Synchronized firing among retinal ganglion cells signals motion reversal

We show that when a moving object suddenly reverses direction, there is a brief, synchronous burst of firing within a population of retinal ganglion cells. This burst can be driven by either the leading or trailing edge of the object. The latency is constant for movement at different speeds, objects of different size, and bright versus dark contrasts. The same ganglion cells that signal a motion reversal also respond to smooth motion. We show that the brain can build a pure reversal detector using only a linear filter that reads out synchrony from a group of ganglion cells. These results indicate that not only can the retina anticipate the location of a smoothly moving object, but that it can also signal violations in its own prediction. We show that the reversal response cannot be explained by models of the classical receptive field and suggest that nonlinear receptive field subunits may be responsible.     

Synchronized cluster firing,a distinct form of sensory neuron activation,drives spontaneous pain

1. Download : Download high-res image (221KB)
2. Download : Download full-size image

     

Funding in the firing line

With large charities such as the Wellcome Trust or the Gates Foundation committed to funding research, is there a risk that politicians could cut public funding for science?Towards the end of 2010, with the British economy reeling from the combined effects of the global recession, the burst bubble of property speculation and a banking crisis, the country came close to cutting its national science and research budget by up to 25%. UK Business Secretary Vince Cable argued, “there is no justification for taxpayers'' money being used to support research which is neither commercially useful nor theoretically outstanding” (BBC, 2010). The outcry from UK scientists was both passionate and reasoned until, in the end, the British budget slashers blinked and the UK government backed down. The Chancellor of the Exchequer, George Osborne, announced in October that the government would freeze science and research funding at £4.6 billion per annum for four years, although even this represents about a 10% cut in real terms, because of inflation.“there is no justification for taxpayers'' money being used to support research which is neither commercially useful nor theoretically outstanding”There has been a collective sigh of relief. Sir John Savill, Chief Executive of the Medical Research Council (UK), said: “The worst projections for cuts to the science budget have not been realised. It''s clear that the government has listened to and acted on the evidence showing investment in science is vital to securing a healthy, sustainable and prosperous future.”Yet Britain is unusual compared with its counterparts elsewhere in the European Union (EU) and the USA, because private charities, such as the Wellcome Trust (London, UK) and Cancer Research UK (London, UK), already have budgets that rival those of their government counterparts. It was this fact, coupled with UK Prime Minister David Cameron''s idea of the ‘big society''—a vision of smaller government, increased government–private partnerships and a bigger role for non-profit organizations, such as single-disease-focused charities—that led the British government to contemplate reducing its contribution to research, relying on the private sector to pick up the slack.Jonathan Grant, president of RAND Europe (London, UK)—a not-for-profit research institute that advises on policy and decision-making—commented: “There was a strong backlash and [the UK Government] pulled back from that position [to cut funding]. But that''s the first time I''ve really ever seen it floated as a political idea; that government doesn''t need to fund cancer research because we''ve got all these not-for-profits funding it.”“…that''s the first time I''ve really ever seen it floated as a political idea; that government doesn''t need to fund cancer research because we''ve got all these not-for-profits funding it”But the UK was not alone in mooting the idea that research budgets might have to suffer under the financial crisis. Some had worried that declining government funding of research would spread across the developed world, although the worst of these fears have not been realized.Peter Gruss, President of the Max Planck Society (Munich, Germany), explained that his organization receives 85% of its more-than €1.5 billion budget from the public purses of the German federal government, German state ministries and the EU, and that not all governments have backed away from their commitment to research. In fact, during the crisis, the German and US governments boosted their funding of research with the goal of helping the economic recovery. In 2009, German Chancellor Angela Merkel''s government, through negotiation with the German state science ministries, approved a windfall of €18 billion in new science funding, to be spread over the next decade. Similarly, US President Barack Obama''s administration boosted spending on research with a temporary stimulus package for science, through the American Recovery and Reinvestment Act.Even so, Harry Greenberg, Senior Associate Dean for Research at Stanford University (California, USA) pointed out that until the US government injected stimulus funding, the budget at the National Institutes of Health (NIH; Bethesda, Maryland, USA) had essentially “been flat as a pancake for five or six years, and that means that it''s actually gone down and it''s having an effect on people being able to sustain their research mission.”Similarly, Gruss said that the research community should remain vigilant. “I think one could phrase it as there is a danger. If you look at Great Britain, there is the Wellcome Trust, a very strong funding organization for life sciences and medical-oriented, health-oriented research. I think it''s in the back of the minds of the politicians that there is a gigantic foundation that supports that [kind of research]. I don''t think one can deny that. There is an atmosphere that people like the Gates family [Bill and Melinda Gates Foundation] invests in health-related issues, particularly in the poorer countries [and that] maybe that is something that suffices.”The money available for research from private foundations and charities is growing in both size and scope. According to Iain Mattaj, Director General of the European Molecular Biology Laboratory (EMBL; Heidelberg, Germany), this growth might not be a bad thing. As he pointed out, private funding often complements government funding, with charities such as the Wellcome Trust going out of their way to leverage government spending without reducing government contributions. “My feeling is that the reason that the UK government is freezing research funding has all to do with economics and nothing to do with the fact that there are potentially private funders,” he said. “Several very large charities in particular are putting a lot of money into health research. The Gates Foundation is the biggest that has just come on the scene, but the Howard Hughes Medical Institute [HHMI; Chevy Chase, Maryland, USA] and the Wellcome Trust are very big, essentially private charities which have their own agendas.”…charities such as the Wellcome Trust [go] out of their way to leverage government spending without reducing government contributions​contributionsOpen in a separate window© CorbisBut, as he explained, these charities actually contribute to the overall health research budget, rather than substituting funds from one area to another. In fact, they often team up to tackle difficult research questions in partnership with each other and with government. Two-thirds of the €140 million annual budget of EMBL comes from the European states that agree to fund it, with additional contributions from private sources such as the Wellcome Trust and public sources such as the NIH.Yet over the years, as priorities have changed, the focus of those partnerships and the willingness to spend money on certain research themes or approaches has shifted, both within governments and in the private sector. Belief in the success of US President Richard Nixon''s famous ‘war on cancer'', for example, has waned over the years, although the fight and the funding continues. “I don''t want to use the word political, because of course the decisions are sometimes political, but actually it was a social priority to fight cancer. It was a social priority to fight AIDS,” Mattaj commented. “For the Wellcome Trust and the Gates Foundation, which are fighting tropical diseases, they see that as a social necessity, rather than a personal interest if you like.”Nevertheless, Mattaj is not surprised that there is an inclination to reduce research spending in the UK and many smaller countries battered by the economic downturn. “Most countries have to reduce public spending, and research is public spending. It may be less badly hit than other aspects of public spending. [As such] it''s much better off than many other aspects of public spending.”A shift away from government funding to private funding, especially from disease-focused charities, worries some that less funding will be available for basic, curiosity-driven research—a move from pure research to ‘cure'' research. Moreover, charities are often just as vulnerable to economic downturns, so relying on them is not a guarantee of funding in harsh economic times. Indeed, greater reliance on private funding would be a return to the era of ‘gentlemen scientists'' and their benefactors (Sidebar A).

Sidebar A | Gentlemen scientists

Greater reliance on private funding would return science to a bygone age of gentlemen scientists relying on the largesse of their wealthy sponsors. In 1831, for example, naturalist Charles Darwin''s (1809–1882) passage on the HMS Beagle was paid for by his father, albeit reluctantly. According to Laura Snyder, an expert on Victorian science and culture at St John''s University (New York, USA), by the time Darwin returned to England in 1836, the funding game had changed and government and private scientific societies had begun to have a bigger role. When Sir John Frederick William Herschel (1791–1871), an English mathematician, astronomer, chemist, experimental photographer and inventor, journeyed to Cape Colony in 1833, the British government offered to give him a free ride aboard an Admiralty ship. “Herschel turned them down because he wanted to be free to do whatever he wanted once he got to South Africa, and he didn''t want to feel beholden to government to do what they wanted him to do,” Snyder explained, drawing from her new book The Philosophical Breakfast Club, which covers the creation of the modern concept of science.Charles Babbage (1791–1871), the mathematician, philosopher, inventor and mechanical engineer who originated the concept of a programmable computer, was a member of the same circle as Herschel and William Whewell (1794–1866), a polymath, geologist, astronomer and theologian, who coined the word ''scientist''. Although he was wealthy, having inherited £100,000 in 1827—valued at about £13.3 million in 2008—Babbage felt that government should help pay for his research that served the public interest.“Babbage was asking the government constantly for money to build his difference engine,” Snyder said. Babbage griped about feeling like a tradesman begging to be paid. “It annoyed him. He felt that the government should just have said, ''We will support the engine, whatever it is that you need, just tell us and we''ll write you a check''. But that''s not what the government was about to do.”Instead, the British government expected Babbage to report on his progress before it loosened its purse strings. Snyder explained, “What the government was doing was a little bit more like grants today, in the sense that you have to justify getting more money and you have to account for spending the money. Babbage just wanted an open pocketbook at his disposal.”In the end the government donated £17,000, and Babbage never completed the machine.Janet Rowley, a geneticist at the University of Chicago, is worried that the change in funding will make it more difficult to obtain money for the kind of research that led to her discovery in the 1970s of the first chromosomal translocations that cause cancer. She calls such work ‘fishing expeditions''. She said that the Leukemia & Lymphoma Society (White Plains, New York, USA), for example—a non-profit funder of research—has modified its emphasis: “They have now said that they are going to put most of their resources into translational work and trying to take ideas that are close to clinical application, but need what are called incubator funds to ramp up from a laboratory to small-scale industrial production to increase the amount of compound or whatever is required to do studies on more patients.”This echoes Vince Cable''s view that taxpayers should not have to spend money on research that is not of direct economic, technological or health benefit to them. But if neither charities nor governments are willing to fund basic research, then who will pay the bill?…if neither charities nor governments are willing to fund basic research, then who will pay the bill?Iain Mattaj believes that the line between pure research and cure research is actually too blurred to make these kinds of funding distinctions. “In my view, it''s very much a continuum. I think many people who do basic research are actually very interested in the applications of their research. That''s just not their expertise,” he said. “I think many people who are at the basic end of research are more than happy to see things that they find out contributing towards things that are useful for society.”Jack Dixon, Vice President and Chief Scientific Officer at HHMI, also thinks that the line is blurry: “This divide between basic research and translational research is somewhat arbitrary, somewhat artificial in nature. I think every scientist I know who makes important, basic discoveries likes to [...] see their efforts translate into things that help humankind. Our focus at the Hughes has always been on basic things, but we love to see them translated into interesting products.” Even so, HHMI spends less than US $1 billion annually on research, which is overshadowed by the $30 billion spent by the NIH and the relatively huge budgets of the Wellcome Trust and Cancer Research UK. “We''re a small player in terms of the total research funding in the US, so I just don''t see the NIH pulling back on supporting research,” Dixon said.By way of example, Brian Druker, Professor of Medicine at the Oregon Health & Science University (Portland, Oregon, USA) and a HHMI scientist, picked up on Rowley''s work with cancer-causing chromosomal translocations and developed the blockbuster anti-cancer drug, imatinib, marketed by Novartis. “Brian Druker is one of our poster boys in terms of the work he''s done and how that is translated into helping people live longer lives that have this disease,” Dixon commented.There is a similar view at Stanford. The distinction between basic and applied is “in the eye of the beholder,” Greenberg said. “Basic discovery is the grist for the mill that leads to translational research and new breakthroughs. It''s always been a little difficult to convey, but at least here at Stanford, that''s number one. Number two, many of our very basic researchers enjoy thinking about the translational or clinical implications of their basic findings and some of them want to be part of doing it. They want some benefit for mankind other than pure knowledge.”“Basic discovery is the grist for the mill that leads to translational research and new breakthroughs”If it had not backed down from the massive cuts to the research budget that were proposed, the intention of the UK Government to cut funding for basic, rather than applied, research might have proven difficult to implement. Identifying which research will be of no value to society is like trying to decide which child will grow up to be Prime Minister. Nevertheless, most would agree that governments have a duty to get value-for-money for the taxpayer, but defining the value of research in purely economic or translational terms is both short-sighted and near impossible. Even so, science is feeling the economic downturn and budgets are tighter than they have been for a long time. As Greenberg concluded, “It''s human nature when everybody is feeling the pinch that you think [yours] is bigger than the next guy''s, but I would be hard pressed to say who is getting pinched, at least in the biomedical agenda, more than who else.”     

Spatiotemporal firing patterns in the cerebellum

Neurons are generally considered to communicate information by increasing or decreasing their firing rate. However, in principle, they could in addition convey messages by using specific spatiotemporal patterns of spiking activities and silent intervals. Here, we review expanding lines of evidence that such spatiotemporal coding occurs in the cerebellum, and that the olivocerebellar system is optimally designed to generate and employ precise patterns of complex spikes and simple spikes during the acquisition and consolidation of motor skills. These spatiotemporal patterns may complement rate coding, thus enabling precise control of motor and cognitive processing at a high spatiotemporal resolution by fine-tuning sensorimotor integration and coordination.     

Synchronized dichogamy and dioecy in neotropicalLauraceae

In hermaphrodite neotropicalLauraceae a highly evolved dichogamous system is present which represents a kind of temporal dioecy. This system involves the existence of two flower morphs which are characterized by reciprocal phases of receptivity of the stigmas and pollen release. In some genera (Persea, Cinnamomum), nectar is produced as a reward for the flower visitors, while in other genera (Aniba, Clinostemon, Licaria), nectar is absent and pollen seems to be the only reward. This implies that in this case the flowers in the female stage must be deceptive flowers. In dioecious species of the generaOcotea andNectandra, both the male and female flowers attract the visitors with nectar. The pollen-ovule ratio of theLauraceae is comparatively low. — The type of reproductive system that characterizes theLauraceae, comprising functional dioecy, small, inconspicuously coloured flowers, pollination by small bees, and large, one-seeded fruits dispersed by birds, is quite prominent among trees of various families in the tropical lowland forest. The relationship between the different modes of flowering within theLauraceae and the causes for the correlation of their reproductive traits are discussed.     

Synchronized growth ofMycobacterium phlei

Three synchronization methods, cold shock, starvation, centrifugation and their combinations were used in order to induce synchronized division inMycobacterium phlei PA. It was found that a combination of cold shock with a preceding centrifugation is the optimum method for the synchronized growth of the culture, its use resulting in three synchronized cell divisions.     

Synchronized slow-amplitude modulations in the electromyograms of shivering muscles

The electromyograms (EMG) of shivering human subjects exposed to 0 degrees C air in an environmental chamber were analyzed to detect slow-amplitude modulations (SAMs, less than 1 Hz) in the EMGs of widely separated muscles and to study the relationship of these SAMs to respiration rate and skin temperature. Distinct amplitude modulations were observed in the raw EMGs during shivering. The peaks in EMG activity occurred simultaneously in the majority of the monitored muscles in all subjects. Pearson correlations between the average rectified EMGs of 93% of the muscles were significant (P less than 0.05). Visual analysis of the EMG and respiration signals indicated that the peaks in muscular activity occurred 6-12 times/min, whereas respiration ranged from 10 to 23 cycles/min. For all subjects respiration was at a higher frequency than amplitude modulation in the EMG. Comparison of EMG records with expiratory flow rate traces in shivering subjects indicated no one-to-one correlation between the occurrence of respiration and EMG amplitude modulations. Respiratory flow rate and average rectified EMG showed significant correlation in only 33% of the cases. In addition, skin temperature changes could not be correlated with the SAMS.     

Synchronized oscillations in the visual cortex — a synergetic model

We present an oscillator network model for the synchronization of oscillatory neuronal activity underlying visual processing. The single neuron is modeled by means of a limit cycle oscillator with an eigenfrequency corresponding to visual stimulation. The eigenfrequency may be time dependent. The mutual coupling strengths are unsymmetrical and activity dependent, and they scatter within the network. Synchronized clusters (groups) of neurons emerge in the network due to the visual stimulation. The different clusters correspond to different visual stimuli. There is no limitation of the number of stimuli. Distinct clusters do not perturb each other, although the coupling strength between all model neurons is of the same order of magnitude. Our analysis is not restricted to weak coupling strength. The scatter of the couplings causes shifts of the cluster frequencies. The model's behavior is compared with the experimental findings. The coupling mechanism is extended in order to model the influence of bicucullin upon the neural network. We additionally investigate repulsive couplings, which lead to constant phase differences between clusters of the same frequency. Finally, we consider the problem of selective attention from the viewpoint of our model.     

Ultraviolet Inactivation and Photoreactivation in Synchronized Chlorella

Synchronous cultures of Chlorella pyrenoidosa have been used in studies of the action of UV-irradiation during different stages in the life cycle on cell division capacity. These experiments show that there is a considerably higher sensitivity to UV-irradiation during the first hours of the life cycle. The variations in photoreactivating capacity of UV-damaged cells during a life cycle have been investigated. The results from these investigations show that the photoreactivating capacity varies and that it is higher in young daughter cells (autospores) and 12–15 hour cells. These variations can be due to variations in the activity of the photoreactivating enzyme during the life cycle.     

Enkephalin in the goldfish retina

Enkephalin-like immunoreactive amacrine cells were visualized using the highly sensitive avidin-biotin method. The somas of these cells were situated in the inner nuclear and ganglion cell layers. Enkephalin-stained processes were observed in layers 1, 3, and 5 of the inner plexiform layer. The biosynthesis of sulfur-containing compounds in the goldfish retina was studied by means of a pulse-chase incubation with 35S-methionine. A 35S-labeled compound, which comigrated with authentic Met5-enkephalin on high-performance liquid chromatography (HPLC), was synthesized and was bound competitively by antibodies to enkephalin and by opiate receptors. This compound was tentatively identified as "Met5-enkephalin." The newly synthesized 35S-Met5-enkephalin was released upon depolarization of the retina with a high K+ concentration. This K+-stimulated release was greatly suppressed by 5 mM Co2+, suggesting that the release was Ca2+ dependent. Using a double-label technique, enkephalin immunoreactivity and gamma-aminobutyric acid (GABA) uptake were colocalized to some amacrine cells, whereas others labeled only for enkephalin or GABA. The possible significance of enkephalin-GABA interactions is also discussed.     

N-Acetyltransferase in the chick retina

Summary N-acetyltransferase activity has similar circadian rhythms controlled by environmental lighting in the eyes and pineal glands of chicks (Gallus domesticus). The interactions of the two eyes and the pineal gland were examined by using patches of black tape to reduce the intensity of light reaching the eyes and/or the pineal gland. Suppression of N-acetyltransferase activity (normally 80%) by extending the light into the dark-time was used to test the effects of light. On the basis of the test, the eyes respond to light independently of each other and of the pineal gland; the pineal gland, however, responds to light perceived by the eyes.     

Direction selectivity in the retina

The neuronal circuitry underlying the generation of direction selectivity in the retina has remained elusive for almost 40 years. Recent studies indicate that direction selectivity may be established within the radial dendrites of 'starburst' amacrine cells and that retinal ganglion cells may acquire their direction selectivity by the appropriate weighting of excitatory and inhibitory inputs from starburst dendrites pointing in different directions. If so, this would require unexpected complexity and subtlety in the synaptic connectivity of these CNS neurons.     

Neuronal diversity in the retina

The listing of cell types present in the retina is nearing completion, the first time this can be said for any significantly complex sample of the central nervous system. Mammalian retinas contain approximately 55 separate neuronal types. The functions of 22 of them are known or can be strongly inferred. For these 22, in every instance, a cell defined as a 'type' by structural criteria carries out a distinct and individual physiological function. Electrophysiological experiments continue to reveal new features of the retina's handling of information, and there is every reason to believe that the remaining 33 types of cell will also have distinct physiological functions. Further subtleties clearly exist in both peripheral and central visual coding.     

N-Methyl-d-aspartate receptors in the retina

The vertebrate retina is a “genuine neural center” (Ramón y Cajal), in which glutamate is a major excitatory neurotransmitter. Both N-methyl-d-aspartate (NMDA) and non-NMDA receptors are expressed in the retina. Although non-NMDA receptors and/or metabotropic glutamate receptors are generally thought to be responsible for mediating the transfer of visual signals in the outer retina, there is recent evidence suggesting that NMDA receptors are also expressed in photoreceptors, as well as horizontal and bipolar cells. In the inner retina, NMDA receptors, in addition to other glutamate receptor subtypes, are abundantly expressed to mediate visual signal transmission from bipolar cells to amacrine and ganglion cells, and could be involved in modulation of inhibitory feedback from amacrine cells to bipolar cells. NMDA receptors are extrasynaptically expressed in ganglion cells (and probably amacrine cells) and may play physiological roles in a special mode. Activity of NMDA receptors may be modulated by neuromodulators, such as d-serine and others. This article discusses retinal excitotoxicity mediated by NMDA receptors.     

Hemopexin in the human retina: Protection of the retina against heme-mediated toxicity

The existence of the blood-retinal barrier means that proteins that protect the retina from damage by reactive oxygen species must either be made locally or specifically transported across the barrier cells; however, such transepithelial transport does not seem to occur. Among the circulatory proteins that protect against iron-catalyzed production of free radicals are apo-transferrin, which binds ferric iron and has previously been shown to be made by cells of the neural retina (Davis and Hunt, 1993, J. Cell Physiol., 156:280–285), and the extracellular antioxidant, apo-hemopexin, which binds free heme (iron-protoporphyrin IX). Since hemorrhage and heme release can be important contributing factors in retinal disease, evidence of a hemopexin-based retinal protection system was sought. The human retina has been shown to contain apo-hemopexin which is probably synthesized locally since its mRNA can be detected in retinal tissue dissected from human donor eyes. It is likely that the retina contains a mechanism for the degradation of hemopexin-bound heme since the blood-retinal barrier also precludes the exit of heme-hemopexin from the retina. Retinal pigment epithelial cells have been found to bind and internalize heme-hemopexin in a temperature-dependent, saturable, and specific manner, analogous to the receptor-mediated endocytic system of hepatoma cells. Moreover, the binding of heme-hemopexin to the cells stimulates the expression of heme oxygenase-1, metallothionein-1, and ferritin. © 1996 Wiley-Liss, Inc.     

Photosynthetic Activity during the Division Cycle in Synchronized Euglena gracilis

Axenic populations of the photosynthetic protozoan Euglena gracilis, grown with autotrophic nutrition, were synchronized with respect to cell division by culture on an alternating light-dark cycle. No cell divisions occurred in the light periods; approximately 100% of the cells divided in the dark periods. In such cultures, the synthesis of photosynthetic pigments and accumulation of polysaccharide were confined to the light periods. The capacity for photosynthesis, however, increased continuously over the entire light-dark cycle, and is thus not directly correlated with pigment content. A correlation was seen between photosynthetic capacity and protein content, suggesting that enzymatic mechanisms of the photosynthetic apparatus might be the limiting factor. Estimates of total photosynthetic activity indicate that about 5 x 10(-6) calories are required for the synthesis of a new cell.     

Induction of Synchronized Fissions in Telotrochidium henneguyi

SYNOPSIS. Cultures of Telotrochidium henneguyi , begun with logarithmic phase cells, were employed in an effort to produce synchronized fission by heat treatment. The cells tolerated a temperature range of 20–50 C; temperatures above 50 were lethal. When cells were exposed to a single shock for 30 min, 30–40 produced 0–50% encystment with total excystment after 10 min exposure to room temperature (heat shock range). No encystment occurred between 20–30 (intershock range). Encystment and excystment time varied directly with temperature between 40–50.
The most effective procedure for inducing synchronized fission consisted of 6 cycle program of 38/28 C (shock temperature/intershock temperature) administered for 15/15 (shock/intershock duration in min). Division indices (DI = cells dividing/total population X 100 =%) ranged from 12–66% with a mean of 37.25%. In control cells, division indices ranged from 2–20% with an average of 12%. Inferences from these independently derived findings are discussed.