantly more potent in slices from RGS-insensitive Galpha(o)(G184S) heterozygous (Galpha(o)+/GS) mice compared with either Galpha(i2)(G184S) heterozygous (Galpha(i2)+/GS) or control mice (EC(50) = 2.5 versus 19 and 23 nM, respectively). Together, these findings indicate that the inhibitory effect of EPI on hippocampal CA3 epileptiform activity uses an alpha(2A)AR/Galpha(o) protein-mediated pathway under strong inhibitory control by RGS proteins. This suggests a possible role for RGS inhibitors or selective alpha(2A)AR agonists as a novel antiepileptic drug therapy.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/fisiología , Hipocampo/efectos de los fármacos , Proteínas RGS/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Antagonistas de Receptores Adrenérgicos alfa 2 , Animales , Epinefrina/farmacología , Femenino , Hipocampo/fisiología , Imidazoles/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Norepinefrina/farmacología , Oximetazolina/farmacología , Toxina del Pertussis/farmacologíaRESUMEN
This study documents outcomes, including student career choices, of the North Dakota Institutional Development Award Networks of Biomedical Research Excellence program that provides 10-week, summer undergraduate research experiences at the University of North Dakota School of Medicine and Health Sciences. Program evaluation initiated in 2008 and, to date, 335 students have completed the program. Of the 335, 214 students have successfully completed their bachelor's degree, 102 are still undergraduates, and 19 either did not complete a bachelor's degree or were lost to follow-up. The program was able to track 200 of the 214 students for education and career choices following graduation. Of these 200, 76% continued in postgraduate health-related education; 34.0% and 20.5% are enrolled in or have completed MD or PhD programs, respectively. Other postbaccalaureate pursuits included careers in pharmacy, optometry, dentistry, public health, physical therapy, nurse practitioner, and physician's assistant, accounting for an additional 21.5%. Most students electing to stop formal education at the bachelor's degree also entered fields related to health care or science, technology, engineering, and mathematics (19.5%), with only a small number of the 200 students tracked going into service or industries which lacked an association with the health-care workforce (4.5%). These student outcomes support the concept that participation in summer undergraduate research boosts efforts to populate the pipeline of future researchers and health professionals. It is also an indication that future researchers and health professionals will be able to communicate the value of research in their professional and social associations. The report also discusses best practices and issues in summer undergraduate research for students originating from rural environments.
RESUMEN
alpha(1)-Adrenergic receptors (ARs) are not well defined in the central nervous system. The particular cell types and areas that express these receptors are uncertain because of the lack of high avidity antibodies and selective ligands. We have developed transgenic mice that either systemically overexpress the human alpha(1A)-AR subtype fused with the enhanced green fluorescent protein (EGFP) or express the EGFP protein alone under the control of the mouse alpha(1A)-AR promoter. We confirm our transgenic model against the alpha(1A)-AR knockout mouse, which expresses the LacZ gene in place of the coding region for the alpha(1A)-AR. By using these models, we have now determined cellular localization of the alpha(1A)-AR in the brain, at the protein level. The alpha(1A)-AR or the EGFP protein is expressed prominently in neuronal cells in the cerebral cortex, hippocampus, hypothalamus, midbrain, pontine olivary nuclei, trigeminal nuclei, cerebellum, and spinal cord. The types of neurons were diverse, and the alpha(1A)-AR colocalized with markers for glutamic acid decarboxylase (GAD), gamma-aminobutyric acid (GABA), and N-methyl-D-aspartate (NMDA) receptors. Recordings from alpha(1A)-AR EGFP-expressing cells in the stratum oriens of the hippocampal CA1 region confirmed that these cells were interneurons. We could not detect expression of the alpha(1A)-AR in mature astrocytes, oligodendrocytes, or cerebral blood vessels, but we could detect the alpha(1A)-AR in oligodendrocyte progenitors. We conclude that the alpha(1A)-AR is abundant in the brain, expressed in various types of neurons, and may regulate the function of oligodendrocyte progenitors, interneurons, GABA, and NMDA receptor containing neurons.
Asunto(s)
Antígenos/metabolismo , Encéfalo/citología , Neuronas/fisiología , Oligodendroglía/metabolismo , Proteoglicanos/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Células Madre , Ácido gamma-Aminobutírico/metabolismo , Agonistas de Receptores Adrenérgicos alfa 1 , Animales , Encéfalo/metabolismo , Diferenciación Celular/fisiología , Expresión Génica/fisiología , Proteínas Fluorescentes Verdes/metabolismo , Inmunohistoquímica/métodos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratones , Ratones Transgénicos , Neuronas/clasificación , Neuronas/efectos de los fármacos , Norepinefrina/análogos & derivados , Norepinefrina/farmacología , Técnicas de Placa-Clamp/métodos , Ensayo de Unión Radioligante/métodos , Receptores Adrenérgicos alfa 1/deficiencia , beta-Galactosidasa/metabolismoRESUMEN
The CA1 region of the rat hippocampus exhibits both alpha and beta adrenergic receptor (AR) responses, however, the specific AR subtypes involved and the neuronal expression patterns for these receptors are not well understood. We have employed single cell real time RT-PCR in conjunction with cell-specific immunohistochemical markers to determine the AR expression patterns for hippocampal neurons located in CA1, a region often implicated in learning and memory processes. Cytoplasmic samples were taken from 55 individual cells located in stratum oriens, pyramidale, or radiatum and reverse transcribed. All successfully amplified pyramidal neuron samples (n = 17) expressed mRNA for the beta2AR, with four cells additionally expressing mRNA for the beta1AR subtype. Positive interneurons from stratum oriens (n = 10) and stratum radiatum (n = 8) expressed mRNA for the alpha1A and/or alpha(1B)AR (n = 9/18) only when coexpressing transcripts for somatostatin. Interneurons containing neuropeptide Y or cholecystokinin (n = 9/18) were not positive for any of the nine AR subtypes, suggesting that CA1 interneuron AR expression is limited to a subset of somatostatin-positive cells. These findings suggest that only a select number of AR subtypes are transcriptionally expressed in CA1 and that these receptors are selective to specific neuronal cell types.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Hipocampo/citología , Neuronas/metabolismo , Receptores Adrenérgicos/metabolismo , Animales , Northern Blotting/métodos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Proteínas Quinasas Dependientes de Calcio-Calmodulina/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Inmunohistoquímica/métodos , Isoenzimas/genética , Isoenzimas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos/clasificación , Receptores Adrenérgicos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Somatostatina/metabolismoRESUMEN
Norepinephrine (NE) has demonstrated proconvulsant and antiepileptic properties; however, the specific pharmacology of these actions has not been clearly established. To address this, we studied the effect of NE on hippocampal CA3 epileptiform activity. Frequency changes of burst discharges in response to NE were biphasic; low concentrations increased the number of bursts, while higher concentrations reduced their frequency, suggesting the involvement of multiple adrenergic receptor (AR) types. This hypothesis was confirmed when, in the presence of betaAR blockade, increasing concentrations of NE caused a monophasic decrease in epileptiform activity. Antagonists selective for alpha1 or alpha2ARs were then used to determine which alphaAR type was involved. While discriminating concentrations of the alpha1AR antagonists prazosin and terazosin had no effect, selective amounts of the alpha2AR antagonists RS79948 and RX821002 significantly reduced the potency of NE in decreasing epileptiform activity. Furthermore, this antiepileptic action of NE persisted when all GABA-mediated inhibition was blocked. This data suggests that, under conditions of impaired GABAergic inhibition, the excitatory and inhibitory effects of NE on hippocampal CA3 epileptiform activity are mediated primarily via beta and alpha2ARs, respectively. Moreover, our results imply that the antiepileptic effect of alpha2AR activation in CA3 is not dependent on the GABAergic system.
Asunto(s)
Hipocampo/fisiopatología , Red Nerviosa/fisiopatología , Receptores Adrenérgicos/fisiología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Animales Recién Nacidos , Conducta Animal , Bicuculina , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Antagonistas del GABA/farmacología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Red Nerviosa/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Norepinefrina/farmacología , Fentolamina/farmacología , Ácidos Fosfínicos/farmacología , Pindolol/farmacología , Propanolaminas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Astrocytes perform crucial supportive functions, including neurotransmitter clearance, ion buffering, and metabolite delivery. They can also influence blood flow and neuronal activity by releasing gliotransmitters in response to intracellular Ca(2+) transients. However, little is known about how astrocytes are engaged during different behaviors in vivo. Here we demonstrate that norepinephrine primes astrocytes to detect changes in cortical network activity. We show in mice that locomotion triggers simultaneous activation of astrocyte networks in multiple brain regions. This global stimulation of astrocytes was inhibited by alpha-adrenoceptor antagonists and abolished by depletion of norepinephrine from the brain. Although astrocytes in visual cortex of awake mice were rarely engaged when neurons were activated by light stimulation alone, pairing norepinephrine release with light stimulation markedly enhanced astrocyte Ca(2+) signaling. Our findings indicate that norepinephrine shifts the gain of astrocyte networks according to behavioral state, enabling astrocytes to respond to local changes in neuronal activity.
Asunto(s)
Potenciales de Acción/fisiología , Astrocitos/metabolismo , Red Nerviosa/metabolismo , Norepinefrina/metabolismo , Estimulación Luminosa/métodos , Animales , Ratones , Ratones Transgénicos , Corteza Visual/metabolismoRESUMEN
The α1-adrenergic receptor (α1AR) subtypes, α1AAR and α1BAR, have differential effects in the heart and central nervous system. Long-term stimulation of the α1AAR subtype prolongs lifespan and provides cardio- and neuro-protective effects. We examined the lifespan of constitutively active mutant (CAM)-α1BAR mice and the incidence of cancer in mice expressing the CAM form of either the α1AAR (CAM-α1AAR mice) or α1BAR. CAM-α1BAR mice have a significantly shortened lifespan when compared with wild-type (WT) animals; however, the effect was sex dependent. Female CAM-α1BAR mice lived significantly shorter lives, while the median lifespan of male CAM-α1BAR mice was not different when compared with that of WT animals. There was no difference in the incidence of cancer in either sex of CAM-α1BAR mice. The incidence of cancer was significantly decreased in CAM-α1AAR mice when compared with that in WT, and no sex-dependent effects were observed. Further study is warranted on cancer incidence after activation of each α1AR subtype and the effect of sex on lifespan following activation of the α1BAR. The implications of a decrease in cancer incidence following long-term α1AAR stimulation could lead to improved treatments for cancer.
Asunto(s)
Envejecimiento , Regulación Neoplásica de la Expresión Génica , Longevidad/fisiología , Neoplasias Experimentales/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Animales , Femenino , Estudios de Seguimiento , Masculino , Ratones , Ratones Transgénicos , Neoplasias Experimentales/epidemiología , Transducción de Señal , Factores de TiempoRESUMEN
Many tissues of the body cannot only repair themselves, but also self-renew, a property mainly due to stem cells and the various mechanisms that regulate their behavior. Stem cell biology is a relatively new field. While advances are slowly being realized, stem cells possess huge potential to ameliorate disease and counteract the aging process, causing its speculation as the next panacea. Amidst public pressure to advance rapidly to clinical trials, there is a need to understand the biology of stem cells and to support basic research programs. Without a proper comprehension of how cells and tissues are maintained during the adult life span, clinical trials are bound to fail. This review will cover the basic biology of stem cells, the various types of stem cells, their potential function, and the advantages and disadvantages to their use in medicine. We will next cover the role of G protein-coupled receptors in the regulation of stem cells and their potential in future clinical applications.
Asunto(s)
Receptores Acoplados a Proteínas G/metabolismo , Células Madre/metabolismo , Animales , Humanos , Células Madre Neoplásicas/metabolismoRESUMEN
The endogenous catecholamine norepinephrine (NE) exhibits anti-epileptic properties, however it is not well understood which adrenergic receptor (AR) mediates this effect. The aim of this study was to investigate alpha(1)-adrenergic receptor activation in region CA1 of the hippocampus, a subcortical structure often implicated in temporal lobe epilepsies. Using cell-attached and whole-cell recordings in rat hippocampal slices, we confirmed that selective alpha(1)-AR activation increases action potential firing in a subpopulation of CA1 interneurons. We found that this response is mediated via the alpha(1A)-AR subtype, initiated by sodium influx, and appears independent of second messenger signaling. In CA1 pyramidal cells, alpha(1A)-AR activation decreases activity due to increased pre-synaptic GABA and somatostatin release. Examination of post-synaptic receptor involvement revealed that while GABA(A) receptors mediate the majority of alpha(1A)-adrenergic effects on CA1 pyramidal cells, significant contributions are also made by GABA(B) and somatostatin receptors. Finally, to test whether alpha(1A)-AR activation could have potential therapeutic implications, we performed AR agonist challenges using two in vitro epileptiform models. When GABA(A) receptors were available, alpha(1A)-AR activation significantly decreased epileptiform bursting in CA1. Together, our findings directly link stimulation of the alpha(1A)-AR subtype to release of GABA and somatostatin at the single cell level and suggest that alpha(1A)-AR activation may represent one mechanism by which NE exerts anti-epileptic effects within the hippocampus.
Asunto(s)
Hipocampo/citología , Hipocampo/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Receptores Adrenérgicos alfa 1/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Animales Recién Nacidos , Relación Dosis-Respuesta a Droga , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/fisiología , Antagonistas del GABA/farmacología , Hipocampo/efectos de los fármacos , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Masculino , Inhibición Neural/efectos de los fármacos , Neuronas/efectos de los fármacos , Compuestos Organofosforados/farmacología , Técnicas de Placa-Clamp , Fenilefrina/farmacología , Picrotoxina/farmacología , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/farmacología , Somatostatina/farmacología , Tetrodotoxina/farmacología , Factores de TiempoRESUMEN
Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive-compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of alpha(1)-adrenergic receptors (alpha(1)-ARs). Yet, it is unclear whether increased alpha(1)-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant alpha(1A)-ARs (CAM alpha(1A)-AR) or CAM alpha(1B)-ARs were used to examine the effects of alpha(1A)- and alpha(1B)-AR signaling on rodent behavioral models of depression, OCD, and anxiety. CAM alpha(1A)-AR mice, but not CAM alpha(1B)-AR mice, exhibited antidepressant-like behavior in the tail suspension test and forced swim test. This behavior was reversed by prazosin, a selective alpha(1)-AR inverse agonist, and mimicked by chronically treating wild type mice with cirazoline, an alpha(1A)-AR agonist. Marble burying behavior, commonly used to model OCD in rodents, was significantly decreased in CAM alpha(1A)-AR mice but not in CAM alpha(1B)-AR mice. In contrast, no significant differences in anxiety-related behavior were observed between wild type, CAM alpha(1A)-AR, and CAM alpha(1B)-AR animals in the elevated plus maze and light/dark box. This is the first study to demonstrate that alpha(1A)- and alpha(1B)-ARs differentially modulate antidepressant-like behavior in the mouse. These data suggest that alpha(1A)-ARs may be a useful therapeutic target for the treatment of depression.
Asunto(s)
Antidepresivos/farmacología , Encéfalo/metabolismo , Catecolaminas/metabolismo , Trastorno Depresivo/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/fisiopatología , Modelos Animales de Enfermedad , Femenino , Imidazoles/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos CBA , Pruebas Neuropsicológicas , Prazosina/farmacología , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
The entorhinal cortex is closely associated with the consolidation and recall of memories, Alzheimer disease, schizophrenia, and temporal lobe epilepsy. Norepinephrine is a neurotransmitter that plays a significant role in these physiological functions and neurological diseases. Whereas the entorhinal cortex receives profuse noradrenergic innervations from the locus coeruleus of the pons and expresses high densities of adrenergic receptors, the function of norepinephrine in the entorhinal cortex is still elusive. Accordingly, we examined the effects of norepinephrine on neuronal excitability in the entorhinal cortex and explored the underlying cellular and molecular mechanisms. Application of norepinephrine-generated hyperpolarization and decreased the excitability of the neurons in the superficial layers with no effects on neuronal excitability in the deep layers of the entorhinal cortex. Norepinephrine-induced hyperpolarization was mediated by alpha(2A) adrenergic receptors and required the functions of Galpha(i) proteins, adenylyl cyclase, and protein kinase A. Norepinephrine-mediated depression on neuronal excitability was mediated by activation of TREK-2, a type of two-pore domain K(+) channel, and mutation of the protein kinase A phosphorylation site on TREK-2 channels annulled the effects of norepinephrine. Our results indicate a novel action mode in which norepinephrine depresses neuronal excitability in the entorhinal cortex by disinhibiting protein kinase A-mediated tonic inhibition of TREK-2 channels.