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Azheimer´s disease (AD) is a progressive neurodegenerative disorder clinically characterized by memory loss and cognitive damage. It presents two main hallmarks: the neurofibrillary tangles formed by the aggregation of p-Tau protein and the senile plaques composed by aggregates of the Aß-42 peptide. It is suggested that in a situation of cholinergic deficit, an imbalance between the excitatory glutamatergic and the inhibitory GABAergic tones may be responsible for cognitive and non-cognitive behavioral disturbances. Participation in a regular exercise program is increasingly proposed as an intervention that could prevent or reduce cognitive and mood disorders of age-associated dementias, mainly in AD. In this work we characterized homozygous 3xTgAD mice on both cognitive and behavioral psychiatric symptoms of dementia (BPSD) and the underlying neuronal changes in order to evaluate the proposed therapeutic effects of physical exercise. Voluntary exercise showed a neuroprotective effect at early stages of AD, including both cognitive and BPSD-like behaviors. Data obtained from neurotransmitter binding experiments showed that exercise improves the functionality of GABAergic receptor, while NMDA receptor was apparently in a more advanced stage of dysfunction because its functional parameters were only partially recovered. Altered expression levels of these receptors subunits, as well as synaptic markers (synaptophysin, PSD95) and neuroprotection-related proteins (Sirt1, GDNF) were normalized by the physical exercise treatment. This work provides more evidence to demonstrate the validity of voluntary exercise as a promising co-adjuvant therapy to prevent or ameliorate AD symptoms and its relevance to be included in our lifestyle.

eurodegenerative diseases such as Alzheimer's disease (AD) can be understood in the context of the aging of neuroimmune communication. Although the contribution to AD of the immune cells present in the brain is accepted, the role of the peripheral immune system is less well known. The present review examines the behavior and the function and redox state of peripheral immune cells in a triple-transgenic mouse model (3×Tg-AD). These animals develop both beta-amyloid plaques and neurofibrillary tangles with a temporal- and regional-specific profile that closely mimics their development in the human AD brain. We have observed age and sex-related changes in several aspects of behavior and immune cell functions, which demonstrate premature aging. Lifestyle strategies such as physical exercise and environmental enrichment can improve these aspects. We propose that the analysis of the function and redox state of peripheral immune cells can be a useful tool for measuring the progression of AD.

The 3xTg-AD mouse develops a progressive Alzheimer's disease- (AD-) like brain pathology that causes cognitive- and neuropsychiatric-like symptoms of dementia. Since its neuroimmunoendocrine axis is likewise impaired, this mouse is also useful for modelling complex age-related neurodegeneration. This study analyzed behavioral, physiological, neurochemical, pathological and immunoendocrine alterations in male and female 3xTg-AD mice and assayed the effects of a short therapy of forced physical exercise at the moderate pathology stage of 6 months of age. Gender effects were observed in most AD-related pathology and dysfunctions. Five weeks of treadmill training produced beneficial effects, such as the reduction of brain oxidative stress and GABA-A receptor dysfunction in males and improvement of sensorimotor function in females. In both sexes, exercise decreased the brain amyloid β 42/40 ratio levels. The results highlight the importance of analyzing experimental therapies in both mouse model genders in order to improve our understanding of the disease and develop more appropriate therapies.

El ejercicio físico mejora la funcionalidad del receptor GABA-A en los ratones 3xtgad

Consultable des del TDX, Títol obtingut de la portada digitalitzada, Només un petit percentatge d'entre tots els individus que experimenten amb drogues d'abús esdevenen addictes. La vulnerabilitat per a desenvolupar un trastorn addictiu està relacionada amb trets de personalitat impulsiva o amb apetència per la novetat. Les soques de rata Romanes, genèticament seleccionades per alta (RHA) o baixa (RLA) adquisició de l'evitació activa en dos sentits, són un model de laboratori vàlid de les divergències en apetència per la novetat i substàncies gratificants que s'observen en humans. A més a més, aquestes soques de rata difereixen en la funcionalitat del sistema dopaminèrgic. Se sap que les rates RHA beuen etanol voluntàriament mentre que les rates RLA mostren aversió. En aquesta tesis, les rates Romanes s'empren com a model de vulnerabilitat addictiva. L'objectiu de la tesis ha consistit en entendre els mecanismes neurobiològics que sustenten les diferències de vulnerabilitat addictiva entre les dues soques de rata Romanes. El treball s'ha dividit en 3 fases experimentals. En primer lloc, es va avaluar la resposta conductual de les rates Romanes a la injecció d'una dosi baixa d'etanol. Tal i com s'observa en humans amb elevat risc d'esdevenir alcohòlics, les rates RHA van ser menys sensibles als efectes conductuals d'aquesta dosi. En la segona fase, es varen estudiar els cervells de rates Romanes naïve per tal de caracteritzar vàries dianes moleculars del sistema dopaminèrgic i neuropèptids relacionats: es van quantificar diferents subtipus de receptor de dopamina per mitjà de la tècnica d'autoradiografia de receptors així com els nivells d'expressió d'ARNm per diferents neuropèptids mitjançant la tècnica d'hibridació in situ. Comparades amb les rates RLA, les rates RHA presenten majors nivells de receptors D1 i D3 així com també d'ARNm per la DYN a nivell de l'escorça del nucli accumbens (NAc). En canvi, presenten menors nivells d'expressió del receptor D3 a nivell de les illes de Calleja. A més a més, quan s'administra un agonista D3, Hundreds of millions of people experiment with drugs of abuse, but only a small percentage of them become addicted. Vulnerability to develop addiction has been associated with impulsivity or novelty-seeking. The Roman rats, genetically selected for high (RHA) or low (RLA) active avoidance acquisition in the two-way shuttle box, appear to be a valid laboratory model of divergent novelty and substance-seeking profiles and differ in the functionality of the dopaminergic system. So far, it is known that RHA rats drink ethanol voluntarily whereas RLA rats show aversion to it. In the present thesis, the Roman rats have been used as a model of differences in vulnerability to addiction. The aim of the thesis was to understand the neurobiological mechanisms that underlie such differences in vulnerability between the two Roman rat strains. The work has been divided in 3 experimental blocks. First, we studied the behavioral response to an injection of a low dose of ethanol in the Roman rats. Like those humans that have higher risk to develop alcoholism, RHA rats were less sensitive to the effects of low-dose of ethanol. Second, brains of naïve Roman rats were studied in order to characterize several molecular targets of the dopaminergic system and related neuropeptides: dopamine receptor subtypes were quantified by means of receptor autoradiography and mRNA coding for neuropeptides were quantified using in situ hybridization histochemistry. When compared to RLA rats, RHA showed higher binding of D1 and D3 dopamine receptor subtypes and DYN mRNA expression in the nucleus accumbens (NAc) shell, although they showed lower basal binding of D3 receptors in the Calleja islands. Moreover, a challenge with a D3 agonist resulted in greater inhibition of locomotor activity as well as supression of NGFI-A mRNA as measured with in situ hybridization in the Calleja magna in RLA rats when compared to RHA rats. These results provide further evidences of the differences in dopamine function b

A computerized method for the evaluation of behavioral responses induced by neurotoxicants in rats is described. A dynamic image analysis system was adapted for the measurement of the duration, vigor and averaged velocity of motor activity (locomotor or not) of behavioral responses induced chemically in rats. Three known animal models of epilepsy: systemic administration of kainic acid, pentylenetetrazole and 4-aminopyridine were used for reference. The method, based on the concurrent measurement of the quantity and quality of the movements, allowed the systematic evaluation of the behavior patterns induced. Three different levels of analysis were used. Firstly, we measured the time spent by the animal performing physical movements during long successive intervals (30 min) of the test, a motor activity analysis similar to that obtained with other motor activity recording devices. Secondly, the system was designed to distinguish movements energetically or forcefully performed by the animal according to a previously defined vigor level and then we determined the presence of vigorous and non-vigorous activity throughout the test at 2 rain interval. Finally, we applied the method to perform a more detailed analysis of the motor characteristic of behavioral components exhibited by the animals determining the velocity and vigor of movements over short intervals of time (5 sec). Thus, motor activity profiles, the vigor of the motor responses and the description of behavioral components were used for the comparative analysis of behavior induced by the aforementioned convulsant agents.

Putrescine has been suggested to have an inhibitory effect on the excitability of the central nervous system. In the present study we found that 2 and 3 weeks after status epilepticus induced by kainic acid, rats had increased concentrations of putrescine (3- and 1.7-fold, respectively) and spermidine (1.6- and 1.4-fold, respectively) in the hippocampus. These animals exhibited a higher susceptibility to pentylentetrazol than the saline group. In addition, several hours after the pentylentetrazol injection, the concentration of putrescine and spermidine increased again in the brain and also in the plasma. In conclusion, increased hippocampal putrescine and spermidine concentrations seem to be linked with a lower threshold of excitability.

The relationship between the behavioral effects and motor activity induced by N-methyl-D-aspartate (NMDA) (150 mg/kg, ip) and brain polyamine concentration was studied in male Wistar rats. Motor activity was evaluated by an automated subtraction analysis system to measure the duration and vigor of any kind of movement. The behavioral modifications exhibited by the nonconvulsant NMDA-treated rats were evaluated according to the composition and sequence of behavioral components as: hypoactivity (pattern A), partially stereotyped activity (pattern B), and generalized stereotyped activity (pattern C). The concentration of polyamines in the frontal cortex and hippocampus was measured 8 and 24 h after drug injection. A relationship was found between the concentration of putrescine in both regions and the motor activity. In addition, the concentrations of putrescine also correlated with the vigor of the movements performed. Moreover, the putrescine concentration in the frontal cortex and hippocampus paralleled the behavioral patterns. The histological examination of the frontocortical and hippocampal areas did not reveal any evidence of damage. In conclusion, partially or generalized stereotyped activity elicited by systemic NMDA administration induces an increase in putrescine in the brain not linked to histological damage.

The systemic administration of polyamines (s.c.) produced a dose-dependent motor depression. With high doses the depressant effect was long-lasting and the animals showed signs of toxicity. ED50 values for spermine, spermidine and putrescine were 38, 90 and 251 mg/kg respectively. The motor depression induced by the systemic administration of N-methyl-D-aspartate (NMDA; 25 mg/kg i.p.) was used as a model for studying the interactions between polyamines and the NMDA receptor. Results indicate that (1) the motor effects elicited by NMDA are very similar to those induced by polyamines at ED50 doses; (2) polyamines, even at non-active doses, potentiate the motor depressant effect induced by NMDA; (3) the NMDA receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine (MK-801; 0.5 mg/kg i.p.), abolishes the depressant effect elicited by NMDA and by polyamines, even at toxic doses; (4) amphetamine (1.5 mg/kg i.p.) does not counteract the motor depressant effects of NMDA or polyamines. On the other hand, the adenosine receptor antagonist, theophylline (30 mg/kg i.p.), counteracts NMDA- but not polyamine-induced motor depression. The concentration of polyamines in the brain is modified after their systemic administration at high doses and at the ED50 dose of putrescine. In conclusion, the data suggest that the NMDA receptor could be a target mediating the motor effect elicited by polyamines. They also show that the quantitative analysis of the motor effects elicited by non-convulsant doses of NMDA might be a powerful tool for studying in vivo the interaction between neurotransmission systems involved in the regulation of motor activity.

The motor responses (such as stereotypic behavior or convulsions) induced in rats by N-methyl-D-aspartate (NMDA) administered systemically were followed by a rapid, moderate increase in the putrescine concentration in plasma which preceded an increase in this mine in the brain. This effect was not observed following the convulsions evoked by pentylentetrazol, picrotoxinine, lindane or 4-aminopyridine. However, all the convulsants assayed induced a mild increase in the concentration of putrescine in the frontal cortex and hippocampus. A differential activation of the ornithine decarboxylase (ODC)/polyamine system in both cerebral and peripheral tissues could account for these results.