Hypothalamic cell diversity: non-neuronal codes for long-distance volume transmission by neuropeptides

[Display omitted] •A kaleidoscope of neuronal identities exists in the hypothalamus with many subtypes innervating ventricular ependyma.•Ependyma are molecularly heterogeneous and regionalized along the ventricular surface.•Ependymocytes can convert synaptic input into metabolic output by releasing neuropeptides into the cerebrospinal fluid.•Integration of ependymal cells into neuronal circuitry could produce a combinatorial code for volume transmission reflecting the diversity of environmental challenges.•Integration of ependymal cells into neuronal circuitry could produce a combinatorial code for volume transmission.•Volume transmission can best suit the diversity of environmental challenges. Volume transmission is a mode of intercellular communication using cerebral liquor to deliver signal molecules over long distances and allow their action for extended periods. For hypothalamic neuropeptides, nerve endings amongst ependymal cells are seen as a site of release into the cerebrospinal fluid. Recent single-cell RNA-seq data identify tanycytes and ventricular ependyma as alternative sources by being unexpectedly rich in neuroactive substances. This notion, coupled with circuit analysis showing regionalized innervation of periventricular ependyma by intrahypothalamic neurons, could allow for the integration of hypothalamic neuronal activity patterns with brain-wide activity changes upon metabolic challenges through phasic volume transmission primed by neuron–ependyma coupling. Here, we discuss emerging data for an ependymal interface and its breaches in neuropsychiatric disease.