Altered PVN-to-CA2 hippocampal oxytocin pathway and reduced number of oxytocin-receptor expressing astrocytes in heart failure rats

Abstract

Oxytocinergic actions within the hippocampal CA2 are important for neuromodulation, memory processing and social recognition. However, the source of the OTergic innervation, the cellular targets expressing the OT receptors (OTRs) and whether the PVN-to-CA2 OTergic system is altered during heart failure (HF), a condition recently associated with cognitive and mood decline, remains unknown. Using immunohistochemistry along with retrograde monosynaptic tracing, RNAscope and a novel OTR-Cre rat line, we show that the PVN (but not the supraoptic nucleus) is an important source of OTergic innervation to the CA2. These OTergic fibers were found in many instances in close apposition to OTR expressing cells within the CA2. Interestingly, while only a small proportion of neurons were found to express OTRs (~15%), this expression was much more abundant in CA2 astrocytes (~40%), an even higher proportion that was recently reported for astrocytes in the central amygdala. Using an established ischemic rat heart failure (HF) model, we found that HF resulted in robust changes in the PVN-to-CA2 OTergic system, both at the source and target levels. Within the PVN, we found an increased OT immunoreactivity, along with a diminished OTR expression in PVN neurons. Within the CA2 of HF rats, we observed a blunted OTergic innervation, along with a diminished OTR expression, which appeared to be restricted to CA2 astrocytes. Taken together, our studies highlight astrocytes as key cellular targets mediating OTergic PVN inputs to the CA2 hippocampal region. Moreover, provides the first evidence for an altered PVN-to-CA2 OTergic system in HF rats, which could potentially contribute to previously reported cognitive and mood impairments in this animal model.

Analysis of the hypothalamic oxytocin system and oxytocin receptor‐expressing astrocytes in a mouse model of Prader–Willi syndrome

“…In addition, we analyzed the dorsal hippocampus of WT and Magel2 tm1.Stw based on our recent finding that the dorsal CA2 in rats harbors OTR‐positive astrocytes 25 . Consistent with previous reports in mouse 56 and in contrast to the rat hippocampus, 25 the OTR mRNA signal in the dorsal hippocampus was exclusively confined to CA2 (Figure S4A). However, unexpectedly, we found almost no OTR+ astrocytes in the dorsal hippocampus (< 2%, Figure S4B), which is in stark contrast to the previously reported 40% for the rat CA2 25 .…”

“…However, unexpectedly, we found almost no OTR+ astrocytes in the dorsal hippocampus (< 2%, Figure S4B), which is in stark contrast to the previously reported 40% for the rat CA2. 25 Thus, these data represent the first account of species variability in the number of brain region-specific OTR-positive astrocytes and suggest that OTergic modulation of astrocytes might be different in rats and mice. However, information about the OTergic system in mouse models of PWS is still scarce and, to date, no information about OTRexpressing astrocytes in Magel2 tm1.Stw mice exists.…”

“…The presence and function of OTR-expressing astrocytes in the CeA has been described. 24 In addition, we recently reported OTR-positive astrocytes in dorsal CA2 in rats, 25 which appeared to be affected by myocardial infarction. Thus, we were curious to investigate potential alterations to OTR-positive astrocytes in our transgenic We observed that 12%-25% of astrocytes were OTR-positive across all conditions, which is consistent with our previous results.…”

Hippocampal astrocytes modulate anxiety-like behavior

“…Therefore, we can speculate that certain neurotransmitter/neuropeptide released in the hippocampus upon anxiogenic stimuli may lead to astrocyte Ca 2+ elevation in physiological condition. In this regard, it is of note that hippocampal astrocytes express oxytocin receptor 27 , and oxytocin released in amygdala activate astrocyte Ca 2+ signal through oxytocin receptor and mediate its anxiolytic effects 11 . Besides, astrocytes express receptors for dopamine and serotonin, key neuropeptides regulating mood and emotion 28,29 .…”

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader-Willi syndrome

“…The presence and function of OTR-expressing astrocytes in the CeA has been described (24). In addition, we recently reported OTR-positive astrocytes in dorsal CA2 in rats (25), which seemed to be affected by myocardial infarction. Thus, we were curious to investigate potential alterations to OTR-positive astrocytes in our transgenic Magel2 tm1 .…”