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Blast-related traumatic brain injury (bTBI) is a major cause of neurological disorders in the U.S. military that can adversely impact some civilian populations as well and can lead to lifelong deficits and diminished quality of life. Among these types of injuries, the long-term sequelae are poorly understood because of variability in intensity and number of the blast exposure, as well as the range of subsequent symptoms that can overlap with those resulting from other traumatic events (e.g., post-traumatic stress disorder). Despite the valuable insights that rodent models have provided, there is a growing interest in using injury models using species with neuroanatomical features that more closely resemble the human brain. With this purpose, we established a gyrencephalic model of blast injury in ferrets, which underwent blast exposure applying conditions that closely mimic those associated with primary blast injuries to warfighters. In this study, we evaluated brain biochemical, microstructural, and behavioral profiles after blast exposure using in vivo longitudinal magnetic resonance imaging, histology, and behavioral assessments. In ferrets subjected to blast, the following alterations were found: 1) heightened impulsivity in decision making associated with pre-frontal cortex/amygdalar axis dysfunction; 2) transiently increased glutamate levels that are consistent with earlier findings during subacute stages post-TBI and may be involved in concomitant behavioral deficits; 3) abnormally high brain N -acetylaspartate levels that potentially reveal disrupted lipid synthesis and/or energy metabolism; and 4) dysfunction of pre-frontal cortex/auditory cortex signaling cascades that may reflect similar perturbations underlying secondary psychiatric disorders observed in warfighters after blast exposure., Competing Interests: No competing financial interests exist. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. Research was conducted under an IACUC-approved animal use protocol in an AAALAC International - accredited facility with a Public Health Services Animal Welfare Assurance and in compliance with the Animal Welfare Act and other federal statutes and regulations relating to laboratory animals., (© Shiyu Tang et al., 2024; Published by Mary Ann Liebert, Inc.)

Fetal Alcohol Spectrum Disorders (FASD) are one of the most common causes of mental disability in the world. Despite efforts to increase public awareness of the risks of drinking during pregnancy, epidemiological studies indicate a prevalence of 1-6% in all births. There is growing evidence that deficits in sensory processing may contribute to social problems observed in FASD. Multisensory (MS) integration occurs when a combination of inputs from two sensory modalities leads to enhancement or suppression of neuronal firing. MS enhancement is usually linked to processes that facilitate cognition and reaction time, whereas MS suppression has been linked to filtering unwanted sensory information. The rostral portion of the posterior parietal cortex (PPr) of the ferret is an area that shows robust visual-tactile integration and displays both MS enhancement and suppression. Recently, our lab demonstrated that ferrets exposed to alcohol during the "third trimester equivalent" of human gestation show less MS enhancement and more MS suppression in PPr than controls. Here we complement these findings by comparing in vivo electrophysiological recordings from channels located in shallow and deep cortical layers. We observed that while the effects of alcohol (less MS enhancement and more MS suppression) were found in all layers, the magnitude of these effects were more pronounced in putative layers V-VI. These findings extend our knowledge on the sensory deficits of FASD., (Copyright © 2024 Elsevier Inc. All rights reserved.)

It is well known that the nervous system adjusts itself to its environment during development. Although a great deal of effort has been directed towards understanding the developmental processes of the individual sensory systems (e.g., vision, hearing, etc.), only one major study has examined the maturation of multisensory processing in cortical neurons. Therefore, the present investigation sought to evaluate multisensory development in a different cortical region and species. Using multiple single-unit recordings in anaesthetised ferrets (n = 18) of different ages (from postnatal day 80 to 300), we studied the responses of neurons from the rostral posterior parietal (PPr) area to presentations of visual, tactile and combined visual-tactile stimulation. The results showed that multisensory neurons were infrequent at the youngest ages (pre-pubertal) and progressively increased through the later ages. Significant response changes that result from multisensory stimulation (defined as multisensory integration [MSI]) were observed in post-pubertal adolescent animals, and the magnitude of these integrated responses also increased across this age group. Furthermore, non-significant multisensory response changes were progressively increased in adolescent animals. Collectively, at the population level, MSI was observed to shift from primarily suppressive levels in infants to increasingly higher levels in later stages. These data indicate that, like the unisensory systems from which it is derived, multisensory processing shows developmental changes whose specific time course may be regionally and species-dependent., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Exposure to substances of abuse during pregnancy can have long-lasting effects on offspring. Alcohol is one of the most widely used substances of abuse that leads to the most severe consequences. Recent studies in the United States, Canada, and the United Kingdom showed that between 1% and 7% of all children exhibit signs and symptoms of fetal alcohol spectrum disorder (FASD). Despite preventive campaigns, the rate of children with FASD has not decreased during recent decades. Alcohol consumption often accompanies exposure to such drugs as tobacco, cocaine, opioids, and cannabis. These interactions can be synergistic and exacerbate the deleterious consequences of developmental alcohol exposure. The present review focuses on interactions between alcohol and cannabis exposure and the potential consequences of these interactions., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Fetal alcohol spectrum disorder (FASD) is one of the most common causes of mental disabilities in the world with a prevalence of 1%-6% of all births. Sensory processing deficits and cognitive problems are a major feature in this condition. Because developmental alcohol exposure can impair neuronal plasticity, and neuronal plasticity is crucial for the establishment of neuronal circuits in sensory areas, we predicted that exposure to alcohol during the third trimester equivalent of human gestation would disrupt the development of multisensory integration (MSI) in the rostral portion of the posterior parietal cortex (PPr), an integrative visual-tactile area. We conducted in vivo electrophysiology in 17 ferrets from four groups (saline/alcohol; infancy/adolescence). A total of 1157 neurons were recorded after visual, tactile and combined visual-tactile stimulation. A multisensory (MS) enhancement or suppression is characterized by a significantly increased or decreased number of elicited spikes after combined visual-tactile stimulation compared to the strongest unimodal (visual or tactile) response. At the neuronal level, those in infant animals were more prone to show MS suppression whereas adolescents were more prone to show MS enhancement. Although alcohol-treated animals showed similar developmental changes between infancy and adolescence, they always 'lagged behind' controls showing more MS suppression and less enhancement. Our findings suggest that alcohol exposure during the last months of human gestation would stunt the development of MSI, which could underlie sensory problems seen in FASD., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is the result of global hypoxic-ischemic brain injury in neonates due to asphyxia during birth and is one of the most common causes of severe, long-term neurologic deficits in children. Methods: Resting state fMRI (rs-fMRI) was used to assess potential functional disruptions in the primary and association motor areas in HIE neonates (n = 16) compared to healthy controls (n = 11)., Results: Results demonstrate reduced intra-hemispheric resting state functional connectivity (rs-FC) between primary motor regions (upper extremity and facial motor regions) as well as reduced inter-hemispheric rs-FC in the HIE group. In addition, HIE neonates demonstrated increased rs-FC between motor regions and frontal, temporal and parietal cortices but decreased rs-FC with the cerebellum., Discussion: These preliminary results provide initial evidence for the disruption of functional communication with the motor network in neonates with HIE. Further studies are necessary to both validate these findings in a larger dataset as well as to determine if rs-fMRI measurements collected at birth may have the potential to serve as a prognostic marker in addition to the traditional combination of clinical measurements and conventional MRI.

The transcription factor cAMP response element-binding protein (CREB) is involved in a myriad of cellular functions in the central nervous system. For instance, the role of CREB via phosphorylation at the amino-acid residue Serine (Ser)133 in expressing plasticity-related genes and activity-dependent neuronal plasticity processes has been extensively demonstrated. However, much less is known about the role of CREB phosphorylation at Ser142 and Ser143. Here, we employed a viral vector containing a dominant negative form of CREB, with serine-to-alanine mutations at residue 142 and 143 to specifically block phosphorylation at both sites. We then transfected this vector into primary neurons in vitro or intracortically injected it into mice in vivo , to test whether these phosphorylation events were important for activity-dependent plasticity. We demonstrated by immunohistochemistry of cortical neuronal cultures that the expression of Arc, a known plasticity-related gene, requires triple phosphorylation of CREB at Ser133, Ser142, and Ser143. Moreover, we recorded visually-evoked field potentials in awake mice before and after a 7-d period of monocular deprivation (MD) to show that, in addition to CREB phosphorylation at Ser133, ocular dominance plasticity (ODP) in the visual cortex also requires CREB phosphorylation at Ser142/143. Our findings suggest that Ser142/143 phosphorylation is an additional post-translational modification of CREB that triggers the expression of specific target genes and activity-dependent neuronal plasticity processes., (Copyright © 2021 Pulimood et al.)

There has been a significant push in recent years to deploy fundamental knowledge and methods of photochemistry toward biological ends. Photoreactive groups have enabled chemists to activate biological function using the concept of photocaging. By granting spatiotemporal control over protein activation, these photocaging methods are fundamental in understanding biological processes. Peptides and proteins are an important group of photocaging targets that present conceptual and technical challenges, requiring precise chemoselectivity in complex polyfunctional environments. This review focuses on recent advances in photocaging techniques and methodologies, as well as their use in living systems. Photocaging methods include genetic and chemical approaches that require a deep understanding of structure-function relationships based on subtle changes in primary structure. Successful implementation of these ideas can shed light on important spatiotemporal aspects of living systems.

Objective: Vinpocetine has been shown to enhance memory in animal models, with possible cognitive benefit in humans. The present study sought to demonstrate if vinpocetine can enhance cognition in healthy volunteers or patients with epilepsy. In addition, we compare blood levels of vinpocetine and its active metabolite (apovincaminic acid; AVA) in humans and animals to further characterize factors related to possible therapeutic benefit., Methods: The cognitive effects of vinpocetine were assessed in healthy adult volunteers (n = 8) using a double-blind, randomized, crossover design at single doses (placebo, 10, 20, and 60 mg oral). Cognitive effects of vinpocetine in patients with focal epilepsy (n = 8) were tested using a double-blind, randomized, crossover design at single doses (placebo, 20 mg oral) followed by one-month open label at 20 mg oral three times a day. The neuropsychological battery included both computerized and non-computerized tests. Levels of vinpocetine and AVA in the human studies were compared to levels in 45 mice across time dosed at 5-20 mg/kg intraperitoneal of vinpocetine., Results: No significant cognitive benefits were seen in healthy volunteers or patients with epilepsy. No appreciable side effects occurred. Vinpocetine and AVA levels were lower in humans than animals., Conclusions: Vinpocetine was well tolerated, but was not associated with positive cognitive effects. However, blood levels obtained in humans were substantially less than levels in animals obtained from dosages known to be effective in one model. This suggests that higher dosages are needed in humans to assess vinpocetine's cognitive efficacy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Heterogeneity and focalization are the most common epidemiological characteristics of endemic countries in the Americas, where malaria transmission is moderate and low. During malaria elimination, the first step is to perform a risk stratification exercise to prioritize interventions. This study aimed to identify malaria risk strata in the ecoepidemiological regions of Colombia., Methods: This was a descriptive and retrospective study using cumulative malaria cases in 1,122 municipalities of Colombia from 2010 to 2019. To identify the strata, the criteria proposed by PAHO were adapted. To classify the receptive areas (strata 2, 3, and 4) and nonreceptive areas (stratum 1), 1,600 m above sea level, ecotypes, main malaria vector presence, Plasmodium species prevalence and occurrence of malaria cases were used. The area occupied by the receptive municipalities, the cumulative burden, and the at-risk population in the regions were calculated., Results: Ninety-one percent of the Colombian territory is receptive to the transmission of malaria and includes 749 municipalities with 9,734,271 (9,514,243-9,954,299) million at-risk inhabitants. Stratum 4 accounted for 96.7% of the malaria burden, and cases were concentrated primarily in the Pacific and Uraba-Bajo Cauca-Sinu-San Jorge regions. Plasmodium vivax predominates in most of the receptive municipalities, except in the municipalities of the Pacific region, where P. falciparum predominates. Anopheles albimanus, An. nuneztovari s.l., and An. darlingi were the main vectors in receptive areas., Conclusions: In Colombia, 91.2% of the territory is receptive to the transmission of malaria and is characterized by being both heterogeneous and focused. Stratum 4 contains the greatest burden of disease, with a relatively greater proportion of municipalities with a predominance of P. vivax. However, there is a low proportion of municipalities with P. falciparum mainly in the Pacific region. These findings suggest that the latter be prioritized within the malaria elimination plan in Colombia., Competing Interests: The authors have declared that no competing interests exist.

Background: Postnatal exposure to red blood cell transfusion (RBCT) in premature infants is an important risk factor for Retinopathy of Prematurity (ROP) progression. We hypothesized that higher number and earlier timing of RBCT are associated with worse ROP severity and result in laser treatment at an earlier postmenstrual age (PMA) in very low birth weight (≤1500 g, VLBW) infants., Methods: A retrospective medical record review of 631 VLBW infants over a 5-year period was performed. Demographic features and potential clinical risk factors including number of RBCT, ROP severity, and progression to laser treatment were collected to evaluate predictors of severe ROP. ANCOVA, pairwise post-hoc analyses, and multivariate regression were used to determine associations between frequency and timing of RBCT and ROP severity., Results: Of the 456 eligible infants, 61 developed severe ROP (13%). There was significant correlation between number of RBCTs and ROP severity, adjusted for gestational age and birthweight (Adjusted R2 = 0.53; p < 0.001). Compared to infants with No/Mild and Type 2 ROP, infants with Type 1 ROP received more RBCTs, with higher number of RBCTs per week during the first month of life (mean RBCT in ROP No/Mild 5.7±0.4 vs Type 2 16.3±1.8 vs Type 1 22.4±1.5, p = 0.042). Laser-treated infants received a higher number of RBCTs than non-treated infants (mean RBCT 22.3 vs. 6.5, p < 0.001) but no correlation was observed between number of RBCTs and PMA at time of laser treatment., Conclusion: Higher number of RBCTs in early postnatal life of VLBW infants was associated with more severe ROP.

Light is a uniquely powerful tool for spatiotemporal control of molecular structure, necessitating the development of new photocaging approaches. This communication describes the design, synthesis, and reactivity of two new photoreactive boronic acid reagents for backbone N-H modification and subsequent photocleavage.

Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide-rhodium(ii) conjugates tests our ability to use cooperative organic-inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.

Background: Mercury, lead, and cadmium are developmental neurotoxicants. We predict that preterm newborns requiring packed red blood cell (PRBC) transfusions may be exposed to neurotoxic doses. We explored the relationship between donor concentration, number of donors, number of transfusions and mercury, lead and cadmium exposure., Methods: Single-donor PRBCs were analyzed for mercury, lead and cadmium concentration. Dose per transfusion was calculated and compared to intravenous reference doses (IVRfDs). Linear regression analyses were performed to correlate donor and infant exposure., Results: Thirty-six infants received 268 transfusions from 94 donors. Number of donors and transfusions were significantly correlated with birthweight and gestational age. All three metals were detected in ≥95% of donor PRBCs. Number of donors was significantly associated with cumulative dose, and there was a significant correlation between mercury and lead doses/transfusion. IVRfDs were exceeded for mercury and lead in 8.6% and 38% of transfusions, respectively. None exceeded the IVRfD for cadmium. For lead, infants exposed to three donors had more transfusions exceeding IVRfD than those exposed to 1-2 donors., Conclusions: Preterm infants are exposed to heavy metals via transfusions. Doses exceeded the IVRfDs for mercury and lead. Cadmium did not pose a risk. Prescreening donor blood could reduce exposure risk.

Atovaquone, a US Food and Drug Administration-approved antiparasitic drug previously shown to reduce interleukin-6/STAT3 signaling in myeloma cells, is well tolerated, and plasma concentrations of 40 to 80 µM have been achieved with pediatric and adult dosing. We conducted preclinical testing of atovaquone with acute myeloid leukemia (AML) cell lines and pediatric patient samples. Atovaquone induced apoptosis with an EC50 <30 µM for most AML lines and primary pediatric AML specimens. In NSG mice xenografted with luciferase-expressing THP-1 cells and in those receiving a patient-derived xenograft, atovaquone-treated mice demonstrated decreased disease burden and prolonged survival. To gain a better understanding of the mechanism of atovaquone, we performed an integrated analysis of gene expression changes occurring in cancer cell lines after atovaquone exposure. Atovaquone promoted phosphorylation of eIF2α, a key component of the integrated stress response and master regulator of protein translation. Increased levels of phosphorylated eIF2α led to greater abundance of the transcription factor ATF4 and its target genes, including proapoptotic CHOP and CHAC1. Furthermore, atovaquone upregulated REDD1, an ATF4 target gene and negative regulator of the mechanistic target of rapamycin (mTOR), and caused REDD1-mediated inhibition of mTOR activity with similar efficacy as rapamycin. Additionally, atovaquone suppressed the oxygen consumption rate of AML cells, which has specific implications for chemotherapy-resistant AML blasts that rely on oxidative phosphorylation for survival. Our results provide insight into the complex biological effects of atovaquone, highlighting its potential as an anticancer therapy with novel and diverse mechanisms of action, and support further clinical evaluation of atovaquone for pediatric and adult AML., (© 2019 by The American Society of Hematology.)

S-Arylation of cysteine residues is an increasingly powerful tool for site-specific modification of proteins, providing novel structure and electronic perturbation. The present work demonstrates an operationally-simple cysteine arylation reaction 2-nitro-substituted arylboronic acids, promoted by a simple nickel(ii) salt. The process exhibits strikingly fast reaction rates under physiological conditions in purely aqueous media with excellent selectivity toward cysteine residues. Cysteine arylation of natural proteins and peptides allows attachment of useful reactive handles for stapling, imaging, or further conjugation.

Side-chain modifications that respond to external stimuli provide a convenient approach to control macromolecular structure and function. Responsive modification of backbone amide structure represents a direct and powerful alternative to impact folding and function. Here, we describe a new photocaging method using histidine-directed backbone modification to selectively modify peptides and proteins at the amide N-H bond. A new vinylogous photocleavage method allows photorelease of the backbone modification and, with it, restoration of function.

Brain tissue from 1068 donors was analyzed for RNA quality as a function of postmortem interval (PMI) and years in storage. Approximately 83% of the cortical and cerebellar samples had an RNA integrity number (RIN) of 6 or greater, indicating their likely suitability for real-time quantitative polymerase chain reaction research. The average RIN value was independent of the PMI, up to at least 36 hours. The RNA quality for specific donated brains could not be predicted based on the PMI. Individual samples with a low PMI could have a poor RIN value, while a sample with a PMI over 36 hours may have a high RIN value. The RIN values for control brain donors, all of whom died suddenly and unexpectedly, were marginally higher than for individuals with clinical brain disorders. Polymerase chain reaction (PCR) analysis of samples confirmed that RIN values were more critical than PMI for determining suitability of tissue for molecular biological studies and samples should be matched by their RIN values rather than PMI. Importantly, PCR analysis established that tissue stored up to 23 years at -80°C yielded high-quality RNA. These results confirm that postmortem human brain tissue collected by brain and tissue banks over decades can serve as high quality material for the study of human disorders.

Background: Children with fetal alcohol spectrum disorders (FASD) often have deficits associated with multisensory processing. Because ethanol (EtOH) disrupts activity-dependent neuronal plasticity, a process that is essential for refining connections during cortical development, we hypothesize that early alcohol exposure results in alterations in multisensory cortical networks, which could explain the multisensory processing deficits seen in FASD. Here, we use a gyrencephalic animal model to test the prediction that early alcohol exposure alters the functional connectivity and microstructural features of the rostral posterior parietal cortex (PPr), a visual-tactile integrative area., Methods: Ferrets were exposed to moderate doses of EtOH during the brain growth spurt period. Functional connectivity and microstructural features were assessed using resting-state functional magnetic resonance imaging and ex vivo diffusion kurtosis imaging (DKI), respectively, when the animals reached juvenile age and adulthood, respectively., Results: While the whole brain volume was smaller in alcohol-treated animals, the relative size of the frontal brain area was larger when compared to control animals. Altered functional connectivity was observed in alcohol-treated animals, where increased connectivity was observed between PPr and the region that provides its major visual inputs (the caudal portion of the parietal cortex), but not with the region that provides its major somatosensory inputs (tertiary somatosensory cortex). DKI revealed reduced microstructural tissue complexity in all investigated sensory areas of alcohol-treated animals., Conclusions: In this study, we observed alterations in cortical functional connectivity and microstructural integrity in a cortical area involved in multisensory processing in a ferret FASD model. These findings indicate an alteration in cortical networks that may be related to the multisensory processing deficiencies observed in FASD., (Copyright © 2018 by the Research Society on Alcoholism.)

How the newborn brain adapts to its new multisensory environment has been a subject of debate. Although an early theory proposed that the brain acquires multisensory features as a result of postnatal experience, recent studies have demonstrated that the neonatal brain is already capable of processing multisensory information. For multisensory processing to be functional, it is a prerequisite that multisensory convergence among neural connections occur. However, multisensory connectivity has not been examined in human neonates nor are its location(s) or afferent sources understood. We used resting state functional MRI (fMRI) in two independent cohorts of infants to examine the functional connectivity of two cortical areas known to be multisensory in adults: the intraparietal sulcus (IPS) and the superior temporal sulcus (STS). In the neonate, the IPS was found to demonstrate significant functional connectivity with visual association and somatosensory association areas, while the STS showed significant functional connectivity with the visual association areas, primary auditory cortex, and somatosensory association areas. Our findings establish that each of these areas displays functional communication with cortical regions representing various sensory modalities. This demonstrates the presence of cortical areas with converging sensory inputs, representing that the functional architecture needed for multisensory processing is already present within the first weeks of life.

The transcription factors CREB (cAMP response element binding factor), SRF (serum response factor), and MEF2 (myocyte enhancer factor 2) play critical roles in the mechanisms underlying neuronal plasticity. However, the role of the activation of these transcription factors in the different components of plasticity in vivo is not well known. In this study, we tested the role of CREB, SRF, and MEF2 in ocular dominance plasticity (ODP), a paradigm of activity-dependent neuronal plasticity in the visual cortex. These three proteins bind to the synaptic activity response element (SARE), an enhancer sequence found upstream of many plasticity-related genes (Kawashima et al., 2009; Rodríguez-Tornos et al., 2013), and can act cooperatively to express Arc , a gene required for ODP (McCurry et al., 2010). We used viral-mediated gene transfer to block the transcription function of CREB, SRF, and MEF2 in the visual cortex, and measured visually evoked potentials in awake male and female mice before and after a 7 d monocular deprivation, which allowed us to examine both the depression component (Dc-ODP) and potentiation component (Pc-ODP) of plasticity independently. We found that CREB, SRF, and MEF2 are all required for ODP, but have differential effects on Dc-ODP and Pc-ODP. CREB is necessary for both Dc-ODP and Pc-ODP, whereas SRF and MEF2 are only needed for Dc-ODP. This finding supports previous reports implicating SRF and MEF2 in long-term depression (required for Dc-ODP), and CREB in long-term potentiation (required for Pc-ODP). SIGNIFICANCE STATEMENT Activity-dependent neuronal plasticity is the cellular basis for learning and memory, and it is crucial for the refinement of neuronal circuits during development. Identifying the mechanisms of activity-dependent neuronal plasticity is crucial to finding therapeutic interventions in the myriad of disorders where it is disrupted, such as Fragile X syndrome, Rett syndrome, epilepsy, major depressive disorder, and autism spectrum disorder. Transcription factors are essential nuclear proteins that trigger the expression of gene programs required for long-term functional and structural plasticity changes. Our results elucidate the specific role of the transcription factors CREB, SRF, and MEF2 in the depression and potentiation components of ODP in vivo , therefore better informing future attempts to find therapeutic targets for diseases where activity-dependent plasticity is disrupted., (Copyright © 2017 the authors 0270-6474/17/376628-10$15.00/0.)

Severe and moderate traumatic brain injury (sTBI) often results in long-term cognitive deficits such as reduced processing speed and attention. The intraparietal sulcus (IPS) is a neocortical structure that plays a crucial role in the deeply interrelated processes of multi-sensory processing and top down attention. Therefore, we hypothesized that disruptions in the functional and structural connections of the IPS may play a role in the development of such deficits. To examine these connections, we used resting state magnetic resonance imaging (rsfMRI and diffusion kurtosis imaging (DKI) in a cohort of 27 patients with sTBI (29.3 ± 8.9 years) and 27 control participants (29.8 ± 10.3 years). Participants were prospectively recruited and received rsfMRI and neuropsychological assessments including the Automated Neuropsychological Assessment Metrics (ANAM) at greater than 6 months post-injury. A subset of participants received a DKI scan. Results suggest that patients with sTBI performed worse than control participants on multiple subtests of the ANAM suggesting reduced cognitive performance. Reduced resting state functional connectivity between the IPS and cortical regions associated with multi-sensory processing and the dorsal attention network was observed in the patients with sTBI. The patients also showed reduced structural integrity of the superior longitudinal fasciculus (SLF), a key white matter tract connecting the IPS to anterior frontal areas, as measured by reduced mean kurtosis (MK) and fractional anisotropy (FA) and increased mean diffusivity (MD). Further, this reduced structural integrity of the SLF was associated with a reduction in overall cognitive performance. These findings suggest that disruptions in the structural and functional connectivity of the IPS may contribute to chronic cognitive deficits experienced by these patients.

Exposure to alcohol and valproic acid (VPA) during pregnancy can lead to fetal alcohol spectrum disorders and fetal valproate syndrome, respectively. Altered social behavior is a hallmark of both these conditions and there is ample evidence showing that developmental exposure to alcohol and VPA affect social behavior in rodents. However, results from rodent models are somewhat difficult to translate to humans owing to the substantial differences in brain development, morphology, and connectivity. Since the cortex folding pattern is closely related to its specialization and that social behavior is strongly influenced by cortical structures, here we studied the effects of developmental alcohol and VPA exposure on the play behavior of the ferret, a gyrencephalic animal known for its playful nature. Animals were injected with alcohol (3.5g/kg, i.p.), VPA (200mg/kg, i.p.) or saline (i.p) every other day during the brain growth spurt period, between postnatal days 10 and 30. The play behavior of pairs of the same experimental group was evaluated 3 weeks later. Both treatments induced significant behavioral differences compared to controls. Alcohol and VPA exposed ferrets played less than saline treated ones, but while animals from the alcohol group displayed a delay in start playing with each other, VPA treated ones spent most of the time close to one another without playing. These findings not only extend previous results on the effects of developmental exposure to alcohol and VPA on social behavior, but make the ferret a great model to study the underlying mechanisms of social interaction., (Copyright © 2016. Published by Elsevier Ltd.)

Fetal alcohol spectrum disorder is the most common cause of mental disabilities in the western world. It has been quite established that acute alcohol exposure can dramatically affect astrocyte function. Because the effects of early alcohol exposure on cell physiology can persist into adulthood, we tested the hypothesis that ethanol exposure in ferrets during a period equivalent to the last months of human gestation leads to persistent changes in astrocyte secretome in vitro. Animals were treated with ethanol (3.5 g/kg) or saline between postnatal day (P)10-30. At P31, astrocyte cultures were made and cells were submitted to stable isotope labeling by amino acids. Twenty-four hour conditioned media of cells obtained from ethanol- or saline-treated animals (ET-CM or SAL-CM) were collected and analyzed by quantitative mass spectrometry in tandem with liquid chromatography. Here, we show that 65 out of 280 quantifiable proteins displayed significant differences comparing ET-CM to SAL-CM. Among the 59 proteins that were found to be reduced in ET-CM we observed components of the extracellular matrix such as laminin subunits α2, α4, β1, β2, and γ1 and the proteoglycans biglycan, heparan sulfate proteoglycan 2, and lumican. Proteins with trophic function such as insulin-like growth factor binding protein 4, pigment epithelium-derived factor, and clusterin as well as proteins involved on modulation of proteolysis such as metalloproteinase inhibitor 1 and plasminogen activator inhibitor-1 were also reduced. In contrast, pro-synaptogeneic proteins like thrombospondin-1, hevin as well as the modulator of extracelular matrix expression, angiotensinogen, were found increased in ET-CM. The analysis of interactome maps through ingenuity pathway analysis demonstrated that the amyloid beta A4 protein precursor, which was found reduced in ET-CM, was previously shown to interact with ten other proteins that exhibited significant changes in the ET-CM. Taken together our results strongly suggest that early exposure to teratogens such as alcohol may lead to an enduring change in astrocyte secretome. Despite efforts in prevention, fetal alcohol spectrum disorders are a major cause of mental disabilities. Here, we show that developmental exposure to alcohol lead to a persistent change in the pattern of proteins secreted (secretome) by astrocytes. This study is also the first mass spectrometry-based assessment of the astrocyte secretome in a gyrencephalic animal. Cover Image for this issue: doi: 10.1111/jnc.13320., (© 2016 International Society for Neurochemistry.)

Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte-secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Myrciaria dubia is an Amazonian fruit shrub that produces numerous bioactive phytochemicals, but is best known by its high L-ascorbic acid (AsA) content in fruits. Pronounced variation in AsA content has been observed both within and among individuals, but the genetic factors responsible for this variation are largely unknown. The goals of this research, therefore, were to assemble, characterize, and annotate the fruit transcriptome of M. dubia in order to reconstruct metabolic pathways and determine if multiple pathways contribute to AsA biosynthesis., Results: In total 24,551,882 high-quality sequence reads were de novo assembled into 70,048 unigenes (mean length = 1150 bp, N50 = 1775 bp). Assembled sequences were annotated using BLASTX against public databases such as TAIR, GR-protein, FB, MGI, RGD, ZFIN, SGN, WB, TIGR&#95;CMR, and JCVI-CMR with 75.2 % of unigenes having annotations. Of the three core GO annotation categories, biological processes comprised 53.6 % of the total assigned annotations, whereas cellular components and molecular functions comprised 23.3 and 23.1 %, respectively. Based on the KEGG pathway assignment of the functionally annotated transcripts, five metabolic pathways for AsA biosynthesis were identified: animal-like pathway, myo-inositol pathway, L-gulose pathway, D-mannose/L-galactose pathway, and uronic acid pathway. All transcripts coding enzymes involved in the ascorbate-glutathione cycle were also identified. Finally, we used the assembly to identified 6314 genic microsatellites and 23,481 high quality SNPs., Conclusions: This study describes the first next-generation sequencing effort and transcriptome annotation of a non-model Amazonian plant that is relevant for AsA production and other bioactive phytochemicals. Genes encoding key enzymes were successfully identified and metabolic pathways involved in biosynthesis of AsA, anthocyanins, and other metabolic pathways have been reconstructed. The identification of these genes and pathways is in agreement with the empirically observed capability of M. dubia to synthesize and accumulate AsA and other important molecules, and adds to our current knowledge of the molecular biology and biochemistry of their production in plants. By providing insights into the mechanisms underpinning these metabolic processes, these results can be used to direct efforts to genetically manipulate this organism in order to enhance the production of these bioactive phytochemicals. The accumulation of AsA precursor and discovery of genes associated with their biosynthesis and metabolism in M. dubia is intriguing and worthy of further investigation. The sequences and pathways produced here present the genetic framework required for further studies. Quantitative transcriptomics in concert with studies of the genome, proteome, and metabolome under conditions that stimulate production and accumulation of AsA and their precursors are needed to provide a more comprehensive view of how these pathways for AsA metabolism are regulated and linked in this species.

The Bax gene is a member of the Bcl-2 gene family and its pro-apoptotic Bcl-associated X (Bax) protein is believed to be crucial in regulating apoptosis during neuronal development as well as following injury. With the advent of mouse genomics, mice lacking the pro-apoptotic Bax gene (Bax KO) have been extensively used to study how cell death helps to determine synaptic circuitry formation during neurodevelopment and disease. Surprisingly, in spite of its wide use and the association of programmed neuronal death with motor dysfunctions and depression, the effects of Bax deletion on mice spontaneous locomotor activity and depression-like traits are unknown. Here we examine the behavioral characteristics of Bax KO male mice using classical paradigms to evaluate spontaneous locomotor activity and depressive-like responses. In the open field, Bax KO animals exhibited greater locomotor activity than their control littermates. In the forced swimming test, Bax KO mice displayed greater immobility times, a behavior despair state, when compared to controls. Collectively, our findings corroborate the notion that a fine balance between cell survival and death early during development is critical for normal brain function later in life. Furthermore, it points out the importance of considering depressive-like and hyperactivity behavioral phenotypes when conducting neurodevelopmental and other studies using the Bax KO strain., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Deficits in neuronal plasticity underlie many neurobehavioral and cognitive problems presented in fetal alcohol spectrum disorder (FASD). Our laboratory has developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance plasticity (ODP). For instance, a few days of monocular deprivation results in a robust reduction of visual cortex neurons' responsiveness to stimulation of the deprived eye in normal animals, but not in ferrets with early alcohol exposure. Previously our laboratory demonstrated that overexpression of serum response factor (SRF) exclusively in astrocytes can improve neuronal plasticity in FASD. Here, we test whether neuronal overexpression of SRF can achieve similar effects., Methods: Ferrets received 3.5 g/kg alcohol intraperitoneally (25% in saline) or saline as control every other day between postnatal day 10 to 30, which is roughly equivalent to the third trimester of human gestation. Animals were given intracortical injections of a Herpes Simplex Virus-based vector to express either green fluorescent protein or a constitutively active form of SRF in infected neurons. They were then monocularly deprived by eyelid suture for 4 to 5 days after which single-unit recordings were conducted to determine whether changes in ocular dominance had occurred., Results: Overexpression of a constitutively active form of SRF by neurons restored ODP in alcohol-treated animals. This effect was observed only in areas near the site of viral infection., Conclusions: Overexpression of SRF in neurons can restore plasticity in the ferret model of FASD, but only in areas near the site of infection. This contrasts with SRF overexpression in astrocytes which restored plasticity throughout the visual cortex., (Copyright © 2015 by the Research Society on Alcoholism.)

Background: Neuronal plasticity deficits are thought to underlie abnormal neurodevelopment in fetal alcohol spectrum disorders and in animal models of this condition. Previously, we found that alcohol exposure during a period that is similar to the last months of gestation in humans disrupts ocular dominance plasticity (ODP), as measured in superficial cortical layers. We hypothesize that exposure to alcohol can differentially affect the potentiation and depression of responses that are necessary for activity-dependent sprouting and pruning of neuronal networks. ODP is an established paradigm that allows the assessment of activity-dependent depression and potentiation of responses in vivo., Methods: Mouse pups were exposed to 3.6 to 5 g/kg of ethanol in saline daily or every other day between postnatal days 4 and 9. Visual cortex plasticity was then assessed during the critical period for ODP using 2 techniques that separately record in layers 4 (visually evoked potentials [VEPs]) and 2/3 (optical imaging of intrinsic signals [OI])., Results: We discovered a layer-specific effect of early alcohol exposure. Recording of VEPs from layer 4 showed that while the potentiation component of ODP was disrupted in animals treated with alcohol when compared with saline controls, the depression component of ODP (Dc-ODP) was unaltered. In contrast, OI from layers 2/3 showed that Dc-ODP was markedly disrupted in alcohol-treated animals when compared with controls., Conclusions: Combined with our previous work, these findings strongly suggest that developmental alcohol exposure has a distinct and layer-specific effect on the potentiation and depression of cortical responses after monocular deprivation., (Copyright © 2015 by the Research Society on Alcoholism.)

The 2013 Fetal Alcohol Spectrum Disorders Study Group (FASDSG) meeting was held in Orlando (Grand Cypress), FL with the theme "Developing Brain-Based Interventions for Individuals with Fetal Alcohol Spectrum Disorders." Children with fetal alcohol spectrum disorders have significant impairments in cognitive functioning and behavioral regulation skills, which lead to a lifetime of challenges for themselves and their families; thus, developing interventions that remediate or compensate for these deficits is of great importance. The conference included 2 keynote presentations, FASt data talks, award presentations, and updates by government agencies. In addition, a lively panel discussion addressed the challenges faced by FASDSG researchers in the translation of intervention strategies developed in preclinical studies to clinical trials and, ultimately, to clinical practice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Alcohol consumption during pregnancy can lead to a multitude of neurological problems in offspring, varying from subtle behavioral changes to severe mental retardation. These alterations are collectively referred to as Fetal Alcohol Spectrum Disorders (FASD). Early alcohol exposure can strongly affect the visual system and children with FASD can exhibit an amblyopia-like pattern of visual acuity deficits even in the absence of optical and oculomotor disruption. Here, we test whether early alcohol exposure can lead to a disruption in visual acuity, using a model of FASD to mimic alcohol consumption in the last months of human gestation. To accomplish this, mice were exposed to ethanol (5 g/kg i.p.) or saline on postnatal days (P) 5, 7, and 9. Two to three weeks later we recorded visually evoked potentials to assess spatial frequency detection and contrast sensitivity, conducted electroretinography (ERG) to further assess visual function and imaged retinotopy using optical imaging of intrinsic signals. We observed that animals exposed to ethanol displayed spatial frequency acuity curves similar to controls. However, ethanol-treated animals showed a significant deficit in contrast sensitivity. Moreover, ERGs revealed a market decrease in both a- and b-waves amplitudes, and optical imaging suggest that both elevation and azimuth maps in ethanol-treated animals have a 10-20° greater map tilt compared to saline-treated controls. Overall, our findings suggest that binge alcohol drinking restricted to the last months of gestation in humans can lead to marked deficits in visual function.

Objective: The purposes of this article are to review the treatment options for late-stage biventricular heart failure, discuss the clinical indications for total artificial heart (TAH) implantation, illustrate the expected imaging findings after uncomplicated TAH implantation, and highlight the radiologic findings of common and uncommon complications associated with TAH implantation through case examples., Conclusion: TAH implantation is an effective therapeutic option for the treatment of patients with end-stage biventricular heart failure. The duration of implantation varies depending on a particular patient's medical condition and the eventual availability of a human heart for orthotopic transplantation. TAH recipients often undergo imaging with conventional radiography, CT, or both for the assessment of device-related issues, many of which are life-threatening and require emergency management. As the clinical use of the TAH increases and becomes more commonplace, it is imperative that radiologists interpreting imaging studies recognize both the expected and the unexpected imaging findings that affect patient care.

Background: Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND), including memory dysfunction, continue to be a major clinical manifestation of HIV type-1 infection. Viral proteins released by infected glia are thought to be the principal triggers of inflammation and bystander neuronal injury and death, thereby driving key symptomatology of HAND., Methods: We used a glial fibrillary acidic protein-driven, doxycycline-inducible HIV type-1 transactivator of transcription (Tat) transgenic mouse model and examined structure-function relationships in hippocampal pyramidal cornu ammonis 1 (CA1) neurons using morphologic, electrophysiological (long-term potentiation [LTP]), and behavioral (Morris water maze, fear-conditioning) approaches., Results: Tat induction caused a variety of different inclusions in astrocytes characteristic of lysosomes, autophagic vacuoles, and lamellar bodies, which were typically present within distal cytoplasmic processes. In pyramidal CA1 neurons, Tat induction reduced the number of apical dendritic spines, while disrupting the distribution of synaptic proteins (synaptotagmin 2 and gephyrin) associated with inhibitory transmission but with minimal dendritic pathology and no evidence of pyramidal neuron death. Electrophysiological assessment of excitatory postsynaptic field potential at Schaffer collateral/commissural fiber-CA1 synapses showed near total suppression of LTP in mice expressing Tat. The loss in LTP coincided with disruptions in learning and memory., Conclusions: Tat expression in the brain results in profound functional changes in synaptic physiology and in behavior that are accompanied by only modest structural changes and minimal pathology. Tat likely contributes to HAND by causing molecular changes that disrupt synaptic organization, with inhibitory presynaptic terminals containing synaptotagmin 2 appearing especially vulnerable., (Published by Elsevier Inc.)

The brain is extremely vulnerable to teratogenic insults during the brain growth spurt, a period that starts during the third trimester of human gestation and is characterized by synaptogenesis establishment of neuronal circuits. While the treatment of epilepsy during pregnancy increases the risk of neurodevelopmental disorders in offspring, the consequences of exposure to anticonvulsants during the brain growth spurt remain poorly known. Here we investigate whether exposure to sodium valproate (VPA) during a similar period in rats impairs spatial learning of juvenile rats. Long-Evans rats were exposed to VPA (200mg/kg) or saline solution (SAL) every other day between postnatal day (PN) 4 and PN10. At PN23 and PN30, Morris water maze performance was evaluated during 6 consecutive days. In the group of animals which started their tests at PN23, the VPA exposure impaired both, swimming speed and learning/memory performance. Interestingly, no differences were observed between VPA and control animals tested from PN30 to PN35. Our data suggests that the neurobehavioral deficits caused by VPA exposure during the brain growth spurt are transitory., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Neuronal plasticity deficits underlie many of the cognitive problems seen in fetal alcohol spectrum disorders (FASD). We have developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. Recently, we showed that this deficit could be reversed by overexpression of serum response factor (SRF) in the primary visual cortex during the period of monocular deprivation (MD). Surprisingly, this restoration was observed throughout the extent of visual cortex and most of the cells transfected by the virus were positive for the astrocytic marker GFAP rather than the neuronal marker NeuN. Here we test whether overexpression of SRF exclusively in astrocytes is sufficient to restore OD plasticity in alcohol-exposed ferrets. To accomplish that, first we exposed cultured astrocytes to Sindbis viruses carrying either a constitutively active form of SRF (SRF+), a dominant negative (SRF-) or control Green Fluorescent Protein (GFP). After 24h, these astrocytes were implanted in the visual cortex of alcohol-exposed animals or saline controls one day before MD. Optical imaging of intrinsic signals showed that alcohol-exposed animals that were implanted with astrocytes expressing SRF, but not SRF- or GFP, showed robust restoration of OD plasticity in all visual cortex. These findings suggest that overexpression of SRF exclusively in astrocytes can improve neuronal plasticity in FASD., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

There is growing evidence that deficits in neuronal plasticity underlie the cognitive problems seen in fetal alcohol spectrum disorders (FASD). However, the mechanisms behind these deficits are not clear. Here we test the effects of early alcohol exposure on ocular dominance plasticity (ODP) in mice and the reversibility of these effects by phosphodiesterase (PDE) inhibitors. Mouse pups were exposed to 5 g/kg of 25% ethanol i.p. on postnatal days (P) 5, 7 and 9. This type of alcohol exposure mimics binge drinking during the third trimester equivalent of human gestation. To assess ocular dominance plasticity animals were monocularly deprived at P21 for 10 days, and tested using optical imaging of intrinsic signals. During the period of monocular deprivation animals were treated with vinpocetine (20mg/kg; PDE1 inhibitor), rolipram (1.25mg/kg; PDE4 inhibitor), vardenafil (3mg/kg; PDE5 inhibitor) or vehicle solution. Monocular deprivation resulted in the expected shift in ocular dominance of the binocular zone in saline controls but not in the ethanol group. While vinpocetine successfully restored ODP in the ethanol group, rolipram and vardenafil did not. However, when rolipram and vardenafil were given simultaneously ODP was restored. PDE4 and PDE5 are specific to cAMP and cGMP respectively, while PDE1 acts on both of these nucleotides. Our findings suggest that the combined activation of the cAMP and cGMP cascades may be a good approach to improve neuronal plasticity in FASD models., (Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.)

Background: A web-based registry was used to prospectively study patients after minimally invasive surgery with monitoring to determine freedom from atrial fibrillation (AF) (clinicaltrials.gov/ct2/show/NCT00747838). This is a report showing the utility and feasibility of the registry., Methods: All patients had symptomatic AF refractory to medical treatment. Surgical ablation was performed using bipolar radiofrequency (RF) energy with a clamp around pulmonary veins and additional RF was delivered to ablate ganglionic plexi and create linear lesions. After a 3-month blanking period, prolonged electrocardiogram monitoring was done at 6 months, 1 year, and 2 years. Success was defined as no episodes of AF and atrial tachyarrhythmias greater than 30 seconds by monitoring., Results: A total of 118 patients were studied from 4 institutions from June 2006 to February 2011. Seventy-two patients were male (61%). The mean age was 64±9 years. CHADS2 (Congestive heart failure, Hypertension, age greater than 75, Diabetes and Stroke score for risk of thromboembolic events in patients with atrial fibrillation) was 1.3. Warfarin was used in 92 (78%), antiarrhythmic medications in 108 (92%), and 35 (30%) had previous catheter ablation. Paroxysmal AF was present in 80 (68%), persistent AF present in 35 (30%), and long-standing persistent present in 3 (2%). The mean left atrial size was 4.4 cm. The surgical approach was bilateral minithoracotomy in 69 (58%) and totally thoracoscopic in 49 (42%). The left atrial appendage was excluded or excised in 112 (95%) patients. There were no deaths related to the procedure. Only 5 (4%) patients required ventilation greater than 24 hours; permanent pacemaker was needed in 3 (2%) patients. Mean length of hospital stay was 5 days. At a mean follow-up of 16.5 months, 80% of patients were free of AF off antiarrhythmic medications with long-term monitoring. Quality of life data showed significant improvement at 6 and 12 months., Conclusions: The STAR (stable angina in practice) registry is an effective web-based tool for long-term follow-up of patients after surgery for AF. Minimally invasive surgery with lesions created by bipolar RF energy is an effective treatment for AF in carefully selected patients., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The ingestion of alcohol during pregnancy can result in a group of neurobehavioral abnormalities collectively known as fetal alcohol spectrum disorders (FASD). During the past decade, studies using animal models indicated that early alcohol exposure can dramatically affect neuronal plasticity, an essential property of the central nervous system responsible for the normal wiring of the brain and involved in processes such as learning and memory. The abnormalities in neuronal plasticity caused by alcohol can explain many of the neurobehavioral deficits observed in FASD. Conversely, improving neuronal plasticity may have important therapeutic benefits. In this review, the author discuss the mechanisms that lead to these abnormalities and comment on recent pharmacological approaches that have been showing promising results in improving neuronal plasticity in FASD.

Epilepsy is one of the most common neurologic disorders and affects 0.5 to 1% of pregnant women. The use of antiepileptic drugs, which is usually continued throughout pregnancy, can cause in offspring mild to severe sensory deficits. Neuronal selectivity to stimulus orientation is a basic functional property of the visual cortex that is crucial for perception of shapes and borders. Here we investigate the effects of early exposure to valproic acid (Val) and levetiracetam (Lev), commonly used antiepileptic drugs, on the development of cortical neuron orientation selectivity and organization of cortical orientation columns. Ferrets pups were exposed to Val (200mg/kg), Lev (100mg/kg) or saline every other day between postnatal day (P) 10 and P30, a period roughly equivalent to the third trimester of human gestation. Optical imaging of intrinsic signals or single-unit recordings were examined at P42-P84, when orientation selectivity in the ferret cortex has reached a mature state. Optical imaging of intrinsic signals revealed decreased contrast of orientation maps in Val- but not Lev- or saline-treated animals. Moreover, single-unit recordings revealed that early Val treatment also reduced orientation selectivity at the cellular level. These findings indicate that Val exposure during a brief period of development disrupts cortical processing of sensory information at a later age and suggest a neurobiological substrate for some types of sensory deficits in fetal anticonvulsant syndrome., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Neuronal plasticity is an essential property of the brain that is impaired in different neurological conditions. Phosphodiesterase type 1 (PDE1) inhibitors can enhance levels of the second messengers cAMP/cGMP leading to the expression of neuronal plasticity-related genes, neurotrophic factors, and neuroprotective molecules. These neuronal plasticity enhancement properties make PDE1 inhibitors good candidates as therapeutic agents in many neurological conditions. However, the lack of specificity of the drugs currently available poses a challenge to the systematic evaluation of the beneficial effect of these agents. The development of more specific drugs may pave the way for the use of PDE1 inhibitors as therapeutic agents in cases of neurodevelopmental conditions such as fetal alcohol spectrum disorders and in degenerative disorders such as Alzheimer's and Parkinson's.

Classic experiments have indicated that monocular deprivation (MD) for a few days during a critical period of development results in a decrease in the strength of connections mediating responses to the deprived eye, leading to a dramatic breakdown of cortical neuron binocularity. Despite the substantial functional change in the visual cortex, recovery from the effects of MD can be obtained if binocular vision is promptly restored. While great efforts have been made to elucidate the mechanisms regulating loss of deprived eye function, the mechanisms that underlie the recovery of cortical binocularity are poorly understood. Here, we examined whether activation of the N-methyl-d-aspartate receptor (NMDAR) is required for the recovery of cortical binocularity by pharmacologically blocking the NMDAR using d,l-2-amino-5-phosphonopentanoic (APV). Ferrets (n = 10) were monocularly deprived for 6 days, and osmotic minipumps, filled with APV (5.6 mg/ml) or saline, were surgically implanted into the primary visual cortex. One day after surgery, the deprived eye was reopened, and the animals were allowed 24 h of binocular vision. Extracellular recordings showed that intracortical infusion of the NMDAR antagonist, APV, prevented recovery of cortical binocularity while preserving neuronal responsiveness. These findings provide an important new insight for a specific role of NMDARs in the recovery of cortical binocularity from the effects of MD.

Deficits in learning and memory have been extensively observed in animal models of fetal alcohol spectrum disorders (FASD). Here we use the Morris maze to test whether vinpocetine, a phosphodiesterase type 1 inhibitor, restores learning performance in rats exposed to alcohol during the third trimester equivalent of human gestation. Long Evans rats received ethanol (5g/kg i.p.) or saline on alternate days from postnatal day (P) 4 to P10. Two weeks later (P25), the latency to find a hidden platform was evaluated (2 trials per day spaced at 40-min inter-trial intervals) during 4 consecutive days. Vinpocetine treatment started on the first day of behavioral testing: animals received vinpocetine (20mg/kg i.p.) or vehicle solution every other day until the end of behavioral procedures. Early alcohol exposure significantly affected the performance to find the hidden platform. The average latency of ethanol-exposed animals was significantly higher than that observed for the control group. Treatment of alcohol-exposed animals with vinpocetine restored their performance to control levels. Our results show that inhibition of PDE1 improves learning and memory deficits in rats early exposed to alcohol and provide evidence for the potential therapeutic use of vinpocetine in FASD., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: There is growing evidence that deficits in neuronal plasticity account for some of the neurological problems observed in fetal alcohol spectrum disorders (FASD). Recently, we showed that early alcohol exposure results in a permanent impairment in visual cortex ocular dominance (OD) plasticity in a ferret model of FASD. This disruption can be reversed, however, by treating animals with a Phosphodiesterase (PDE) type 1 inhibitor long after the period of alcohol exposure., Aim: Because the mammalian brain presents different types of PDE isoforms we tested here whether inhibition of PDE type 4 also ameliorates the effects of alcohol on OD plasticity., Material and Methods: Ferrets received 3.5 g/Kg alcohol i.p. (25% in saline) or saline as control every other day between postnatal day (P) 10 to P30, which is roughly equivalent to the third trimester equivalent of human gestation. Following a prolonged alcohol-free period (10 to 15 days), ferrets had the lid of the right eye sutured closed for 4 days and were examined for ocular dominance changes at the end of the period of deprivation., Results: Using in vivo electrophysiology we show that inhibition of PDE4 by rolipram does not restore OD plasticity in alcohol-treated ferrets., Conclusion: This result suggests that contrary to PDE1, PDE4 inhibition does not play a role in the restoration of OD plasticity in the ferret model of FASD.

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Recently, we showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. For instance, a few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility, and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single-unit recordings, we observed that overexpression of a constitutively active form of SRF, but neither its dominant-negative nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. This finding suggests that overexpression of SRF in astrocytes may reduce the deficits in neuronal plasticity seen in models of FASD.