Imagine your brain is a cozy room with two types of guests: the excitatory glutamatergic neurons and the inhibitory GABAergic neurons. Well, during menopause, it seems like these guests start acting up, causing hot flashes. Scientists discovered that when estrogen levels drop, there’s a change in the neural population in a specific area of the brain called the preoptic area (POA). Proteomics revealed that proteins related to glutamatergic and GABAergic synapses are affected. Further research using techniques like RNAscope and Western blotting confirmed that there’s a decrease in glutamatergic neurons and an increase in GABAergic neurons in the POA. When chemogenetically activated or inhibited, these neurons had different effects on body temperature. They also found changes in the expression of specific proteins related to these neuron types and estrogen receptors. Interestingly, estrogen therapy corrected these abnormal changes. This suggests that during menopause, estrogen might influence the transcription and expression of certain proteins involved in neural function, ultimately leading to hot flashes. To dive deeper into the exciting research behind this discovery, check out the full article!

During menopause, when estrogen levels are low, abnormalities in the hypothalamic preoptic area (POA) of the thermoregulatory center can cause hot flashes. However, the involved neural population has not been identified. Proteomics showed that under low estrogen, differentially expressed proteins in the hypothalamus were associated with glutamatergic and GABAergic synapses. RNAscope, Western blotting and qRT-PCR indicated that the number of glutamatergic neurons in the POA was decreased, while the number of GABAergic neurons was increased. Chemogenetics showed that the rat body temperature decreased slowly after glutamatergic neurons were activated and increased quickly after glutamatergic neurons were inhibited, while it increased quickly after GABAergic neurons were activated and decreased slowly after GABAergic neurons were inhibited. RNAscope, immunofluorescence, Western blotting and qRT-PCR further showed that glutamate decarboxylase (GAD) 1 expression in the POA was increased, while GAD2 expression in the POA was decreased; that thermosensitive transient receptor potential protein (ThermoTRP) M (TRPM) 2 expression in glutamatergic neurons was decreased, while TRPM8 expression in GABAergic neurons was increased; and that estrogen receptor (ER) α and β expression in the POA was decreased, and ERα and ERβ expressed in both glutamatergic and GABAergic neurons. Estrogen therapy corrected these abnormalities. In addition, CUT&Tag and Western blot after injection of agonists and inhibitors of ERs showed that ERα and ERβ were both transcription factors in glutamatergic and GABAergic synapses. Mechanistically, during menopause, estrogen may regulate the transcription and expression of GADs and ThermoTRPs through ERs, impacting the number and function of glutamatergic and GABAergic neurons, resulting in unbalanced heat dissipation and production in the POA and ultimately triggering hot flashes.

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