Looking beneath the surface: the importance of subcortical structures in frontotemporal dementia.

Funder: National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research UnitFunder: Alzheimer's Research UK, Brain Research Trust and The Wolfson FoundationFunder: Medical Research CouncilFunder: Alzheimer’s Society and Alzheimer’s Research UKFunder: NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research FacilityFunder: DRI LtdWhilst initial anatomical studies of frontotemporal dementia focussed on cortical involvement, the relevance of subcortical structures to the pathophysiology of frontotemporal dementia has been increasingly recognized over recent years. Key structures affected include the caudate, putamen, nucleus accumbens, and globus pallidus within the basal ganglia, the hippocampus and amygdala within the medial temporal lobe, the basal forebrain, and the diencephalon structures of the thalamus, hypothalamus and habenula. At the most posterior aspect of the brain, focal involvement of brainstem and cerebellum has recently also been shown in certain subtypes of frontotemporal dementia. Many of the neuroimaging studies on subcortical structures in frontotemporal dementia have been performed in clinically defined sporadic cases. However, investigations of genetically- and pathologically-confirmed forms of frontotemporal dementia are increasingly common and provide molecular specificity to the changes observed. Furthermore, detailed analyses of sub-nuclei and subregions within each subcortical structure are being added to the literature, allowing refinement of the patterns of subcortical involvement. This review focuses on the existing literature on structural imaging and neuropathological studies of subcortical anatomy across the spectrum of frontotemporal dementia, along with investigations of brain-behaviour correlates that examine the cognitive sequelae of specific subcortical involvement: it aims to 'look beneath the surface' and summarize the patterns of subcortical involvement have been described in frontotemporal dementia

Looking beneath the surface: the importance of subcortical structures in frontotemporal dementia

Data availability: Data sharing is not applicable to this review article as no new data were generated or analysed in this study. Source study data may be available from the authors cited.Copyright © The Author(s) (2021). Whilst initial anatomical studies of frontotemporal dementia focussed on cortical involvement, the relevance of subcortical structures to the pathophysiology of frontotemporal dementia has been increasingly recognized over recent years. Key structures affected include the caudate, putamen, nucleus accumbens, and globus pallidus within the basal ganglia, the hippocampus and amygdala within the medial temporal lobe, the basal forebrain, and the diencephalon structures of the thalamus, hypothalamus and habenula. At the most posterior aspect of the brain, focal involvement of brainstem and cerebellum has recently also been shown in certain subtypes of frontotemporal dementia. Many of the neuroimaging studies on subcortical structures in frontotemporal dementia have been performed in clinically defined sporadic cases. However, investigations of genetically- and pathologically-confirmed forms of frontotemporal dementia are increasingly common and provide molecular specificity to the changes observed. Furthermore, detailed analyses of sub-nuclei and subregions within each subcortical structure are being added to the literature, allowing refinement of the patterns of subcortical involvement. This review focuses on the existing literature on structural imaging and neuropathological studies of subcortical anatomy across the spectrum of frontotemporal dementia, along with investigations of brain–behaviour correlates that examine the cognitive sequelae of specific subcortical involvement: it aims to ‘look beneath the surface’ and summarize the patterns of subcortical involvement have been described in frontotemporal dementia.The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust and The Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer's Society grant (AS-PG-16-007). MB is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). MB’s work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council (MRC), Alzheimer’s Society and Alzheimer’s Research UK. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). JBR and MM were supported by the Cambridge University Centre for Parkinson-Plus, the Medical Research Council (SUAG/051 G101400) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care

Arenguline lähenemine emotsionaalse käitumisega seotud geenide Wfs1 ja Lsampʼi funktsiooni uurimisel

Väitekirja elektrooniline versioon ei sisalda publikatsioonePsühhiaatriliste häirete kujunemises mängib olulist rolli aju areng. Geenid, mis osalevad emotsioonidega seotud ajupiirkondade arengus ja funktsioneerimises, on olulised psühhiaatriliste häirete seisukohalt. Wfs1 ja Lsamp geenid osalevad hirmu- ja ärevuskäitumise regulatsioonis. Wfs1 (Wolframi sündroom 1), nagu nimigi ütleb, on seotud samanimelise haruldase sündroomiga, mille sümptomid on diabetes insipidus, diabetes mellitus, nägemisnärvi kärbumine ja sensorineuraalne kurtus, sageli kaasnevad ka psühhiaatrilised häired. Wfs1 valk mängib olulist rolli insuliini sekretsioonis ja pankrease β-rakkude ellujäämise tagamises, selle funktsioonist ajus on vähem teada. Lsamp (limbilise süsteemiga seotud membraanivalk) osaleb neuriitide väljakasvu, aksonite sihtmärgini jõudmise ja sünaptogeneesi reguleerimises. Lsamp geenil on kaks evolutsiooniliselt konserveerunud alternatiivset esimest eksonit koos eraldi promootoritega, sellise struktuuri funktsionaalne tähtsus on teadmata. Nii Wfs1 kui Lsamp geeni puhul on näidatud kindlate alleelide seotust meeleolu- ja ärevushäirete, skisofreenia ja suitsidaalsusega. Enda doktoritöös uurisin Wfs1 ja Lsamp`i funktsiooni arengulisest vaatevinklist. Selgus, et Wfs1 ekspressioon on evolutsiooniliselt konserveerunud dopamiinergilist sisendit saavates ajupiirkondades, ning et Wfs1 suhtes puudulike hiirte hipokampuses on D1-tüüpi dopamiini retseptorite hulk suurenenud. Arengu käigus ekspresseerus Wfs1 ajutiselt paljudes ajupiirkondades; see laialdane ekspressioon polnud seotud arengulise endoplasmaatilise retiikulumi stressi vastuse regulatsiooniga, mis on üks Wfs1 põhilisi funktsioone täiskasvanud organismis. Lsamp`i puhul näitasime, et selle alternatiivsed promootorid on aktiivsed erinevate funktsioonidega ajupiirkondades: 1a-promootor on põhiline limbilises süsteemis, samas kui 1b-promootori aktiivsus piiritleb sensoorseid juhteteid. Lsamp`i promootorite aktiivsus hiirte hipokampuses, ventraalses striatumis ja temporaalsagaras korreleerus sotsiaalse- ja ärevusega seotud käitumise näitajatega. Saadud tulemused aitavad paremini mõista Wfs1 ja Lsamp`i rolli psühhiaatriliste häirete väljakujunemises ning näitavad suunda edasisteks uuringuteks.Genes that are involved in the development and functioning of the emotional circuits of the brain are highly susceptible targets in psychiatric diseases. Wfs1 and Lsamp, two genes studied in the present thesis, are both involved in the regulation of anxiety- and fear-related behaviour in the adult brain. Wfs1 (Wolfram syndrome 1) is a causative gene for Wolfram syndrome, a rare genetic disorder characterized by diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness. Often, the core symptoms are accompanied by psychiatric manifestations. Wfs1 is important for the survival and functioning of pancreatic β-cells, its roles in the nervous system are not well understood. Lsamp (Limbic system associated membrane protein) is involved in regulating neurite outgrowth, axon targeting and synaptogenesis in the limbic system. Lsamp has two alternative first exons with separate promoters, the role of this conserved gene structure is unknown. Allelic variants of both, Wfs1 and Lsamp, are associated with depression, anxiety disorders, bipolar disorder, schizophrenia and suicidality. We took advantage of the neurodevelopmental approach to study the functions of Wfs1 and Lsamp in the brain. Wfs1 showed evolutionarily conserved expression in the dopaminoceptive brain regions. Relating to this, Wfs1-deficient mice had increased number of D1-type dopamine receptor ligand binding sites in the hippocampi compared to wild-type mice. During the development, Wfs1 was transiently expressed in many brain regions. The widespread expression of Wfs1 in early postnatal mouse brain was not involved in the regulation of developmental endoplasmic reticulum stress, which has previously been shown to be one of the main functions of Wfs1 in the adult organism. The activity pattern of the two alternative promoters of Lsamp was complementary in the mouse brain: 1a promoter was prevailing in the limbic-related structures, while the activity of 1b promoter mainly delineated sensory pathways. The activity of Lsamp promoters in the hippocampus, ventral striatum and temporal lobe correlated with measures of anxiety and social behaviour of mice. The present results help to understand the role of Wfs1 and Lsamp in the context of psychiatric diseases and point direction for further research

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

The Neuroscience of Positive Emotions and Affect:Implications for Cultivating Happiness and Wellbeing

This review paper provides an integrative account regarding neurophysiological correlates of positive emotions and affect that cumulatively contribute to the scaffolding for happiness and wellbeing in humans and other animals. This paper reviews the associations among neurotransmitters, hormones, brain networks, and cognitive functions in the context of positive emotions and affect. Consideration of lifespan developmental perspectives are incorporated, and we also examine the impact of healthy social relationships and environmental contexts on the modulation of positive emotions and affect. The neurophysiological processes that implement positive emotions are dynamic and modifiable, and meditative practices as well as flow states that change patterns of brain function and ultimately support wellbeing are also discussed. This review is part of "The Human Affectome Project" (http://neuroqualia.org/background.php), and in order to advance a primary aim of the Human Affectome Project, we also reviewed relevant linguistic dimensions and terminology that characterizes positive emotions and wellbeing. These linguistic dimensions are discussed within the context of the neuroscience literature with the overarching goal of generating novel recommendations for advancing neuroscience research on positive emotions and wellbeing

The neuroscience of social feelings:mechanisms of adaptive social functioning

Social feelings have conceptual and empirical connections with affect and emotion. In this review, we discuss how they relate to cognition, emotion, behavior and well-being. We examine the functional neuroanatomy and neurobiology of social feelings and their role in adaptive social functioning. Existing neuroscience literature is reviewed to identify concepts, methods and challenges that might be addressed by social feelings research. Specific topic areas highlight the influence and modulation of social feelings on interpersonal affiliation, parent-child attachments, moral sentiments, interpersonal stressors, and emotional communication. Brain regions involved in social feelings were confirmed by meta-analysis using the Neurosynth platform for large-scale, automated synthesis of functional magnetic resonance imaging data. Words that relate specifically to social feelings were identfied as potential research variables. Topical inquiries into social media behaviors, loneliness, trauma, and social sensitivity, especially with recent physical distancing for guarding public and personal health, underscored the increasing importance of social feelings for affective and second person neuroscience research with implications for brain development, physical and mental health, and lifelong adaptive functioning

Neural correlates of fear: insights from neuroimaging

Fear anticipates a challenge to one's well-being and is a reaction to the risk of harm. The expression of fear in the individual is a constellation of physiological, behavioral, cognitive, and experiential responses. Fear indicates risk and will guide adaptive behavior, yet fear is also fundamental to the symptomatology of most psychiatric disorders. Neuroimaging studies of normal and abnormal fear in humans extend knowledge gained from animal experiments. Neuroimaging permits the empirical evaluation of theory (emotions as response tendencies, mental states, and valence and arousal dimensions), and improves our understanding of the mechanisms of how fear is controlled by both cognitive processes and bodily states. Within the human brain, fear engages a set of regions that include insula and anterior cingulate cortices, the amygdala, and dorsal brain-stem centers, such as periaqueductal gray matter. This same fear matrix is also implicated in attentional orienting, mental planning, interoceptive mapping, bodily feelings, novelty and motivational learning, behavioral prioritization, and the control of autonomic arousal. The stereotyped expression of fear can thus be viewed as a special construction from combinations of these processes. An important motivator for understanding neural fear mechanisms is the debilitating clinical expression of anxiety. Neuroimaging studies of anxiety patients highlight the role of learning and memory in pathological fear. Posttraumatic stress disorder is further distinguished by impairment in cognitive control and contextual memory. These processes ultimately need to be targeted for symptomatic recovery. Neuroscientific knowledge of fear has broader relevance to understanding human and societal behavior. As yet, only some of the insights into fear, anxiety, and avoidance at the individual level extrapolate to groups and populations and can be meaningfully applied to economics, prejudice, and politics. Fear is ultimately a contagious social emotion

Lycium barbarum (wolfberry) polysaccharide facilitates ejaculatory behaviour in male rats

Poster Session AOBJECTIVE: Lycium barbarum (wolfberry) is a traditional Chinese medicine, which has been considered to have therapeutic effect on male infertility. However, there is a lack of studies support the claims. We thus investigated the effect of Lycium barbarum polysaccharide (LBP), a major component of wolfberry, on male rat copulatory behavior. METHOD: Sprague-Dawley rats were divided into two groups (n=8 for each group). The first group received oral feeding of LBP at dosage of 1mg/kg daily. The control group received vehicle (0.01M phosphate-buffered saline, served as control) feeding daily for 21 days. Copulatory tests were conducted at 7, 14 and 21 days after initiation of treatment. RESULTS: Compared to control animals, animals fed with 1mg/kg LBP showed improved copulatory behavior in terms of: 1. Higher copulatory efficiency (i.e. higher frequency to show intromission rather than mounting during the test), 2. higher ejaculation frequency and 3. Shorter ejaculation latency. The differences were found at all time points (Analyzed with two-tailed student’s t-test, p<0.05). There is no significant difference found between the two groups in terms of mount/intromission latency, which indicates no difference in time required for initiation of sexual activity. Additionally, no difference in mount frequency and intromission frequency was found. CONCLUSION: The present study provides scientific evidence for the traditional use of Lycium barbarum on male sexual behavior. The result provides basis for further study of wolfberry on sexual functioning and its use as an alternative treatment in reproductive medicine.postprintThe 30th Annual Meeting of the Australian Neuroscience Society, in conjunction with the 50th Anniversary Meeting of the Australian Physiological Society (ANS/AuPS 2010), Sydney, Australia, 31 January-3 February 2010. In Abstract Book of ANS/AuPS, 2010, p. 177, abstract no. POS-TUE-19

The Role of Amygdala Subregions in the Neurobiology of Social Anxiety Disorder

Social anxiety is characterised by fear and/or avoidance of social situations in which an individual may be scrutinised by others. Social anxiety is thought to exist as a spectrum, with individuals on the high-end experiencing frequent and severe anxiety in the context of social situations. When severe social anxiety is accompanied by distress and functional impairment, a diagnosis of social anxiety disorder (SAD) can be made. SAD is a prevalent and debilitating disorder that can be unremitting and pervasive in the absence of intervention. Current psychotherapeutic and pharmacotherapeutic treatments for SAD demonstrate limited efficacy in remitting symptoms. Therefore, it is important to achieve a better understanding of the neurobiological mechanisms implicated in this disorder and identify potential neural treatment targets to develop more efficacious treatments. This thesis aimed to further investigate the neurobiological mechanisms implicated in SAD (vs. controls) and the associations between neural functioning and social anxiety as a dimensional symptom, with a focus on the amygdala and four of its subregions (the amygdalostriatal, basolateral, centromedial, and superficial subregions). This was due to previous findings in the neuroimaging literature in SAD having consistently implicated the amygdala, albeit with mixed findings of both increased and decreased functioning in those with SAD compared to controls. In the literature to date, however, most studies had examined the amygdala as a singular homogenous region due to methodological limitations in being able to examine the functionally and structurally distinct subnuclei that make up this region. By examining the amygdala subregions through the use of multiband functional magnetic resonance imaging (fMRI), this thesis additionally sought to determine whether the mixed findings in the literature to date may be a result of amygdala subregion-specific activity and connectivity patterns. This was achieved through three research studies. Firstly, Study 1 involved a comprehensive systematic review that summarised the literature on resting-state neuroimaging in SAD with a focus on fMRI studies and findings specific to the amygdala and its subregions (Chapter 3). This was followed by two empirical studies which investigated the role of the amygdala and its subregions during resting-state (Study 2) and emotion processing (Study 3) fMRI paradigms (Chapters 5 and 6, respectively). Findings from the systematic review (Study 1) highlighted the mixed findings in the resting-state neuroimaging literature in SAD to date, along with methodological limitations relating to neuroimaging acquisition and analysis. The empirical studies sought to address these limitations and demonstrated differing amygdala subregion activity and connectivity patterns at rest and during emotion processing. In the resting-state fMRI study (Study 2), there were no statistically significant differences in functional connectivity of the amygdala and its subregions in those with SAD compared to controls. However, social anxiety severity was found to be positively associated with connectivity between the superficial subregion and the supramarginal gyrus. The superficial subregion, along with the basolateral and centromedial subregions, were also implicated in the task-based emotion processing fMRI study (Study 3). In response to happy, angry, and fearful faces, those with SAD (vs. controls) had hyperactivation of the superficial subregion, hypoconnectivity between the superficial subregion and the precuneus, and hyperconnectivity between the basolateral subregion and broader brain regions (i.e., the pre/postcentral gyrus and the supramarginal gyrus). Additionally, social anxiety severity was positively associated with superficial and centromedial activation. Overall, the findings from this thesis provide novel information to the current understanding of the neurobiology of SAD by demonstrating amygdala subregion-specific alterations. This has important implications for research, theory, and clinical practice that are detailed in the thesis discussion (Chapter 7). Briefly, in terms of research, findings from the thesis provide support for the continuing investigation of SAD using both dimensional and categorical approaches. This was evident by the findings from the two empirical papers which demonstrated positive associations between subregional activity and connectivity patterns and social anxiety severity. With regards to theory, differences in neural patterns that were observed at rest (Study 2) and during emotion processing (Study 3) provide support for distinct neurobiological models to be constructed based on whether those with SAD are in the absence or presence of social stimuli. This is in contrast to the most recently proposed neurobiological model of SAD which was informed by a combination of resting-state and task-based fMRI data. Finally, with regards to clinical practice, the findings from this thesis provide preliminary evidence of the superficial, basolateral, and centromedial subregions of the amygdala as being potential treatment targets that can be used to inform the development of more efficacious treatments for SAD

Studying Glutamatergic Gliotransmission as a Functional Model to Assess Physio-Pathological Conditions and Receptor Cross-Talk

SUMMARY This thesis is divided into two parts; in the first part, we characterized the effect of acute stress on the astrocytic glutamate release in the prefrontal cortex of rat brain. In the second part, we evaluate the interaction of the Oxytocin receptor (OXTR) with both Adenosine receptor A2A and Dopamine D2 receptors in the brain striatum of male rats. First Part: Stress is known to disturb the physiological homeostasis of the body (McEwen et al., 2000). The number of studies demonstrated that stress leads to damage the prefrontal cortex the brain and results in the modulation in the secretion of various neurotransmitters (Karats Oreos and McEwen, 2011, Sousa and Almeida, 2012). Stress was recognized as a predominant risk factor for many diseases, together with cardiovascular, metabolic, and neuropsychiatric diseases. Among the latter, stress interacts with the variable genetic background of vulnerability in the pathogenesis of mood anxiety disorder (Laura et al., 2010). It may be acute or chronic, can involve neuropsychiatric components such as stress, depression, mood, and anxiety (Laura et al., 207) and produces many behavioral and neurochemical changes, as determined in human (De Kloet et al., 2005, Kim &amp; Diamond 2002). Studies in the literature truly indicated that acute stress have an effect on glutamatergic neurotransmission in the prefrontal cortex, inducing changes in glutamate release, receptor and glutamate clearance and metabolism (Popoli et al., 2012: Licznerski and Duman 3013). The effects of acute footshock stress on glutamate release and transmission were still unknown. In this study, we investigated the release of glutamate from astrocytes. The analyses have been performed in the prefrontal cortex (PFC) at different time intervals straight away after 40 min of stress and 6 and 24 hours after stress start, to monitor the early and delayed effects of acute stress on glutamate release. After the acute stress, animals were subjected to sucrose test to distinguish vulnerable and resilient rats. Second Part: There has been a growing interest in the investigation of the role of astrocytes in neurodegenerative and neuropsychiatric diseases and their complex neuron-astrocytes network function. The receptor\u2013receptor interactions (RRI) can have an important function in the signalling transduction pathways. A previous well established study evaluate the interactions between the G-protein coupled receptors of adenosine A2A receptors (A2A) and dopamine D2 receptors (D2) in several experimental models (Ferr\ue9 et al., 2008), while it\u2019s barely investigated in astrocytes. Growing evidence shows that adult striatal astrocytes largely express both D2 and A2A receptors (Cervetto et at., 2017). Moreover, the presence of A2A-D2 heteroreceptor complexes has led to a new perspective of molecular mechanisms involved in Parkinson\u2019s disease (PD), providing novel drug targets. Therefore in the present study, we investigate the physical and functional interactions of A2A and D2 with another G protein-coupled receptors i.e. OXTR in astrocytes processes from adult rat striatum. We also evaluate the effect of this interaction on the astrocytic glutamate release in rat striatum