Faculty Bibliography

Seizure induction in laboratory animals is followed by many changes in structure and function, and one of these is an increase in neurogenesis-the birth of new neurons. This phenomenon may be relevant to temporal lobe epilepsy (TLE), because one of the regions of the brain where seizure-induced neurogenesis is most robust is the dentate gyrus-an area of the brain that has been implicated in the pathophysiology of TLE. Although initial studies predicted that neurogenesis in the dentate gyrus would be important to normal functions, such as learning and memory, the new neurons that are born after seizures may not necessarily promote normal function. There appears to be a complex functional and structural relationship between the new dentate gyrus neurons and preexisting cells, both in the animal models of TLE and in tissue resected from patients with intractable TLE. These studies provide new insights into the mechanisms of TLE, and suggest novel strategies for intervention that could be used to prevent or treat TLE

Consistent evidence shows both genetic and stress-related risks on child and adolescent anxiety, yet few studies have considered the degree to which genetic effects are moderated by stress (gene-environment interaction). We used longitudinal data from both a child and adolescent sample of twins to examine three novel issues on the presence of gene-environment interaction on anxiety symptoms. First, we assessed moderation of genetic risks on anxiety symptoms by negative life events in each age group. Second, by distinguishing between "stable" and "age-specific" genetic factors, we explored the continuity of gene-environment interaction across time and/or its emergence at specific ages. Third, we compared the presence of gene-environment interaction across different symptom types (general, panic, social, and separation). Genetic effects on separation anxiety symptoms in childhood (mean age = 8 years, 6 months) and panic anxiety symptoms in adolescence (mean age = 15 years) increased across independent negative life events. Shared environmental effects on separation anxiety symptoms and non shared environmental effects on general anxiety symptoms in adolescence were also moderated by negative life events. We interpret these preliminary findings tentatively in the context of gene-environment interaction on anxiety in general, and on early separation and later panic anxiety in particular.

New neurons are continuously generated in the subgranular zone of the hippocampus throughout adulthood, and there is increasing interest as to whether these new neurons become functionally integrated into memory circuits. This protocol describes the immunohistochemical procedures to visualize the recruitment of new neurons into circuits supporting spatial memory in intact mice. To label adult-generated granule cells, mice are injected with the proliferation marker 5-bromo-2'-deoxyuridine (BrdU). At different delays after BrdU treatment, mice are trained to locate a hidden platform in the Morris water maze, and spatial memory can then be tested in a probe test with the platform removed from the pool. Ninety minutes after this probe test, mice are perfused and tissue is sectioned. Immunohistochemical procedures are used to quantify BrdU-labeled cells and expression of the immediate early gene, Fos. Because Fos expression is regulated by neuronal activity, the degree of overlap between BrdU-labeled and Fos-labeled neurons provides an indication of whether adult-generated granule neurons have been incorporated into spatial memory circuits.

Non-rapid eye movement sleep has been strongly implicated in consolidation of both declarative and procedural memory in humans. Elevated sleep-spindle density in slow-wave sleep after learning has been shown recently in humans. It has been proposed that sleep spindles, 12-15 Hz oscillations superimposed on slow waves (<1 Hz), in concert with high-frequency hippocampal sharp waves/ripples, promote neural plasticity underlying remote memory formation. The present study reports the first indication of learning-associated increase in spindle density in the rat, providing an animal model to study the role of brain oscillations in memory consolidation during sleep. An odor-reward association task, analogous in many respects to human paired-associate learning, is rapidly learned and leads to robust memory in rats. Rats learned the task over 10 massed trials within a single session, and EEG was monitored for 3 h after learning. Learning-induced increase in spindle density is reliably reproduced in rats in two different learning situations, differing primarily in the behavioral component of the task. This increase in spindle density is also present after reactivation of remote memory and in situations when memory update is required; it is not observed after noncontingent exposure to reward and training context. The latter results substantially extend findings in humans. The magnitude of increase (approximately 25%) and the time window of maximal effect (approximately 1 h after sleep onset) were remarkably similar to human data, making this a valid rodent model to study network interactions through the use of simultaneous unit recordings and local field potentials during postlearning sleep

The prefrontal cortex (PFC) is known to subserve working memory (WM) processes. Brain imaging studies of WM using delayed response tasks (DRTs) have shown memory-load-dependent activation increases in dorsal prefrontal cortex (PFC) regions. These activation increases are believed to reflect manipulation of to-be-remembered information in the service of memory-consolidation. This speculation has been based on observations of similar activation increases in tasks that overtly require manipulation by instructing participants to reorder to-be-remembered list items. In this study, we tested the assumption of functional equivalence between these two types of WM tasks. Participants performed a DRT under two conditions with memory loads ranging from 3 to 6 letters. In an 'item-order' condition, participants were required to remember letters in the order in which they were presented. In a 'reordering' condition, participants were required to remember the letters in alphabetical order. Load-related activation increases were observed during the encoding and maintenance periods of the order maintenance condition, whereas load-related activation decreases were observed in the same periods of the reordering condition. These results suggest that (1) the neural substrates associated with long-list retention and those associated with reordering are not equivalent, (2) cognitive processes associated with long-list retention may be more closely approximated by item-order maintenance than by reordering, and (3) multiple forms of WM manipulation are dissociable on the basis of fMRI data

In survey sampling there is often a need to coordinate the selection of pairs of samples drawn from two overlapping populations so as to maximize or minimize their expected overlap, subject to constraints on the marginal probabilities determined by the respective designs. For instance, maximizing the expected overlap between repeated samples can stabilize the resulting estimates of change and reduce the costs of first contacts; minimizing the expected overlap can avoid overburdening respondents with multiple surveys. We focus on the important special case in which both samples are selected by simple random sampling without replacement (SRSWOR) conducted independently within each stratum. Optimizing the expected sample overlap can be formulated as a linear programming problem known as a transportation problem (TP). We show that by appropriately grouping and ordering the possible samples in each survey, one can reduce the initial TP to a much smaller TP amenable to solution by an algorithm known as the Northwest Corner Rule (NWCR). The proposed NWCR method proceeds in two easily implemented steps: first selecting the numbers of births (new units) and deaths (deleted units) by a random selection from a hypergeometric distribution, and then selecting the births and deaths by SRSWOR. We formally prove properties of the NWCR solutions, including a minimal variance property of the minimal overlap solution. In a simulation study, the NWCR method compares favorably with a popular method based on assignment of permanent random numbers to each sampling unit. $$:

OBJECTIVE: The corpus callosum is the primary anatomical substrate for interhemispheric communication, which is important for a range of adaptive and cognitive behaviors in early development. Previous studies that have measured the corpus callosum in developmental populations have been limited by the use of rather arbitrary methods of subdividing the corpus callosum. The purpose of this study was to measure the corpus callosum in a clinical group of developmentally delayed children using a subdivision that more accurately reflected the anatomical properties of the corpus callosum. METHOD: The authors applied tractography to subdivide the corpus callosum into regions corresponding to the cortical regions to and from which its fibers travel in a clinical group of very young children with developmental delay, a precursor to general mental retardation, in comparison with typically developing children. RESULTS: The data demonstrate that the midsagittal area of the entire corpus callosum is reduced in children presenting with developmental delay, reflected in the smaller area of each of the fiber-based callosal subdivisions. In addition, while the area of each subdivision was strongly and significantly correlated with the corresponding cortical white matter volume in comparison subjects, this correlation was prominently absent in the developmentally delayed group. CONCLUSIONS: A fiber-based subdivision successfully separates lobar regions of the corpus callosum, and the areas of these regions distinguish a developmentally delayed clinical group from the comparison group. This distinction was evident both in the area measurements themselves and in their correlation to the white matter volumes of the corresponding cortical lobes.