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<h1>Abstract <em></em></h1><p>This essay will present actual research around the concept of Post- Traumatic Stress Disorder, how it can reveal itself in school children and how it can influence young people’s learning ability and capacity to retain knowledge.</p><p>The purpose is, above all, to clearly diagnose PTSD so that children with this complex of problems can receive good possibilities in learning and understanding.</p><p>The question at hand is responded to by interviewees with an expertise on the subject and one “story”, collectively with literary studies.</p><p>The results illustrate that there can be neurological and biological, as well as social explanations for PTSD but it is seldom a permanent diagnosis. It is though something to take very seriously. PTSD can lead to severe psychobiological consequences, mostly by causing damage in one particular part of the brain, known as hippocampus. The hippocampus is essential in terms of memory and concentration. Other negative effects caused by PTSD might be a disturbed cognition, difficulties in the ability to store information or a deterioration of language. All of these consequences affect the child’s ability to learn in a negative way.</p><p>The essay demonstrates how educators can simplify a PTSD diagnosed child’s difficulties and how school time can be adjusted to fit their needs. The importance of educator’s getting deep knowledge of the diagnosis is emphasized. Children with this diagnosis need an individual designed study plan and one must take much consideration with the learning difficulty that hinder these young people.<em></em></p>

Abstract This essay will present actual research around the concept of Post- Traumatic Stress Disorder, how it can reveal itself in school children and how it can influence young people’s learning ability and capacity to retain knowledge. The purpose is, above all, to clearly diagnose PTSD so that children with this complex of problems can receive good possibilities in learning and understanding. The question at hand is responded to by interviewees with an expertise on the subject and one “story”, collectively with literary studies. The results illustrate that there can be neurological and biological, as well as social explanations for PTSD but it is seldom a permanent diagnosis. It is though something to take very seriously. PTSD can lead to severe psychobiological consequences, mostly by causing damage in one particular part of the brain, known as hippocampus. The hippocampus is essential in terms of memory and concentration. Other negative effects caused by PTSD might be a disturbed cognition, difficulties in the ability to store information or a deterioration of language. All of these consequences affect the child’s ability to learn in a negative way. The essay demonstrates how educators can simplify a PTSD diagnosed child’s difficulties and how school time can be adjusted to fit their needs. The importance of educator’s getting deep knowledge of the diagnosis is emphasized. Children with this diagnosis need an individual designed study plan and one must take much consideration with the learning difficulty that hinder these young people.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 1999. / Vita. Includes bibliographical references (leaves 88-105).

Immunocytochemical studies have demonstrated that nerve fibers containing immunoreactive oxytocin and vasopressin project to many areas of the central nervous system, including the hippocampus and the lateral septum (Buijs, 1980; Sofroniew and Weindl, 1978). Biochemical, physiological and behavioral studies of the effects of these peptides on the CNS have indicated that they are involved in functions as diverse as the control of serotonin turnover (Auerbach and Lipton, 1982), the regulation of body temperature (Kasting et. al., 1979) and the retention of conditioned behavior (de Wied et. al., 1974; Koob and Bloom, 1982). The presence of immunoreactive vasopressin (iAVP) in the hippocampus of Wistar rats was confirmed by radioimmunoassay. The vasopressin content of the dorsal hippocampus was 30.3 ± 7.3 pg iAVP/mg soluble protein and that of the ventral hippocampus was 81.4 ± 8.3 pg iAVP/mg soluble protein, while tissue from the cerebral cortex contained no detectable vasopressin. That this immunoreactivity was due to vasopressin was confirmed by the absence of immunoreactivity in hippocampal or cortical tissue from Brattleboro rats, which are genetically unable to synthesize vasopressin. Vasopressin applied by iontophoresis was found to increase the activity of neurones in the lateral septum and in the hippocampus of the anesthetized rat. There was no obvious difference between the response of spontaneously active cells and the response of cells excited by continuous iontophoresis of glutamate or acetylcholine. Repeated application of vasopressin resulted in a decline in the magnitude of the response, but at least part of this decline was due to progressive blockage of the micropipette barrel rather than to tachyphylaxis. Oxytocin, tested only in the septum, was without effect. When applied by superfusion onto rat hippocampal slices, the NHP peptides were found to increase the activity of 88% of spontaneously active cells and to induce activity in many neurones that were not spontaneously active. Arginine vasopressin, lysine vasopressin, arginine vasotocin, and oxytocin were found to be of roughly equivalent potency, producing a dose dependent response in the range 10⁻⁹-10⁻⁶M. Most cells were tested with more than one peptide and were always found to respond either to all or to none of them. There was no decline in responsiveness when cells were subjected to repeated applications of peptide, but continuous application caused the cells to become unresponsive. Following continuous application of oxytocin, a cell failed to respond to both oxytocin and vasopressin, as would be expected if the two peptides were acting on the same receptor. The analogues ddOT, ddAVP, and Gly⁷0T were also active, but the oxytocin fragment PLG had no effect, and the vasopressin fragment DGAVP was extremely weak. The response to the peptides could be blocked by vasopressin antagonists. The peptide sensitive cells appeared to be pyramidal cells rather than interneurones, since the peptide induced activity could be inhibited for about 200-600 msec by electrical stimulation of the stratum radiatum. / Arts, Faculty of / Philosophy, Department of / Graduate

In the hippocampus, tetanic stimulation of an input results in a long lasting potentiation (LLP) of synaptic transmission involving that input. While high frequency tetanic stimulations are preferred to elicit LLP, low frequency tetanus induces homosynaptic and heterosynaptic depressions. The present investigations were conducted to (1) analyse the characteristics of pulses in orthodromic and antidromic tetanic stimulations and relate them to post-tetanic changes in evoked potentials (2) determine if potentiation and depression co-occur and (3) determine whether an established LLP in one input is subsequently modified by the initiation of LLP in another input (to the same CAlb neurons) or whether LLP can be reversed by homosynaptic and heterosynaptic depressions and lastly (4) determine how interference or enhancements of calcium and potassium fluxes with pharmacological substances related to potentiation and depression. Experiments were conducted on transversely sectioned rat hippocampal slices. Evoked potentials in subfield CAlb were elicited with stimulations of CAlb axons, commissural (Com), or Schaffer collaterals (Sch). Sch terminal excitability was tested with a stimulating electrode placed in the Sch/CAlb synaptic regions. Recordings were made with microelectrodes positioned in the CAlb cell bodies and/or dendritic regions, and in field CA3. It was found that potentiation and depressions co-occur. Presynaptic volleys accompanied all tested tetanic trains. Similarly, antidromic trains discharged CAlb neurons continuously but did not cause LLP. Low frequency tetanic trains caused facilitated synchronous discharges of CAlb neurons during significant portions of these trains. In contrast, few if any syn- chronous discharges followed high frequency tetanus. Yet high frequency tetanus elicited LLP and low frequency tetanus caused homo- and heterosynaptic depressions. An established LLP could be masked but not reversed by homo- and heterosynaptic depressions but this LLP was not interrupted by subsequently induced LLP of a separate input. Iontophoretic L-glutamate on CAlb cell bodies caused depression which was more pronounced if a tetanus was evoked during L-glutamate ejections. The depressions to low frequency tetanus and L-glutamate were counteracted by verapamil. Lastly, barium and 4-aminopyridine potentiations were reversed with washing. Applications of these drugs did not alter Sch terminal excitability. Tetanus induced during the presence of 4-aminopyridine still elicited LLP. It is concluded that homo- and heterosynaptic depressions are partly due to the accumulation of calcium into the CAlb neurons. The magnitude of calcium entry into presynaptic and postsynaptic regions is governed by the tetanic frequencies evoked. The results are consistent with a presynaptic mediated LLP. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The electrophysiological properties of dentate granule cells and hippocampal pyramidal neurons were examined with extracellular and intracellular recording techniques in the hippocampal slice. Intracellular analysis revealed that there may exist two populations of granule cells distinguishable by the presence or absence of non-linear current-voltage (I-V) membrane properties (anomalous rectification, AR). The granule cells exhibiting AR also maintained greater resting membrane potentials and action potential (AP) amplitude values. The membrane input resistance (Rn) and time constant (Tc) measurements were similar between the populations in response to hyperpolarizing current injection, but granule cells displaying AR had significantly higher Rn and Tc values in response to depolarizing pulses. Both groups also responded to maintained depolarizing current injection with repetitive AP discharges; however, this response accommodated. Upon termination of the depolarizing current injection, an afterhyperpolarization (AHP) resulted, the amplitude of which appeared to depend on the duration of the depolarizing pulse and not on the number of APs generated during the pulse. Stimulation of either the lateral (LPP) or medial (MPP) perforant paths evoked a monosynaptic EPSP followed by a depolarizing afterpotential (DAP) and a long afterhyperpolarization (LHP). In contrast, antidromic stimulation elicited a depolarizing-IPSP (D-IPSP) and a LHP. Both the DAP and D-IPSP were reversed by membrane depolarization, whereas, the LHP was inverted by membrane hyperpolarization. In all cases, however, the EPSP could not be inverted. Afterpotentials were associated with an increase in conductance, but the change accompanying the LHP was less than the DAP and D-IPSP. In addition, by reducing the [Ca]₀ and increasing the [Mg]₀, the DAP was attenuated and the LHP eliminated. Similar results were also obtained with the GABAB agonist, baclofen. Paired pulse stimulation of either the LPP or MPP resulted in the potentiation of the intracellular EPSP at condition-test (C-T) intervals less than 100 ms; however, simultaneous extracellular records from the granule cell layer (GCL) illustrated depression of the EPSP. The discrepancy between the extra- and intracellular recordings was shown to be related to the presence of the DAP. In addition, the MPP evoked test EPSP at C-T intervals greater than 150 ms exhibited inhibition regardless of whether it was recorded inside or outside the granule cell and this EPSP depression was partially due to the granule cell LHP. The LPP evoked test EPSP potentiated at all C-T intervals less than 1s when recorded from the outer molecular layer (OML) but was inhibited at both the GCL and intracellular recording sites. These data confirmed that postsynaptic processes contribute to the short-term alterations observed with paired pulse stimulation. The typical inhibition-potentiation-inhibition sequence of the perforant path (PP) evoked population spike (PS) was noted at C-T intervals of 20, 80 and 400 ms, respectively. The inhibition of the PS at 20 ms was abolished with perfusion of the GABA antagonist, bicuculline. In contrast, the PS inhibition at 400ms was unaffected by this treatment but was slightly attenuated by the gKca antagonist TEA. A number of factors appeared to contribute to the potentiation of the PS: 1) reduction in AP threshold; 2) the presence of the DAP; and 3) extrasynaptic events. In addition to the PS data from normal tissue, hippocampal slices from chronically kindled rats exhibited depression of the PS at all C-T intervals tested. This augmentation of inhibition was dependent on the presence of hippocampal afterdischarges but not on motor seizures. Perfusing the kindled slices with either bicuculline or lowered [Cl]₀ did not markedly reverse the enhanced inhibition at C-T intervals which displayed dramatic facilitation in normal slices. Intracellular recordings of granule cells obtained from kindled slices also exhibited an increase in the Rn and Tc. Both the alterations in inhibition and membrane characteristics appear to be localized to.the granule cells, since these changes were not observed in CA1 pyramidal neurons. These data indicate that short-term and long-term alterations in granule cell neuronal excitability are partially due to changes in the postsynaptic membrane. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

In the hippocampus, transient tetanic stimulations of inputs, or brief simultaneous pairings of conditioning intracellular postsynaptic depolarizations with activated presynaptic afferents at low stimulation frequencies, result in input specific long-term potentiation (LTP) of synaptic transmission. LTP lasts for hours in vitro, or weeks in vivo, and it is thought to be involved in memory and learning. Experimental evidence in the literature suggests that postsynaptic mechanisms mediate LTP induction, whereas presynaptic mechanisms are involved in its maintenance. Since LTP is thought to be generated by postsynaptic mechanisms and to be subsequently maintained by presynaptic processes, this suggests the presence of feedback interactions during LTP development, however, the experimental evidence for such interactions is presently not available. Consequently, the present studies were conducted to examine possible feedback interactions between postsynaptic and presynaptic elements in the hippocampus. Furthermore, the experiments tested the hypothesis that substances released during tetanic stimulations caused the release of endogenous substances that interacted with activated afferents resulting in alterations in presynaptic functions and LTP production. Experiments were conducted using transversely sectioned guinea pig hippocampal slices. Briefly, physiological medium containing 3.5 mNi Ba++ and 0.5 mM Ca (denoted as Ba medium) was used to induce the asynchronous release of transmitters, observed as evoked miniature EPSPs (minEPSPs) in CA1b neurons after stimulation of the stratum radiatum. During transient Ba++ applications, short bursts of evoked minEPSPs were observed following stimulations of the stratum radiatum or conditioning depolarizing current injections into CA1b neurons. Moreover, the frequencies of minEPSPs were significantly increased immediately after simultaneous stimulations of the stratum radiatum and conditioning depolarizing current injections into CA1b neurons. Significant increases in the frequencies of evoked minEPSPs were also observed during LTP induced by tetanic stimulations. The above increases in the frequencies of evoked minEPSPs were attributed, in part, to presynaptic changes resulting in increases in transmitters released. However, a thorough quanta! analysis is requirea to substantiate this conclusion. In order to determine whether any substances released during tetanic stimulations were involved in the mooulation of presynaptic functions and induction of LTP, samples were collected from guinea pig hippocampus and rabbit neocortex. It was found that samples that were collected during tetanic stimulations of the guinea pig hippocampus in vivo or rabbit neocortex in vivo produced LTP in the guinea pig hippocampal slice in vitro. Applications of these samples after heating and cooling failed to induce LTP. Subsequent studies demonstrated that PC-12 cells incubated in growth medium treated with samples collected during tetanic stimulations of the rabbit neocortex developed extensive neurite growths. In contrast, PC-12 cell cultures incubated in (1) heated and cooled samples, (2) samples collected in the absence of tetanic stimulations of the rabbit neocortex, or (3) plain growth medium, failed to develop neurite growths. In addition, PC-12 cell cultures that were incubatea in growth medium containing samples collected during tetanic stimulations plus saccharin (10 mM), a substance known to inhibit N6F-dependent neurite growth, failed to develop neurites. In separate experiments it was found that saccharin could block (1) the synaptic potentiating effects of the above collected and applied endogenous substances, and (2) LTP induced with tetanic stimulations, in the guinea pig hippocampus in vitro. The concentrations of saccharin used in these studies had insignificant effects on resting membrane potentials, input resistances, spontaneous or evoked responses of CA1b neurons. Furthermore, CA1b neuronal depolarizations induced by N-methyl-DL-aspartate (NMDA) or with tetanic stimulations of the stratum radiatum, were not altered by saccharin applications. In addition, saccharin had insignificant effects on paired-pulse facilitation, post-tetanic potentiations, minEPSP frequencies in CA1b neurons, and Schaffer collaterals terminal excitability. These results suggest that saccharin blocked LTP through mechanisms different from either non-specific alterations in CA1b cell properties or NMDA receptor activation. Perhaps the agent antagonized LTP at a step beyond NMDA receptor activation. That saccharin blocked LTP caused by the applied neocortical sample as well as by tetanic stimulation of the stratum radiatum, and that saccharin also blocked neurite growth in PC-12 cells induced by the neocortical samples, raises the prospect that growth related substances are involved in LTP generation. In other control experiments, it was found that the potentiating effects of the collected endogenous substances were not antagonised by atropine or dihydro-e-erythroidine. Heated and then cooled solutions of glutamate (a putative transmitter at the Schaffer col laterals-CA1b synapses) still maintained their actions on the CA1b population spike. While brief applications of 2.5 μg/ml exogenous NGF (from Vipera lebetina) during low frequency stimulations of the stratum radiatum did not consistently induce LTP, this peptide significantly facilitated the development of LTP when applied in association with tetanic stimulations of weak inputs in the CA1b area. These weak inputs could not support LTP if tetanized in the absence of the exogenous NGF. The results of the studies in this thesis suggested that postsynaptic depolarizations modulated presynaptic functions in the hippocampus. Tetanic stimulations in hippocampus and neocortex caused the release of diffusible substances, which were probably growth related macromolecules, that interacted with activated presynaptic afferents and/or subsynaptic dendritic elements resulting in LTP development. The precise locus of actions of these agents awaits further investigations. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The ionotropic glutamate AMPA ((R,S)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor mediates the majority of excitatory transmission in the CNS. AMPA receptors play a crucial role in both basal neurotransmission and synaptic plasticity events (such as long-term potentiation, LTP). Compounds that ‘potentiate’ AMPA receptor function (‘Ampakines’) are known to positively modulate glutamatergic AMPA receptor-gated currents, by slowing the deactivation and desensitisation rate of the receptors, in the presence of the endogenous agonist glutamate. Ampakines have been shown to facilitate LTP induction, improve cognition, and as such have potential in the treatment of conditions such as depression and psychoses (schizophrenia). The main aim of this thesis was to investigate the functional actions of two novel Ampakines, Org 26576 and Org 24448, in the mouse brain. The studies described in this thesis were designed to address this and are outlined as follows: 1. Characterisation and validation of an in vivo semi-quantitative model of [14C]-2-deoxyglucose autoradiography in the C57Bl/6J mouse The first study sought to develop and characterise a model of [14C]-2-deoxyglucose autoradiography, to allow measurement of regional alterations in local cerebral glucose use (LCGU) in the mouse CNS. Following intraperitoneal injection of [14C]-2-deoxyglucose in C57Bl/6J mice, the radiolabelled brains were sectioned and exposed to x-ray film. The resultant autoradiograms were semi-quantitatively analysed for relative optical densities in predetermined regions of interest. The baseline LCGU values in different brain regions were found to be consistent with previously published data. The model was also able to replicate the effects of a well-characterised compound, the NMDA receptor antagonist MK-801 (0.5 mg/kg), in respect to functional cerebral changes. Characteristic effects such as prominent increases in LCGU in the limbic system, and decreases in the somatosensory cortex were reproduced in the model. Thus the semi-quantitative [14C]-2-deoxyglucose model was reproducible and accurate and thus could be further used to investigate the effects of the novel Ampakines, Org 26576 and Org 24448, on cerebral function. 2. Investigation into the effects of acute administration of the novel Ampakines Org 26576 and Org 24448 on functional activity in the murine cerebrum Following the establishment of the methodology, regional alterations in LCGU in response to the Ampakines Org 26576 and Org 24448 were investigated using [14C]-2-deoxyglucose autoradiography. Both Org 26576 and Org 24448 produced regionally selective, dose-dependent increases in LCGU in the mouse cerebrum when administered acutely (~1 hr). The compounds displayed similar yet functionally distinct profiles of activation, the highest levels of activation occurred in areas of the limbic system (hippocampus), sensory systems, and various nuclei (raphe nucleus). Their effects were blocked by pre-administration of the potent selective AMPA receptor antagonist, NBQX (10 mg/kg), which itself had minimal effects on LCGU. These data provide an anatomical basis for the cerebral activation induced by these compounds, which are directly AMPA receptor mediated. Areas activated also closely correlated with brain regions implicated in various psychiatric conditions, and as such is suggestive of a potential therapeutic benefit of these compounds in conditions such as depression and schizophrenia. 3. Investigation into the effects of chronic administration of the novel Ampakines Org 26576 and Org 24448 on functional activity, neurogenesis and receptor/signalling alterations in the murine cerebrum Following the demonstration that acute administration of Org 26576 and Org 24448 displayed regionally selective and dose-dependent alterations in LCGU, the effect of chronic administration of the Ampakines Org 26576 and Org 24448 on regional functional alterations ([14C]-2-deoxyglucose autoradiography), neurogenesis (BrdU labelling), and proteins levels (GluR, MAPK, LynK and CREB) (Western blot analysis) were investigated. Chronic administration (7 and 28 days) of Org 26576 (1 mg/kg) and Org 24448 (10 mg/kg) induced functional cerebral increases in the mouse cerebrum particularly in areas of the mesocorticolimbic system, which were not only rapid in onset, with significant effects visible after 7 days administration; but importantly were also persistent and long lasting. Chronic administration of the compounds had no significant effect on the level of neurogenesis or on the levels AMPA receptor subunits (GluR1,2,3), and signalling pathways (MAPK/LynK-CREB pathway), implicated in AMPA/Ampakine signalling, in the murine hippocampus. These data show that the Ampakines Org 26576 and Org 24448 when administered chronically can potentiate complex neural networks intimately associated with disease states, the effects of which are maintained over prolonged periods. There was no evidence that this involved an effect on neurogenesis or the MAPK/LynK-CREB signalling pathway. 4. Modulation of AMPA receptor kinetics by Org 26576 and Org 24448 influences synaptic plasticity in the murine hippocampus The ability of Org 26576 and Org 24448 to modify baseline kinetic properties of AMPA receptors and a paradigm of synaptic plasticity, LTP, in the mouse hippocampus was investigated using electrophysiology. Both Org 26576 and Org 24448 produced dose-dependant increases in fEPSP amplitude without affecting the half-width of responses, in acute hippocampal slices. Concentrations of both compounds, equating to functionally active levels witnessed in vivo, potentiated a stable form of LTP; whilst higher EC50 concentrations prevented the maintenance of LTP. These results are suggestive that Org 26576 and Org 24448 are effective in boosting the neural correlate of cognition, LTP, and may have potential in treating cognitive deficits, for example those associated with depression, schizophrenia or Alzheimer’s disease. The data presented in this thesis illustrate that the novel Ampakines Org 26576 and Org 24448 centrally modulate brain regions and circuitry intimately associated with conditions such as depression and schizophrenia (psychoses), with effects that are rapid in onset and persistent over chronic periods of administration. Specifically targeting the glutamatergic system through the use of these compounds may provide an innovative approach to treat various conditions that may be partly due to a compromise of normal excitatory glutamatergic neurotransmission.