Ultra-sparse Connectivity within the Lateral Hypothalamus

• Published in: Current biology Vol. 30; no. 20; pp. 4063 - 4070.e2
• Main Authors: Burdakov, Denis, Karnani, Mahesh M.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 19.10.2020; Elsevier; Cell Press
• Subjects: Action Potentials - physiology; Animals; Brain Waves - physiology; Connectome; gamma oscillation; Hypothalamic Area, Lateral - cytology; Hypothalamic Area, Lateral - physiology; Hypothalamic Hormones - metabolism; lateral hypothalamus; Life Sciences; MCH; Melanins - metabolism; Membrane Potentials - physiology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neocortex - physiology; Neurons - physiology; Optogenetics; orexin; Orexins - metabolism; patch clamp; Patch-Clamp Techniques; Pituitary Hormones - metabolism; synaptic connectivity; synaptic connectivity; patch clamp; MCH; orexin; lateral hypothalamus; gamma oscillation
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2020.07.061

The lateral hypothalamic area (LH) is a vital controller of arousal, feeding, and metabolism [1, 2], which integrates external and internal sensory information. Whereas sensory and whole-body output properties of LH cell populations have received much interest, their intrinsic synaptic organization has remained largely unstudied. Local inhibitory and excitatory connections could help integrate and filter sensory information and mutually inhibitory connections [3] could allow coordinating activity between LH cell types, some of which have mutually exclusive behavioral effects, such as LH VGLUT2 and VGAT neurons [4–7] and orexin- (ORX) and melanin-concentrating hormone (MCH) neurons [8–10]. However, classical Golgi staining studies did not find interneurons with locally ramifying axons in the LH [11, 12], and nearby subthalamic and thalamic areas lack local synaptic connectivity [13, 14]. Studies with optogenetic circuit mapping within the LH have demonstrated only a minority of connections when a large pool of presynaptic neurons was activated [15–19]. Because multiple patch clamp has not been used to study LH connectivity, aside from a limited dataset of MCH neurons where no connections were discovered [15], we used quadruple whole-cell recordings to screen connectivity within the LH with standard methodology we previously used in the neocortex [20–22]. Finding a lack of local connectivity, we used optogenetic circuit mapping to study the strength of LH optogenetic responses and network oscillations, which were consistent with ultra-sparse intrinsic connectivity within the LH. These results suggest that input from other brain structures is decisive for selecting active populations in the LH. [Display omitted] •LH neurons within <300 μm are almost never connected synaptically•Local optogenetic responses are consistent with ultra-sparse connectivity•Local beta-gamma oscillations cannot be driven optogenetically in the LH It is unknown how neural activity is coordinated among lateral hypothalamic area (LH) neurons, which generate fundamental behavioral actions such as attack and evasion. Burdakov and Karnani show there is near-zero local connectivity in the LH, suggesting that incoming synaptic input is integrated primarily within individual neurons.