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1.
Proc Natl Acad Sci U S A ; 116(14): 7077-7082, 2019 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-30877244

RESUMEN

Extensive evidence indicates that the basolateral amygdala (BLA) interacts with other brain regions in mediating stress hormone and emotional arousal effects on memory consolidation. Brain activation studies have shown that arousing conditions lead to the activation of large-scale neural networks and several functional connections between brain regions beyond the BLA. Whether such distal interactions on memory consolidation also depend on BLA activity is not as yet known. We investigated, in male Sprague-Dawley rats, whether BLA activity enables prelimbic cortex (PrL) interactions with the anterior insular cortex (aIC) and dorsal hippocampus (dHPC) in regulating glucocorticoid effects on different components of object recognition memory. The glucocorticoid receptor (GR) agonist RU 28362 administered into the PrL, but not infralimbic cortex, immediately after object recognition training enhanced 24-hour memory of both the identity and location of the object via functional interactions with the aIC and dHPC, respectively. Importantly, posttraining inactivation of the BLA by the noradrenergic antagonist propranolol abolished the effect of GR agonist administration into the PrL on memory enhancement of both the identity and location of the object. BLA inactivation by propranolol also blocked the effect of GR agonist administration into the PrL on inducing changes in neuronal activity within the aIC and dHPC during the postlearning consolidation period as well as on structural changes in spine morphology assessed 24 hours later. These findings provide evidence that BLA noradrenergic activity enables functional interactions between the PrL and the aIC and dHPC in regulating stress hormone and emotional arousal effects on memory.


Asunto(s)
Androstanoles/farmacología , Complejo Nuclear Basolateral/metabolismo , Corteza Cerebral/metabolismo , Glucocorticoides/metabolismo , Memoria/efectos de los fármacos , Red Nerviosa/metabolismo , Receptores de Glucocorticoides/agonistas , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo
2.
Proc Natl Acad Sci U S A ; 114(34): 9176-9181, 2017 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-28790188

RESUMEN

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.


Asunto(s)
Complejo Nuclear Basolateral/efectos de los fármacos , Hipocampo/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Norepinefrina/farmacología , Agonistas alfa-Adrenérgicos/farmacología , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Moléculas de Adhesión Celular Neuronal/genética , Metilación de ADN/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Discriminación en Psicología/fisiología , Proteínas de la Matriz Extracelular/genética , Agonistas de Receptores de GABA-A/farmacología , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Memoria a Largo Plazo/fisiología , Muscimol/farmacología , Proteínas del Tejido Nervioso/genética , Norepinefrina/administración & dosificación , Ratas Sprague-Dawley , Proteína Reelina , Serina Endopeptidasas/genética , Transcriptoma/efectos de los fármacos
3.
Hippocampus ; 28(8): 586-601, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29742815

RESUMEN

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long-term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long-term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long-term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum, Lieberman, Briner, Leonardo, & Dranovsky, ), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.


Asunto(s)
Proliferación Celular/fisiología , Hipocampo/citología , Células-Madre Neurales/fisiología , Neurogénesis/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Antivirales/farmacología , Bromodesoxiuridina/metabolismo , Proliferación Celular/efectos de los fármacos , Desoxiuridina/farmacología , Proteínas de Dominio Doblecortina , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/diagnóstico por imagen , Antígeno Ki-67/metabolismo , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Asociadas a Microtúbulos/metabolismo , Nestina/genética , Nestina/metabolismo , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuropéptidos/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Caracteres Sexuales , Valganciclovir/farmacología
4.
Proc Natl Acad Sci U S A ; 111(51): 18333-8, 2014 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-25489086

RESUMEN

Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The experiments first examined whether the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are released by aversive training. Inhibitory avoidance training with higher footshock intensity produced increased levels of AEA in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) shortly after training in comparison with levels assessed in rats trained with lower footshock intensity or unshocked controls exposed only to the training apparatus. In contrast, 2-AG levels were not significantly elevated. The additional finding that posttraining infusions of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which selectively increases AEA levels at active synapses, administered into the basolateral complex of the amygdala (BLA), hippocampus, or mPFC enhanced memory strongly suggests that the endogenously released AEA modulates memory consolidation. Moreover, in support of the view that this emotional training-associated increase in endocannabinoid neurotransmission, and its effects on memory enhancement, depends on the integrity of functional interactions between these different brain regions, we found that disruption of BLA activity blocked the training-induced increases in AEA levels as well as the memory enhancement produced by URB597 administered into the hippocampus or mPFC. Thus, the findings provide evidence that emotionally arousing training increases AEA levels within prefrontal-limbic circuits and strongly suggest that this cannabinoid activation regulates emotional arousal effects on memory consolidation.


Asunto(s)
Ácidos Araquidónicos/metabolismo , Emociones , Endocannabinoides/metabolismo , Sistema Límbico/fisiología , Memoria , Alcamidas Poliinsaturadas/metabolismo , Corteza Prefrontal/fisiología , Amidohidrolasas/antagonistas & inhibidores , Animales , Reacción de Prevención , Benzamidas/farmacología , Carbamatos/farmacología , Glicéridos/metabolismo , Sistema Límbico/enzimología , Corteza Prefrontal/enzimología , Ratas , Receptor Cannabinoide CB1/agonistas
5.
Proc Natl Acad Sci U S A ; 109(9): 3504-9, 2012 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-22331883

RESUMEN

There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3-3 mg/kg) to male Sprague-Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal ß-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212-2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences.


Asunto(s)
Ácidos Araquidónicos/fisiología , Moduladores de Receptores de Cannabinoides/fisiología , Endocannabinoides , Miedo/fisiología , Glucocorticoides/fisiología , Glicéridos/fisiología , Hipocampo/fisiología , Memoria/fisiología , Receptor Cannabinoide CB1/fisiología , Estimulación Acústica , Antagonistas Adrenérgicos beta/farmacología , Animales , Nivel de Alerta/fisiología , Benzoxazinas/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Corticosterona/administración & dosificación , Corticosterona/farmacología , Electrochoque , Emociones/fisiología , Miedo/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Morfolinas/farmacología , Naftalenos/farmacología , Piperidinas/farmacología , Propranolol/farmacología , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores de Glucocorticoides/fisiología
6.
Neurobiol Learn Mem ; 112: 2-16, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24583373

RESUMEN

The amygdala has long been known to play a key role in supporting memory for emotionally arousing experiences. For example, classical fear conditioning depends on neural plasticity within this anterior medial temporal lobe region. Beneficial effects of emotional arousal on memory, however, are not restricted to simple associative learning. Our recollection of emotional experiences often includes rich representations of, e.g., spatiotemporal context, visceral states, and stimulus-response associations. Critically, such memory features are known to bear heavily on regions elsewhere in the brain. These observations led to the modulation account of amygdala function, which postulates that amygdala activation enhances memory consolidation by facilitating neural plasticity and information storage processes in its target regions. Rodent work in past decades has identified the most important brain regions and neurochemical processes involved in these modulatory actions, and neuropsychological and neuroimaging work in humans has produced a large body of convergent data. Importantly, recent methodological developments make it increasingly realistic to monitor neural interactions underlying such modulatory effects as they unfold. For instance, functional connectivity network modeling in humans has demonstrated how information exchanges between the amygdala and specific target regions occur within the context of large-scale neural network interactions. Furthermore, electrophysiological and optogenetic techniques in rodents are beginning to make it possible to quantify and even manipulate such interactions with millisecond precision. In this paper we will discuss that these developments will likely lead to an updated view of the amygdala as a critical nexus within large-scale networks supporting different aspects of memory processing for emotionally arousing experiences.


Asunto(s)
Amígdala del Cerebelo/fisiología , Emociones/fisiología , Memoria/fisiología , Red Nerviosa/fisiología , Amígdala del Cerebelo/metabolismo , Animales , Humanos
7.
Neurosci Biobehav Rev ; 142: 104849, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36116576

RESUMEN

Two-thirds of individuals experience adversity during childhood such as neglect, abuse or highly-stressful events. Early-life adversity (ELA) increases the life-long risk of developing mood and substance use disorders. Reward-related deficits has emerged as a key endophenotype of such psychiatric disorders. Animal models are invaluable for studying how ELA leads to reward deficits. However, the existing literature is heterogenous with difficult to reconcile findings. To create an overview, we conducted a systematic review containing multiple meta-analyses regarding the effects of ELA on reward processes overall and on specific aspects of reward processing in animal models. A comprehensive search identified 120 studies. Most studies omitted key details resulting in unclear risk of bias. Overall meta-analysis showed that ELA significantly reduced reward behaviors (SMD: -0.42 [-0.60; -0.24]). The magnitude of ELA effects significantly increased with longer exposure. When reward domains were analyzed separately, ELA only significantly dampened reward responsiveness (SMD: -0.525[-0.786; -0.264]) and social reward processing (SMD: -0.374 [-0.663; -0.084]), suggesting that ELA might lead to deficits in specific reward domains.


Asunto(s)
Recompensa , Estrés Psicológico , Animales , Afecto , Estrés Psicológico/psicología
8.
Clin Hemorheol Microcirc ; 41(4): 251-61, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19318718

RESUMEN

This study aimed to investigate the short and long-term effects of resistance exercise training (RET) performed at different intensities (moderate and submaximal) on red blood cell (RBC) deformability and aggregation. 14 young male subjects were divided into two groups: Moderate intensity group performed 3 sets of 12 repetitions at an intensity corresponding to 70% of one-repetition maximum (1RM) whereas submaximal intensity group performed 3 sets of 6 repetitions at 85% of 1RM for 6 weeks. Blood samples were obtained just before and immediately after the RET on the first and last day of the program. Hemorheological parameters were determined using an ektacytometer (LORCA), hematological parameters were evaluated by a hematology analyzer. RBC deformability was found to increase in both groups immediately after the RET but this elevation was significant only in the moderate intensity group on the first day. RBC aggregation significantly increased in both groups immediately after the RET on the first and last day of the program. It is concluded that RET performed at an intensity corresponding to 70% of 1RM alters RBC deformability more than training performed at 85% of 1RM. On the other hand, both training protocols affect RBC aggregation in a similar way.


Asunto(s)
Agregación Eritrocitaria , Deformación Eritrocítica , Entrenamiento de Fuerza , Adulto , Humanos , Masculino , Adulto Joven
9.
Sci Rep ; 9(1): 4120, 2019 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-30858462

RESUMEN

Early life stress predisposes to mental illness and behavioral dysfunction in adulthood, but the mechanisms underlying these persistent effects are poorly understood. Stress throughout life impairs the structure and function of the hippocampus, a brain system undergoing considerable development in early life. The long-term behavioral consequences of early life stress may therefore be due in part to interference with hippocampal development, in particular with assembly of the dentate gyrus (DG) region of the hippocampus. We investigated how early life stress produces long-term alterations in DG structure by examining DG assembly and the generation of a stable adult stem cell pool in routine housing and after stress induced by the limited bedding/nesting paradigm in mice. We found that early life stress leads to a more immature, proliferative DG than would be expected for the animal's age immediately after stress exposure, suggesting that early life stress delays DG development. Adult animals exposed to early life stress exhibited a reduction in the number of DG stem cells, but unchanged neurogenesis suggesting a depletion of the stem cell pool with compensation in the birth and survival of adult-born neurons. These results suggest a developmental mechanism by which early life stress can induce long-term changes in hippocampal function by interfering with DG assembly and ultimately diminishing the adult stem cell pool.


Asunto(s)
Giro Dentado/crecimiento & desarrollo , Células-Madre Neurales/citología , Neurogénesis , Estrés Psicológico/patología , Animales , Proliferación Celular , Giro Dentado/patología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Células-Madre Neurales/fisiología
10.
Transfus Apher Sci ; 39(2): 101-8, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18707921

RESUMEN

Platelet transfusions are increasingly being used to treat thrombocytopenic conditions. Because of anticoagulation, changes in blood composition and extracorporeal circulation, donor apheresis may cause alterations in hemorheology. This study aimed at investigating the effects of thrombocytapheresis on donor blood rheology. The effect of nitric oxide (NO) on donor red blood cell (RBC) deformability after thrombocytapheresis was also studied. Platelets were collected by a Haemonetics MCS 3p cell seperator. Blood samples were obtained before and 15 min after thrombocytapheresis. RBC deformability and aggregation were measured using an ektacytometer, whole blood viscosity (WBV) was determined with a cone-plate rotational viscometer. Donor RBCs were shown to be less deformable at all stress levels except 0.30 Pa after thrombocytapheresis and NO donor sodium nitroprusside (SNP, 10(-6) M) reversed the reduced deformability caused by thrombocytapheresis. It was observed that donor apheresis induces a decrement in RBC aggregation and WBV measured at standard hematocrit (Hct). No significant alterations were observed in WBV values determined at native Hct values. Thrombocytapheresis also resulted in a decrement in fibrinogen, total protein, cholesterol and albumin levels whereas Hct was found to be increased and serum glucose, triglyceride, hemoglobin levels unaltered after apheresis. These results suggest that, thrombocytapheresis causes alterations in hemorheological parameters and hence in the perfusion of the microvasculature of the donors and NO appears to have a protective effect on the impairment observed in RBC deformability.


Asunto(s)
Donantes de Sangre , Hemorreología , Óxido Nítrico/fisiología , Plaquetoferesis , Adulto , Anticoagulantes/farmacología , Glucemia/análisis , Proteínas Sanguíneas/análisis , Viscosidad Sanguínea , Colesterol/sangre , Agregación Eritrocitaria , Deformación Eritrocítica/efectos de los fármacos , Fibrinógeno/análisis , Hematócrito , Humanos , Masculino , Microcirculación , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/uso terapéutico , Nitroprusiato/farmacología , Nitroprusiato/uso terapéutico , Albúmina Sérica/análisis , Triglicéridos/sangre
11.
Psychoneuroendocrinology ; 91: 41-49, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29524763

RESUMEN

Early-life stress (ELS) creates life-long vulnerability to stress-related anxiety disorders through altering stress and fear systems in the brain. The endocannabinoid system has emerged as an important regulator of the stress response through a crosstalk with the glucocorticoid system, yet whether it plays a role in the persistent effects of ELS remains unanswered. By combining, behavioral, pharmacological and biochemical approaches in adult male rats, we examined the impact of ELS on the regulation of endocannabinoid function by stress and glucocorticoids. We employed a postnatal limited-nesting/bedding induced ELS between postnatal days 2-9 in rats. Exposure to postnatal ELS compromised the ability of both acute stress and glucocorticoid administration to mobilize the endocannabinoid ligand 2-arachidonoyl glycerol (2-AG) in the hippocampus of adult male rats. These findings suggest that ELS compromises the coupling of the glucocorticoid and endocannabinoid systems in the hippocampus. Since 2-AG signaling is essential in mediating glucocorticoid-induced suppression of fear recall, we further examined the impact of ELS on the ability of glucocorticoids to suppress fear memory recall. While ELS did not affect normative fear recall, it impaired the ability of glucocorticoids to dampen fear recall. Notably, bypassing glucocorticoids and directly amplifying hippocampal 2-AG signaling with a monoacyl glycerol lipase inhibitor produced a suppression of fear memory recall in animals exposed to ELS. These findings suggest that ELS results in an uncoupling of glucocorticoid-endocannabinoid signaling in the hippocampus, which, in turn, relates to alterations in stress regulation of memory recall. These data provide compelling evidence that ELS-induced deficits in the glucocorticoid-endocannabinoid coupling following stress could predispose susceptibility to stress-related psychopathology.


Asunto(s)
Endocannabinoides/fisiología , Miedo/efectos de los fármacos , Miedo/fisiología , Animales , Ansiedad/fisiopatología , Trastornos de Ansiedad , Ácidos Araquidónicos/farmacología , Corticosterona/farmacología , Endocannabinoides/metabolismo , Endocannabinoides/farmacología , Glucocorticoides/metabolismo , Glucocorticoides/fisiología , Glicéridos/farmacología , Hipocampo/metabolismo , Sistema Límbico/fisiología , Masculino , Memoria/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Glucocorticoides/metabolismo , Estrés Psicológico/fisiopatología
12.
Neuropsychopharmacology ; 43(6): 1276-1283, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29090682

RESUMEN

Historically, preclinical stress studies have often omitted female subjects, despite evidence that women have higher rates of anxiety and depression. In rodents, many stress susceptibility and resilience studies have focused on males as one commonly used paradigm-chronic social defeat stress-has proven challenging to implement in females. We report a new version of the social defeat paradigm that works in female mice. By applying male odorants to females to increase resident male aggressive behavior, we find that female mice undergo repeated social defeat stress and develop social avoidance, decreased sucrose preference, and decreased time in the open arms of the elevated plus maze relative to control mice. Moreover, a subset of the female mice in this paradigm display resilience, maintaining control levels of social exploration and sucrose preference. This method produces comparable results to those obtained in male mice and will greatly facilitate studying female stress susceptibility.


Asunto(s)
Modelos Animales de Enfermedad , Dominación-Subordinación , Estrés Psicológico , Animales , Reacción de Prevención , Enfermedad Crónica , Sacarosa en la Dieta , Conducta Exploratoria , Conducta Alimentaria , Femenino , Masculino , Ratones Endogámicos C57BL , Odorantes , Resiliencia Psicológica
13.
Psychoneuroendocrinology ; 67: 207-15, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26923851

RESUMEN

Acute stress and elevated glucocorticoid hormone levels are well known to impair the retrieval of hippocampus-dependent 'declarative' memory. Recent findings suggest that stress might also impair the retrieval of non-hippocampal memories. In particular, stress shortly before retention testing was shown to impair the retrieval of striatal stimulus-response associations in humans. However, the mechanism underlying this stress-induced retrieval impairment of non-hippocampal stimulus-response memory remains elusive. In the present study, we investigated whether an acute elevation in glucocorticoid levels mediates the impairing effects of stress on retrieval of stimulus-response memory. Male Sprague-Dawley rats were trained on a stimulus-response task in an eight-arm radial maze until they learned to associate a stimulus, i.e., cue, with a food reward in one of the arms. Twenty-four hours after successful acquisition, they received a systemic injection of vehicle, corticosterone (1mg/kg), the corticosterone-synthesis inhibitor metyrapone (35mg/kg) or were left untreated 1h before retention testing. We found that the corticosterone injection impaired the retrieval of stimulus-response memory. We further found that the systemic injection procedure per se was stressful as the vehicle administration also increased plasma corticosterone levels and impaired the retrieval of stimulus-response memory. However, memory retrieval was not impaired when rats were tested 2min after the systemic vehicle injection, before any stress-induced elevation in corticosterone levels had occurred. Moreover, metyrapone treatment blocked the effect of injection stress on both plasma corticosterone levels and memory retrieval impairment, indicating that the endogenous corticosterone response mediates the stress-induced memory retrieval impairment. None of the treatments affected rats' locomotor activity or motivation to search for the food reward within the maze. These findings show that stress may affect memory processes beyond the hippocampus and that these stress effects are due to the action of glucocorticoids.


Asunto(s)
Corticosterona/sangre , Inyecciones/psicología , Recuerdo Mental/efectos de los fármacos , Metirapona/farmacología , Estrés Psicológico/sangre , Estrés Psicológico/psicología , Animales , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Motivación/efectos de los fármacos , Ratas
14.
Neuropsychopharmacology ; 40(6): 1485-94, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25547713

RESUMEN

Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.


Asunto(s)
Complejo Nuclear Basolateral/fisiología , Endocannabinoides/metabolismo , Glucocorticoides/metabolismo , Consolidación de la Memoria/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Complejo Nuclear Basolateral/efectos de los fármacos , Catéteres de Permanencia , Hormona Liberadora de Corticotropina/metabolismo , Electrochoque , Inmunohistoquímica , Masculino , Consolidación de la Memoria/efectos de los fármacos , Plasticidad Neuronal/fisiología , Norepinefrina/metabolismo , Ratas Sprague-Dawley
15.
Neuropsychopharmacology ; 40(8): 1979-89, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25669604

RESUMEN

Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory.


Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Recuerdo Mental/efectos de los fármacos , Reconocimiento en Psicología/efectos de los fármacos , Estrés Psicológico/complicaciones , Hormona Adrenocorticotrópica/sangre , Animales , Arginina Vasopresina/farmacocinética , Corticosterona/sangre , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Humanos , Masculino , Piperazinas/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de Oxitocina/metabolismo , Receptores de Vasopresinas/metabolismo , Sulfonamidas/farmacología , Factores de Tiempo , Tritio/farmacocinética
16.
PLoS One ; 8(5): e62741, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23667516

RESUMEN

BACKGROUND: Endocannabinoids (ECs) and related N-acyl-ethanolamides (NAEs) play important roles in stress response regulation, anxiety and traumatic memories. In view of the evidence that circulating EC levels are elevated under acute mild stressful conditions in humans, we hypothesized that individuals with traumatic stress exposure and post-traumatic stress disorder (PTSD), an anxiety disorder characterized by the inappropriate persistence and uncontrolled retrieval of traumatic memories, show measurable alterations in plasma EC and NAE concentrations. METHODS: We determined plasma concentrations of the ECs anandamide (ANA) and 2-arachidonoylglycerol (2-AG) and the NAEs palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA) by HPLC-MS-MS in patients with PTSD (n = 10), trauma-exposed individuals without evidence of PTSD (n = 9) and in healthy control subjects (n = 29). PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events. RESULTS: Individuals with PTSD showed significantly higher plasma concentrations of ANA (0.48 ± 0.11 vs. 0.36 ± 0.14 ng/ml, p = 0.01), 2-AG (8.93 ± 3.20 vs. 6.26±2.10 ng/ml, p<0.01), OEA (5.90 ± 2.10 vs. 3.88 ± 1.85 ng/ml, p<0.01), SEA (2.70 ± 3.37 vs. 0.83 ± 0.47, ng/ml, p<0.05) and significantly lower plasma levels of OLDA (0.12 ± 0.05 vs. 0.45 ± 0.59 ng/ml, p<0.05) than healthy controls. Moreover, PTSD patients had higher 2-AG plasma levels (8.93 ± 3.20 vs. 6.01 ± 1.32 ng/ml, p = 0.03) and also higher plasma concentrations of PEA (4.06 ± 1.87 vs. 2.63±1.34 ng/ml, p<0.05) than trauma-exposed individuals without evidence of PTSD. CAPS scores in trauma-exposed individuals with and without PTSD (n = 19) correlated positively with PEA (r = 0.55, p = 0.02) and negatively with OLDA plasma levels (r = -0.68, p<0.01). CAPS subscores for intrusions (r = -0.65, p<0.01), avoidance (r = -0.60, p<0.01) and hyperarousal (r = -0.66, p<0.01) were all negatively related to OLDA plasma concentrations. CONCLUSIONS: PTSD appears to be associated with changes in plasma EC/NAE concentrations. This may have pathophysiological and diagnostic consequences but will need to be reproduced in larger cohorts.


Asunto(s)
Amidas/sangre , Amidas/química , Endocannabinoides/sangre , Trastornos por Estrés Postraumático/sangre , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Hidrocortisona/sangre , Masculino , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/psicología , Estrés Psicológico/sangre , Tortura , Guerra
17.
J Vis Exp ; (59): e3528, 2012 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-22314779

RESUMEN

Stereotaxic surgery for the implantation of cannulae into specific brain regions has for many decades been a very successful experimental technique to investigate the effects of locally manipulated neurotransmitter and signaling pathways in awake, behaving animals. Moreover, the stereotaxic implantation of electrodes for electrophysiological stimulation and recording studies has been instrumental to our current understanding of neuroplasticity and brain networks in behaving animals. Ever-increasing knowledge about optimizing surgical techniques in rodents(1-4), public awareness concerning animal welfare issues and stringent legislation (e.g., the 2010 European Union Directive on the use of laboratory animals(5)) prompted us to refine these surgical procedures, particularly with respect to implementing new procedures for oxygen supplementation and the continuous monitoring of blood oxygenation and heart rate levels during the surgery as well as introducing a standardized protocol for post-surgical care. Our observations indicate that these modifications resulted in an increased survival rate and an improvement in the general condition of the animals after surgery (e.g. less weight loss and a more active animal). This video presentation will show the general procedures involved in this type of stereotaxic surgery with special attention to our several modifications. We will illustrate these surgical procedures in rats, but it is also possible to perform this type of surgery in mice or other small laboratory animals by using special adaptors for the stereotaxic apparatus(6).


Asunto(s)
Bienestar del Animal/ética , Investigación Conductal/métodos , Encéfalo/cirugía , Neurociencias/métodos , Técnicas Estereotáxicas/ética , Técnicas Estereotáxicas/veterinaria , Animales , Investigación Conductal/ética , Encéfalo/fisiología , Ratones , Neurociencias/ética , Ratas , Resultado del Tratamiento
18.
PLoS One ; 6(7): e21855, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21765921

RESUMEN

The study of the neural basis of emotional empathy has received a surge of interest in recent years but mostly employing human neuroimaging. A simpler animal model would pave the way for systematic single cell recordings and invasive manipulations of the brain regions implicated in empathy. Recent evidence has been put forward for the existence of empathy in rodents. In this study, we describe a potential model of empathy in female rats, in which we studied interactions between two rats: a witness observes a demonstrator experiencing a series of footshocks. By comparing the reaction of witnesses with or without previous footshock experience, we examine the role of prior experience as a modulator of empathy. We show that witnesses having previously experienced footshocks, but not naïve ones, display vicarious freezing behavior upon witnessing a cage-mate experiencing footshocks. Strikingly, the demonstrator's behavior was in turn modulated by the behavior of the witness: demonstrators froze more following footshocks if their witness froze more. Previous experiments have shown that rats emit ultrasonic vocalizations (USVs) when receiving footshocks. Thus, the role of USV in triggering vicarious freezing in our paradigm is examined. We found that experienced witness-demonstrator pairs emitted more USVs than naïve witness-demonstrator pairs, but the number of USVs was correlated with freezing in demonstrators, not in witnesses. Furthermore, playing back the USVs, recorded from witness-demonstrator pairs during the empathy test, did not induce vicarious freezing behavior in experienced witnesses. Thus, our findings confirm that vicarious freezing can be triggered in rats, and moreover it can be modulated by prior experience. Additionally, our result suggests that vicarious freezing is not triggered by USVs per se and it influences back onto the behavior of the demonstrator that had elicited the vicarious freezing in witnesses, introducing a paradigm to study empathy as a social loop.


Asunto(s)
Empatía/fisiología , Congelación , Modelos Psicológicos , Animales , Conducta Animal/fisiología , Miedo , Femenino , Humanos , Ratas , Ratas Long-Evans , Conducta Social , Espectrografía del Sonido
19.
Int J Neurosci ; 117(7): 971-83, 2007 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-17613108

RESUMEN

Animal tissues are exposed to sulfite used as a preservative in food and drugs, and generated from the catabolism of sulfur-containing amino acids. Sulfite, which is a very reactive and potentially toxic molecule, is detoxified by the enzyme sulfite oxidase (SOX). Laboratory animals can be made deficient in SOX by the administration of a high-tungsten/low molybdenum regimen. It has been suggested that SOX deficient rats might be used as a model for the prediction of sulfite toxicity in humans. The aim of this study was to investigate the effects of ingested sulfite on hippocampus superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities in SOX competent and deficient rats. Hippocampus SOD, CAT and GPx activities were found to be significantly increased by sulfite treatment in SOX competent groups. On the other hand, exposure to sulfite had no effect on antioxidant status in hippocampus of SOX deficient rats. In conclusion, these results suggest that hippocampus antioxidant capacity where defense mechanism against the oxidative challenge is up regulated by sulfite in SOX competent rats. This up regulation mechanism in antioxidant enzymes against to sulfite related oxidative stress is not observed in SOX deficient rats and remains to be explained.


Asunto(s)
Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Hipocampo/enzimología , Sulfito-Oxidasa/metabolismo , Sulfitos/toxicidad , Superóxido Dismutasa/metabolismo , Administración Oral , Animales , Antioxidantes/metabolismo , Catalasa/efectos de los fármacos , Activación Enzimática , Conservantes de Alimentos/toxicidad , Glutatión Peroxidasa/efectos de los fármacos , Hipocampo/efectos de los fármacos , Masculino , Ratas , Sulfito-Oxidasa/deficiencia , Sulfitos/administración & dosificación , Superóxido Dismutasa/efectos de los fármacos , Regulación hacia Arriba
20.
Arch Toxicol ; 81(1): 11-7, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-16721596

RESUMEN

Aluminum (Al) is a nonessential element and humans are constantly exposed to Al as a result of an increase in industrialization and improving technology practices. Al toxicity can induce several clinical disorders such as neurotoxicity, gastrointestinal toxicity, hepatotoxicity, bone diseases, and anemia. This study aimed at evaluating the possible effects of short term and low dose Al exposure on hemorheological and hematological parameters in rats. Fourteen young, male Wistar albino rats were divided into two groups: 1 mg/200 g body weight of aluminum sulfate (Al(2)(SO(4))(3) was injected intraperitoneally to the first group for two weeks, three times a week. The animals of the control group received only physiological saline solution during this period. At the end of the experimental period, anticoagulated blood samples were collected and hematological parameters were determined using an electronic hematology analyzer. Red blood cell (RBC) deformability and aggregation were measured using an ektacytometer (LORCA) and plasma and whole blood viscosities were determined with a Wells-Brookfield cone-plate rotational viscometer. Significant decreases in mean corpuscular volume (MCV), red blood cell (RBC) deformability at low shear stress levels, the aggregation half time (t1/2) and the amplitude (AMP) of aggregation and significant increments in whole blood viscosity (WBV) at native and 40% hematocrit (Hct) of Al-treated rats have been observed. In conclusion, low dose Al(2)(SO(4))(3) exposure for a short-time may be responsible for alterations in either rheological properties of blood or hemorheological properties through a remarkable effect on RBC membrane mechanical properties . These alterations may also play an important role in the development of anemia in the Al-treated animals.


Asunto(s)
Compuestos de Alumbre/toxicidad , Viscosidad Sanguínea/efectos de los fármacos , Agregación Eritrocitaria/efectos de los fármacos , Deformación Eritrocítica/efectos de los fármacos , Compuestos de Alumbre/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Índices de Eritrocitos/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Hematócrito , Hematología/métodos , Hemoglobinometría/métodos , Hemorreología/métodos , Inyecciones Intraperitoneales , Masculino , Ratas , Ratas Wistar
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