Changes in learning-resource use across physicians' learning episodes*

Introduction: This study explores the numbers of learning resources physicians use at each stage in self-directed learning episodes addressing general problems.

Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments

The microtubule-associated protein τ is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer's disease (AD) and patients with several other tauopathies. Here, we show that the abnormally hyperphosphorylated τ from AD brain cytosol (AD P-τ) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35°C during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-τ inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six τ isoforms into tangles of PHF and straight filaments, and the microtubule binding domains/repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that τ self-assembles by association of the microtubule binding domains/repeats and that the abnormal hyperphosphorylation promotes the self-assembly of τ into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.

Activity of primate inferotemporal neurons related to a sought target in pair-association task.

Visual long-term memory in primates has been assessed by using the pair-association (PA) task, in which a subject retrieves and chooses the paired associate of a cue picture. Our previous studies on single neurons in the anterior inferotemporal (AIT) cortex suggested their roles in representing paired associates in the mind. To test the possibility that the delay activity of AIT neurons is related to a particular picture as a sought target, we devised the PA with color switch (PACS) task. In the PACS task, the necessity for memory retrieval and its initiation time were controlled by a color switch in the middle of the delay period. A control task, in which there is no color switch, corresponds to the conventional delayed matching-to-sample (DMS) task where the monkey chooses the same picture as a cue. We found that AIT neurons started to respond just after the color switch in the PACS task, when the cue-optimal picture's associate was presented as a cue. In contrast, they showed no response change in the DMS task. We confirmed that this effect is not due to the visual response to colors. Furthermore, when the cue-optimal picture was presented as a cue, these neurons showed suppression after the color switch in the PACS task. These results suggest that the activity of AIT neurons mediates gating mechanisms that preferentially pass information about a sought target, even when the sought target is retrieved from long-term memory.

Formation of mnemonic neuronal responses to visual paired associates in inferotemporal cortex is impaired by perirhinal and entorhinal lesions.

Functional roles of the cortical backward signal in long-term memory formation were studied in monkeys performing a visual pair-association task. Before the monkeys learned the task, the anterior commissure was transected, disconnecting the anterior temporal cortex of each hemisphere. After training with 12 pairs of pictures, single units were recorded from the inferotemporal cortex of the monkeys as the control. By injecting a grid of ibotenic acid, we unilaterally lesioned the entorhinal and perirhinal cortex, which provides massive direct and indirect backward projections ipsilaterally to the inferotemporal cortex. After the lesion, the monkeys fixated the cue stimulus normally, relearned the preoperatively learned set (set A), and learned a new set (set B) of paired associates. Then, single units were recorded from the same area as for the prelesion control. We found that (i) in spite of the lesion, the sampled neurons responded strongly and selectively to both the set A and set B patterns and (ii) the paired associates elicited significantly correlated responses in the control neurons before the lesion but not in the cells tested after the lesion, either for set A or set B stimuli. We conclude that the ability of inferotemporal neurons to represent association between picture pairs was lost after the lesion of entorhinal and perirhinal cortex, most likely through disruption of backward neural signals to the inferotemporal neurons, while the ability of the neurons to respond to a particular visual stimulus was left intact.