Resource: A multi-species multi-timepoint transcriptome database and webpage for the pineal gland and retina.

The website and database https://snengs.nichd.nih.gov provides RNA sequencing data from multi-species analysis of the pineal glands from zebrafish (Danio rerio), chicken (White Leghorn), rat (Rattus novegicus), mouse (Mus musculus), rhesus macaque (Macaca mulatta), and human (Homo sapiens); in most cases, retinal data are also included along with results of the analysis of a mixture of RNA from tissues. Studies cover day and night conditions; in addition, a time series over multiple hours, a developmental time series and pharmacological experiments on rats are included. The data have been uniformly re-processed using the latest methods and assemblies to allow for comparisons between experiments and to reduce processing differences. The website presents search functionality, graphical representations, Excel tables, and track hubs of all data for detailed visualization in the UCSC Genome Browser. As more data are collected from investigators and improved genomes become available in the future, the website will be updated. This database is in the public domain and elements can be reproduced by citing the URL and this report. This effort makes the results of 21st century transcriptome profiling widely available in a user-friendly format that is expected to broadly influence pineal research.

Tissue-specific transcriptome sequencing analysis expands the non-human primate reference transcriptome resource (NHPRTR).

The non-human primate reference transcriptome resource (NHPRTR, available online at http://nhprtr.org/) aims to generate comprehensive RNA-seq data from a wide variety of non-human primates (NHPs), from lemurs to hominids. In the 2012 Phase I of the NHPRTR project, 19 billion fragments or 3.8 terabases of transcriptome sequences were collected from pools of ∼ 20 tissues in 15 species and subspecies. Here we describe a major expansion of NHPRTR by adding 10.1 billion fragments of tissue-specific RNA-seq data. For this effort, we selected 11 of the original 15 NHP species and subspecies and constructed total RNA libraries for the same ∼ 15 tissues in each. The sequence quality is such that 88% of the reads align to human reference sequences, allowing us to compute the full list of expression abundance across all tissues for each species, using the reads mapped to human genes. This update also includes improved transcript annotations derived from RNA-seq data for rhesus and cynomolgus macaques, two of the most commonly used NHP models and additional RNA-seq data compiled from related projects. Together, these comprehensive reference transcriptomes from multiple primates serve as a valuable community resource for genome annotation, gene dynamics and comparative functional analysis.

The non-human primate reference transcriptome resource (NHPRTR) for comparative functional genomics.

RNA-based next-generation sequencing (RNA-Seq) provides a tremendous amount of new information regarding gene and transcript structure, expression and regulation. This is particularly true for non-coding RNAs where whole transcriptome analyses have revealed that the much of the genome is transcribed and that many non-coding transcripts have widespread functionality. However, uniform resources for raw, cleaned and processed RNA-Seq data are sparse for most organisms and this is especially true for non-human primates (NHPs). Here, we describe a large-scale RNA-Seq data and analysis infrastructure, the NHP reference transcriptome resource (http://nhprtr.org); it presently hosts data from12 species of primates, to be expanded to 15 species/subspecies spanning great apes, old world monkeys, new world monkeys and prosimians. Data are collected for each species using pools of RNA from comparable tissues. We provide data access in advance of its deposition at NCBI, as well as browsable tracks of alignments against the human genome using the UCSC genome browser. This resource will continue to host additional RNA-Seq data, alignments and assemblies as they are generated over the coming years and provide a key resource for the annotation of NHP genomes as well as informing primate studies on evolution, reproduction, infection, immunity and pharmacology.

Daily Rhythm in Plasma N-acetyltryptamine.

Normal physiology undergoes 24-h changes in function that include daily rhythms in circulating hormones, most notably melatonin and cortical steroids. This study focused on N-acetyltryptamine, a little-studied melatonin receptor mixed agonist-antagonist and the likely evolutionary precursor of melatonin. The central issue addressed was whether N-acetyltryptamine is physiologically present in the circulation. N-acetyltryptamine was detected by LC-MS/MS in daytime plasma of 3 different mammals in subnanomolar levels (mean ± SEM: rat, 0.29 ± 0.05 nM, n = 5; rhesus macaque, 0.54 ± 0.24 nM, n = 4; human, 0.03 ± 0.01 nM, n = 32). Analysis of 24-h blood collections from rhesus macaques revealed a nocturnal increase in plasma N-acetyltryptamine (p < 0.001), which varied from 2- to 15-fold over daytime levels among the 4 animals studied. Related RNA sequencing studies indicated that the transcript encoding the tryptamine acetylating enzyme arylalkylamine N-acetyltransferase (AANAT) is expressed at similar levels in the rhesus pineal gland and retina, thereby indicating that either tissue could contribute to circulating N-acetyltryptamine. The evidence that N-acetyltryptamine is a physiological component of mammalian blood and exhibits a daily rhythm, together with known effects as a melatonin receptor mixed agonist-antagonist, shifts the status of N-acetyltryptamine from pharmacological tool to candidate for a physiological role. This provides a new opportunity to extend our understanding of 24-h biology.

Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory.

Tumor necrosis factor α (TNF) is a proinflammatory cytokine with established roles in host defense and immune system organogenesis. We studied TNF function and found a previously unidentified physiological function that extends its effect beyond the host into the developing offspring. A partial or complete maternal TNF deficit, specifically in hematopoietic cells, resulted in reduced milk levels of the chemokines IP-10, MCP-1, MCP-3, MCP-5 and MIP-1ß, which in turn augmented offspring postnatal hippocampal proliferation, leading to improved adult spatial memory in mice. These effects were reproduced by the postpartum administration of a clinically used anti-TNF agent. Chemokines, fed to suckling pups of TNF-deficient mothers, restored both postnatal proliferation and spatial memory to normal levels. Our results identify a TNF-dependent 'lactrocrine' pathway that programs offspring hippocampal development and memory. The level of ambient TNF is known to be downregulated by physical activity, exercise and adaptive stress. We propose that the maternal TNF-milk chemokine pathway evolved to promote offspring adaptation to post-weaning environmental challenges and competition.

Disrupted activity in the hippocampal-accumbens circuit of type III neuregulin 1 mutant mice.

Neuregulin 1 (Nrg1), a schizophrenia susceptibility gene, is involved in fundamental aspects of neurodevelopment. Mice lacking any one of the several isoforms of Nrg1 have a variety of schizophrenia-related phenotypes, including deficits in working memory and sensorimotor gating, loss of spines in pyramidal neurons in the ventral subiculum, loss of dendrites in cortical pyramidal cells, loss of parvalbumin-positive interneurons in the prefrontal cortex, and altered plasticity in corticolimbic synapses. Mice heterozygous for a disruption in exon 7 of the Nrg1 gene lack Type III (cysteine-rich-domain-containing) isoforms and have sensorimotor gating deficits that may involve changes in the activity of a circuit involving projections from the ventral hippocampus (vHPC) to medium spiny neurons in the nucleus accumbens (nACC). To explore the neural basis of these deficits, we examined electrophysiological activity in the nACC and vHPC of these mice. Under urethane anesthesia, bursts of spontaneous activity propagated from the vHPC to the nACC in both wild-type and mutant mice. However, these bursts were weaker in mutant nACC, with reduced local field potential amplitude and spiking activity. Single units in mutant nACC fired less frequently within the bursts, and more frequently outside of the bursts. Moreover, within-burst nACC spiking was less modulated by vHPC activity, as determined by phase-locking to the low-frequency oscillatory components of the bursts. These data suggest that the efficacy of vHPC input to the nACC is reduced in the Type III Nrg1 heterozygotes, supporting a role for Nrg1 in the functional profile of hippocampal-accumbens synapses.