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  • 1.
    Benedict, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Interindividual Variance in Adult Hippocampal Neurogenesis: A Matter of Lifestyle?2013In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 23, no 12, p. 1484-1485Article in journal (Refereed)
  • 2. Ferreira, Daniel
    et al.
    Hansson, Oskar
    Barroso, José
    Molina, Yaiza
    Machado, Alejandra
    Hernández-Cabrera, Juan Andrés
    Muehlboeck, J-Sebastian
    Stomrud, Erik
    Nägga, Katarina
    Lindberg, Olof
    Ames, David
    Kalpouzos, Grégoria
    Fratiglioni, Laura
    Bäckman, Lars
    Graff, Caroline
    Mecocci, Patrizia
    Vellas, Bruno
    Tsolaki, Magda
    Kłoszewska, Iwona
    Soininen, Hilkka
    Lovestone, Simon
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wahlund, Lars-Olof
    Simmons, Andrew
    Westman, Eric
    The interactive effect of demographic and clinical factors on hippocampal volume: A multicohort study on 1958 cognitively normal individuals2017In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 27, no 6, p. 653-667Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is characterized by hippocampal atrophy. Other factors also influence the hippocampal volume, but their interactive effect has not been investigated before in cognitively healthy individuals. The aim of this study is to evaluate the interactive effect of key demographic and clinical factors on hippocampal volume, in contrast to previous studies frequently investigating these factors in a separate manner. Also, to investigate how comparable the control groups from ADNI, AIBL, and AddNeuroMed are with five population-based cohorts. In this study, 1958 participants were included (100 AddNeuroMed, 226 ADNI, 155 AIBL, 59 BRC, 295 GENIC, 279 BioFiNDER, 398 PIVUS, and 446 SNAC-K). ANOVA and random forest were used for testing between-cohort differences in demographic-clinical variables. Multiple regression was used to study the influence of demographic-clinical variables on hippocampal volume. ANCOVA was used to analyze whether between-cohort differences in demographic-clinical variables explained between-cohort differences in hippocampal volume. Age and global brain atrophy were the most important variables in explaining variability in hippocampal volume. These variables were not only important themselves but also in interaction with gender, education, MMSE, and total intracranial volume. AddNeuroMed, ADNI, and AIBL differed from the population-based cohorts in several demographic-clinical variables that had a significant effect on hippocampal volume. Variability in hippocampal volume in individuals with normal cognition is high. Differences that previously tended to be related to disease mechanisms could also be partly explained by demographic and clinical factors independent from the disease. Furthermore, cognitively normal individuals especially from ADNI and AIBL are not representative of the general population. These findings may have important implications for future research and clinical trials, translating imaging biomarkers to the general population, and validating current diagnostic criteria for Alzheimer's disease and predementia stages.

  • 3.
    Moulin, Thiago C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Schiöth: Functional Pharmacology. Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Petiz, Lyvia L.
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Rayêe, Danielle
    Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Winne, Jessica
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Maia, Roberto G.
    Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
    Lima da Cruz, Rafael V.
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Amaral, Olavo B.
    Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazi.
    Leão, Richardson N.
    Brain Institute, Federal University of Rio Grande do Norte, Rio Grande do Norte, Brazil.
    Chronic in vivo optogenetic stimulation modulates neuronal excitability, spine morphology, and Hebbian plasticity in the mouse hippocampus2019In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 29, no 8, p. 755-761Article in journal (Refereed)
    Abstract [en]

    Prolonged increases in excitation can trigger cell‐wide homeostatic responses in neurons, altering membrane channels, promoting morphological changes, and ultimately reducing synaptic weights. However, how synaptic downscaling interacts with classical forms of Hebbian plasticity is still unclear. In this study, we investigated whether chronic optogenetic stimulation of hippocampus CA1 pyramidal neurons in freely moving mice could (a) cause morphological changes reminiscent of homeostatic scaling, (b) modulate synaptic currents that might compensate for chronic excitation, and (c) lead to alterations in Hebbian plasticity. After 24 hr of stimulation with 15‐ms blue light pulses every 90 s, dendritic spine density and area were reduced in the CA1 region of mice expressing channelrhodopsin‐2 (ChR2) when compared to controls. This protocol also reduced the amplitude of mEPSCs for both the AMPA and NMDA components in ex vivo slices obtained from ChR2‐expressing mice immediately after the end of stimulation. Finally, chronic stimulation impaired the induction of LTP and facilitated that of LTD in these slices. Our results indicate that neuronal responses to prolonged network excitation can modulate subsequent Hebbian plasticity in the hippocampus.

  • 4.
    Nordin, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Persson, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Stening, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Herlitz, Agneta
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Söderlund, Hedvig
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Structural whole-brain covariance of the anterior and posterior hippocampus: Associations with age and memory2018In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 28, no 2, p. 151-163Article in journal (Refereed)
    Abstract [en]

    The hippocampus (HC) interacts with distributed brain regions to support memory and shows significant volume reductions in aging, but little is known about age effects on hippocampal whole-brain structural covariance. It is also unclear whether the anterior and posterior HC show similar or distinct patterns of whole-brain covariance and to what extent these are related to memory functions organized along the hippocampal longitudinal axis. Using the multivariate approach partial least squares, we assessed structural whole-brain covariance of the HC in addition to regional volume, in young, middle-aged and older adults (n = 221), and assessed associations with episodic and spatial memory. Based on findings of sex differences in both memory and brain aging, we further considered sex as a potential modulating factor of age effects. There were two main covariance patterns: one capturing common anterior and posterior covariance, and one differentiating the two regions by capturing anterior-specific covariance only. These patterns were differentially related to associative memory while unrelated to measures of single-item memory and spatial memory. Although patterns were qualitatively comparable across age groups, participants' expression of both patterns decreased with age, independently of sex. The results suggest that the organization of hippocampal structural whole-brain covariance remains stable across age, but that the integrity of these networks decreases as the brain undergoes age-related alterations.

  • 5.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Stening, Eva
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Nordin, Kristin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Söderlund, Hedvig
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Predicting episodic and spatial memory performance from hippocampal resting-state functional connectivity: Evidence for an anterior-posterior division of function2018In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 28, no 1, p. 53-66Article in journal (Refereed)
    Abstract [en]

    fMRI studies have identified distinct resting-state functional connectivity (RSFC) networks associated with the anterior and posterior hippocampus. However, the functional relevance of these two networks is still largely unknown. Hippocampal lesion studies and task-related fMRI point to a role for the anterior hippocampus in non-spatial episodic memory and the posterior hippocampus in spatial memory. We used Relevance Vector Regression (RVR), a machine-learning method that enables predictions of continuous outcome measures from multivariate patterns of brain imaging data, to test the hypothesis that patterns of whole-brain RSFC associated with the anterior hippocampus predict episodic memory performance, while patterns of whole-brain RSFC associated with the posterior hippocampus predict spatial memory performance. Magnetic resonance imaging (MRI) and memory assessment took place at two separate occasions. The anterior and posterior RSFC largely corresponded with previous findings, and showed no effect of laterality. Supporting the hypothesis, RVR produced accurate predictions of episodic performance from anterior, but not posterior, RSFC, and accurate predictions of spatial performance from posterior, but not anterior, RSFC. In contrast, a univariate approach could not predict performance from resting-state connectivity. This supports a functional dissociation between the anterior and posterior hippocampus, and indicates a multivariate relationship between intrinsic functional networks and cognitive performance within specific domains, that is relatively stable over time.

  • 6.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Söderlund, Hedvig
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Hippocampal hemispheric and long-axis differentiation of stimulus content during episodic memory encoding and retrieval: An activation likelihood estimation meta-analysis2015In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 25, no 12, p. 1614-1631Article in journal (Refereed)
    Abstract [en]

    While there is ample evidence that the hippocampus is functionally heterogeneous along its longitudinal axis, there is still no consensus regarding its exact organization. Whereas spatial memory tasks frequently engage the posterior hippocampus, the regions engaged during episodic memory are more varying and may depend on the specific nature of the stimuli. Here, we investigate the effect of stimulus content on the location of hippocampal recruitment during episodic memory encoding and retrieval of pictorial and verbal material with a meta-analysis approach, using activation likelihood estimation and restricting the analysis to the hippocampus. Verbal material was associated with left-lateralized anterior activation, compared to pictorial material that recruited a more posterior aspect of the hippocampus, primarily within the right hemisphere. This effect held for encoding of both single items and item-item associations but was less clear during retrieval. The findings lend further support to a functional subdivision of the hippocampus along its longitudinal axis and indicate that the content of episodic memories is one factor that determines the location of hippocampal recruitment.

  • 7. Rauramaa, Tuomas
    et al.
    Pikkarainen, Maria
    Englund, Elisabet
    Ince, Paul G.
    Jellinger, Kurt
    Paetau, Anders
    Parkkinen, Laura
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cardiovascular diseases and hippocampal infarcts2011In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 21, no 3, p. 281-287Article in journal (Refereed)
    Abstract [en]

    The prevalence of hippocampal lesions such as hippocampal infarcts have not been studied in detail even though hippocampal alterations are known to be associated with various clinical conditions such as age-related degenerative disorders and epilepsy. Methods: Here we defined the hippocampal infarcts and assessed the prevalence of this lesion in large unselected population of 1,245 subjects age ranging from 1 to 99 years (mean age 79 +/- 1 S.E.M). Furthermore, we assessed the association of these lesions with various cardio- and cerebro-vascular disorders and other neurodegenerative lesions. The prevalence of hippocampal infarct in the study population of 1,245 subjects was 12%, increasing to 13% when only those with a clinically diagnosed cognitive impairment (n = 311) were analyzed. Large hemispheric brain infarcts were seen in 31% of the study subjects and these lesions were strongly associated with cardiovascular risk factors such as hypertension (43%), coronary disease (32%), myocardial infarct (22%), atrial fibrillation (20%), and heart failure (20%). In contrast, hippocampal infarcts displayed a significant association only with large hemispheric brain infarct, heart failure, and cardiovascular index as assessed postmortem. It is noteworthy that only widespread hippocampal infarcts were associated with clinical symptoms of cognitive impairment or epilepsy. The surprisingly low prevalence of 12% of hippocampal infarcts in aged population found here and the failure to detect an association between this lesion and various cerebro- cardio-vascular lesions is intriguing. Whether susceptibility to ischemia in line with susceptibility to neuronal degeneration in this region is influenced by still undetermined risk- factors need further investigation. Furthermore it should be noted that the size of the hippocampal tissue damage, i.e., small vs. large cystic infarcts is of significance regarding clinical alterations.

  • 8.
    Söderlund, Hedvig
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Moscovitch, Morris
    Kumar, Namita
    Mandic, Marina
    Levine, Brian
    As time goes by: Hippocampal connectivity changes with remoteness of autobiographical memory retrieval2012In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 22, no 4, p. 670-679Article in journal (Refereed)
    Abstract [en]

    The hippocampus is crucial for episodic autobiographical memory retrieval. Functional neuroimaging evidence suggests that it is similarly engaged in recent and remote retrieval when memories are matched on vividness and personal importance. Far fewer studies have investigated the nature of hippocampal-neocortical coactivation in relation to memory remoteness. The purpose of this study was to examine hippocampal activity and functional connectivity as a function of memory age. Unlike most studies of autobiographical memory, we included autobiographical memories formed in the days and weeks before scanning, in addition to truly remote memories on the order of months and years. Like previous studies, we found that the hippocampus was active bilaterally regardless of memory age, with anterior activity increasing up to 1 yr and then decreasing, and with posterior activity being less sensitive to memory age. More importantly, hippocampal functional connectivity varied with memory age. Retrieving recent memories (=1 yr) showed a late coactivation of the hippocampus and areas of the autobiographical memory network, whereas retrieving remote memories (10 yrs) showed an early negative coactivation of the hippocampus and left inferior frontal gyrus followed by a positive coactivation with anterior cingulate. This finding may reflect that the hippocampus is more strongly integrated with the autobiographical memory network for recent than for remote memories, and that more effort is required to recover remote memories.

  • 9. Viereckel, Thomas
    et al.
    Kostic, Milos
    Bähner, Florian
    Draguhn, Andreas
    Both, Martin
    Effects of the GABA-uptake blocker NNC-711 on spontaneous sharp wave-ripple complexes in mouse hippocampal slices.2013In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 23, no 5Article in journal (Refereed)
    Abstract [en]

    The precise temporal and spatial activity patterns of neurons in cortical networks are organized by different state-dependent types of network oscillations. GABAergic inhibition plays a key role in the underlying mechanisms of such oscillations and it has been suggested that the duration of widely distributed phasic inhibitory postsynaptic potentials (IPSPs) determines the frequency of the resulting network oscillation. Here, we test this hypothesis in an in vitro model of sharp wave-ripple (SPW-R) complexes, a particularly fast pattern of network oscillations at ∼200 Hz which is involved in memory consolidation. We recorded SPW-R in mouse hippocampal slices in the absence and presence of NCC-711, an inhibitor of GABA uptake. The resulting prolongation of IPSP resulted in reduced occurrence of SPW-R, whereas the superimposed fast oscillations as well as the precision of rhythmic cell synchronization remained stable. Application of Diazepam which is a positive modulator of the GABAA receptor led to consistent results. We conclude that phasic inhibition is a major regulator of network excitability in CA3 (where SPW-Rs are generated), but does not set the frequency of hippocampal ripples.

  • 10.
    Winne, Jessica
    et al.
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Franzon, Rafael
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    de Miranda, Aron
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Malfatti, Thawann
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Patriota, Joao
    Univ Fed Rio Grande do Norte, Inst Brain, Ave Nascimento de Castro 2155, Natal, RN, Brazil.
    Mikulovic, Sanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Leao, Katarina E.
    Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Leão, Richardson N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Fed Rio Grande do Norte, Inst Brain, Neurodynam Lab, Natal, RN, Brazil.
    Salicylate induces anxiety-like behavior and slow theta oscillation and abolishes the relationship between running speed and fast theta oscillation frequency2019In: Hippocampus, ISSN 1050-9631, E-ISSN 1098-1063, Vol. 29, no 1, p. 15-25Article in journal (Refereed)
    Abstract [en]

    Salicylate intoxication is a cause of tinnitus in humans and it is often used to produce tinnitus-like perception in animal models. Here, we assess whether salicylate induces anxiety-like electrophysiological and behavioral signs. Using microwire electrode arrays, we recorded local field potential in the ventral and, in some experiments dorsal hippocampus, in an open field arena 1 hr after salicylate (300 mg/kg) injection. We found that animals treated with salicylate moved dramatically less than saline treated animals. Salicylate-treated animals showed a strong 4-6 Hz (type 2) oscillation in the ventral hippocampus (with smaller peaks in dorsal hippocampus electrodes). Coherence in the 4-6 Hz-theta band was low in the ventral and dorsal hippocampus when compared to movement-related theta coherence (7-10 Hz). Moreover, movement related theta oscillation frequency decreased and its dependency on running speed was abolished. Our results suggest that salicylate-induced theta is mostly restricted to the ventral hippocampus. Slow theta has been classically associated to anxiety-like behaviors. Here, we show that salicylate application can consistently generate low frequency theta in the ventral hippocampus. Tinnitus and anxiety show strong comorbidity and the increase in ventral hippocampus low frequency theta could be part of this association.

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