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14 November 2011. If asked to describe what you ate for dinner last night, chances are you would picture the meal in your mind before responding. Older adults have trouble with these sorts of mental imagery tasks. A functional brain imaging study in the November 2 Journal of Neuroscience offers insight into this deficit—the aging mind’s vision doesn’t shut down; it gets blurred, the study suggests. Moreover, this age-related imagery decline seems to correlate with poor visual memory, suggesting the brain really needs to “see” what it is trying to recall. In another recent advance reported in the November 3 Science, researchers blocked synaptic transmission along certain circuits in transgenic mice, allowing the scientists to probe neural pathways underlying specific types of memory. The two studies are representative of the progress neuroscientists are making in understanding learning and memory.

When people look at something or picture it in their minds, neurons in the visual cortex start firing, but that’s not all. Mental imagery also activates prefrontal cortical areas that help the brain process information in a goal-oriented manner, by focusing on relevant stimuli and ignoring distractions in a process known as top-down modulation (Kosslyn et al., 1997; Ishai et al., 2000). This capability underlies spatial navigation and other visual memory functions that tend to worsen with age. In behavioral studies, seniors who performed more slowly and less accurately in memory tasks that required mental imagery reported having problems visualizing images in their minds (Briggs et al., 1999). “What was missing was quantitative neural data that spoke to this [subjective report],” said lead investigator Adam Gazzaley of the University of California, San Francisco.

As described in their paper, first author Jonathan Kalkstein and colleagues used functional magnetic resonance imaging (fMRI) to measure brain activity in 14 seniors (average age 69.8 years) and 14 young people (average age 26.6 years) as they fixated on moving images. While inside the MRI scanner, subjects saw a series of pictures—either celebrity faces or moving dots. In later “imagine” trials, the participants did not see the images but were instead prompted to visualize them.

During the “view” series, fMRI blood oxygen level-dependent (BOLD) signal went up in the fusiform gyrus—the facial recognition center—when faces were shown, and in the middle temporal gyrus when the images were moving dots. Activity in these visual areas was about the same in older and younger adults as they viewed actual images.

However, differences cropped up when participants were asked to picture those images in their minds. If prompted to imagine a celebrity’s face, young participants activated the brain’s face-selective area, but not the motion-selective area—and if asked to picture the moving dots, the latter area lit up, but not the former. The older participants, on the other hand, activated both areas of the visual cortex no matter what they were prompted to visualize. Like the young participants, “older adults were generating visual activity while they were imagining, but the big difference is they were not doing it selectively,” Gazzaley said. “This is evidence that older adults are not achieving as fine a resolution of the images they’re trying to create in their minds.”

Furthermore, the age-related imagery deficit seems to correlate with a drop in memory performance. Older participants were given the Continuous Visual Memory Test (CVMT). The lower-performing half had poorer motion imagery relative to young adults, whereas seniors with above-median CVMT scores did not have this visual imagery deficit.

Gazzaley said he hopes to design an adaptive training program to see if promoting mental imagery in seniors could improve visual memory.

Mouse Models—Dissecting Neural Pathways in Finer Detail
While fMRI offers scientists a powerful glimpse at the brain areas that mediate certain kinds of memory, figuring out precisely which neural networks are involved requires fine manipulations that are off limits in people—but could be done in mouse models. In an online Science paper published November 3, Susumu Tonegawa of the Picower Institute for Learning and Memory at MIT and colleagues generated a transgenic mouse to show that temporal association memory requires a specific branch of the hippocampal-entorhinal network.

First author Junghyup Suh and colleagues used a triple-transgenic strategy developed in the Tonegawa lab to block neurotransmitter release from a specific type of presynaptic cell in a temporally controlled manner. The “block” is carried out by tetanus toxin light chain (TeTxLC), which cleaves a protein (VAMP2) needed for fusion of synaptic vesicles with the presynaptic membrane. However, through transgenic crosses, expression of the toxin is tightly restricted to cells where two different promoters are active—in this case, one (Oxr1) that drives expression in entorhinal cortex layer III, and another (CamKII) that is active in excitatory neurons. The system has yet another level of control—doxycycline, which blocks toxin expression, overriding the activity of both promoters. In the present study, the researchers maintained the mice on a doxycycline diet until a month or two before doing behavioral tests. When the animals were switched to a doxycycline-free diet, tetanus toxin became expressed only at entorhinal cortex layer III inputs to the hippocampus, thereby achieving selective inhibition of synaptic transmission along this pathway.

Triple-transgenic mice with this selective block had no obvious molecular abnormalities in the entorhinal cortex, and looked normal in tests of anxiety, motor coordination, and pain sensitivity. However, the mice had problems with fear conditioning and temporal association memory, or the ability to link one event with another in time. Several years ago, Tonegawa’s group used this triple-transgenic approach to block synaptic transmission from the CA3 hippocampal area into the entorhinal cortex, and showed that this pathway is required for fast, one-trial contextual learning (Nakashiba et al., 2008). The team is trying to further delineate the neural circuits needed for spatial working memory and fear conditioning by using optogenetic methods to stimulate or inhibit specific inputs from entorhinal cortex to hippocampus in a much finer temporal window, Suh wrote in an e-mail to ARF.—Esther Landhuis.

References:
Kalkstein J, Checksfield K, Bollinger J, Gazzaley A. Diminished top-down control underlies a visual imagery deficit in normal aging. J Neurosci. 2011 Nov 2;31(44):15768-74. Abstract

Suh J, Rivest AJ, Nakashiba T, Tominaga T, Tonegawa S. Entorhinal Cortex Layer III Input to the Hippocampus Is Crucial for Temporal Association Memory. Science. 3 Nov 2011. Abstract

This is Part 3 of a three-part series. See also Part 1 and Part 2. Download a PDF of the entire series.