[Specific interactions between microglia and oligodendrocytes in white matter in continuous schizophrenia]. / Osobennosti vzaimodeistviya mikroglii i oligodendrotsitov v belom veshchestve pri nepreryvnotekushchei shizofrenii.

OBJECTIVE: To study the ultrastructure of microglia adjacent to oligodendrocytes in white matter of the prefrontal cortex in continuous schizophrenia (CSch) as compared to controls and attack-like schizophrenia (ASch) and to perform correlation analysis between the parameters of microglia and adjacent oligodendrocytes previously detected in both clinical types of schizophrenia. MATERIAL AND METHODS: Electron microscopic morphometric study of microglia adjacent to oligodendrocytes was performed in postmortem white matter of the prefrontal cortex (BA10) in 9 cases of CSch, 8 cases of ASch and 20 healthy controls. Group comparisons were made by ANCOVA and Pearson correlation analyses. RESULTS: The reduction of volume fraction (Vv) and the number of mitochondria in microglia was found in elderly subjects (>50 y.o.) as compared to young controls (60%, p<0.05), and the increase in these parameters of lipofuscin granules were detected in elderly subjects as compared to elderly controls in CSch (470%, 606%, p<0.001). Vv and the number of mitochondria in microglia correlated negatively with area of heterochromatin in microglia (r≥-0.7, p<0.05), and area of lipofuscin correlated positively with area of heterochromatin in microglia (r=0.76, p<0.05) and with illness duration (r=0.7, p<0.05) only in the CSch group. The numerical density of microglia was not changed in both schizophrenia groups. Area of heterochromatin was increased in both groups as compared to controls (p<0.05) and correlated negatively with the numerical density of microglia in the CSch group. The number of mitochondria in oligodendrocytes (reduced in CSch) correlated positively with the number of mitochondria in microglia and negatively with Vv of lipofuscin granules in microglia and with area of microglial nucleus only in the CSch group. CONCLUSION: Specific features of CSch as compared to ASch might be associated with the disturbances of mitochondrial and lipid metabolism in microglia, dysfunction of nucleus and accelerated aging of microglia that might lead to alterations of mitochondrial metabolism in oligodendrocytes.

Susceptibility of subregions of prefrontal cortex and corpus callosum to damage by high-dose oxytocin-induced labor in male neonatal mice.

Induction and augmentation of labor is one of the most common obstetrical interventions. However, this intervention is not free of risks and could cause adverse events, such as hyperactive uterine contraction, uterine rupture, and amniotic-fluid embolism. Our previous study using a new animal model showed that labor induced with high-dose oxytocin (OXT) in pregnant mice resulted in massive cell death in selective brain regions, specifically in male offspring. The affected brain regions included the prefrontal cortex (PFC), but a detailed study in the PFC subregions has not been performed. In this study, we induced labor in mice using high-dose OXT and investigated neonatal brain damage in detail in the PFC using light and electron microscopy. We found that TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were detected more abundantly in infralimbic (IL) and prelimbic (PL) cortex of the ventromedial PFC (vmPFC) in male pups delivered by OXT-induced labor than in the control male pups. These Iba-1-positive microglial cells were engulfing dying cells. Additionally, we also noticed that in the forceps minor (FMI) of the corpus callosum (CC), the number of TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were largely increased and Iba-1-positive microglial cells phagocytosed massive dying cells in male pups delivered by high-dose OXT-induced labor. In conclusion, IL and PL of the vmPFC and FMI of the CC, were susceptible to brain damage in male neonates after high-dose OXT-induced labor.

Altered presynaptic function and number of mitochondria in the medial prefrontal cortex of adult Cyfip2 heterozygous mice.

Variants of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are associated with numerous neurodevelopmental and neuropsychiatric disorders. According to several studies, CYFIP1 regulates the development and function of both pre- and post-synapses in neurons. Furthermore, various studies have evaluated CYFIP2 functions in the postsynaptic compartment, such as regulating dendritic spine morphology; however, no study has evaluated whether and how CYFIP2 affects presynaptic functions. To address this issue, in this study, we have focused on the presynapses of layer 5 neurons of the medial prefrontal cortex (mPFC) in adult Cyfip2 heterozygous (Cyfip2+/-) mice. Electrophysiological analyses revealed an enhancement in the presynaptic short-term plasticity induced by high-frequency stimuli in Cyfip2+/- neurons compared with wild-type neurons. Since presynaptic mitochondria play an important role in buffering presynaptic Ca2+, which is directly associated with the short-term plasticity, we analyzed presynaptic mitochondria using electron microscopic images of the mPFC. Compared with wild-type mice, the number, but not the volume or cristae density, of mitochondria in both presynaptic boutons and axonal processes in the mPFC layer 5 of Cyfip2+/- mice was reduced. Consistent with an identification of mitochondrial proteins in a previously established CYFIP2 interactome, CYFIP2 was detected in a biochemically enriched mitochondrial fraction of the mouse mPFC. Collectively, these results suggest roles for CYFIP2 in regulating presynaptic functions, which may involve presynaptic mitochondrial changes.

Elevated protein synthesis in microglia causes autism-like synaptic and behavioral aberrations.

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism.

Short chain fatty acids, produced as gut microbiome metabolites but also present in the diet, exert broad effects in host physiology. Propionic acid (PPA), along with butyrate and acetate, plays a growing role in health, but also in neurological conditions. Increased PPA exposure in humans, animal models and cell lines elicit diverse behavioural and biochemical changes consistent with organic acidurias, mitochondrial disorders and autism spectrum disorders (ASD). ASD is considered a disorder of synaptic dysfunction and cell signalling, but also neuroinflammatory and neurometabolic components. We examined behaviour (Morris water and radial arm mazes) and the ultrastructure of the hippocampus and medial prefrontal cortex (electron microscopy) following a single intraperitoneal (i.p.) injection of PPA (175 mg/kg) in male adolescent rats. PPA treatment showed altered social and locomotor behaviour without changes in learning and memory. Both transient and enduring ultrastructural alterations in synapses, astro- and microglia were detected in the CA1 hippocampal area. Electron microscopic analysis showed the PPA treatment significantly decreased the total number of synaptic vesicles, presynaptic mitochondria and synapses with a symmetric active zone. Thus, brief systemic administration of this dietary and enteric short chain fatty acid produced behavioural and dynamic brain ultrastructural changes, providing further validation of the PPA model of ASD.

The release of exosomes in the medial prefrontal cortex and nucleus accumbens brain regions of chronic constriction injury (CCI) model mice could elevate the pain sensation.

BACKGROUND: Brain function relies on the capacity of neurons to locally modulate each other at the level of synapses. Therefore, the exosomal pathway may constitute a well-designed mechanism for local and systemic interneuronal transfer of information within functional brain networks. Exosomes bind to and are endocytosed by neurons of different brain regions to play a definite role. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) brain regions are known to involve in pain modulation. Our study observes the roles of exosomal activity in these two dominant regions of the pain-related pathway, and there influence on the analgesic effects in CCI mice. METHODS: We induced pain exosomes in the mPFC and NAc in the mice of chronic constriction injury of the sciatic nerve model to produce neuropathic pain, and assessed changes that might affect analgesic behaviors. These changes were measured through a combination of behavioral, surgical, and other cellular testings. RESULTS: Our study found that pain expression was elevated in mice given exogenous exosomes isolated from CCI mice, especially at the 2 h and 4 h time interval, in mice given exosomes at the mPFC and NAc, respectively. We also found that inhibiting formation of pain exosomes through GW4869 within the mPFC and NAc can elevate the pain threshold. CONCLUSION: Results from our study supported the idea that the release of mPFC and NAc exosomes of CCI model has elevated the pain sensations in the subjected mice. This study will further help in designing new clinical trials, and will revolutionize the drug-induced anesthetic responses.

Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex.

BACKGROUND: Cognitive impairment in schizophrenia, aging, and Alzheimer's disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q. METHODS: Age-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC. RESULTS: C1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM. CONCLUSIONS: These findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

Chronic adolescent exposure to ∆9-tetrahydrocannabinol decreases NMDA current and extrasynaptic plasmalemmal density of NMDA GluN1 subunits in the prelimbic cortex of adult male mice.

Adolescence is a vulnerable period of development when limbic connection of the prefrontal cortex (PFC) involved in emotional processing may be rendered dysfunctional by chronic exposure to delta-9-tetrahydrocannabinol (∆9-THC), the major psychoactive compound in marijuana. Cannabinoid-1 receptors (CB1Rs) largely mediate the central neural effects of ∆9-THC and endocannabinoids that regulate NMDA receptor-dependent synaptic plasticity of glutamatergic synapses in the prelimbic prefrontal cortex (PL-PFC). Thus, chronic occupancy of CB1Rs by ∆9-THC during adolescence may competitively decrease the functional expression and activity of NMDA receptors in the mature PL-PFC. We used a multidisciplinary approach to test this hypothesis in adult C57BL/6J male mice that received vehicle or ∆9-THC in escalating doses (2.5-10 mg/kg/ip) through adolescence (postnatal day 29-43). In comparison with vehicle, the mice receiving ∆9-THC showed a hyperpolarized resting membrane potential, decreased spontaneous firing rate, increased current-induced firing threshold, and decreased depolarizing response to NMDA in deep-layer PL-PFC neurons analyzed by current-clamp recordings. Electron microscopic immunolabeling in the PL-PFC of adult mice that had received Δ9-THC only during adolescence showed a significant (1) decrease in the extrasynaptic plasmalemmal density of obligatory GluN1-NMDA subunits in dendrites of all sizes and (2) a shift from cytoplasmic to plasmalemmal distribution of GluN1 in large dendrites receiving mainly inhibitory-type synapses from CB1R-labeled terminals. From these results and concomitant behavioral studies, we conclude that social dysfunctions resulting from excessive intake of ∆9-THC in the increasingly available marijuana products used by male teens may largely reflect circuit defects in PL-PFC networks communicating through endocannabinoid-regulated NMDA receptors.

Ultrastructural localization of cannabinoid CB1 and mGluR5 receptors in the prefrontal cortex and amygdala.

Stimulation of the postsynaptic metabotropic glutamate receptor mGluR5 triggers retrograde signaling of endocannabinoids that activate presynaptic cannabinoid CB1 receptors on juxtaposing axon terminals. To better understand the synaptic structure that supports mGluR5 mediation of CB1 activation in the prefrontal cortex (PFC) and basolateral amygdala (BLA), we examined electron microscopic dual immunolabeling of these receptors in the prelimbic PFC (prPFC) and BLA of adult male rats. CB1 immunoreactivity was detected in axon terminals that were typically large, complex, and contained dense-core and clear synaptic vesicles. Of terminals forming discernible synaptic specializations, 95% were symmetric inhibitory-type in the prPFC and 90% were inhibitory in the BLA. CB1-immunoreactive terminals frequently contacted dendrites containing mGluR5 adjacent to unlabeled terminals forming excitatory-type synapses. Because most CB1-containing terminals form inhibitory-type synapses, the unlabeled axon terminals forming asymmetric synapses are the likely source of the mGluR5 ligand glutamate. In the prPFC, serial section analysis revealed that GABAergic CB1-containing axon terminals targeted dendrites adjacent to glutamatergic axon terminals, often near dendritic bifurcations. These observations provide ultrastructural evidence that cortical CB1 receptors are strategically positioned for integration of synaptic signaling in response to stimulation of postsynaptic mGluR5 receptors and facilitation of heterosynaptic communication between multiple neurons.

Physical home environment is associated with prefrontal cortical thickness in adolescents.

Biologically embedded experiences alter developmental trajectories in ways that can influence health, learning, and/or behavior. These systematic differences in experiences may contribute to different biological outcomes as individuals grow and develop, including at the neural level. Previous studies of biologically embedded experiences on neurodevelopment have focused on large-scale institutional or economic factors (e.g. socioeconomic status [SES]) and psychosocial factors (e.g. caregiving behavior). Less attention has focused on how the quality of the immediate home settings, such as the physical home environment (PHYS), influences neurodevelopment. Moreover, no study has investigated these effects in adolescents, who undergo significant physical maturation and neurodevelopment that may influence how they respond to their physical environments. The goal of the current study was to examine whether PHYS quality is biologically embedded in the developing adolescent brain as evidenced by cognitive achievement and cortical development in 56 (48% female) healthy adolescents (14-18 years (M = 16.83 years, SD = 1.17). Using in-home assessments of the physical home environment, anatomical brain scans, and indices of academic achievement, we found that adolescents who have more physical problems in the home (e.g. structural hazards, crowding, excessive noise, poorly lit) have thinner prefrontal cortices, which was associated with lower levels of reading achievement, independent of SES and psychosocial factors. By conducting home visits to assess physical characteristics of adolescents' home, we highlight a typically overlooked aspect of the home environment that has relevance for adolescents' cognitive and brain development.

Postnatal development and maturation of layer 1 in the lateral prefrontal cortex and its disruption in autism.

Autism is a neurodevelopmental connectivity disorder characterized by cortical network disorganization and imbalance in excitation/inhibition. However, little is known about the development of autism pathology and the disruption of laminar-specific excitatory and inhibitory cortical circuits. To begin to address these issues, we examined layer 1 of the lateral prefrontal cortex (LPFC), an area with prolonged development and maturation that is affected in autism. We focused on layer 1 because it contains a distinctive, diverse population of interneurons and glia, receives input from feedback and neuromodulatory pathways, and plays a critical role in the development, maturation, and function of the cortex. We used unbiased quantitative methods at high resolution to study the morphology, neurochemistry, distribution, and density of neurons and myelinated axons in post-mortem brain tissue from children and adults with and without autism. We cross-validated our findings through comparisons with neighboring anterior cingulate cortices and optimally-fixed non-human primate tissue. In neurotypical controls we found an increase in the density of myelinated axons from childhood to adulthood. Neuron density overall declined with age, paralleled by decreased density of inhibitory interneurons labeled by calretinin (CR), calbindin (CB), and parvalbumin (PV). Importantly, we found PV neurons in layer 1 of typically developing children, previously detected only perinatally. In autism there was disorganization of cortical networks within layer 1: children with autism had increased variability in the trajectories and thickness of myelinated axons in layer 1, while adults with autism had a reduction in the relative proportion of thin axons. Neurotypical postnatal changes in layer 1 of LPFC likely underlie refinement of cortical activity during maturation of cortical networks involved in cognition. Our findings suggest that disruption of the maturation of feedback pathways, rather than interneurons in layer 1, has a key role in the development of imbalance between excitation and inhibition in autism.

The orbitofrontal cortex projects to the parvafox nucleus of the ventrolateral hypothalamus and to its targets in the ventromedial periaqueductal grey matter.

Although connections between the orbitofrontal cortex (OFC)-the seat of high cognitive functions-the lateral hypothalamus and the periaqueductal grey (PAG) have been recognized in the past, the precise targets of the descending fibres have not been identified. In the present study, viral tracer-transport experiments revealed neurons of the lateral (LO) and the ventrolateral (VLO) OFC (homologous to part of Area 13 in primates) to project to a circumscribed region in the ventrolateral hypothalamus, namely, the horizontally oriented, cylindrical parvalbumin- and Foxb1-expressing (parvafox) nucleus. The fine collaterals stem from coarse axons in the internal capsule and form excitatory synapses specifically with neurons of the parvafox nucleus, avoiding the rest of the hypothalamus. In its further caudal course, this contingent of LO/VLO-axons projects collaterals to the Su3- and the PV2 nuclei, which lie ventral to the aqueduct in the (PAG), where the terminals fields overlap those deriving from the parvafox nucleus itself. The targeting of the parvafox nucleus by the LO/VLO-projections, and the overlapping of their terminal fields within the PAG, suggest that the two cerebral sites interact closely. An involvement of this LO/VLO-driven circuit in the somatic manifestation of behavioural events is conceivable.

The Rat Prefrontal-Cortex Transcriptome: Effects of Aging and Sporadic Alzheimer's Disease-Like Pathology.

Alzheimer's disease (AD) is the most widespread late-life dementia and involves the prefrontal cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. To understand the molecular differences between the effects of aging and AD on the prefrontal cortex, this study characterized the age-dependent changes in gene expression in Wistar rats (control) and OXYS rats (rodents that simulate key characteristics of sporadic AD) using RNA sequencing. We found that major altered biological processes during aging in Wistar rats were associated with immune processes. Gene expression changes during development of AD-like pathology as well as at the preclinical stage were related to neuronal plasticity, catalytic activity, lipid and immune processes, and mitochondria. A comparison of genes between data sets "OXYS rats" and "human AD" revealed similarity in expression alterations of genes related primarily to mitochondrial function; immune, endocrine, and circulatory systems; signal transduction; neuronal and synaptic processes; hypoxia; and apoptosis. Expression changes in mitochondrial processes identified in OXYS rats by RNA sequencing were confirmed by ultrastructural neuronal organelle alterations and low activity of respiratory chain complexes I, IV, and V in cortical mitochondria, suggesting that mitochondrial dysfunction appears to mediate or possibly even initiate the development of AD.

Factors Affecting Ultrastructural Quality in the Prefrontal Cortex of the Postmortem Human Brain.

Electron microscopy (EM) studies of the postmortem human brain provide a level of resolution essential for understanding brain function in both normal and disease states. However, processes associated with death can impair the cellular and organelle ultrastructural preservation required for quantitative EM studies. Although postmortem interval (PMI), the time between death and preservation of tissue, is thought to be the most influential factor of ultrastructural quality, numerous other factors may also influence tissue preservation. The goal of the present study was to assess the effects of pre- and postmortem factors on multiple components of ultrastructure in the postmortem human prefrontal cortex. Tissue samples from 30 subjects were processed using standard EM histochemistry. The primary dependent measure was number of identifiable neuronal profiles, and secondary measures included presence and/or integrity of synapses, mitochondria, and myelinated axonal fibers. Number of identifiable neuronal profiles was most strongly affected by the interaction of PMI and pH, such that short PMIs and neutral pH values predicted the best preservation. Secondary measures were largely unaffected by pre- and postmortem factors. Together, these data indicate that distinct components of the neuropil are differentially affected by PMI and pH in postmortem human brain.

Estrogen Alters the Synaptic Distribution of Phospho-GluN2B in the Dorsolateral Prefrontal Cortex While Promoting Working Memory in Aged Rhesus Monkeys.

Age- and menopause-related deficits in working memory can be partially restored with estradiol replacement in women and female nonhuman primates. Working memory is a cognitive function reliant on persistent firing of dorsolateral prefrontal cortex (dlPFC) neurons that requires the activation of GluN2B-containing glutamate NMDA receptors. We tested the hypothesis that the distribution of phospho-Tyr1472-GluN2B (pGluN2B), a predominant form of GluN2B seen at the synapse, is sensitive to aging or estradiol treatment and coupled to working memory performance. First, ovariectomized young and aged rhesus monkeys (Macaca mulatta) received long-term cyclic vehicle (V) or estradiol (E) treatment and were tested on the delayed response (DR) test of working memory. Then, serial section electron microscopic immunocytochemistry was performed to quantitatively assess the subcellular distribution of pGluN2B. While the densities of pGluN2B immunogold particles in dlPFC dendritic spines were not different across age or treatment groups, the percentage of gold particles located within the synaptic compartment was significantly lower in aged-E monkeys compared to young-E and aged-V monkeys. On the other hand, the percentage of pGluN2B gold particles in the spine cytoplasm was decreased with E treatment in young, but increased with E in aged monkeys. In aged monkeys, DR average accuracy inversely correlated with the percentage of synaptic pGluN2B, while it positively correlated with the percentage of cytoplasmic pGluN2B. Together, E replacement may promote cognitive health in aged monkeys, in part, by decreasing the relative representation of synaptic pGluN2B and potentially protecting the dlPFC from calcium toxicity.

Curcumin Protects Against Chronic Stress-induced Dysregulation of Neuroplasticity and Depression-like Behaviors via Suppressing IL-1ß Pathway in Rats.

Accumulating evidence has accrued demonstrating that inflammatory processes in the central nervous system (CNS) are associated with various neurological disorders including depression. However, whether inflammation-mediated neuronal damage is involved in depression-like behaviors induced by chronic stress and, in particular, whether suppression of inflammation could then serve as a potential strategy in depression therapy remains largely unknown. The present study aimed to investigate the neuronal mechanisms and signaling pathways through which inflammation results in neuronal deterioration in a rat model of depression and thus identify agents with potential roles as antidepressant treatments. Our results showed that chronic unpredictable mild stress (CUMS) exposure induced microglia activation and overexpression of the cytokines interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-a (TNF-α) within the medial prefrontal cortex (mPFC), effects which were paralleled with neuronal structural changes. In contrast, chronic administration of either IL-1ß or nuclear factor κB (NF-κB) antagonists significantly ameliorated this dysregulation of neuronal structure and biochemical parameters such as SSH1 and phospho-cofilin within the mPFC, as well as the display of depression-like behaviors induced by CUMS exposure. More importantly, pretreatment with curcumin (40 mg/kg, i.p., 5 weeks), produced antidepressant-like actions and repressed the inflammatory responses and neuronal structural abnormalities. These findings reveal some of the molecular neuroinflammation pathways associated with depression and suggest new avenues of investigation for the development of potential antidepressant therapies in the treatment of inflammation-related neuronal deterioration in this disorder.

Prenatal stress leads to chromatin and synaptic remodeling and excessive alcohol intake comorbid with anxiety-like behaviors in adult offspring.

Epidemiologic evidence suggests that individuals during their prenatal development may be especially vulnerable to the effects of environmental factors such as stress that predisposes them to psychiatric disorders including alcohol use disorder (AUD) later in life. Currently, the epigenetic mechanisms of anxiety comorbid with AUD induced by prenatal stress (PRS) remain to be elucidated. Here, we examined anxiety-like and alcohol drinking behaviors in adult offspring of prenatally stressed dam (PRS-mice) using elevated plus maze, light/dark box and two-bottle free-choice paradigm. It was found that PRS-mice exhibit heightened anxiety-like behaviors and increased alcohol intake in adulthood and these behavioral deficits were associated with a significant decrease in dendritic spine density (DSD) in medial prefrontal cortex (mPFC) relative to non-stressed mice (NS mice). To determine the mechanisms by which PRS reduces DSD, we examined the expressions of key genes associated with synaptic plasticity, including activity regulated cytoskeleton associated protein (Arc), spinophilin (Spn), postsynaptic density 95 (Psd95), tropomyosin receptor kinase B (TrkB), protein kinase B (Akt), mammalian target of rapamycin (mTOR) and period 2 (Per2) in mPFC of PRS and NS mice. The mRNA levels of these genes were significantly decreased in PRS mice. Methylated DNA and chromatin immunoprecipitation studies revealed hyper DNA methylation or reduced histone H3K14 acetylation on promoters of above genes suggesting that epigenetic dysregulation may be responsible for the deficits in their expression. Findings from this study suggest that prenatal stress induced abnormal epigenetic mechanisms and synaptic plasticity-related events may be associated with anxiety-like and alcohol drinking behaviors in adulthood.

Is intelligence equivalent to executive functions?

BACKGROUND: Since the mid 19th century, cognitive and behavioral neurosciences have attempted to find the neurological bases of intellectual abilities. During the early 20th century the psychometric concept of "intelligence" was coined; and toward the end of the 20th century the neuropsychological concept of "executive functions" was introduced. Controversies, however, remain about the unity or heterogeneity of so-called executive functions. METHODS: It is proposed that two major executive functions could be separated: metacognitive -or intelectual- and emotional/motivational. A similar distinction has been suggested by several authors. Standard definitions of intelligence implicitly assume that executive functions represent the fundamental components of intelligence. RESULTS: Research has demonstrated that, if considered as a whole, executive functions only partially correspond to the psychometric concept of intelligence; whereas some specific executive functions clearly correspond to intelligence, some others do not involve intelligence. CONCLUSIONS: If using a major distinction between metacognitive -or simply "intellectual"-executive functions, and emotional/ motivational -or simply non-intellectual-executive functions, it becomes evident that general intelligence can be equated with metacognitive executive functions but not with emotional/ motivational executive functions.

Mapping pathologic circuitry in schizophrenia.

Schizophrenia is a complex disorder lacking an effective treatment option for the pervasive and debilitating cognitive impairments experienced by patients. Working memory is a core cognitive function impaired in schizophrenia that depends upon activation of distributed neural network, including the circuitry of the dorsolateral prefrontal cortex (DLPFC). Accordingly, individuals diagnosed with schizophrenia show reduced DLPFC activation while performing working-memory tasks. This lower DLPFC activation appears to be an integral part of the disease pathophysiology, and not simply a reflection of poor performance. Thus, the cellular and circuitry alterations that underlie lower DLPFC neuronal activity in schizophrenia must be determined in order to identify appropriate therapeutic targets. Studies using human postmortem brain tissue provide a robust way to investigate and characterize these cellular and circuitry alterations at multiple levels of resolution, and such studies provide essential information that cannot be obtained either through in vivo studies in humans or through experimental animal models. Studies examining neuronal morphology, protein expression and localization, and transcript levels indicate that a microcircuit composed of excitatory pyramidal cells and inhibitory interneurons containing the calcium-binding protein parvalbumin is altered in the DLPFC of subjects with schizophrenia and likely contributes to DLPFC dysfunction.