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Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1–5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.

The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.

Adolescence represents a critical period for the programming of future adult behaviours. Neurogenesis is particularly active during adolescence, with increased number of granule cells and increased hippocampal volume both in animals and humans. Among the factors which can affect neurogenesis during adolescence, stress is considered a major one. Indeed, adolescence is known to be a particularly stressful period in life, with some adolescents suffering from mood disorders and anxiety. While there is increasing interest on the neurogenic changes occurring during the adolescent period, evidence is sparse. We conducted a systematic review summarising changes in hippocampal neurogenesis, neuroplasticity and hippocampal-dependent cognitive functions and behavioural outcomes in stress-induced adolescent animal models of depression, and investigating long-term stress effects on the same outcomes assessing the same animals in adulthood. Overall, the results show a significant reduction in hippocampal cell proliferation, and a concomitant increase in depressive-like behaviours in adolescent animals exposed to stress challenges, however reduction in the number of surviving neurons was accompanied by no changes in both cognition and behaviour. Studies also observed altered neuroplasticity, including a stress-induced decrease in markers of pre- and post-synaptic plasticity, dendritic spine length and density, and long-term potentiation. These changes in neuroplasticity were accompanied by cognitive impairments and depressive-like behaviours. Overall, some of the negative effects observed during adolescence, especially on cell proliferation, neuroplasticity, cognition and behaviour either persisted or worsened during adulthood. Interestingly, treatment during adolescence with antidepressants, glutamate receptor inhibitors, glucocorticoid antagonists, or a healthy diet consisting of omega-3 fatty acids and vitamin A, were able to reverse or prevent these detrimental effects. Future research should aim to investigate the translational impact of these preclinical findings, developing novel tools for the measurement of hippocampal neurogenesis directly in depressed adolescents, and subsequently assessing neurogenic changes in response to stress as well as pharmacological and non-pharmacological interventions.

Emerging spatial technologies including spatial transcriptomics and spatial epigenomics are becoming powerful tools for profiling cellular states in the tissue context. However, current methods capture only one layer of omics information at a time precluding the possibility to examine the mechanistic relationship across the cental dogma of molecular biology. Here, we present two spatial multi-omics technologies for spatially resolved genome-wide joint mapping of epigenome and transcriptome by co-profiling chromatin accessibility and gene expression (spatial-ATAC-RNA-seq) or histone modification and gene expression (spatial-CUT&Tag-RNA-seq) on the same tissue section at a resolution near single cells. They were applied to embryonic and neonatal mouse brain as well as adult human brain to map how epigenetic states or modifications regulate cell type and dynamics in tissue. Although distinct tissue features were identified by either spatial epigenome or spatial transcriptome alone with high concordance, we observed their differential roles in defining cell states. In general, epigenetic state proceeds the development of transcriptional phenotype in relation to epigenetic lineage priming. We also observed high expression canonical markers such as PROX1 in the granular cell layer of the human hippocampus showed low chromatin accessibility that corresponded to a low level of RNA turnover rate, highlighting a divergent need for open chromatin or transcription to control cell identity and dynamics. Spatial epigenome-transcriptome co-profiling is a highly informative tool to study the mechanism of gene expression regulation in tissue and may enable a wide range of applications in life science and biomedical research.

Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness1–4. Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown. In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons. Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.

Infection with the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is associated with onset of neurological and psychiatric symptoms during and after the acute phase of illness1-4. Acute SARS-CoV-2 disease (COVID-19) presents with deficits of memory, attention, movement coordination, and mood. The mechanisms of these central nervous system symptoms remain largely unknown.In an established hamster model of intranasal infection with SARS-CoV-25, and patients deceased from COVID-19, we report a lack of viral neuroinvasion despite aberrant BBB permeability, microglial activation, and brain expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the inferior olivary nucleus of the medulla, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uremia or trauma. In the hippocampus dentate gyrus of both COVID-19 hamsters and humans, fewer cells expressed doublecortin, a marker of neuroblasts and immature neurons.Despite absence of viral neurotropism, we find SARS-CoV-2-induced inflammation, and hypoxia in humans, affect brain regions essential for fine motor function, learning, memory, and emotional responses, and result in loss of adult hippocampal neurogenesis. Neuroinflammation could affect cognition and behaviour via disruption of brain vasculature integrity, neurotransmission, and neurogenesis, acute effects that may persist in COVID-19 survivors with long-COVID symptoms.

Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.

Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context1. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping2–5, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry6 and microfluidic deterministic barcoding5. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.

BACKGROUND: Early life adversity (ELA) increases major depressive disorder (MDD) and suicide risk and potentially affects dentate gyrus (DG) plasticity. We reported smaller DG and fewer granular neurons (GNs) in MDD. ELA effects on DG plasticity in suicide decedents with MDD (MDDSui) and resilient subjects (ELA history without MDD or suicide) are unknown. METHODS: We quantified neural progenitor cells (NPCs), GNs, glia, and DG volume in whole hippocampus postmortem in four groups of drug-free, neuropathology-free subjects (N = 52 total): psychological autopsy-defined MDDSui and control subjects with and without ELA (before 15 years of age). RESULTS: ELA was associated with larger DG (p < .0001) and trending fewer NPCs (p = .0190) only in control subjects in whole DG, showing no effect on NPCs and DG volume in MDDSui. ELA exposure was associated with more GNs (p = .0003) and a trend for more glia (p = .0160) in whole DG in MDDSui and control subjects. MDDSui without ELA had fewer anterior and mid DG GNs (p < .0001), fewer anterior DG NPCs (p < .0001), and smaller whole DG volume (p = .0005) compared with control subjects without ELA. In MDDSui, lower Global Assessment Scale score correlated with fewer GNs and smaller DG. CONCLUSIONS: Resilience to ELA involves a larger DG, perhaps related to more neurogenesis depleting NPCs, and because mature GNs and glia numbers do not differ in the resilient group, perhaps there are effects on process extension and synaptic load that can be examined in future studies. In MDDSui without ELA, smaller DG volume, with fewer GNs and NPCs, suggests less neurogenesis and/or more apoptosis and dendrite changes.

Adult hippocampal neurogenesis is implicated in antidepressant action in rodents and primates, yet relationships to human major depression (MDD) and antidepressant effects are unclear. In postmortem human hippocampus, we found doublecortin (DCX) protein and mRNA+ cells co-expressing neuronal but not astroglial or microglial markers. We defined neuroblasts as DCX+ cells located in the subgranular zone that co-expressed neuron-specific beta-tubulin (TUJ1) or lacked co-expression with neuronal nuclear marker (NeuN). Untreated MDD, regardless of clinical state, had fewer DCX-positive cells and neuroblasts in the rostral dentate gyrus compared with non-psychiatric controls. High-functioning, but not low-functioning, antidepressant-treated MDD, exhibited more DCX/TUJ1+ neuroblasts than untreated MDD. Groups did not differ in number of immature neurons, defined as DCX/NeuN+ cells in the inner granule cell layer. Deficient neuroblasts may be linked to hippocampal-dependent cognitive deficits in MDD. Similar neuroblast number between controls and higher-functioning antidepressant treated subjects warrants evaluation of neuroblasts as a treatment target.

The association of aggression and impulsivity with suicidal behavior (SB) in depression may vary across countries. This study aimed (i) to compare aggression and impulsivity levels, measured with the Brown-Goodwin Scale (BGS) and the Barratt Impulsivity Scale (BIS), respectively, between New York City (NYC) (US), Madrid (Spain) and Florence (Italy) (ANOVA); and (ii) to investigate between-site differences in the association of aggression and impulsivity with previous SB (binary logistic regression). Aggression scores were higher in NYC, followed by Florence and Madrid. Impulsivity levels were higher in Florence than in Madrid or NYC. Aggression and impulsivity scores were higher in suicide attempters than in non-attempters in NYC and in Madrid. SB was associated with aggression in NYC (OR 1.12, 95% CI 1.07–1.16; p < 0.001) and in Florence (OR 1.11, 95% CI 1.01–1.22; p = 0.032). Impulsivity was linked with SB in NYC (OR 1.01, 95% CI 1.00–1.02; p < 0.001) and in Madrid (OR 1.03, 95% CI 1.02–1.05; p < 0.001). The higher suicide rates in NYC, compared to Madrid or Florence, may be, in part, explained by these cross-cultural differences in the contribution of aggression-impulsivity to SB, which should be considered by future research on SB prevention.

SUMMARY Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner., Graphical Abstract, In Brief Besnard et al. show that chronic stress induces a transient elevation in hippocampal Klf9 expression in mice and that KLF9 expression is upregulated in hippocampus of women with MDD. Genetic silencing of Klf9 expression prevents chronic stress-induced enlargements of dendritic spines and maladaptive fear responses in male and female mice.

Structural neuroimaging studies revealed a consistent pattern of volumetric reductions in both hippocampus (HC) and anterior cingulate cortex (ACC) of individuals with major depressive episode(s) (MDE). This study investigated HC and ACC volume differences in currently depressed individuals (n = 150), individuals with a past lifetime MDE history (n = 79) and healthy controls (n = 287).Non-demented individuals were recruited from a cohort of community-dwelling older adults (ESPRIT study). T1-weighted magnetic resonance images and FreeSurfer Software (automated method) were used. Concerning HC, a manual method of measurement dividing HC into head, body, and tail was also used. General Linear Model was applied adjusting for covariates.Current depression was associated with lower left posterior HC volume, using manual measurement, in comparison to healthy status. However, when we slightly changed sub-group inclusion criteria, results did not survive to correction for multiple comparisons.The finding of lower left posterior HC volume in currently depressed individuals but not in those with a past MDE compared to healthy controls could be related to brain neuroplasticity. Additionally, our results may suggest manual measures to be more sensitive than automated methods.

Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human-specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience.

In the current work, we conducted an immunocytochemical search for markers of ongoing neurogenesis (e.g. nestin) in auditory cortex from postmortem sections of autism spectrum disorder (ASD) and age-matched control donors. We found nestin labeling in cells of the vascular system, indicating blood vessels plasticity. Evidence of angiogenesis was seen throughout superior temporal cortex (primary auditory cortex), fusiform cortex (face recognition center), pons/midbrain and cerebellum in postmortem brains from ASD patients but not control brains. We found significant increases in both nestin and CD34, which are markers of angiogenesis localized to pericyte cells and endothelial cells, respectively. This labeling profile is indicative of splitting (intussusceptive), rather than sprouting, angiogenesis indicating the blood vessels are in constant flux rather than continually expanding.

BACKGROUND: Positron Emission Tomography (PET) studies in Major Depressive Disorder (MDD) have reported higher serotonin 1A (5-HT(1A)) autoreceptor binding in the raphe. In males, the difference is so large that it can potentially be used as the first biological marker for MDD. However, the raphe includes several nuclei, which project to different regions of the brain and spinal cord and may be differentially involved in disease. We aimed to identify 5-HT(1A) differences in individual raphe nuclei using PET in order to determine whether use of subnuclei would provide greater sensitivity and specificity of diagnosing MDD. METHODS: We identified individual nuclei using a hybrid set-level technique on an average [(11)C]-WAY100635 PET image derived from 52 healthy volunteers (HV). We delineated three nuclei: dorsal raphe nucleus (DRN), median raphe nucleus (MRN), and raphe magnus (RMg). An atlas image of these nuclei was created and nonlinearly warped to each subject (through an associated MRI) in a separate sample of 41 males (25 HV, 16 MDD) who underwent [(11)C]-WAY100635 PET. RESULTS: 5-HT(1A) binding was elevated in DRN in MDD (p

Background Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems.

Adult hippocampal neurogenesis is critically implicated in rodent models of stress and anxiety as well as behavioral effects of antidepressants. Whereas similar factors such as psychiatric disorder and antidepressant administration are correlated with hippocampal volume in humans, the relationship between these factors and adult neurogenesis is less well understood. To better bridge the gap between rodent and human physiology, we examined the numbers of proliferating neural precursors and immature cells in the hippocampal dentate gyrus (DG) as well as in vivo magnetic resonance imaging (MRI)-estimated whole hippocampal volume in eight socially dominant- or subordinate-like (SL) baboons administered the antidepressant fluoxetine or vehicle. SL baboons had lower numbers of proliferating cells and immature neurons than socially dominant-like baboons. Fluoxetine treatment was associated with a larger whole hippocampal volume but surprisingly resulted in lower numbers of immature neurons. These findings are the first to indicate that adult neurogenesis in the baboon hippocampal DG may be functionally relevant in the context of social stress and mechanisms of antidepressant action.

Background Vascular depression is regarded as a subtype of late-life depression characterized by a distinct clinical presentation and an association with cerebrovascular damage. Although the term is commonly used in research settings, widely accepted diagnostic criteria are lacking and vascular depression is absent from formal psychiatric manuals such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition – a fact that limits its use in clinical settings. Magnetic resonance imaging (MRI) techniques, showing a variety of cerebrovascular lesions, including extensive white matter hyperintensities, subcortical microvascular lesions, lacunes, and microinfarcts, in patients with late life depression, led to the introduction of the term “MRI-defined vascular depression”. Discussion This diagnosis, based on clinical and MRI findings, suggests that vascular lesions lead to depression by disruption of frontal–subcortical–limbic networks involved in mood regulation. However, despite multiple MRI approaches to shed light on the spatiotemporal structural changes associated with late life depression, the causal relationship between brain changes, related lesions, and late life depression remains controversial. While postmortem studies of elderly persons who died from suicide revealed lacunes, small vessel, and Alzheimer-related pathologies, recent autopsy data challenged the role of these lesions in the pathogenesis of vascular depression. Current data propose that the vascular depression connotation should be reserved for depressed older patients with vascular pathology and evident cerebral involvement. Based on current knowledge, the correlations between intra vitam neuroimaging findings and their postmortem validity as well as the role of peripheral markers of vascular disease in late life depression are discussed. Conclusion The multifold pathogenesis of vascular depression as a possible subtype of late life depression needs further elucidation. There is a need for correlative clinical, intra vitam structural and functional MRI as well as postmortem MRI and neuropathological studies in order to confirm the relationship between clinical symptomatology and changes in specific brain regions related to depression. To elucidate the causal relationship between regional vascular brain changes and vascular depression, animal models could be helpful. Current treatment options include a combination of vasoactive drugs and antidepressants, but the outcomes are still unsatisfying.

Background Adult neurogenesis is coupled to angiogenesis in neurogenic niches in the dentate gyrus (DG) and increased by antidepressants in rodents. We hypothesized that, in major depressive disorder (MDD), antidepressants increase neural progenitor cells (NPCs) and capillaries in the human DG. Methods Neural progenitor cells and capillaries, detected on hippocampal sections by immunohistochemistry for neural stem cell protein, were quantified by stereology in matched MDDs (untreated, n = 12), MDD treated with selective serotonin reuptake inhibitors (MDD*SSRI, n = 6) or tricyclic antidepressants (MDD*TCA, n = 6), and nonpsychiatric control subjects ( n = 12), all confirmed by psychological autopsy. Results The MDD*SSRI had a larger capillary area and more NPCs versus MDDs ( p = .034 and p = .008, respectively) and control subjects ( p = .010 and p = .002, respectively) in the whole DG, more NPCs in the anterior ( pes , p = .042) and central (midbody, p = .004) DG, and greater capillary area in the pes ( p = .002) and midbody ( p = .021). The NPC number and capillary area correlated positively in the whole sample ( R 2 = .454, p R 2 = .749, p = .001). We found no NPCs or antidepressant-related angiogenesis in CA1 and parahippocampal gyrus. The DG volume correlated positively with NPC number ( p = .004) and capillary area ( p .001) and differed between groups in whole hippocampus ( p = .013) and midbody ( p = .036). Age negatively correlated with NPC number ( p = .042), capillary area ( p = .037), and bifurcations ( p = .030). No gender effect was detected. Conclusions Antidepressants increase human hippocampal NPCs and angiogenesis selectively in the anterior and mid DG. These results raise the possibility of a causal relationship between angiogenesis and neurogenesis, as seen in other proliferating tissues, and support their possible role in the mechanism of action of antidepressants.

Resumen La disfuncion serotoninergica esta presente en los trastornos del humor y el suicidio. Los autorreceptores somatodrendriticos 5-HT 1A del tronco cerebral regulan la descarga de neuronas serotoninergicas, pero los estudios efectuados sobre la union a los autorreceptores en el nucleo dorsal del rafe (NDR) en muestras de tejidos obtenidas en victimas de suicidio deprimidas describen resultados conflictivos. Tratamos de determinar: 1) la distribucion anatomica de la union al receptor 5-HT 1A en el NDR de muestras de tejidos obtenidas de victimas deprimidas de suicidio y de individuos de control sanos, desde un punto de vista psiquiatrico, fallecidos por causas naturales, y 2) si las diferencias de sexo en la union a 5-HT 1A en el NDR contribuyen a las diferencias observadas en las muestras entre victimas deprimidas de suicidio y los de control. Se analizaron las autorradiografias cuantitativas del receptor de [ 3 H]8-hidroxi-2-(di- n -propil) aminotetralina ([ 3 H]8-OH-DPAT) en las secciones de tejido post mortem, obtenidas previamente, que contenian el NDR de victimas de suicidio libres de farmacos/drogas (n=10) y de controles emparejados (n=10). En el NDR integro de los suicidas deprimidos, comparado con los controles, se observo una menor union total al receptor (fmol/mg de tejido×mm 3 ) (p 1A (fmol/mg de tejido) y la union al receptor (fmol/mg×mm 3 , p 1A fue mayor rostralmente y menor, caudalmente. Las diferencias entre suicidas deprimidos y controles estuvieron presentes en hombres y mujeres, aunque en estas se detecto una mayor union que en hombres. La menor union al autorreceptor en NDR de suicidas deprimidos podria representar una respuesta homeostatica a una menor liberacion de serotonina, con un incremento de la descarga de las neuronas serotoninergicas. La mayor union al autorreceptor en el NDR rostral podria contribuir a una liberacion deficiente de serotonina en la corteza prefrontal ventromedial mediante una menor descarga neuronal.

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase neurogenesis in the dentate gyrus (DG) of rodents and nonhuman primates. We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD). Whole frozen hippocampi from untreated subjects with MDD (N = 5), antidepressant-treated MDD (MDDT, N = 7), and controls (C, N = 7) were fixed, sectioned and immunostained for NPCs and dividing cell markers (nestin and Ki-67 respectively), NeuN and GFAP, in single and double labeling. NPC and dividing cell numbers in the DG were estimated by stereology. Clinical data were obtained by psychological autopsy and toxicological and neuropathological examination performed in all subjects. NPCs decreased with age (p = 0.034). Females had more NPCs than males (p = 0.023). Correcting for age and sex, MDDT receiving SSRIs had more NPCs than untreated MDD (p ≤ 0.001) and controls (p ≤ 0.001), NPCs were not different in SSRIs- and TCAs-treated MDDT (p = 0.169). Dividing cell number, unaffected by age or sex, was greater in MDDT receiving TCAs than in untreated MDD (p ≤ 0.001), SSRI-treated MDD (p = 0.001) and controls (p ≤ 0.001). The NPCs and dividing cells increase in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls (p = 0.009). Antidepressants increase neural progenitor cell number in the anterior human dentate gyrus. Whether this finding is critical or necessary for the antidepressants effect remains to be determined.

Serotonergic dysfunction is present in mood disorders and suicide. Brainstem 5-HT1A somatodendritic autoreceptors regulate serotonin neuron firing but studies of autoreceptor binding in the dorsal raphe nucleus (DRN) in depressed suicides report conflicting results. We sought to determine: (1) the anatomical distribution of 5-HT1A receptor binding in the DRN in depressed suicides and psychiatrically normal controls; and (2) whether sex differences in 5-HT1A binding in the DRN contribute to differences between depressed suicides and controls. Previously collected quantitative receptor autoradiograms of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (3H-8-OH-DPAT) in postmortem tissue sections containing the DRN from drug-free suicide victims (n = 10) and matched controls (n = 10) were analyzed. Less total receptor binding (fmol/mg tissue × mm3) was observed in the entire DRN in depressed suicides compared with controls (p < 0.05). Group differences along the rostrocaudal extent of the DRN were observed for cross-sectional 5-HT1A binding (fmol/mg tissue) and receptor binding (fmol/mg × mm3, p < 0.05). Cross-sectional 5-HT1A DRN binding in depressed suicides compared with controls was higher rostrally and lower caudally. The differences between depressed suicides and controls were present in males and females, although females had more binding than males. Less autoreceptor binding in the DRN of depressed suicides may represent a homeostatic response to less serotonin release, increasing serotonin neuron firing. More autoreceptor binding in rostral DRN might contribute to deficient serotonin release in ventromedial prefrontal cortex by lower neuronal firing.

Deficient serotonin neurotransmission in suicide is indicated by reduced brainstem serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), fewer 5-HT(1A) autoreceptors and reduced cortical serotonin transporter binding in suicide victims. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-HT, and alterations in TPH could explain some of these findings. We sought to determine the amount of TPH immunoreactivity (TPH-IR) in the dorsal (DRN) and median (MRN) raphe nuclei in suicides and controls. Brainstems of suicide victims and controls (n = 11 pairs) were collected at autopsy, matched for age, sex and postmortem interval, frozen and sectioned (20 microm). Immunoautoradiography, using an antibody to label TPH, was performed, slides exposed to film and autoradiograms quantified by a computer-based image analysis system. We examined sections every 1000 microm throughout the whole length of the nucleus, performing statistical analysis only on those subjects for whom the raphe was complete (n = 8 pairs). TPH-IR (microCi/g) was higher in suicides than controls (S: 300.8 +/- 70.8 vs. C: 259.6 +/- 40.7, t = 2.57, df = 7, P = 0.04) in the dorsal raphe nucleus (DRN), and not different between suicides and controls (S: 251.3 +/- 44.2 vs. C: 235.9 +/- 27.4, t = 1.49, df = 7, P = 0.18) in the MRN. DRN TPH-IR was higher in male suicide victims (MS) compared to male controls (MC; MS: 318.4 +/- 54.4 vs. MC: 271.9 +/- 22.5, t = 2.66, df = 6, P = 0.03). The analysis of TPH-IR area and density at each DRN rostrocaudal levels showed higher area and density in suicides compared to controls in the rostral DRN and lower area and density in the caudal DRN. TPH-IR, an index of the amount of TPH enzyme, in the DRN is higher in depressed suicides. More TPH may be an upregulatory homeostatic response to impaired serotonin release or less autoreceptor activation. Alternatively, the serotonin impairment in suicide may be due to hypofunctional serotonin-synthesizing enzyme.

Objective Visual-spatial and executive functions deficits have been reported in obsessive-compulsive disorder (OCD). We investigated their specificity comparing cognitive function in OCD, panic disorder with agoraphobia (PD/A) and controls by a comprehensive neuropsychological battery. Method Fifty-five subjects (25 OCD, 15 PD/A, 15 controls) without current depressive episode underwent structured clinical interview for DSM-IV, Yale-Brown Obsessive Compulsive Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale. Neuropsychological battery assessed: executive functions, visual discrimination, spatial memory and learning, verbal memory, general intellectual functioning. Results OCD showed controlled fluency, visual-spatial construction, learning and memory deficits; PD/A spatial learning impairment. OCD was discriminated from PD/A and controls by three tests scores, predicting group membership for 76.4% of the cases. Conclusion Visual-constructive and controlled fluency deficits seem specific in OCD, while the spatial learning deficit, shared with PD patients, may not be disorder-specific, but anxiety-related. Results support the proposed ventral frontal-striatal circuit involvement in OCD.

Various studies have evaluated the possible role of the −1438 G/A polymorphism within the 5-HT2A receptor gene in the susceptibility to Eating Disorders (EDs). One hundred and forty-eight ED patients (EDp) and 89 control subjects were interviewed by means of the Eating Disorder Examination (EDE) and analyzed for distribution of the −1438 G/A polymorphism. Patients with the AA genotype suffering from Anorexia Nervosa and Bulimia Nervosa showed higher Weight and Shape Concern (P=0.003 and P=0.010, respectively) scores and greater overall severity of the ED psychopathology (EDE total score) (P=0.012). The obtained preliminary data suggest the use of dimensional psychopathological measures in ED genetic studies.

Objective To evaluate health-related quality of life (HRQOL) in patients with systemic sclerosis (SSc) using the Short Form 36 (SF-36) and to correlate SF-36 scores with clinical and biologic markers. Methods The SF-36 was administered to 24 controls and 24 SSc patients. SSc patients also were evaluated for subset (limited SSc [lSSc] and diffuse SSc [dSSc]), age, disease duration, angiotensin-converting enzyme (ACE) levels, autoantibodies, and skin and internal organ involvement. Results The physical summary score (PSS) was lower in SSc patients than in controls (P < 0.05), whereas the mental summary score (MSS) was higher in dSSc than in lSSc patients (P < 0.05). Five of 8 single SF-36 domain scores were lower in SSc patients than in controls (P < 0.05). Vitality was higher in dSSc than in controls (P < 0.001). In SSc, elder age correlated with lower PSS; low ACE levels and high skin score correlated with higher general mental health and role limitations due to physical problems, respectively (P < 0.05). Patients with heart involvement had higher scores in general health perceptions (P < 0.05). Conclusion The SF-36 shows that HRQOL is impaired in patients with SSc. Higher scores in MSS and vitality in patients with dSSc and correlations of high SF-36 scores with specific organ involvement suggest that SSc patients with severe disease are more able to cope with HRQOL modification.

It has been suggested that preexisting thyroid disease (TD) could be a risk factor for the development of eating disorders. The aim of this study was to compare eating attitudes and behavior in female obese patients with and without TD. Thyrotropin (TSH) was determined in 256 patients aged 44.9+/-14.7 years with body mass index (BMI) >30 kg/m(2); eating attitudes and behavior were assessed with the Eating Disorder Examination (EDE). EDE Shape Concern score was significantly higher in patients with previous or current hypothyroidism (N=30) than in the rest of the sample. Among patients without known TD, no difference in eating attitudes was observed between patients with elevated TSH (N=24; 11%) and those with normal thyroid function. The prevalence of binge eating disorder (BED) in the total sample was 9.7%; no difference in prevalence was observed between patients with and without a history of hypothyroidism, and between those with and without previously unknown hypothyroidism. In conclusion, known hypothyroidism is associated with increased shape concern; this does not appear to be related to differences in current levels of thyroid hormones or related hormones.

Background: Eating disorders are frequent among elite performers of certain sports or physical activities; however, little is known about non-professional performers. Method: 113 female non-elite ballet dancers, 54 female gymnasium users, 44 male non-competitive body builders, 105 female controls and 30 male controls were evaluated using the Body Uneasiness Test, the State-Trait Anxiety Inventory, the Beck Depression Inventory, and the Eating Disorder Examination 12th edition (EDE-12). Results: Non-elite ballet dancers reported the highest prevalence of eating disorders (anorexia nervosa 1.8%; bulimia nervosa 2.7%; eating disorders not otherwise specified 22.1%), followed by gymnasium users (anorexia nervosa 2.6%; eating disorders not otherwise specified 18%). Significant differences (p < 0.01) between athletes and their controls were found in the following parameters (median values): Beck Depression Inventory (female dancers 5.7, gymnasium users 6.1, female controls 2.8, body builders 1.6, and male controls 1.3), Body Uneasiness Test (female dancers 1.08, gymnasium users 0.62, female controls 0.54, body builders 0.35, and male controls 0.27), EDE total scores (female dancers 1.6, gymnasium users 1.7, female controls 1.0, body builders 1.0, and male controls 0.4), EDE – restraint subscale scores (female dancers 0.8, gymnasium users 1.6, female controls 0.0, body builders 0.8, and male controls 0.0), EDE – eating concern subscale scores (female dancers 0.4, gymnasium users 0.2, female controls 0.0, body builders 0.0, and male controls 0.0), EDE – weight concern subscale scores (female dancers 2.1, gymnasium users 2.1, female controls 1.6, body builders 1.4, and male controls 0.5), and EDE – shape concern subscale scores (female dancers 2.7, gymnasium users 2.8, female controls 2.0, body builders 2.1, and male controls 0.9). EDE scores were highly related to Body Uneasiness Test scores, especially in non-elite ballet dancers and in non-competitive body builders (p < 0.01). Conclusion: Non-professional performers of sports emphasising thinness or muscularity, such as ballet and body-building, show a high degree of body uneasiness and inappropriate eating attitudes and behaviours.

Modest antidepressant response rates of mood disorders (MD) encourage benzodiazepine (BZD) co-medication with debatable benefit. Adult hippocampal neurogenesis may underlie antidepressant responses, but diazepam co-administration impairs murine neuron maturation and survival in response to fluoxetine. We counted neural progenitor cells (NPCs), mitotic cells, and mature granule neurons post-mortem in dentate gyrus (DG) from subjects with: untreated Diagnostic and Statistical Manual of Mental Disorders (DSM) IV MD (n = 17); antidepressant-treated MD (MD*ADT, n = 10); benzodiazepine-antidepressant-treated MD (MD*ADT*BZD, n = 7); no psychopathology or treatment (controls, n = 18). MD*ADT*BZD had fewer granule neurons vs. MD*ADT in anterior DG and vs. controls in mid DG, and did not differ from untreated-MD in any DG subregion. MD*ADT had more granule neurons than untreated-MD in anterior and mid DG and comparable granule neuron number to controls in all dentate subregions. Untreated-MD had fewer granule neurons than controls in anterior and mid DG, and did not differ from any other group in posterior DG. MD*ADT*BZD had fewer NPCs vs. MD*ADT in mid DG. MD*ADT had more NPCs vs. untreated-MD and controls in anterior and mid DG. MD*ADT*BZD and MD*ADT had more mitotic cells in anterior DG vs. controls and untreated-MD. There were no between-group differences in mid DG in mitotic cells or in posterior DG for any cell type. Our results in mid-dentate, and to some degree anterior dentate, gyrus are consistent with murine findings that benzodiazepines counteract antidepressant-induced increases in neurogenesis by interfering with progenitor proliferation. We also confirmed, in this expanded sample, our previous finding of granule neuron deficit in untreated MD.

The great revolution that took place in physics at the beginning of this century, which led to a total reshaping of the science and a different approach to natural phenomena, could serve as a model for future developments in other disciplines such as neuroscience. When investigated by traditional methods, the complexity of brain mechanisms remains quite elusive; the use of new strategies should, therefore, be a high priority.Although holistic interpretations of brain functions and dysfunctions still seem futuristic, the application of chaos theories may be one way of making these interpretations more understandable. In fact, chaos mathematics can be applied to brain activity, such as that recorded, by electroencephalogram (EEG), and to the interpretation of psychopathology. Similarly, clinical phenomena could be explained in terms of nonlinear dynamics. Moreover, the application of chaos theories to psychiatry might permit the study of the relationships between genetic and environmental factors in determining syndromes and symptoms. This could encourage the development of a nonlinear dynamic psychiatry which, in turn, would allow a better understanding of research findings and, perhaps, open new horizons to psychiatric intervention.

The neuropsychological performance of 19 unmedicated patients with panic disorder (PD) was compared with 15 age- and education-matched control subjects. The test results indicate a selective pattern of neuropsychological dysfunctions in patients with PD, suggestive of an involvement of the right frontal and temporoparietal brain areas.

Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 μm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p

The G/C single-nucleotide polymorphism in the serotonin 1a receptor promoter, rs6295, has previously been linked with depression, suicide and antidepressant responsiveness. In vitro studies suggest that rs6295 may have functional effects on the expression of the serotonin 1a receptor gene (HTR1A) through altered binding of a number of transcription factors. To further explore the relationship between rs6295, mental illness and gene expression, we performed dual epidemiological and biological studies. First, we genotyped a cohort of 1412 individuals, randomly split into discovery and replication cohorts, to examine the relationship between rs6295 and five psychiatric outcomes: history of psychiatric hospitalization, history of suicide attempts, history of substance or alcohol abuse, current posttraumatic stress disorder (PTSD), current depression. We found that the rs6295G allele is associated with increased risk for substance abuse, psychiatric hospitalization and suicide attempts. Overall, exposure to either childhood or non-childhood trauma resulted in increased risk for all psychiatric outcomes, but we did not observe a significant interaction between rs6295 and trauma in modulating psychiatric outcomes. In conjunction, we also investigated the potential impact of rs6295 on HTR1A expression in postmortem human brain tissue using relative allelic expression assays. We found more mRNA produced from the C versus the G-allele of rs6295 in the prefrontal cortex (PFC), but not in the midbrain of nonpsychiatric control subjects. Further, in the fetal cortex, rs6295C allele exhibited increased relative expression as early as gestational week 18 in humans. Finally, we found that the C:G allelic expression ratio was significantly neutralized in the PFC of subjects with major depressive disorder (MDD) who committed suicide as compared with controls, indicating that normal patterns of transcription may be disrupted in MDD/suicide. These data provide a putative biological mechanism underlying the association between rs6295, trauma and mental illness. Moreover, our results suggest that rs6295 may affect transcription during both gestational development and adulthood in a region-specific manner, acting as a risk factor for psychiatric illness. These findings provide a critical framework for conceptualizing the effects of a common functional genetic variant, trauma exposure and their impact on mental health.

New neurons are generated in the granule cell layer of the dentate gyrus (DG) of the hippocampus in adult humans (Eriksson et al, 1998). Our knowledge of adult neurogenesis in humans is quite limited and it could differ from adult neurogenesis in lower mammals. In rodents, neurogenesis is necessary for learning, and some antidepressant effects are lost in the absence of adult neurogenesis, which increases with environmental enrichment and exercise (Olson et al, 2006), as well as with antidepressant treatment (Couillard-Despres et al, 2009). We reported (Boldrini et al, 2009) that selective serotonin reuptake inhibitors and tricyclic antidepressants increase dividing and neural progenitor cells (NPCs) in the DG of depressed subjects (MDD), compared with untreated MDD patients or controls. In humans, antidepressants increase the number of mitotic cells of all phenotypes in the DG, regardless of age. On the other hand, replication of NPCs, as in lower mammals, decreases with age (Couillard-Despres et al, 2009). This might explain why there is a poor antidepressant response in the elderly. The functional relevance of the enhancement of neurogenesis by antidepressants needs to be ascertained by determining whether increased cell proliferation is associated with improvement of symptoms in MDD. In our study (Boldrini et al, 2009), a significant proportion of subjects died by suicide, which would argue against the benefits of antidepressant-induced cell proliferation, as opposed to the potential benefits of cell maturation, survival, and integration into functional neural networks, which should have a greater role in the potential beneficial impact of adult neurogenesis. Exposure to enriched environments, learning, and neurotrophins improve the survival and differentiation of newborn cells. Factors regulating cell survival and integration should be considered when examining the role of adult neurogenesis for antidepressant efficacy. Another open question is the role of neurogenesis in the pathogenesis of MDD. Adult neurogenesis decreases with stress in rodents and is enhanced by environmental enrichment, exercise, and antidepressants. However, blunted cell replication alone does not induce depression-like behavior in mice. Growth factors, which affect neurogenesis, are decreased in MDD. Therefore, impaired hippocampal plasticity may be involved in the pathogenesis of MDD, not merely because of impaired cell replication but also because of impaired cell connectivity and functional integration into brain circuits that regulate emotional responses to the environment. In our study, the antidepressant-induced increase in NPCs and dividing cells was associated with a larger volume of DG. Antidepressant treatment is known to increase hippocampal volume in posttraumatic stress disorder (Bossini et al, 2007), but no similar data are available in depression, although patients with MDD have a smaller hippocampus. The volume increase could be related to a restoration of cell number or neuropil, as antidepressants reverse dendritic shrinkage and improve cell survival, activating the antiapoptotic protein Bcl-2 and brain-derived neurotrophic factor expression in mammals. Future studies must determine whether antidepressant response is linked to increased neurogenesis, but assessing adult neurogenesis in vivo is challenging. In a recent study, magnetic resonance spectroscopy was proposed as a possible method, but the specificity of the molecule used to identify NPCs was questioned and the results have not been replicated. Positron emission tomography has the limitation of low resolution and the unknown consequences of radiolabeling newborn cells. Cerebral blood volume, which correlates with angiogenesis, may prove to be a viable method for detecting neurogenesis in vivo (Pereira et al, 2007). Linking neurogenesis to improvement in depression symptomatology would justify seeking new treatments that increase not only neurogenesis but also plasticity, cell survival, and integration into functional networks.