Sex-Specific Organization and Synaptic Signaling in Prefrontal-Hypothalamic Circuitry

Top-down signaling from the cortex to the hypothalamus is critical to link cognitive and emotional processing to homeostasis and motivation. This study investigates signaling from the medial prefrontal cortex (mPFC) to the posterior hypothalamus (PH), a region that modulates endocrine and autonomic stress responses and motivated behaviors. The function and anatomy of this circuit was examined with patch-clamp electrophysiology and mapping studies in male and female rats. Spontaneous firing properties of PH neurons were determined in a cell-type-specific manner by combining a transgenic glutamic acid decarboxylase-Cre rat with Cre-dependent colorswitch virus to determine postsynaptic cell-type identity. Overall, PH neurons were more excitable in females compared with males, and, in both sexes, data indicated tonic inhibition within the PH, with significantly greater inhibition in males. Using Channelrhodopsin-assisted circuit mapping to query the mPFC→PH circuit, we found that the majority of PH neurons received input from the mPFC. Moreover, sex-specific targeting was evident as males had greater mPFC connectivity with PH glutamate neurons. Retrograde tracing revealed more PH-projecting neurons in females, specifically within the tenia tecta and infralimbic region of the mPFC, with significantly more stress-activated PH-projecting cells in the female prelimbic cortex. Anterograde tracing revealed, surprisingly, no sex differences in mPFC presynaptic terminal density in the PH, despite more PH-projecting cell bodies in the female mPFC. These data help to elucidate the sexual divergence in cortical-hypothalamic signaling and how cognitive and emotional information from the prefrontal cortex may differentially regulate homeostasis and motivation between sexes.