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Beta\u2010hydroxybutyrate (BHB), which is an endogenous ketone body, exerts anti\u2010inflammatory effects, and peripheral administration of BHB induces antidepressant effects in an animal model of depression; however, it is unclear whether BHB specifically mediates these actions in the brain. Thus, we administered BHB directly into the brain in a rodent model of depression using a chronic unpredictable stress (CUS) paradigm.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>BHB was continuously microinjected into the prefrontal cortex (PFC) using osmotic pumps for 21\u00a0days. Behavioral testing included the forced swim test (FST) and the open field test (OFT); the levels of pro\u2010inflammatory cytokines, such as interleukin 1\u03b2 (IL\u20101\u03b2) and tumor necrosis factor \u03b1 (TNF\u2010\u03b1), were quantified in the PFC, and the concentration of corticosterone in blood serum was measured.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>BHB administration into the PFC significantly decreased immobility time in the FST, without significantly altering locomotor activity assessed in the OFT. Also, CUS significantly increased the levels of TNF\u2010\u03b1 in the PFC and decreased serum corticosterone levels; these changes were attenuated by BHB administration. These findings suggest that a small amount of BHB administered into the PFC directly produces antidepressant effects, possibly through anti\u2010inflammatory mechanisms, and can improve hypothalamus\u2010pituitary\u2010adrenal axis responses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>BHB may be a novel therapeutic candidate for the treatment of depression based on the neuro\u2010inflammatory hypothesis, and the PFC is a region implicated in the antidepressant action of BHB.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/npr2.12099","type":"journal-article","created":{"date-parts":[[2020,3,3]],"date-time":"2020-03-03T09:15:43Z","timestamp":1583226943000},"page":"157-165","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Prefrontal cortex infusion of beta\u2010hydroxybutyrate, an endogenous 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