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Background: Schizophrenia is a severe neuropsychiatric disorder characterized by altered perception, mood, and behavior that profoundly impacts patients and society despite its relatively low prevalence. Sex-based differences have been described in schizophrenia epidemiology, symptomatology and outcomes. Different studies explored the impact of schizophrenia in the brain transcriptome, however we lack a consensus transcriptomic profile that considers sex and differentiates specific cerebral regions. Methods: We performed a systematic review on bulk RNA-sequencing studies of post-mortem brain samples. Then, we fulfilled differential expression analysis on each study and summarized their results with regions-specific meta-analyses (prefrontal cortex and hippocampus) and a global all-studies meta-analysis. Finally, we used the consensus transcriptomic profiles to functionally characterize the impact of schizophrenia in males and females by protein-protein interaction networks, enriched biological processes and dysregulated transcription factors. Results: We discovered the sex-based dysregulation of 265 genes in the prefrontal cortex, 1.414 genes in the hippocampus and 66 genes in the all-studies meta-analyses. The functional characterization of these gene sets unveiled increased processes related to immune response functions in the prefrontal cortex in male and the hippocampus in female schizophrenia patients and the overexpression of genes related to neurotransmission and synapses in the prefrontal cortex of female schizophrenia patients. Considering a meta-analysis of all brain regions available, we encountered the relative overexpression of genes related to synaptic plasticity and transmission in females and the overexpression of genes involved in organizing genetic information and protein folding in male schizophrenia patients. The protein-protein interaction networks and transcription factors activity analyses supported these sex-based profiles. Conclusions: Our results report multiple sex-based transcriptomic alterations in specific brain regions of schizophrenia patients, which provides new insight into the role of sex in schizophrenia. Moreover, we unveil a partial overlapping of inflammatory processes in the prefrontal cortex of males and the hippocampus of females. Plain language summary: Schizophrenia is a serious illness characterised by changes in perception, mood and behaviour that profoundly affect patients and society. The frequency, symptoms and progression of schizophrenia are different in women and men, but the biological reason for this is not understood. The identification of disease mechanisms specific in men and women, is relevant because it would allow a better understanding of this pathology, as well as improving the personalisation of diagnoses and treatments for patients. To achieve this goal, in this work we reviewed all available RNA sequencing studies of post-mortem brain samples from women and men affected by schizophrenia. Then, we compared gene expression in each study by sex, and integrated all study results in different brain regions: prefrontal cortex, hippocampus and all-studies. We discovered significant changes between men and women: 265 genes differentially expressed in the prefrontal cortex, 1414 genes in the hippocampus and 66 genes in meta-analyses of all-studies. The study of these genes revealed increased immune response functions in the prefrontal cortex of men and in the hippocampus of women with schizophrenia, as well as increased neurotransmission and synapses in the prefrontal cortex of women with schizophrenia. Our results report multiple gene expression changes in specific brain regions of patients with schizophrenia, providing new insights into the role of sex in schizophrenia. Highlights: • The expression of 265 genes is altered in the prefrontal cortex of schizophrenic patients, being overexpressed in females those related to synaptic transmission. • In the prefrontal cortex of males, overexpressed genes and overactivated transcription factors are linked to immune response and inflammation. • Conversely, genes and transcription factors more activated in the hippocampus of females are related to immune response, whereas those genes more expressed in males are linked to protein processing. • The global meta-analysis unveils groups of long non-coding genes and pseudogenes differentially expressed in males and females. • The effects of schizophrenia are closely related in the prefrontal cortex of males and the hippocampus of females. [ABSTRACT FROM AUTHOR]

Perineuronal nets (PNNs) are specialized structures of the extracellular matrix that surround the soma and proximal dendrites of certain neurons in the central nervous system, particularly parvalbumin-expressing interneurons. Their appearance overlaps the maturation of neuronal circuits and the closure of critical periods in different regions of the brain, setting their connectivity and abruptly reducing their plasticity. As a consequence, the digestion of PNNs, as well as the removal or manipulation of their components, leads to a boost in this plasticity and can play a key role in the functional recovery from different insults and in the etiopathology of certain neurologic and psychiatric disorders. Here we review the structure, composition, and distribution of PNNs and their variation throughout the evolutive scale. We also discuss methodological approaches to study these structures. The function of PNNs during neurodevelopment and adulthood is discussed, as well as the influence of intrinsic and extrinsic factors on these specialized regions of the extracellular matrix. Finally, we review current data on alterations in PNNs described in diseases of the central nervous system (CNS), focusing on psychiatric disorders. Together, all the data available point to the PNNs as a promising target to understand the physiology and pathologic conditions of the CNS. [ABSTRACT FROM AUTHOR]

The progressive aging of the population will notably increase the burden of those diseases which leads to a disabling situation, such as Alzheimer's disease (AD) and ophthalmological diseases that cause a visual impairment (VI). Eye diseases that cause a VI raise neuroplastic processes in the parietal lobe. Meanwhile, the aforementioned lobe suffers a severe decline throughout AD. From this perspective, diving deeper into the particularities of the parietal lobe is of paramount importance. In this article, we discuss the functions of the parietal lobe, review the parietal anatomical and pathophysiological peculiarities in AD, and also describe some of the changes in the parietal region that occur after VI. Although the alterations in the hippocampus and the temporal lobe have been well documented in AD, the alterations of the parietal lobe have been less thoroughly explored. Recent neuroimaging studies have revealed that some metabolic and perfusion impairments along with a reduction of the white and grey matter could take place in the parietal lobe during AD. Conversely, it has been speculated that blinding ocular diseases induce a remodeling of the parietal region which is observable through the improvement of the integration of multimodal stimuli and in the increase of the volume of this cortical region. Based on current findings concerning the parietal lobe in both pathologies, we hypothesize that the increased activity of the parietal lobe in people with VI may diminish the neurodegeneration of this brain region in those who are visually impaired by oculardiseases. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a debilitating chronic condition provoked by a lesion in the nervous system and it induces functional alterations to the noradrenergic locus coeruleus (LC), affecting distinct dimensions of pain, like sensorial hypersensitivity, pain-induced depression, and anxiety. However, the neurobiological changes induced by nerve damage in the LC remain unclear. Here, we analyzed excitatory and inhibitory inputs to the LC, as well as the possible damage that noradrenergic neurons suffer after the induction of neuropathic pain through chronic constriction injury (CCI). Neuropathic pain was induced in male Sprague-Dawley rats, and the expression of the vesicular glutamate transporter 1 or 2 (VGLUT1 or VGLUT2), vesicular GABA transporter (VGAT), and cleaved caspase-3 (CC3) was analyzed by immunofluorescence 7 (CCI7d) or 28 days after the original lesion (CCI28d). While no significant differences in the density of VGLUT1 puncta were evident, CCI7d induced a significant increase in the perisomatic VGLUT2/VGAT ratio relative to Sham-operated and CCI28d animals. By contrast, when the entire region of LC is evaluated, there was a significant reduction in the density of VGLUT2 puncta in CCI28d animals, without changes in VGLUT2/VGAT ratio relative to the CCI7d animals. Additionally, changes in the noradrenergic soma size, and a lower density of mitochondria and lysosomes were evident in CCI28d animals. Interestingly, enhanced expression of the apoptotic marker CC3 was also evident in the CCI28d rats, mainly co-localizing with glial fibrillary acidic protein but not with any neuronal or noradrenergicmarker. Overall, short-termpain appears to lead to an increase of markers of excitatory synapses in the perisomatic region of noradrenergic cells in the LC, an effect that is lost after long-term pain, which appears to activate apoptosis. [ABSTRACT FROM AUTHOR]

This work provides evidence of the presence of immature neurons in the human brain, specifically in the layer II of the cerebral cortex. Using surgical samples from epileptic patients and post-mortem tissue, we have found cells with different levels of dendritic complexity (type I and type II cells) expressing DCX and PSA-NCAM and lacking expression of the mature neuronal marker NeuN. These immature cells belonged to the excitatory lineage, as demonstrated both by the expression of CUX1, CTIP2, and TBR1 transcription factors and by the lack of the inhibitory marker GAD67. The type II cells had some puncta expressing inhibitory and excitatory synaptic markers apposed to their perisomatic and peridendritic regions and ultrastructural analysis suggest the presence of synaptic contacts. These cells did not present glial cell markers, although astroglial and microglial processes were found in close apposition to their somata and dendrites, particularly on type I cells. Our findings confirm the presence of immature neurons in several regions of the cerebral cortex of humans of different ages and define their lineage. The presence of some mature features in some of these cells suggests the possibility of a progressively integration as excitatory neurons, as described in the olfactory cortex of rodents. [ABSTRACT FROM AUTHOR]

The estrous cycle is caused by the changing concentration of ovarian hormones, particularly 17β-estradiol, a hormone whose effect on excitatory circuits has been extensively reported. However, fewer studies have tried to elucidate how this cycle, or this hormone, affects the plasticity of inhibitory networks and the structure of interneurons. Among these cells, somatostatin-expressing O-LM neurons of the hippocampus are especially interesting. They have a role in the modulation of theta oscillations, and they receive direct input from the entorhinal cortex, which place them in the center of hippocampal function. In this study, we report that the expression of polysialylated form of the neural cell adhesion molecule (PSA-NCAM) in the hippocampus, a molecule involved in the plasticity of somatostatin-expressing interneurons in the adult brain, fluctuated through the different stages of the estrous cycle. Likewise, these stages and the expression of PSA-NCAM affected the density of dendritic spines of O-LM cells. We also describe that 17β-estradiol replacement of adult ovariectomized female mice caused an increase in the perisomatic inhibitory puncta in O-LM interneurons as well as an increase in their axonal bouton density. Interestingly, this treatment also induced a decrease in their dendritic spine density, specifically in O-LM interneurons lacking PSA-NCAM expression. Finally, using an ex vivo real-time assay with entorhinal-hippocampal organotypic cultures, we show that this hormone decreased the dynamics in spinogenesis, altogether highlighting the modulatory effect that 17β-estradiol has on inhibitory circuits. [ABSTRACT FROM AUTHOR]

Changes in the physiology, neurochemistry and structure of neurons, particularly of their dendritic spines, are thought to be crucial players in age-related cognitive decline. One of the most studied brain structures affected by aging is the hippocampus, known to be involved in different essential cognitive processes. While the aging-associated quantitative changes in dendritic spines of hippocampal pyramidal cells have already been studied, the relationship between aging and the structural dynamics of hippocampal interneurons remains relatively unknown. Spines are not a frequent feature in cortical inhibitory neurons, but these postsynaptic structures are abundant in a subpopulation of somatostatin expressing interneurons, particularly in oriens-lacunosum moleculare (O-LM) cells in the hippocampal CA1. Previous studies from our laboratory have shown that the spines of these interneurons are highly plastic and influenced by NMDA receptor manipulation. Thus, in the present study, we have investigated the impact of aging on this interneuronal subpopulation. The analyses were performed in 3−, 9−, and 16-month-old GIN mice, a strain in which somatostatin positive interneurons express GFP. We studied the changes in the density of dendritic spines, en passant boutons , and the expression of NMDA receptors (GluN1 and GluN2B) using confocal microscopy and image analysis. We observed a significant decrease in dendritic spine density in 9-month-old animals when compared with 3-month-old animals. We also observed a decrease in the expression of the GluN2B subunit in O-LM cells, but not of that of GluN1, during aging. These results will constitute the basis for more advanced studies of the structure and connectivity of interneurons during aging and their contribution to cognitive decline. [ABSTRACT FROM AUTHOR]

Abstract Background Antidepressants promote neuronal structural plasticity in young-adult rodents, but little is known of their effects on older animals. The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) may mediate these structural changes through its anti-adhesive properties. PSA-NCAM is expressed in immature neurons and in a subpopulation of mature interneurons and its expression is modulated by antidepressants in the telencephalon of young-adult rodents. Results We have analyzed the effects of 14 days of fluoxetine treatment on the density of puncta expressing PSA-NCAM and different presynaptic markers in the medial prefrontal cortex, hippocampus and amygdala of middle-aged (8 months old) rats. The density of puncta expressing PSA-NCAM increased in the dorsal cingulate cortex, as well as in different hippocampal and amygdaloid regions. In these later regions there were also increases in the density of puncta expressing glutamic acid decarboxylase 65/67 (GAD6), synaptophysin (SYN), PSA-NCAM/SYN and PSA-NCAM/GAD6, but a decrease of those expressing vesicular glutamate transporter 1 (VGluT1). Since there is controversy on the effects of antidepressants on neurogenesis during aging, we analyzed the number of proliferating cells expressing Ki67 and that of immature neurons expressing doublecortin or PSA-NCAM. No significant changes were found in the subgranular zone, but the number of proliferating cells decreased in the subventricular zone. Conclusions These results indicate that the effects of fluoxetine in middle-aged rats are different to those previously described in young-adult animals, being more restricted in the mPFC and even following an opposite direction in the amygdala or the subventricular zone.

Type 2 diabetes (T2D) has been considered a public health threat due to its growing prevalence, particularly in the older population. It is important to know the effects of psychosocial stress and its potential consequences for some basic cognitive processes that are important in daily life. Currently, there is very little information about how people with T2D face acute psychosocial stressors, and even less about how their response affects working memory (WM), which is essential for their functionality and independence. Our aim was to characterize the response to an acute laboratory psychosocial stressor and its effects on WM in older people with T2D. Fifty participants with T2D from 52 to 77 years old were randomly assigned to a stress (12 men and 12 women) or control (12 men and 14 women) condition. Mood and physiological (cortisol, C, and salivary alpha-amylase, sAA) responses to tasks were measured. In addition, participants completed a WM test before and after the stress or control task. Our results showed that the TSST elicited higher negative affect and greater C and sAA responses than the control task. No significant differences in WM were observed depending on the exposure to stress or the control task. Finally, participants who showed higher C and sAA responses to the stressor had lower WM performance. Our results indicate that medically treated older adults with T2D show clear, typical mood and physiological responses to an acute psychosocial stressor. Finally, the lack of acute psychosocial stress effects on WM suggests that it could be related to aging and not to this disease, at least when T2D is adequately treated. [ABSTRACT FROM AUTHOR]

Purpose: Descriptive psychopathology (DP, sometimes called psychopathology or phenomenology) is the language of psychiatry and is dedicated to the description of mental symptoms. Due to its importance, there is an ongoing case to put it back at the heart of psychiatry and its training. This study seeks to examine the literature on how to train psychiatry residents in DP, including reported educational interventions and educational methods. Method: The authors conducted a systematic review following the PRISMA and BEME guidelines to identify literature on how to train psychiatry residents in DP. In May 2019, they searched in Embase, ERIC, PsycINFO, PubMed, Scopus, and Web of Science; of 7,199 initial results, 26 sources were finally included for analysis. The assessment tools were the CRAAP test, Kirkpatrick's 4 levels, and (when applicable) the Medical Education Research Study Quality Instrument (MERSQI). Results: The mean CRAAP score was 38.885 of a possible 50 (SD 0.983; range: 36.859–40.910). Fourteen sources (53.8%) had some kind of training evaluation: Kirkpatrick's level 1 was present in nearly all (13) and was the highest in half of them (7). Regarding the educational interventions, the mean MERSQI score was 10.592 of a possible 18 (SD 2.371; range 9.085–12.098). Lectures were the most widely reported educational method (5); among those in clinical settings, the live supervised interview with feedback was the most usual (4). Conclusions: Despite its core importance as the language of psychiatry, the literature about training psychiatry residents in DP is scarce and heterogeneous. General lack of training evaluation and ongoing overemphasis on Kirkpatrick's levels 1–2 at the expense of levels 3–4 are causes for concern. During the review process, the authors identified a selection of educational interventions that could serve as the basis for the design of new training efforts in both clinical and nonclinical settings. Topics for future research are also suggested, such as the role of DP in competency-based training frameworks now in vogue and a series of neglected contents. Finally, the combined use of the CRAAP test and the MERSQI may be useful for future systematic reviews in medical education. [ABSTRACT FROM AUTHOR]

The layer II of the adult piriform cortex (PCX) contains a numerous population of immature neurons. Interestingly, in both mice and rats, most, if not all, these cells have an embryonic origin. Moreover, recent studies from our laboratory have shown that they progressively mature into typical excitatory neurons of the PCX layer II. Therefore, the adult PCX is considered a "non-canonical" neurogenic niche. These immature neurons express the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule critical for different neurodevelopmental processes. Dopamine (DA) is a relevant neurotransmitter in the adult CNS, which also plays important roles in neural development and adult plasticity, including the regulation of PSA-NCAM expression. In order to evaluate the hypothetical effects of pharmacological modulation of dopaminergic neurotransmission on the differentiation of immature neurons of the adult PCX, we studied dopamine D2 receptor (D2r) expression in this region and the relationship between dopaminergic fibers and immature neurons (defined by PSA-NCAM expression). In addition, we analyzed the density of immature neurons after chronic treatments with an antagonist and an agonist of D2r: haloperidol and PPHT, respectively. Many dopaminergic fibers were observed in close apposition to PSA-NCAM-expressing neurons, which also coexpressed D2r. Chronic treatment with haloperidol significantly increased the number of PSA-NCAM immunoreactive cells, while PPHT treatment decreased it. These results indicate a prominent role of dopamine, through D2r and PSA-NCAM, on the regulation of the final steps of development of immature neurons in the adult PCX. [ABSTRACT FROM AUTHOR]