Genetic and non-shared environmental factors (factors experienced by one child to the exclusion of his siblings) have been strongly implicated in the aetiology of Attention Deficit Hyperactivity Disorder (ADHD). Shared environmental factors were not implicated. Pregnancy, labour/delivery and neonatal complications (PLDNC) were often associated to ADHD. However, no investigations aimed at delineating the shared/non-shared nature of these factors were reported. In order to identify PLDNC which are more likely to be non-shared, we recruited 65 children with ADHD and assessed their history for PLDNC. 45 of them had non-affected siblings that were also assessed for PLDNC. Compared to their non-affected siblings, ADHD children had significantly higher neonatal complications (p = 0.01). Furthermore, neonatal complications were associated with higher motor activity (p = 0.04) and attention deficits (p = 0.03) in ADHD diagnosed children, suggesting that neonatal complications are more likely to be non-shared environmental factors of etiological relevance to ADHD.

<p> There are two main patterns of development within animals: direct and indirect. Direct developers are animals such as humans, whose offspring are basically smaller versions of the adult. Indirect developers have a larval stage that can be dramatically different than the adult, and consequently go through a transformation known as metamorphosis. Frogs are a well-known example of vertebrate indirect development, developing first into an aquatic, herbivorous tadpole that later transforms into a terrestrial, carnivorous frog. This transformation is largely regulated by a single hormone&mdash;thyroid hormone (TH). Changes in TH play a vital role in tissue transformations such as, differentiation and growth of the limbs, remodeling of the gut tube and liver, as well as resorption of larval features such as the tail. In addition, the timing of metamorphic changes can differ substantially among species. For instance, the average rate of metamorphosis for a majority of frogs/toads (anurans) is between 3-5 weeks, yet there are a multitude of frogs and toads that take several months or even years to go through this process (Duellman and Trueb, 1994; Gilbert, 2010; Petranka, 2007; Provenzano and Boone, 2009). At the other extreme are frogs that have reduced or even eliminated the free-living larval period such as the Eastern Spadefoot toad, <i>Scaphiopus holbrookii, </i> which has one of the shortest larval periods found in metamorphosing frogs or direct developing frogs, like <i>Eleutherodactylus coqui</i> which have no free-living larval stage. This diversity of developmental patterns sparks many questions about the precise molecular and developmental roles TH has on metamorphosis in frogs. How can a single regulator produce such a wide range of responses, not only between species that differ in metamorphic timing, but also among tissues within a single individual? The vast majority of recent studies that examine tissue specific responses to TH have focused on the genes that code for TH binding proteins or for TH receptors (Hollar et al., 2011; Buchholz et al., 2011). However, a very important aspect is being overlooked in these studies, which is the actual level of the TR proteins themselves. </p><p> There are three distinct mechanisms that regulate tissue responses to TH: deiodinase enzymes, cytosolic thyroid hormone binding proteins (CTHBPs), and thyroid hormone receptors (TRs) (Morvan-Dubois <i>et al.,</i> 2008: Buchholz <i>et al.,</i> 2006). The overall objective of the current study is to develop a technique that will allow protein level analysis of two of the three components implicated in the regulation of tissue specific responses to TH during tadpole metamorphosis: CTHBPs and TRs. I hypothesize that changes in the affinity and/or capacity of thyroid hormone receptors and cytosolic thyroid hormone binding proteins to bind TH throughout metamorphosis underlie the timing and extent of tissue remodeling. In fresh tissue, saturation binding assays suggest a difference in binding capacity among tissues.</p>

<p> Schizophrenia is a prevalent neurological disorder characterized by disrupted neuronal circuitry. Antipsychotic drugs (APDs) are capable of ameliorating the symptoms of schizophrenia with varying efficacy. Clozapine, the "gold-standard" for antipsychotic drug treatment, has been shown by this lab to induce the outgrowth of mediodorsal thalamic (MDT) dendritic arbor in rodents, a brain region which has altered function and decreased regional volume in schizophrenic patients. These studies further explored the ability of APD treatment to restructure dendrite arbor and the mechanisms of clozapine's ability to elaborate MDT arbor. Additionally, glutamate hypofunction is thought to contribute to the schizophrenic disease state. Using a novel model of perinatal glutamate hypofunction, we examined the long-term effects on dendritic architecture of developmental glutamate signaling disruption. </p><p> MDT dysfunction is hypothesized to contribute to cognitive symptoms of schizophrenia. Clozapine has increased efficacy in ameliorating these symptoms. To further understand clozapine's actions to remodel MDT dendritic architecture, we examined whether clozapine-induced morphological alterations are limited to the thalamus or if they also occur in additional regions associated with cognitive schizophrenic pathology, the hippocampus and striatum. We found that clozapine can induce dendritic remodeling in the hippocampus, but the not to the amplitude of remodeling seen in the thalamus, indicating that the MDT is uniquely altered by clozapine treatment and may be an important locus of clozapine's action. </p><p> The mechanisms of clozapine's remodeling of MDT arbor, we examined changes to mRNA and miRNA expression and calcium dynamics in the MDT in response to APD treatment. Clozapine-treatment altered the expression of genes involved in cytoskeletal remodeling, external membrane receptors, and calcium dynamics, as well as increased the rate of calcium influx into thalamic neurons. </p><p> Disruption to glutamate signaling has been hypothesized to contribute to schizophrenic pathology. Disruption to perinatal vesicular glutamate packaging along the corticolimbic axis has long term effects for neuronal morphology and function. Interestingly, we find that disruption along the corticolimbic axis also has downstream effects on MDT dendritic architecture. </p><p> These studies show that the MDT is an important locus of action for clozapine and is capable of remodeling dendritic architecture in response to afferent circuitry dysfunction.</p>

No description available.

The fibrous sheath (FS) is a cytoskeletal structure that encases the axoneme in the principal piece of the spermatozoon tail. In the rat, it is composed of several proteins of which a 75 kDa polypeptide (FS 75) is the most prominent. The objectives of this study were to clone and sequence this protein and to characterize its transcriptional and translational origins during spermatogenesis. We succeeded in isolating two overlapping cDNAs encoding half of the downstream segment of the FS 75 protein. Both clones were obtained by screening a rat testicular phagemid cDNA library with an anti-FS 75 polyclonal antibody. The upstream portion of the FS 75 mRNA containing the initiation codon for translation was obtained by using the Polymerase Chain Reaction (PCR) technique, a pair of specific primers and a lambdagt11 cDNA rat library. The amino acid sequence of the longest possible open reading frame of the rat FS 75 was found to be almost identical to two previously cloned major FS polypeptides of mouse spermatozoa. Sequence analysis of the rat FS 75 cDNA revealed two A&barbelow;-K&barbelow;inase A&barbelow;nchoring P&barbelow;rotein (AKAP) domains and several kinase phosphorylation sites supporting the idea that this protein plays a crucial role in the motility of spermatozoa. The presence of a potential N-mistoylation site suggests that this protein may bind covalently to the inner leaflet of the plasma membrane (PM) which may explain the close relationship between the FS and PM from early development in round spermatids (step 2 of spermiogenesis) to maturation in spermatozoa. Developmental Northern Blot analysis and in situ hybridization revealed that the FS 75 mRNA is mainly haploid expressed with an abundant level of mRNA in round spermatids. Maximum levels of the FS 75 polypeptide, determined by immunocytochemistry, correlated with a rapid decline in corresponding mRNA levels in step 14--16 spermatids. Since transcriptional termination occurs several steps earlier

Cortical synaptic atrophy with aging has long been regarded as the primary substrate of decline in cognitive function. However, little is known about the impact of this structural change on cortical synaptic function. The aim of this thesis was to investigate the functional consequence of age-related synaptic reductions in the parietal cortex. In the first study, I analyzed synaptic density in the parietal cortex and revealed significant age-related presynaptic reductions. Interestingly, I found a preferential disappearance of synapses in deep cortical layers. The functional impact of presynaptic reduction was tested in the second study. Whole cell patch clamp recording of spontaneous synaptic currents (sPSCs) onto layer V pyramidal neurons revealed no age-related change. In contrast, the frequency of action potential - independent miniature postsynaptic currents (mPSCs) was decreased, thus revealing an increase in action potential dependent activity (FrequencysPSCs - frequencymPscs) in aged brains. The third study focused on the ratio between excitation and inhibition in aged impaired and aged unimpaired rats that were divided on the basis of their performance in the Morris Water Maze. Interestingly, I found an imbalance between excitation and inhibition in both aged groups. Finally, to test whether similar age-related modifications occur in other neurotransmitter systems, the fourth study contrasted cholinergic vs. non-cholinergic inputs onto layer V pyramidal neurons. I found a preferential decline in cholinergic inputs onto pyramidal neurons with aging. These findings provide evidence of functional compensation for the lost of synaptic structures in aged brains. However, rather than a general decline in synaptic function, imbalance between different synaptic inputs may be an important cellular substrate for cognitive impairment.

No description available.

Thesis (Ph.D.)--University of California, San Francisco, 2010. / Source: Dissertation Abstracts International, Volume: 71-05, Section: B, page: . Adviser: Michael S. German.

Abstract not available.

This series of studies used an oscillating platform paradigm to investigate the effects of aging on anticipatory and reactive mechanisms of postural control. We hypothesized that young adults would use anticipatory mechanisms in response to predictable postural perturbations and that aging would be characterized by a decrease in anticipatory postural muscle activity resulting in less effective balance control. Young and old healthy adults were asked to maintain standing balance on a force platform that oscillated continuously 20 cm peak-to-peak in the anterior/posterior (A/P) direction at successively increasing frequencies of 0.1, 0.25, 0.5 to 0.61 Hz. Subjects completed trials of externally- and self-triggered perturbations. The effect of mechanical stimulation of the foot plantar surface boundaries on postural responses of older adults was tested. Postural responses to perturbations were characterized using centre of pressure (COP), centre of mass (COM), muscle activity (EMG) and number of steps. A mathematical model representing the body motion in response to continuous sinusoidal platform perturbations was implemented. Young adults used anticipatory adjustments regardless of the degree of predictability of postural challenges in externally- and self-triggered perturbations. Old adults responded to a predictable externally-triggered postural challenge using reactive postural adjustments independent of the frequency of platform oscillation, the direction of perturbation and without adapting over multiple trials. Old adults used anticipatory adjustments only in self-triggered perturbations or when additional sensory stimulation from foot plantar surface boundaries was available. The present series of experiments demonstrated for the first time that cutaneous stimulation of the foot plantar surface boundaries increases stability and facilitates the use of anticipatory control strategies. These results support the importance of cutaneous mechanoreceptors at the boundaries of the foot plantar surface for the control of postural reactions evoked by continuous perturbations. The results from these experiments clearly show that the ability to compensate for an impending and highly predictable perturbation decreases with aging. The age-related difference in the control of standing balance on a continuous oscillating platform recorded in experimental data was partially explained through increased levels of sensory noise and neural delays in the simulated data of old adults. Our results support the concept of a dynamic stability, according to which, in addition to the horizontal location of the COM with respect to the base of support, the magnitude and direction of its corresponding velocity provide critical information pertaining to one's ability to control balance. Based on model work, we demonstrated that the acceleration parameters of a perturbation must be taken into account when calculating stability limits. We derived for the first time the equations for calculating these stability limits related to continuous translations of the base of support.