Genetic Influences on Hippocampal Subfields: An Emerging Area of Neuroscience Research.
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ABSTRACT:
SUBMITTER: Vilor-Tejedor N
PROVIDER: S-EPMC8192059 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent research in psychiatric genetics has led to a move away from simple diathesis-stress models to more complex models of psychopathology incorporating a focus on gene-environment interactions and epigenetics. Our increased understanding of the way biology encodes the impact of life events on organisms has also generated more sophisticated theoretical models concerning the molecular processes at the interface between "nature" and "nurture." There is also increasing consensus that psychotherapy entails a specific type of learning in the context of an emotional relationship (i.e., the therapeutic relationship) that may also lead to epigenetic modifications across different therapeutic treatment modalities. This paper provides a systematic review of this emerging body of research. It is concluded that, although the evidence is still limited at this stage, extant research does indeed suggest that psychotherapy may be associated with epigenetic changes. Furthermore, it is argued that epigenetic studies may play a key role in the identification of biomarkers implicated in vulnerability for psychopathology, and thus may improve diagnosis and open up future research opportunities regarding the mechanism of action of psychotropic drugs as well as psychotherapy. We review evidence suggesting there may be important individual differences in susceptibility to environmental input, including psychotherapy. In addition, given that there is increasing evidence for the transgenerational transmission of epigenetic modifications in animals and humans exposed to trauma and adversity, epigenetic changes produced by psychotherapy may also potentially be passed on to the next generation, which opens up new perspective for prevention science. We conclude this paper stressing the limitations of current research and by proposing a set of recommendations for future research in this area.
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Project description:Childhood stress and genetic factors like the Val66MET polymorphism of the brain derived neurotrophic factor (BDNF) gene are associated with a higher risk for developing major depressive disorder (MDD) and might also influence hippocampal changes. The aim of this study was to determine which hippocampal dentate gyrus and cornu ammonis subfields are altered in MDD compared to healthy controls and which subfields are affected by the BDNF Val66Met polymorphism and child adversity. Adult patients with MDD and healthy matched controls underwent high-resolution magnetic resonance imaging. Automatic segmentation using the programme FreeSurfer was used to segment the hippocampal subfields dentate gyrus (DG/CA4), CA1 and CA2/3. The history of possible childhood adversity was assessed using the Childhood Trauma Questionnaire and the Val66Met BDNF SNP (rs6265) genotypes were obtained. Patients with MDD had significantly smaller CA4/DG and CA2/3 volumes compared to healthy controls. Furthermore, there was a significant interactive effect of BDNF allele and childhood adversity on CA2/3 and CA4/DG volumes. Met allele carriers without childhood adversity had larger and with childhood adversity smaller CA4/DG and CA2/3 volumes than Val-allele homozygotes. Our results highlight stress by gene interactions as relevant for hippocampal volume reductions, in particular for the subfield CA2/3 and dentate gyrus.
| S-EPMC6869047 | biostudies-literature
Project description:The hippocampus comprises several neuronal populations such as CA1, CA2, CA3, and the dentate gyrus (DG), which present different neuronal origins, morphologies, and molecular mechanisms. Laser capture microdissection (LCM) allows selectively collecting samples from target regions and eliminating unwanted cells to obtain more specific results. LCM of hippocampus neuronal populations coupĺed with RNA-seq analysis has the potential to allow the exploration of the molecular machinery unique to each of these subfields. Previous RNA-seq investigation has already provided a molecular blueprint of the hippocampus, however, there is no RNA-seq data specific for each of the rat hippocampal regions. Serial tissue sections covering the hippocampus were produced from frozen brains of adult male Wistar rats, and the hippocampal subfields CA1, CA2, CA3, and DG were identified and isolated by LCM. We found evident segregation of the transcriptomic profile from different regions of the hippocampus and the expression of known, as well as novel, specific marker genes for each region. Gene ontology enrichment analysis of CA1 subfield indicates an enrichment of actin regulation and postsynaptic membrane AMPA receptors genes indispensable for long-term potentiation. CA2 and CA3 transcripts were found associated with the increased metabolic processes. DG expression was enriched for ribosome and spliceosome, both required for protein synthesis and maintenance of cell life. The present findings contribute to a deeper understanding of the differences in the molecular machinery expressed by the rat hippocampal neuronal populations, further exploring underlying mechanisms responsible for each subflied specific functions.
| S-EPMC9561749 | biostudies-literature
Project description:Purpose: In this study, we used LCM and RNA-Seq to characterize differences in the rat hippocampal expression profiles of CA1, CA2, CA3, and DG subfields Methods: Each subfield was bilaterally laser microdissected, collected from the rat's hippocampus (n=4), and submitted to Illuminas for massively parallel sequencing. Results: We found evident segregation of the transcriptomic profile from different regions of the hippocampus. Gene ontology enrichment analysis of CA1 subfield results in actin regulation genes and postsynaptic membrane AMPA receptors that are indispensable for long-term potentiation and learning and memory. CA2 and CA3 transcripts were found associated with the higher metabolic processes. DG expression was enriched for ribosome and spliceosome, both required for protein synthesis and maintenance of cell life. Conclusion: The present findings contribute to a deeper understanding of the differences in the molecular machinery expressed by the rat hippocampal neuronal populations, further exploring underlying mechanisms responsible for each subflied specific functions.
2021-06-30 | GSE179101 | GEO
Project description:The human hippocampus can be subdivided into subfields with unique functional properties and differential vulnerability to disease or neuropsychiatric conditions. Identifying genes that confer susceptibility to such processes is an important goal in developing treatments. Recent advances in automatic subfield segmentation from magnetic resonance images make it possible to use these measures as phenotypes in large-scale genome-wide association studies. Such analyses are likely to rely largely on standard resolution (~1 mm isotropic) T1 -weighted images acquired on 3.0T scanners. Determining whether the genetic architecture of subfields can be detected from such images is therefore an important step. We used Freesurfer v6.0 to segment hippocampal subfields in two large twin studies, the Vietnam Era Twin Study of Aging and the Human Connectome Project. We estimated heritability of subfields and the genetic overlap with total hippocampal volume. Heritability was similar across samples, but little genetic variance remained after accounting for genetic influences on total hippocampal volume. Importantly, we examined genetic relationships between subfields to determine whether subfields can be grouped based on a smaller number of underlying, genetically independent factors. We identified three genetic factors in both samples, but the high degree of cross loadings precluded formation of genetically distinct groupings of subfields. These results confirm the reliability of Freesurfer v6.0 generated subfields across samples for phenotypic analyses. However, the current results suggest that it will be difficult for large-scale genetic analyses to identify subfield-specific genes that are distinct from both total hippocampal volume and other subfields using segmentations generated from standard resolution T1 -weighted images.
| S-EPMC6397064 | biostudies-literature
Project description:Specific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial factors in the development of neurodegenerative diseases. A systematic review on psychosocial factors and hippocampal subfield volumes was performed and showed inconsistent results, highlighting the need for future studies to explore this relationship. The current study aimed to explore the association of psychosocial factors with hippocampal (subfield) volumes, using high-field 7T MRI. Data were from the Memory Depression and Aging (Medea)-7T study, which included 333 participants without dementia. Hippocampal subfields were automatically segmented from T2-weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis [CA]1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent stressful life events, and social support), adjusted for age, sex, and intracranial volume. Neither depression nor anxiety was associated with specific hippocampal (subfield) volumes. A trend for lower total hippocampal volume was found in those reporting childhood maltreatment, and a trend for higher total hippocampal volume was found in those who experienced a recent stressful life event. Among subfields, low social support was associated with lower volume in the CA3 (B = -0.43, 95% CI: -0.72; -0.15). This study suggests possible differential effects among hippocampal (subfield) volumes and psychosocial factors.
| S-EPMC9980899 | biostudies-literature
Project description:Genetic and environmental influences on cortical thickness (CT) and surface area (SA) are thought to vary in a complex and dynamic way across the lifespan. It has been established that CT and SA are genetically distinct in older children, adolescents, and adults, and that heritability varies across cortical regions. Very little, however, is known about how genetic and environmental factors influence infant CT and SA. Using structural MRI, we performed the first assessment of genetic and environmental influences on normal variation of SA and CT in 360 twin neonates. We observed strong and significant additive genetic influences on total SA (a2 = 0.78) and small and nonsignificant genetic influences on average CT (a2 = 0.29). Moreover, we found significant genetic overlap (genetic correlation = 0.65) between these global cortical measures. Regionally, there were minimal genetic influences across the cortex for both CT and SA measures and no distinct patterns of genetic regionalization. Overall, outcomes from this study suggest a dynamic relationship between CT and SA during the neonatal period and provide novel insights into how genetic influences shape cortical structure during early development.
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Project description:The connectivity of the hippocampal trisynaptic circuit, formed by the dentate gyrus, the CA3 and the CA1 region, is well characterized anatomically and functionally in vitro. The functional connectivity of this circuit in vivo remains to be understood. Toward this goal, we investigated the influence of the spontaneous, synchronized oscillations in the neocortical local field potential, reflecting up-down states (UDS) of cortical neurons, on the hippocampus. We simultaneously measured the extracellular local field potential in association cortex and the membrane potential of identified hippocampal excitatory neurons in anesthetized mice. Dentate gyrus granule cells showed clear UDS modulation that was phase locked to cortical UDS with a short delay. In contrast, CA3 pyramidal neurons showed mixed UDS modulation, such that some cells were depolarized during the cortical up state and others were hyperpolarized. CA1 pyramidal neurons, located farther downstream, showed consistent UDS modulation, such that when the cortical and dentate gyrus neurons were depolarized, the CA1 pyramidal cells were hyperpolarized. These results demonstrate the differential functional connectivity between neocortex and hippocampal subfields during UDS oscillations.
| S-EPMC1829281 | biostudies-literature
Project description:The hippocampus has long been implicated in supporting autobiographical memories, but little is known about how they are instantiated in hippocampal subfields. Using high-resolution functional magnetic resonance imaging (fMRI) combined with multivoxel pattern analysis we found that it was possible to detect representations of specific autobiographical memories in individual hippocampal subfields. Moreover, while subfields in the anterior hippocampus contained information about both recent (2 weeks old) and remote (10 years old) autobiographical memories, posterior CA3 and DG only contained information about the remote memories. Thus, the hippocampal subfields are differentially involved in the representation of recent and remote autobiographical memories during vivid recall.
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Project description:Although previous studies have demonstrated that the hippocampus plays a role in pain processing, the role of hippocampal subfields is uncertain. The goal of this study was to examine the relationship between hippocampal subfield volumes and chronic pain in nondemented older adults. The study sample included 86 community-residing adults age 70 or older who were free of dementia and recruited from the Einstein Aging Study. Chronic pain was defined as pain over the last 3 months, that was moderate or severe (minimum rating of 4 out of 10) most, or all of the time. Hippocampal subfield volumes were estimated using FreeSurfer software. We modeled the association between chronic pain and hippocampal and subfield volume using linear regression. The sample had a mean age of 80 and was 58% female. Chronic pain, present in 55% of the sample, was associated with smaller right and total hippocampal volumes, particularly in women, after adjusting for age, education, and intracranial volume (eTICV). In addition, in women, volume was significantly reduced in participants with chronic pain in right CA2-3 (β=-0.35, p=0.010), right CA4-DG (β=-0.35, p=0.011), left presubiculum (β=-0.29, p=0.030), and left fimbria (β=-0.30, p=0.023). In men, chronic pain was not associated with the volume of any of the hippocampal subfield volumes. Chronic pain in women is associated with a reduction in the volume of right hippocampus and also selected hippocampal subfields. Future studies should clarify the mechanisms underlying the association between regional hippocampal volumes and chronic pain, particularly in women.
| S-EPMC4111097 | biostudies-literature