Emotionally relevant experiences form strong and long-lasting memories by critically engaging the stress hormone/neurotransmitter noradrenaline, which mediates and modulates the consolidation of these memories. Noradrenaline acts through adrenergic receptors (ARs), of which β 2 -adrenergic receptors (βARs) are of particular importance. The differential anatomical and cellular distribution of βAR subtypes in the brain suggests that they play distinct roles in memory processing, although much about their specific contributions and mechanisms of action remains to be understood. Here we show that astrocytic rather than neuronal β 2 ARs in the hippocampus play a key role in the consolidation of a fear-based contextual memory. These hippocampal β 2 ARs, but not β 1 ARs, are coupled to the training-dependent release of lactate from astrocytes, which is necessary for long-term memory formation and for underlying molecular changes. This key metabolic role of astrocytic β 2 ARs may represent a novel target mechanism for stress-related psychopathologies and neurodegeneration.astrocyte | memory | hippocampus | β-adrenergic receptor | lactate

Our results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Background Oxytocin (OT) is considered to be a stress buffering hormone, dampening the physiological effects of stress. However, OT can also be anxiogenic. We examined acute and long lasting effects of social defeat on OT neurons in male and female California mice. Methods We used immunohistochemistry for OT and c-fos to examine OT neuron activity immediately after defeat (n = 6-9) as well as two (n = 6-9) and ten weeks (n = 4-5) later. We quantified Oxt mRNA with qPCR (n = 5-9). Intranasal OT was administered to naïve and stressed mice tested in social interaction and resident-intruder tests (n = 8-14). Results Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus (PVN) of both sexes. In the medioventral bed nucleus of the stria terminalis (BNSTmv), defeat increased Oxt mRNA, total OT neurons, and OT/c-fos colocalizations in females but not males. Intranasal OT failed to reverse stress-induced social withdrawal in females, and reduced social interaction behavior in females naïve to defeat. In contrast, intranasal OT increased social interaction in stressed males and reduced freezing in the resident-intruder test. Conclusions Social defeat induces long lasting increases in OT production and OT/c-fos cells in the BNSTmv of females but not males. Intranasal OT largely reversed effects of stress on behavior in males but effects were mixed in females. These results suggest changes in OT sensitive networks contribute to sex differences in behavioral responses to stress.

There is compelling evidence for important sex differences in behavioral and hormonal responses to psychosocial stress. Here we examined the effects of gonadal hormones on behavioral responses to social defeat stress in monogamous California mice (Peromyscus californicus). Three episodes of social defeat induced social withdrawal in intact females but not males. Gonadectomy blocked corticosterone responses to defeat in females and sensitized male corticosterone responses. However, gonadectomy had no effects on social interaction behavior, suggesting that social withdrawal is not dependent on gonadal hormones in the adult California mouse. In contrast, defeat reduced exploratory behavior in the open field test for intact but not castrated males. We also examined the effects of social defeat on social interaction behavior when California mice were raised on corncob bedding, which has estrogenic properties. In this dataset of over 300 mice, we observed that social defeat did not induce social withdrawal when females were raised on corncob bedding. This finding suggests that the use of corncob in rodent studies could mask important sex differences in the effects of stress on brain and behavior. Although gonadal hormones do not affect social withdrawal behavior in adults, our data suggest that hormones may act earlier in development to induce a more resilient social phenotype.

Glycogenolysis and lactate transport from astrocytes to neurons is required for long-term memory formation, but the role of this lactate is poorly understood. Here we show that the Krebs cycle substrates pyruvate and ketone body B3HB can functionally replace lactate in rescuing memory impairment caused by inhibition of glycogenolysis or expression knockdown of glia monocarboxylate transporters (MCTs) 1 and 4 in the dorsal hippocampus of rats. In contrast, either metabolite is unable to rescue memory impairment produced by expression knockdown of MCT2, which is selectively expressed by neurons, indicating that a critical role of astrocytic lactate is to provide energy for neuronal responses required for long-term memory. These responses include learning-induced mRNA translation in both excitatory and inhibitory neurons, as well as expression of Arc/Arg3.1. Thus, astrocytic lactate acts as an energy substrate to fuel learning-induced de novo neuronal translation critical for long-term memory.