Model Of Attention Deficit Hyperactivity Disorder Research Articles

Central amygdala is related to the reduction of aggressive behavior by monosodium glutamate ingestion during the period of development in an ADHD model rat.

Monosodium glutamate (MSG), an umami substance, stimulates the gut-brain axis communication via gut umami receptors and the subsequent vagus nerves. However, the brain mechanism underlying the effect of MSG ingestion during the developmental period on aggression has not yet been clarified. We first tried to establish new experimental conditions to be more appropriate for detailed analysis of the brain, and then investigated the effects of MSG ingestion on aggressive behavior during the developmental stage of an ADHD rat model. Long-Evans, WKY/Izm, SHR/Izm, and SHR-SP/Ezo were individually housed from postnatal day 25 for 5 weeks. Post-weaning social isolation (PWSI) was given to escalate aggressive behavior. The resident-intruder test, that is conducted during the subjective night, was used for a detailed analysis of aggression, including the frequency, duration, and latency of anogenital sniffing, aggressive grooming, and attack behavior. Immunohistochemistry of c-Fos expression was conducted in all strains to predict potential aggression-related brain areas. Finally, the most aggressive strain, SHR/Izm, a known model of attention-deficit hyperactivity disorder (ADHD), was used to investigate the effect of MSG ingestion (60 mM solution) on aggression, followed by c-Fos immunostaining in aggression-related areas. Bilateral subdiaphragmatic vagotomy was performed to verify the importance of gut-brain interactions in the effect of MSG. The resident intruder test revealed that SHR/Izm rats were the most aggressive among the four strains for all aggression parameters tested. SHR/Izm rats also showed the highest number of c-Fos + cells in aggression-related brain areas, including the central amygdala (CeA). MSG ingestion significantly decreased the frequency and duration of aggressive grooming and attack behavior and increased the latency of attack behavior. Furthermore, MSG administration successfully increased c-Fos positive cell number in the intermediate nucleus of the solitary tract (iNTS), a terminal of the gastrointestinal sensory afferent fiber of the vagus nerve, and modulated c-Fos positive cells in the CeA. Interestingly, vagotomy diminished the MSG effects on aggression and c-Fos expression in the iNTS and CeA. MSG ingestion decreased PWSI-induced aggression in SHR/Izm, which was mediated by the vagus nerve related to the stimulation of iNTS and modulation of CeA activity.

Comparative Pharmacokinetics Research of 13 Bioactive Components of Jieyu Pills in Control and Attention Deficit Hyperactivity Disorder Model Rats Based on UPLC-Orbitrap Fusion MS.

Jieyu Pills (JYPs), a Chinese medicine consisting of 10 herbal elements, have displayed promising clinical effectiveness and low by-effects in the treatment of depression. Prior investigations mostly focused on elucidating the mechanism and therapeutic efficacy of JYPs. In our earlier study, we provided an analysis of the chemical composition, serum pharmacochemistry, and concentrations of the main bioactive chemicals found in JYPs. However, our precise understanding of the pharmacokinetics and metabolism remained vague. This study involved a comprehensive and meticulous examination of the pharmacokinetics of 13 bioactive compounds in JYPs. Using UPLC-Orbitrap Fusion MS, we analyzed the metabolic characteristics and established the pharmacokinetic parameters in both control rats and model rats with attention deficit hyperactivity disorder (ADHD) following oral administration of the drug. Before analysis, plasma samples that were collected at different time intervals after the administration underwent methanol pre-treatment with Puerarin used as the internal standard (IS) solution. Subsequently, the sample was chromatographed on a C18 column employing gradient elution. The mobile phase consisted of methanol solution containing 0.1% formic acid in water. The electrospray ionization source (ESI) was utilized for ionization, whereas the scanning mode employed was selected ion monitoring (SIM). The UPLC-Orbitrap Fusion MS method was subjected to a comprehensive validation process to assess its performance. The method demonstrated excellent linearity (r ≥ 0.9944), precise measurements (RSD < 8.78%), accurate results (RE: -7.88% to 8.98%), and appropriate extraction recoveries (87.83-102.23%). Additionally, the method exhibited minimal matrix effects (87.58-101.08%) and satisfactory stability (RSD: 1.52-12.42%). These results demonstrated adherence to the criteria for evaluating and determining biological material. The 13 bioactive compounds exhibited unique pharmacokinetic patterns in vivo. In control rats, all bioactive compounds except Ferulic acid exhibited linear pharmacokinetics within the dose ranges. In the ADHD model, the absorption rate and amount of most of the components were both observed to have increased. Essentially, this work is an important reference for examining the metabolism of JYPs and providing guidelines for clinical therapy.

The relative reinforcing efficacy of nicotine in an adolescent rat model of attention-deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is an independent risk factor for tobacco use disorder. Individuals with ADHD are more likely to begin smoking at a younger age, become a daily smoker sooner, smoke more cigarettes per day, and exhibit greater nicotine dependence than individuals without ADHD. It is unclear whether these findings are due to the reinforcing efficacy of nicotine per se being greater among individuals with ADHD. The purpose of the present study was to examine this issue using an animal model of ADHD, the spontaneously hypertensive rat (SHR) strain. Adolescent SHR and Wistar (control) rats were given access to a typically reinforcing nicotine unit dose (30 μg/kg), a threshold reinforcing nicotine dose (4 μg/kg), or saline under an FR 1 (week 1) and FR 2 (week 2) schedule during 23 h sessions to examine acquisition of self-administration. Behavioral economic demand elasticity was then evaluated at the 30 μg/kg dose through an FR escalation procedure. At the 30 μg/kg dose, SHR rats exhibited a lower average response rate, lower mean active to inactive lever discrimination ratio, and lower proportion of rats acquiring self-administration compared to control rats. During demand assessment, SHR rats showed no significant difference from Wistars in demand intensity (Q0) or elasticity (α; i.e., reinforcing efficacy). In addition, no strain difference in acquisition measures were observed at the 4 μg/kg dose. These findings suggest that the increased risk of tobacco use disorder in adolescents with ADHD may not be attributable to a greater reinforcing efficacy of nicotine, and that other aspects of tobacco smoking (e.g., non-nicotine constituents, sensory factors) may play a more important role. A policy implication of these findings is that a nicotine standard to reduce initiation of tobacco use among adolescents in the general population may also be effective among those with ADHD.

Rat model of attention-deficit hyperactivity disorder exhibits delayed recovery from acute incisional pain due to impaired descending noradrenergic inhibition

Chronic pain and attention-deficit hyperactivity disorder (ADHD) frequently coexist. However, the common pathology is still unclear. Attenuated noradrenergic endogenous analgesia can produce acute pain chronification, and dysfunction of noradrenergic systems in the nervous system is relevant to ADHD symptoms. Noxious stimuli-induced analgesia (NSIA) is measured to estimate noradrenergic endogenous analgesia in spontaneously hypertensive rats (SHR) as an ADHD model and control. Recovery of pain-related behaviors after paw incision was assessed. Contributions of noradrenergic systems were examined by in vivo microdialysis and immunohistochemistry. The SHR showed attenuated NSIA and needed a more extended period for recovery from acute pain. These results suggest ADHD patients exhibit acute pain chronification due to pre-existing attenuated noradrenergic endogenous analgesia. Immunohistochemistry suggests abnormal noradrenaline turnover and downregulation of the target receptor (alpha2a adrenoceptor). Standard ADHD treatment with atomoxetine restored NSIA and shortened the duration of hypersensitivity after the surgery in the SHR. NSIA protocol activated the locus coeruleus, the origin of spinal noradrenaline, of both strains, but only the control exhibited an increase in spinal noradrenaline. This result suggests dysfunction in the noradrenaline-releasing process and can be recognized as a novel mechanism of attenuation of noradrenergic endogenous analgesia.

Sex-specific responses to juvenile stress on the dopaminergic system in an animal model of attention-deficit hyperactivity disorder

The etiology of attention-deficit hyperactivity disorder (ADHD) strongly suggests a genetic component as the main cause; however, environmental factors such as early adverse experiences in childhood may play an interactive role with the genetic susceptibility. Spontaneously hypertensive rats (SHRs), a genetic ADHD model, and control Wistar Kyoto rats (WKYs) were subjected to chronic unpredictable mild stress during the juvenile period. The behavioral characteristics were monitored, and dopamine-related factors in the core regions of dopaminergic pathways were measured. Higher ADHD symptom-related behaviors were observed in response to juvenile stress in male SHRs than control WKYs. For the SHRs subjected to juvenile stress, hyperactivity in males, recognition in females, and depressant potential in both sexes were markedly observed. In the expression of 17 dopamine-related genes and proteins, greater changes were detected in male SHRs subjected to juvenile stress, especially in dopamine metabolic factors. Dopamine clearance factors involved in dopamine degradation and transport, especially catechol-O-methyltransferase (COMT) and dopamine transporter (DAT), showed sex-specific differences induced by juvenile stress in dopamine metabolite assays. Moreover, stressed male SHRs treated with methylphenidate showed better improvement in behavior than the females, resulting in different levels of COMT and DAT amelioration. These results suggest that juvenile stress potentially increased the incidence of ADHD in a genetic rat model, which showed sex-specific differences based on the expression of COMT and DAT. Therefore, our results could help develop gender-specific diagnostics and healthcare options for juvenile stress in patients with ADHD.

Animal Models of ADHD?

To describe animals that express abnormal behaviors as a model of Attention-Deficit Hyperactivity Disorder (ADHD) implies that the abnormalities are analogous to those expressed by ADHD patients. The diagnostic features of ADHD comprise inattentiveness, impulsivity, and hyperactivity and so these behaviors are fundamental for validation of any animal model of this disorder. Several experimental interventions such as neurotoxic lesion of neonatal rats with 6-hydroxydopamine (6-OHDA), genetic alterations, or selective inbreeding of rodents have produced animals that express each of these impairments to some extent. This article appraises the validity of claims that these procedures have produced a model of ADHD, which is essential if they are to be used to investigate the underlying cause(s) of ADHD and its abnormal neurobiology.

Length impairments of the axon initial segment in rodent models of attention-deficit hyperactivity disorder and autism spectrum disorder

The axon initial segment (AIS) is a structural neuronal compartment of the proximal axon that plays key roles in sodium channel clustering, action potential initiation, and signal propagation of neuronal outputs. Mutations in constitutive genes of the AIS, such as ANK3, have been identified in patients with neurodevelopmental disorders. Nevertheless, morphological changes in the AIS in neurodevelopmental disorders have not been characterized. In this study, we investigated the length of the AIS in rodent models of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We observed abnormalities in AIS length in both animal models. In ADHD model rodents, we observed shorter AIS length in layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC) and primary somatosensory barrel field (S1BF). Further, we observed shorter AIS length in S1BF L5 neurons. In ASD model mice, we observed shorter AIS length in L2/3 and L5 neurons of the S1BF. These results suggest that impairments in AIS length are common phenomena in neurodevelopmental disorders such as ADHD and ASD and may be conserved across species. Our findings provide novel insight into the potential contribution of the AIS to the pathophysiology and pathogenesis of neurodevelopmental disorders.

Lack of Cdk5 activity is involved on Dopamine Transporter expression and function: Evidences from an animal model of Attention-Deficit Hyperactivity Disorder

Attention deficit/Hyperactivity disorder (ADHD) is one of the most diagnosed psychiatric disorders nowadays. The core symptoms of the condition include hyperactivity, impulsiveness and inattention. The main pharmacological treatment consists of psychostimulant drugs affecting Dopamine Transporter (DAT) function. We have previously shown that genetically modified mice lacking p35 protein (p35KO), which have reduced Cdk5 activity, present key hallmarks resembling those described in animal models useful for studying ADHD. The p35KO mouse displays spontaneous hyperactivity and shows a calming effect of methylphenidate or amphetamine treatment. Interestingly, dopaminergic neurotransmission is altered in these mice as they have an increased Dopamine (DA) content together with a low DA turnover. This led us to hypothesize that the lack of Cdk5 activity affects DAT expression and/or function in this animal model. In this study, we performed biochemical assays, cell-based approaches, quantitative fluorescence analysis and functional studies that allowed us to demonstrate that p35KO mice exhibit decreased DA uptake and reduced cell surface DAT expression levels in the striatum (STR). These findings are supported by in vitro observations in which the inhibition of Cdk5 activity in N2a cells induced a significant increase in constitutive DAT endocytosis with a concomitant increase in DAT localization to recycling endosomes. Taken together, these data provide evidences regarding the role of Cdk5/p35 in DAT expression and function, thus contributing to the knowledge of DA neurotransmission physiology and also providing therapeutic options for the treatment of DA pathologies such as ADHD.

An Approach for Stabilizing Abnormal Neural Activity in ADHD Using Chaotic Resonance.

Reduced integrity of neural pathways from frontal to sensory cortices has been suggested as a potential neurobiological basis of attention-deficit hyperactivity disorder. Neurofeedback has been widely applied to enhance reduced neural pathways in attention-deficit hyperactivity disorder by repeated training on a daily temporal scale. Clinical and model-based studies have demonstrated that fluctuations in neural activity underpin sustained attention deficits in attention-deficit hyperactivity disorder. These aberrant neural fluctuations may be caused by the chaos–chaos intermittency state in frontal-sensory neural systems. Therefore, shifting the neural state from an aberrant chaos–chaos intermittency state to a normal stable state with an optimal external sensory stimulus, termed chaotic resonance, may be applied in neurofeedback for attention-deficit hyperactivity disorder. In this study, we applied a neurofeedback method based on chaotic resonance induced by “reduced region of orbit” feedback signals in the Baghdadi model for attention-deficit hyperactivity disorder. We evaluated the stabilizing effect of reduced region of orbit feedback and its robustness against noise from errors in estimation of neural activity. The effect of chaotic resonance successfully shifted the abnormal chaos-chaos intermittency of neural activity to the intended stable activity. Additionally, evaluation of the influence of noise due to measurement errors revealed that the efficiency of chaotic resonance induced by reduced region of orbit feedback signals was maintained over a range of certain noise strengths. In conclusion, applying chaotic resonance induced by reduced region of orbit feedback signals to neurofeedback methods may provide a promising treatment option for attention-deficit hyperactivity disorder.

Distinct long non-coding RNA and mRNA expression profiles in the hippocampus of an attention deficit hyperactivity disorder model in spontaneously hypertensive rats and control wistar Kyoto rats

The incidence of attention deficit hyperactivity disorder (ADHD) in children is increasing. Long non-coding RNAs (lncRNAs) participate in many biological processes involved in the regulation of gene expression. Although numerous lncRNAs have been proven to be crucial in brain development and associated with its degeneration, changes in lncRNA expression profiles during ADHD progression and their possible roles remain unclear. The purpose of this study is to investigate the expression profiles of lncRNAs in hippocampus from an ADHD model in spontaneously hypertensive rats (SHRs) and in normal control Wistar Kyoto (WKY) rats. We determined the expression profiles of lncRNAs and mRNAs in SHRs and WKY rats using microarray analysis technology. Then, differentially expressed lncRNAs were confirmed by real-time polymerase chain reaction (RT-PCR). Gene Ontology (GO) and pathway analysis of differentially expressed mRNAs or nearby genes was used to predict the possible functions of the lncRNAs. A gene co-expression network was established to study the relationship between expression of lncRNAs and related mRNAs. A total of 267 differentially expressed lncRNAs (including 144 upregulated and 123 downregulated) and 311 differentially expressed mRNAs were identified in SHRs, compared to those in WKY rats. Subsequently, 15 lncRNAs were selected and confirmed by RT-PCR analysis. GO and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway analysis showed that the dysregulated lncRNAs are involved in brain developmental processes and neuronal function and maintenance. Co-expression network analysis revealed the close relationship between the differentially expressed lncRNAs and mRNAs. Additionally, co-expression analysis of dysregulated lncRNAs with their downstream genes, which are reported in nervous system and regulation of learning and memory, indicated that lncRNA NONRATT0006598.2 was related to Baiap2 gene, which may participate in ADHD progress. Our findings contribute to understand the importance of lncRNAs and mRNAs in the progression of ADHD, and identify potential therapeutic targets for ADHD treatment.

Restoration of Cdk5, TrkB and Soluble N-ethylmaleimide-Sensitive Factor Attachment Protein Receptor Proteins after Chronic Methylphenidate Treatment in Spontaneous Hypertensive Rats, a Model for Attention-Deficit Hyperactivity Disorder.

ObjectiveSynaptic vesicle mobilization and neurite outgrowth regulation molecules were examined in modulation of effects of methylphenidate (MPH) in Spontaneous Hypertensive Rats (SHRs), a model for attention-deficit hyperactivity disorder (ADHD). Methods We compared the changes in the protein expression level of Cyclin dependent kinase 5 (Cdk5) and molecular substrates of Cdk5; tropomyosin receptor kinase B (TrkB), syntaxin 1A (STX1A) and synaptosomal-associated protein 25 (SNAP25). Comparisons were made in prefrontal cortex of vehicle (distilled water i.p. for 7 days)-treated SHRs, vehicle-treated Wistar Kyoto Rats (WKYs) and MPH (2 mg/kg i.p. for 7 days) treated SHRs. ResultsThe Cdk5 level of vehicle-treated SHRs was significantly decreased compared to the Cdk5 level of vehicle-treated WKY rats, but was restored to the expression level of vehicle-treated WKYs in MPH-treated SHR. The ratio of p25/p35 was significantly decreased in MPH-treated SHR compared to vehicle-treated SHR. Moreover, TrkB, STX1A and SNAP25 of vehicle-treated SHRs were significantly decreased compared to vehicle-treated WKY rats, but were restored to the expression level of vehicle-treated WKYs in MPH-treated SHR. ConclusionThe results show that Cdk5, TrkB, STX1A, and SNAP25 were involved in the modulation of MPH effects in prefrontal cortex of SHRs and play important role in treatment of ADHD.

Acute Atomoxetine Selectively Modulates Encoding of Reward Value in Ventral Medial Prefrontal Cortex.

A recent neurocognitive model of attention-deficit hyperactivity disorder (ADHD) has proposed a primary deficit in reward function as well as in executive function to account for underlying neural substrates of ADHD symptoms. Atomoxetine has been widely used as a non-stimulant medication for ADHD with little abuse liability. Although animal studies have reported that atomoxetine increases extracellular levels of both noradrenaline and dopamine in the prefrontal cortex, which receives input from a mesocorticolimbic pathway involved in reward function, there have been few studies in humans concerning the effects of atomoxetine in terms of reward function. Therefore, we investigated whether a single dose of atomoxetine (acute atomoxetine) affects reward processing in healthy adults. We used functional magnetic resonance imaging and adopted the monetary incentive delay task to separately examine neural responses to monetary reward anticipation in the nucleus accumbens and outcome in the ventral medial prefrontal cortex (vmPFC). The experiment was designed as a randomized, placebo-controlled within-subjects cross-over trial. Fourteen healthy adults completed two series of studies, taking either atomoxetine or placebo. Atomoxetine significantly decreased vmPFC activation during gain outcome compared to placebo. In gain anticipation, however, atomoxetine did not show a significant increase in the nucleus accumbens activation compared with placebo. These results suggest that atomoxetine affects reward value encoding through selective modulation of vmPFC activity related to reward outcome. Therefore, such modulatory action may partly contribute to a therapeutic effect of atomoxetine for a group of ADHD patients with increased activity in vmPFC.

Response-inhibition capacity in spontaneously hypertensive and Wistar rats: acquisition of fixed minimum interval performance and responsiveness to D-amphetamine.

Reduced response-inhibition capacity is a defining feature of attention-deficit hyperactivity disorder. The fixed minimum interval (FMI) schedule has been systematically validated to assess such capacity in rats. On each FMI trial, the first lever press initiates an inter-response time (IRT); a potentially consummatory response terminates the IRT; only IRTs longer than a target interval result in access to food. Despite task validity, steady-state FMI performance in the most common animal model of attention-deficit hyperactivity disorder, the spontaneously hypertensive rat (SHR), is similar to normotensive control performance, even though SHR performs at lower levels, especially during acquisition, in similar response-withholding tasks. To determine whether such limitations of the model are specific to stable-state performance, this experiment compared FMI 6-s performance in SHR and Wistar rats during acquisition and in steady state, and assessed the effect of acute D-amphetamine (AMP) administration (0.1, 0.5, and 1.0 mg/kg) on steady-state performance. Median latencies to first lever press were consistently shorter in SHR than in Wistar rats; IRTs were shorter for SHR than for Wistar rats during acquisition, but substantially less so during asymptotic performance. AMP dose-dependently reduced latencies, shortened IRTs, and, at the highest dose, increased the proportion of IRTs under schedule control. These results suggest that, relative to Wistar rats, SHR have a reduced capacity to learn to withhold a reinforced response; once the FMI is acquired, high doses of D-AMP disrupt withholding performance in both strains, but they also enhance the responsiveness of both strains to reinforcement contingencies.

Diagnostic model for attention-deficit hyperactivity disorder based on interregional morphological connectivity

Previous brain morphology-related diagnostic models for attention-deficit hyperactivity disorder (ADHD) were based on regional features. However, building a model of individual interregional morphological connectivity is a challenging task. This study aimed to identify children with ADHD utilizing a novel interregional morphological connectivity model and discover the discriminative patterns in patients. Therefore, novel interregional morphological patterns rather than regional patterns were extracted via surface-based analysis. The interregional morphological features were trained and tested using a hybrid machine learning method, which was implemented using the leave-one-out cross-validation (LOOCV) method to produce the optimized discriminative model and discriminative patterns. The inclusion of interregional morphological connectivity significantly improved the performance of the diagnostic models compared to the performance of the model constructed using regional features. The optimized discriminative model exhibited a total accuracy of 74.65%, a sensitivity of 75% and a specificity of 74.29%. The brain regions displaying altered morphological connectivity included the insula, the caudal anterior cingulate cortex, the frontal pole, and the postcentral cortex, among others. In addition, the altered connections correlated with the clinical symptoms. In summary, patients with ADHD exhibited altered morphological connectivity, which might be a potential biomarker for the classification of ADHD. The discriminative features will potentially benefit studies investigating the brain network mechanisms of ADHD.

Monosodium glutamate ingestion during the development period reduces aggression mediated by the vagus nerve in a rat model of attention deficit-hyperactivity disorder

We used an umami substance, monosodium glutamate (MSG), as a simple stimulant to clarify the mechanism of the formation of emotional behavior. A 60 mM MSG solution was fed to spontaneously hypertensive rats (SHR), used as a model of attention-deficit hyperactivity disorder, from postnatal day 25 for 5 weeks kept in isolation. Emotional behaviors (anxiety and aggression) were then assessed by the open-field test, cylinder test and social interaction test. MSG ingestion during the developmental period resulted in a significant reduction in aggressive behavior but had few effects on anxiety-like behavior. Several experiments were performed to identify the reason for the reduced aggression with MSG intake. Blood pressure in the MSG-treated SHR was comparable to that of the controls during development. Argyrophil III staining to detect the very early phase of neuronal damage revealed no evidence of injury by MSG in aggression-related brain areas. Assessment of plasma amino acids revealed that glutamate levels remained constant (∼80 μM) with MSG ingestion, except for a transient increase after fasting (∼700 μM). However, lactate dehydrogenase assay in an in vitro blood-brain barrier model showed that cell toxicity was not induced by indirect MSG application even at 700 μM, confirming that MSG ingestion caused minimal neuronal damage. Finally, vagotomy at the sub-diaphragmatic level before MSG ingestion blocked its effect on aggressive behavior in the isolated SHR. The data suggest that MSG ingestion during the developmental period can reduce aggressive behavior in an attention deficit-hyperactivity disorder model rat, mediated by gut-brain interaction.

GIT1 regulates synaptic structural plasticity underlying learning.

The signaling scaffold protein GIT1 is expressed widely throughout the brain, but its function in vivo remains elusive. Mice lacking GIT1 have been proposed as a model for attention deficit-hyperactivity disorder, due to alterations in basal locomotor activity as well as paradoxical locomotor suppression by the psychostimulant amphetamine. Since we had previously shown that GIT1-knockout mice have normal locomotor activity, here we examined GIT1-deficient mice for ADHD-like behavior in more detail, and find neither hyperactivity nor amphetamine-induced locomotor suppression. Instead, GIT1-deficient mice exhibit profound learning and memory defects and reduced synaptic structural plasticity, consistent with an intellectual disability phenotype. We conclude that loss of GIT1 alone is insufficient to drive a robust ADHD phenotype in distinct strains of mice. In contrast, multiple learning and memory defects have been observed here and in other studies using distinct GIT1-knockout lines, consistent with a predominant intellectual disability phenotype related to altered synaptic structural plasticity.

Sleep Disturbance and Hyperactivity Detected by Actigraphy in Rats with Allergic Rhinitis or Attention-Deficit Hyperactivity Disorder.

Actigraphy is an easy and noninvasive method used to monitor human ultradian cycles. However, to our knowledge, it has been not applied to experiments with rodents. Therefore, using actigraphy, we assessed the ultradian cycles and behavior of rats. Rats with or without allergic rhinitis wore an actigraphy device, and triaxial acceleration was recorded. The counts that represent physical activity were lower from 8:00 to 20:00 than those from 20:00 to 8:00 in control rats, suggesting that their sleep phase was from 8:00 to 20:00 and their awake phase from 20:00 to 8:00. The counts from 8:00 to 10:00 were significantly higher in allergic rhinitis rats than in control rats (p < 0.01), suggesting the presence of difficulty with sleep induction in rats with allergic rhinitis. The counts from 18:00 to 20:00 were also significantly higher in allergic rhinitis rats than in control rats (p < 0.05), suggesting the presence of early awakening in rats with allergic rhinitis. Moreover, the counts were significantly higher in allergic rhinitis rats than in control rats from 20:00 to 8:00. These results suggest that rats with allergic rhinitis experienced hyperactivity disorder during the daytime. Additionally, hyperreactivity and difficulty with sleep induction were observed in 6-hydroxydopamine-lesioned rats, an animal model of attention-deficit hyperactivity disorder. This study shows for the first time that actigraphy can be successfully used for behavioral analysis in rodents. These rat models could be useful for analyzing the mechanisms involved in sleep disturbances and hyperactivity disorder.

Exploring the Validity of Proposed Transgenic Animal Models of Attention-Deficit Hyperactivity Disorder (ADHD).

Attention-deficit/hyperactivity disorder (ADHD) is a common, behavioral, and heterogeneous neurodevelopmental condition characterized by hyperactivity, impulsivity, and inattention. Symptoms of this disorder are managed by treatment with methylphenidate, amphetamine, and/or atomoxetine. The cause of ADHD is unknown, but substantial evidence indicates that this disorder has a significant genetic component. Transgenic animals have become an essential tool in uncovering the genetic factors underlying ADHD. Although they cannot accurately reflect the human condition, they can provide insights into the disorder that cannot be obtained from human studies due to various limitations. An ideal animal model of ADHD must have face (similarity in symptoms), predictive (similarity in response to treatment or medications), and construct (similarity in etiology or underlying pathophysiological mechanism) validity. As the exact etiology of ADHD remains unclear, the construct validity of animal models of ADHD would always be limited. The proposed transgenic animal models of ADHD have substantially increased and diversified over the years. In this paper, we compiled and explored the validity of proposed transgenic animal models of ADHD. Each of the reviewed transgenic animal models has strengths and limitations. Some fulfill most of the validity criteria of an animal model of ADHD and have been extensively used, while there are others that require further validation. Nevertheless, these transgenic animal models of ADHD have provided and will continue to provide valuable insights into the genetic underpinnings of this complex disorder.

The Importance of Vagus Nerve Afferent in the Formation of Emotions in Attention-Deficit Hyperactivity Disorder Model Rat

It is of interest to know how environmental stimuli contribute to the formation of emotion during development. In a rat model of attention-deficit hyperactivity disorder, monosodium L- glutamate (MSG), a taste substance of umami, was administered for 5 weeks during developmental period, followed by emotional behavior tests such as open-field test and social interaction test in adulthood. Although no significant change was observed in anxiety-like behavior, MSG intake caused a reduction in aggressive behavior. Vagotomy under the level of diaphragm resulted in eliminating the MSG effect on aggression, indicating the importance of neuronal activity of the vagus nerve in this effect. Futher studies will focus on futher questions regarding the gut-brain axis such as the change of microbiota and the mechanism of the axis in the brain.

Rearing in an enriched environment attenuated hyperactivity and inattention in the Spontaneously Hypertensive Rats, an animal model of Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder, characterized by symptoms of hyperactivity, inattention, and impulsivity. It is commonly treated with psychostimulants that typically begins during childhood and lasts for an extended period of time. However, there are concerns regarding the consequences of chronic psychostimulant treatment; thus, there is a growing search for an alternative management for ADHD. One non-pharmacological management that is gaining much interest is environmental enrichment. Here, we investigated the effects of rearing in an enriched environment (EE) on the expression of ADHD-like symptoms in the Spontaneously Hypertensive Rats (SHRs), an animal model of ADHD. SHRs were reared in EE or standard environment (SE) from post-natal day (PND) 21 until PND 49. Thereafter, behavioral tests that measure hyperactivity (open field test [OFT]), inattention (Y-maze task), and impulsivity (delay discounting task) were conducted. Additionally, electroencephalography (EEG) was employed to assess the effects of EE on rat's brain activity. Wistar-Kyoto (WKY) rats, the normotensive counterpart of the SHRs, were used to determine whether the effects of EE were specific to a particular genetic background. EE improved the performance of the SHRs and WKY rats in the OFT and Y-maze task, but not the delay discounting task. Interestingly, EE induced significant EEG changes in WKY rats, but not in the SHRs. These findings show that rearing environment may play a role in the expression of ADHD-like symptoms in the SHRs and that EE may be considered as a putative complementary approach in managing ADHD symptoms.