Treatment In Adulthood Research Articles

The Impact of Neonatal Methamphetamine on Spatial Learning and Memory in Adult Female Rats.

The present study was aimed at evaluating cognitive changes following neonatal methamphetamine exposure in combination with repeated treatment in adulthood of female Wistar rats. Pregnant dams and their pups were used in this study. One half of the offspring were treated indirectly via the breast milk of injected mothers, and the other half of pups were treated directly by methamphetamine injection. In the group with indirect exposure, mothers received methamphetamine (5 mg/ml/kg) or saline (1 ml/kg) between postnatal days (PD) 1–11. In the group with direct exposure, none of the mothers were treated. Instead, progeny were either: (1) treated with injected methamphetamine (5 mg/ml/kg); or (2) served as controls and received sham injections (no saline, just a needle stick) on PD 1–11. Learning ability and memory consolidation were tested on PD 70–90 in the Morris Water Maze (MWM) using three tests: Place Navigation Test, Probe Test, and Memory Recall Test. Adult female progeny were injected daily, after completion of the last trial of MWM tests, with saline or methamphetamine (1 mg/ml/kg). The effects of indirect/direct neonatal methamphetamine exposure combined with acute adult methamphetamine treatment on cognitive functions in female rats were compared. Statistical analyses showed that neonatal drug exposure worsened spatial learning and the ability to remember the position of a hidden platform. The study also demonstrated that direct methamphetamine exposure has a more significant impact on learning and memory than indirect exposure. The acute dose of the drug did not produce any changes in cognitive ability. Analyses of search strategies (thigmotaxis, scanning) used by females during the Place Navigation Test and Memory Recall Test confirmed all these results. Results from the present study suggested extensive deficits in learning skills and memory of female rats that may be linked to the negative impact of neonatal methamphetamine exposure.

Parenting style during childhood is associated with the development of chronic pain and a patient's need for psychosomatic treatment in adulthood

The aim of this study is to investigate the relation between parenting style and chronic pain and the patients' need for psychosomatic treatment in adulthood.We compared 4 combinations of 2 parenting style subscales, high and low care and overprotection, among the following 4 age- and sex-matched groups: community-dwelling subjects without chronic pain (n = 100), community-dwelling subjects with chronic pain (n = 100), outpatients with chronic pain (n = 50), and inpatients with chronic pain (n = 50). Parenting style was assessed for both the mother and father by use of the Parental Bonding Instrument questionnaire. The parenting style associated with the worst outcome was defined as both low care and high overprotection, as reported in previous studies.The frequency of reported adverse parenting style was significantly higher among chronic pain patients than community-dwelling subjects without chronic pain (all P < .05). The odds ratios for an adverse parenting style significantly increased through the categories after adjusting for demographic factors and the pain visual analog scale (P for trend <.01).These findings suggest that parental low care and high overprotection during childhood contribute to the future risk of chronic pain and the patients' need for psychosomatic treatment in adulthood.

Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders

SummaryAberrant expression ratio of Cl− transporters, NKCC1 and KCC2, is implicated in several brain conditions. NKCC1 inhibition by the FDA-approved diuretic drug, bumetanide, rescues core symptoms in rodent models and/or clinical trials with patients. However, bumetanide has a strong diuretic effect due to inhibition of the kidney Cl− transporter NKCC2, creating critical drug compliance issues and health concerns. Here, we report the discovery of a new chemical class of selective NKCC1 inhibitors and the lead drug candidate ARN23746. ARN23746 restores the physiological intracellular Cl− in murine Down syndrome neuronal cultures, has excellent solubility and metabolic stability, and displays no issues with off-target activity in vitro. ARN23746 recovers core symptoms in mouse models of Down syndrome and autism, with no diuretic effect, nor overt toxicity upon chronic treatment in adulthood. ARN23746 is ready for advanced preclinical/manufacturing studies toward the first sustainable therapeutics for the neurological conditions characterized by impaired Cl− homeostasis.

Dealing With Uncertainty and Lack of Knowledge in Diverse Sex Development: Controversies on Early Surgery and Questions of Consent.

IntroductionDiverse sex development (dsd) is an umbrella term for different congenital conditions with incongruence of chromosomal, gonadal, and phenotypic sex characteristics. These are accompanied by various uncertainties concerning health-related, medical, psychosocial, and legal issues that raise controversial discussion.AimThe aim of this exploratory study was to investigate 3 questions: What are the most controversial and disputed issues in the context of intersex/dsd? Which issues are associated with the biggest knowledge gaps? Which issues involve the greatest difficulty or uncertainty in decision-making? A further aim was to investigate whether the group of persons concerned, the parents of intersex children, and the group of experts in the field had differing views regarding these questions.MethodsA self-developed questionnaire was distributed among persons concerned, parents of children with intersex/dsd, and experts in the field. It contained open and multiple-choice questions. The answers from 29 participants were entered into data analysis. A mixed-method approach was applied. Quantitative data were analysed descriptively. Qualitative data were analysed according to the principles of qualitative content analysis.Main Outcome MeasureParticipants answered questions on the most controversial and disputed issues, issues associated with the biggest knowledge gaps, and issues associated with the most difficulty or uncertainty in decision-making.ResultsThe findings indicate that controversial issues and uncertainties mainly revolve around surgical interventions but also around the question of how to adequately consider the consent of minors and how to deal with intersex in the family. Significant differences were found between persons concerned and parents vs academic experts in the field regarding the perceptions of procedure of diagnostic investigation and/or treatment in adulthood, on legal questions concerning marriage/registered civil partnerships, and on lack of psychosocial counseling close to place of residence.ConclusionThe necessity of irreversible gonadal and genital surgery in early childhood is still a matter of strong controversy. To ensure the improvement in well-being of intersex persons, including a sexual health perspective, the positive acceptance of bodily variance is an important prerequisite. Psychosocial support regarding one-time decisions as well as ongoing and changing issues of everyday life appears to be an important means in reaching overall quality of life.Lampalzer U, Briken P, Schweizer K. Dealing With Uncertainty and Lack of Knowledge in Diverse Sex Development: Controversies on Early Surgery and Questions of Consent—A Pilot Study. Sex Med 2020;8:472–489.

ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability.

Oligophrenin-1 (Ophn1) encodes a Rho GTPase activating protein whose mutations cause X-linked intellectual disability (XLID) in humans. Loss of function of Ophn1 leads to impairments in the maturation and function of excitatory and inhibitory synapses, causing deficits in synaptic structure, function and plasticity. Epilepsy is a frequent comorbidity in patients with Ophn1-dependent XLID, but the cellular bases of hyperexcitability are poorly understood. Here we report that male mice knock-out (KO) for Ophn1 display hippocampal epileptiform alterations, which are associated with changes in parvalbumin-, somatostatin- and neuropeptide Y-positive interneurons. Because loss of function of Ophn1 is related to enhanced activity of Rho-associated protein kinase (ROCK) and protein kinase A (PKA), we attempted to rescue Ophn1-dependent pathological phenotypes by treatment with the ROCK/PKA inhibitor fasudil. While acute administration of fasudil had no impact on seizure activity, seven weeks of treatment in adulthood were able to correct electrographic, neuroanatomical and synaptic alterations of Ophn1 deficient mice. These data demonstrate that hyperexcitability and the associated changes in GABAergic markers can be rescued at the adult stage in Ophn1-dependent XLID through ROCK/PKA inhibition.SIGNIFICANCE STATEMENT In this study we demonstrate enhanced seizure propensity and impairments in hippocampal GABAergic circuitry in Ophn1 mouse model of X-linked intellectual disability (XLID). Importantly, the enhanced susceptibility to seizures, accompanied by an alteration of GABAergic markers were rescued by Rho-associated protein kinase (ROCK)/protein kinase A (PKA) inhibitor fasudil, a drug already tested on humans. Because seizures can significantly impact the quality of life of XLID patients, the present data suggest a potential therapeutic pathway to correct alterations in GABAergic networks and dampen pathological hyperexcitability in adults with XLID.

Changes in Neuroimmune and Neuronal Death Markers after Adolescent Alcohol Exposure in Rats are Reversed by Donepezil

Adolescent intermittent ethanol (AIE) exposure diminishes neurogenesis and dendritic spine density in the dentate gyrus. The cholinesterase inhibitor, donepezil (Aricept), reverses AIE effects on dendritic spines, possibly by interacting with inflammatory and/or epigenetic mediators after AIE exposure. This study tests the hypothesis that donepezil reverses AIE-induced neuroimmune, and epigenetic changes in the adult dentate gyrus. Adolescent Sprague-Dawley male rats (PD30-43) were given 10 intermittent, intragastric doses of ethanol (5.0 g/kg) or isovolumetric water (AIW). Twenty-one days later half of the animals from each group were treated with either donepezil or isovolumetric water (i.g.) once daily for four days. Two hours after the last donepezil or water dose animals were sacrificed and brains prepared for immunohistochemical analyses. AIE reduced immunoreactivity for doublecortin (DCX) and increased immunoreactivity for activated caspase-3 and death receptor-3 in adulthood, suggesting an enduring attenuation of neurogenesis and an increase in progenitor death. These effects were reversed by donepezil treatment in adulthood. AIE also increased immunoreactivity for the inflammatory signaling molecules HMGB1 and RAGE, as well as the activated phosphorylated transcription factor pNFκB p65, and the gene silencing marker dimethylated histone H3K9. All of these AIE effects were also reversed by donepezil, with the exception of HMGB1.

The clinical presentation in adulthood of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is a chronic systemic inflammatory disease, which affects children and adolescents, characterized by significant differences when compared to inflammatory rheumatisms in adulthood. Today, in a panorama enriched in the last decades with great improvements in the diagnostic and therapeutic field, a far from negligible portion and an increasing number of patients with JIA require the continuation of treatments in adulthood. This specific population of patients, given the high incidence of extra-articular manifestations, residual irreversible disabilities, comorbidities related to an inflammatory process and extended immunosuppressive treatments during the age of development, requires precise attentions in the follow-up and a multidisciplinary approach characterized by different clinical, psychological and social aspects.

Prenatal EDC Exposure Followed by Chronic Treatment with Estradiol Affects Brain Monoamine Levels in Female Rats

In utero exposure to low doses of endocrine disrupting chemicals (EDCs), in particular the widely prevalent plasticizers bisphenol A (BPA) and di(2‐ethylhexyl) phthalate (DEHP), has been shown to produce long‐lasting behavioral effects in rats. Additionally, changes in estrogen are associated with the development of affective disorders in women; however, the underlying neurobiological mechanisms are unclear. A previous study from our lab found that chronic estradiol treatment led to decreased dopamine (DA) levels within the central amygdala (CeA). This study was conducted to further examine the cumulative effects of prenatal exposure to EDCs followed by chronic estradiol exposure in adult female rats on DA levels in stress‐related brain areas. Dams were orally administered saline (control; 10 μL/kg), BPA (B; 5 μg/kg), DEHP (D; 7.5 mg/kg) or a combination of BPA+DEHP (B+D) during days 6 through 21 of pregnancy. Adult female offspring were sham‐implanted or implanted with pellets that release 17β‐estradiol (E2) for 90 days (20 ng/day; Innovative Research America). The offspring then underwent a battery of behavioral tests at the end of treatment. Brains collected from the offspring were sectioned and the CeA, hippocampus (HC), and prefrontal cortex (PFC) were microdissected and analyzed for levels of DA using High‐Performance Liquid Chromatography (HPLC). Prenatal exposure to DEHP and/or B+D, but not B, was significantly associated with reductions in DA levels in the CeA and PFC. Within the CeA, only B+D‐E2 treated offspring showed a significant decrease in DA (p&lt;0.05) in comparison with control offspring. Levels of DA were found to be lower in the PFC as well, particularly in D‐sham (p&lt;0.05), D‐E2 (p&lt;0.01), and B+D‐E2 (p&lt;0.05) offspring compared to controls. No differences were observed in hippocampal DA levels in any of the treatment groups. These results indicate that prenatal exposure to DEHP or a mixture of EDCs in females may lead to alterations in monoamine levels in a region‐specific manner, and E2 treatment in adulthood may exacerbate these effects.Support or Funding InformationUniversity of Georgia Research Foundation and start‐up funds.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Unilateral application of cathodal tDCS reduces transcallosal inhibition and improves visual acuity in amblyopic patients

Amblyopia is a neurodevelopmental disorder characterized by visual acuity and contrast sensitivity loss, refractory to pharmacological and optical treatments in adulthood. We studied the response of the visual cortex to transcranial Direct Current Stimulation (tDCS) applied over the primary visual area (V1) contralateral to the “lazy eye”. Visual acuity (logMAR) was assessed before (T0), immediately after (T1) and 60′ following the application of cathodal tDCS (2.0 mA, 20′). At each time point, Visual Evoked Potentials (VEPs) triggered by grating stimuli of different contrasts (K90%, K20%) were recorded in both hemispheres and compared to those obtained in healthy volunteers. Cathodal tDCS improved visual acuity (Holm–Sidak, p

Development of the transition-age program (TAP): Review of a pilot psychosocial multidisciplinary transition program in a Level 4 epilepsy center

Approximately 50% of patients diagnosed with epilepsy in childhood will need treatment in adulthood. Transition from pediatric to adult epilepsy care is challenging, and an unsuccessful transition can have detrimental effects. Researchers emphasize the importance of addressing possible barriers to transition in a multidisciplinary setting. In this paper, we describe a transition program implemented in a Level 4 epilepsy center in the Midwest. This program involves a psychosocial multidisciplinary team including a pediatric neuropsychologist, pediatric psychologist, and social worker who meet jointly with patient and his/her caregiver(s) before and after the transition. The pretransition visit involves assessment of transition readiness, screening for neurobehavioral comorbidities, provision of education regarding epilepsy care during the transition period, goal-setting, and development of a portable summary. The posttransition visit revisits goals and provides additional individualized recommendations and/or referrals for intervention as clinically indicated. The goal of this program is to facilitate a smooth transition from pediatric to adult providers to ensure optimal epilepsy care and quality of life.

Do children with Dravet syndrome continue to benefit from stiripentol for long through adulthood?

To evaluate continuing stiripentol treatment in adulthood in Dravet syndrome (DS). Longitudinal data were collected from the last visit prior to age 15years (V15y ) to the last visit in adulthood (Vadult ) in the 40 DS patients (32 typical, eight atypical) of a French historical cohort (Paris) of subjects who continued stiripentol from childhood or adolescence to adulthood. At Vadult (18-40years, median = 23years), all the patients were still receiving stiripentol (exposure = 3-24years, median = 18years), associated with clobazam (40/40), valproate (39/40), and topiramate (21/40). Between V15y and Vadult , stiripentol was interrupted in five patients (two for adverse events) but reintroduced following seizure aggravation. Loss of appetite affected 15 of 40 patients but resolved after reducing the dose of stiripentol or valproate; no other new stiripentol-related adverse events were reported. Mean stiripentol dose was progressively decreased from 39 to 25mg/kg/d (P=0.0002), whereas clobazam (0.27mg/kg/d) and valproate (14mg/kg/d) remained stable. At Vadult , 37 of 40 patients still had generalized tonic-clonic seizures, but none still had status epilepticus (vs three at V15y ) and only one had myoclonia. During adulthood, generalized tonic-clonic seizure frequency and duration continued to decrease (P=0.02, P=0.008) and 10 patients experienced seizure-free periods≥ 1years (up to 5years). All patients already had intellectual disability at V15y , but retardation was more severe at Vadult (P=0.03). Furthermore, neurological/gait condition had declined (two patients became bedridden) and behavior had worsened (P<0.0002). Nevertheless, the 33 patients on stiripentol from infancy/childhood (<15years) tended to have better seizure outcome in midadulthood than the seven treated from adolescence (>15years) and the DS patients treated from adult age or stiripentol-naive subjects reported in the literature. The efficacy and safety of the stiripentol/valproate/clobazam combination started at pediatric age are maintained at very long term during adulthood. Such prolonged stiripentol therapy tends to positively impact the late prognosis of epilepsy, especially when initiated before adolescence.

Sex differences in the traumatic stress response: the role of adult gonadal hormones

BackgroundOur previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones?MethodsFor the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined.ResultsWe now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females.ConclusionsWe propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.

Early-life sickness may predispose Siberian hamsters to behavioral changes following alterations of the gut microbiome in adulthood

Although it is well-established that the immune system plays an important role in the development of physiology and behavior, the gut microbiome has recently become of interest in the study of developmental origins of behavior. Studies suggest that the effects of early-life immune activation may not occur until a secondary stressor is introduced, though the precise nature and timing of the stressor may be critical in the response. Further, recent work suggests that the microbiome and the immune system develop in parallel, and therefore any perturbations to one of these systems early in life will likely affect the other. Here, we sought to determine whether early-life activation of the immune system had long-term consequences on how the gut microbiome responds to antibiotic treatment in adulthood and whether those changes influence adult same-sex social behavior. In order to test the hypothesis that an early-life immune challenge makes individuals more vulnerable to the effects of antibiotics, we mimicked an early-life infection by injecting pups at postnatal day 3 and 5 with lipopolysaccharide (LPS; cell wall component of gram-negative bacteria) or saline, and subsequently exposed the same animals to antibiotic treatment (known to influence microbial community composition and behavior) or water in adulthood. We tracked physiology across development, and paired males and females with a novel individual of the same age and sex in adulthood to score same-sex behavior (e.g., aggression, investigation, grooming) before antibiotic treatment, immediately following treatment, and after recovery from antibiotics. LPS-treated females exhibited impaired reproductive physiology and function in adulthood (e.g., smaller ovaries and abnormal estrous cycles), and female and male gut microbial communities were strongly affected by antibiotic treatment in adulthood, but only slightly affected by postnatal LPS alone. Interestingly, LPS-treated males exhibited more robust changes in their behavioral response following adult antibiotic treatment, including decreased investigation and increased grooming, suggestive of changes in anxiety-like behaviors. These data suggest that males may be more vulnerable than females to behavioral abnormalities after being predisposed to an immune challenge early in life. Collectively, these results provide novel evidence that some of the sex-specific behavioral consequences of an early-life immune challenge may not transpire until an individual is faced with a secondary challenge, and the context in which an individual is exposed can greatly influence the response.

Prenatal undernutrition decreases the anorectic response to septic doses of lipopolysaccharides in adulthood in male rats

Prenatal undernutrition affects some physiological functions after birth, and such changes are associated with the pathogenesis of various diseases. Recently, we have reported that prenatally undernourished male rats exhibited stronger febrile and anorectic responses to immune stress induced by moderate-dose lipopolysaccharide (LPS) treatment in adulthood. In the present study, we evaluated the effects of prenatal undernutrition on stress responses to the administration of a septic dose (3 mg/kg) of LPS in later life, mainly focusing on changes in hypothalamic proinflammatory cytokine expression. We also evaluated the expression of hypothalamic and peripheral reproductive factors because it has been suggested that the stress responses of reproductive functions are affected by prenatal and neonatal stress and nutritional conditions. As a result, we found that prenatal undernutrition attenuated the anorectic response to septic-dose LPS treatment in adulthood in male rats. In addition, it attenuated the LPS-induced suppression of serum testosterone levels and the changes in hypothalamic proinflammatory cytokine (interleukin (IL)-1β, tumor necrosis factor-α, and IL-6) expression induced by septic-dose LPS treatment in adulthood. These results suggest that prenatal undernutrition attenuates stress and reproductive responses under severe immune stress conditions. The downregulation of hypothalamic stress-related factor expression might be involved in such attenuated stress responses, which could be one of the protective mechanisms used to prevent excessive immune responses and aid survival.

Correlation Between the Responses to Growth Hormone (GH) Treatment During Childhood and Adulthood in a Monocentric Cohort of GH-Deficient Patients.

Our aim was to analyze a cohort of patients with childhood-onset growth hormone deficiency (GHD) to evaluate if there is some correlation between the response to GH treatment during childhood and adulthood, respectively. This was an observational retrospective monocentric cohort study of 47 patients treated with GH during childhood and adulthood. Changes in growth parameters during childhood were compared with the increase of IGF-I z-score and other indexes of GH response (body composition, lipid profile) after 1 year of treatment in adulthood. The only significant positive correlation was observed between final growth velocity during the last year of childhood GH treatment and increase in IGF-I z-score in GH-treated adults (r=0.592, p=< 0.01). No correlation was observed between growth-promoting effects of GH as child and metabolic changes induced by GH as adult. We also observed a negative correlation between weight at the end of childhood GH treatment and the IGF-I response during first year of treatment in adults (r=- 0.335, p <0.05). No significant positive correlation could be observed between the main parameters that evaluate response to GH treatment in children and adults. However, the final growth velocity, which may be considered as one of the main criteria of end of GH treatment in children, was identified as parameter that could predict future response to GH treatment in adulthood.

Unilateral Application of Cathodal tDCS Reduces Transcallosal Inhibition and Improves Visual Acuity in Amblyopic Patients.

Objective: Amblyopia is a neurodevelopmental disorder characterized by visual acuity and contrast sensitivity loss, refractory to pharmacological and optical treatments in adulthood. In animals, the corpus callosum (CC) contributes to suppression of visual responses of the amblyopic eye. To investigate the role of interhemispheric pathways in amblyopic patients, we studied the response of the visual cortex to transcranial Direct Current Stimulation (tDCS) applied over the primary visual area (V1) contralateral to the “lazy eye.”Methods: Visual acuity (logMAR) was assessed before (T0), immediately after (T1) and 60’ following the application of cathodal tDCS (2.0 mA, 20’) in 12 amblyopic patients. At each time point, Visual Evoked Potentials (VEPs) triggered by grating stimuli of different contrasts (K90%, K20%) were recorded in both hemispheres and compared to those obtained in healthy volunteers.Results: Cathodal tDCS improved visual acuity respect to baseline (p < 0.0001), whereas sham polarization had no significant effect. At T1, tDCS induced an inhibitory effect on VEPs amplitudes at all contrasts in the targeted side and a facilitation of responses in the hemisphere ipsilateral to the amblyopic eye; compared with controls, the facilitation persisted at T2 for high contrasts (K90%; Holm–Sidak post hoc method, p < 0.001), while the stimulated hemisphere recovered more quickly from inhibition (Holm–Sidak post hoc method, p < 0.001).Conclusions: tDCS is a promising treatment for amblyopia in adults. The rapid recovery of excitability and the concurrent transcallosal disinhibition following perturbation of cortical activity may support a critical role of interhemispheric balance in the pathophysiology of amblyopia.

F142. Corpus callosum and amblyopia: New evidence for an old debate

Introduction Amblyopia is a neurodevelopmental disorder characterized by visual acuity and contrast sensitivity loss, refractory to pharmacological and mechanical treatments in adulthood. In animal models, the corpus callosum (CC) plays a critical role in the development of the ocular dominance, thus strengthening the hypothesis of an involvement of both striate and extrastriate areas in the pathogenesis of amblyopia. To investigate the role of interhemispheric pathways in amblyopia, we studied the response of the visual cortex to transcranial Direct Current Stimulation (tDCS) applied over the primary visual area (V1) contralateral to the amblyopic eye. Methods Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts (K90%, K50%, K20%) were recorded in both hemispheres before and after inactivation of the occipital cortex of one side via cathodal tDCS (2.0 mA, 20′). VEPs were recorded before (T0), immediately after (T1) and 60′ following tDCS (T2). The display was either centered on the vertical meridian (central stimulation) or positioned in the right hemifield (with its inner edge at a distance of 1 degree from the fixation point). Visual acuity was tested at each time interval, to assess behavioral changes between active and sham stimulation. Results Cathodal tDCS improved visual acuity respect to baseline (recovery of 8.4 ± 3.3 letters, Holm-Sidak post hoc method p Conclusion tDCS is a promising treatment for amblyopia in adults. The rapid recovery of excitability and the persistent transcallosal disinhibition following perturbation of cortical activity strongly supports a critical role of interhemispheric balance in the pathophysiology of amblyopia.

Early‐Life Sickness May Predispose Individuals to Behavioral Changes Following Gut Dysbiosis in Adulthood

Although it is well‐established that the immune system plays an important role in the development of physiology and behavior, the gut microbiome has recently become of interest in the study of developmental origins of behavior. Some studies suggest that the effects of early‐life immune activation may not occur until a secondary stressor is introduced, though the precise nature and timing of the stressor may be critical in the response. In order to test the hypothesis that early‐life immune stress makes an individual more vulnerable to future insults, we mimicked an early‐life infection by injecting pups at postnatal day 3 and 5 with lipopolysaccharide (LPS; cell wall component of gram‐negative bacteria) or saline, and subsequently exposed the same animals to antibiotic treatment (known to influence microbial community composition ad behavior) or water in adulthood. We tracked physiology across development, and paired males and females with a novel individual of the same sex in adulthood to score behavior before antibiotic treatment, immediately following treatment, and after recovery from antibiotics. LPS‐treated females exhibited impaired reproductive physiology and function in adulthood (e.g., smaller ovaries and abnormal estrous cycles), and female and male gut microbial communities were strongly affected by antibiotic treatment in adulthood, but only slightly affected by postnatal LPS alone. Interestingly, LPS‐treated males exhibited more robust changes in their behavioral response following adult antibiotic treatment, including decreased investigation and increased grooming. These data suggest that males may be more vulnerable than females to behavioral abnormalities after being predisposed to an immune challenge early in life. Collectively, these results provide evidence that some of the sex‐specific behavioral consequences of a stressor may not transpire until an individual is faced with a secondary stressor, and the context in which an individual is exposed can greatly influence the response.Support or Funding InformationNational Institute of Child Health and Human Development (T32HD49336); National Science Foundation, Division of Integrative Organismal Systems (1656414); and Indiana UniversityThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Perinatal Outcomes of Women Diagnosed with Attention-Deficit/Hyperactivity Disorder: An Australian Population-Based Cohort Study.

Attention-deficit/hyperactivity disorder (ADHD) is common and may require treatment in adulthood. We aimed to investigate the treatment patterns and perinatal outcomes of women with any history of stimulant treatment for ADHD. We used health records of the New South Wales (NSW, Australia) population to compare perinatal outcomes of women treated with stimulants (dexamphetamine or methylphenidate) for ADHD from 1982 to 2012 who gave birth between 1994 and 2012, with perinatal outcomes of women with no known ADHD or stimulant treatment (comparison cohort). Five comparison women, matched by maternal age and infant year of birth, were selected for each treated woman. Pregnancy outcome odds ratios in the two groups were adjusted for confounders including maternal age and smoking. Of 5056 women treated for ADHD with stimulant medication, 3351 (66.3%) had stimulant treatment documented before the index pregnancy but not within 1 year before the expected date of delivery, 175 (3.5%) had stimulant treatment before and possibly during pregnancy (stimulant prescription within the 12months directly before the expected date of the index birth and earlier), and 1530 (30.2%) had no stimulant treatment until after the index pregnancy. Treatment for ADHD at any time (before, before and during and only after the index pregnancy) was associated with reduced likelihood of spontaneous labour-odds ratios (ORs) 0.7 [0.7, 0.8], 0.7 [0.5, 0.9], and 0.7 [0.7, 0.8], respectively-and increased risk of caesarean delivery (1.2 [1.1, 1.3], 1.3 [0.9, 1.8], 1.3 [1.1, 1.4]); active neonatal resuscitation (1.2 [1.0, 1.3], 1.7 [1.1, 2.7], 1.3 [1.0, 1.7]); and neonatal admission > 4h (1.2 [1.1, 1.3], 1.7 [1.2, 2.4], 1.2 [1.0, 1.4]). Treatment before or before and during pregnancy was, in addition, associated with increased risk of pre-eclampsia (1.2 [1.0, 1.4], 1.5 [0.8, 2.6]); preterm birth < 37 weeks (1.2 [1.0, 1.3], 1.4 [0.9, 2.3]); and 1-min Apgar < 7 (1.2 [1.1, 1.3], 2.0 [1.4, 2.9]). Stimulant prescribing was low during pregnancy (3.5% of women received such a prescription) and dropped during the 12 months before the due date from an average of 24.7 prescriptions per month in the first 6months to 4.5 per month in the final 6months. Compared with no treatment,ADHD stimulant treatment at any time was associated with small increases in the risk of some adverse pregnancy outcomes; treatment before, or before and during pregnancy, was associated with additional adverse outcomes, even after a treatment-free period of several years. None of these associations can be confidently attributed to stimulant treatment; in all cases ADHD per se or correlates of it could be responsible for the association.

Consequences of NMDA Receptor Deficiency Can Be Rescued in the Adult Brain

NMDA receptors (NMDAR) are important in the formation of activitydependent connections in the brain. In sensory pathways, NMDAR disruption during discrete developmental periods has enduring effects on wiring and function. Yet, it is not clear whether NMDAR-limited critical periods exist for higher-order circuits governing mood and cognition. This question is urgent for neurodevelopmental disorders, like schizophrenia, that have NMDAR hypofunction and treatment-resistant cognitive symptoms. As proof of concept, we developed a novel mouse model where developmental NMDAR deficits can be ameliorated by inducible Cre recombinase. Rescue of NMDARs in either adolescence or adulthood yields surprisingly strong improvements in higher-order behavior. Similar levels of behavioral plasticity are observed regardless of intervention age, with degree of plasticity dependent on the specific behavioral circuit. These results reveal higher-order brain function as amenable to treatment in adulthood and identify NMDAR as a key target for cognitive dysfunction.