The role of funded partnerships in working towards decreasing COVID-19 vaccination disparities, United States, March 2021-December 2022.

During the COVID-19 vaccination rollout from March 2021- December 2022, the Centers for Disease Control and Prevention funded 110 primary and 1051 subrecipient partners at the national, state, local, and community-based level to improve COVID-19 vaccination access, confidence, demand, delivery, and equity in the United States. The partners implemented evidence-based strategies among racial and ethnic minority populations, rural populations, older adults, people with disabilities, people with chronic illness, people experiencing homelessness, and other groups disproportionately impacted by COVID-19. CDC also expanded existing partnerships with healthcare professional societies and other core public health partners, as well as developed innovative partnerships with organizations new to vaccination, including museums and libraries. Partners brought COVID-19 vaccine education into farm fields, local fairs, churches, community centers, barber and beauty shops, and, when possible, partnered with local healthcare providers to administer COVID-19 vaccines. Inclusive, hyper-localized outreach through partnerships with community-based organizations, faith-based organizations, vaccination providers, and local health departments was critical to increasing COVID-19 vaccine access and building a broad network of trusted messengers that promoted vaccine confidence. Data from monthly and quarterly REDCap reports and monthly partner calls showed that through these partnerships, more than 295,000 community-level spokespersons were trained as trusted messengers and more than 2.1 million COVID-19 vaccinations were administered at new or existing vaccination sites. More than 535,035 healthcare personnel were reached through outreach strategies. Quality improvement interventions were implemented in healthcare systems, long-term care settings, and community health centers resulting in changes to the clinical workflow to incorporate COVID-19 vaccine assessments, recommendations, and administration or referrals into routine office visits. Funded partners' activities improved COVID-19 vaccine access and addressed community concerns among racial and ethnic minority groups, as well as among people with barriers to vaccination due to chronic illness or disability, older age, lower income, or other factors.

"The stress can be unbearable, but the good times are like finding gold": A phase one modelling survey to inform the development of a self-help positive reappraisal coping intervention for caregivers of those with autism spectrum disorder.

Caregivers of individuals with ASD can experience various practical, psychological, and social demands and need effective ways of coping to ameliorate the negative effects of caregiving. Numerous coping strategies are available, but the literature shows that caregivers can still struggle to cope, suggesting that interventions to support coping efforts could be beneficial. The MRC framework advocates the systematic development and evaluation of interventions, and this study was conducted to inform the future development of a self-help Positive Reappraisal Coping Intervention (PRCI) for these caregivers. The aim was to establish whether positive reappraisal coping strategies were used and associated with greater psychological wellbeing, prior to developing such an intervention. METHOD: Caregivers of individuals with ASD (N = 112) responded to items from an existing PRCI (Lancastle, 2006; Lancastle & Boivin, 2008), by writing about aspects of caregiving that reflected the meaning of each item. They also completed questionnaires assessing resilience, caregiving burden, and positive and negative emotions. RESULTS: Participants provided significantly more positive responses than negative responses to PRCI items, demonstrating their use of positive reappraisal coping. Thematic analyses showed that positive responses focused on factors such as their loved one's personality and achievements, the contributions caregivers had made to this person's progress, the support received, and their own personal development. Positive reappraisal coping was associated with greater resilience, more positive and less negative emotions, and a lesser sense of caregiver burden. CONCLUSION: This modelling study suggests that positive reappraisal strategies were used by caregivers and associated with greater psychological wellbeing. The findings will inform the development of a self-help PRCI for the caregivers of those with ASD. Future studies will systematically evaluate that PRCI to determine the nature of intervention effects and mediators and moderators of effects.

Absence of carboxypeptidase E leads to adult hippocampal neuronal degeneration and memory deficits.

Molecules that govern the formation, integrity, and function of the hippocampus remain an important area of investigation. Here we show that absence of the proneuropeptide processing enzyme, carboxypeptidase E (CPE) in CPE knock-out (KO) mice had a profound effect on memory, synaptic physiology, and the cytoarchitecture of the hippocampus in these animals. Adult CPE-KO mice displayed deficits in memory consolidation as revealed by the water-maze, object preference, and social transmission of food preference tests. These mice also showed no evoked long-term potentiation. Additionally, CPE-KO mice at 4 weeks of age and older, but not at 3 weeks of age, exhibited marked degeneration specifically of the pyramidal neurons in the hippocampal CA3 region which normally expresses high levels of CPE. Immunohistochemistry revealed that the neuronal marker, NeuN, was reduced, while the glial marker, GFAP, was increased, characteristic of gliosis in the CA3 area of CPE-KO mice. Calbindin staining indicated early termination of the mossy fibers before reaching the CA1 region in these mice. Thus, absence of CPE leads to degeneration of the CA3 neurons and perturbation of the cytoarchitecture of the hippocampus. Ex vivo studies showed that overexpression of CPE in cultured hippocampal neurons protected them against H(2)O(2) oxidative-stress induced cell death. These findings taken together indicate that CPE is essential for the survival of adult hippocampal CA3 neurons to maintain normal cognitive function.

Regardless of genotype, offspring of VIP-deficient female mice exhibit developmental delays and deficits in social behavior.

Pharmacological studies indicate that vasoactive intestinal peptide (VIP) may be necessary for normal embryonic development in the mouse. For example, VIP antagonist treatment before embryonic day 11 resulted in developmental delays, growth restriction, modified adult brain chemistry and reduced social behavior. Here, developmental milestones, growth, and social behaviors of neonates of VIP-deficient mothers (VIP +/-) mated to VIP +/- males were compared with the offspring of wild type mothers (VIP +/+) mated to VIP +/+ and +/- males, to assess the contributions of both maternal and offspring VIP genotype. Regardless of their own genotype, all offsprings of VIP-deficient mothers exhibited developmental delays. No delays were seen in the offspring of wild type mothers, regardless of their own genotype. Body weights were significantly reduced in offspring of VIP-deficient mothers, with VIP null (-/-) the most affected. Regardless of genotype, all offspring of VIP-deficient mothers expressed reduced maternal affiliation compared with wild type offspring of wild type mothers; +/- offspring of wild type mothers did not differ in maternal affiliation from their wild type littermates. Play behavior was significantly reduced in all offsprings of VIP-deficient mothers. Maternal behavior did not differ between wild type and VIP-deficient mothers, and cross-fostering of litters did not change offspring development, indicating that offspring deficits were induced prenatally. This study illustrated that the VIP status of a pregnant mouse had a greater influence on the growth, development and behavior of her offspring than the VIP genotype of the offspring themselves. Deficiencies were apparent in +/+, +/- and -/- offspring born to VIP-deficient mothers; no deficiencies were apparent in +/- offspring born to normal mothers. These results underscore the significant contribution of the uterine environment to normal development and indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders with social behavior deficits such as autism.

Vasoactive intestinal peptide (VIP) regulates activity-dependent neuroprotective protein (ADNP) expression in vivo.

Vasoactive intestinal peptide (VIP) is an important mediator of development during the neural tube closure period of embryogenesis and may regulate, in part, the expression of activity-dependent neuroprotective protein (ADNP), which is essential for neural tube closure and embryogenesis. To evaluate the impact of VIP expression in vivo on ADNP and the related protein ADNP2 the current study examined gene expression in adult wild-type (VIP +/+) and VIP null (VIP -/-) offspring of VIP deficient mothers (VIP+/-) comparing them to wild-type offspring of wild-type mothers. Quantitative real time polymerase chain reaction (PCR), using an ABI Prisma cycler revealed regionally specific reductions of ADNP mRNA in the brains of VIP null mice compared with the brains of wild-type offspring of a wild-type mother. ADNP was significantly reduced in the cortex and hypothalamus of VIP null mice, but not in the hippocampus or thalamus. ADNP2 exhibited a similar pattern but reached a statistically significant reduction only in the hypothalamus. The mRNA for ADNP and ADNP2 also tended to be reduced in the cortex and hippocampus of the wild-type littermates of the VIP null mice, indicating that the VIP genotype of the mother may have had an impact on the ADNP expression of her offspring, regardless of their own VIP genotype. These results showed that VIP regulated brain ADNP expression in a regionally specific manner and indicated that both maternal and offspring VIP genotype may influence ADNP expression in the brain.

Blockage of VIP during mouse embryogenesis modifies adult behavior and results in permanent changes in brain chemistry.

Vasoactive intestinal peptide (VIP) regulates growth and development during the early postimplantation period of mouse embryogenesis. Blockage of VIP with a VIP antagonist during this period results in growth restriction, microcephaly, and developmental delays. Similar treatment of neonatal rodents also causes developmental delays and impaired diurnal rhythms, and the adult brains of these animals exhibit neuronal dystrophy and increased VIP binding. These data suggest that blockage of VIP during the development of the nervous system can result in permanent changes to the brain. In the current study, pregnant mice were treated with a VIP antagonist during embryonic days 8 through 10. The adult male offspring were examined in tests of novelty, paired activity, and social recognition. Brain tissue was examined for several measures of chemistry and gene expression of VIP and related compounds. Glial cells from the cortex of treated newborn mice were plated with neurons and examined for VIP binding and their ability to enhance neuronal survival. Treated adult male mice exhibited increased anxiety-like behavior and deficits in social behavior. Brain tissue exhibited regionally specific changes in VIP chemistry and a trend toward increased gene expression of VIP and related compounds that reached statistical significance in the VIP receptor, VPAC-1, in the female cortex. When compared to control astrocytes, astrocytes from treated cerebral cortex produced further increases in neuronal survival with excess synaptic connections and reduced VIP binding. In conclusion, impaired VIP activity during mouse embryogenesis resulted in permanent changes to both adult brain chemistry/cell biology and behavior with aspects of autism-like social deficits.

Social approach behaviors in oxytocin knockout mice: comparison of two independent lines tested in different laboratory environments.

Oxytocin mediates social affiliation behaviors and social memory in rodents. It has been suggested that disruptions in oxytocin contribute to the deficits in reciprocal social interactions that characterize autism. The present experiments employed a new social approach task for mice which is designed to detect low levels of sociability, representing the first diagnostic criterion for autism. Two lines of oxytocin knockout mice were tested, the National Institute of Mental Health line in Bethesda, and the Baylor/Emory line at the University of North Carolina in Chapel Hill. Similar methods were used for each line to evaluate tendencies to spend time with a stranger mouse versus with an inanimate novel object with no social valence. Adult C57BL/6J males were tested identically, as controls to confirm the robustness of the methods used in the social task. Comprehensive phenotyping of general health, neurological reflexes, olfactory and other sensory abilities, and motor functions was employed to assess both lines. No genotype differences were detected in any of the control measures for either line. Normal sociability, measured as time spent with a novel stranger mouse as compared to time spent with a novel object, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls. Normal preference for social novelty, measured as time spent with a second novel stranger as compared to time spent with a more familiar mouse, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls, with minor exceptions. Similar behavioral results from two independent targeted gene mutations, generated with different targeting vectors, bred on different genetic backgrounds, and tested in different laboratory environments, corroborates the negative findings on sociability in oxytocin mutant mice. Intact tendencies to spend time with another mouse versus with a novel object, in both lines of oxytocin knockouts, supports an interpretation that oxytocin plays a highly specific role in social memory, but is not essential for general spontaneous social approach in mice.

Neonatal mice of the Down syndrome model, Ts65Dn, exhibit upregulated VIP measures and reduced responsiveness of cortical astrocytes to VIP stimulation.

The Ts65Dn segmental mouse model of Down syndrome (DS) possesses a triplication of the section of chromosome 16 that is most homologous to the human chromosome 21 that is trisomic in DS. This model exhibits many of the characteristics of DS including small size, developmental delays, and a decline of cholinergic systems and cognitive function with age. Recent studies have shown that vasoactive intestinal peptide (VIP) systems are upregulated in aged Ts65Dn mice and that VIP dysregulation during embryogenesis is followed by the hypotonia and developmental delays as seen in both DS and in Ts65Dn mice. Additionally, astrocytes from aged Ts65Dn brains do not respond to VIP stimulation to release survival-promoting substances. To determine if VIP dysregulation is age-related in Ts65Dn mice, the current study examined VIP and VIP receptors (VPAC-1 and VPAC-2) in postnatal day 8 Ts65Dn mice. VIP and VPAC-1 expression was significantly increased in the brains of trisomic mice compared with wild-type mice. VIP-binding sites were also significantly increased in several brain areas of young Ts65Dn mice, especially in the cortex, caudate/putamen, and hippocampus. Further, in vitro treatment of normal neurons with conditioned medium from VIP-stimulated Ts65Dn astrocytes from neonatal mice did not enhance neuronal survival. This study indicates that VIP anomalies are present in neonatal Ts65Dn mice, a defect occurs in the signal transduction mechanism of the VPAC-1 VIP receptor, cortical astrocytes from neonatal brains are dysfunctional, and further, that VIP dysregulation may play a significant role in DS.

The expression of activity-dependent neuroprotective protein (ADNP) is regulated by brain damage and treatment of mice with the ADNP derived peptide, NAP, reduces the severity of traumatic head injury.

NAP is a short octapeptide sequence (single letter code, NAPVSIPQ) that protects neurons against a wide variety of insults. The NAP sequence was identified by peptide structure/function scanning of activity-dependent neuroprotective protein (ADNP), a gene product essential for brain formation. To further evaluate the in vivo efficacy of NAP neuroprotection we used a mouse model of head trauma; a condition that presents a risk factor for the development of Alzheimer's disease in injured patients. In the mouse model, NAP treatment (prophylactic or curative) indicated improvement in longitudinal clinical, biochemical and anatomical outcomes. Furthermore, closed head injury was associated with a delayed increase in the expression of the immune cell surface glycoprotein Mac-1 (CD11B antigen) at the injury site that was decreased in NAP-treated mice. Additional experiments with Mac-1-deficient mice suggested partial protection against death related to severe head injury. NAP protection in Mac-1-deficient mice against adverse clinical outcome was concomitant with the time period when increases in Mac-1 transcripts were observed in the Mac-1 expressing mice ( approximately four weeks after the injury). The expression of ADNP (the NAP parent protein) was also increased at the injured brain site four weeks after the traumatic event, only in Mac-1 expressing mice. Here, using immunocytochemistry, we localized the increase in ADNP to microglia and astrocyte-like cells. The increase in ADNP in injured brains is now suggested to be a part of an endogenous compensatory mechanism and NAP treatment provides an additional protection. Toxicology studies suggest NAP as safe for further clinical development.

Sexual dimorphism of activity-dependent neuroprotective protein in the mouse arcuate nucleus.

Activity-dependent neuroprotective protein (ADNP) is a highly conserved vasoactive intestinal peptide (VIP) responsive gene that is expressed abundantly in the brain and in the body and is essential for brain formation and embryonic development. Since, VIP exhibits sexual dimorphism in the hypothalamus, the potential differential expression of ADNP in male and female mice was investigated. Real-time polymerase chain reaction revealed sexual dimorphism in ADNP mRNA expression as well as fluctuations within the estrus cycle. Immunohistochemistry with an antibody to ADNP showed specific staining in the arcuate nucleus of the hypothalamus. ADNP-like immunoreactivity in the arcuate nucleus also exhibited fluctuations during the estrus cycle. Here, brain sections at proestrus were the most immunoreactive and brain sections at estrus--the least. Furthermore, male arcuate nucleus ADNP-like immunoreactivity was significantly lower than that of the female estrus. Many neuropeptides, neurotransmitters and proteins are localized to the arcuate nucleus where they contribute to the regulation of reproductive cyclicity and energy homeostasis. The results presented here suggest that ADNP has a part in the estrus cycle as an affecter or an effector.

Prostate Cancer: Cases of Rare Presentation and Rare Metastasis.

Prostate cancer is the second most common cancer in men. Diagnosis of early disease is based on prostate biopsy which is carried out because of symptoms of prostatism or asymptomatic rise in PSA. On the other side, advanced disease can locally invade and metastasise to lymph nodes, bones, lungs, etc. Initial presentation of prostate cancer in form of brain metastasis is extremely seldom. Similarly, prostate cancer, which metastasised to the breast, is very rare too. Here, we discuss two unique cases of prostate cancer, one of them had an initial presentation of brain metastasis from prostate adenocarcinoma and the other case had an established diagnosis of prostate cancer metastasised to the breast. In theory, cancer can cause metastatic spread to any part of the body; however diversity into such presentation or progression from prostate cancer has not been frequently noticed.

The carboxypeptidase E knockout mouse exhibits endocrinological and behavioral deficits.

A carboxypeptidase E (CPE) knockout (KO) mouse was generated by deletion of exons 4 and 5 from the CPE gene, and its phenotype was characterized. KO mice became obese by 10-12 wk of age and reached 60-80 g by 40 wk. At this age, body fat content was more than double that in the wild-type (WT) controls. The null animals consumed more food overall, were less physically active during the light phase of the light-dark cycle, and burned fewer calories as fat than WT littermates. Fasting levels of glucose and insulin-like immunoreactivity in plasma were elevated in both male and female KO mice at approximately 20 wk; males recovered fully and females partially from this state by 32 wk. At this time, insulin-like immunoreactivity in the plasma, identified as proinsulin, was 50-100 times higher than that of the WT animals. The KO mice showed impaired glucose clearance and were insulin resistant. High levels of leptin and no circulating fully processed cocaine- and amphetamine-related transcript, a peptide that is responsive to leptin-induced feedback inhibition of feeding, were found in serum. The KO mice were subfertile and showed deficits in GnRH processing in the hypothalamus. Behavioral analyses revealed that KO animals showed diminished reactivity to stimuli and had reduced muscle strength and coordination, as well as visual placing and toe-pinch reflexes. These data demonstrate that CPE KO mice display a wide range of neural and endocrine abnormalities and suggest that CPE may have additional physiological roles beyond those ascribed to peptide processing and sorting of prohormones in cells.

VIP as a trophic factor in the CNS and cancer cells.

The effects of vasoactive intestinal peptide (VIP) on the proliferation of central nervous system (CNS) and cancer cells were investigated. VIP has important actions during CNS development. During neurogenesis, VIP stimulates the proliferation and differentiation of brain neurons. Addition of VIP to embryonic mouse spinal cord cultures increases neuronal survival and activity dependent neurotrophic factor (ADNF) secretion from astroglial cells. VIP is an integrative regulator of brain growth and development during neurogenesis and embryogenesis. Also, VIP causes increased proliferation of human breast and lung cancer cells in vitro. VIP binds with high affinity to cancer cells, elevates the cAMP and increases gene expression of c-fos, c-jun, c-myc and vascular endothelial cell growth factor. The effects of VIP on cancer cells are reversed by VIPhybrid, a synthetic VPAC(1) receptor antagonist. VIPhyb inhibits the basal growth of lung cancer cells in vitro and tumors in vivo and potentiates the ability of chemotherapeutic drugs to kill cancer cells. Due to the high density of VPAC(1) receptors in cancer cells, VIP has been radiolabeled with 123I, 18F and 99mTc to image tumors. It remains to be determined if radiolabeled VIP analogs will be useful agents for early detection of cancer in patients.

Vasoactive intestinal peptide regulation of nerve growth factor in the embryonic mouse.

Vasoactive intestinal peptide (VIP), a regulator of embryonic growth, increased the concentration of nerve growth factor (NGF)-like immunoreactivity in the conditioned medium of cultured explanted embryonic day (E) 9.5 neural tube preparations compared to control preparations. VIP treatment also induced an increase of NGF-like immunoreactivity (NGF-IR) within the neural tube preparation tissue. A 60 kDa isoform was the primary form of NGF detected. VIP is shown to be a regulator of NGF in the E9.5 embryonic mouse and stimulates the release of a high molecular weight isoform of NGF.

Vasoactive intestinal peptide mRNA and immunoreactivity are decreased in fetal alcohol syndrome model.

Vasoactive intestinal peptide (VIP) regulates growth in the early post-implantation embryo. Previous work has demonstrated that peptide agonists (SALLRSIPA and NAPVSIPQ) from downstream mediators that are regulated by VIP were able to prevent the alcohol-induced fetal death, growth restriction and microcephaly associated with fetal alcohol syndrome. Here we evaluated the role of VIP in this mouse model of fetal alcohol syndrome, to determine if fetal or maternal levels of VIP are altered. In addition, we evaluated whether peptide treatment would alter the effects of alcohol on VIP levels. Treatment groups included control, alcohol, and alcohol+peptides. VIP levels were measured with enzyme immunoassay [EIA] (Peninsula Laboratories, Belmont, CA). Quantitation of VIP expression was measured with rt-PCR using mimic cDNA primers. Embryo/decidual VIP levels were similar in control and alcohol-treated groups 6 h after treatment. However, in the embryo/deciduas at 12 and 24 h, VIP levels were below the EIA's detection limit in the alcohol-treated groups, and significantly lower than the control or peptide-pretreated groups (p<0.05). Maternal cortex VIP levels were undetectable and significantly lower in the alcohol-treated group than control or peptide+alcohol group at 6 and 12 h (p<0.001). VIP mRNA expression was quantitated in the embryo and deciduas, with a significant decline noted at 6 h to 58% of control levels (p=0.02). Pretreatment with the peptides attenuated the alcohol-induced decrease in VIP mRNA. These studies demonstrate that treatment with alcohol can decrease the expression and immunoreactivity of VIP in both maternal and fetal tissues. This alcohol-induced loss of a recognized regulator of embryonic growth and differentiation may contribute to the sequelae of toxicity observed in fetal alcohol syndrome.

Complex array of cytokines released by vasoactive intestinal peptide.

A complex mixture of five cytokines has been shown to be released by vasoactive intestinal peptide (VIP). Cytokines were measured in paired samples of culture medium and astroglial cytosol by capillary electrophoresis. This is the first description of VIP-mediated release for TNF-alpha, IL-3, G-CSF and M-CSF from astrocyte cultures. Kinetic studies after VIP treatment demonstrated a gradual but incomplete depletion of cytosolic cytokine levels, with differences observed among the cytokines. Significant increases in release were apparent within 15-30 min for all cytokines. As the recognized VIP receptors (VPAC1 and VPAC2) are linked to adenylate cyclase and also interact with pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), both this homologous peptide and 8-bromo cAMP were investigated and compared to VIP-mediated release. Treatment with 1 mM 8-bromo cAMP produced cytokine release similar in amount to 0.1 nM PACAP-38, but significantly less (<50%) in comparison to 0.1 nM VIP. PACAP-38 and VIP exhibited similar EC(50)'s for the release of G-CSF and TNF-alpha; however, the maximal release was 4-6 times greater for VIP than for PACAP-38. This similarity in potency suggested a VPAC-like receptor; however, the greater efficacy for VIP in comparison to PACAP-38, combined with a lack of cAMP production at subnanomolar concentrations of VIP, suggested a mechanism not currently associated with VPAC receptors. For M-CSF, IL-3 and IL-6, the EC(50)'s of VIP were 3-30 times more potent than those of PACAP-38 in producing release. These studies suggested that multiple mechanisms mediate cytokine release in astrocytes: (1) a low efficacy release produced by PACAP-38 that is cAMP-mediated and (2) a high efficacy, VIP-preferring mechanism that was not linked to cAMP. In summary, subnanomolar concentrations of VIP released a complex array of cytokines from astrocytes that may contribute to the mitogenic and neurotrophic properties of this neuropeptide in the central nervous system.

Deficits in social behavior and reversal learning are more prevalent in male offspring of VIP deficient female mice.

Blockage of vasoactive intestinal peptide (VIP) receptors during early embryogenesis in the mouse has been shown to result in developmental delays in neonates, and social behavior deficits selectively in adult male offspring. Offspring of VIP deficient mothers (VIP +/-) also exhibited developmental delays, and reductions in maternal affiliation and play behavior. In the current study, comparisons among the offspring of VIP deficient mothers (VIP +/-) mated to VIP +/- males with the offspring of wild type (WT) mothers mated to VIP +/- males allowed assessment of the contributions of both maternal and offspring VIP genotype to general health measures, social behavior, fear conditioning, and spatial learning and memory in the water maze. These comparisons revealed few differences in general health among offspring of WT and VIP deficient mothers, and all offspring exhibited normal responses in fear conditioning and in the acquisition phase of spatial discrimination in the water maze. WT mothers produced offspring that were normal in all tests; the reduced VIP in their VIP +/- offspring apparently did not contribute to any defects in the measures under study. However, regardless of their own VIP genotype, all male offspring of VIP deficient mothers exhibited severe deficits in social approach behavior and reversal learning. The deficits in these behaviors in the female offspring of VIP deficient mothers were less severe than in their male littermates, and the extent of their impairment was related to their own VIP genotype. This study has shown that intrauterine conditions had a greater influence on behavioral outcome than did genetic inheritance. In addition, the greater prevalence of deficits in social behavior and the resistance to change seen in reversal learning in the male offspring of VIP deficient mothers indicate a potential usefulness of the VIP knockout mouse in furthering the understanding of neurodevelopmental disorders such as autism.

Vasoactive intestinal peptide in neurodevelopmental disorders: therapeutic potential.

Vasoactive intestinal peptide (VIP) mediates important events during the development of the nervous system. VIP can stimulate neuronogenesis as well as differentiation and neurite outgrowth; it can promote the survival of neurons and assist in neuronal repair; it is also anti-inflammatory and can modulate immune responses. In addition, VIP is necessary for the normal growth and development of the early postimplantation mouse embryo during the period when the major embryonic events are neural tube formation, neuronogenesis and expansion of the vascular system. Receptors for VIP appear during early postimplantation embryogenesis in the rodent and exhibit changing localization patterns throughout the development of the brain. During embryogenesis, unregulated VIP may have major and permanent consequences on the formation of the brain and may be a participating factor in disorders of neurodevelopment. VIP has been linked to autism, Down syndrome and fetal alcohol syndrome. This paper will review the role of VIP in neurodevelopment, its known involvement in neurodevelopmental disorders and propose ways in which VIP might be of therapeutic value.

Vasoactive intestinal peptide antagonist treatment during mouse embryogenesis impairs social behavior and cognitive function of adult male offspring.

Vasoactive intestinal peptide (VIP) is a regulator of rodent embryogenesis during the period of neural tube closure. VIP enhanced growth in whole cultured mouse embryos; treatment with a VIP antagonist during embryogenesis inhibited growth and development. VIP antagonist treatment during embryogenesis also had permanent effects on adult brain chemistry and impaired social recognition behavior in adult male mice. The neurological deficits of autism appear to be initiated during neural tube closure and social behavior deficits are among the key characteristics of this disorder that is more common in males and is frequently accompanied by mental retardation. The current study examined the blockage of VIP during embryogenesis as a model for the behavioral deficits of autism. Treatment of pregnant mice with a VIP antagonist during embryonic days 8 through 10 had no apparent effect on the general health or sensory or motor capabilities of adult offspring. However, male offspring exhibited reduced sociability in the social approach task and deficits in cognitive function, as assessed through cued and contextual fear conditioning. Female offspring did not show these deficiencies. These results suggest that this paradigm has usefulness as a mouse model for aspects of autism as it selectively impairs male offspring who exhibit the reduced social behavior and cognitive dysfunction seen in autism. Furthermore, the study indicates that the foundations of some aspects of social behavior are laid down early in mouse embryogenesis, are regulated in a sex specific manner and that interference with embryonic regulators such as VIP can have permanent effects on adult social behavior.

Alpha-2A adrenergic receptor subtype gene expression in the intestines of cocaine-exposed rat embryos.

Cocaine has become a popular illicit drug in our society, and pregnant women are not immune from this epidemic. Recently, there have been several references in the literature describing an association between prenatal cocaine exposure and the subsequent development of necrotizing enterocolitis in the neonate, but the mechanism underlying this relationship remains speculative. Because alpha-2 adrenergic receptors are thought to play a role in the autoregulatory mechanism in the newborn intestine that responds to hypoxia and ischemia, we examined the expression of this receptor in the intestine of embryonic rats exposed to low- and high-dose cocaine in utero. Pregnant Sprague Dawley rats were injected daily with either saline, low-dose cocaine, or high-dose cocaine beginning on embryonic d 5 (E 5) and continuing to E 20. Mothers were killed on E 16, E 17, E 18, E 19, and E 20. Embryos were frozen and stored at -80 degrees C. In situ hybridization was performed on 20- micro m sections with 35S-labeled oligonucleotide probes specific for the alpha-2A adrenergic receptor subtype. Densitometric analysis revealed a significant decrease in the alpha-2A receptor expression in the intestine of both the low-dose and high-dose cocaine-exposed animals compared with controls. This down-regulation was demonstrated by E 17, and continued through the remainder of gestation. These changes may limit the normal adaptation to vasoconstriction, thus exacerbating the already insufficient compensatory mechanisms for responding to ischemic injury, and thus may be one of the important factors predisposing cocaine-exposed infants to necrotizing enterocolitis.