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.

Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response.

High-affinity transporters for norepinephrine (NE) and serotonin (5-HT), which ensure neurotransmitter clearance at the synapse, are the principal targets of widely used antidepressant drugs. Antidepressants targeting these high-affinity transporters, however, do not provide positive treatment outcomes for all patients. Other monoamine transport systems, with lower affinity, have been detected in the brain, but their role is largely unknown. Here we report that OCT2, a member of the polyspecific organic cation transporter (OCT) family, is expressed notably in the limbic system and implicated in anxiety and depression-related behaviors in the mouse. Genetic deletion of OCT2 in mice produced a significant reduction in brain tissue concentrations of NE and 5-HT and in ex vivo uptake of both these neurotransmitters in the presence of the dual 5-HT-NE transport blocker, venlafaxine. In vivo clearance of NE and 5-HT evaluated using microiontophoretic electrophysiology was diminished in the hippocampus of OCT2(-/-) mice in the presence of venlafaxine, thereby affecting postsynaptic neuronal activity. OCT2(-/-) mice displayed an altered sensitivity to acute treatments with NE- and/or 5-HT-selective transport blockers in the forced-swim test. Moreover, the mutant mice were insensitive to long-term venlafaxine treatment in a more realistic, corticosterone-induced, chronic depression model. Our findings identify OCT2 as an important postsynaptic determinant of aminergic tonus and mood-related behaviors and a potential pharmacological target for mood disorders therapy.

Nuclear Medicine Technologists' Perception and Current Assessment of Quality: A Society of Nuclear Medicine and Molecular Imaging Technologist Section Survey.

In 2015, the Society of Nuclear Medicine and Molecular Imaging Technologist Section (SNMMI-TS) launched a multiyear quality initiative to help prepare the technologist workforce for an evidence-based health-care delivery system that focuses on quality. To best implement the quality strategy, the SNMMI-TS first surveyed technologists to ascertain their perception of quality and current measurement of quality indicators. Methods: An internet survey was sent to 27,989 e-mail contacts. Questions related to demographic data, perceptions of quality, quality measurement, and opinions on the minimum level of education are discussed in this article. Results: A total of 4,007 (14.3%) responses were received. When asked to list 3 words or phrases that represent quality, there were a plethora of different responses. The top 3 responses were image quality, quality control, and technologist education or competency. Surveying patient satisfaction was the most common quality measure (80.9%), followed by evaluation of image quality (78.2%). Evaluation of image quality (90.3%) and equipment functionality (89.4%) were considered the most effective measures. Technologists' differentiation between quality, quality improvement, quality control, quality assurance, and quality assessment seemed ambiguous. Respondents were confident in their ability to assess and improve quality at their workplace (91.9%) and agreed their colleagues were committed to delivering quality work. Of note, 70.7% of respondents believed that quality is directly related to the technologist's level of education. Correspondingly, respondents felt there should be a minimum level of education (99.5%) and that certification or registry should be required (74.4%). Most respondents (59.6%) felt that a Bachelor's degree should be the minimum level of education, followed by an Associate's degree (40.4%). Conclusion: To best help nuclear medicine technologists provide quality care, the SNMMI-TS queried technologists to discern perceptions of quality in nuclear medicine. The results show that technologists believe image quality and quality control are the most important determinants. Most respondents felt that quality is directly related to the level of education of the technologist acquiring the scan. However, the responses obtained also demonstrated variation in perception of what represents quality. The SNMMI-TS can use the results of the study as a benchmark of current technologists' knowledge and performance of quality measures and target educational programs to improve the quality of nuclear medicine and molecular imaging.

Brain structures involved in the sexual behaviour of Ile de France rams with different sexual preferences and levels of sexual activity.

Using Fos, as a marker, we analysed the brain structures of rams, with different libidos or sexual preferences that had been activated by contact with males or females. Ile de France rams aged from 1.5 to 7 years were used. Fos immunoreactivity (Fos IR) was analysed in rams with high (HL) or low libido (LL) after 90 min of direct contact with females (HL DirF n=7 or LL DirF n=7) or in rams of high libido having indirect contact through a fence, with females (HL IndF n=6) or males (HL IndM n=5) and finally, in males who preferred other males as partners by indirect contact through a fence with males (MO IndM n=4). Direct or indirect contact with a preferred sexual partner (LL DirF, HL Dir F, HL IndF, MO IndM) induced the appearance of Fos-IR cells in several diencephalic and cortical structures. Conversely, indirect contact with males did not induce Fos-IR in males interested in females (HL IndM). In the medial preoptic area (MPOA), the paraventricular nucleus and the medial bed nucleus of the stria terminalis the cell density of Fos IR cells was higher in HL Dir F than in LL DirF suggesting involvement in sexual motivation whereas only the MPOA seemed involved the consummatory component of sexual behaviour (Fos IR density HL DirF>HL IndF). The enthorinal cortex was the only structure specifically activated by males attracted to other males (Fos IR density MO IndM>HL IndM) whereas Fos IR density did not differ between the HL IndF and HL IndM groups.

Periodic maternal separation decreases hippocampal neurogenesis without affecting basal corticosterone during the stress hyporesponsive period, but alters HPA axis and coping behavior in adulthood.

Although not directly evaluated, the early rise of glucocorticoid (GC) levels, as occur after exposure to adverse early life experience, are assumed to affect hippocampal ontogeny by altering the hippocampus negative feedback on adult HPA axis. To test whether hippocampal ontogeny is affected by early exposure to stress we estimated the survival of recently formed hippocampal granule cells in rat pups subjected to periodic maternal separation (180 min/day; MS180) from postnatal days (PND) 1 to 14. Accordingly, MS180 pups injected with bromodeoxyuridine (BrdU, 50 mg/kg, ip) at PND 5 showed decreased density of doublecortin (DCX) positive BrdU-labeled cells at PND 15. MS180 and AFR pups showed similar corticosterone (CORT) basal levels between PND 3 and 12, whereas adult MS180 rats presented with higher CORT levels than AFR adults. Nonetheless, both AFR and MS180 pups and adults showed similar transient increments of CORT levels in response to stress. In addition, MS180 had no effect on the adult anxiety-like behavior evaluated in the elevated plus maze, but evoked a passive coping strategy in the forced swimming test. The data show that the decrease in hippocampal neurogenesis is an early onset phenomenon, and suggests that adverse experiences alter hippocampal ontogeny without chronic elevation of GC levels.

Restricted role of CRF1 receptor for the activity of brainstem catecholaminergic neurons in the negative state of morphine withdrawal.

RATIONALE: Evidence suggests that corticotropin-releasing factor (CRF) system is an important mediator in the negative symptoms of opioid withdrawal. OBJECTIVES: We used genetically engineered mice lacking functional CRF receptor-1 (CRF1R) levels to study the role for CRF/CRF1R pathways in the negative affective states of opioid withdrawal. METHODS: Wild-type and CRF1R(-/-) offspring of CRF1R(+/-) breeders were identified by PCR analysis of tail DNA and were rendered dependent on morphine via intraperitoneal injection of increasing doses of morphine (10-60 mg/kg). Negative state associated with opioid withdrawal was examined by using conditioned place aversion (CPA), TH expression and TH phosphorylation were measured in different brain regions involved in addictive behaviours using immunohistochemistry. RESULTS: The weight loss in morphine withdrawn CRF1R(-/-) animals was significantly (p < 0.05) lower versus wild-type. The aversion for environmental cues paired with opioid withdrawal was lower (p < 0.001) in the CRF1R-deficient versus wild-type. Using dual immunolabeling for c-Fos, data show that naloxone-induced withdrawal increases the number of TH positive neurons phosphorylated at Ser40 or Ser31 that coexpress c-Fos in the nucleus of tractus solitarius (NTS)-A2 from wild-type and CRF(-/-) deficient mice. By contrast, the number of phospho-Ser40 or phospho-Ser31 positive neurons expressing c-Fos was lower in the ventrolateral medulla (VLM)-A1 in CRF(-/-)-deficient mice. CONCLUSION: Our study demonstrates an increased activity of brainstem catecholaminergic neurons after CPA induced by morphine withdrawal suggesting that CRF1R is implicated in the activation of A1 neurons and provides evidence that this receptor is involved in the body weight loss and in the negative aversive effects of morphine withdrawal.

Pre-treatment with the mGlu2/3 receptor agonist LY379268 attenuates DOI-induced impulsive responding and regional c-Fos protein expression.

RATIONALE: Overactivation of serotonin (5-hydroxytryptamine, 5-HT)(2A) receptors causes impulsivity and attentional deficits. Since 5-HT(2A) receptors are known to entertain antagonistic interactions with metabotropic glutamate (mGlu)2/3 receptors, this interaction may provide an alternative target for a novel class of antipsychotics. OBJECTIVES/METHODS: The study characterizes interactions between 5-HT(2A) and mGlu2/3 receptors implicated in impulse control. Hooded Lister rats were trained in a 5-choice serial reaction time task (5-CSRTT) and treated with the 5-HT(2A/2C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride (DOI, 0.1 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg). In addition, associated drug-induced changes in neuronal activity were assessed via c-Fos immunoreactivity (Fos IR), and co-localization of c-Fos and GABAergic markers was detected using double immunofluorescence labeling. RESULTS: Systemic DOI caused impulsive overresponding that was attenuated in animals pre-treated with LY379268. LY379268 itself had no significant effect on the rats' performance in the 5-CSRTT. DOI enhanced Fos IR within fronto-cortical and limbic brain structures, and this effect was blocked by LY379268 pre-treatment. Double immunofluorescence labeling showed a specific co-localization of DOI-elicited Fos IR with GABAergic (GAD(67)-positive) cells lacking the calcium-binding protein parvalbumin while LY379268 increased Fos IR in GABAergic and non-GABAergic cells. CONCLUSION: Our results suggest that impulsivity is possibly due to a primary increase in Glu transmission mediated via 5-HT(2A) receptor activation. Thus, mGlu2/3 receptor agonists might have some potential for treating motor impulsivity-related impairments while their cognitive enhancing effects were not confirmed in this study.

Zenk expression in auditory regions changes with breeding condition in male Black-capped chickadees (Poecile atricapillus).

Black-capped chickadees (Poecile atricapillus) produce different vocalizations at different times of year: the fee-bee song is produced by males primarily in spring, whereas the chick-a-dee call is produced year-round but most frequently in the fall and winter. We wanted to determine if neural response to playback in auditory regions of the songbird brain varied with season in parallel to production. We captured adult male black-capped chickadees from the wild in either breeding condition or non-breeding condition and within 24-48 h of bringing them into the laboratory setting, played them recordings of either conspecific vocalizations (fee-bee songs or chick-a-dee calls), heterospecific vocalizations (Song Sparrow, Melospiza melodia, song), or silence. We then measured ZENK protein immunoreactivity (Zenk-ir) in caudomedial nidopallium (NCM) and caudomedial mesopallium (CMM), two regions important for perception of conspecific vocalizations. We found that, overall, non-breeding birds had greater Zenk-ir than breeding birds. In addition, we found that birds in non-breeding condition had significantly greater Zenk-ir to heterospecific song than birds in breeding condition, but this difference was not seen in birds that heard conspecific songs or calls. Finally, in NCMd chickadees had greater response to playback of conspecific vocalizations (when combining song and call groups) than playback of heterospecific vocalizations but only while in breeding condition. Our results qualify the claim that Zenk-ir is biased toward conspecific vocalizations, and indicate that specificity of neural response varies with season. Variation could be a result of increased production and perceptual demand in spring, or hormonal changes in breeding birds, possibly because chickadees display vocal plasticity in chick-a-dee calls in the fall, requiring a degree of neural plasticity across seasons.