Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder. Cortical thinning of the anterior mid-cingulate cortex (aMCC) and insula has been previously reported in IBS (Davis et al., 2008). The aim of the present study was to examine cortical and subcortical structural gray matter integrity in IBS with particular attention to individual disease symptoms and personality characteristics such as pain catastrophizing. Eleven IBS patients and 16 age-matched healthy subjects (female, right-handed) underwent structural MRI. Voxel Based Morphometry and Cortical Thickness Analysis revealed that the IBS group had increased gray matter density in the hypothalamus, cortical thinning in the aMCC, strong (r = -66; p=0.015), a negative correlation between dorsolateral prefrontal cortex and pain catastrophizing and anterior insula thickness was positively correlated to pain duration (r = 0.77, p=0.003) when controlling for age. These abnormalities may contribute to chronic pain in IBS.

Lamina formation in the developing cortex requires precise generation, migration and differentiation of cortical neurons. Cortical projection neurons originate from progenitors of the embryonic dorsal telencephalon. The transcription factor Pax6 is expressed in apical progenitors (APs) throughout corticogenesis in a rostro-lateralhigh to caudo-mediallow gradient. The current studies focus on elucidating the spatial and temporal role of Pax6 in cortical development. I first analysed the cortex of PAX77 transgenic mice that overexpress Pax6 in its normal domains of expression. I show that Pax6 overexpression acts cell-autonomously to reduce the proliferation of late cortical progenitors specifically, resulting in the formation of thinner superficial layers in the PAX77 cortex. Increased levels of Pax6 lengthen the cell cycle of APs and drive the system towards neurogenesis. These effects are specific to late stages of corticogenesis, when superficial layer neurons are normally generated, in cortical regions that express Pax6 at the highest levels. The number of superficial layer neurons is reduced in postnatal PAX77 mice, while radial migration and lamina specification of cortical neurons are not affected by Pax6 overexpression. Then, Pax6 was conditionally inactivated in cortical progenitors at mid- or late-stages of corticogenesis by using a tamoxifen-inducible Emx1-CreER line. I report a novel requirement of Pax6 for continuous suppression of ventral fates and concurrent maintenance of an appropriate dorsal identity in cortical progenitors. Pax6 ablation at either mid- or late-stages of corticogenesis increases the proliferation of late cortical progenitors at all levels across the rostral-caudal axis. In the absence of Pax6 from mid-corticogenesis, late-born neurons are severely under-represented and misspecified in superficial layers of the mutant cortex. Notably, Pax6 inactivation during late corticogenesis also affects superficial laminar fate; although the numbers of late-born cortical neurons are not severely affected in superficial layers of the mutant cortex, substantial numbers of late-born cells fail to migrate to appropriate laminar positions and accumulate in the ventricular zone (VZ) of the postnatal mutant cortex. Collectively, these gain- and loss-of-function studies suggest that disruption of Pax6 levels during different developmental time points leads ultimately to impaired formation of superficial cortical layers but through different cellular and molecular mechanisms.

This work examines the link between low-level cortical acoustic processing and higher-level cortical phonemic processing. Specifically, using functional magnetic resonance imaging, it looks at 1) whether or not the vowels [ɑ] and [i] are distinguishable in regions of interest defined by the first two resonant frequencies (formants) of those vowels and 2) whether or not that neural discrimination ability changes based on anatomical region. The formant-frequency based regions of interest are found to respond differentially to [ɑ] and [i] with the response to [ɑ] statistically significantly greater than the response to [i] in the averaged [ɑ] formant-frequency based region. Unexpectedly, the response to [i] is numerically but not statistically significantly greater than the response to [ɑ] in the averaged [i] formant-frequency based region. Additionally, there is not a significant interaction of this pattern with anatomical region, although early cortical auditory regions appear to show the pattern while later ones do not. Further investigation into the results leads to the hypotheses that they could be due to task-specific neural processing strategies and that the link between lower and higher-level cortical auditory processing is more complex than originally hypothesized.

The entorhinal cortex (EC) is a vital structure in the mammalian brain, implicated in the processes of learning and memory, and a possible site for the generation of seizures in temporal lobe epilepsy. Neurones in the EC are constantly bombarded with inhibitory and excitatory neurotransmitter. This background activity is thought to exert significant control on the excitability and function of neurones in cortical networks, with changes in the levels and proportion of background inhibition (IBg) and excitation (EBg) driving rhythmic oscillations in membrane potential, and even underlying the generation of epileptic seizures.

Human brain evolution granted us cognitive and behavioral capabilities that are unique amongst animals. SRGAP2 is a gene that was specifically duplicated in the human lineage and plays roles in the regulation of cortical development and synapse dynamics. As paralogs of one of the few known genes that regulates excitatory and inhibitory synapses concurrently, the duplications of SRGAP2 were well-positioned during human evolution to gain novel functions leading to the cognitive and behavioral phenotypes exhibited in humans. SRGAP2C, a human-specific paralog of the ancestral SRGAP2 gene, inhibits every known function of SRGAP2 and induces a phenotype similar to SRGAP2 knockdown. This induces neoteny in the maturation of synapses in mice, allowing us to study a putatively “human-like” phenotype in the mouse brain. While studies have been conducted on the effects of SRGAP2 manipulation in juvenile and young adult mice, its effects on older mice has yet to be determined. In this dissertation, we perform longitudinal imaging experiments to determine the effects of SRGAP2 manipulation in the cortex of adult mice. In Chapter 3, we first examine the effects of SRGAP2 knockdown on the spine dynamics on apical dendrites of layer 5 pyramidal cells in the barrel cortex of adult mice, determining how it regulates spine density, turnover, and survival at baseline and in response to sensory deprivation. In Chapter 4, we study how SRGAP2 knockdown affects the clustered formations of new dendritic spines on the apical dendrites of layer 5 pyramidal cells in the barrel cortex of adult mice. Together, these results represent the first demonstration of SRGAP2 regulating on synapse dynamics in vivo and show that SRGAP2 knockdown can be used to model human brain evolution in adult mice.

No description available.

acase@tulane.edu / 1 / Jeremiah Hartner

Direct cortico-motoneuronal (CM) connections of corticospinal tract neurons are a distinctive feature of the primate motor system which are known to be important for the capacity to perform independent finger movements. However, it is still unclear how the appropriate combinations of CM cells are recruited to produce the selective (fractionated) control over muscles of the upper limb that is necessary for independent finger movements. I have investigated whether GABAergic intracortical inhibitory (ICI) circuits in human motor cortex contribute to the selection of the appropriate CM cells during a motor task requiring selective activation of one of several intrinsic hand muscles. Behaviour of ICI circuits during voluntary contraction was compared for the dominant and non-dominant hemisphere of right-handed subjects, as hemispheric differences in ICI may contribute to preferential use of the right hand for fine motor tasks. Finally, I investigated the range of forces over which ICI contributes to selective activation of a hand muscle. Neurologically normal adult human subjects were recruited for all experiments. Surface electrodes recorded electromyographic activity of abductor pollicis brevis (APB), first dorsal interosseous and abductor digiti minimi muscles during controlled isometric contractions of APB at different force levels while subjects attempted to keep the other two muscles relaxed using visual feedback of EMG. Paired-pulse transcranial magnetic stimulation (TMS) was used to assess ICI at rest and during selective activation of a hand muscle. TMS intensity and interstimulus interval were varied in different trials. Data were compared for two different directions of induced current in the brain; posteriorly directed current (PA stimulation) and anteriorly directed current (AP stimulation). ICI is suppressed for corticospinal neurons controlling the muscle targeted for selective activation; no change in ICI was seen for corticospinal neurons controlling the muscles required to be relaxed. This indicates that differential modulation of ICI in human motor cortex contributes to selective activation of a hand muscle. The direction of current flow induced in the brain proved to be critical for demonstrating this effect. It was observed with AP stimulation but not PA stimulation. I argue that this is due to preferential activation by PA stimulation of interneurons producing I1 waves in corticospinal neurons. These interneurons are not acted upon by ICI circuits. This problem makes the conventional PA paired-pulse TMS technique unreliable for the assessment of ICI during voluntary contraction. With AP stimulation it was demonstrated that ICI is not modulated during weak selective activation of a hand muscle (&lt5percent of maximal voluntary contraction), but ICI effects on CM cells controlling the target muscle are progressively suppressed at higher levels of activation. The present study is the first to examine hemispheric differences in ICI during selective isometric contraction of an intrinsic hand muscle. No hemispheric differences were observed. These studies have demonstrated a functional role for ICI in fractionation of hand muscle activity in normal subjects. It also provides an improved basis for investigating the changes in ICI with TMS in various neurological conditions in which it has been reported that GABAergic inhibition is abnormal. / Thesis (Ph.D.)--School of Molecular and Biochemical Science, 2004.

Thesis (Ph. D. in Biomedical Engineering)--Vanderbilt University, Dec. 2007. / Title from title screen. Includes bibliographical references.

The work of this thesis concerns how cortical memories are stored and retrieved. In particular, large-scale simulations are used to investigate the extent to which associative attractor theory is compliant with known physiology and in vivo dynamics. The first question we ask is whether dynamical attractors can be stored in a network with realistic connectivity and activity levels. Using estimates of biological connectivity we demonstrated that attractor memories can be stored and retrieved in biologically realistic networks, operating on psychophysical timescales and displaying firing rate patterns similar to in vivo layer 2/3 cells. This was achieved in the presence of additional complexity such as synaptic depression and cellular adaptation. Fast transitions into attractor memory states were related to the self-balancing inhibitory and excitatory currents in the network. In order to obtain realistic firing rates in the network, strong feedback inhibition was used, dynamically maintaining balance for a wide range of excitation levels. The balanced currents also led to high spike train variability commonly observed in vivo. The feedback inhibition in addition resulted in emergent gamma oscillations associated with attractor retrieval. This is congruent with the view of gamma as accompanying active cortical processing. While dynamics during retrieval of attractor memories did not depend on the size of the simulated network, above a certain size the model displayed the presence of an emergent attractor state, not coding for any memory but active as a default state of the network. This default state was accompanied by oscillations in the alpha frequency band. Such alpha oscillations are correlated with idling and cortical inhibition in vivo and have similar functional correlates in the model. Both inhibitory and excitatory, as well as phase effects of ongoing alpha observed in vivo was reproduced in the model in a simulated threshold-stimulus detection task. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper8: In press.</p>