Neuronal Pathway for Depth Perception Teased Out in Primates

Precisely how we perceive and interpret the three-dimensional world remains a mystery to scientists, but a recent study from the lab of Richard Born, HMS professor of neurobiology, may have brought us a step closer to understanding this process. In the February Nature Neuroscience, Born and colleagues identify a pathway within the primate visual cortex that is specifically responsible for carrying and integrating information regarding depth of moving stimuli.

Courtesy Richard Born

This MRI scan of a monkey brain (with white eye socket to the right) shows the visual cortex and areas V1, V2, V3, and MT. The arrows depict the approximate tracks of recording electrodes. The indirect neuronal pathway inactivated in this study is indicated by the white arrows between V1 and MT that pass through V2 and V3. The direct pathway is indicated in pink and was left intact.

Depth is an illusion generated by the brain’s visual cortex through a computation known as binocular disparity—in which visual input received separately from each eye is compared. This visual information is initially conveyed to the primary visual cortex (V1) via the thalamus, where it is then relayed to other visual areas (V2, V3, V4) in a hierarchical manner. Although signals of binocular disparity and motion occur throughout the visual cortex, these signals are thought to be integrated within an area known as the middle temporal visual cortex (MT). Here, neurons have been found to signal both direction and speed as well as depth changes of moving stimuli.

Transferral of visual depth and motion information to MT occurs either directly or indirectly (via areas V2 and V3). A common hypothesis has been that the indirect pathway was redundant, but recent observations suggest it plays a complementary role to that of the direct pathway.

Born and his group set about investigating the latter hypothesis by observing the impact of selective inactivation of the indirect neural route on monkeys’ ability to perceive direction and depth of moving stimuli. First author and graduate student Carlos Ponce recorded neurons in the MT of awake rhesus monkeys while the animals observed moving stimuli positioned at various binocular disparities (depths) on a screen. Using this experimental setup, he saw that prior to inactivation, the neurons selectively increased their firing rate to movement, changes in depth, or both. When the indirect neuronal pathway from V1 to MT was inactivated, however, neuronal firing to depth but not to motion was altered significantly.

Ponce also investigated the behavioral impact of this inactivation by measuring the monkeys’ eye movements while they tracked a moving stimulus with changing depth. In line with their neuronal-firing pattern, the monkeys also demonstrated behavioral impairments with tracking visual depth.

“What we are showing here is a very clean experiment demonstrating the role of the indirect pathway from V1 to MT in visual processing,” said Ponce. “Monkeys, like humans, are very good at separating out different surfaces based on motion and depth. So in this experiment, if we could ask the monkey what aspects of a computerized stimulus he could see after we inactivated the indirect pathway, we would predict that he could tell us the direction in which the stimulus was moving but not whether it was nearer or farther on the screen.”

“This is very fundamental neuroscience research,” said Ponce. “Our next step is to further explore these pathways, possibly using sophisticated molecular techniques, which would enable us to understand this process more fully. This is important if we want to know how we make spatial sense of the world.”

—Yvonna Reekie

New Genetic Regions Tied to Blood Lipid Level And Heart Disease

Researchers have been scouring the human genome for variants that can be linked with susceptibility to coronary heart disease. Lipids—such as cholesterol and triglycerides—are known determinants of the disease and though their levels are often tied to lifestyle factors such as diet, the tendency to develop high blood lipid levels can be inherited.

Using genetic information from more than 27,000 people, drawn from their own and two other genome-wide association studies, Sekar Kathiresan, an HMS instructor in medicine at Massachusetts General Hospital, and colleagues report in the February Nature Genetics that they have identified 18 loci containing variants that correlate with blood lipid levels in humans, six of which had not been discovered in previous associations.

The lipid-associated genetic variants look like they may also correlate with risk of heart disease. A previous study published by a British research group last year showed that variants within specific regions of the genome directly correlated with susceptibility to coronary heart disease. What their study had not shown, however, was a link between these variants and cholesterol, a leading risk factor for the disease.

Interestingly, another study published in the February Nature Genetics demonstrates that there is some common ground between lipid-associated variants and variants previously linked with susceptibility to heart disease. “We were really excited to see that one of the genetic variants we found to be associated with cholesterol levels, was also linked to heart disease by the British group,” said Kathiresan.

“This is a significant development,” he said. “Previous studies looking for genetic loci underlying cardiovascular traits have used far smaller group sizes, which inevitably made the discovery process very slow. The great thing about our study was that instead of competing with other groups, we actually joined forces, which helped us to uncover many new genetic regions related to lipid levels.”

While these are promising findings, there is still a lot of work to do. As Kathiresan points out: “Each of these regions individually has a very modest impact on lipid levels, and it is only when they are looked at in combination that they have a significant correlation with cardiovascular disease or disease traits.” Kathiresan and his group at the Broad Institute are now performing studies to both extend and refine these results to isolate specific genes linked to lipid levels and susceptibility to heart disease.

“A clearer understanding of the genetic underpinnings of cardiovascular traits will have a huge impact on medical advancement” said Kathiresan. “It will not only further our knowledge of disease mechanisms but will also provide us with new targets for future drug therapies. It may even enable us to produce clinical diagnostic tests to identify vulnerable individuals early and to treat them before the disease takes hold.”

—Yvonna Reekie

Deciphering Structure of HIV Coat Region Raises Hopes for Vaccine

The human immunodeficiency virus (HIV) wears one of the most distinctive coats in all of microbiology—and one of the slipperiest. What makes the virus so difficult to detect is its ability to change the structure of its envelope.

HMS researchers have worked out the structure of a hidden, more-conserved region on this notoriously changeable coat—a finding that could answer a longstanding mystery. Though antibodies rarely attack HIV, there is one that can block infection, but it has been unclear how. It now appears that this antibody gains unexpected access to the newly described region. The findings, reported in the January Immunity, could boost efforts to derive an antibody-based vaccine against HIV.

The HIV coat—frequently depicted as a layer of spikelike structures—consists of two proteins, glycoprotein 120 (gp120)—the head—and glycoprotein 41 (gp41)—the actual spike. Mikyung Kim, Ellis Reinherz, and colleagues focused on a region at the base of gp41, the membrane proximal ectodomain region (MPER). Using a trio of imaging techniques—nuclear magnetic resonance imaging (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR)—they discovered that MPER assumes an L-shaped structure consisting of two helical arms joined by a flexible hinge. The hinge, along with parts of the arms, is buried in the viral membrane. Upon contact with a host CD4 cell, the MPER hinge flips open, essentially allowing the virus to get a foothold on the cell.

Targeting such a wily protein would appear to be a difficult feat. Yet it now appears that at least one antibody does exactly that, the so-called broadly neutralizing antibody (BNAb) 4E10. Using their imaging methods, Reinherz, an HMS professor of medicine, Kim, an HMS instructor in medicine, both at Dana–Farber Cancer Institute, and colleagues discovered that 4E10 homes in on the hinge area and pulls out key portions of MPER buried inside the membrane. It then latches onto these newly exposed sections, forming a tighter bond with the virus, thereby blunting its ability to fuse with the cell membrane.

“The new features of MPER that we’ve discovered may be useful targets for antibody-based vaccines if they can be held in proper configuration,” said Kim. “One way of doing this would be to place them in a synthetic lipid coat on nanoparticles. If the antibodies aren’t confused by other elements of the virus’s protein envelope, this approach may elicit a strong immune response to viral presence.”

—Misia Landau

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