Enhanced Dopamine D1 and BDNF Signaling in the Adult Dorsal Striatum but not Nucleus Accumbens of Prenatal Cocaine Treated Mice

Previous work from our group and others utilizing animal models have demonstrated long-lasting structural and functional alterations in the meso-cortico-striatal dopamine pathway following prenatal cocaine (PCOC) treatment. We have shown that PCOC treatment results in augmented D1-induced cyclic AMP (cAMP) and cocaine-induced immediate-early gene expression in the striatum of adult mice. In this study we further examined basal as well as cocaine or D1-induced activation of a set of molecules known to be mediators of neuronal plasticity following psychostimulant treatment, with emphasis in the dorsal striatum (Str) and nucleus accumbens (NAc) of adult mice exposed to cocaine in utero. Basally, in the Str of PCOC treated mice there were significantly higher levels of (1) CREB and Ser133 P-CREB (2) Thr34 P-DARPP-32 and (3) GluA1 and Ser 845 P-GluA1 when compared to prenatal saline (PSAL) treated mice. In the NAc there were significantly higher basal levels of (1) CREB and Ser133 P-CREB, (2) Thr202/Tyr204 P-ERK2, and (3) Ser845 P-GluA1. Following acute administration of cocaine (15 mg/kg, i.p.) or D1 agonist (SKF 82958; 1 mg/kg, i.p.) there were significantly higher levels of Ser133 P-CREB, Thr34 P-DARPP-32, and Thr202/Tyr204 P-ERK2 in the Str that were evident in all animals tested. However, these cocaine-induced increases in phosphorylation were significantly augmented in PCOC mice compared to PSAL mice. In sharp contrast to the observations in the Str, in the NAc, acute administration of cocaine or D1 agonist significantly increased P-CREB and P-ERK2 in PSAL mice, a response that was not evident in PCOC mice. Examination of Ser 845 P-GluA1 revealed that cocaine or D1 agonist significantly increased levels in PSAL mice, but significantly decreased levels in the PCOC mice in both the Str and NAc. We also examined changes in brain-derived neurotrophic factor (BDNF). Our studies revealed significantly higher levels of the BDNF precursor, pro-BDNF, and one of its receptors, TrkB in the Str of PCOC mice compared to PSAL mice. These results suggest a persistent up-regulation of molecules critical to D1 and BDNF signaling in the Str of adult mice exposed to cocaine in utero. These molecular adaptations may underlie components of the behavioral deficits evident in exposed animals and a subset of exposed humans, and may represent a therapeutic target for ameliorating aspects of the PCOC-induced phenotype

The rewarding and locomotor-sensitizing effects of repeated cocaine administration are distinct and separable in mice

Repeated psychostimulant exposure progressively increases their potency to stimulate motor activity in rodents. This behavioral or locomotor sensitization is considered a model for some aspects of drug addiction in humans, particularly drug craving during abstinence. However, the role of increased motor behavior in drug reward remains incompletely understood. Intracranial self-stimulation (ICSS) was measured concurrently with locomotor activity to determine if acute intermittent cocaine administration had distinguishable effects on motor behavior and perception of brain stimulation-reward (BSR) in the same mice. Sensitization is associated with changes in neuronal activity and glutamatergic neurotransmission in brain reward circuitry. Expression of AMPA receptor subunits (GluR1 and GluR2) and CRE binding protein (CREB) was measured in the ventral tegmental area (VTA), dorsolateral striatum (STR) and nucleus accumbens (NAc) before and after a sensitizing regimen of cocaine, with and without ICSS. Repeated cocaine administration sensitized mice to its locomotor stimulating effects but not its ability to potentiate BSR. ICSS increased GluR1 in the VTA but not NAc or STR, demonstrating selective changes in protein expression with electrical stimulation of discrete brain structures. Repeated cocaine reduced GluR1, GluR2 and CREB expression in the NAc, and reductions of GluR1 and GluR2 but not CREB were further enhanced by ICSS. These data suggest that the effects of repeated cocaine exposure on reward and motor processes are dissociable in mice, and that reduction of excitatory neurotransmission in the NAc may predict altered motor function independently from changes in reward perception

Neurobehavioral Disorder Associated With Prenatal Alcohol Exposure

Children and adolescents affected by prenatal exposure to alcohol who have brain damage that is manifested in functional impairments of neurocognition, self-regulation, and adaptive functioning may most appropriately be diagnosed with neurobehavioral disorder associated with prenatal exposure. This Special Article outlines clinical implications and guidelines for pediatric medical home clinicians to identify, diagnose, and refer children regarding neurobehavioral disorder associated with prenatal exposure. Emphasis is given to reported or observable behaviors that can be identified as part of care in pediatric medical homes, differential diagnosis, and potential comorbidities. In addition, brief guidance is provided on the management of affected children in the pediatric medical home. Finally, suggestions are given for obtaining prenatal history of in utero exposure to alcohol for the pediatric patient

Inclusive Masculinity in a Fraternal Setting

This ethnographic research uses thirty-two in-depth interviews and two years of par-ticipant observation on a large chapter of a national fraternity to examine the construc-tion of masculinity among heterosexual men. Whereas previous studies of masculine construction maintain that most men in fraternities attempt to bolster their masculinity through the approximation of requisites of hegemonic masculinity, this research shows that there also exists a more inclusive form of masculinity institutionalized in the fra-ternal system: one based on social equality for gay men, respect for women, and racial parity and one in which fraternity men bond over emotional intimacy

Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC) mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC) and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF) protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals

Exogenous infusion of BDNF protein into the IL of PCOC mice normalizes the deficit in recall of an extinguished cue-conditioned fear.

<p>(<b>a</b>) Overview of the experimental paradigm. Guide cannulae, targeting the infralimbic subdivision of the mPFC bilaterally were surgically implanted into the mice after which they were allowed to recover for 5-7 days before behavioral testing. Immediately after the animals went through extinction training session 2 on day 3 of the behavioral paradigm, vehicle (0.9% saline; VEH) or recombinant BDNF protein (BDNF) was infused into the infralimbic cortex and animals were tested 24 hours later for extinction recall. (<b>b</b>) Percent freezing to the tone. On day 1, both prenatal treatment groups showed significant levels of acquisition with no difference in freezing between PSAL and PCOC mice. On days 2 and 3, both prenatal treatment groups showed significant within-session extinction with no difference in freezing between PSAL and PCOC mice. Immediately after day 3, recombinant BDNF or VEH was infused into the IL bilaterally. On day 4, PCOC VEH mice showed significantly increased freezing compared to PSAL VEH mice demonstrating a deficit in extinction recall (*p<0.05). However, PCOC BDNF mice showed significantly decreased freezing compared to PCOC VEH mice indicating a rescue of the behavioral deficit (††p<0.01). Error bars represent the mean ± SEM (PSAL VEH n=11 from 11 litters, BDNF n=9 from 9 litters; PCOC VEH n=9 from 9 litters; BDNF n=11 from 11 litters). <b>c</b>) Schematic representation of the guide cannula placements in animals that were used for behavioral testing. (<b>d</b>) A representative image of guide cannulae targeting the IL bilaterally.</p

Pediatric Neurology Research in the Twenty-First Century: Status, Challenges, and Future Directions Post-COVID-19.

BackgroundThe year 2020 marked a fundamental shift in the pediatric neurology field. An impressive positive trajectory of advances in patient care and research faced sudden global disruptions by the coronavirus disease 2019 pandemic and by an international movement protesting racial, socioeconomic, and health disparities. The disruptions revealed obstacles and fragility within the pediatric neurology research mission. However, renewed commitment offers unique opportunities for the pediatric neurology research community to enhance and prioritize research directions for the coming decades.MethodsThe Research Committee of the Child Neurology Society evaluated the challenges and opportunities facing the pediatric neurology research field, including reviewing published literature, synthesizing publically available data, and conducting a survey of pediatric neurologists.ResultsWe identified three priority domains for the research mission: funding levels, active guidance, and reducing disparities. Funding levels: to increase funding to match the burden of pediatric neurological disease; to tailor funding mechanisms and strategies to support clinical trial efforts unique to pediatric neurology; and to support investigators across their career trajectory. Active guidance: to optimize infrastructure and strategies, to leverage novel therapeutics, enhance data collection, and improve inclusion of children in clinical trials. Reducing disparities: to reduce health disparities in children with neurological disease, to develop proactive measures to enhance workforce diversity and inclusion, and increase avenues to balance work-life obligations for investigators.ConclusionsIn this uniquely challenging epoch, the pediatric neurology research community has a timely and important mission to re-engage the public and government, advancing the health of children with neurological conditions

Decreased mature BDNF protein and phosphorylated TrkB protein levels in the mPFC of prenatal cocaine exposed mice during fear extinction.

<p>(<b>a</b>) In the mPFC, there was significantly decreased mBDNF protein in PCOC mice compared to PSAL mice on day 3 and day 4. (<b>b</b>) In the hippocampus, there was no change in mBDNF protein levels at baseline, day 3 or day 4. (<b>c</b>) In the mPFC of PCOC mice compared to PSAL mice there was no change in total TrkB levels at baseline. However, at day 3 there was a trend (p=0.08) towards decreased TrkB protein levels in the mPFC of PCOC mice compared to PSAL mice. (<b>d</b>) There was no change in total TrkB protein levels in the hippocampus of PCOC mice at baseline or at day 3. (<b>e</b>) In the mPFC of PCOC mice compared to PSAL mice there was no change in P-Tyrosine protein levels at baseline but significantly decreased P-Tyrosine levels on day 3. (<b>f</b>) There was no change in P-Tyrosine protein levels in the hippocampus of PCOC mice at baseline or day 3. (*p<0.05, **p<0.01, ***p<0.001 PCOC vs. PSAL). Error bars represent the mean ± SEM (mBDNF - Baseline: PSAL n=9 from 9 litters, PCOC n=11 from 11 litters; Day 3: PSAL n=8 from 8 litters, PCOC n=8 from 8 litters; Day 4: PSAL n=8 from 8 litters; PCOC n=8 from 8 litters; TrkB/ P-Tyrosine - Baseline: PSAL n=8 from 8 litters, PCOC n=8 from 8 litters; Day 3: PSAL n=9 from 9 litters, PCOC n=8 from 8 litters).</p