Differential effects of a selective dopamine D1-like receptor agonist on motor activity and c-fos expression in the frontal-striatal circuitry of SHR and Wistar-Kyoto rats

BACKGROUND: Molecular genetic studies suggest the dopamine D1 receptor (D1R) may be implicated in attention-deficit/hyperactivity disorder (ADHD). As little is known about the potential motor role of D1R in ADHD, animal models may provide important insights into this issue. METHODS: We investigated the effects of a full and selective D1R agonist, SKF-81297 (0.3, 3 and 10 mg/kg), on motor behaviour and expression of the plasticity-associated gene, c-fos, in habituated young adult male Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). RESULTS: SHR rats were more behaviourally active than WKY rats after injection with vehicle. The 0.3 mg/kg dose of SKF-81297 increased motor behaviour (locomotion, sifting, rearing, and sniffing) in both SHR and WKY rats. Total grooming was also stimulated, but only in WKY rats. The same dose increased c-fos mRNA expression in the piriform cortex of both strains. The 3 mg/kg dose increased sifting and sniffing in both strains. Locomotion was also stimulated towards the end of the testing period. The intermediate dose decreased total rearing in both strains, and produced a significant increase in c-fos mRNA in the striatum, nucleus accumbens, olfactory tuberculum, and in the cingulate, agranular insular and piriform cortices. The 10 mg/kg dose of SKF-81297 produced a biphasic effect on locomotion, which was characterized by an initial decrease followed by later stimulation. The latter stimulatory effect was more pronounced in SHR than in WKY rats when compared to their respective vehicle-injected groups. The 10 mg/kg dose also stimulated sifting and sniffing in both strains. Both the 3 and 10 mg/kg doses had no effect on total grooming. The 10 mg/kg dose induced significantly higher levels of c-fos mRNA expression in the nucleus accumbens and adjacent cortical regions (but not striatum) of SHR when compared to WKY rats. CONCLUSION: The present results suggest a potential alteration in D1R neurotransmission within the frontal-striatal circuitry of SHR involved in motor control. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD

Calcyon mRNA expression in the frontal-striatal circuitry and its relationship to vesicular processes and ADHD

<p>Abstract</p> <p>Background</p> <p>Calcyon is a single transmembrane protein predominantly expressed in the brain. Very recently, calcyon has been implicated in clathrin mediated endocytosis, a critical component of synaptic plasticity. At the genetic level, preliminary evidence supports an association between attention-deficit/hyperactivity disorder (ADHD) and polymorphisms in the calcyon gene. As little is known about the potential role of calcyon in ADHD, animal models may provide important insights into this issue.</p> <p>Methods</p> <p>We examined calcyon mRNA expression in the frontal-striatal circuitry of three-, five-, and ten-week-old Spontaneously Hypertensive Rats (SHR), the most commonly used animal model of ADHD, and Wistar-Kyoto (WKY; the strain from which SHR were derived). As a complement, we performed a co-expression network analysis using a database of mRNA gene expression profiles of multiple brain regions in order to explore potential functional links of calcyon to other genes.</p> <p>Results</p> <p>In all age groups, SHR expressed significantly more calcyon mRNA in the medial prefrontal and orbital frontal cortices than WKY rats. In contrast, in the motor cortex, dorsal striatum and nucleus accumbens, calcyon mRNA expression was only significantly elevated in SHR in younger animals. In both strains, calcyon mRNA levels decreased significantly with age in all regions studied. In the co-expression network analysis, we found a cluster of genes (many of them poorly studied so far) strongly connected to calcyon, which may help elucidate its role in the brain. The pair-wise relations of calcyon with other genes support its involvement in clathrin mediated endocytosis and, potentially, some other membrane/vesicular processes. Interestingly, no link was found between calcyon and the dopamine D1 receptor, which was previously shown to interact with the C-terminal of calcyon.</p> <p>Conclusion</p> <p>The results indicate an alteration in calcyon expression within the frontal-striatal circuitry of SHR, especially in areas involved in cognitive processes. These findings extend our understanding of the molecular alterations in SHR, a heuristically useful model of ADHD.</p

Brain development and ADHD

Abstract Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by excessive inattention, hyperactivity, and impulsivity, either alone or in combination. Neuropsychological findings suggest that these behaviors result from underlying deficits in response inhibition, delay aversion, and executive functioning which, in turn, are presumed to be linked to dysfunction of frontalstriatal-cerebellar circuits. Over the past decade, magnetic resonance imaging (MRI) has been used to examine anatomic differences in these regions between ADHD and control children. In addition to quantifying differences in total cerebral volume, specific areas of interest have been prefrontal regions, basal ganglia, the corpus callosum, and cerebellum. Differences in gray and white matter have also been examined. The ultimate goal of this research is to determine the underlying neurophysiology of ADHD and how specific phenotypes may be related to alterations in brain structure. © 2006 Published by Elsevier Ltd. Keywords: ADHD; Development; Brain; Magnetic resonance imaging; Phenotypes; Basal ganglia; Cerebellum According to the DSM-IV-TR, Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by excessive inattention, hyperactivity, and impulsivity, either alone or in combination (American Psychiatric Association, 2000). Neuropsychological findings suggest that these overt behavioral signs result from underlying deficits in response inhibition, delay aversion, and executive functioning. In turn, these hypothesized psychological deficits are presumed to be linked to dysfunction of frontal-striatal-cerebellar circuits. In particular, much attention has been paid to the neural circuits connecting the prefrontal cortex and the basal ganglia, which likely modulate response inhibition. Further, the cerebellum, which has traditionally been viewed as a motor coordination center, has also been shown to be closely linked to non-motor regions of the cerebral cortex and to play a role in executive functions such as cognitive planning. Over the past decade, magnetic resonance imaging (MRI) has been used to examine anatomic differences in these regions between ADHD and control children. In addition to quantifying differences in total cerebral volume, specific areas of interest have been prefrontal regions, basal ganglia, the corpus callosum, and cerebellum. Differences in gray and white matter have also been examined. The ultimate goal of this research is to determine the underlying neurophysiology of ADHD and how specific phenotypes may be related to alterations in brain structure. The findings of these studies will be discussed in the following review

MEG event-related desynchronization and synchronization deficits during basic somatosensory processing in individuals with ADHD

<p>Abstract</p> <p>Background</p> <p>Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised.</p> <p>Methods</p> <p>We used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms.</p> <p>Results</p> <p>Healthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8–12 Hz) and beta (15–30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls.</p> <p>Conclusion</p> <p>Our findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input (e.g., detection of a tactile stimulus, stimulus predictability) and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing.</p

Altered intrinsic functional connectivity of the cingulate cortex in children with severe temper outbursts

Severe temper outbursts (STO) in children are associated with impaired school and family functioning and may contribute to negative outcomes. These outbursts can be conceptualized as excessive frustration responses reflecting reduced emotion regulation capacity. The anterior cingulate cortex (ACC) has been implicated in negative affect as well as emotional control, and exhibits disrupted function in children with elevated irritability and outbursts. This study examined the intrinsic functional connectivity (iFC) of a region of the ACC, the anterior midcingulate cortex (aMCC), in 5- to 9-year-old children with STO (n = 20), comparing them to children with attention-deficit/hyperactivity disorder (ADHD) without outbursts (ADHD; n = 18). Additional analyses compared results to a sample of healthy children (HC; n = 18) and examined specific associations with behavioral and emotional dysregulation. Compared to the ADHD group, STO children exhibited reduced iFC between the aMCC and surrounding regions of the ACC, and increased iFC between the aMCC and precuneus. These differences were also seen between the STO and HC groups; ADHD and HC groups did not differ. Specificity analyses found associations between aMCC-ACC connectivity and hyperactivity, and between aMCC-precuneus iFC and emotion dysregulation. Disruption in aMCC networks may underlie the behavioral and emotional dysregulation characteristic of children with STO

Liquid Phase Hydrodechlorination of Dieldrin and DDT over Pd/C and Raney-Ni

Selectivity and product distribution of hydrodechlorination (HDCl) of dieldrin and DDT are studied in different liquid phase systems, namely in: (1) in ethanol; and (2) in the supported ionic liquid heterogeneous catalytic system (multiphase system), composed by the organic phase and aqueous KOH, a quaternary ammonium ionic liquid promoter (Aliquat 336), and a metal catalyst, e.g. 5% Pd/C, 5% Pt/C, or Raney-Ni. At 50 8C and atmospheric pressure of hydrogen, a quantitative hydrodechlorination of DDT in the biphasic system with ionic liquid layer is achieved in 40 min and in 4 h with Raney-Ni and Pd/C, respectively, while the reaction on Pt/C or on Pd/C without Aliquat 336 is slow. Dieldrin undergoes partial dechlorination, with high selectivity achievable only for its mono- and bi-dechlorination products. Dechlorination pathways and reactivity of different types of organic chlorine atoms versus the catalyst nature and other conditions are discussed

Activity of ulilysin, an archaeal PAPP-A-related gelatinase and IGFBP protease

Human growth and development are conditioned by insulin-like growth factors (IGFs), which have also implications in pathology. Most IGF molecules are sequestered by IGF-binding proteins (IGFBPs) so that exertion of IGF activity requires disturbance of these complexes. This is achieved by proteolysis mediated by IGFBP proteases, among which the best characterised is human PAPP-A, the first member of the pappalysin family of metzincins. We have previously identified and studied the only archaeal homologue found to date, Methanosarcina acetivorans ulilysin. This is a proteolytically functional enzyme encompassing a pappalysin catalytic domain and a pro-domain involved in maintenance of latency of the zymogen, proulilysin. Once activated, the protein hydrolyses IGFBP-2 to -6 and insulin chain β in vitro. We report here that ulilysin is also active against several other substrates, viz (azo)casein, azoalbumin, and extracellular matrix components. Ulilysin has gelatinolytic but not collagenolytic activity. Moreover, the proteolysis-resistant skeletal proteins actin and elastin are also cleaved, as is fibrinogen, but not plasmin and α1-antitrypsin from the blood coagulation cascade. Ulilysin develops optimal activity at pH 7.5 and strictly requires peptide bonds preceding an arginine residue, as determined by means of a novel fluorescence resonance energy transfer assay, thus pointing to biotechnological applications as an enzyme complementary to trypsi

Personality Is Reflected in the Brain's Intrinsic Functional Architecture

Personality describes persistent human behavioral responses to broad classes of environmental stimuli. Investigating how personality traits are reflected in the brain's functional architecture is challenging, in part due to the difficulty of designing appropriate task probes. Resting-state functional connectivity (RSFC) can detect intrinsic activation patterns without relying on any specific task. Here we use RSFC to investigate the neural correlates of the five-factor personality domains. Based on seed regions placed within two cognitive and affective ‘hubs’ in the brain—the anterior cingulate and precuneus—each domain of personality predicted RSFC with a unique pattern of brain regions. These patterns corresponded with functional subdivisions responsible for cognitive and affective processing such as motivation, empathy and future-oriented thinking. Neuroticism and Extraversion, the two most widely studied of the five constructs, predicted connectivity between seed regions and the dorsomedial prefrontal cortex and lateral paralimbic regions, respectively. These areas are associated with emotional regulation, self-evaluation and reward, consistent with the trait qualities. Personality traits were mostly associated with functional connections that were inconsistently present across participants. This suggests that although a fundamental, core functional architecture is preserved across individuals, variable connections outside of that core encompass the inter-individual differences in personality that motivate diverse responses

Situating the default-mode network along a principal gradient of macroscale cortical organization

Understanding how the structure of cognition arises from the topographical organization of the cortex is a primary goal in neuroscience. Previous work has described local functional gradients extending from perceptual and motor regions to cortical areas representing more abstract functions, but an overarching framework for the association between structure and function is still lacking. Here, we show that the principal gradient revealed by the decomposition of connectivity data in humans and the macaque monkey is anchored by, at one end, regions serving primary sensory/motor functions and at the other end, transmodal regions that, in humans, are known as the default-mode network (DMN). These DMN regions exhibit the greatest geodesic distance along the cortical surface-and are precisely equidistant-from primary sensory/motor morphological landmarks. The principal gradient also provides an organizing spatial framework for multiple large-scale networks and characterizes a spectrum from unimodal to heteromodal activity in a functional metaanalysis. Together, these observations provide a characterization of the topographical organization of cortex and indicate that the role of the DMN in cognition might arise from its position at one extreme of a hierarchy, allowing it to process transmodal information that is unrelated to immediate sensory input

DREAM: A Toolbox to Decode Rhythms of the Brain System

Rhythms of the brain are generated by neural oscillations across multiple frequencies. These oscillations can be decomposed into distinct frequency intervals associated with specific physiological processes. In practice, the number and ranges of decodable frequency intervals are determined by sampling parameters, often ignored by researchers. To improve the situation, we report on an open toolbox with a graphical user interface for decoding rhythms of the brain system (DREAM). We provide worked examples of DREAM to investigate frequency-specific performance of both neural (spontaneous brain activity) and neurobehavioral (in-scanner head motion) oscillations. DREAM decoded the head motion oscillations and uncovered that younger children moved their heads more than older children across all five frequency intervals whereas boys moved more than girls in the age of 7 to 9 years. It is interesting that the higher frequency bands contain more head movements,