Region-specific neural corticosterone patterns differ from plasma in a male songbird.

The adrenal hormone corticosterone (CORT) acts on brain to mediate physiology and behavior. In songbirds, behavioral effects of CORT vary across species, environmental conditions, and life history stage, with several mechanisms proposed to account for these divergent results. Although blood CORT levels are well characterized, few studies measure CORT within the brain itself. Here we used in vivo microdialysis to measure CORT in two regions of the zebra finch brain, the hippocampus (HP) and caudal nidopallium (cNp). Our results show that we can successfully measure physiological levels of CORT in brain within 15- to 30-minute intervals of dialysate collection. Moreover, we found that levels in the cNp were generally lower than levels in the HP. Surprisingly, whereas plasma CORT levels increased in response to a standard stressor, no stress-induced surge was detected in the HP or cNp. In addition, although a diel CORT rhythm was observed in plasma, the rhythm in brain was attenuated and only observed when levels were integrated over a 4-hour time period. Regional differences in brain CORT levels were reflected in local mRNA expression levels of the CORT-inactivating enzyme 11ß-hydroxysteroid dehydrogenase type 2 with levels elevated in the cNp relative to the HP. Region-specific CORT metabolism may therefore play a role in buffering the brain from CORT fluctuations.

Context-specific effects of estradiol on spatial learning and memory in the zebra finch.

Estradiol is known to impact cognitive function including spatial learning and memory, with studies focused largely on rodent models. Estrogens can be produced peripherally or centrally as neuroestrogens, and the specific role for neuroestrogens in memory processes remains unresolved. Many songbirds possess remarkable spatial memory capabilities and also express the estrogen synthetic enzyme aromatase abundantly in the hippocampus, suggesting that locally-produced estrogens may promote the acquisition or retrieval of spatial memories in these birds. We examined the effect of estradiol on spatial memory in three contexts in the zebra finch: retrieval after discrimination training, retrieval after familiarization but without discrimination training, and memory acquisition, using a combination of estradiol implants and oral dosing with the aromatase inhibitor fadrozole (FAD). Retrieval of spatial memory in both contexts was impaired when estradiol production was blocked. However, spatial memory acquisition was enhanced when estradiol production was inhibited whereas estradiol replacement impaired acquisition. These results provide evidence for a context-specific role of estradiol in songbird spatial memory, results that find accord with some mammalian studies but have not yet been observed in birds.

Anti-myelin antibodies modulate clinical expression of childhood multiple sclerosis.

Anti-myelin basic protein (MBP) antibodies in pediatric-onset MS and controls were characterized. Serum samples were obtained from 94 children with MS and 106 controls. Paired CSF and serum were obtained from 25 children with MS at time of their initial episode of acute demyelinating syndrome (ADS). Complementary assays were applied across samples to evaluate the presence, and the physical binding properties, of anti-MBP antibodies. While the prevalence and titers of serum anti-MBP antibodies against both immature and mature forms of MBP were similar in children with MS and in controls, binding characteristics and formal Surface Plasmon Resonance (SPR) studies indicated surprisingly high binding affinities of all pediatric anti-MBP antibodies. Serum levels of anti-MBP antibodies correlated significantly with their CSF levels, and their presence in children with MS was associated with significantly increased risk of an acute disseminated encephalomyelitis-like initial clinical presentation. While antibodies to both immature and mature forms of MBP can be present as part of the normal pediatric humoral repertoire, these anti-myelin antibodies are of surprisingly high affinity, can access the CNS during inflammation, and have the capacity to modulate disease expression. Our findings identify an immune mechanism that could contribute to the observed heterogeneity in spectrum of clinical presentations in early-onset MS.

CNS aquaporin-4 autoimmunity in children.

BACKGROUND: In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. METHODS: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. RESULTS: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4-18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). CONCLUSIONS: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.

Interferon beta-1a in children with multiple sclerosis is well tolerated.

BACKGROUND: Multiple sclerosis is a chronic demyelinating disease rare in children. Currently marketed disease modifying therapies are limited to adults. OBJECTIVE: To determine the tolerability of interferon beta-1a (IFNB-1 a) 30 mcg injected intramuscularly once a week in children with clinically definite relapsing-remitting multiple sclerosis (RRMS). DESIGN/METHODS: A standardized questionnaire was sent to neurologists in the United States to determine the tolerability of IFNB-1 a in patients younger than 16 years. RESULTS: Tolerability data were available for 9 of 33 children who were reported to initiate IFNB-1 a. Mean age on initiating treatment was 12.7 years (range 8 - 15) and mean duration of therapy was 17 months (range 5 - 36). No patient discontinued therapy due to an adverse event. CONCLUSIONS: Preliminary data indicate that weekly intramuscular injections of IFNB-1 a are well tolerated.