The subject of the thesis is a study of the projections from low threshold oral and face afferents to the cerebral cortex and of descending motor control mechanisms originating in the cerebral cortex or the hypothalamus and influencing the jaw reflexes.Cats anaesthetized with chi oral ose were used for the experiments. Ipsi- and contralateral nerves from the oral cavity and the face were stimulated electrically. Cortical potentials were averaged and recorded. The location of the projections was related to the cytoarchi-tectonic areas of the cerebral cortex. It was found that the afferents projected to separate maximum points in areas 3a, 3b, 5a and 6aß. The projections to areas 3a and 3b were somatotopically organized, but the layout of the projections on the cortex was not facelike.The effect of monopolar anodal stimulation of the cerebral cortex on the monosynaptic jaw closing and the di synaptic jaw opening reflexes was investigated. A sequence of facilitation and inhibition of both reflexes was elicited by cortical stimulation. The effects were of short latency (2.5 ms) and could start with either facilitation or inhibition. The timecourse of the sequence was sinuslike with a period of 10 ms. The largest effect originated in the "sensory" areas 3a and 3b and not in the "motor" areas 4y and 6ag. It is suggested, that a tri gemino-cortico-tri geminai loop via area 3a may function in reflex modulation of jaw movements.The hypothalamic effects on the jaw reflexes were evoked by electrical stimulation in those parts of the hypothalamus, which are w known to generate defence, attack or feeding responses. A tenfold facilitation of the jaw closing reflex and a facilitation followed by almost complete inhibition of the jaw opening reflex were observed in the anaesthetized animal with intact cerebral cortex. The effects remained but were diminished in amplitude after cortical ablation. The descending path was located in the ventral midbrain tegmentum.It is suggested that the observed hypothalamo-tri geminai mechanism may exercise a tonic influence on the trigeminal motoneurones, thereby controlling the set points of the biting force and the rest position. The implications of this hypothesis on the etiology of bruxism and the myofascial pain-dysfunction are discussed. / <p>Härtill 3 rapporter.</p> / digitalisering@umu

Cerebral cortex, classified as gray matter, is the superficial layer of the cerebrum. In recent years, many studies have shown the abnormality of cortical thickness is possibly correlated to the disease or disorder in central nervous system, such as Alzheimer¡¦s disease and lissencephaly. Therefore, this purpose of this work is to implement the measurement of the cortical thickness. In general, two approaches, surface-based and voxel-based methods, have been proposed to measure the cortical thickness. In this thesis, a procedure of the voxel-based method using Laplace¡¦s equation was developed on the basis of a 2008 publication reported by Chloe Hutton et al to obtain voxel-based cortical thickness (VBCT) map. The result of our home-made program was further compared with those calculated by Hutton¡¦s program, whic h was generously provided by the author. The difference between two implementations was consisted of four main parts. First of all, different strategies of the tissue classification were used to define boundary condition of Laplace¡¦s equation. When grey matter, white matter, and cerebrospinal fluid were classified by maximizing the tissue probability, Hutton¡¦s program tends to search more voxels of cerebrospinal fluid in sulci by skeletonizing the non-parenchyma area. Second, the algorithm of layer growing also differs. The single layer obtained by the 26-neighborhood algorithm in our program would be obviously thicker than that provided by Hutton¡¦s program using 6-neighborhood. Third, compared with a fixed step size (usually 0.5 mm) porposed in the main reference to track cortical streamline, we designed a variable step size, reducing the underestimation of cortical thickness. The last but not the least, the connecting points of the cortical streamline usually are not grid points, thus requiring interpolation to estimate the stepping gradient. We adapted the linear interpolation for better accuracy when Hutton et al searched for the closest grid point for replacement to achieve faster computation.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 99-131).

Representing a major public health concern, suicide is a leading cause of death worldwide. Generally regarded as a behavior with a multitude of state and trait dependent risk factors (e.g. psychiatric disorders, substance abuse, genetics), explanations as to why certain individuals commit suicide while others do not are complex. Of interest is in studying potential trait dependent variables involved in the neurobiology of suicide, particularly at the cellular level. Knowledge of the cellular integrity may aid in explaining the observed macroscopic alterations and ultimately the behavioral correlates associated with suicidality. Therefore we set out to summarize extant knowledge of the cellular alterations occurring in the brains of major depressive and suicide individuals. Following this, we conducted our own cellular investigation in a region known to be altered in major depression and suicide, a supracallosal area of BA24a. Neuronal and glial cell densities as well as neuronal cell sizes were assessed in upper and lower cortical layers between sudden-death controls and MDD suicide subjects. Secondary analyses were also conducted to examine the effect of alcohol on depressed suicides. Analyses of cell densities and neuronal soma sizes between controls and MDD suicide subjects did not reveal any significant differences. Further analyses showed increased glial cell densities in alcoholic depressed suicides. Future studies are necessary to examine explicit changes in the cellular compositions occurring in alcoholic dependent individuals. Staining techniques aimed at targeting specific subtypes of neurons and glial cells will help determine if these cell populations do in fact have an influential role in suicide and MDD.

This thesis focused on the spatiotemporal patterning of classical excitatory and inhibitory synaptic contacts accounting for the majority of cerebral cortical connections, in relation to ageing and cognitive status. These investigations tested the hypothesis that higher CNS functions depend on the balance between excitatory and inhibitory synaptic connections. Glutamatergic and GABAergic presynaptic bouton densities were determined in aged animals segregated according to their cognitive status into aged and cognitively unimpaired (AU) and aged and cognitively impaired (AI), using the Morris water maze. These two groups were compared in terms of behaviour and the pattern of excitatory and inhibitory synapses. It was evident that an excitatory and inhibitory presynaptic decline is associated with age-related cognitive impairments; whereby both glutamatergic and GABAergic boutons gradually diminish from young to AU to AI. Nevertheless, the balance between excitatory and inhibitory presynaptic inputs was maintained. To determine whether postsynaptic sites differed with respect to ageing and cognitive impairments, excitatory and inhibitory postsynaptic scaffold proteins were investigated in the same cohort of segregated aged animals. There was an imbalance in density ratio between immunoreactive sites of excitatory versus inhibitory postsynaptic scaffold proteins in AI animals. This resulted from a marked decrease in the density of excitatory postsynaptic sites. To further investigate ultrastructural aspects of excitatory synapses I carried out electron microscopical studies of cerebral cortex to measure the abundance of NR2 receptor subunits of the NMDA receptor- a receptor site directly associated with excitatory postsynaptic scaffold proteins. This study revealed that NR2 immunoreactive sites were largely preserved during age-related cognitive decline with an uneven profile distribution. Finally, protein expression of specific receptor subunits and key proteins representative of excitatory and inhibitory postsynaptic sites was investigated by semi-quantitative Western blot analyses in selected cortical areas. It was clear that many of these postsynaptic proteins are affected by age and cognitive status. The most striking change was a marked up-regulation in neuroligin-1 in AI animals, which may affect the delicate balance between excitatory versus inhibitory synaptic inputs. Another notable finding was the down-regulated expression of GluR2 receptor subunits in AI animals, which should have implications for neuronal Ca2+ regulation. In conclusion, we have demonstrated the greater vulnerability of excitatory postsynaptic sites in aged and cognitively impaired animals.

Repetitive presentation of any non-significant stimulus to an animal results in a decrement in the animal's response to that stimulus. This phenomenon, termed habituation, is distinguishable from fatigue and receptor adaptation in that it is long-lasting and in that the habituation is fairly specific to the repeated stimulus. The prevailing view of habituation is that it, like learning in general, results from an increase in the efficacy of neural transmission, but, unlike learning, this increased efficacy primarily affects inhibitory interneurons (e.g., Soko1ov, 1960; Hernandez-Peon, 1960; Jouvet, 1961). Within this broad framework, disagreements exist regarding the source of the inhibitory influences. [...]

Mild head injury or concussion accounts for as many as 90% of all traumatic brain injuries and can sometime result in long-lasting and disabling post-concussion symptoms (PCS), even in the absence of detectable structural damage to the brain by morphological imaging. To date, the nature of persistent PCS following mild head injury remains poorly understood as objective and scientifically valid diagnostic tools are practically absent. This, in turn, likely accounts for missed diagnoses, prevents accurate assessment of the severity of the injury and creates difficulties for achieving proper patient management. / This dissertation describes 4 functional magnetic resonance imaging (fMRI) studies designed to establish whether there is a pathological basis to persistent PCS following cerebral concussion in male athletes. Study 1 was intended to evaluate the feasibility of using fMRI to detect changes in brain activation following concussion. The results showed that concussed athletes displayed reduced prefrontal activities compared to a healthy control group when performing a working memory task. In Study 2, we examined the relationship between self-reported PCS and the pattern of brain activity measured by fMRI. The severity of self-reported PCS was found to be associated with blood oxygen level dependent (BOLD) activation patterns in the region of interest: the higher the PCS score the lower the BOLD signal. In Study 3, we used serial fMRI approach to investigate brain activation pattern in the course of injury recovery. The results showed that symptom resolution was accompanied by a return to normal BOLD response patterns. Study 4 was designed to investigate the nature of depression, a common PCS, following concussion. Concussed athletes with depression showed less activation in the dorsolateral prefrontal cortex, and attenuated deactivation in the medial prefrontal region, consistent with functional neuroimaging findings in major depression. Again, depression severity correlated with the strength of the fMRI signal in the region of interests. / Taken together, these results demonstrate the value of functional MRI in the evaluation of cerebral concussion, and provide evidence of an underlying pathology in persistent PCS following concussion.

Sleep is essential for mammals and possibly for all animals. Advancing our knowledge of sleep regulation is crucial for the development of interventions in sleep-related health and social problems. With this aim, this study utilizes laboratory mice to explore sleep regulatory mechanisms at behavioral, molecular, and genetic levels. Sleep is regulated by the interaction of circadian and homeostatic processes. The circadian clock facilitates sleep to occur at a favorable time of the day. Normal mice, such as the C57BL/6J (B6) strain, sleep mostly during the day and initiate activities at dark onset. Here, I show mice of the CAST/EiJ (CAST) strain initiate activity unusually early (hours before dark). The circadian gating of photic phase-shifting responses was phase-lagged in the CAST mice relative to their activity rhythms, implying an altered coupling between the clock and its output. Light failed to suppress activity in the CAST mice, allowing full expression of the early activity. A previously identified quantitative trait locus that contributes to the advanced circadian phase was also confirmed and refined to a smaller genomic region. The circadian oscillation and light-induction of clock-genes Per1 and Per2 expression was not different between B6 and CAST mice in the suprachiasmatic nucleus (SCN) of the brain, where the mammalian master circadian clock is located. However, in the cerebral cortex and paraventricular hypothalamic nucleus of CAST mice, Per mRNA oscillations were phase-advanced coordinately with their advanced behavioral rhythms. These data thus provide direct evidence that the cause of the early runner phenotype is located downstream of the master circadian clock. The rhythms of cortical Per expression may not be a result of direct SCN effector mechanisms, but rather driven by activity-rest and sleep-wake. I further show that prolonged waking induces cortical Per expression, and this induction persisted in SCN-lesioned animals. SCN Per expression in intact animals was not affected. Thus, a homeostatic drive, independent of the SCN clock, regulates cortical Per expression, although a possible circadian influence in the intact animals was also suggested by detailed analyses. These data may suggest a molecular mechanism bridging the circadian and homeostatic processes for sleep regulation and functions.

Brain atrophy has been used as a marker for disease progression in Multiple Sclerosis (MS). SIENA, an automated tool for measuring brain volume change, was tested to see whether MRI slice thickness and gap presence affect longitudinal atrophy measures. Isotropic global scan-rescan images were used to simulate 3 mm and 5 mm axial slice thicknesses with 1 and 2mm gaps, respectively. SIENA remained accurate and precise with increasing slice thickness and gap presence. Furthermore, symmetric pre-registration was crucial for scans with larger slice-thickness and gaps. / SIENA was used to observe atrophy in children who have experienced a Clinically Isolated Syndrome (CIS) of the type leading to MS (CIS-MS). Brain atrophy was present within the first three months after a CIS event, and then subsided over the rest of the year. If the first acute episode was excluded, there was no significant difference in atrophy rates between the CIS-MS group and the CIS group, and no significant difference between those with T2-weighted brain lesions versus those who had none.

Long-term potentiation (LTP) is an activity-dependent increase in the efficacy of synaptic transmission. In concert with long-term depression (LTD), this synaptic plasticity likely underlies some types of learning and memory. It has been suggested that for LTP/LTD to act as effective memory storage mechanisms, homeostatic regulation is required. This need for plasticity regulation is incorporated into the Bienenstock, Cooper and Munro (BCM) theory by a threshold determining LTD/LTP induction, which is altered by the previous history of activity (Bienenstock et al., 1982). The present work aimed to test key predictions of the BCM model. This was done using field and intracellular recordings in area CA1 of hippocampal slices from young, adult male Sprague-Dawley rats. The first prediction tested was that following a strong, high-frequency priming stimulation all synapses on primed cells will show inhibition of subsequent LTP and facilitation of LTD induction (heterosynaptic metaplasticity). This was confirmed using two independent Schaffer collateral pathways to the same CA1 pyramidal cells. Following priming stimulation to one pathway, LTP induction was heterosynaptically inhibited and LTD facilitated. To more fully investigate whether all synapses show metaplastic changes, the priming stimulation was given in a different dendritic compartment, in stratum oriens, prior to LTP induction in stratum radiatum. This experiment supported the conclusion that all synapses show inhibited LTP following priming. A second prediction of the BCM model is that metaplasticity induction is determined by the history of cell firing. To investigate this, cells were hyperpolarized during priming to completely prevent somatic action potentials. Under these conditions inhibitory priming of LTP was still observed, and thus somatic action potentials are not critical for the induction of the effect. The next aim was to determine the mechanism underlying heterosynaptic metaplasticity. One way in which plasticity induction can be altered is through changes in gamma-aminobutyric acid (GABA)-mediated inhibition of pyramidal cells. For this reason, it was tested whether blocking all GABAergic inhibition, for the duration of the experiment, would prevent priming of LTP. However, priming inhibited subsequent LTP and it was concluded that GABAergic changes do not underlie either the induction, or expression, of the metaplastic state. Proposed revisions to the BCM model predict that postsynaptic elevations in intracellular Ca�⁺ determine the induction of metaplasticity. There are many potential sources for postsynaptic Ca�⁺ elevations, including entry through N-methyl-D-asparate receptors (NMDARs) or voltage-dependent calcium channels (VDCCs), or release from intracellular stores. Results of the present work demonstrate that the inhibition of LTP is dependent on the release of Ca�⁺ from intracellular stores during priming; however this release is not triggered by Ca�⁺ entry through NMDARs or VDCCs, or via activation of metabotropic glutamate receptors. Overall, the present results show that, in accordance with the BCM model, a high level of prior activity induces a cell-wide metaplastic state, such that LTD is facilitated and LTP is inhibited. In contrast to predictions of the BCM model, this is not mediated by cell-firing during priming. Instead the release of Ca�⁺ from intracellular stores is critical for induction of the metaplastic state.