Sphingolipids and DHA Improve Cognitive Deficits in Aged Beagle Dogs.

Canine cognitive dysfunction syndrome (CDS) is a disorder found in senior dogs that is typically defined by the development of specific behavioral signs which are attributed to pathological brain aging and no other medical causes. One way of objectively characterizing CDS is with the use of validated neuropsychological test batteries in aged Beagle dogs, which are a natural model of this condition. This study used a series of neuropsychological tests to evaluate the effectiveness of supplementation with a novel lipid extract containing porcine brain-derived sphingolipids (Biosfeen®) and docosahexaenoic acid (DHA) for attenuating cognitive deficits in aged Beagles. Two groups (n = 12), balanced for baseline cognitive test performance, received a daily oral dose of either test supplement, or placebo over a 6-month treatment phase. Cognitive function was evaluated using the following tasks: delayed non-matching to position (DNMP), selective attention, discrimination learning retention, discrimination reversal learning, and spatial discrimination acquisition and reversal learning. The effect of the supplement on brain metabolism using magnetic resonance spectroscopy (MRS) was also examined. A significant decline (p = 0.02) in DNMP performance was seen in placebo-treated dogs, but not in dogs receiving the supplement, suggesting attenuation of working memory performance decline. Compared to placebo, the supplemented group also demonstrated significantly improved (p = 0.01) performance on the most difficult pattern of the spatial discrimination task and on reversal learning of the same pattern (p = 0.01), potentially reflecting improved spatial recognition and executive function, respectively. MRS revealed a significant increase (p = 0.048) in frontal lobe glutamate and glutamine in the treatment group compared to placebo, indicating a physiological change which may be attributed to the supplement. Decreased levels of glutamate and glutamine have been correlated with cognitive decline, suggesting the observed increase in these metabolites might be linked to the positive cognitive effects found in the present study. Results of this study suggest the novel lipid extract may be beneficial for counteracting age-dependent deficits in Beagle dogs and supports further investigation into its use for treatment of CDS. Additionally, due to parallels between canine and human aging, these results might also have applicability for the use of the supplement in human cognitive health.

Efficacy of a Therapeutic Diet on Dogs With Signs of Cognitive Dysfunction Syndrome (CDS): A Prospective Double Blinded Placebo Controlled Clinical Study.

Cognitive dysfunction syndrome (CDS) is a common condition in senior dogs, which may be analogous to dementia such as Alzheimer's disease (AD) in people. In humans, AD has been associated with many risk factors such as reduced cerebral glucose metabolism, docosahexaenoic acid (DHA) deficiency, chronic oxidative stress, and chronic inflammation. By targeting some of these risk factors, we have developed two nutritional solutions (medium chain triglyceride, MCT and Brain Protection Blend, BPB) to enhance cognitive function and slow aging-induced cognitive decline. These have been positively evaluated in colony housed senior dogs and cats. The objective of this clinical study was to evaluate the effects of diets with MCTs and the BPB on client-owned dogs with CDS. Participating veterinary clinics screened senior dogs for signs of CDS as determined by a Senior Canine Behavior Questionnaire and a Canine Medical Health Questionnaire. Eighty-seven dogs were randomly enrolled into one of three diet groups with 29 dogs per group: Control, 6.5% MCT oil + BPB (6.5% MCT diet), 9% MCT oil + BPB (9% MCT diet). Diets were fed for a period of 90 days, and each dog's CDS signs were re-evaluated at day 30 and day 90. All 6 categories of the CDS signs were significantly improved (p <0.05) in the dogs given the 6.5% MCT diet at the end of the 90-day study. Control only improved in 4 out 6 categories. The 9% MCT diet only improved in dogs that accepted the diet. The results from this dog study confirm the benefits of MCT and BPB in managing clinical signs of CDS in dogs. The results support our hypothesis that targeting known risk factors associated with brain aging and AD is able to improve symptoms of CDS in dogs. These data may facilitate the development of similar nutrient blends to manage MCI and AD.

Development and validation of the Patient-Physician Relationship Scale among patients with irritable bowel syndrome.

BACKGROUND: An effective patient-physician relationship (PPR) is essential to the care of patients with irritable bowel syndrome (IBS). We sought to develop and validate an IBS-specific instrument to measure expectations of the PPR. METHODS: We conducted structured focus groups about PPRs with 12 patients with IBS. Qualitative analysis was used to generate a questionnaire (the Patient-Physician Relationship Scale [PPRS]), which was modified with input from content experts and usability testing. For validation, we administered it online to US adults with IBS. Participants also completed the Functional Bowel Disorder Severity Index, the Rome III Adult Functional gastrointestinal (GI) Disorder Criteria Questionnaire, and modified versions of the Communication Assessment Tool (CAT-15) and Patient-Doctor Relationship Questionnaire (PDRQ-9). We performed principal components factor analysis for the PPRS. KEY RESULTS: The PPRS contained 32 questions with responses on a 7-item Likert scale. Themes included interpersonal features, clinical care expectations, and aspects of communication. One thousand and fifty-four eligible individuals completed the survey (88% completion rate). Most participants were middle aged (mean 48 years, SD 16.3), white (90%), and female (86%). Factor analysis showed only one relevant factor, relating to quality of PPR. The final scale ranged from possible-96 to +96 (mean 62.0, SD 37.6). It correlated moderately with the CAT-15 (r=.40, P<.001) and PDRQ-9 (r=.30, P<.001), establishing concurrent validity. CONCLUSIONS & INFERENCES: We describe the development and validation of the first questionnaire for use in measuring patient expectations of the PPR, which can be used for future outcomes studies and training physicians.

Pattern separation and goal-directed behavior in the aged canine.

The pattern separation task has recently emerged as a behavioral model of hippocampus function and has been used in several pharmaceutical trials. The canine is a useful model to evaluate a multitude of hippocampal-dependent cognitive tasks that parallel those in humans. Thus, this study was designed to evaluate the suitability of pattern separation task(s) for detecting age-related changes in canines. We also assessed the dogs' ability to show pattern separation and discrimination reversal, which provides a novel extension of the pattern separation learning literature. Our data show that aged dogs are impaired on a complex pattern separation task (six-well task) relative to easier tasks (four-well or six-well pattern discrimination task), and that the age-related deficits are due to loss of perceptual and inhibitory control in addition to the loss of spatial discrimination and pattern separation ability. Our data also suggest that aged animals show pattern separation deficits when the objects are brought progressively closer together while changing the location of both correct and incorrect objects. However, if the location of any one object is fixed the animals tend to use alternate strategies. Overall, these data provide important insight into age-related pattern separation deficits in a higher animal model and offers additional means for evaluating the impact of lifestyle and pharmaceutical interventions on episodic memory in preclinical trials.

Patterns of impaired oral health-related quality of life dimensions.

How dental patients are affected by oral conditions can be described with the concept of oral health-related quality of life (OHRQoL). This concept intends to make the patient experience measurable. OHRQoL is multidimensional, and Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact were suggested as its four dimensions and consequently four scores are needed for comprehensive OHRQoL assessment. When only the presence of dimensional impact is measured, a pattern of affected OHRQoL dimensions would describe in a simple way how oral conditions influence the individual. By determining which patterns of impact on OHRQoL dimensions exist in prosthodontic patients and general population subjects, we aimed to identify in which combinations oral conditions' functional, painful, aesthetical and psychosocial impact occurs. Data came from the Dimensions of OHRQoL Project with Oral Health Impact Profile (OHIP)-49 data from 6349 general population subjects and 2999 prosthodontic patients in the Learning Sample (N = 5173) and the Validation Sample (N = 5022). We hypothesised that all 16 patterns of OHRQoL dimensions should occur in these individuals who suffered mainly from tooth loss, its causes and consequences. A dimension was considered impaired when at least one item in the dimension was affected frequently. The 16 possible patterns of impaired OHRQoL dimensions were found in patients and general population subjects in both Learning and Validation Samples. In a four-dimensional OHRQoL model consisting Oral Function, Oro-facial Pain, Oro-facial Appearance and Psychosocial Impact, oral conditions' impact can occur in any combination of the OHRQoL dimensions.

Effect of mitochondrial cofactors and antioxidants supplementation on cognition in the aged canine.

A growing body of research has focused on modifiable risk factors for prevention and attenuation of cognitive decline in aging. This has led to an unprecedented interest in the relationship between diet and cognitive function. Several preclinical and epidemiologic studies suggest that dietary intervention can be used to improve cognitive function but randomized controlled trials are increasingly failing to replicate these findings. Here, we use a canine model of aging to evaluate the effects of specific components of diet supplementation which contain both antioxidants and a combination of mitochondrial cofactors (lipoic acid [LA] and acetyl-l-carnitine) on a battery of cognitive functions. Our data suggest that supplementation with mitochondrial cofactors, but not LA or antioxidant alone, selectively improve long-term recall in aged canines. Furthermore, we found evidence that LA alone could have cognitive impairing effects. These results contrast to those of a previous longitudinal study in aged canine. Our data demonstrate that one reason for this difference may be the nutritional status of animals at baseline for the 2 studies. Overall, this study suggests that social, cognitive, and physical activity together with optimal dietary intake (rather than diet alone) promotes successful brain aging.

Diurnal changes in core body temperature, day/night locomotor activity patterns, and actigraphy-generated behavioral sleep in aged canines with varying levels of cognitive dysfunction.

Core body temperature (CBT) rhythm, locomotor activity, and actigraphy-sleep were evaluated in geriatric dogs with cognitive dysfunction. Dogs (n=33; 9-16 yrs) performed a spatial working memory task and divided into three memory groups: Low, Moderate, and High, with subsequent evaluation of learning and attention. Rectal CBT was recorded 6 times over a 17.5 h period and Actiwatch® activity monitoring system for 5 days while housed indoors with 12 h light/dark schedule. Rhythm of daily activity data was evaluated using the traditional cosinor analysis and generation of non-parametric measures of interdaily stability, intradaily variability, and relative amplitude. CBT differed with time (F (5, 130)=11.36, p<0.001), and was the highest at 19:00C. CBT at 19:00 was positively related (p<0.01) to memory (r(31)=0.50) and 3-domain cognitive performance index (memory, learning, attention; r(31)=0.39). Total daytime or night-time activity did not differ between memory groups, but hourly counts at 8:00 were positively related (p<0.05) to memory (r(31)=0.52), learning (r(31)=0.36), and 3-domain cognitive performance index (r(31)=0.53). There were no significant differences between age or memory groups for any circadian rhythm measures. Daytime naps were inversely related to memory accuracy (r(31)=-0.39; p<0.05) and BT at 15:00 (r(30)=-0.51; p<0.01). Lower peak BT and increased napping may predict some aspects of cognitive performance of working memory, learning, and/or attention processes in these geriatric dogs, but minimal diurnal rhythm disruption of locomotor activity is observed when these cognitive processes decline.

Olfactory discrimination and generalization of ammonium nitrate and structurally related odorants in Labrador retrievers.

A critical aspect of canine explosive detection involves the animal's ability respond to novel, untrained odors based on prior experience with training odors. In the current study, adult Labrador retrievers (N = 15) were initially trained to discriminate between a rewarded odor (vanillin) and an unrewarded odor (ethanol) by manipulating scented objects with their nose in order to receive a food reward using a canine-adapted discrimination training apparatus. All dogs successfully learned this olfactory discrimination task (≥80 % correct in a mean of 296 trials). Next, dogs were trained on an ammonium nitrate (AN, NH4NO3) olfactory discrimination task [acquired in 60-240 trials, with a mean (±SEM) number of trials to criterion of 120.0 ± 15.6] and then tested for their ability to respond to untrained ammonium- and/or nitrate-containing chemicals as well as variants of AN compounds. Dogs did not respond to sodium nitrate or ammonium sulfate compounds at rates significantly higher than chance (58.8 ± 4.5 and 57.7 ± 3.3 % correct, respectively). Transfer performance to fertilizer-grade AN, AN mixed in Iraqi soil, and AN and flaked aluminum was significantly higher than chance (66.7 ± 3.2, 73.3 ± 4.0, 68.9 ± 4.0 % correct, respectively); however, substantial individual differences were observed. Only 53, 60, and 64 % of dogs had a correct response rate with fertilizer-grade AN, AN and Iraqi soil, and AN and flaked aluminum, respectively, that were greater than chance. Our results suggest that dogs do not readily generalize from AN to similar AN-based odorants at reliable levels desired for explosive detection dogs and that performance varies significantly within Labrador retrievers selected for an explosive detection program.

Cognitive domains in the dog: independence of working memory from object learning, selective attention, and motor learning.

Cognition in dogs, like in humans, is not a unitary process. Some functions, such as simple discrimination learning, are relatively insensitive to age; others, such as visuospatial learning can provide behavioral biomarkers of age. The present experiment sought to further establish the relationship between various cognitive domains, namely visuospatial memory, object discrimination learning (ODL), and selective attention (SA). In addition, we also set up a task to assess motor learning (ML). Thirty-six beagles (9-16 years) performed a variable delay non-matching to position (vDNMP) task using two objects with 20- and 90-s delay and were divided into three groups based on a combined score (HMP = 88-93 % accuracy [N = 12]; MMP = 79-86 % accuracy [N = 12]; LMP = 61-78 % accuracy [N = 12]). Variable object oddity task was used to measure ODL (correct or incorrect object) and SA (0-3 incorrect distractor objects with same [SA-same] or different [SA-diff] correct object as ODL). ML involved reaching various distances (0-15 cm). Age did not differ between memory groups (mean 11.6 years). ODL (ANOVA P = 0.43), or SA-same and SA-different (ANOVA P = 0.96), performance did not differ between the three vDNMP groups, although mean errors during ODL was numerically higher for LMP dogs. Errors increased (P < 0.001) for all dogs with increasing number of distractor objects during both SA tasks. vDNMP groups remained different (ANOVA P < 0.001) when re-tested with vDNMP task 42 days later. Maximum ML distance did not differ between vDNMP groups (ANOVA P = 0.96). Impaired short-term memory performance in aged dogs does not appear to predict performance of cognitive domains associated with object learning, SA, or maximum ML distance.

Molecular psychiatry of zebrafish.

Due to their well-characterized neural development and high genetic homology to mammals, zebrafish (Danio rerio) have emerged as a powerful model organism in the field of biological psychiatry. Here, we discuss the molecular psychiatry of zebrafish, and its implications for translational neuroscience research and modeling central nervous system (CNS) disorders. In particular, we outline recent genetic and technological developments allowing for in vivo examinations, high-throughput screening and whole-brain analyses in larval and adult zebrafish. We also summarize the application of these molecular techniques to the understanding of neuropsychiatric disease, outlining the potential of zebrafish for modeling complex brain disorders, including attention-deficit/hyperactivity disorder (ADHD), aggression, post-traumatic stress and substance abuse. Critically evaluating the advantages and limitations of larval and adult fish tests, we suggest that zebrafish models become a rapidly emerging new field in modern molecular psychiatry research.

Exercise enhances memory consolidation in the aging brain.

Exercise has been shown to reduce age-related losses in cognitive function including learning and memory, but the mechanisms underlying this effect remain poorly understood. Memory formation occurs in stages that include an initial acquisition phase, an intermediate labile phase, and then a process of consolidation which leads to long-term memory formation. An effective way to examine the mechanism by which exercise improves memory is to introduce the intervention (exercise), post-acquisition, making it possible to selectively examine memory storage and consolidation. Accordingly we evaluated the effects of post-trial exercise (10 min on a treadmill) on memory consolidation in aged canines both right after, an hour after, and 24 h after acute exercise training in concurrent discrimination, object location memory (OLM), and novel object recognition tasks. Our study shows that post-trial exercise facilitates memory function by improving memory consolidation in aged animals in a time-dependent manner. The improvements were significant at 24 h post-exercise and not right after or 1 h after exercise. Aged animals were also tested following chronic exercise (10 min/day for 14 consecutive days) on OLM or till criterion were reached (for reversal learning task). We found improvements from a chronic exercise design in both the object location and reversal learning tasks. Our studies suggest that mechanisms to improve overall consolidation and cognitive function remain accessible even with progressing age and can be re-engaged by both acute and chronic exercise.

Acquisition of a visual discrimination and reversal learning task by Labrador retrievers.

Optimal cognitive ability is likely important for military working dogs (MWD) trained to detect explosives. An assessment of a dog's ability to rapidly learn discriminations might be useful in the MWD selection process. In this study, visual discrimination and reversal tasks were used to assess cognitive performance in Labrador retrievers selected for an explosives detection program using a modified version of the Toronto General Testing Apparatus (TGTA), a system developed for assessing performance in a battery of neuropsychological tests in canines. The results of the current study revealed that, as previously found with beagles tested using the TGTA, Labrador retrievers (N = 16) readily acquired both tasks and learned the discrimination task significantly faster than the reversal task. The present study confirmed that the modified TGTA system is suitable for cognitive evaluations in Labrador retriever MWDs and can be used to further explore effects of sex, phenotype, age, and other factors in relation to canine cognition and learning, and may provide an additional screening tool for MWD selection.

Noninvasive measurements of body composition and body water via quantitative magnetic resonance, deuterium water, and dual-energy x-ray absorptiometry in cats.

OBJECTIVE: To compare quantitative magnetic resonance (QMR), dual-energy x-ray absorptiometry (DXA), and deuterium oxide (D2O) dilution methods for measurement of total body water (TBW), lean body mass (LBM), and fat mass (FM) in healthy cats and to assess QMR precision and accuracy. ANIMALS: Domestic shorthair cats (58 and 32 cats for trials 1 and 2, respectively). PROCEDURES: QMR scans of awake cats performed with 2 units were followed by administration of D2O tracer (100 mg/kg, PO). Cats then were anesthetized, which was followed by QMR and DXA scans. Jugular blood samples were collected before and 120 minutes after D2O administration. RESULTS: QMR precision was similar between units (coefficient of variation < 2.9% for all measures). Fat mass, LBM, and TBW were similar for awake or sedated cats and differed by 4.0%, 3.4%, and 3.9%, respectively, depending on the unit. The QMR minimally underestimated TBW (1.4%) and LBM (4.4%) but significantly underestimated FM (29%), whereas DXA significantly underestimated LBM (9.2%) and quantitatively underestimated FM (9.3%). A significant relationship with D2O measurement was detected for all QMR (r(2) > 0.84) and DXA (r(2) > 0.84) measurements. CONCLUSIONS AND CLINICAL RELEVANCE: QMR was useful for determining body composition in cats; precision was improved over DXA. Quantitative magnetic resonance can be used to safely and rapidly acquire data without the need for anesthesia, facilitating frequent monitoring of weight changes in geriatric, extremely young, or ill pets. Compared with the D2O dilution method, QMR correction equations provided accurate data over a range of body compositions.

Noninvasive measurements of body composition and body water via quantitative magnetic resonance, deuterium water, and dual-energy x-ray absorptiometry in awake and sedated dogs.

OBJECTIVE: To compare quantitative magnetic resonance (QMR), dual-energy x-ray absorptiometry (DXA), and deuterium oxide (D2O) methods for measurement of total body water (TBW), lean body mass (LBM), and fat mass (FM) in healthy dogs and to assess QMR accuracy. ANIMALS: 58 Beagles (9 months to 11.5 years old). PROCEDURES: QMR scans were performed on awake dogs. A D2O tracer was administered (100 mg/kg, PO) immediately before dogs were sedated, which was followed by a second QMR or DXA scan. Jugular blood samples were collected before and 120 minutes after D2O administration. RESULTS: TBW, LBM, and FM determined via QMR were not significantly different between awake or sedated dogs, and means differed by only 2.0%, 2.2%, and 4.3%, respectively. Compared with results for D2O dilution, QMR significantly underestimated TBW (10.2%), LBM (13.4%), and FM (15.4%). Similarly, DXA underestimated LBM (7.3%) and FM (8.4%). A significant relationship was detected between FM measured via D2O dilution and QMR (r(2) > 0.89) or DXA (r(2) > 0.88). Even though means of TBW and LBM differed significantly between D2O dilution and QMR or DXA, values were highly related (r(2) > 0.92). CONCLUSIONS AND CLINICAL RELEVANCE: QMR was useful for determining body composition in dogs and can be used to safely and rapidly acquire accurate data without the need for sedation or anesthesia. These benefits can facilitate frequent scans, particularly in geriatric, extremely young, or ill pets. Compared with the D2O dilution method, QMR correction equations provided accurate assessment over a range of body compositions.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease.

Cognitive enhancement in middle-aged and old cats with dietary supplementation with a nutrient blend containing fish oil, B vitamins, antioxidants and arginine.

Cognitive dysfunction syndrome is a major disease affecting old cats and is the consequence of severe and irreversible loss of brain cells and brain atrophy. The present study focused on the hypothesis that the optimal strategy for promoting successful brain ageing is to target risk factors associated with brain ageing and dementia. We used a nutritional strategy involving supplementation with a blend of nutrients (antioxidants, arginine, B vitamins and fish oil) to test this hypothesis. Middle-aged and old cats between 5·5 and 8·7 years of age were assigned to cognitively equivalent control or treatment groups based on prior cognitive experience and performance on baseline cognitive tests. The cats in the treatment group were maintained on a diet supplemented with the nutrient blend and the cats in the control group were maintained on the identical base diet without the additional supplementation. After an initial wash-in period, all cats were tested on a battery of cognitive test protocols. The cats fed the test diet showed significantly better performance on three of four test protocols: a protocol assessing egocentric learning, a protocol assessing discrimination and reversal learning and a protocol focused on acquisition of a spatial memory task. The results support the hypothesis that brain function of middle-aged and old cats can be improved by the nutrient blend that was selected to minimise or eliminate the risk factors associated with brain ageing and dementia.

Evaluation of cognitive learning, memory, psychomotor, immunologic, and retinal functions in healthy puppies fed foods fortified with docosahexaenoic acid-rich fish oil from 8 to 52 weeks of age.

OBJECTIVE: To assess effects of foods fortified with docosahexaenoic acid (DHA)-rich fish oil on cognitive, memory, psychomotor, immunologic, and retinal function and other measures of development in healthy puppies. DESIGN: Evaluation study. ANIMALS: 48 Beagle puppies. PROCEDURES: Puppies were assigned to 3 groups after weaning (n = 16/group) and received 1 of 3 foods (low-DHA, moderate-DHA, or high-DHA food) as their sole source of nutrition until 1 year of age. Visual discrimination learning and memory tasks, psychomotor performance tasks, and physiologic tests including blood and serum analysis, electroretinography, and dual-energy x-ray absorptiometry were performed at various time points. Anti-rabies virus antibody titers were evaluated 1, 2, 4, and 8 weeks after vaccination at 16 weeks of age. RESULTS: Foods had similar proximate analysis results but varied in concentration of DHA from fish oil; the high-DHA food also contained higher concentrations of vitamin E, taurine, choline, and l-carnitine than did other foods. The high-DHA group had significantly better results for reversal task learning, visual contrast discrimination, and early psychomotor performance in side-to-side navigation through an obstacle-containing maze than did the moderate-DHA and low-DHA groups. The high-DHA group had significantly higher anti-rabies antibody titers 1 and 2 weeks after vaccination than did other groups. Peak b-wave amplitudes during scotopic electroretinography were positively correlated with serum DHA concentrations at all evaluated time points. CONCLUSIONS AND CLINICAL RELEVANCE: Dietary fortification with fish oils rich in DHA and possibly other nutrients implicated in neurocognitive development following weaning improved cognitive, memory, psychomotor, immunologic, and retinal functions in growing dogs.

The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.

Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs.

Aging has been shown to disrupt performance on tasks that require intact visual search and discrimination abilities in human studies. The goal of the present study was to determine if canines show age-related decline in their ability to perform a novel simultaneous visual search task. Three groups of canines were included: a young group (N = 10; 3 to 4.5 years), an old group (N = 10; 8 to 9.5 years), and a senior group (N = 8; 11 to 15.3 years). Subjects were first tested for their ability to learn a simple two-choice discrimination task, followed by the visual search task. Attentional demands in the task were manipulated by varying the number of distracter items; dogs received an equal number of trials with either zero, one, two, or three distracters. Performance on the two-choice discrimination task varied with age, with senior canines making significantly more errors than the young. Performance accuracy on the visual search task also varied with age; senior animals were significantly impaired compared to both the young and old, and old canines were intermediate in performance between young and senior. Accuracy decreased significantly with added distracters in all age groups. These results suggest that aging impairs the ability of canines to discriminate between task-relevant and -irrelevant stimuli. This is likely to be derived from impairments in cognitive domains such as visual memory and learning and selective attention.