Distinct patterns of brain Fos expression in Carioca High- and Low-conditioned Freezing Rats.

BACKGROUND: The bidirectional selection of high and low anxiety-like behavior is a valuable tool for understanding the neurocircuits that are responsible for anxiety disorders. Our group developed two breeding lines of rats, known as Carioca High- and Low-conditioned Freezing (CHF and CLF), based on defensive freezing in the contextual fear conditioning paradigm. A random selected line was employed as a control (CTL) comparison group for both CHF and CLF lines of animals. The present study performed Fos immunochemistry to investigate changes in neural activity in different brain structures among CHF and CLF rats when they were exposed to contextual cues that were previously associated with footshock. RESULTS: The study indicated that CHF rats expressed high Fos expression in the locus coeruleus, periventricular nucleus of the hypothalamus (PVN), and lateral portion of the septal area and low Fos expression in the medial portion of the septal area, dentate gyrus, and prelimbic cortex (PL) compared to CTL animals. CLF rats exhibited a decrease in Fos expression in the PVN, PL, and basolateral nucleus of the amygdala and increase in the cingulate and perirhinal cortices compared to CTL animals. CONCLUSIONS: Both CHF and CLF rats displayed Fos expression changes key regions of the anxiety brain circuitry. The two bidirectional lines exhibit different pattern of neural activation and inhibition with opposing influences on the PVN, the main structure involved in regulating the hypothalamic-pituitary-adrenal neuroendocrine responses observed in anxiety disorders.

Synaptic plasticity in Alzheimer's disease and healthy aging.

The strength and efficiency of synaptic connections are affected by the environment or the experience of the individual. This property, called synaptic plasticity, is directly related to memory and learning processes and has been modeled at the cellular level. These types of cellular memory and learning models include specific stimulation protocols that generate a long-term strengthening of the synapses, called long-term potentiation, or a weakening of the said long-term synapses, called long-term depression. Although, for decades, researchers have believed that the main cause of the cognitive deficit that characterizes Alzheimer's disease (AD) and aging was the loss of neurons, the hypothesis of an imbalance in the cellular and molecular mechanisms of synaptic plasticity underlying this deficit is currently widely accepted. An understanding of the molecular and cellular changes underlying the process of synaptic plasticity during the development of AD and aging will direct future studies to specific targets, resulting in the development of much more efficient and specific therapeutic strategies. In this review, we classify, discuss, and describe the main findings related to changes in the neurophysiological mechanisms of synaptic plasticity in excitatory synapses underlying AD and aging. In addition, we suggest possible mechanisms in which aging can become a high-risk factor for the development of AD and how its development could be prevented or slowed.

Neuro-«lo que sea¼: inicio y auge de una pseudociencia para el siglo XXI / Neuro-"whatever": Beginnings of a new pseudoscience for the XXI century

El paso del estado sésil al movimiento activo, requirió del desarrollo de un sistema nervioso capaz de coordinar el movimiento hacia fuentes de alimentación y el escape de posibles amenazas. En respuesta a los cambios en los ambientes macro- y micro-, los sistemas nerviosos fueron integrando habilidades cada vez mejores culminando en el «ensayo mental¼ (León & Cárdenas, 2011): el animal podía «imaginar¼ las consecuencias de algunas de sus acciones (causas y efectos), sin requerir ejecutarlas: la diferencia entre la vida y la muerte. Ya en los albores de la humanidad, esa necesidad imperiosa de buscar causas -ahora en una esfera plenamente mental- se plasmó en la creación de conceptualizaciones animistas de la naturaleza y por ello las primeras manifestaciones culturales fueron las explicaciones del universo en términos de mitos, leyendas, cuentos e historias transmitidas generacionalmente. El desarrollo de las tecnologías que fortalecían la unión cultural y las alianzas entre clanes, impulsó el desarrollo del conocimiento científico que mejoraba la tecnología y satisfacía más profundamente la sed de explicación del mundo. Fue la primera gran escisión entre ciencia y tecnología. Para el común, el impacto de la tecnología sobre la vida diaria es mucho más evidente que el de la ciencia, visión inmediatista que aún hoy rige, lastimosamente, a muchos organismos de gestión de la ciencia y la tecnología en muchos países. La separación ciencia (comprensible por pocos) / tecnología (usable por todos) hizo que paulatinamente se fuera desconociendo el real valor de la ciencia y permitió que muchas formas de conocimiento no científico, mucho más fácil de comprender y de transmitir -las «pseudociencias¼ (pseudo = que quiere ser, pero no es)- fueran instaurándose. Este conocimiento es «comprobado¼ por casos únicos que alguna vez sucedieron o que alguien reporto que vio o escucho (sin importar la veracidad del reporte). Ritos, mitos, magia, leyendas, alquimia y otras muchas ideas surgieron de esa forma.

Behavioral Effects of Systemic, Infralimbic and Prelimbic Injections of a Serotonin 5-HT2A Antagonist in Carioca High- and Low-Conditioned Freezing Rats.

The role of serotonin (5-hydroxytryptamine [5-HT]) and 5-HT2A receptors in anxiety has been extensively studied, mostly without considering individual differences in trait anxiety. Our laboratory developed two lines of animals that are bred for high and low freezing responses to contextual cues that are previously associated with footshock (Carioca High-conditioned Freezing [CHF] and Carioca Low-conditioned Freezing [CLF]). The present study investigated whether ketanserin, a preferential 5-HT2A receptor blocker, exerts distinct anxiety-like profiles in these two lines of animals. In the first experiment, the animals received a systemic injection of ketanserin and were exposed to the elevated plus maze (EPM). In the second experiment, these two lines of animals received microinjections of ketanserin in the infralimbic (IL) and prelimbic (PL) cortices and were exposed to either the EPM or a contextual fear conditioning paradigm. The two rat lines exhibited bidirectional effects on anxiety-like behavior in the EPM and opposite responses to ketanserin. Both systemic and intra-IL cortex injections of ketanserin exerted anxiolytic-like effects in CHF rats but anxiogenic-like effects in CLF rats. Microinjections of ketanserin in the PL cortex also exerted anxiolytic-like effects in CHF rats but had no effect in CLF rats. These results suggest that the behavioral effects of 5-HT2A receptor antagonism might depend on genetic variability associated with baseline reactions to threatening situations and 5-HT2A receptor expression in the IL and PL cortices. Highlights -CHF and CLF rats are two bidirectional lines that are based on contextual fear conditioning.-CHF rats have a more "anxious" phenotype than CLF rats in the EPM.-The 5-HT2A receptor antagonist ketanserin had opposite behavioral effects in CHF and CLF rats.-Systemic and IL injections either decreased (CHF) or increased (CLF) anxiety-like behavior.-PL injections either decreased (CHF) anxiety-like behavior or had no effect (CLF).

Running wheel training does not change neurogenesis levels or alter working memory tasks in adult rats.

BACKGROUND: Exercise can change cellular structure and connectivity (neurogenesis or synaptogenesis), causing alterations in both behavior and working memory. The aim of this study was to evaluate the effect of exercise on working memory and hippocampal neurogenesis in adult male Wistar rats using a T-maze test. METHODS: An experimental design with two groups was developed: the experimental group (n = 12) was subject to a forced exercise program for five days, whereas the control group (n = 9) stayed in the home cage. Six to eight weeks after training, the rats' working memory was evaluated in a T-maze test and four choice days were analyzed, taking into account alternation as a working memory indicator. Hippocampal neurogenesis was evaluated by means of immunohistochemistry of BrdU positive cells. RESULTS: No differences between groups were found in the behavioral variables (alternation, preference index, time of response, time of trial or feeding), or in the levels of BrdU positive cells. DISCUSSION: Results suggest that although exercise may have effects on brain structure, a construct such as working memory may require more complex changes in networks or connections to demonstrate a change at behavioral level.

Effect of Overcrowding on Hair Corticosterone Concentrations in Juvenile Male Wistar Rats.

In many species, chronic stress due to overcrowding during the juvenile period triggers several metabolic and behavioral pathologies in adulthood. The aim of this study was to determine whether a chronic stress condition (overcrowding) induces changes in plasma and hair corticosterone concentrations, overall growth, and organ weights in young Wistar rats. The experimental subjects were divided into 2 groups (control and overcrowded); the overcrowded subjects were exposed to overcrowding during days 38 through 65 after birth. Plasma and hair corticosterone concentrations were higher in overcrowded rats compared with control subjects. In addition, overcrowding reduced body and organ weight gains. These results demonstrate that measuring the concentration of corticosterone in hair samples is an effective, noninvasive method for monitoring chronic stress in rats.

Contribution of the parafascicular nucleus in the spontaneous object recognition task.

The parafascicular (PF) nucleus, a posterior component of the intralaminar nuclei of the thalamus, is considered to be an essential structure in the feedback systems of basal ganglia-thalamo-cortical circuits critically involved in cognitive processes. The specific role played by multimodal information encoded in PF neurons in learning and memory processes is still unclear. We conducted two experiments to investigate the role of the PF in the spontaneous object recognition (SOR) task. The behavioral effects of pretraining rats with bilateral lesions of PF with N-methyl-D-aspartate (NMDA) were compared to vehicle controls. In the first experiment, rats were tested on their ability to remember the association immediately after training trials and in the second experiment after a 24h delay. Our findings provide evidence that PF lesions critically affect both SOR tests and support its role in that non-spatial form of relational memory.

The effects of pentylenetetrazol, chlordiazepoxide and caffeine in rats tested in the elevated plus-maze depend on the experimental illumination.

The so-called anxiolytic and anxiogenic drugs are considered to cause, respectively, increases and decreases in plus-maze open arm exploration, without modifying locomotor activity occurring in the closed arms in an elevated plus-maze when the animals are tested in an illuminated environment. Simply testing animals in the dark also increases open arm exploration, which may be interpreted as an anxiolytic effect. We investigated the effects of two GABAergic drugs, pentylenetetrazol (10 and 20 mg/kg) and chlordiazepoxide (1.5 and 3 mg/kg), and one non-GABAergic drug, caffeine (10 and 30 mg/kg) on anxiety levels of rats tested in the elevated plus-maze under two illumination conditions, light or dark. All animals explored more the open arms in the dark. In the light, pentylenetetrazol decreased open arm exploration while chlordiazepoxide had the opposite effect. Neither pentylenetetrazol nor chlordiazepoxide had any effect in the dark. Caffeine, increased open arms exploration in both illumination conditions. These results indicate that light triggers aversion, a response mediated by GABA since the GABAergic drugs, but not caffeine, were ineffective when the rats were tested in the dark.

Efecto de la aplicación aguda de fluoxetina sobre una tarea de miedo condicionado al contexto en ratas sometidas a restricción comportamental / Effect of acute Fluoxetine application on a context fear conditioned task in behaviorally restrained rats Laura A

Para estudiar el efecto del aumento comportamental o farmacológico de la ansiedad sobre la adquisición del miedo condicionado al contexto, 32 ratas Wistar (275±25 gm) divididas en dos grupos (restricción comportamental y control) recibieron fluoxetina (ig, 4 mg/kg; 1ml) o solución salina (ig, 0.9%). Luego fueron entrenadas en una tarea de miedo condicionado al contexto. El ANOVA de dos vías mostró diferencias significativas para el factor tratamiento (F[1,28] = 25.261; P < 0.001). Los sujetos tratados con fluoxetina presentaron menor tiempo de congelamiento (Student Newman-Keuls; P < 0.05). No hubo diferencias significativas para la restricción, ni para la interacción entre factores (F[1,28] = 0.115; P = 0.737 y F[1,28] = 0.016; P = 0.899). Así, la restricción no alteró la adquisición del miedo condicionado indicando que el aumento de liberación de 5-HT así inducido, no es comparable al inducido por fluoxetina. La fluoxetina deterioró la adquisición de la respuesta de miedo, indicando que el mecanismo por el cual la ansiedad interrumpe el aprendizaje puede ser serotoninérgico...

In order to study the effect of behavioral or pharmacologically enhanced anxiety on the acquisition of contextual fear conditioning, thirty two Wistar rats (275±25 gm) were divided in two groups (behavioral restriction and control). Half of each group received saline solution (ig.; 0.9%) or fluoxetine (ig.; 4mg/Kg) before the fear conditioning procedure. The two way ANOVA showed significant differences for treatment (F[1,28] = 25.261; P < 0.001). Student Newman-Keuls showed that subjects treated with fluoxetine had lower freezing times. There were no significant differences nor for restriction neither for the interaction between the factors (F[1,28] = 0.115; P = 0.737 y F[1,28] = 0.016; P = 0.899). Thus, the restriction procedure used did not modify the acquisition of the conditioned fear response suggesting that the putative 5-HT enhancement induced is not comparable to that induced by fluoxetine. Acute fluoxetine disrupted the acquisition of the conditioned fear response, suggesting that the mechanism by means of which anxiety disrupts learning could be serotonergic in nature...

Efectos de la aplicación intrahipocampal del péptido BLMP-101 sobre una tarea de memoria espacial en ratas Wistar / Effects of intrahypocampal administration of the BLMP-101 peptide on a spatial memory task in Wistar rats

El péptido BLMP-101 posee potencial para el tratamiento de deficiencias de la memoria. Esta investigación tuvo como objetivo corroborar los resultados obtenidos en investigaciones anteriores con respecto a la evaluación del péptido BLMP-101, en cuanto a la efectividad del péptido diseñado por el grupo de Bioquímica Computacional y estructural de la Pontificia Universidad Javeriana. Sin embargo, y a diferencia de las investigaciones anteriores, el objetivo del presente estudio consistió en medir la efectividad del BLMP-101, en dosis diferentes y haciendo la aplicación intrahipocampal del péptido, para corroborar sus efectos en la facilitación de la memoria espacial. Se utilizaron 31 ratas Wistar divididas en cuatro grupos, tres experimentales y uno de comparación. El grupo de comparación, fue inyectado con solución salina y a uno de los grupos experimentales se le administró NMDA y, a los otros dos, dosis diferentes del péptido BLMP-101 (0.3, 3.0 ug/ul). Los resultados sugieren que el péptido BLMP-101 con dosis de 3.0 ug/ul, facilitan la memoria espacial, mejor que el NMDA.

The BLMP-101 peptide has the potential features to treat memory deficiency. The herein research aimed at corroborating the results obtained in previous researches and tests conducted on the effectiveness of the peptide BLMP-101 designed by the Computational and Structural Biochemestry Unit of the Pontificia Universidad Javeriana, Colombia. However, and unlike previous researches, the objective of this paper measured the effectiveness of the BLMP-101peptide, when supplied in different dozes and through intrahipocampal application to confirm its effects to facilitate spatial memory. 31 Wistar rats were used into 4 different groups: three treatment groups and one control group. The control group was infused with saline solution, and one of the treatment groups was infused with NMDA, while the other two experimental groups were infused with different dozes of the BLMP-101peptide (0.3, 3.0 ug/ul). Results suggest that the BLMP-101 peptide, when supplied in 3.0 ug/ul, facilitates spatial memory showing better results than the NMDA.

Effects of chronic intracerebroventricular 3,4-methylenedioxy-N-methamphetamine (MDMA) or fluoxetine on the active avoidance test in rats with or without exposure to mild chronic stress.

In despite the similarity of mechanisms of action between both selective serotonin reuptake inhibitors (SSRI) and MDMA (main compound of "Ecstasy") there are relatively few reports on the effects of the later on animal models of depression. There are many animal models designed to create or to assess depression. Mild chronic stress (MCS) is a procedure designed to create depression. MCS includes the chronic exposure of the animal to several stressors. After that, rats show behavioural changes associated to depression. In the other hand, the active avoidance task (AAT) is an experimental situation in which an animal has to accomplish a particular behaviour in order to avoid the application of a stressor. Animals exhibiting depression fail to acquire avoidance responses as rapidly as normal animals do. In order to assess the effect of MDMA on the acquisition of an active avoidance response, forty-five rats were divided in two groups exposed or not exposed to MCS. Rats also received chronic intracerebroventricular MDMA (0.2microg/microl; 1microl), fluoxetine (2.0microg/microl; 1microl) or saline solution (0.9%; 1microl). Our results showed that the effect of MDMA depends upon the level of stress. MDMA treated animals showed better acquisition (F([2,37])=7.046; P=0.003) and retention (F([2,37])=3.900; P=0.029) of the avoidance response than fluoxetine or saline treated animals when exposed to MCS. This finding suggests that MDMA (and no fluoxetine) was able to change the aversive valence of the stressors maybe enhancing coping strategies. This effect could serve as a protective factor against helplessness and maybe post-traumatic stress.

Redundancia de la información visual en el condicionamiento aversivo: papel del colículo superior / Redundancy of visual information in aversive conditioning: role of the superior colliculus

Una característica de casi todos los sistemas biológicos es el procesamiento en paralelo o distribuido,el cual otorga al sistema una redundancia funcional que garantiza la permanencia de procesosincluso en ausencia de porciones del sistema. En el sistema visual existen tres vías que simultáneamentese encargan de varios aspectos de la percepción. El procesamiento realizado por la ramacolicular de este sistema está muy relacionado con los sistemas de valoración emocional límbicos,gracias a la vía colículo superior —núcleo suprageniculado— amígdala. En el presente trabajo seevaluó el efecto de la inactivación del colículo superior en la formación de un condicionamientoaversivo visual. Para esto ratas Wistar recibieron una microinyección intracolicular de lidocaína (1%)durante la adquisición del condicionamiento. Los resultados obtenidos mostraron claramente que elcolículo superior no es una estructura indispensable para la formación de tal condicionamiento, loque sugiere que otros sistemas de relevo subcortical deben estar implicados. A partir de ello esposible hipotetizar nuevas formas de aproximación al estudio de las características de redundanciafuncional en el sistema visual.

A relevant feature of biological systems is the distributed processing. This kind of informationprocessing ensures a functional redundancy that allows a functional level even in the absence ofsome regions of the system. In the case of visual system, the parallel processing relies on threesimultaneous pathways, each one of them carrying out certain aspects of visual information processing.The collicular branch of this parallel system is related to emotional aspects. This pathway transmitsinformation from the superior colliculus to the amygdala, via the suprageniculate nucleus. Here wetest the effect of the transient inhibition of the superior colliculus on the acquisition of a classicalaversive conditioning. Wistar rats received an intracollicular microinjection of lidocaine (1%)immediately before the training session. Our results clearly show that the superior colliculus is notthe main structure involved in the acquisition of this kind of associative learning suggesting thecontribution of other subcortical structures.

Contribution of the dopaminergic system to the effect of chronic fluoxetine in the rat forced swim test

Chronic administration of selective serotonin reuptake inhibitors (SSRI) enhances dopaminergic activity. However, the role of enhanced dopaminergic transmission in the therapeutic effects of this kind of antidepressants is still unclear. Drugs producing dopaminergic activation lead to an increment in general activity. Thus, it is reasonable to assume that some of the therapeutic effects of SSRIs are due to dopaminergic enhanced functionality. The forced swim test (FST) is a widely used test in the screening of new compounds with potential antidepressant activity. In this study the effects of pretreatment with low doses of the DA release inductor cocaine and the D2, D3 and D4 antagonist haloperidol were analyzed in the FST on rats submitted to chronic intragastric administration of the SSRI fluoxetine. Our results show that animals treated with fluoxetine and pre-treated with cocaine had significantly higher latencies than saline or haloperidol pre-treated subjects. Among both fluoxetine and saline treated animals, those pre-treated with cocaine had significant lesser immobility time. Haloperidol pre-treated animals had significantly higher immobility time than those pre-treated with saline. From these results, it is clear that the pharmacological modification of dopaminergic systems leads to behavioral changes in rats treated with both saline and fluoxetine. The FST does not have enough precision as to distinguish between dopaminergic and nondopaminergic components in the antidepressant effects of SSRIs, for this reason the use of the FST in combination to other models is mandatory.

Contribution of the dopaminergic system to the effect of chronic fluoxetine in the rat forced swim test

Chronic administration of selective serotonin reuptake inhibitors (SSRI) enhances dopaminergic activity. However, the role of enhanced dopaminergic transmission in the therapeutic effects of this kind of antidepressants is still unclear. Drugs producing dopaminergic activation lead to an increment in general activity. Thus, it is reasonable to assume that some of the therapeutic effects of SSRIs are due to dopaminergic enhanced functionality. The forced swim test (FST) is a widely used test in the screening of new compounds with potential antidepressant activity. In this study the effects of pretreatment with low doses of the DA release inductor cocaine and the D2, D3 and D4 antagonist haloperidol were analyzed in the FST on rats submitted to chronic intragastric administration of the SSRI fluoxetine. Our results show that animals treated with fluoxetine and pre-treated with cocaine had significantly higher latencies than saline or haloperidol pre-treated subjects. Among both fluoxetine and saline treated animals, those pre-treated with cocaine had significant lesser immobility time. Haloperidol pre-treated animals had significantly higher immobility time than those pre-treated with saline. From these results, it is clear that the pharmacological modification of dopaminergic systems leads to behavioral changes in rats treated with both saline and fluoxetine. The FST does not have enough precision as to distinguish between dopaminergic and nondopaminergic components in the antidepressant effects of SSRIs, for this reason the use of the FST in combination to other models is mandatory.(AU)

The distribution of fos immunoreactivity in rat brain following freezing and escape responses elicited by electrical stimulation of the inferior colliculus.

Several sources of evidence indicate that the inferior colliculus also integrates acoustic information of an aversive nature besides its well-known role as a relay station for auditory pathways. Gradual increases of the electrical stimulation of this structure cause in a hierarchical manner alertness, freezing and escape behaviors. Independent groups of animals implanted with bipolar electrodes into the inferior colliculus received electrical stimulation at one of these aversive thresholds. Control animals were submitted to the same procedure but no current was applied. Next, analysis of Fos protein expression was used to map brain areas activated by the inferior colliculus stimulation at each aversive threshold and in the controls. Whereas alertness elicited by stimulation of the inferior colliculus did not cause any significant labeling in any structure studied in relation to the respective control, electrical stimulation applied at the freezing threshold increased Fos-like immunoreactivity in the central amygdaloid nucleus and entorhinal cortex. In contrast, escape response enhanced Fos-like immunoreactivity in the nucleus cuneiform and the dorsal periaqueductal gray matter of the mesencephalon. This evidence supports the notion that freezing and escape behaviors induced by electrical stimulation of the inferior colliculus activate different neural circuitries in the brain. Both defensive behaviors caused significant expression of c-fos in the frontal cortex, hippocampus and basolateral amygdaloid nucleus. This indistinct pattern of c-fos distribution may indicate a more general role for these structures in the modulation of fear-related behaviors. Therefore, the present data bring support to the notion that amygdala, dorsal hippocampus, entorhinal cortex, frontal cortex, dorsal periaqueductal gray matter and cuneiform nucleus altogether play a role in the integration of aversive states generated at the level of the inferior colliculus.