No description available.

The ability of migrating neurons and growth cones to navigate through their environment is crucial for the correct development of the brain. Cells and growth cones may be guided by electrical, chemical or topographical cues in their environment. Pax6 is a transcription factor vital for brain development. Pax6-/- mutant mice die perinatally with defects in neuronal proliferation and differentiation, cortical cell migration and axon guidance, yet it is not clear which guidance cues Pax6-/- mutant neurons fail to interpret. Dissociated cultured cells were used to study the cell-autonomous effects of Pax6 mutation on guidance of growth cones and migrating neural precursors by environmental cues. Neurites from mouse embryonic cortical neurons aligned perpendicular to 1 μm-wide, 130 nm-deep substratum grooves. Pax6-/- mutation abolished contact-mediated neurite guidance by these grooves. Laminin induced a switch from perpendicular to parallel alignment to grooves, via a β1 integrin-independent mechanism. Blocking cAMP signalling abolished perpendicular alignment to polylysine-coated grooves, but enhanced parallel alignment to laminin-coated grooves. Pax6 null mutation or overexpression also caused specific defects in contact-guided migration by cortical cells. An electric field applied to E16.5 cortical neurons increased the frequency of extension of neurites aligned perpendicular to the field axis. Pax6-/- mutant cells responded to an electric field with reduced anodal extension, but no significant increase in perpendicular neurite extension. Electrical cues were prioritised over topographical cues when presented in combination. Taken together, data suggest that Pax6 mutant cortical cells do not completely lack the ability to detect extracellular guidance cues, but they respond differently to wild-type cells. In combination with other defects identified in the cortex, this may contribute to the cell migration and axon guidance phenotypes in the brain of the Pax6-/- embryo. This study also identified novel Pax6 expression in the trigeminal ganglion, where it may regulate axon guidance and neurogenesis.

No description available.

The relationship of personality disorders and persistent post concussive syndrome (PPCS) in mild head injury was investigated. Personality disorders were measured with the Millon Clinical Multiaxial Inventory-II (MCM-II). Mild head injury referrals were compared to a moderate head injury group, (n=46), and to a non-head injured neurological control group, (n=93). There was little evidence to suggest that the mild traumatic brain injury (TBI) group had more personality disorders than either of the two comparison groups. The mild TBI group did endorse more passive-aggressive, aggressive-sadistic, self-defeating and borderline personality traits; however, the overall scores were below ranges which indicate a personality disorder. The relationship between personality disorders (the MCMl-Il) and emotional status, as measured by the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) was also examined. Neither maladaptive personality characteristics or psychological distress were related to performance on neuropsychological tests. The results are discussed within the context of physiological and psychological determinants of the PPCS. / Graduate

Hydrocephalus is a common neurological condition characterized by altered cerebrospinal fluid (CSF) flow that results in ventricular expansion due to an accumulation of CSF inside the cranial vault. It is the second most frequent congenital neurologic malformation, but it can manifest at any age, as it is associated with multiple acquired etiologies related to CSF blockage or impaired CSF absorbance. The type and severity of brain damage is dependent on the age of onset, the rate of ventricular enlargement, the magnitude of ventriculomegaly, and how near the impaired brain structure(s) is/are to the cerebral ventricles. The purpose of this thesis was to gain an understanding of potential pharmacological therapies for treating pediatric hydrocephalus that are aimed to supplement commonly used surgical procedures, such as ventricular shunting and endoscopic third ventriculostomy (ETV). In this endeavour, we experimentally induced hydrocephalus by injection of kaolin (aluminum silicate) into the cisterna magna of juvenile rats at 3 weeks age and ferrets at 2 weeks age to mimic the human condition in infants and children. Prior to drug testing, we characterized the ferret model of hydrocephalus and examined the behavioural, brain structural, cellular, and neurobiochemical changes associated with the condition. From there, we treated hydrocephalic rats for 2 weeks with a combination of antioxidant agents, including α-tocopherol, L-ascorbic acid, coenzyme Q10 (CoQ10), reduced glutathione, and reduced lipoic acid to determine if they showed any improvements compared to sham-treated hydrocephalic rats. Afterwards, we used MgSO4 to treat hydrocephalic ferrets for 2 weeks and compared their outcome to sham-treated hydrocephalic ferrets. In both experiments, the pharmacological therapies did not show any significant biochemical and neurological benefits, nor did the animals improve behaviourally compared to sham-treated animals. Overall, it is suggested that therapeutic benefits were not observed in these studies potentially because ventriculomegaly was not severe enough, the route and/or timing of treatment was not maximally effective, or these treatments should be supplemented with surgical interventions to determine their potential synergistic effects, which would be expected to be implemented in the clinical setting. In conclusion, surgical procedures for treating hydrocephalus are rife with complications, which adds to its morbidity and mortality, so it is important to investigate new therapeutic avenues to effectively treat and hopefully cure hydrocephalus one day. / October 2016

Three groups of goldfish were prepared; naive, avoidance-conditioned and pseudo-conditioned animals. Five pseudo-conditioned fish were avoidance trained later and found to have no measurable acquisition of the avoidance conditioning paradigm. Several protein fractions were found to have significantly different rates of synthesis when compared across groups. The possible involvement of these proteins in the memory storage process was discussed.

Legibus almae hujus Academiae, quae, omnes eos lauream Appollinarem ambientes, aliquid progressus sui in scientia medica testimonium, in publicam proferre sanciunt, obtemperanti, de Apoplexia Sanguinea in Paginis sequentibus pauca, mihi in animo est disserere; morbus, quo, sive symptomatum saevitiam, accessus rapiditatem, stragesve luctuosas, quas inter homines quotidie edit, nullus medici attentionem peritiamque majore jure sibi vindicat.

It has long been acknowledged that inhibitory interneurons play a crucial role in regulating the input-output functions of principal cells in the hippocampus. The investigations we conducted focus on one specific population of interneurons, expressing the protein parvalbumin. The thesis describes three different studies, aimed to characterize anatomical and functional aspects of parvalbumin positive interneurons in the mouse hippocampal formation. The first study examines long-range projections of these neurons from CA1 and subiculum to distant regions of the brain, finding potential targets mainly in septal, thalamic and hypothalamic areas. The second study investigates the role of parvalbumin-positive interneurons of the dentate gyrus in spatial memory. Behavioural experiments with radial arm and Morris water maze have been carried out to understand how these GABAergic interneurons regulate information flow during reference and working memory. Finally, a third study describes basic anatomical features of parvalbuminpositive dendritic spines in the dentate gyrus. Their characteristics have been widely studied in principal neurons but little is known about spines in interneurons. Here I show a peculiar distribution of spines on apical dendrites of these cells, with a predominant localization within the inner third of the molecular layer. All studies utilized a combination of transgenic Cre-expressing mice and Creactivatable AAVs. For the first and third study AAV-based neuronal labeling was applied to visualize neurons, including their projections and their spines, respectively, through expression of fluorescent proteins. For the second study instead two genetic tools have been used in order to disrupt the neurotransmission from parvalbuminpositive interneurons and examine the effects on behavioral task performance.

The whole-cell patch-clamp technique was established in the laboratory in order to investigate the modulation of excitatory amino acid-mediated synaptic transmission in the rat hippocampal slice. Following the successful development of the technique the basic properties of excitatory amino acid-mediated synaptic transmission in the CA3-CA1 pathway were studied. Stimulation of the SCCFs (Schaffer collateral-commissural fibres) under conditions in which the inhibitory transmission was blocked resulted in a compound EPSC (excitatory postsynaptic current) mediated by AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartic acid) receptors. Application of a brief high-frequency stimulus to the SCCFs resulted in a long-lasting potentiation of the EPSC. Various compounds were applied to the slice to establish whether tetanus-induced potentiation could be mimicked pharmacologically. No potentiation was observed with perfusion of the ionotropic glutamate-receptor agonists L-glutamate, NMDA or AMPA, the latter two producing a transient depression of the EPSC. Following this a series of experiments were performed that investigated the consequences of mGluR (metabotropic glutamate receptor) activation. Perfusion with the selective agonist 1S,3R-ACPD ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid) resulted in a small depression of both the compound EPSC and the isolated NMDA receptor-mediated EPSC. In the presence of AA (arachidonic acid (10M)), 1S,3R-ACPD produced a slight potentiation of the response that was not blocked by the NMDA receptor antagonist D-AP5 (D-(-)-2-amino-5-phosphonopentanoic acid). The co-application of 1S,3R-ACPD and NMDA also produced a slight enhancement of the EPSC, as did AA when applied alone. These findings are consistent with an involvement of mGluRs in the induction of LTP, when activated in the presence of AA.

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2019 / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 179-192). / From riding a bike to brushing our teeth, we learn many of our motor skills through trial and error. Many biologically based trial and error learning models depend on a teaching signal from dopamine neurons. Dopamine neurons increase their firing rates to signal outcomes that are better than expected and decrease their firing rates to signal outcomes that are worse than expected. This dopamine signal is thought to control learning by triggering synaptic changes in the basal ganglia. What are the origins of this dopaminergic teaching signal? How do synaptic changes in the basal ganglia lead to changes in behavior? In this thesis, I study these questions in a model of skill learning - the songbird. In the first part of my thesis, I develop a computational model of song learning. This model incorporates a dopaminergic reinforcement signal in VTA and dopamine-dependent synaptic plasticity in the singing-related part of the basal ganglia. / I demonstrate that this model can provide explanations for a variety of experimental results from the literature. In the second part of my thesis, I investigate a potential source of the dopaminergic error signal in VTA. I performed the first recordings from one cortical input to VTA: the dorsal intermediate arcopallium (AId). Previous studies disagree on the role of Ald in behavior. Some studies argue that AId contributes vocal error information to VTA. Other studies suggest that AId is not involved in the computation of error signals, but is instead responsible for controlling head and body movements. I directly tested these hypotheses by recording single neurons in AId during singing and during natural movements. My results support a motor role for AId - AId neurons had highly significant changes in activity during head and body movements. Meanwhile, following vocal errors Aid neurons had small but marginally significant decrease in firing rate. / In a more detailed analysis, I developed an automated behavior classification algorithm to categorize zebra finch behavior and related these behavior classes to the activity of single units in Aid. My results support the hypothesis that AId is part of a general-purpose motor control network in the songbird brain. / by Michael E. Stetner. / Ph. D. / Ph.D. Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences