Affirming NIH's commitment to addressing structural racism in the biomedical research enterprise.

NIH has acknowledged and committed to ending structural racism. The framework for NIH's approach, summarized here, includes understanding barriers; developing robust health disparities/equity research; improving its internal culture; being transparent and accountable; and changing the extramural ecosystem so that diversity, equity, and inclusion are reflected in funded research and the biomedical workforce.

Consequences of early experiences and exposure to oxytocin and vasopressin are sexually dimorphic.

In the socially monogamous prairie vole, we have observed that small changes in early handling, as well as early hormonal manipulations can have long-lasting and sexually dimorphic effects on behavior. These changes may be mediated in part by changes in parental interactions with their young, acting on systems that rely on oxytocin (OT) and arginine vasopressin (AVP). Knowledge of both endogenous and exogenous influences on systems that rely on OT and AVP may be helpful in understanding sexually dimorphic developmental disorders, such as autism, that are characterized by increased anxiety and deficits in social behavior.

Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice.

Cocaine and Amphetamine-Regulated Transcript (CART) peptides are implicated in a wide range of behaviors including in the reinforcing properties of psychostimulants, feeding and energy balance and stress and anxiety responses. We conducted a complex trait analysis to examine natural variation in the regulation of CART transcript abundance (CARTta) in the hypothalamus. CART transcript abundance was measured in total hypothalamic RNA from 26 BxD recombinant inbred (RI) mouse strains and in the C57BL/6 (B6) and DBA/2J (D2) progenitor strains. The strain distribution pattern for CARTta was continuous across the RI panel, which is consistent with this being a quantitative trait. Marker regression and interval mapping revealed significant quantitative trait loci (QTL) on mouse chromosome 4 (around 58.2 cM) and chromosome 11 (between 20-36 cM) that influence CARTta and account for 31% of the between strain variance in this phenotype. There are numerous candidate genes and QTL in these chromosomal regions that may indicate shared genetic regulation between CART expression and other neurobiological processes referable to known actions of this neuropeptide.

Genetic analysis of the hypothalamic neurotensin system.

This study used B x D recombinant inbred mice to detect and localize genes that control the hypothalamic neurotensin (NT) system. Abundance of transcripts that encode NT and NT receptors 1, 2, and 3 (NTR1, NTR2, and NTR3) in total hypothalamic RNA was the quantitative trait measured. Analysis of transcript abundance data revealed associations with quantitative trait loci (QTL) for NT transcript abundance (NTta) on chromosome 1, 3, 6, 7, 8, and 9; for NTR1ta on chromosome 3, 8, 12, and X; for NTR2ta on chromosome 2, 4, 9, 10, 12, 13, and 17; for NTR3ta on chromosome 1, 7, 11, and 12. NTta QTL on chromosomes 3, 7, and 8 coincide with QTL previously identified that impact NT peptide content and NTR2ta QTL on chromosome 2 and 12 coincide with genes previously associated with NTR2 receptor abundance. The NTta, NTR1ta, and NTR3ta QTL were not linked to their respective structural genes, but there is a highly significant (p<0.001) association for NTR2ta on chromosome 12 that includes the Ntsr2 structural gene. There are areas of potential shared genetic regulation between NTta and NTR3ta on chromosome 1 and 7 and for all three receptors on proximal chromosome 12. The NTta QTL on chromosome 9 includes the dopamine D2 receptor (Drd2) gene and QTL involved in responses to dopaminergic agents (Hts), antipsychotics (Hpic1) and cocaine (Cocrb8), and ethanol (Etohc3). These results further strengthen the hypothesis that the NT system is involved in mediating the actions of antipsychotic agents and drugs of abuse.

Genetic analysis of the hypothalamic corticotropin-releasing factor system.

The goal of this study was to use BxD recombinant inbred mice to search for genes that control the hypothalamic corticotrophin-releasing factor (CRF) system. The specific phenotype that was measured was abundance of transcripts that encode CRF, CRF receptor (Crf-R1), CRF binding protein, and arginine vasopressin (AVP) in total hypothalamic RNA. The strain distribution patterns for the transcript abundances for each target were continuously distributed, consistent with these being quantitative traits. Marker regression and interval mapping revealed associations with quantitative trait loci (QTL) for CRF transcript abundance on chromosome 1 (at 89.2 cM), chromosome 12 (between 54-58 cM), and chromosome 13 (between 26-30 cM); for Crf-R1 transcript abundance on chromosome 7 (at 1.5 cM), chromosome 12 (at 37 cM), and chromosome X (at 30 cM); for CRF binding protein transcript abundance on chromosome 7 (at 48.5 cM), chromosome 8 (at 65 cM), and chromosome 12 (at 19 cM); and for AVP transcript abundance on chromosome 7 (at 1 cM), chromosome 12 (at 13 cM), and chromosome 13 (at 45 cM). The transcript abundance QTL were not linked to their respective structural genes. Interval mapping on chromosome 7 reveals substantial overlap between QTL that control AVP and Crf-R1 transcript abundance and on chromosome 12 for QTL that control CRF and Crf-R1, which may indicate loci that coordinate regulation of the CRF system. There are QTL for all four targets on chromosome 12. There are a number of neurodevelopmental genes in very close proximity to the transcript abundance QTL that are potential candidate genes.

Are behavioral effects of early experience mediated by oxytocin?

Early experiences can alter adaptive emotional responses necessary for social behavior as well as physiological reactivity in the face of challenge. In the highly social prairie vole (Microtus ochrogaster), manipulations in early life or hormonal treatments specifically targeted at the neuropeptides oxytocin (OT) and arginine vasopressin (AVP), have long-lasting, often sexually dimorphic, consequences for social behavior. Here we examine the hypothesis that behavioral changes associated with differential early experience, in this case handling the family during the first week of life, may be mediated by changes in OT or AVP or their brain receptors. Four early treatment groups were used, differing only in the amount of manipulation received during the first week of life. MAN1 animals were handled once on post-natal day 1; MAN1 treatment produces a pattern of behavior usually considered typical of this species, against which other groups were compared. MAN1-7 animals were handled once a day for post-natal days 1-7, MAN 7 animals were handled once on post-natal day 7, and MAN0 animals received no handling during the first week of life. When tested following weaning, males in groups that had received manipulation during the first few days of life (MAN1 and MAN1-7) displayed higher alloparenting than other groups. Neuroendocrine measures, including OT receptor binding and OT and AVP immunoreactivity, varied by early treatment. In brain areas including the nucleus accumbens, bed nucleus of stria terminalis and lateral septum, MAN0 females showed increased OT receptor binding. MAN1 animals also displayed higher numbers of immunoreactive OT cell bodies in the supraoptic nucleus. Taken together these findings support the broader hypothesis that experiences in the first few days of life, mediated in part by sexually dimorphic changes in neuropeptides, especially in the receptor for OT, may have adaptive consequences for sociality and emotion regulation.