Abstract
Single-cell heterogeneity confounds efforts to understand how a population of cells organizes into cellular networks that underlie tissue-level function. This complexity is prominent in the mammalian suprachiasmatic nucleus (SCN). Here, individual neurons exhibit a remarkable amount of asynchronous behavior and transcriptional heterogeneity. However, SCN neurons are able to generate precisely coordinated synaptic and molecular outputs that synchronize the body to a common circadian cycle by organizing into cellular networks. To understand this emergent cellular network property, it is important to reconcile single-neuron heterogeneity with network organization. In light of recent studies suggesting that transcriptionally heterogeneous cells organize into distinct cellular phenotypes, we characterized the transcriptional, spatial, and functional organization of 352 SCN neurons from mice experiencing phase-shifts in their circadian cycle. Using the community structure detection method and multivariate analytical techniques, we identified previously undescribed neuronal phenotypes that are likely to participate in regulatory networks with known SCN cell types. Based on the newly discovered neuronal phenotypes, we developed a data-driven neuronal network structure in which multiple cell types interact through known synaptic and paracrine signaling mechanisms. These results provide a basis from which to interpret the functional variability of SCN neurons and describe methodologies toward understanding how a population of heterogeneous single cells organizes into cellular networks that underlie tissue-level function.
Highlights
The principal biological clock in mammals resides in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronizes circadian oscillations and behavioral rhythms throughout the body
We collected 352 single SCN neurons from mice kept either in constant darkness for 2 days or kept in darkness for 2 days and exposed to a lightpulse (LP) at a clock time corresponding to 2 h after lights-out of the previous 12 h light-dark cycle [Zeitgeber time (ZT) 14; LP mice n = 6]
As Vip, Avp, and Adcyap1 are involved in circadian regulation and were some of the major contributors to gene expression variation in the LP neurons (Figure 2D), we examined how well a biased classification approach, one based on the expression levels of these three genes, would be able to categorize transcriptional phenotypes of SCN neurons
Summary
The principal biological clock in mammals resides in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronizes circadian oscillations and behavioral rhythms throughout the body. Synchronization, which enables coordinated anticipation of the 24 h daily light/dark cycle, results from coherent, rhythmic output signals generated and adjusted by the SCN in response to photic inputs. This oscillatory behavior of the SCN arises from neurons, which exhibit. Single-Neuron Network Organization autonomous circadian rhythms, interacting with one another via synaptic and paracrine signaling mechanisms to form cellular interaction networks that synchronize the oscillatory behavior of individual SCN neurons (Mohawk et al, 2012). Distinct spatial localization and transcriptional responses in VIP+ and AVP+ neurons have made these neuropeptides convenient neuronal phenotypic markers that have provided insight into the function and spatial organization of the photic input–oscillator–output system that entrains the SCN to a light/dark cycle (Gerkema et al, 1994; Jin et al, 1999; Van der Zee et al, 2002; Hamada et al, 2004)
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