Direct pyrogenic input from prostaglandin EP3 receptor‐expressing preoptic neurons to the dorsomedial hypothalamus

Abstract

Fever is induced by a neuronal mechanism in the brain. Prostaglandin (PG) E2 acts as a pyrogenic mediator in the preoptic area (POA) probably through the EP3 subtype of PGE receptor expressed on GABAergic neurons, and this PGE2 action triggers neuronal pathways for sympathetic thermogenesis in peripheral effector organs including brown adipose tissue (BAT). To explore pyrogenic efferent pathways from the POA, we determined projection targets of EP3 receptor-expressing POA neurons with a special focus on rat hypothalamic regions including the dorsomedial hypothalamic nucleus (DMH), which is known as a center for autonomic responses to stress. Among injections of cholera toxin b-subunit (CTb), a retrograde tracer, into hypothalamic regions at the rostrocaudal level of the DMH, injections into the DMH, lateral hypothalamic area (LH) and dorsal hypothalamic area (DH) resulted in EP3 receptor immunolabelling in substantial populations of CTb-labeled neurons in the POA. Bilateral microinjections of muscimol, a GABA(A) receptor agonist, into the DMH and a ventral region of the DH, but not those into the LH, inhibited thermogenic (BAT sympathetic nerve activity, BAT temperature, core body temperature and expired CO2) and cardiovascular (arterial pressure and heart rate) responses to an intra-POA PGE2 microinjection. Further immunohistochemical observations revealed a close association of POA-derived GABAergic axon swellings with DMH neurons projecting to the medullary raphe regions where sympathetic premotor neurons for febrile and thermoregulatory responses are localized. These results suggest that a direct projection of EP3 receptor-expressing POA neurons to the DMH/DH region mediates febrile responses via a GABAergic mechanism.

Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis

“…Third, separate GABAergic neurons may represent cold-sensitive and warm-sensitive neurons in the POA (Nakamura and Morrison, 2008), and stimulating both populations simultaneously may offset each other's function.…”

“…This modulates the SNA in BAT, a heat generating tissue that regulates core temperature (Nakamura, 2011). Previous studies have suggested that cold-inhibited and warm-activated GABAergic POA neurons innervate BAT-related DMH/DHA and rostral raphe pallidus (rRPa) neurons (Nakamura et al, 2002(Nakamura et al, , 2005(Nakamura et al, , 2009Yoshida et al, 2009). Indeed, cold exposure potently stimulates while warm/thermoneutral exposure strongly inhibits BAT thermogenesis.…”

Single Nigrostriatal Dopaminergic Neurons Form Widely Spread and Highly Dense Axonal Arborizations in the Neostriatum

“…Xiong et al, 1989;Schlesinger, 1993;Piper et al, 1994;Strauss and Strauss, 1994;Lundstrom, 1999). Furthermore, since a large amount of palGFP is produced and distributed not only on the somatodendritic membrane but also on the axonal membrane of infected neurons (Furuta et al, 2001), the vector has been used as a highly sensitive anterograde tracer in the CNS (Nakamura et al, 2002(Nakamura et al, , 2004(Nakamura et al, , 2005Ito et al, 2007). In the present study, we used the recombinant Sindbis virus vector as a tool for single-neuron labeling of dopaminergic neurons.…”

Histaminergic Modulation of Body Temperature and Energy Expenditure

“…Studies using combined retrograde labeling and immunocytochemistry revealed that EP3 prostanoid receptor-positive GABAergic PO/AH neurons project to the sympathetic premotor neurons in the rostral raphe pallidus (rRPA). The projections are either direct or via the dorsomedial hypothalamus (DMH) [16,17]. Bilateral microinjections of GABA-A receptor agonists or antagonists into the rRPa or DMH, blocked the fever induced by intra-PO/AH PGE2 applications.…”