Novel insights into the spatial and temporal complexity of hypothalamic organization through precision methods allowing nanoscale resolution.

The mammalian hypothalamus contains an astounding heterogeneity of neurons to achieve its role in coordinating central responses to virtually any environmental stressor over the life-span of an individual. Therefore, while core features of intrahypothalamic neuronal modalities and wiring patterns are stable during vertebrate evolution, integration of the hypothalamus into hierarchical brain-wide networks evolved to coordinate its output with emotionality, cognition and conscious decision-making. The advent of single-cell technologies represents a recent milestone in the study of hypothalamic organization by allowing the dissection of cellular heterogeneity and establishing causality between opto- and chemogenetic activity modulation of molecularly-resolved neuronal contingents and specific behaviours. Thus, organizational rules to accumulate an unprecedented variety of hierarchical neuroendocrine command networks into a minimal brain volume are being unravelled. Here, we review recent understanding at nanoscale resolution on how neuronal heterogeneity in the mammalian hypothalamus underpins the diversification of hormonal and synaptic output and keeps those sufficiently labile for continuous adaptation to meet environmental demands. Particular emphasis is directed towards the dissection of neuronal circuitry for aggression and food intake. Mechanistic data encompass cell identities, synaptic connectivity within and outside the hypothalamus to link vegetative and conscious levels of innate behaviours, and context- and circadian rhythm-dependent rules of synaptic neurophysiology to distinguish hypothalamic foci that either tune the body's metabolic set-point or specify behaviours. Consequently, novel insights emerge to explain the evolutionary advantages of non-laminar organization for neuroendocrine circuits coincidently using fast neurotransmitters and neuropeptides. These are then accrued into novel therapeutic principles that meet therapeutic criteria for human metabolic diseases.