Outre le stress chronique, la douleur chronique représente une cause majeure de dépression. En effet, environ 50% des patients qui souffrent d’une douleur chronique développent des troubles de l’humeur. Les perturbations des structures cérébrales impliquées dans la perception de la douleur pourraient contribuer à cette comorbidité, dont les mécanismes restent pourtant mal compris. Nous avons étudié l’implication du cortex cingulaire antérieur (CCA) dans les conséquences sensorielles et émotionnelles de la douleur neuropathique dans un modèle murin. Nous avons montré qu’une lésion du CCA ou une inhibition des neurones pyramidaux du CCA préviennent l’émergence des désordres émotionnels dans notre modèle. De plus, nos résultats indiquent que ces conséquences émotionnelles coïncident avec une hyperactivité neuronale dans le CCA. En conclusion, nous montrons que le CCA est une structure clé pour la dépression induite par la douleur neuropathique. / Besides chronic stress, chronic pain is one of the prevalent determinants for depression. Indeed, around 50% of chronic pain patients develop mood disorders. Alterations in brain regions implicated in pain processing may also be involved in affective processing, thus potentially be responsible of mood disorders. However, the underlying mechanisms of this comorbidity are not yet elucidated. Here, we studied the role of the anterior cingulate cortex (ACC) in the somatosensory, aversive and anxiodepressive consequences of neuropathic pain. We showed that a permanent lesion or temporal inhibition of ACC pyramidal neurons blocked the development or suppressed the expression of an anxiodepressive phenotype in neuropathic mice. In addition, anxiodepressive-like behavior coincided with ACC hyperactivity. In conclusion we show that the ACC is a critical hub for neuropathic pain-induced depression.

Complicated grief, or persistent complex bereavement disorder, is a condition that affects approximately 10% of bereaved individuals and is marked by intense longing and yearning for the deceased. Little is known about the neurocognitive mechanisms contributing to this syndrome, but previous research suggests that reward pathways in the brain may play a role. The present study was designed with this theory in mind, aiming to understand reward processing in those experiencing complicated and non-complicated grief as well as to differentiate the "wanting" and "liking" phases of reward processing in bereavement. Twenty-five older adults were categorized based on grief severity into one of three groups: complicated grief (CG), non-complicated grief (NCG) and non-bereaved married controls (NB). Neural activation was examined using fMRI while participants viewed a countdown on the screen (anticipation) followed by a photo of their (living or deceased) spouse. There was no significantly differential activation between the three groups for the spouse v. stranger photo contrast, nor for anticipation period v. spouse photo. However, these two contrasts were also run separately in the three groups. Each group produced significant activation, in similar and distinct regions, primarily associated with emotion and visual processing. In addition, post-hoc analyses were conducted using self-reported yearning scores as a regressor across all bereaved participants, which revealed that greater symptoms of yearning predicted greater activation in the subgenual anterior cingulate cortex (sgACC). This region of the brain has been previously linked to depression and suggests that symptoms of yearning may present an opportune place to intervene to improve outcomes in CG.

The anterior cingulate cortex (ACC) is part of the cognitive and emotional brain circuitry that mediates social interaction. Imbalances between inhibitory, GABAergic neurons, and excitatory, glutamatergic neurons, in this region are essential to brain circuity during social responses and are thought to be involved with behaviors associated with autism spectrum disorder (ASD). Enriched cell populations of glutamatergic neurons, obtained through laser capture microdissection, were used for gene expression studies of GABAergic receptors (GABRA1, GABRA4, and GABBR1). Additionally, proteins that impact GABAergic synapses (Spinophilin, CPLX1, mTOR, IGF1R, PSD95, PARP1) were investigated using Western Blotting with punchdissected homogenate brain tissue from ACC and frontal cortical brain regions. No significant differences in gene expression nor protein were identified between ASD and control brain donors. Evidence of GABAergic synaptic pathology was not found; however, future studies of alternative GABAergic markers and increased study numbers are needed to confirm these findings in ASD human tissue.

This study served as a pilot study of cingulate gyrus surface areas and their relation to intelligence in individuals with hydrocephalus. Surface areas of the corpus callosum and cingulate gyrus regions were compared between individuals with early hydrocephalus (n = 9) and controls (n = 7). Subsequently, the surface areas were correlated with full-scale intelligence scores and the verbal and nonverbal discrepancy scores. Corpus collosum surface areas were significantly smaller in participants with hydrocephalus. These areas also robustly correlated with full-scale intelligence scores. Although the cingulate gyrus did not differ significantly between the groups, the cingulate gyrus regions were increasingly divergent the more posterior the region. Additionally, the caudal anterior and the posterior cingulate gyrus regions had only moderate positive correlations with full-scale intelligence scores. Although the participants with hydrocephalus had a significantly lower mean performance IQ compared to verbal IQ, the discrepancy scores did not correlate significantly with any of the regions of interest.

Background: Altered brain morphology was one of the first pathobiological findings associated with autism spectrum disorder. These gross abnormalities, documented in both white and gray matter areas in autistic brains, are postulated to contribute to disrupted neuronal communication. For example, glutamatergic pyramidal neurons in the anterior cingulate cortex (ACC) have decreased size and increased cell density in autism. Objectives: We sought to determine whether autism-related gene expression abnormalities exist in the ACC that might underlie previously observed cell morphological alterations found in this brain region. Specifically, levels of expression of genes associated with glutamatergic neurotransmission were measured in pyramidal neurons and surrounding astrocytes in the ACC of postmortem brain tissues from autism donors and matched developmentally normal control donors. Methods: Postmortem brain tissues were obtained from 6-8 age-matched pairs of male subjects who had autism and developmentally normal control males (age range 6-37). Laser-guided microdissection was used to capture pure populations of pyramidal neurons and astrocytes from layer III of the ACC. The expression of glutamate-related genes was measured in RNA isolates by reverse transcription followed by end-point PCR using three stable reference genes to normalize expression levels. Results: ACC pyramidal neurons from autism subjects demonstrated significantly reduced gene expressions of the obligatory glutamatergic NMDA receptor subunit NR1, a glutamate transporter SLC1A1, and the glutamate receptor anchoring protein GRIP1. There was also a robust reduction in the gene expression of the brain-derived neurotrophic factor (BDNF) receptor NTRK2 in autism pyramidal neurons, with gene expression levels of BDNF itself unaffected. No gene expression abnormalities were observed in ACC astrocytes surrounding the pyramidal neurons from autistic subjects. Conclusions: Autism spectrum disorder is associated with a reduction in the expression of genes associated with glutamatergic neurotransmission and downstream BDNF signaling in pyramidal neurons of the ACC. These findings suggest that glutamatergic signaling is compromised in these excitatory neurons in autism and raise hope that drugs or other treatments may be developed to overcome these pathobiological deficits.

Background: The anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD). Functional brain imaging studies demonstrate abnormalities of the ACC in ASD as compared to typically developing control patients. However, little is known regarding the cellular basis of these functional deficits in ASD. Pyramidal neurons in the ACC are excitatory glutamatergic neurons and key cellular mediators of the neural output of the ACC. This study was designed to investigate the potential role of ACC pyramidal neurons in ASD brain pathology. Methods: Postmortem ACC tissue from carefully matched ASD and typically developing control donors was obtained from two national brain collections. Pyramidal neurons and surrounding astrocytes were separately collected from layer III of the ACC by laser capture microdissection. Isolated RNA was subjected to reverse transcription and endpoint PCR to determine gene expression levels for 16 synaptic genes relevant to glutamatergic neurotransmission. Cells were also collected from the prefrontal cortex (Brodmann area 10) to examine those genes demonstrating differences in expression in the ACC comparing typically developing and ASD donors. Results: The level of NTRK2 expression was robustly and significantly lower in pyramidal neurons from ASD donors as compared to typically developing donors. Levels of expression of GRIN1, GRM8, SLC1A1, and GRIP1 were modestly lower in pyramidal neurons from ASD donors, but statistical significance for these latter genes did not survive correction for multiple comparisons. No significant expression differences of any genes were found in astrocytes laser captured from the same neocortical area. In addition, expression levels of NTRK2 and other synaptic genes were normal in pyramidal neurons laser captured from the prefrontal cortex. Conclusions: These studies demonstrate a unique pathology of neocortical pyramidal neurons of the ACC in ASD. NTRK2 encodes the tropomyosin receptor kinase B (TrkB), transmission through which neurotrophic factors modify differentiation, plasticity, and synaptic transmission. Reduced pyramidal neuron NTRK2 expression in the ACC could thereby contribute to abnormal neuronal activity and disrupt social behavior mediated by this brain region.

A hallmark of higher-order cortical regions is their functional heterogeneity, but it is not well understood how these areas are able to encode diverse behavioral information. The anterior cingulate cortex (ACC), for example, is known to be important in a large range of behaviors, including, decision making, emotional regulation and social cognition. In support of this, previous work shows activation of the ACC to anxiety-related and social stimuli but does not use cellular resolution or cell-type specific techniques to elucidate the possible heterogeneity of its subcircuits. In this work, I investigate how subpopulations of neurons or microcircuits within the ACC encode these different kinds of stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to alter the activity of clusters of pyramidal excitatory neurons, often by inhibiting other types of inhibitory cells. Prior to this research, it was unknown whether the activity of VIP cells in the ACC (VIPACC) encodes anxiety-related or social information and whether all VIPACC activate similarly to the same behavioral stimuli. Using in vivo Ca2+ imaging and 3D-printed miniscopes in freely behaving mice to monitor VIPACC activity, I have identified distinct subpopulations of VIPACC that preferentially activate to either anxiogenic, anxiolytic, social, or non-social stimuli. I also demonstrate that these stimulus-selective subpopulations are largely non-overlapping and that clusters of cells may co-activate, improving their encoding. Finally, I used trans-synaptic tracing to map monosynaptic inputs to VIP and other interneuron subtypes in the ACC. I found that VIPACC receive widespread inputs from regions implicated in emotional regulation and social cognition and that some inputs differ between types of ACC interneurons. Overall, these data demonstrate that the ACC is not homogeneous – there is marked functional heterogeneity within one interneuron population in the ACC and connective heterogeneity across ACC cell types. This work contributes to our broader understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

Background: The anterior cingulate cortex (ACC) is a brain area involved in modulating behavior associated with social interaction, disruption of which is a core feature of autism spectrum disorder (ASD). Functional brain imaging studies demonstrate abnormalities of the ACC in ASD as compared to typically developing control patients. However, little is known regarding the cellular basis of these functional deficits in ASD. Pyramidal neurons in the ACC are excitatory glutamatergic neurons and key cellular mediators of the neural output of the ACC. This study was designed to investigate the potential role of ACC pyramidal neurons in ASD brain pathology. Methods: Postmortem ACC tissue from carefully matched ASD and typically developing control donors was obtained from two national brain collections. Pyramidal neurons and surrounding astrocytes were separately collected from layer III of the ACC by laser capture microdissection. Isolated RNA was subjected to reverse transcription and endpoint PCR to determine gene expression levels for 16 synaptic genes relevant to glutamatergic neurotransmission. Cells were also collected from the prefrontal cortex (Brodmann area 10) to examine those genes demonstrating differences in expression in the ACC comparing typically developing and ASD donors. Results: The level of NTRK2 expression was robustly and significantly lower in pyramidal neurons from ASD donors as compared to typically developing donors. Levels of expression of GRIN1, GRM8, SLC1A1, and GRIP1 were modestly lower in pyramidal neurons from ASD donors, but statistical significance for these latter genes did not survive correction for multiple comparisons. No significant expression differences of any genes were found in astrocytes laser captured from the same neocortical area. In addition, expression levels of NTRK2 and other synaptic genes were normal in pyramidal neurons laser captured from the prefrontal cortex. Conclusions: These studies demonstrate a unique pathology of neocortical pyramidal neurons of the ACC in ASD. NTRK2 encodes the tropomyosin receptor kinase B (TrkB), transmission through which neurotrophic factors modify differentiation, plasticity, and synaptic transmission. Reduced pyramidal neuron NTRK2 expression in the ACC could thereby contribute to abnormal neuronal activity and disrupt social behavior mediated by this brain region.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24842号 / 医博第5010号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋, 良輔, 教授 林, 康紀, 教授 井上, 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bakgrund: Smärta definieras som en subjektiv upplevelse där upplevelsen till viss del formas i hjärnan genom komplexa processer. Långvarig stress har visat sig leda till förändring i smärtkänsligheten vilket kanske förklaras av att akut stress förändrar aktivitet i främre delar av hjärnan. Anterior cingulate cortex (ACC) är ett frontalt hjärnområde med en roll i den emotionella upplevelsen av smärta. Det finns indikationer på förändringar i ACC av den hämmande transmittorsubstansen GABA, och den stimulerande transmittorsubstansen glutamat, vid vissa smärttillstånd.  Motiv: I dagsläget saknas kunskap om hur stress påverkar smärtkänslighet samt hur det påverkar grundnivåerna av transmittorsubstanserna GABA och glutamat.  Syfte: Att studera samband mellan skattad stress och skattad smärta, samt studera samband mellan skattad stress, smärta, GABA och glutamat i två ACC regioner.  Metod: En experimentell pilotstudie med kvantitativ design utfördes med 10 friska deltagare. Percieved Stress Questionnaire användes för skattning av stressnivåer före smärtprovokation och Numeric Rating Scale användes för att skatta smärta vid smärtprovokation. GABA- och glutamatnivåer i två ACC regioner mättes med hjälp av Magnetic Resonans Spectroscopi.  Resultat: Spearmans test visade att det fanns ett signifikant positivt samband mellan skattad stress och skattad smärta (r=.86, p=.001). Det fanns även signifikant positivt samband mellan skattad stress och glutamat (r=.778, p=.008), skattad smärta och glutamat (r=.729, p=.017). Samt ett signifikant negativt samband mellan skattad stress och GABA (r= -.687, p=.028), skattad smärta och GABA (r=-.667, p=.035) i två ACC regioner.  Konklusion: Resultatet indikerar att sambandet mellan stress och smärta kan förklaras av förändringar i transmittorsubstansnivåer i två ACC regioner. Denna kunskap kan bidra till ökad förståelse hos vårdpersonalen för individuella skillnader i smärtkänslighet och hur komplex situationen kring patienter med smärta är, vilket motiverar till omvårdnadsåtgärder som minskar stress och smärta. / Background: Pain is defined as a subjective experience that some extent is formed through complex processes in the brain. Prolonged stress can affect pain sensitivity, which may be explained by changes in frontal parts of the brain. The anterior cingulate cortex (ACC) is a frontal brain area that plays a role in the emotional experience of pain. In certain pain conditions, there are indications of changes in the neurotransmitter level GABA and glutamate in ACC. Motive: At present, there is a lack of knowledge about how stress affects pain sensitivity and how it affects the basic levels of the neurotransmitter GABA and glutamate in ACC.  Aim: To study the correlation between rated stress and pain, and study the correlation between rated stress, pain, GABA, and glutamate in ACC.  Methods: An experimental pilot study was performed with 10 healthy participants. The Perceived Stress Questionnaire was used to rate stress levels before pain provocation and the Numeric Rating Scale was used to rate pain during pain provocation. GABA and glutamate levels were measured in ACC by Magnetic Resonance Spectroscopy.  Result: Spearman´s test showed a significant positive correlation between rated stress and rated pain (r = .86, p = .001). There was a significant positive relationship between rated stress and glutamate (r = .778, p = .008), rated pain and glutamate (r = .729, p = .017) and a significant negative correlation between rated stress and GABA (r = -.687, p = .028), rated pain and GABA (r = -.667, p = .035) in ACC.  Conclusion: The results indicate that the correlation between stress and pain can be explained by changes in transmitter levels in the ACC region. This knowledge can contribute to increased understanding among healthcare professionals for individual differences in pain sensitivity and the complexity of pain conditions.