RESUMEN
Sleep loss is known to potently suppress adult hippocampal cell proliferation and neurogenesis. Whether sleep suppression following acute administration of stimulant drugs also decreases hippocampal cell proliferation is not known. The present study examined the effect of three mechanistically distinct stimulants (caffeine, methamphetamine and modafinil) on cell proliferation. To maximize sleep suppression, these drugs were administered to rats (three i.p. injections, once every 4 h) during their sleep period (i.e. 12-h light phase). At the end of the light phase, 5-bromo-2'-deoxyuridine (200 mg/kg, i.p.) was injected and animals were killed 2 h later. Polygraphic recordings and locomotor activity measurements confirmed the wake-promoting and sleep-suppressing actions of each treatment. Results indicate that caffeine (20 mg/kg), methamphetamine (1.5 mg/kg) and modafinil (300 mg/kg) differentially suppressed sleep (45-91%) and selectively reduced cell proliferation in the hilus (12-44%), these results being significant for both caffeine and modafinil. When the same experiment was repeated in the dark (active) phase, the suppressant effect on hippocampal cell proliferation was either absent or greatly attenuated. In a further experiment, the effect of acute modafinil treatment in the light phase was shown to persist for 3 weeks after BrdU administration. We hypothesize that the differential effect of the stimulant drugs in the light vs. dark phase is attributable primarily to sleep suppression in the light. As abuse of stimulant drugs invariably leads to disrupted sleep in humans, our results suggest that they may, at least in part, decrease hippocampal neurogenesis via sleep loss and thereby adversely affect hippocampal-dependent processes.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Hipocampo/citología , Hipocampo/efectos de los fármacos , Factores de Edad , Animales , Hipocampo/fisiología , Masculino , Polisomnografía/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Sueño/efectos de los fármacos , Sueño/fisiología , Factores de TiempoRESUMEN
There has been ongoing controversy as to whether selective serotonin reuptake inhibitors (SSRIs) exhibit the same antidepressant efficacy and risk profile within different age groups. Although the etiology of such potential differences is currently not clear, age-dependent differences in the rate of hippocampal neurogenesis offer one possibility. In the current studies we have therefore examined whether fluoxetine, the prototypical selective serotonin reuptake inhibitor, differentially modulates neurogenesis in adolescent, young adult, and aged rats. Proliferation in the dentate gyrus was measured by assaying expression of the endogenous proliferative marker, Ki67. Survival of proliferating cells was assayed by staining with BrdU. We confirmed previous reports that the rate of neurogenesis, as well as the survival of proliferating cells, decreases significantly with age. Moderate decreases were found in young adult rats relative to adolescent rats, and profound decreases were found in aged rats. We additionally found that age did not alter the response to 25 days of treatment with fluoxetine. In fact, we did not observe enhancement of hippocampal neurogenesis, nor enhancement of proliferating cell survival, in any of the three age groups despite using doses of fluoxetine which have been reported to be effective. In addition to finding no age-dependent effects, our data question the general reproducibility of previously reported fluoxetine effects in animals.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Fluoxetina/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Factores de Edad , Análisis de Varianza , Animales , Biomarcadores/metabolismo , Bromodesoxiuridina/metabolismo , Recuento de Células/métodos , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Giro Dentado/citología , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Fluoxetina/administración & dosificación , Hipocampo/citología , Hipocampo/metabolismo , Técnicas para Inmunoenzimas/métodos , Inyecciones Intraperitoneales , Antígeno Ki-67/metabolismo , Masculino , Neuronas/citología , Neuronas/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
BACKGROUND: Recent evidence indicates that new neurons are produced in the adult hippocampus, and play a functional role in cognitive processes such as learning and memory. In animals, new neuron production is suppressed by increasing age, gamma-aminobutyric acid receptor activity, reductions in basal forebrain activity and brain norepinephrine levels, and decreased environmental stimuli. Similarities between these effects and those of anesthetic administration suggest that anesthetics may modulate new cell production, and raise the possibility that postoperative cognitive dysfunction may result, in part, from anesthetic-induced suppression of adult neurogenesis. To test this hypothesis, we investigated the effects of prolonged anesthesia with four different anesthetics on hippocampal cell proliferation in young and older rats. METHODS: Young (approximately 3 mo) and older, middle-aged (approximately 12 mo) male Sprague-Dawley rats received one of four anesthetics (propofol, isoflurane, dexmedetomidine, and ketamine) for 8 h. Rats breathed spontaneously, and anesthesia was titrated to loss of righting reflex and tolerance of clip-style pulse oximetry. Six hours into the anesthetic, rats received 200 mg/kg bromodeoxyuridine (BrdU) intraperitoneally and were killed hours later. Frozen hippocampal sections were collected and processed for BrdU using an immunoperoxidase technique. BrdU(+) cells in the dentate gyrus were then counted, and compared with unanesthetized controls to determine the degree of new cell production. All four anesthetics were given to young rats. Older rats received isoflurane and ketamine, and also received isoflurane during their dark phase. RESULTS: Forty-two young, and 26 older, middle-aged rats were studied. When compared with controls, prolonged anesthesia in young rats with any drug had no effect on the number of BrdU(+) cells. BrdU labeling was also unaffected in older rats given isoflurane for 8 h during the light phase. Older rats had significantly lower BrdU(+) cell counts than younger rats. In older rats, ketamine anesthesia reduced BrdU(+) cell counts by 26% when compared with unanesthetized controls. Older rats given isoflurane for 8 h during their dark phase demonstrated no difference in BrdU labeling when compared with unanesthetized controls. CONCLUSION: Despite using multiple, mechanistically distinct drugs, we found no effect of prolonged anesthesia on adult hippocampal cell proliferation in young rats, a slight suppressive effect of ketamine in older rats, and no circadian effect with isoflurane. These data indicate that anesthetics are unlikely to alter cell proliferation, and by extension that anesthetic-induced inhibition of cell proliferation is unlikely to play a major role in postoperative cognitive impairment. The contrast between our findings, current concepts of anesthetic action, and known modifiers of cell proliferation suggest an incomplete understanding of the pharmacological and behavioral factors governing new neuron production.
Asunto(s)
Anestésicos/farmacología , Proliferación Celular/efectos de los fármacos , Dexmedetomidina/farmacología , Hipocampo/efectos de los fármacos , Isoflurano/farmacología , Ketamina/farmacología , Neuronas/efectos de los fármacos , Propofol/farmacología , Factores de Edad , Animales , Bromodesoxiuridina , Ritmo Circadiano , Giro Dentado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hipocampo/citología , Técnicas para Inmunoenzimas , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Adult Sprague-Dawley rats were exposed to a single session of 100 inescapable tail shocks (IS). Bromodeoxyuridine (BrdU) was administered 1 h, 2 days or 7 days later and hippocampal cell proliferation (CP) was assessed after a 2-h survival period. Measures of plasma corticosterone (CORT) levels were also obtained. Despite a large increase in CORT immediately following IS, no associated change in CP was observed. In fact, the only significant change in CP was seen 7 days after IS, at a time when CORT was unchanged from control levels. These data raise questions about the general nature of the relationship between CORT and CP. They also suggest that, under some conditions, changes in hippocampal CP may emerge only after an "incubation period".
Asunto(s)
Proliferación Celular , Corticosterona/sangre , Desamparo Adquirido , Hipocampo/citología , Estrés Psicológico/fisiopatología , Análisis de Varianza , Animales , Hipocampo/fisiología , Masculino , Análisis por Apareamiento , Ratas , Ratas Sprague-Dawley , Método Simple Ciego , Estadísticas no Paramétricas , Estrés Psicológico/sangre , Factores de TiempoRESUMEN
Stressful experiences can affect hippocampal structure and function and can suppress new cell birth in the adult hippocampus in several species. Here we examine how repeated intermittent social defeat affects cell proliferation in the dentate gyrus (DG) in mice. Adult male CFW mice were subjected to 10 daily social defeat episodes, 3 defeat episodes within one day or a single defeat episode. Intruder mice were injected with 5-bromo-2'-deoxyuridine (BrdU, 200mg/kg, i.p.) 1h after the last fight, and incorporation of BrdU into proliferating cells in the DG was quantified. In a third experiment, aggressive resident mice were allowed to fight with an intruder mouse every day for 10 days, and these residents were injected with BrdU 1h after the last aggressive encounter. There was a significant decrease in cell proliferation in mice that received 10 social defeats, confirming and extending earlier results. This decrease is correlated with the intensity of the defeat experiences, as quantified by frequency of attack bites. Cell proliferation was slightly inhibited after a single defeat, although this effect was not significant. Three defeats within a 5-h period had no effect on levels of proliferation. Offensive aggressive stress in the residents did not result in any changes in hippocampal cell proliferation. These data indicate that repeated intermittent social defeat experienced over multiple days suppresses proliferation in the DG, and this may have important implications for our understanding of hippocampal changes related to stress psychopathologies.
Asunto(s)
Proliferación Celular , Giro Dentado/citología , Dominación-Subordinación , Estrés Psicológico/fisiopatología , Agresión/fisiología , Animales , Giro Dentado/fisiología , Masculino , Ratones , Medio SocialRESUMEN
Single unit activity of presumed serotonergic neurons in the medulla [n. raphe obscurus (NRO) and pallidus (NRP)] or the mesencephalon [n. raphe dorsalis (DRN)] was recorded in adult male cats during prolonged treadmill locomotion. Treadmill speed was set at a moderate level (0.4 m/s) in order to induce long-duration locomotion. The typical time to "fatigue" (failure to keep pace, falling behind and reluctance to continue) was approximately 40 min in both groups, at which point cats typically displayed marked panting and vocalization. The activity of DRN neurons was unchanged from baseline during the locomotion trial and during the recovery phase. By contrast, the activity of NRO/NRP neurons decreased steadily across the locomotion trial, reaching a mean decrease of approximately 50% (during the first min after the treadmill was turned off). Full recovery of single unit activity to a level approximating the baseline discharge rate required 30-45 min. Possible mechanisms underlying these changes are discussed as is the role of serotonin and fatigue in human pathology.
Asunto(s)
Bulbo Raquídeo/fisiología , Mesencéfalo/fisiología , Actividad Motora/fisiología , Fatiga Muscular/fisiología , Neuronas/fisiología , Núcleos del Rafe/fisiología , Serotonina/fisiología , Animales , Gatos , Electroencefalografía , Electromiografía , Movimientos Oculares/fisiología , Modelos AnimalesRESUMEN
Marijuana is a widely abused illicit drug known to cause significant cognitive impairments. Marijuana has been hypothesized to target neurons in the hippocampus because of the abundance of cannabinoid receptors present in this structure. While there is no clear evidence of neuropathology in vivo, suppression of brain mitogenesis, and ultimately neurogenesis, may provide a sensitive index of marijuana's more subtle effects on neural mechanisms subserving cognitive functions. We examined the effects of different doses and treatment regimens of Delta(9)-tetrahydrocannabinol (THC), the main active ingredient in marijuana, on cell proliferation in the dentate gyrus of adult male mice. Following drug treatment, the thymidine analog 5-bromo-2'-deoxyuridine (BrdU; 200 mg/kg, i.p.) was administered two hours prior to sacrifice to assess cell proliferation, the first step in neurogenesis. Administration of THC produced dose-dependent catalepsy and suppression of motor activity. The number of BrdU-labeled cells was not significantly changed from vehicle control levels following either acute (1, 3, 10, 30 mg/kg, i.p.), sequential (two injections of 10 or 30 mg/kg, i.p., separated by 5 h), or chronic escalating (20 to 80 mg/kg, p.o.; for 3 weeks) drug administration. Furthermore, acute administration of the potent synthetic cannabinoid receptor agonist R-(+)-WIN 55,212-2 (WIN; 5 mg/kg, i.p.) also had no significant effect on cell proliferation. These findings provide no evidence for an effect of THC on hippocampal cell proliferation, even at doses producing gross behavioral intoxication. Whether marijuana or THC affects neurogenesis remains to be explored.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Dronabinol/farmacología , Alucinógenos/farmacología , Actividad Motora/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Bromodesoxiuridina , Recuento de Células/métodos , Giro Dentado/citología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inmunohistoquímica/métodos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Hippocampal cell proliferation and concomitant motor activity were examined in adult male mice (C57BL/6J) across a 12:12h light-dark cycle. 5-Bromo-2'-deoxyuridine (BrdU) (200 mg/kg, i.p.) was administered at six equally spaced time points across 24h. A significant change in cell proliferation was found in the hilus (light phase>dark phase), but not in the granule cell layer (GCL)/subgranular zone (SGZ). Since it is generally believed that proliferating cells in the hilus and GCL/SGZ give rise primarily to glia and neurons, respectively, these data suggest a possible circadian influence on gliogenesis, rather than neurogenesis.
Asunto(s)
Proliferación Celular , Ritmo Circadiano/fisiología , Hipocampo/citología , Neuroglía/fisiología , Neuronas/fisiología , Animales , Bromodesoxiuridina/metabolismo , Recuento de Células/métodos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Adult male albino rats were exposed to varying numbers of tailshocks (0, 10, 50 or 100). The following day, their escape latencies in a shuttlebox were measured in order to estimate the degree of learned helplessness (LH) produced by the varying number of shocks. Only the groups exposed to 50 or 100 shocks displayed evidence of LH. In a parallel experiment, c-fos activation was used to determine the degree of activation of raphe serotonergic neurons (FosIR+5-HT) and locus coeruleus (LC) noradrenergic neurons (FosIR+TH) produced by the same shock conditions. Compared to unhandled cage controls, all shock groups (0 shocks was a restrained group) significantly activated both raphe and LC neurons. The 50 and 100 shock groups had significantly higher degrees of activation of serotonergic neurons in the rostral raphe groups and the LC than the 0 and 10 shock groups. These data are consistent with the hypothesis that activation of rostral raphe serotonergic neurons and LC noradrenergic neurons beyond a certain threshold may be critical for the development of LH. The relevance of these results for elucidating the neural bases of psychopathology is discussed.
Asunto(s)
Electrochoque/efectos adversos , Desamparo Adquirido , Neuronas/fisiología , Norepinefrina/metabolismo , Serotonina/metabolismo , Análisis de Varianza , Animales , Conducta Animal , Recuento de Células/métodos , Reacción de Fuga/fisiología , Reacción de Fuga/efectos de la radiación , Inmunohistoquímica/métodos , Locus Coeruleus/citología , Locus Coeruleus/metabolismo , Masculino , Proteínas Oncogénicas v-fos/metabolismo , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Esquema de Refuerzo , Cola (estructura animal)/inervación , Cola (estructura animal)/efectos de la radiación , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Animal studies examining the effects of stress upon brain serotonergic neurons have not presented a clearcut and consistent picture. One stressor that has been shown to exert a consistently strong effect on serotonin release and c-fos activation in the dorsal raphe nucleus of rats is a series of inescapable electrical shocks. Using immunohistochemical double labeling for c-fos activation and serotonin, we examined the effects of delivering 100 inescapable tailshocks to rats on serotonergic neuronal activation throughout the brainstem raphe system. This stimulus exerted a consistent and strong activation of the entire midline brain stem system of serotonergic neurons. The implications of these findings for animal models of human psychopathology are discussed.
Asunto(s)
Electrochoque/métodos , Neuronas/efectos de la radiación , Núcleos del Rafe/efectos de la radiación , Serotonina/metabolismo , Animales , Recuento de Células , Inmunohistoquímica/métodos , Masculino , Neuronas/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleos del Rafe/citología , Ratas , Ratas Sprague-DawleyRESUMEN
This study investigated the action of 5-HT(1A) receptor antagonists on cell proliferation in the dentate gyrus of adult rats. Three antagonists (NAN-190, p-MPPI and WAY-100635) all produced a statistically significant approximately 30% reduction in the number of BrdU-immunoreactive cells in the dentate gyrus. This suggests that 5-HT(1A) receptor activity is important during naturally occurring cell proliferation in the dentate gyrus, and perhaps neurogenesis, and is one of the many factors involved in its regulation.
Asunto(s)
Giro Dentado/citología , Giro Dentado/efectos de los fármacos , Inhibidores de Crecimiento/farmacología , Receptores de Serotonina/fisiología , Antagonistas de la Serotonina/farmacología , Animales , División Celular/efectos de los fármacos , División Celular/fisiología , Giro Dentado/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT1RESUMEN
The dentate gyrus continues to produce granule neurons throughout life. Mossy fibers, the axons of granule neurons, undergo atypical sprouting in both clinical and experimental mesial temporal lobe epilepsy. Mossy fiber sprouting (MFS) has been hypothesized to underlie the network reorganization that is thought to produce spontaneously recurring seizures, possibly via the formation of new recurrent excitatory circuits. Hippocampal neurogenesis may be a critical step in the development of MFS, given that it is enhanced by at least 2-fold in the aftermath of pilocarpine-induced status epilepticus. Since it is known that serotonin (5-HT) 1A receptor activation also increases granule cell genesis in the dentate gyrus in rats, and reciprocally, that blockade of this receptor decreases it, we examined whether 5-HT(1A) receptor blockade would prevent the seizure-induced enhancement of neurogenesis. The ability to block seizure-induced neurogenesis would provide a test for its role in the network reorganization, especially in regards to MFS, which might underlie seizure development. In the present study, it was found that blockade of the 5-HT(1A) receptor before and after pilocarpine treatment prevented seizure-induced hippocampal cell proliferation and survival, and, its prevention by chronic treatment with a 5-HT(1A) receptor antagonist (WAY-100,635) did not prevent the development of MFS or spontaneously recurring seizures. Taken together, these results suggest that 5-HT(1A) receptor activation is a critical step in the activation of seizure-induced cell proliferation and survival in the dentate gyrus, however, not for the onset of spontaneously recurrent seizures and MFS.
Asunto(s)
Giro Dentado/citología , Giro Dentado/metabolismo , Pilocarpina/toxicidad , Receptores de Serotonina/fisiología , Estado Epiléptico/metabolismo , Animales , División Celular/efectos de los fármacos , División Celular/fisiología , Giro Dentado/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Estado Epiléptico/inducido químicamenteRESUMEN
Activity-based anorexia (ABA) is an animal model of anorexia nervosa that mimics core features of the clinical psychiatric disorder, including severe food restriction, weight loss, and hyperactivity. The ABA model is currently being used to study starvation-induced changes in the brain. Here, we examined hippocampal cell proliferation in animals with ABA (or the appropriate control conditions). Adolescent female Sprague-Dawley rats were assigned to 4 groups: control (24h/day food access), food-restricted (1h/day food access), exercise (24h/day food and wheel access), and ABA (1h/day food access, 24h/day wheel access). After 3 days of ABA, 5-bromo-2'-deoxyuridine (BrdU; 200mg/kg, i.p.) was injected and the rats were perfused 2h later. Brains were removed and subsequently processed for BrdU and Ki67 immunohistochemistry. The acute induction of ABA reduced cell proliferation in the dentate gyrus. This effect was significant in the hilus region of the dentate gyrus, but not in the subgranular zone, where adult neurogenesis occurs. Marked decreases in cell proliferation were also observed in the surrounding dorsal hippocampus and in the corpus callosum. These results indicate a primary effect on gliogenesis rather than neurogenesis following 3 days of ABA. For each brain region studied (except SGZ), there was a strong positive correlation between the level of cell proliferation and body weight/food intake. Future studies should examine whether these changes are maintained following long-term weight restoration and whether alterations in neurogenesis occur following longer exposures to ABA.
Asunto(s)
Anorexia/psicología , Proliferación Celular , Hipocampo/citología , Actividad Motora/fisiología , Análisis de Varianza , Animales , Antimetabolitos , Conducta Animal/fisiología , Peso Corporal/fisiología , Bromodesoxiuridina , Restricción Calórica , Cuerpo Calloso/citología , Ingestión de Alimentos/fisiología , Femenino , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Neurogénesis/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Brain disorders and environmental factors can affect neurogenesis and gliogenesis in the hippocampus. These studies investigated the effects of chronic exposure to tobacco smoke on progenitor cell proliferation and the survival and phenotype of new cells in the dentate gyrus of adolescent rats. The rats were exposed to tobacco smoke for 4h/day for 14 days. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU, 200mg/kg, ip) was administered 2h into the 4-h smoke exposure session on day 14. The rats were sacrificed 2-4h after the administration of BrdU. To investigate cell survival, the same dose of BrdU was administered 24h before the start of the 14-day smoke exposure period. These rats were sacrificed 24h after the last smoke exposure session. Tobacco smoke exposure decreased both the number of dividing progenitor cells (-19%) and the number of surviving new cells (-20%), labeled with BrdU in the dentate gyrus. The decrease in cell proliferation was not associated with an increase in apoptotic cell death, as shown by TUNEL analysis. Colocalization studies indicated that exposure to tobacco smoke decreased the number of new immature neurons (BrdU/DCX-positive) and transition neurons (BrdU/DCX/NeuN-positive) and increased the number of new glial cells (BrdU/GFAP-positive). These findings demonstrate that exposure to tobacco smoke diminishes neurogenesis and promotes gliogenesis in the dentate gyrus of adolescent rats. These effects may play a role in the increased risk for depression and cognitive impairment in adolescent smokers.
Asunto(s)
Giro Dentado/citología , Giro Dentado/fisiología , Inhibición Neural/fisiología , Neurogénesis/fisiología , Neuroglía/citología , Neuroglía/fisiología , Fumar/efectos adversos , Factores de Edad , Animales , Proliferación Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Proteína Doblecortina , Masculino , Inhibición Neural/efectos de los fármacos , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/fisiología , Neurogénesis/efectos de los fármacos , Neuroglía/efectos de los fármacos , Ratas , Ratas Wistar , Fumar/patologíaRESUMEN
Sleep loss/disruption has been shown to suppress adult hippocampal neurogenesis. Whether the administration of hypnotic drugs, by promoting sleep, especially in older subjects, who typically exhibit poor sleep, has a beneficial effect on neurogenesis parameters is unknown. We examined the effects of zolpidem, a widely prescribed nonbenzodiazepine hypnotic, on cell proliferation and survival in the dentate gyrus of young ( approximately 2 1/2 months) and old ( approximately 13 months) male Sprague-Dawley rats. Zolpidem (5, 10 or 20 mg/kg, i.p.) or vehicle was administered twice daily, at the beginning and middle of the sleep period, for either 2 days (acute study) or 21 days (chronic study). Proliferation and cell survival were measured by staining for Ki67 or 5-bromo-2'-deoxyurdine (BrdU), respectively. Acute administration of zolpidem produced a suppression of cell proliferation, which attained statistical significance only in the aged animals. The magnitude of the suppressive effect was larger in the hilus than in the subgranular zone (SGZ). In contrast, chronic administration of zolpidem produced little or no effect on proliferation in either age group, despite marked differences in basal proliferation levels between the two age groups. Similarly, there was little change in cell survival following chronic zolpidem administration in young versus old animals. A slight reduction of cell survival in the granular cell layer (GCL)/SGZ was observed in young animals and a slight augmentation in aged animals. To the extent that zolpidem improves sleep, these data suggest little or no benefit of hypnotic drug treatment on neurogenesis parameters in young or old rats.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Giro Dentado/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Neuronas/efectos de los fármacos , Piridinas/farmacología , Envejecimiento , Análisis de Varianza , Animales , Peso Corporal/efectos de los fármacos , Bromodesoxiuridina , Giro Dentado/citología , Giro Dentado/crecimiento & desarrollo , Inmunohistoquímica , Antígeno Ki-67/metabolismo , Masculino , Neuronas/citología , Neuronas/fisiología , Fotomicrografía , Ratas , Ratas Sprague-Dawley , Sueño , ZolpidemRESUMEN
Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.
Asunto(s)
Neurogénesis/fisiología , Neuronas/patología , Privación de Sueño/patología , Privación de Sueño/fisiopatología , Adulto , Proliferación Celular , Ritmo Circadiano/fisiología , Trastornos del Conocimiento/epidemiología , Citocinas/fisiología , Giro Dentado/fisiopatología , Depresión/epidemiología , Hipocampo/patología , Hipocampo/fisiopatología , Humanos , Aprendizaje/fisiología , Trastornos de la Memoria/epidemiología , Trastornos del Humor/epidemiología , Privación de Sueño/epidemiología , Fases del Sueño/fisiología , Estrés Psicológico/epidemiología , Estrés Psicológico/fisiopatologíaRESUMEN
Single-unit activity of serotonergic neurons in the nuclei raphe obscurus (NRO) and raphe pallidus (NRP) were recorded in conjunction with heart rate in freely moving cats in response to systemic administration of vasoactive drugs and to graded haemorrhage. Bolus administration of phenylephrine hydrochloride and sodium nitroprusside (20 microg/kg, i.v.) produced a marked, transient reflex bradycardia (-42 b.p.m.) and tachycardia (+60 b.p.m.), respectively. The activity of NRO/NRP serotonergic neurons remained unchanged after phenylephrine and nitroprusside administration. The administration of hydralazine (1 mg/kg, i.v.), a long-acting vasodilator, produced sustained tachycardia (+60 b.p.m.), which was not accompanied by changes in neuronal activity, despite prolonged reflex activation of the sympathetic nervous system. The initial withdrawal of up to 15% of total blood volume increased heart rate (+12 b.p.m.), whereas the removal of 22.5% of total blood decreased heart rate (-44 b.p.m.). The activity of NRO/NRP serotonergic neurons remained unaltered throughout graded haemorrhage trials, despite the changes in sympathetic outflow. Thus, serotonergic NRO and NRP neurons appear to be insensitive to alterations in blood pressure and baroreceptor activity, and this lack of responsiveness does not support a specific role for these cells in cardiovascular regulation. Furthermore, these neurons do not appear to be involved in physiological mechanisms underlying alterations in autonomic outflow invoked by hypertension and hypotension. Taken within the context of our previous work, the present data suggest that medullary serotonergic neurons may modulate autonomic outflow, but only in relation to their primary role in motor control.
Asunto(s)
Potenciales de Acción/fisiología , Fenómenos Fisiológicos Cardiovasculares , Neuronas/metabolismo , Núcleos del Rafe/citología , Serotonina/metabolismo , Vigilia/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Conducta Animal , Gatos , Electrocardiografía/métodos , Electromiografía/métodos , Electrooculografía/métodos , Frecuencia Cardíaca/efectos de los fármacos , Hemorragia/fisiopatología , Hidralazina/farmacología , Masculino , Neuronas/fisiología , Donantes de Óxido Nítrico/farmacología , Nitroprusiato/farmacología , Fenilefrina/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Fases del Sueño/efectos de los fármacos , Fases del Sueño/fisiología , Vasodilatadores/farmacologíaRESUMEN
The waning and waxing of neurogenesis in brain areas such as the dentate gyrus is proposed as a key factor in the descent into and recovery from clinical depression, respectively. A decrease in neurogenesis could occur due to genetic factors, stress (especially because of the involvement of adrenal corticoids), and/or a decline in serotonergic neurotransmission. An increase in neurogenesis could be brought about by several factors, but especially those that activate the serotonin 5-HT(1A) receptor. The possible interaction of immune system factors, especially the proinflammatory cytokines, with adult brain neurogenesis is discussed.
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Encéfalo/metabolismo , Citocinas/efectos adversos , Giro Dentado/metabolismo , Trastorno Depresivo/inmunología , Mitosis , Neuronas/metabolismo , Animales , Citocinas/metabolismo , Trastorno Depresivo/metabolismo , Hipocampo/metabolismo , Humanos , Receptores de Serotonina/metabolismo , Receptores de Serotonina 5-HT1 , Serotonina/metabolismo , Estrés Fisiológico/metabolismoRESUMEN
Serotonergic single-unit activity during glucoregulatory challenges was studied in the nuclei raphe obscurus (NRO) and raphe pallidus (NRP) of freely moving cats. Systemic insulin administration (2-4 IU/kg, i.v.) suppressed neuronal activity by approximately 40% in direct relationship to blood glucose levels and in inverse relationship to plasma catecholamine levels. NRO and NRP serotonergic neurons displayed a temporary recovery in unit activity in response to i.v. glucose administration (500 mg/kg), which temporarily reversed insulin-induced hypoglycemia. The neuronal responses to insulin and subsequent glucose administration were also directly related to changes in integrated nuchal electromyographic activity. Serotonergic unit activity remained unchanged after glucose loading (500 mg/kg, i.v.), which produced a four-fold increase in blood glucose. Thus, medullary serotonergic neurons appear to be sensitive to reductions, but not increases, in blood glucose. The observed inverse relationship between unit activity and plasma catecholamines does not support a postulated sympathoexcitatory role for these neurons. Instead, the parallel changes in single-unit activity and integrated muscle activity support the hypothesis that the activity of medullary serotonergic neurons is linked to motor output. These neurons may modulate autonomic outflow, but only in relationship to their primary role in motor control. Finally, medullary serotonergic neurons may play a protective role in maintaining glucose homeostasis by disfacilitating the output of the somatomotor system, and hence diminishing muscle energy demands, when peripheral glucose availability is low.
Asunto(s)
Potenciales de Acción/fisiología , Fibras Adrenérgicas/fisiología , Hipoglucemia/fisiopatología , Bulbo Raquídeo/fisiología , Neuronas Motoras/fisiología , Núcleos del Rafe/fisiología , Serotonina/fisiología , Potenciales de Acción/efectos de los fármacos , Fibras Adrenérgicas/efectos de los fármacos , Animales , Glucemia/efectos de los fármacos , Glucemia/fisiología , Gatos , Hipoglucemia/inducido químicamente , Insulina/farmacología , Masculino , Bulbo Raquídeo/efectos de los fármacos , Neuronas Motoras/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/fisiología , Núcleos del Rafe/efectos de los fármacosRESUMEN
In the mammalian brain, serotonergic neurons in the medulla (n. raphe magnus, obscurus, and pallidus) send dense projections into the spinal cord, especially to the dorsal horn, intermediolateral column, and ventral horn. We have conducted a series of studies examining the single unit activity of these neurons in behaving cats. The experiments were directed at determining whether changes in unit activity were related to pain (n. raphe magnus), autonomic activity (n. raphe obscurus and pallidus), or motor activity (n. raphe obscurus and pallidus). The strongest relationship was between neuronal activity and motor output, especially tonic and repetitive motor activity. We hypothesize that the primary functions of this motor-related activity are to facilitate motor output, suppress processing of some forms of afferent activity, and to coordinate autonomic functioning with the current motor demand.