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Objective: We prospectively examined associations between intakes of antioxidants (vitamins C, vitamin E, and carotene) and cognitive function and decline among elderly men and women of the Cache County Study on Memory and Aging in Utah. Participants and Design: In 1995, 3831 residents 65 years of age or older completed a baseline survey that included a food frequency questionnaire and cognitive assessment, Cognitive function was assessed using an adapted version of the Modified Mini-Mental State examination (3MS) at baseline and at three subsequent follow-up interviews spanning approximately 7 years. Multivariable-mixed models were used to estimate antioxidant nutrient effects on average 3MS score over time. Results: Increasing quartiles of vitamin C intake alone and combined with vitamin E were associated with higher baseline average 3MS scores (p-trend = 0.013 and 0.02 respectively); this association appeared stronger for food sources compared to supplement or food and supplement sources combined. Study participants with lower levels of intake of vitamin C, vitamin E and carotene had a greater acceleration of the rate of 3MS decline over time compared to those with higher levels of intake. Conclusion: High antioxidant intake from food and supplement sources of vitamin C, vitamin E, and carotene may delay cognitive decline in the elderly. [ABSTRACT FROM AUTHOR]

Background: Non-pharmacologic interventions can potentially improve cognitive function, sleep, and/or mood in patients with attention-deficit/hyperactive disorder (ADHD), post-concussion syndrome (PCS), or memory loss., Objective: We evaluated the benefits of a brain rehabilitation program in an outpatient neurology practice that consists of targeted cognitive training, lifestyle coaching, and electroencephalography (EEG)-based neurofeedback, twice weekly (90 minutes each), for 12 weeks., Methods: 223 child and adult patients were included: 71 patients with ADHD, 88 with PCS, and 64 with memory loss (mild cognitive impairment or subjective cognitive decline). Patients underwent a complete neurocognitive evaluation, including tests for Verbal Memory, Complex Attention, Processing Speed, Executive Functioning, and Neurocognition Index. They completed questionnaires about sleep, mood, diet, exercise, anxiety levels, and depression-as well as underwent quantitative EEG-at the beginning and the end of the program., Results: Pre-post test score comparison demonstrated that all patient subgroups experienced statistically significant improvements on most measures, especially the PCS subgroup, which experienced significant score improvement on all measures tested ( p ≤0.0011; d z ≥0.36). After completing the program, 60% to 90% of patients scored higher on cognitive tests and reported having fewer cognitive and emotional symptoms. The largest effect size for pre-post score change was improved executive functioning in all subgroups (ADHD d z = 0.86; PCS d z = 0.83; memory d z = 1.09)., Conclusion: This study demonstrates that a multimodal brain rehabilitation program can have benefits for patients with ADHD, PCS, or memory loss and supports further clinical trials in this field., Competing Interests: The authors have no conflict of interest to report. The first two authors (M.F. and N.K.) are employees of NeuroGrow Brian Fitness Center, a private neurology practice located in Northern Virginia., (© 2023 – The authors. Published by IOS Press.)

Artificial photosynthesis, an umbrella term, is a chemical process that biomimetics natural photosynthesis. In natural photosynthesis, electrons from the water-oxidation reaction are used for carbon dioxide reduction. Herein, we report the reducion of aldehydes and ketones to corresponding alcohols in a simple undivided cell. This reaction utilized inexpensive nickel foam electrodes (1 cm 2 ) and LiClO 4 (0.05 M) as a commercially accessible electrolyte in an aqueous medium. Under electrochemical conditions, a series of alcohols (21 examples) produces high selectivity in good yields (up to 100%). Usage the current method, 10 mmol (1060 mg) of benzaldehyde is also successfully reduced to benzyl alcohol (757 mg, 70% isolated yield) without any by‑products. This route to alcohols matched several green chemistry principles: (a) atom economy owing to the use of H 2 O as the solvent and the source of hydrogen, (b) elimination of the homogeneous metal catalyst, (c) use of smooth reaction conditions, (d) waste inhibition due to low volumetric of by-products, and (e) application of safe EtOH co-solvent. Moreover, the ability of the system to operate with alkyne and alkene compounds enhanced the practical efficiency of this process., (© 2022. The Author(s).)

Purpose: To assess the clinical efficacy of the fluocinolone acetonide (FA) intravitreal implant ( Iluvien , Alimera Sciences ) over a 12-month period in a population resistant to treatment with first-line anti-VEGF agents., Methods: This study is a retrospective cohort study assessing functional and anatomical outcomes in 13 eyes of 12 patients treated for diabetic macular oedema (DMO) with a single fluocinolone implant (FA) ( Iluvien) under real-world conditions. The follow-up period includes the time of first intravitreal treatment (incl anti-VEGF or short-lasting steroids) given until 12 months post FA implant insertion. Primary outcomes were best corrected visual acuity (BCVA), measured using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale, and central foveal thickness (CFT), measured using Topcon 3DOCT-2000 (Topcon Inc) SD-OCT imaging. Mean BCVA and CFT were measured before anti-VEGF treatment, after anti-VEGF treatment, at the time of Iluvien implant insertion, and 6 and 12 months after Iluvien implant insertion. The t-paired sample test was used to ascertain statistical significance of changes in comparison of two samples while the ANOVA analysis was used in comparison of three or more samples., Results: The baseline BCVA (SD) of the cohort prior to initiation of anti-VEGF treatment was 47.45 (12.27) ETDRS letters whilst the mean CFT (SD) was 579 (203) microns. Following completion of anti-VEGF therapy, the mean improvement in vision was 8.9 ETDRS letters (p = 0.1) whilst the mean reduction in CFT was 197 microns (p = 0.028). Mean BCVA (SD) at the time of insertion of the FA implant was 55.15 (11.16) ETDRS letters and mean (SD) CFT at time of insertion of the FA was 454.62 μm (109.51). Following the 12-month treatment period with the FA implant, BCVA (SD) was 62.15 (10.25) ETDRS letters (p = 0.0331) and the mean (SD) CFT was 404.36 μm (142.92), a change of -50.26 μm from baseline (p = 0.0369)., Conclusions: This study has shown that statistically significant improvements in BCVA and CFT can be achieved over a 12-month period with the Iluvien implant. The implant has been shown to be a safe option in the treatment of DMO and may have a role to play in achieving good functional and anatomical outcomes in DMO while also reducing the frequency of follow-up appointments required to maintain stable vision in the working-age population.

Purpose: The Persian language is a member of the Western Iranian branch of the Indo-Iranian family within the Indo-European language family. Here, we aimed to study phonological development in Persian-speaking children., Method: The speech samples were collected from 387 children, aged 3-6 years old, using two picture-naming tasks: Persian Articulation and Phonology tests, which were used to study phonetic and phonemic inventories, phoneme accuracy, and the age of error patterns suppression., Result: Vowels are acquired at three or earlier. Acquisition of all consonants in the initial position precedes that of the final position. Older children had higher values in phoneme accuracy compared with those of the younger children. Although no significant effects of gender on phonological development were found, girls had higher accuracy scores compared with boys. Final devoicing and cluster reduction were the last error patterns which were suppressed by 6.0., Conclusion: The results showed that the accuracy of children's productions grew with age and the number of error patterns decreased. It seems that there are some similarities between phonological developments in different languages; however, it is still important to study language specific tendencies to be used in clinical settings and speech sound development research.

Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

Objectives: To adapt the LittlEARS ® Auditory Questionnaire into Persian and evaluate the psychometric properties of the Persian version of the questionnaire for children with normal hearing., Methods: A "back-translation" method was used to translate and adapt the LittlEARS Auditory Questionnaire into Persian. The translated version was first evaluated by means of an expert-appraisal method. After having improved the Persian version of LittlEARs with the results obtained from that evaluation, various psychometric analyses were carried out to determine the validity and reliability. A group of 240 Persian speaking parents of children below 24 months of age with normal hearing completed the LittlEARS ® Auditory Questionnaire. Various psychometric analyses (scale analysis and item analysis) were conducted., Results: In the current study, the following scale and item characteristics were investigated: Corrected item-total correlations ranged from 0.14 to 0.74; Cronbach's alpha coefficient value was 0.960; the split-half reliability r was 0.734; predictive accuracy Guttman's lambda was 0.965; the correlation between the overall score and age of the children was 0.808 (p < 0.001). The regression curve, which reflects the age-dependence of auditory behavior, was produced. The regression analysis that was conducted to obtain normative data showed that 80% of the variance in the total scores could be explained by age., Conclusion: The data obtained from psychometric analysis support the use of the Persian version of the LittlEARS Auditory Questionnaire as a reliable and valid tool to assess the development of auditory behavior in Persian speaking children who are 24 months old or younger., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: Pre-linguistic vocalizations including early consonants, vowels, and their combinations into syllables are considered as important predictors of the speech and language development. The purpose of this study was to examine vowel development in babblings of normally developing Persian-learning infants., Methods: Eight typically developing 6-8-month-old Persian-learning infants (3 boys and 5 girls) participated in this 4-month longitudinal descriptive-analytic study. A weekly 30-60-minute audio- and video-recording was obtained at home from the comfort state vocalizations of infants and the mother-child interactions. A total of 74:02:03 hours of vocalizations were phonetically transcribed. Seven vowels comprising /i/,/e/,/a/,/u/,/o/,/ɑ/, and /ә/ were identified in the babblings. The inter-rater reliability was obtained for 20% of vocalizations. The data were analyzed by repeated measures ANOVA and Pearson's correlation coefficient using SPSS software version 20., Results: The results showed that two vowels /a/ (46.04) and /e/ (23.60) were produced with the highest mean frequency of occurrence, respectively. Regarding front/back dimension, the front vowels were the most prominent ones (71.87); in terms of height, low (46.78) and mid (32.45) vowels occurred maximally. A good inter-rater reliability was obtained (0.99, P < .01)., Conclusion: The increased frequency of occurrence of the low and mid front vowels in the current study was consistent with previous studies on the emergence of vowels in pre-linguistic vocalization in other languages.

Reducing cognitive decline in patients with Mild Cognitive Impairment (MCI) may slow their progression to develop dementia. In this 12-week single-arm intervention trial, elderly patients (n = 127, age 70.69 +/-10.53, 63% female) with a diagnosis of MCI were enrolled in a multi-disciplinary Brain Fitness Program. The main outcome measure was changes in a battery of 10 cognitive domains. Each patient received weekly personalized cognitive stimulation, neurofeedback training, and brain coaching/counseling for eating a Mediterranean diet, taking omega-3 supplements, increasing fitness, and practicing mindfulness meditation. The post-program testing showed 84% of the patients experienced statistically significant improvements in their cognitive function (p< 0.05). Among the random sample of 17 patients who had a post-program quantitative MRI, 12 patients had either no atrophy or an actual growth above the baseline volume of their hippocampus. These preliminary findings support the concept that a personalized Brain Fitness Program can improve cognitive function and either reverse or grow the volume of hippocampus in elderly with MCI., Competing Interests: Dr. Majid Fotuhi, Brooke Lubinski, and Tracy Riloff were employees of the clinical practice. Dr Raji is a consultant for Brainreader ApS. The authors otherwise have nothing to disclose regarding conflict of interests.

The hippocampus is particularly vulnerable to the neurotoxic effects of obesity, diabetes mellitus, hypertension, hypoxic brain injury, obstructive sleep apnoea, bipolar disorder, clinical depression and head trauma. Patients with these conditions often have smaller hippocampi and experience a greater degree of cognitive decline than individuals without these comorbidities. Moreover, hippocampal atrophy is an established indicator for conversion from the normal ageing process to developing mild cognitive impairment and dementia. As such, an important aim is to ascertain which modifiable factors can have a positive effect on the size of the hippocampus throughout life. Observational studies and preliminary clinical trials have raised the possibility that physical exercise, cognitive stimulation and treatment of general medical conditions can reverse age-related atrophy in the hippocampus, or even expand its size. An emerging concept--the dynamic polygon hypothesis--suggests that treatment of modifiable risk factors can increase the volume or prevent atrophy of the hippocampus. According to this hypothesis, a multidisciplinary approach, which involves strategies to both reduce neurotoxicity and increase neurogenesis, is likely to be successful in delaying the onset of cognitive impairment with ageing. Further research on the constellation of interventions that could be most effective is needed before recommendations can be made for implementing preventive and therapeutic strategies.

Individuals over 80 years of age represent the most rapidly growing segment of the population, and late-life dementia has become a major public health concern worldwide. Development of effective preventive and treatment strategies for late-life dementia relies on a deep understanding of all the processes involved. In the centuries since the Greek philosopher Pythagoras described the inevitable loss of higher cognitive functions with advanced age, various theories regarding the potential culprits have dominated the field, ranging from demonic possession, through 'hardening of blood vessels', to Alzheimer disease (AD). Recent studies suggest that atrophy in the cortex and hippocampus-now considered to be the best determinant of cognitive decline with aging-results from a combination of AD pathology, inflammation, Lewy bodies, and vascular lesions. A specific constellation of genetic and environmental factors (including apolipoprotein E genotype, obesity, diabetes, hypertension, head trauma, systemic illnesses, and obstructive sleep apnea) contributes to late-life brain atrophy and dementia in each individual. Only a small percentage of people beyond the age of 80 years have 'pure AD' or 'pure vascular dementia'. These concepts, formulated as the dynamic polygon hypothesis, have major implications for clinical trials, as any given drug might not be ideal for all elderly people with dementia.

Vestibular migraine (VM), also known as migraine-associated vertigo, is a common cause of dizziness in adults. We performed a comprehensive literature search regarding treatment for VM or migraine-associated vertigo during the period of 1990-2008 and used, individually or in combination, the search terms VM, migraine-associated vertigo, migraine-associated dizziness, migrainous vertigo, migraine and vertigo, migraine and disequilibrium, and headache and vertigo. We found nine publications that address treatment strategies for VM. One small randomized clinical trial found some benefit from the use of zolmitriptan for abortive treatment of VM. The other eight observational studies showed marginal improvement with migraine prophylactic medications such as nortriptyline, verapamil, or metoprolol. Until more specific treatment options become available, patients with VM need to be managed with similar prophylactic and abortive strategies as those used for migraine in adults.

Long-chain omega-3 fatty acids could have neuroprotective properties against dementia, which is becoming a major global public health issue. We conducted a systematic review of the literature to establish the association between eating fish (a source of long-chain omega-3 fatty acids) or taking long-chain omega-3 fatty acid supplements and the risk of cognitive decline or Alzheimer disease (AD). We identified eleven observational studies and four clinical trials. All three observational studies that used cognitive decline as an outcome reported significant benefits, whereas only four of eight observational studies that used incidence of AD or dementia as an outcome reported positive findings. None of four small clinical trials provided convincing evidence for the use of this approach in the prevention or treatment of any form of dementia. In summary, the existing data favor a role for long-chain omega-3 fatty acids in slowing cognitive decline in elderly individuals without dementia, but not for the prevention or treatment of dementia (including AD). This apparent dichotomy might reflect differences in study designs with regard to participants, dosages, the ratio of long-chain omega-3 to omega-6 fatty acids, or the choice of outcome measurements. Large clinical trials of extended duration should help to provide definitive answers.

Purpose: To report the utility of a coronary technique to facilitate carotid stenting in patients with difficult arch anatomies., Technique: When confronted with challenging arch anatomy that prevents engaging the common carotid artery (CCA) with the guiding sheath using standard techniques, an 8-F left Amplatz guiding catheter (AL1) is placed at the origin of the innominate artery. A 0.014-inch coronary guidewire is advanced into the external carotid artery (ECA), and a small monorail coronary balloon is inflated in a small branch of the ECA. The balloon/guidewire combination facilitates maneuvering a 0.035-inch Amplatz super-stiff guidewire through the ECA and then advancing the guiding catheter into the CCA., Conclusion: This anchoring technique can be a helpful method for cannulating the CCA in patients with a complex arch when the ECA is patent.

Studies have shown less cognitive decline and lower risk of Alzheimer's disease in elderly individuals consuming either antioxidant vitamins or nonsteroidal anti-inflammatory drugs (NSAIDs). The potential of added benefit from their combined use has not been studied. We therefore analyzed data from 3,376 elderly participants of the Cache County Study who were given the Modified Mini-Mental State examination up to three times during a period of 8 years. Those who used a combination of vitamins E and C supplements and NSAIDs at baseline declined by an average 0.96 fewer points every 3 years than nonusers (P < .05). This apparent effect was attributable entirely to participants with the APOE epsilon4 allele, whose users declined by 2.25 fewer points than nonusers every 3 years (P < .05). These results suggest that among elderly individuals with an APOE epsilon4 allele, there is an association between using antioxidant supplements in combination with NSAIDs and less cognitive decline over time.

Background: The immunophilins are proteins that mediate actions of immunosuppressant drugs such as FK506 and cyclosporin A by binding to calcineurin, inhibiting its phosphatase activity, and increasing the phosphorylation level of transcription factors required for interleukin 2 formation. Though concentrations in the brain greatly exceed levels in immune tissues, no function has been previously established for nervous system immunophilins. Nitric oxide (NO) has been implicated in neurotransmitter release. FK506 appears to inhibit NO production by maintaining NO synthase in a highly phosphorylated and thereby inactivated state. Accordingly, we examined effects of FK506 and cyclosporin A on neurotransmitter release in PC12 cells treated with nerve growth factor (NGF) and in rat brain striatal synaptosomes., Materials and Methods: We monitored effects of immunophilin ligands on [3H]-neurotransmitter release from PC12 cells differentiated with NGF. Rat brain striatal synaptosomes were loaded with radiolabeled transmitters and treated with FK506 or cyclosporin A prior to initiating neurotransmitter release with N-methyl-D-aspartate (NMDA) or potassium depolarization. Striatal synaptosomes were also loaded with 32P-orthophosphate and treated with FK506. 32P-labeled synaptic vesicle proteins were isolated from these synaptosomes in an attempt to relate specific FK506-dependent phosphorylation of vesicle proteins with the effects of FK506 on neurotransmitter release. Identification of proteins targetted by FK506 was made by immunoblot analysis and immunoprecipitation., Results: Low nanomolar concentrations of the immunosuppressant drugs FK506 and cyclosporin A (CsA) inhibit transmitter release from PC-12 cells and from NMDA-stimulated brain synaptosomes. By contrast, the immunosuppressants augment depolarization-induced transmitter release from synaptosomes. Synapsin I, a synaptic vesicle phosphoprotein, displays enhanced phosphorylation in the presence of FK506., Conclusions: Inhibition of transmitter release in PC-12 cells and NMDA-treated synaptosomes by immunosuppressants may reflect augmented phosphorylation of NO synthase, reducing its catalytic activity. This fits with the requirement of NO for transmitter release in PC12 cells and NMDA-treated synaptosomes. Stimulation by immunosuppressants of transmitter release in potassium depolarized synaptosomes may result from augmented phosphorylation of synapsin I, whose phosphorylation is known to facilitate transmitter release. Thus, immunophilins may modulate release of numerous neurotransmitters both by influencing NO formation and the phosphorylation state of synaptic vesicle-associated proteins.

The immunosuppressant drugs cyclosporin A and FK506 bind to small, predominantly soluble proteins cyclophilin and FK506 binding protein, respectively, to mediate their pharmacological actions. The immunosuppressant actions of these drugs occur through binding of cyclophilin-cyclosporin A and FK506 binding protein-FK506 complexes to the calcium-calmodulin-dependent protein phosphatase, calcineurin, inhibiting phosphatase activity. Utilizing immunohistochemistry, in situ hybridization and autoradiography, we have localized protein and messenger RNA for FK506 binding protein, cyclophilin and calcineurin. All three proteins and/or messages exhibit a heterogenous distribution through the brain and spinal cord, with the majority of the localizations being neuronal. We observe a striking co-localization of FK506 binding protein and calcineurin in most brain regions and a close similarity between calcineurin and cyclophilin. FK506 binding protein and cyclophilin localizations largely correspond to those of calcineurin, although cyclophilin is enriched in some brain areas that lack calcineurin. The dramatic similarities in localization of FK506 binding proteins and cyclophilins with calcineurin suggest related functions.

Metabotropic glutamate receptors (mGluRs) have been implicated in a number of hippocampal functions including learning and memory. Five subtypes have been molecularly and pharmacologically characterized. Using in situ hybridization with oligonucleotide probes selective for these five mGluRs, we have found that each has a unique pattern of expression in the hippocampus and entorhinal cortex. mGluR1 is expressed predominantly in the dentate gyrus and CA3. mGluR2 is enriched in the dentate gyrus and inner layer of the entorhinal cortex. mGluR3 is also expressed in these two structures, but unlike all the other mGluRs, is found in white matter areas as well. mGluR4 is present predominantly in CA2 while mGluR5 is concentrated in most regions of the hippocampus and entorhinal cortex. Comparative analysis of the distributions of these receptors with that of the components of their putative downstream signal transduction mechanisms suggests that mGluR5 may be the main subtype of mGluR which mediates the excitatory actions of glutamate in CA1 and could contribute to the elevation of calcium levels found in CA1 pyramidal neurons in long term potentiation and in ischemic/hypoxic injury. mGluR2 and mGluR3, the main subtypes contributing to the inhibitory actions of glutamate, are absent in CA1. Thus, the mGluR-mediated excitatory actions of glutamate can occur in all regions of the hippocampus whereas the mGluR-mediated inhibitory actions of glutamate may be restricted to the dentate gyrus and CA3.

The neurochemical organization of the basal ganglia has been studied extensively with respect to neurotransmitters, neuropeptides, and their receptors. The chemoarchitecture of the striatum has been found particularly striking, because it distinguishes many substances by their relative distributions within the striosome and matrix compartments of the striatum. Very little is yet known about the differential distribution of second messenger systems in the basal ganglia, however, and no information is available about whether the distribution of second messenger systems is related to the prominent neurochemical compartmentalization of the striatum. We have examined the distribution of the phosphoinositide second messenger system in the primate basal ganglia and substantia nigra, as detected with polyclonal antisera against the inositol 1,4,5-trisphosphate receptor (IP3R), and monoclonal antisera against phospholipase C beta (PLC beta) and phospholipase C gamma (PLC gamma). In the striatum, immunostaining for each of the three proteins was present predominantly in medium-sized neuronal perikarya and in the neuropil. Circumscribed zones of enhanced IP3R, PLC beta, and PLC gamma immunoreactivity appeared in a background of generally weaker staining, and these zones corresponded to striosomes as identified by calbinidin D28k and substance P immunostaining in adjacent sections. Thus, the richest representation of the phosphoinositide system in the primate striatum appears to be in striosomes. In the substantia nigra pars compacta, neurons and neuropil were immunopositive, but in the substantia nigra pars reticulata and in each segment of the globus pallidus, immunostaining was mainly confined to the neuropil. Perikaryal PCL gamma immunoreactivity in the absence of detectable PLC beta or IP3R immunolabeling was found in the magnocellular neurons embedded in the medullary layer between the putamen and the globus pallidus. These observations demonstrate that the phosphoinositide second messenger system is selectively enhanced in neuronal subsystems of the basal ganglia, including striosomes, and suggest that signaling by phosphoinositide pathways elicits discrete effects on input-output processing by the basal ganglia.

The type 1 metabotropic glutamate receptor (mGluR1) is through to act via the phosphoinositide (PI) system with the associated formation of inositol 1,4,5-trisphosphate (IP3) and Ca2+ release. Utilizing immunohistochemistry and in situ hybridization, we have localized protein and mRNA, respectively, for the mGluR1 and the IP3 receptor (IP3R). We have also localized glutamate-linked PI turnover by autoradiography with 3H-cytidine. We observe a striking contrast in localizations of mGluR1 and IP3R both for protein and mRNA. For instance, mGluR1 occurs in the apparent absence of IP3R in neurons of the stratum oriens of the CA1 hippocampus, islands of Calleja, anterodorsal nucleus of thalamus, lateral nucleus of hypothalamus, and the granular cell layer and the deep nuclei of cerebellum. mGluR1 actions in these brain regions may primarily be mediated through the protein kinase C limb of the PI system, as they contain moderate amounts of 3H-phorbol ester binding. The subthalamic nucleus, red nucleus, and Darkshevich's nucleus, which possess high levels of mGluR1, are devoid of both IP3R immunoreactivity and 3H-phorbol ester binding. These reciprocal localizations suggest that mGluR1 actions in many brain areas may not primarily involve IP3, reflecting instead influences on protein kinase C or other second messengers.

We have localized CDRK and DRK1, two novel K+ channels of the Shab subfamily by immunohistochemistry. The two channels are closely related in structure with about 90% amino acid identity in the N-terminal and middle portions and 60% identity in the C-terminal region. We observe striking differences in cellular localizations of the two channels. DRK1 tends to localize to cell bodies and proximal dendrites discretely, while CDRK is diffusely present in cell bodies and is also found on fibers in specific brain areas. In the cerebral cortex DRK1 is localized to pyramidal cells, whereas CDRK occurs in small cells, presumably interneurons. These localizations may reflect specialized delayed rectifier functions and targeting properties manifested differentially by K+ channel subfamily members.

The second messenger inositol 1,4,5-trisphosphate triggers the release of intracellular Ca2+ stores upon binding to the inositol 1,4,5-trisphosphate receptor protein, a calcium channel that has been purified and molecularly cloned. To clarify the roles of inositol 1,4,5-trisphosphate receptor in the central nervous system, we have examined in detail the distribution of inositol 1,4,5-trisphosphate receptors in the rat brain and spinal cord using immunohistochemical methods. Inositol 1,4,5-trisphosphate receptors are present in neuronal cells, fibers and terminals in a wide distribution of areas throughout the central nervous system. These include a number of areas not previously reported, such as the olfactory bulb, thalamic nuclei and dorsal horn of the spinal cord. In addition, we have noted a strikingly high density of inositol 1,4,5-trisphosphate receptors in circumventricular organs and neuroendocrine structures such as the area postrema, choroid plexus, subcommisural organ, pineal gland and pituitary. The distribution of inositol 1,4,5-trisphosphate receptors in discrete structures throughout the central nervous system, including interconnected neuronal systems and neuroendocrine and circumventricular organ structures, presumably reflects the importance of Ca2+ release mediated by the phosphoinositide second messenger system in control of diverse physiological processes.

The immunophilins cyclophilin and FK506 binding protein (FKBP) are small, predominantly soluble proteins that bind the immunosuppressant drugs cyclosporin A and FK506, respectively, with high affinity, and which seem to mediate their pharmacological actions. The Ca(2+)-dependent protein phosphatase, calcineurin, binds the cyclophilin-cyclosporin A and FKBP-FK506 complexes, indicating that calcineurin might mediate the actions of these drugs. A physiological role for the immunophilins in the nervous system is implied by a close homology between the structure of NINA A, a protein in the neural retina of Drosophila, and cyclophilin, as well as by the high density of FKBP messenger RNA in brain tissue. Here we report that the levels of FKBP and mRNA in rat brain are extraordinarily high and that their regional localization is virtually identical to that of calcineurin, indicating that there may be a physiological link between calcineurin and the immunophilins. We also show that at low concentrations FK506 and cyclosporin A enhance the phosphorylation of endogenous protein substrates in brain tissue and in intact PC12 cells, indicating that these drugs may inhibit phosphatase activity by interacting with the immunophilin-calcineurin complexes.

Nitric oxide is a free radical that has been recently recognized as a neural messenger molecule. Nitric oxide synthase has now been purified and molecularly cloned from brain. Using specific antibodies and oligonucleotide probes, we have localized brain nitric oxide synthase to discrete neuronal populations in the rat and primate brain. Nitric oxide synthase is exclusively neuronal, and its localization is absolutely coincident with NADPH diaphorase staining in both rat and primate.

NADPH diaphorase staining neurons, uniquely resistant to toxic insults and neurodegenerative disorders, have been colocalized with neurons in the brain and peripheral tissue containing nitric oxide synthase (EC 1.14.23.-), which generates nitric oxide (NO), a recently identified neuronal messenger molecule. In the corpus striatum and cerebral cortex, NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in medium to large aspiny neurons. These same neurons colocalize with somatostatin and neuropeptide Y immunoreactivity. NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in the pedunculopontine nucleus with choline acetyltransferase-containing cells and are also colocalized in amacrine cells of the inner nuclear layer and ganglion cells of the retina, myenteric plexus neurons of the intestine, and ganglion cells of the adrenal medulla. Transfection of human kidney cells with NO synthase cDNA elicits NADPH diaphorase staining. The ratio of NO synthase to NADPH diaphorase staining in the transfected cells is the same as in neurons, indicating that NO synthase fully accounts for observed NADPH staining. The identity of neuronal NO synthase and NADPH diaphorase suggests a role for NO in modulating neurotoxicity.

Food-deprived rats were offered food in small meal segments, and latency to initiate feeding and time to complete it were recorded for each segment. Bilateral microinjections of d-amphetamine into nucleus accumbens dramatically increased the mean speed with which meal segments were eaten, but had no reliable effect on mean latency to initiate eating of new segments; l-amphetamine had similar but weaker effects. While mean eating speed was increased, this increase resulted from a decrease in the frequency of slow trials and not from an increase in the absolute speed of the fastest trials. These data suggest that amphetamine facilitates feeding by some other means than simple improvement of the motoric capacity of the animal, and they indicate that nucleus accumbens is an important site for amphetamine's established but not widely appreciated facilitory effects on feeding.