1.
2.
Sigvartsen, Niels Petter, et al.
(författare)
Temporal difference modelling of aversive conditioning and extinction : An fMRI study
2009
Ingår i: Front. Neur. Conference Abstract.
Konferensbidrag (övrigt vetenskapligt/konstnärligt) abstract
The prediction error (PE) signal from temporal difference (TD) models have been shown to correlate with activity in specific brain regions in both human and animals during conditioning tasks. One of the key regions involved is the ventral striatum (VS). The purpose of this study was to investigate how the TD model predicted VS activations during aversive conditioning and extinction. Functional Magnetic Resonance Imaging (fMRI) Blood-Oxygen Level Dependent (BOLD) data were acquired on a 1.5 T GE Signa scanner. Thirty-three healthy subjects completed a 33% partially reinforced classical conditioning paradigm using coloured circles as the conditioned stimulus (CS) and aversive cutaneous electrical stimulation (CES) as the unconditioned stimulus (US). After a short break a second scanning session was performed where the subjects were divided into three groups (N=11 in each group): 1) a control group that repeated the paradigm; 2) an extinction group that repeated the paradigm with the CES turned off without their knowledge; and 3) an intervention group that were told that the CES would be turned off before they repeated the paradigm. Thus, in the second session the extinction and intervention groups saw the CS but without US. A modified TD algorithm was used to generate a salience PE signal vector which was used as a regressor in the fMRI analyses. Pre-processing and analyses of data were done using SPM5. Final analysis of the first session and preliminary analysis of the control and extinction groups from the second session are reported here. Analysis of the first session included all 33 subjects and PE activations bilaterally in the VS, anterior insula and anterior cingulate were obtained. Analyses from the second session showed that activations were predicted by salience PE bilaterally in the VS and the anterior insula in the control group while the extinction group recruited the VS and the ventro-medial PFC. The findings from the first session and the control group in the second session replicated previous studies. However, the results of the second session in the extinction group extend that fMRI BOLD behave according to salience PE to a more general level in aversive learning ranging from acquisition to maintenance to extinction of associations.
3.
Tehranian, Roya, 1969-
(författare)
On inflammatory cytokines and β-amyloid peptides in acute and chronic neurodegeneration
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Insults to the brain as well as neurodegenerative diseases are known to elicit inflammatory responses. Inflammation in the brain can on one hand initiate processes that are harmful to the injured tissue and exacerbate the damage, leading to neuronal degeneration and glial activation, and on the other hand activate processes that may be necessary for repair mechanisms and regeneration. Among the mediators of inflammatory response in the brain are the inflammatory cytokines. The most studied are interleukin-1 (IL)-1, IL-6 and tumor necrosis factor-alfa (TNF- ). Although the expression of these cytokines is low under normal conditions in the brain, it can be rapidly induced in response to injury.This thesis is focused on the role of IL-1 family of proteins, namely the agonists IL-1 and and the endogenous IL-1 receptor antagonist (IL-1ra), and IL-6, in different experimental models of neurodegeneration. In order to study the role of IL-1 family of proteins during inflammation in an excitotoxic model of brain injury, adult rats were injected systemically with kainic acid, a glutamate analogue known to evoke seizures and neuronal cell loss in the rat brain. Using the combined technique of reverse-transcriptase coupled to PCR (RT-PCR) and in situ hybridization histochemistry, an upregulation of microglial mRNA expression of IL-1 and IL-1ra was found in brain areas with neuronal degeneration, such as the hippocampus and amygdala. IL-1ra mRNA was induced at later time point than IL-1 mRNA and was identified as the transcript coding for the secreted isoform of IL-1ra. This suggets that upregulation of these cytokines is a part of an inflammtory response associated with neurodegeneration and that the effect of IL-1 may be regulated by the expression of IL-1ra in this model. In order to study the role played by IL-1 in inflammation associated with traumatic brain injury (TBI), an experimental model was inflicted on transgenic mice. Heterozygous overexpression of the human secreted isoform of IL-1ra in the brain decreased the induction of IL-1 and IL-6 after injury. Using a neurological severity score (NSS), which mainly reflects motor recovery, we found that these animals recovered faster as compared to their non-transgenic littermates.Furthermore, the proinflammatory cytokine expression was studied by RT-PCR in a mouse model of Alzheimer's disease (AD). The Tg2576 mice strain overexpress -amyloid (A ) precursor protein with the "Swedish" mutation linked to familiar AD and exhibits some of the neuropathology associated with AD, such as the deposition of insoluble extracellular amyloid fibrils (amyloid plaques) in specific brain regions. Analysis of expression of cytokines in the brain of Tg2576 mice revealed an early induction of IL-6 in the hippocampus and cerebral cortex that precedes the formation of amyloid plaques. This finding is interesting since in AD brain IL-6 is detected in microglia in the vicinity of diffuse plaques (non-fibrillar). Thus, the result from this study suggests that increased IL-6 expression may be an early event in AD inflammation.The main constituent of amyloid plaques in the AD brain is the A peptide. The synthetic peptide A (25-35), a neurotoxic fragment of the full-length A peptide was studied for its ability to activate glial cells in culture and induce cytokine expression, as well as for its influence on G-protein coupled signalling in rat brain tissue. A (25-35) treatment of mixed astroglial cultures resulted in marked induction of IL-6 mRNA as studied by RT-PCR. Together with the results from the Tg2576 mice these results suggest a role for IL-6 in AD pathogenesis.Alteration in cellular signal transduction has also been reported in AD brain. A (25-35) was shown to stimulate the enzymatic activities of GTPase and adenylate cyclase in membrane preparations from rat hippocampus and cerebral cortex, which are particularly affected regions in AD brain. Using Pertussis toxin treated membranes, the stimulatory effect on GTPase activity was totally abolished, suggesting that Gi/Go type of G-proteins mediated the effect of the A peptide.
4.
Gezelius, Henrik, 1977-
(författare)
Studies of Spinal Motor Control Networks in Genetically Modified Mouse Models
2009
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Spinal neurons are important in several aspects motor control. For example, the neurons essential for locomotor movements reside in the ventral spinal cord. In this thesis, different motor control functions are being related to neuronal populations defined by their common expression of a gene. First, a targeted disruption of the gene for vesicular glutamate transporter 2 (Vglut2/ Slc17a6) is described. The mutant animals die at birth because of their inability to breathe. The neuronal network in the brainstem, responsible for inspiration, was shown to become non-functional by the targeted deletion of Vglut2. To our surprise, it was still possible to induce rhythmic activity with normal left/right alternation in spinal cords isolated from VGLUT2-null embryos. Inconsistent reports of Vglut1 expression in the spinal cord made us re-evaluate the Vglut1 and Vglut2 expressions. While Vglut2 expression was widespread in the spinal cord, Vglut1 expression was restricted to a few cells dorsal to the central canal. Taken together, the data suggest that, glutamatergic signaling is mandatory to drive the bilateral breathing, but not needed for coordination of basal alternating spinal locomotor rhythm. Next, a screen for genes with restricted ventral expression was made. Some of the genes found could be connected to the characteristics of specific neuronal cell populations. For example, fast motor neurons were shown to express the genes Calca and Chodl. Further, we found the Chrna2 expression selectively in putative Renshaw cells. It seems likely that the gene product, the alpha2 subunit of the nicotinergic receptor, could be linked to the unique connection of motor neurons to Renshaw cells. We used the Chrna2 promoter to drive expression of Cre recombinase in a transgenic mouse. The Cre activity was present in most neurons labeled with Renshaw cell markers, which should make it a useful tool for functional studies of this population. The studies presented here show how the genes expressed in subsets of neurons can be used to target populations of neurons for functional studies of neuronal systems.
5.
Habib, Reza, et al.
(författare)
Neural Correlates of Availability and Accessibility in Memory
2008
Ingår i: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 8:7, s. 1720-1726
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt) abstract
Failure to remember can be due to not having information available in memory or to an inability to access information that is available. We used functional magnetic resonance imaging to examine brain responses during encoding and successive cued recall and associative recognition tests of paired associates. Items were classified into 3 categories based on performance on the 2 retrieval tests: 1) successfully remembered (both recalled and recognized), 2) inaccessible (not recalled but later recognized), and 3) forgotten (neither recalled nor recognized). During cued recall, availability in memory was signaled in a network of regions including bilateral medial temporal lobe, left middle temporal cortex, and the parietal cortex. Memory access resulted in heightened activity in these regions as well as in left inferior frontal cortex. Encoding-related activity in hippocampus and inferior temporal cortex predicted subsequent availability and left inferior frontal activity predicted subsequent access. These results suggest that failure to access information that is available in memory may reflect weaker memory representations.
6.
Pálsson, Sigurdur Páll, 1960
(författare)
Population studies on depression in the elderly. Prevalence, incidence and relation to cognitive function and dementia
2000
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Aims: To study the prevalence and incidence of depression in relation to cognitive function, dementia and brain atrophy in a representative sample of elderly persons. Methods: 70 and 74-year-old women (n=501) were studied in 1992-93 as part of the fourth phase of the Prospective Population Study of Women in Gothenburg, Sweden. These women had previously been examined in 1968-69, 1973-74 and 1980-81. Another representative sample (N=392, 166 men and 226 women) was studied at the age of 70, in 1970-71, as part of the Gerontological and Geriatric Population Studies in Gothenburg, Sweden (H70). These subjects were invited for follow-up examinations at 75, 79, 81, 83, 85 and 88 years of age. An extended sample was examined at the age of 85 (n=494), including 100 of the original sample. The investigation included a psychiatric examination, interview of a close informant, a neu-ropsychological examination and a CT scan of the head. The diagnoses were made according to the DSM-IIIR criteria. Dementia syndrome was diagnosed according to the ICD-9 in the longitudinal examinations. Case records were examined regarding information on lifetime depression and dementia. Results:Paper I. The prevalence of depression in 70 and 74-year-old women was 11.6 %, including 8.4% with major depression (MDD). Among those who were currently mentally healthy, 43.0 % had a history of previous depression. Women with current major depression had lower scores on the MMSE than the mentally healthy women. This association was only found in women with the lower level of education. Current depressives, previous depressives and mentally healthy women without a history of depression did not differ regarding brain atrophy or white matter lesions on CT. The association between MDD and lower cognitive performance was independent of structural brain changes on CT.Paper II. The incidence of depression was 12/ per 1000 person-years in men and 30/ per 1000 person-years in women between the ages of 70 and 85 (p=0.001). The incidence increased from 17/ per 1000 person-years (men 8.7, women 23.2, p=0.007) between the ages of 70 and 79 to 44/ per 1000 person- years (men 27.0, women 52.8, p=0.166) between 79 and 85 (age difference RR 2.6; p< 0.001, men RR 3.1; p=0.036, women RR 2.3; p=0.003). A diagnosis of depression was associated with increased mortality and refusal rate during the 15-year follow-up. Previous episodes of depression were associated with an increased risk of new episodes. The prevalence of depression increased from 5.6% at the age of 70 to 13.0% at the age of 85. The lifetime prevalence of depression was 23% in men and 45% in women. Paper III. Among 85-year-olds with low education, the depressed performed worse than the mentally healthy in the Mini Mental State Examination, whereas this distinction was not evident among individuals with higher education. Measures of brain atrophy were similar in depressed and mentally healthy 85-year-olds. Early-onset major depression but not late-onset depression was associated with an increased three-year incidence of dementia.Paper IV. Individuals with major depression performed worse than those mentally healthy in tests of verbal ability, inductive logical reasoning, spatial ability, perceptual speed and secondary memory. There were no differences between the groups regarding basic arithmetics and primary memory. There were no differences between early and late-onset depressives. Individuals with low motivation during the neuropsychiatric examination were more cognitively impaired in the psychological tests. Decreased concentration and psychomotor retardation were the individual symptoms of MDS that typically contributed to lower test scores. Paper V. History of depression did not increase the risk of dementia in men and women compared to those never depressed during the 18-year follow-up period.
7.
Persson, Anders I., 1973
(författare)
Opioids regulate proliferation of neural progenitors. A study on the effects of opioids on adult rat hippocampal progenitors in vitro and in vivo
2003
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The opioid receptors were among the first pharmacologically described brain receptors. These opioid receptors have thereafter been shown to mediate effects on proliferation and differentiation in both the embryonal and adult central nervous system. The aim of this thesis was to investigate if cultured hippocampal progenitors from the adult rat brain expressed opioids and opioid receptors and to investigate a possible regulation by opioids on proliferation, differentiation and gene expression in these cultures. Furthermore, we wanted to extend the results and investigate if endogenous opioids regulated hippocampal proliferation in vivo by using opioid receptor antagonists in both non-running and voluntary running rats, a situation associated with increased levels of endogenous opioids. Hippocampal progenitors were found to release b-endorphin that bound to mu- (MOR) and delta- (DOR) but not kappa- (KOR) opioid receptors in vitro. Incubation with MOR or DOR antagonists reduced proliferation whereas stimulation with b-endorphin increased proliferation in these cultures, respectively. The opioid-induced proliferation involved both intracellular calcium and phosphatidylinositol 3-kinase that stimulated phosphorylation of mitogen-activated protein kinase (MAPK). Incubation with naloxone for ten days increased neurogenesis and reduced astrogliogenesis and oligodendrogenesis whereas stimulation with b-endorphin increased oligodendrogenesis but had no effect on astrogliogenesis. Using cDNA arrays, the levels of endogenous opioids were found to regulate gene expression for several cell cycle and oligodendrocyte-specific proteins. Stimulation with b-endorphin also increased Id1, but not Id3 mRNA levels. Down-regulation of Id1 protein using antisense oligonucleotides was suggested to antagonize the opioid-induced oligodendrogenesis.Using bromodeoxyuridine (BrdU), we observed a five-fold increase in hippocampal proliferation after nine days of wheel running in spontaneously hypertensive rats, a rat strain known to run voluntary. This increased BrdU labelling was reduced by peripheral administration of a preferential MOR, but not a DOR antagonist. In non-running rats, MOR and DOR antagonists increased hippocampal proliferation. In non-running, but not in running rats, the opioid receptor antagonists reduced adrenal gland weights and plasma levels of corticosterone. This stress hormone is known to reduce hippocampal neurogenesis. Running rats had three-fold higher levels of hippocampal Met-enkephalin-Arg-Phe levels compared to non-running rats, indicating increased opioid activity in hippocampus during running. These findings demonstrate that the levels of endogenous opioids, acting on MORs and DORs, regulate proliferation of adult rat hippocampal progenitors both in vitro and in vivo. Endogenous opioids were also shown to regulate differentiation and gene expression in cultures of hippocampal progenitors. Finally, we show that exercise robustly increases proliferation of hippocampal progenitors and that such an effect is partly mediated by endogenous opioids.
8.
Vazin, Tandis, 1979-
(författare)
Generation of Dopaminergic Neurons from Human Embryonic Stem Cells
2008
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Since the first successful derivation of human embryonic stem cells (hESC), rapid progress has been attained in the development of strategies in differentiation of these cells into various neural lineages, with the fundamental objective of using these cells for replacement and repair of damaged neuronal circuits in the central nervous system (CNS). Of particular interest are midbrain dopaminergic (mDA) neurons, which play a central role in regulation of voluntary movement. Degeneration or loss of function of mDA neurons in the nigrostriatal pathway is associated with Parkinson disease (PD). Stromal-Derived Inducing Activity (SDIA) is recognized as one of the most efficient methods in restricting ESC differentiation to a dopaminergic lineage, and refers to the property of mouse stromal cell lines such as PA6 or MS5 to cause ESC to differentiate to DA neurons. Although this strategy has been extensively used to generate mDA neurons from hESC, the biochemical nature of SDIA is yet unknown. In the present study mDA neurons were generated from the BG01V2 hESC line by SDIA. To examine whether SDIA exerts its effect directly on hESC and is responsible for early dopaminergic induction, neural progenitor cells (NPC) were enyzmatically isolated from the co-cultures and allowed to differentiate in feeder-free conditions. The isolated cells were committed to a mesencephalic neural lineage, and were capable of maintaining their phenotype and developing into postmitotic mDA neurons in feeder-free conditions. The mDA neurons showed neuronal excitability and dopamine transporter function. The in vitro proliferation and differentiation of the NPC was also investigated by a BrDU incorporation assay. Next, the maintenance of cellular memory and capacity for proliferation of the mesencephalic NPC was assessed. The NPC could be expanded in vitro by five-fold as neurospheres for up to two weeks while retaining their DA differentiation potential, but did not retain a stable phenotype over extended periods of time. Preliminary transplantation experiments of neurospheres in striatal lesioned animals indicated, however, that these cells could survive and conserve their phenotype in vivo. To gain additional insight into the biochemical role of SDIA in early dopaminergic induction of hESC, the separate contributions of cell surface activity and secreted factors were examined. The data revealed that the PA6 cell surface activity promoted cell survival and was mainly responsible for enhanced neurogenesis of hESC, whereas secreted factors provided DA lineage-specific instructions. In order to identify the soluble factors responsible for the DA phenotype-inducing component of SDIA, the gene expression profile of PA6 cells was compared to that of cell lines lacking the DA-inducing property. A number of soluble factors known to be associated with CNS development that were highly expressed in PA6 cells were identified as potential DA differentiation-inducing candidates. These differentially-expressed genes included stromal cell-derived factor 1 (SDF-1/CXCL12), pleiotrophin (PTN), insulin-like growth factor 2 (IGF2), and ephrin B1 (EFNB1). When these factors, termed SPIE, were applied to the hESC, they induced dopaminergic neuronal differentiation of hESC line, BG01V2 and other karyotypically normal hESC lines in vitro. Thus, it appears that SPIE comprises the DA phenotype-inducing property of SDIA. This may provide a simple and direct means of differentiating hESC to form DA neurons in a single step, without a requirement for co-culture, animal cell lines, or animal products.
9.
Rönnbäck, Lars, et al.
(författare)
»Trött i hjärnan« osynligt handikapp som kan ge stora problem: Störd glutamatreglering kan förklara bristande informationsfiltrering
2007
Ingår i: Läkartidningen. - 1652-7518 .- 0023-7205. ; 104:14-15, s. 1137-1142
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt) abstract
Cognitive impairment with decreased concentration capacity and mental fatigue makes rehabilitation from a stroke, brain trauma, meningitis or neuroinflammation difficult, and often hampers going back to work. According to our hypothesis, down regulation of the glutamate transport protein GLT-1 in the hippocampus and cerebral cortex is one pathogenic factor underlying mental fatigue. Glutamate is one major signal substance for information intake and processing in the brain. The GLT-1 protein, localised to astrocytes and, upon activation, also microglial cells, is considered to play key roles in the regulation of extracellular glutamate. A slight disturbance of the astroglial regulation of extracellular glutamate could lead to local microglial activation with the production of proinflammatory cytokines, astrocyte swelling, and, due to such swelling, decreased extracellular space. During these conditions, there is a decrease in both the glutamate release and the neuronal transmission. It is proposed that this decreased transmission could be one correlate at the cellular level to the mental exhaustion that the person could experience. Pharmacological treatment, probably with glial cells as targets, could restore dysfunction in the glutamate transmission and make the person less susceptible to pathological mental fatigue.
10.
Adlerz, Linda, 1974-
(författare)
Processing of the amyloid precursor protein and its paralogues amyloid precursor-like proteins 1 and 2
2007
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder which is histopathologically characterised by amyloid plaques and neurofibrillary tangles. Amyloid plaques consist of the amyloid β-peptide (Aβ) that can form aggregates in the brain. Aβ is generated from the amyloid precursor protein (APP) through proteolytic cleavage. APP belongs to a conserved protein family that also includes the two paralogues, APP-like proteins 1 and 2 (APLP1 and APLP2). Despite the immense amount of research on APP, motivated by its implication in AD, the function of this protein family has not yet been determined. In this thesis, we have studied the expression and proteolytic processing of the APP protein family. Our results are consistent with previous findings that suggest a role for APP during neuronal development. Treatment of cells with retinoic acid (RA) resulted in increased synthesis. In addition, we observed that RA treatment shifted the processing of APP from the amyloidogenic to the non-amyloidogenic pathway. The proteins in the APP family have been hard to distinguish both with respect to function and proteolytic processing. However, for development of new drugs with APP processing enzymes as targets this is of great importance. Our studies suggest similarities, but also differences in the mechanism regulating the processing of the different paralogues. We found that brain-derived neurotrophic factor (BDNF) had different impact on the members of the APP family. Most interestingly, we also found that the mechanism behind the increased processing in response to IGF-1 was not identical between the homologous proteins. In summary, our results indicate that in terms of regulation APLP1 and APLP2 differ more from each other than from APP. Our studies open up the possibility of finding means to selectively block Aβ production without interfering with the processing and function of the paralogous proteins.
