Miroslava Stefanova

Consequences of long-term treatment with agomelatine on depressive-like behavior and neurobiological abnormalities in pinealectomized rats

Previous data have shown that the rat model of melatonin deficit can cause a number of neurobiological aberrations. The aim of the present study was to determine whether the antidepressant drug agomelatine, a MT1/MT2 melatoninergic receptor agonist/5-HT2C receptor antagonist is able to prevent some of the behavioral, biochemical and cellular abnormalities induced by pinealectomy. The injection of agomelatine (40 mg/kg, i.p. for 5 weeks)/vehicle started after pinealectomy/sham procedure in Wistar rats. Animals were tested in different behavioral tests for anxiety and depression during the period of agomelatine treatment (chronic effect) and two months later (plastic effect). The effect of agomelatine on KCl-evoked serotonin (5-HT) release from the hippocampus, the activity of the hypothalamic-pituitary-adrenal (HPA) axis and neuronal loss in pinealectomized rats were assessed. Our results showed that agomelatine not only did not prevent the disturbed emotional arousal/anxiety behavior in pinealectomized rats during the treatment but the enhanced motor activity and decreased anxiety state was still observed two months after the discontinuation of treatment. However, the drug corrected a depressive-like behavior (chronic and plastic effect), alleviated the enhanced KCl-evoked 5-HT release in the hippocampus, recovered the suppressed negative feedback inhibition of HPA axis and exerted a neuroprotection in pinealectomized rats. Our findings suggest that pinealectomy can model melancholic depression disorder while the antidepressant action of agomelatine is associated with a correction of 5-HT release in the hippocampus, dysregulated HPA system and neuroprotection in limbic structures.

Age-related changes in fine motion direction discriminations

The present study used an equivalent noise method to characterize the sources of reduced performance in fine discrimination of motion with age. We varied the density of the displays, the speed and speed variability and the temporal correlation of dots’ motion in successive frames to assess their effect on the sensitivity to motion direction. The results showed that, in all experimental conditions, the older observers had higher levels of internal noise. Both age groups used the stimulus information less efficiently at slow speed and most efficiently when the moving elements were uncorrelated across frames. The older observers were less efficient than the younger observers in all conditions except at high speed where the efficiency of the two age groups was the same. We fitted two biologically plausible models to the experimental data: a modified version of the local-to-global direction encoding model (Dakin et al. in Vis Res 45:3027–3049, 2005) and a model for pooling of motion information in medial temporal area (MT) where the neuronal responses were correlated (Huang and Lisberger in J Neurophysiol 101:3012–3030, 2009). The modeling results indicate that the correlation in neuronal responses is essential to characterize the influence of speed and speed variability on the sensitivity to direction information. For the younger observers, a single set of parameters can account for the effect of noise and the spatio-temporal parameters of the stimuli, while, for the older observers, a change in the correlation of neuronal activity and the directional tuning bandwidth with the levels of external noise is needed. The findings are discussed with respect to optimal use of the dynamic information to overcome the negative effect of aging.

Effect of peptide and nonpeptide antagonists of angiotensin II receptors on noradrenaline release in hypothalamus of rats with angiotensin II-induced increase of water intake

Angiotensin II (Ang II) administered intracerebroventriculary (icv) at a dose that induces drinking behavior in rats significantly increased K(+)-stimulated release of [(3)H] noradrenaline (NA) in hypothalamus without affecting basal [(3)H] NA release. The observed difference between the effects of Ang II on basal and K(+)-stimulated [(3)H]NA release may possibly be due to the fact that peptides are released after increased neuronal activity. It can be suggested that Ang II is important primarily in pathological states and that NA plays a substantial role in the brain Ang II-induced drinking response. The imidazolic nonpeptidic compound 2-n-butyl-4-chloro-5-hydroxymethyl-1-{[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazole potassium salt (DuP 753, losartan), its active metabolite 2-n-butyl-4-chloro-1-{[2-(1H-tetrazol-5-yl)- biphenyl-4-yl]methyl}imidazole-5-carboxylic acid (EXP 3174) and peptide Ang II analogue, sarmesin, antagonized the Ang II-induced effect on [(3)H]NA release, in spite of the differences in their chemical structures. Thus, the drugs tested inhibited K(+)-stimulated [(3)H]NA release in hypothalamus, acting via the angiotensin (AT)(1) receptor subtype. We could not reject the possibility of a non-receptor mechanism of action for DuP753, EXP3174 and sarmesin. This research allows us to suggest a neurochemical mechanism for the modulatory role of these drugs on the NA-ergic system. The Ang II receptor antagonists studied may become important therapeutic agents, which act preferentially on pathologically activated systems. These agents may be of use for the prevention of excessive ingestion of water in some neuropsychotic diseases.

Effect of endurance training on seizure susceptibility, behavioral changes and neuronal damage after kainate-induced status epilepticus in spontaneously hypertensive rats

The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a model of hypertension and epilepsy suggesting a potential influence of hippocampal 5-HT on a comorbid depression. However, this beneficial impact does not prevent the development of epilepsy and concomitant brain damage.

Echo State Network for Classification of Human Eye Movements During Decision Making

The paper develops further a recently proposed author’s approach for classification of dynamic data series using a class of Recurrent Neural Network (RNN) called Echo state network (ESN). It exploits the Intrinsic Plasticity (IP) tuning of ESN reservoir of neurons to fit their dynamics to the data fed into the reservoir input. A novel approach for ranking of a data base of dynamic data series into groups using the length of the multidimensional vector of reservoir state achieved after consecutive feeding of each time series into the ESN is proposed here. It is tested on eye tracker recordings of human eye movements during visual stimulation and decision making process. The preliminary results demonstrated the ability of the proposed technique to discriminate dynamic data series.