Figure 7. Model illustrating proposed neurocircuitry by which ArcN NPY neurons inhibit SNA.

Activation of ArcN NPY (red) neurons (e.g., by either systemic or local CNO administration) inhibits “presympathetic” neurons in both the PVN and DMH, and SNA decreases. The neuropathway by which NPY inputs into the DMH decrease SNA may be mediated in part by a direct projection to the RVLM, but also indirect projections (dashed line). On the other hand, our anatomical data (Figure 2) and previous studies in rats (4) suggest that ArcN-to-PVN NPY inputs directly inhibit presympathetic neurons that project to the RVLM (and possibly also the spinal cord). However, if so, then the failure of blockade of PVN NPY1R to reverse the effects of systemic CNO requires a mechanistic explanation. We hypothesize that reversal of CNO-induced NPY inhibition of PVN presympathetic neurons via PVN NPY1R blockade increases SNA; however, since DMH (and potentially other) neurons that drive the increase in SNA (green neuron) are still inhibited by the CNO-evoked activation of NPY1R, SNA does not reach a maximum. In contrast, we hypothesize that blockade of NPY1R in the DMH unmasks an unfettered excitatory input to RVLM neurons, resulting in a large increase in SNA.