ObjectiveThe nicotinamide‐nucleotide adenylyltransferase protein Nmnat1 is a potent inhibitor of axonal degeneration in models of acute axonal injury. Hyperphosphorylation and aggregation of the microtubule‐associated protein Tau are associated with neurodegeneration in Alzheimer's Disease and other disorders. Previous studies have demonstrated that other Nmnat isoforms can act both as axonoprotective agents and have protein chaperone function, exerting protective effects in drosophila and mouse models of tauopathy. Nmnat1 targeted to the cytoplasm (cytNmnat1) is neuroprotective in a mouse model of neonatal hypoxia‐ischemia, but the effect of cytNmnat1 on tauopathy remains unknown.MethodsWe examined the impact of overexpression of cytNmnat1 on tau pathology, neurodegeneration, and brain functional connectivity in the P301S mouse model of chronic tauopathy.ResultsOverexpression of cytNmnat1 preserved cortical neuron functional connectivity in P301S mice in vivo. However, whereas Nmnat1 overexpression decreased the accumulation of detergent‐insoluble tau aggregates in the cerebral cortex, it exerted no effect on immunohistochemical evidence of pathologic tau phosphorylation and misfolding, hippocampal atrophy, or inflammatory markers in P301S mice.InterpretationOur results demonstrate that cytNmnat1 partially preserves neuronal function and decreases biochemically insoluble tau in a mouse model of chronic tauopathy without preventing tau phosphorylation, formation of soluble aggregates, or tau‐induced inflammation and atrophy. Nmnat1 might thus represent a therapeutic target for tauopathies.

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Despite numerous findings detailing the negative impact of stress on female reproductive health, the means by which stress acts on the CNS and periphery to compromise reproductive success remains poorly understood. As a result, the current study sought to clarify the neuroendocrine mechanisms by which stress acts on the brain to deleteriously influence pregnancy outcomes. Reproduction is regulated by the hypothalamo-pituitary-gonadal (HPG) axis, with hypothalamic gonadotropin-releasing hormone (GnRH) neurons representing the final, common pathway of this axis. Cells expressing the inhibitory neuropeptide, RFamide-related peptide-3 (RFRP-3), lie upstream of the GnRH system and are markedly regulated by environmental and psychosocial factors, including stress. In the present study, we asked whether RFRP-3 neurons mediate the effects of stress on pregnancy outcomes through the regulation of prolactin secretion, as prolactin is critical for pregnancy maintenance. More specifically, because specialized hypothalamic dopaminergic neurons, namely tubero-infundibular dopaminergic (TIDA) neurons, are major regulators of prolactin secretion, we hypothesized that RFRP-3 neurons directly target TIDA cells to negatively influence fetal development. To test this possibility, we subjected pregnant mice to chronic restraint stress for the first half of pregnancy and performed a broad screen of hypothalamic neuroendocrine function compared to non-stressed controls. Stressed mice exhibited elevated baseline concentrations of corticosterone that remained high at least 6 days after the final exposure to stress. Whereas progesterone concentrations were reduced by stress early in pregnancy, stressed mice recovered typical progesterone secretion during late gestation. These early, stressful experiences resulted in persistent developmental delays, reduced embryo weight, and abnormal placental histology. Significantly, a small percentage of TIDA cells receive close contacts from RFRP-3 axons, providing a mechanism for the control of prolactin secretion by stress. However, contrary to expectation, the percentage of TIDA neurons receiving input from RFRP-3 cells was not impacted by stress. Together, these findings identify a potential pathway of control for the impact of stress on neuroendocrine factors critical to pregnancy success, although further work using more sensitive approaches is needed to examine the putative role of RFRP-3 on stress-induced pregnancy outcomes.

Psychological stress, both leading up to and during pregnancy, is associated with increased risk for negative pregnancy outcomes. Although the neuroendocrine circuits that link the stress response to reduced sexual motivation and mating are well-described, the specific pathways by which stress negatively impacts gestational outcomes remain unclear. Using a mouse model of chronic psychological stress during pregnancy, we investigated 1) how chronic exposure to stress during gestation impacts maternal reproductive neuroendocrine circuitry, and 2) whether stress alters developmental outcomes for the fetus or placenta by mid-pregnancy. Focusing on the stress-responsive neuropeptide RFRP-3, we identified novel contacts between RFRP-3-immunoreactive (RFRP-3-ir) cells and tuberoinfundibular dopaminergic neurons in the arcuate nucleus, thus providing a potential pathway linking the neuroendocrine stress response directly to pituitary prolactin production and release. However, neither of these cell populations nor circulating levels of pituitary hormones were affected by chronic stress. Conversely, circulating levels of steroid hormones relevant to gestational outcomes (progesterone and corticosterone) were altered in chronically-stressed dams across gestation, and those dams were qualitatively more likely to experience delays in fetal development. Together, these findings suggest that, up until at least mid-pregnancy, mothers appear to be relatively resilient to the effects of elevated glucocorticoids on reproductive neuroendocrine system function. We conclude that understanding how chronic psychological stress impacts reproductive outcomes will require understanding individual susceptibility and identifying reliable neuroendocrine changes resulting from gestational stress.