The female gonadal steroid 17β-estradiol is a pleiotropic hormone that has widespread actions not only in reproductive tissues but also has pronounced effects in the central nervous system (CNS).  For over forty years, my laboratory has been studying the actions of estradiol in the CNS, specifically in hypothalamic neurons that control homeostasis and behavior using molecular, electrophysiological and more recently optogenetic techniques.

In collaboration with Drs. Oline Ronnekleiv and Tom Scanlan in the Department, we developed a novel non-steroidal compound, STX (US Patent 7,196,119) that mimics the rapid membrane actions of estradiol in hypothalamic neurons.  We discovered that STX and estradiol act directly on these neurons via a G protein-coupled receptor to alter their activity.  This unique membrane-associated estrogen receptor is Gq-coupled to activation of a phospholipase C-protein kinase C-protein kinase a pathway leading to desensitization of μ-opioid and GABA_B receptors in POMC and Kisspeptin neurons, but sensitization of these Gαi,o-coupled receptors in NPY/AgRP neurons. We use two different experimental models.  One model is the female guinea pig whose reproductive cycle mimics that of the human and therefore is ideal for doing whole-animal experiments.  Another model is the transgenic female mouse in which we can target POMC-Cre, NPY/AgRP-Cre or Kisspeptin-Cre neurons to deliver viral vectors to express channel-rhodopsin for elucidating downstream synaptic targets that are responsive to gonadal and metabolic hormones.  In addition, we target these neurons with CRISPR single-guide RNA viruses to selectively delete channels and transporters that are responsible for generating neuronal activity.  

Estradiol is known to control feeding behavior, energy homeostasis and core body temperature, and STX appears to mimic all of these CNS actions of estrogen in female rodents. In addition, estradiol has neuroprotective effects on higher cognitive functions. Indeed, we have found that STX is as efficacious as estradiol to prevent hippocampal neuron loss following global ischemia in middle-aged rats. Furthermore, STX protects against amyloid toxicity in cultured hippocampal neurons, while sustained oral STX protects against amyloid toxicity in a mouse model of Alzheimer’s disease. Therefore, STX appears to mimic many of the "neuroprotective" actions of estradiol in the CNS.

We have recently discovered that insulin and leptin depolarize and excite POMC and Kisspeptin neurons in the arcuate nucleus via activation of canonical transient receptor potential (TRPC) channels.  We are presently investigating how the Gαq-mER signaling pathway cross talks with insulin and leptin signaling to promote its actions and protect against the development of insulin resistance in obese states.