Neurotransmitter organization of the nucleus of Edinger-Westphal and its projection to the avian ciliary ganglion

Two morphologically distinct types of preganglionic endings are observed in the avian ciliary ganglion: boutonal and cap-like. Boutonal endings synapse on ciliary ganglion neurons (called choroidal neurons) innervating choroidal blood vessels, while cap-like endings synapse on ciliary ganglion neurons (called ciliary neurons) controlling the lens and pupil. Some of both types of preganglionic endings contain the neuropeptides substance P (SP) and/or leucine-enkephalin (LENK). Although both types of preganglionic terminals are also known to be cholinergic, there has been no direct evidence that SP and LENK are found in cholinergic endings in the ciliary ganglion. The present studies in pigeons, which involved the use of single- and double-label immunohistochemical techniques, were undertaken to examine this issue, as well as to (1) determine the relative percentages of the boutonal and cap-like endings that contain SP, LENK, or both SP and LENK; and (2) determine if the two different types of terminals in the ciliary ganglion arise from different subdivisions of the nucleus of Edinger-Westphal (EW). Single- and double-label immunohistochemical studies revealed that all neurons of EW, regardless of whether they contained immunohistochemically detectible amounts of SP or LENK, are cholinergic. In the medial subdivision of EW (EWM), which was found to contain approximately 700 neurons, 20.2% of these neurons were observed to contain both SP and LENK, while 11.6% were observed to contain SP only and 10.7% were observed to contain LENK only. In contrast, in lateral EW (EWL), which was found to contain approximately 500 neurons, 16.2% of the neurons were observed to contain both SP and LENK, while 19.2% of the neurons were observed to contain SP only and 12.6% were observed to contain LENK only. Retrograde-labeling studies involving horseradish peroxidase injections into the ciliary ganglion revealed that EW was the sole source of input to the ciliary ganglion and all, or nearly all, neurons in EW innervate the ciliary ganglion. Immunohistochemical labeling of the ciliary ganglion neurons with an antiserum against choline acetyltransferase revealed that approximately 900 choroidal neurons and approximately 600 ciliary neurons are present in the ganglion, all of which receive cholinergic preganglionic endings. Of the choroidal neurons, 94% receive butonal terminals containing both SP and LENK, while only 2% receive SP+ only boutonal endings and 2% receive LENK+ only butonal endings. Of the ciliary neurons, 25% receive cap-like endings containing both SP and LENK, 30% receive cap-like endings containing only SP and 3% receive cap-like endings containing only LENK. Total unilateral lesions of EW resulted in the loss of all SP+ or LENK+ terminals in the ipsilateral ganglion. Subtotal EW lesions that spared either part of EWM or part of EWL revealed that boutonal endings arise from EWM neurons and cap-like endings from EWL neurons. The present results suggest that the choroidal neurons, which regulate choroidal blood flow, may be relatively uniform in their functional properties since they nearly all receive boutonal endings from EWM that co-contain SP, LENK, and acetylcholine. In contrast, the ciliary neurons, which receive their preganglionic input from EWL, may consist of at least three major functionally distinct subgroups: (1) those receiving SP/LENK/acetylcholine-containing cap-like endings; (2) those receiving SP/acetylcholine-containing cap-like endings; and (3) those receiving acetylcholine-containing cap-like endings. The functional diversity of ciliary neurons may in part be related to the fact that some ciliary neurons innervate the iris and others the ciliary body

A Visual Pathway Links Brain Structures Active during Magnetic Compass Orientation in Migratory Birds

The magnetic compass of migratory birds has been suggested to be light-dependent. Retinal cryptochrome-expressing neurons and a forebrain region, “Cluster N”, show high neuronal activity when night-migratory songbirds perform magnetic compass orientation. By combining neuronal tracing with behavioral experiments leading to sensory-driven gene expression of the neuronal activity marker ZENK during magnetic compass orientation, we demonstrate a functional neuronal connection between the retinal neurons and Cluster N via the visual thalamus. Thus, the two areas of the central nervous system being most active during magnetic compass orientation are part of an ascending visual processing stream, the thalamofugal pathway. Furthermore, Cluster N seems to be a specialized part of the visual wulst. These findings strongly support the hypothesis that migratory birds use their visual system to perceive the reference compass direction of the geomagnetic field and that migratory birds “see” the reference compass direction provided by the geomagnetic field

Kiwi Forego Vision in the Guidance of Their Nocturnal Activities

BACKGROUND: In vision, there is a trade-off between sensitivity and resolution, and any eye which maximises information gain at low light levels needs to be large. This imposes exacting constraints upon vision in nocturnal flying birds. Eyes are essentially heavy, fluid-filled chambers, and in flying birds their increased size is countered by selection for both reduced body mass and the distribution of mass towards the body core. Freed from these mass constraints, it would be predicted that in flightless birds nocturnality should favour the evolution of large eyes and reliance upon visual cues for the guidance of activity. METHODOLOGY/PRINCIPAL FINDINGS: We show that in Kiwi (Apterygidae), flightlessness and nocturnality have, in fact, resulted in the opposite outcome. Kiwi show minimal reliance upon vision indicated by eye structure, visual field topography, and brain structures, and increased reliance upon tactile and olfactory information. CONCLUSIONS/SIGNIFICANCE: This lack of reliance upon vision and increased reliance upon tactile and olfactory information in Kiwi is markedly similar to the situation in nocturnal mammals that exploit the forest floor. That Kiwi and mammals evolved to exploit these habitats quite independently provides evidence for convergent evolution in their sensory capacities that are tuned to a common set of perceptual challenges found in forest floor habitats at night and which cannot be met by the vertebrate visual system. We propose that the Kiwi visual system has undergone adaptive regressive evolution driven by the trade-off between the relatively low rate of gain of visual information that is possible at low light levels, and the metabolic costs of extracting that information

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Motion processing with wide-field neurons in the retino-tecto-rotundal pathway

The retino-tecto-rotundal pathway is the main visual pathway in non-mammalian vertebrates and has been found to be highly involved in visual processing. Despite the extensive receptive fields of tectal and rotundal wide-field neurons, pattern discrimination tasks suggest a system with high spatial resolution. In this paper, we address the problem of how global processing performed by motion-sensitive wide-field neurons can be brought into agreement with the concept of a local analysis of visual stimuli. As a solution to this problem, we propose a firing-rate model of the retino-tecto-rotundal pathway which describes how spatiotemporal information can be organized and retained by tectal and rotundal wide-field neurons while processing Fourier-based motion in absence of periodic receptive-field structures. The model incorporates anatomical and electrophysiological experimental data on tectal and rotundal neurons, and the basic response characteristics of tectal and rotundal neurons to moving stimuli are captured by the model cells. We show that local velocity estimates may be derived from rotundal-cell responses via superposition in a subsequent processing step. Experimentally testable predictions which are both specific and characteristic to the model are provided. Thus, a conclusive explanation can be given of how the retino-tecto-rotundal pathway enables the animal to detect and localize moving objects or to estimate its self-motion parameters

Mammal-Like Organization of the Avian Midbrain Central Gray and a Reappraisal of the Intercollicular Nucleus

In mammals, rostrocaudal columns of the midbrain periaqueductal gray (PAG) regulate diverse behavioral and physiological functions, including sexual and fight-or-flight behavior, but homologous columns have not been identified in non-mammalian species. In contrast to mammals, in which the PAG lies ventral to the superior colliculus and surrounds the cerebral aqueduct, birds exhibit a hypertrophied tectum that is displaced laterally, and thus the midbrain central gray (CG) extends mediolaterally rather than dorsoventrally as in mammals. We therefore hypothesized that the avian CG is organized much like a folded open PAG. To address this hypothesis, we conducted immunohistochemical comparisons of the midbrains of mice and finches, as well as Fos studies of aggressive dominance, subordinance, non-social defense and sexual behavior in territorial and gregarious finch species. We obtained excellent support for our predictions based on the folded open model of the PAG and further showed that birds possess functional and anatomical zones that form longitudinal columns similar to those in mammals. However, distinguishing characteristics of the dorsal/dorsolateral PAG, such as a dense peptidergic innervation, a longitudinal column of neuronal nitric oxide synthase neurons, and aggression-induced Fos responses, do not lie within the classical avian CG, but in the laterally adjacent intercollicular nucleus (ICo), suggesting that much of the ICo is homologous to the dorsal PAG

Niemann-Pick disease type C

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations

Cholesterol Perturbation in Mice Results in p53 Degradation and Axonal Pathology through p38 MAPK and Mdm2 Activation

Perturbation of lipid metabolism, especially of cholesterol homeostasis, can be catastrophic to mammalian brain, as it has the highest level of cholesterol in the body. This notion is best illustrated by the severe progressive neurodegeneration in Niemann-Pick Type C (NPC) disease, one of the lysosomal storage diseases, caused by mutations in the NPC1 or NPC2 gene. In this study, we found that growth cone collapse induced by genetic or pharmacological disruption of cholesterol egress from late endosomes/lysosomes was directly related to a decrease in axonal and growth cone levels of the phosphorylated form of the tumor suppressor factor p53. Cholesterol perturbation-induced growth cone collapse and decrease in phosphorylated p53 were reduced by inhibition of p38 mitogen-activated protein kinase (MAPK) and murine double minute (Mdm2) E3 ligase. Growth cone collapse induced by genetic (npc1−/−) or pharmacological modification of cholesterol metabolism was Rho kinase (ROCK)-dependent and associated with increased RhoA protein synthesis; both processes were significantly reduced by P38 MAPK or Mdm2 inhibition. Finally, in vivo ROCK inhibition significantly increased phosphorylated p53 levels and neurofilaments in axons, and axonal bundle size in npc1−/− mice. These results indicate that NPC-related and cholesterol perturbation-induced axonal pathology is associated with an abnormal signaling pathway consisting in p38 MAPK activation leading to Mdm2-mediated p53 degradation, followed by ROCK activation. These results also suggest new targets for pharmacological treatment of NPC disease and other diseases associated with disruption of cholesterol metabolism

Age and Diet Affect Gene Expression Profiles in Canine Liver Tissue

BACKGROUND: The liver plays a central role in nutrient and xenobiotic metabolism, but its functionality declines with age. Senior dogs suffer from many of the chronic hepatic diseases as elderly humans, with age-related alterations in liver function influenced by diet. However, a large-scale molecular analysis of the liver tissue as affected by age and diet has not been reported in dogs. METHODOLOGY/PRINCIPAL FINDINGS: Liver tissue samples were collected from six senior (12-year old) and six young adult (1-year old) female beagles fed an animal protein-based diet (APB) or a plant protein-based diet (PPB) for 12 months. Total RNA in the liver tissue was extracted and hybridized to Affymetrix GeneChip® Canine Genome Arrays. Using a 2.0-fold cutoff and false discovery rate <0.10, our results indicated that expression of 234 genes was altered by age, while 137 genes were differentially expressed by diet. Based on functional classification, genes affected by age and/or diet were involved in cellular development, nutrient metabolism, and signal transduction. In general, gene expression suggested that senior dogs had an increased risk of the progression of liver disease and dysfunction, as observed in aged humans and rodents. In particular for aged liver, genes related to inflammation, oxidative stress, and glycolysis were up-regulated, whereas genes related to regeneration, xenobiotic metabolism, and cholesterol trafficking were down-regulated. Diet-associated changes in gene expression were more common in young adult dogs (33 genes) as compared to senior dogs (3 genes). CONCLUSION: Our results provide molecular insight pertaining to the aged canine liver and its predisposition to disease and abnormalities. Therefore, our data may aid in future research pertaining to age-associated alterations in hepatic function or identification of potential targets for nutritional management as a means to decrease incidence of age-dependent liver dysfunction

Plasticity in D1-Like Receptor Expression Is Associated with Different Components of Cognitive Processes

Dopamine D1-like receptors consist of D1 (D1A) and D5 (D1B) receptors and play a key role in working memory. However, their possibly differential contribution to working memory is unclear. We combined a working memory training protocol with a stepwise increase of cognitive subcomponents and real-time RT-PCR analysis of dopamine receptor expression in pigeons to identify molecular changes that accompany training of isolated cognitive subfunctions. In birds, the D1-like receptor family is extended and consists of the D1A, D1B, and D1D receptors. Our data show that D1B receptor plasticity follows a training that includes active mental maintenance of information, whereas D1A and D1D receptor plasticity in addition accompanies learning of stimulus-response associations. Plasticity of D1-like receptors plays no role for processes like response selection and stimulus discrimination. None of the tasks altered D2 receptor expression. Our study shows that different cognitive components of working memory training have distinguishable effects on D1-like receptor expression