Anita Cybulska-Klosowicz

The worldwide increase in cognitive decline, both in aging and with psychiatric disorders, warrants a search for pharmacological treatment. Although dopaminergic treatment approaches represent a major step forward, current dopamine transporter (DAT) inhibitors are not sufficiently specific as they also target other transporters and receptors, thus showing unwanted side effects. Herein, we describe an enantiomerically pure, highly specific DAT inhibitor, S-CE-123, synthetized in our laboratory. Following binding studies to DAT, NET and SERT, GPCR and kinome screening, pharmacokinetics and a basic neurotoxic screen, S-CE-123 was tested for its potential to enhance and/or rescue cognitive functions in young and in aged rats in the non-invasive reward-motivated paradigm of a hole-board test for spatial learning. In addition, an open field study with young rats was carried out. We demonstrated that S-CE-123 is a low-affinity but highly selective dopamine reuptake inhibitor with good bioavailability. S-CE-123 did not induce hyperlocomotion or anxiogenic or stereotypic behaviour in young rats. Our compound improved the performance of aged but not young rats in a reward-motivated task. The well-described impairment of the dopaminergic system in aging may underlie the age-specific effect. We propose S-CE-123 as a possible candidate for developing a tentative therapeutic strategy for age-related cognitive decline and cognitive dysfunction in psychiatric disorders.

Growing evidence indicates that disruptions in the brain’s functional connectivity play an important role in the pathophysiology of ADHD. The present study investigates alterations in resting-state EEG source connectivity and rich-club organization in children with inattentive (ADHD_I) and combined (ADHD_C) ADHD compared with typically developing children (TD) under the eyes-closed condition. EEG source analysis was performed by eLORETA in different frequency bands. The lagged phase synchronization (LPS) and graph theoretical metrics were then used to examine group differences in the topological properties and rich-club organization of functional networks. Compared with the TD children, the ADHD_I children were characterized by a widespread significant decrease in delta and beta LPS, as well as increased theta and alpha LPS in the left frontal and right occipital regions. The ADHD_C children displayed significant increases in LPS in the central, temporal and posterior areas. Both ADHD groups showed small-worldness properties with significant increases and decreases in the network degree in the θ and β bands, respectively. Both subtypes also displayed reduced levels of network segregation. Group differences in rich-club distribution were found in the central and posterior areas. Our findings suggest that resting-state EEG source connectivity analysis can better characterize alterations in the rich-club organization of functional brain networks in ADHD patients.

Despite the increasing body of research on Attention Deficit Hyperactivity Disorder (ADHD), the results of the studies assessing the relationship between executive function deficit and the risk of obesity in people with ADHD are incongruent. Our study aimed to assess the relationship between measures of executive functions and body weight and Body Mass Index (BMI) in children and adolescents with ADHD and control subjects. The study group consisted of 58 subjects aged from 8 to 17 years with ADHD. The Control group consisted of 62 healthy age and sex-matched participants from primary and secondary schools. Weight, height, and BMI measurements were standardized. The Sustained Attention to Response Test (SART) and the Attention Network Test (ANT) were used to assess executive functions. Based on the analysis of the correlation and analysis of moderation, we found that subjects with higher weight in the study group presented a lower efficiency of the inhibition processes and gave more impulsive and incorrect answers. The occurrence of impulsive reactions might contribute to the risk of excessive weight in children and adolescents with ADHD.

Numerous studies indicate that Attention Deficit/Hyperactivity Disorder (ADHD) is related to some developmental trends, as its symptoms change widely over time. Nevertheless, the etiology of this phenomenon remains ambiguous. There is a disagreement whether ADHD is related to deviations in brain development or to a delay in brain maturation. The model of deviated brain development suggests that the ADHD brain matures in a fundamentally different way, and does not reach normal maturity at any developmental stage. On the contrary, the delayed brain maturation model assumes that the ADHD brain indeed matures in a different, delayed way in comparison to healthy age-matched controls, yet eventually reaches proper maturation. We investigated age-related changes in resting-state EEG activity to find evidence to support one of the alternative models. A total of 141 children and teenagers participated in the study; 67 diagnosed with ADHD and 74 healthy controls. The absolute power of delta, theta, alpha and beta frequency bands was analyzed. We observed a significant developmental pattern of decreasing absolute EEG power in both groups. Nonetheless, ADHD was characterized by consistently lower absolute EGG power, mostly in the theta frequency band, in comparison to healthy controls. Our results are in line with the deviant brain maturation theory of ADHD, as the observed effects of age-related changes in EEG power are parallel but different in the two groups.

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Fear-conditioning is one of the most widely used paradigms in attempts to unravel the processes and mechanisms underlying learning and plasticity. In most of the Pavlovian conditioning paradigms auditory stimulus is used as a conditioned stimulus (CS), but conditioning can be accomplished also to tactile CS. The whisker-to-barrel tactile system in mice offers convenient way to investigate the brain pathways and mechanisms of learning, and plasticity of the brain cortex. To support a claim that an animal learns during conditioning session and that the plastic changes are associative in nature, objective measures of behavior are necessary. Multiple types of conditioned responses can develop, depending on the training situation, CS and unconditioned stimulus (UCS) characteristics. These include physiological responses, such as salivation, heart rate, galvanic skin reaction, and also behavioral responses, such as startle reflex potentiation or suppression of the ongoing behavior. When studying learning with the whisker system in behaving mice, stimulation of individual whiskers in a well-controlled manner may require animal restrain with a disadvantage of only limited behavioral responses observed. Stimulation of whiskers in the neck-restraining apparatus evokes head movements. When whiskers stimulation (CS) is paired with an aversive UCS during conditioning, the head movements decrease in the course of the training. This reaction, called minifreezing, resembles freezing response, frequently used behavioral measure, however applicable only in freely moving animals. This article will review experimental evidences confirming that minifreezing is a relevant index of association formation between the neutral CS and the and the aversive UCS.

Matrix metalloproteinases (MMPs) are fine modulators of brain plasticity and pathophysiology. The inhibition of MMPs shortly after ischaemic stroke reduces the infarct size and has beneficial effects on post‐stroke behavioural recovery. Our previous studies have shown that photothrombotic cortical stroke disrupts use‐dependent plasticity in the neighbouring cortex. The aim of the present study was to check whether the inhibition of MMPs after photothrombosis rescued the plastic capacity of the barrel cortex. To induce plasticity in adult mice, a unilateral deprivation of all vibrissae except row C was applied. The deprivation started immediately after stroke and lasted 7 days. This procedure, in control (non‐stroke) animals, results in an enlargement of functional representation of the spared row, as shown with [¹⁴C]2‐deoxyglucose uptake mapping. In mice with stroke induced by photothrombosis in the vicinity of the barrel cortex, vibrissae deprivation did not result in an enlargement of the cortical representation of the spared row C of vibrissae, which confirmed our previous results. However, when mice were injected with the broad‐spectrum inhibitor of MMPs FN‐439 (10 mg/kg, i.v.) immediately before a stroke, an enlargement of the representation of the spared row similar to the enlargement found in sham mice was observed. These results indicate the involvement of MMPs in the impairment of use‐dependent plasticity in the vicinity of an ischaemic lesion.