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1 in 20 live births in the United States is affected by prenatal alcohol exposure annually, creating a major public health crisis. The teratogenic impact of alcohol on physical growth, neurodevelopment, and behavior is extensive, together resulting in clinical disorders which fall under the umbrella term of Fetal Alcohol Spectrum Disorders (FASD). FASD-related impairments to executive function and perceptual learning are prevalent among affected youth and are linked to disruptions to corpus callosum growth and myelination in adolescence. Targeted interventions that support neurodevelopment in FASD-affected youth are nonexistent. We evaluated the capacity of an adolescent exercise intervention, a stimulator of myelinogenesis, to upregulate corpus callosum myelination in a rat model of FASD (third trimester-equivalent alcohol exposure). This study employs in vivo diffusion tensor imaging (DTI) scanning to investigate the effects of: (1) neonatal alcohol exposure and (2) an adolescent exercise intervention on corpus callosum myelination in a rodent model of FASD. DTI scans were acquired twice longitudinally (pre- and post-intervention) in male and female rats using a 9.4 Tesla Bruker Biospec scanner to assess alterations to corpus callosum myelination noninvasively. Fractional anisotropy values as well as radial/axial diffusivity values were compared within-animal in a longitudinal study design. Analyses using mixed repeated measures ANOVA’s confirm that neonatal alcohol exposure in a rodent model of FASD delays the trajectory of corpus callosum growth and myelination across adolescence, with a heightened vulnerability in the male brain. Alterations to corpus callosum volume are correlated with reductions to forebrain volume which mediates an indirect relationship between body weight gain and corpus callosum growth. While we did not observe any significant effects of voluntary aerobic exercise on corpus callosum myelination immediately after completion of the 12-day intervention, we did observe a beneficial effect of exercise intervention on corpus callosum volume growth in all rats. In line with clinical findings, we have shown that prenatal alcohol exposure leads to hypomyelination of the corpus callosum in adolescence and that the severity of damage is sexually dimorphic. Further, exercise intervention improves corpus callosum growth in alcohol-exposed and control rats in adolescence.

BackgroundThe phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.MethodsDuring the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.ResultsCBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex.ConclusionThe CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

The main objective of this study was to develop and evaluate therapeutic efficacy and safety following systemic delivery of a peptide analgesic into the CNS using an oil-in-water nanoemulsion system.We have formulated a safe and effective, omega-3 rich polyunsaturated fatty acid containing oil-in-water nanoemulsion formulation, for encapsulating and delivering chemically-modified DALDA, a potent mu-opioid peptide analogue, to the CNS. One of the challenges with CNS delivery is the lack of a non-invasive bioanalytical technique to confirm CNS uptake and therapeutic efficacy. Using blood oxygen-level dependent (BOLD) functional magenetic resonance imaging (fMRI), we provide quantitative evidence of nanoemulsion-based delivery and analgesic activity of DALDA analogue in capsaicin-induced awake rat model of pain.Nanoemulsion formulation effectively encapsulated the modified analgesic peptide and demonstrated efficacy in the capsaicin- pain induced functional magnetic resonance imaging model in rodents. Preliminary safety evaluations show that the nanoemulsion system was well tolerated and did not cause any acute negative effects.Overall, these results show tremendous opportunity for the development of modified peptide analgesic-encapsulated nanoemulsion formulations for CNS delivery and therapeutic efficacy.

Pretargeting with bispecific monoclonal antibodies (bsMAb) for tumor imaging was developed to enhance target to background activity ratios. Visualization of tumors was achieved by the delivery of mono- and divalent radiolabeled haptens. To improve the ability to image tumors with bsMAb, we have combined the pretargeting approach with targeting of high specific activity radiotracer labeled negatively charged polymers. The tumor antigen-specific antibody was replaced with bombesin (Bom), a ligand that binds specifically to the growth receptors that are overexpressed by many tumors including prostate cancer. Bomanti- diethylenetriaminepentaacetic acid (DTPA) bispecific antibody complexes were used to demonstrate pretargeting and imaging of very small human prostate cancer xenografts targeted with high specific activity ¹¹¹In- or ⁹⁹mTc-labeled negatively charged polymers.Bispecific antibody complexes consisting of intact anti-DTPA antibody or Fab′ linked to Bom via thioether bonds (Bom-bsCx or Bom-bsFCx, respectively) were used to pretarget PC-3 human prostate cancer xenografts in SCID mice. Negative control mice were pretargeted with Bom or anti-DTPA Ab. 111In-Labeled DTPA-succinyl polylysine (DSPL) was injected intravenously at 24 h (7.03 ± 1.74 or 6.88 ± 1.89 MBq ¹¹¹In-DSPL) after Bom-bsCx or 50 ± 5.34 MBq of ⁹⁹mTc-DSPL after Bom-bsFCx pretargeting, respectively. Planar or single photon emission computed tomography (SPECT)/CT gamma images were obtained for up to 3 h and only planar images at 24 h. After imaging, all mice were killed and biodistribution of 111In or 99mTc activities were determined by scintillation counting.Both planar and SPECT/CT imaging enabled detection of PC-3 prostate cancer lesions less than 1-2 mm in diameter in 1-3 h post 111In-DSPL injection. No lesions were visualized in Bom or anti-DTPA Ab pretargeted controls. 111In-DSPL activity in Bom-bsCx pretargeted tumors (1.21 ± 0.36 %ID/g) was 5.4 times that in tumors pretargeted with Bom or anti-DTPA alone (0.22 ± 0.08, p = 0.001). PC-3 xenografts pretargeted with Bom-bsFCx and targeted with ⁹⁹mTc-DSPL were visualizable by 1-3 h. Exquisite tumor uptake at 24 h (6.54 ± 1.58 %ID/g) was about 15 times greater than that of Bom pretargeted controls (0.44 ± 0.17, p = 0.002).Pretargeting prostate cancer with Bom-bsCx or Bom-bsFCx enabled fast delivery of high specific radioactivity ¹¹¹In- or ⁹⁹mTc-labeled polymer-drug conjugates resulting in visualization of lesions smaller than 1- 2 mm in diameter within 3 h.

Physiological changes (such as heart rate and respiration rate) associated with strong pharmacological stimuli could change the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) mapping signals, independent of neural activity.This study investigates whether the physiological changes per se associated with systemic cocaine administration (1 mg/kg) contaminate the BOLD fMRI signals by measuring BOLD and cerebral blood flow (CBF) fMRI and estimating the cerebral metabolic rate of oxygen (CMRO(2)) changes.BOLD and CBF fMRI was performed, and changes in CMRO(2) were estimated using the BOLD biophysical model.After systemic cocaine administration, blood pressure, heart rate, and respiration rate increased, fMRI signals remained elevated after physiological parameters had returned to baseline. Cocaine induced changes in the BOLD signal within regions of the reward pathway that were heterogeneous and ranged from -1.2 to 5.4%, and negative changes in BOLD were observed along the cortical surface. Changes in CBF and estimated CMRO(2) were heterogeneous and positive throughout the brain, ranging from 14 to 150% and 10 to 55%, respectively.This study demonstrates a valuable tool to investigate the physiological and biophysical basis of drug action on the central nervous system, offering the means to distinguish the physiological from neural sources of the BOLD fMRI signal.

Background Social subjugation is a very significant and natural stressor in the animal kingdom. Adult animals defeated and subjugated during establishment of dominance hierarchies or territorial encounters can be highly submissive in future agonistic interactions. While much is know about the biological and behavioral consequences of winning and losing fights in adulthood, little is known about adolescence; a developmental period noted for impulsivity and heightened agonistic behavior. The present studies were undertaken to determine if the behavioral and neuroendocrine consequences of social subjugation are comparable in adolescent versus adult Syrian golden hamsters (Mesocricetus auratus). Male siblings were studied from adolescence into adulthood following exposure to counterbalanced episodes of either a benign stressor, i.e., isolation in a novel cage, or the more severe stressor of social subjugation. Results As adults, hamsters with a history of social subjugation in adolescence show high levels of aggression toward intruders as compared to siblings subjugated in adulthood. Sibling controls subjugated in adulthood are highly submissive with little or no aggressive behavior. However, when subjugated in adulthood, hamsters with the earlier history of subjugation are no different than their sibling controls, i.e., adult subjugation promotes submissive behavior. Sexual motivation is high in adult hamsters with adolescent subjugation and testosterone levels remained stable over adulthood. In contrast, sibling controls subjugated in adulthood show lower levels of sexual motivation and reduced levels of testosterone. Release of cortisol during agonistic encounters is blunted in animals subjugated in adolescence but not adulthood. Measures of anxiety are reduced in hamsters with adolescent subjugation as compared to their sibling controls. Conclusion These data demonstrate a pronounced difference in behavior and neuroendocrinology between adolescent and adult hamsters in their response to social subjugation and suggest adolescence is a resilient period in development.

Background: Alterations in arginine vasopressin regulation and secretion have been proposed as one possible biochemical abnormality in patients with obsessive-compulsive disorder. In golden hamsters, arginine vasopressin microinjections into the anterior hypothalamus trigger robust grooming and flank marking, a stereotyped scent marking behaviors. The intensity and repetition of the behaviors induced by arginine vasopressin is somewhat reminiscent of Obsessive Compulsive Disorder in humans. The present experiments were carried out to test whether pharmacological agents used to alleviate obsessive compulsive disorder could inhibit arginine vasopressin-induced flank marking and grooming. Results: Male golden hamsters were treated daily for two weeks with either vehicle, fluoxetine, clomipramine, or desipramine (an ineffective drug), before being tested for arginine vasopressininduced flank marking and grooming. Flank marking was significantly inhibited in animals treated with fluoxetine or clomipramine but unaffected by treatment with desipramine. Grooming behavior was not affected by any treatment. Conclusion: These data suggest that arginine vasopressin-induced flank marking may serve as an animal model for screening drugs used in the control of Obsessive Compulsive Disorder.