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Connectional Architecture of a Mouse Hypothalamic Circuit Node Controlling Social Behavior

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Connectional Architecture of a Mouse Hypothalamic Circuit Node Controlling Social Behavior Connectional architecture of a mouse hypothalamic circuit node controlling social behavior Liching Loa,b,c,1, Shenqin Yaod,1, Dong-Wook Kima,c, Ali Cetind, Julie Harrisd, Hongkui Zengd, David J. Andersona,b,c,2, and Brandon Weissbourda,b,c,2 aDivision of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125; bHoward Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; cTianqiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, CA 91125; and dAllen Institute for Brain Science, Seattle, WA 98109 Contributed by David J. Anderson, December 12, 2018 (sent for review October 11, 2018; reviewed by Clifford B. Saper and Richard B. Simerly) Type 1 estrogen receptor-expressing neurons in the ventrolateral Examples of collateralization to multiple targets, as seen in mono- subdivision of the ventromedial hypothalamus (VMHvlEsr1) play a amine neuromodulatory systems (16, 30), are few due to limitations causal role in the control of social behaviors, including aggression. in the number of tracers that can be used simultaneously (31). Here we use six different viral-genetic tracing methods to system- Type 1 estrogen receptor (Esr1)-expressing neurons in the atically map the connectional architecture of VMHvlEsr1 neurons. ventromedial hypothalamic nucleus (VMH) control social and These data reveal a high level of input convergence and output defensive behaviors, as well as metabolic states (6, 7, 9, 32; divergence (“fan-in/fan-out”) from and to over 30 distinct brain reviewed in refs. 33–38). Unlike the ARCAgrp and the MPOAGal regions, with a high degree (∼90%) of bidirectionality, including populations, which are primarily GABAergic (24), VMHvlEsr1 both direct as well as indirect feedback. Unbiased collateralization neurons are mainly glutamatergic (39). Inputs and outputs of the mapping experiments indicate that VMHvlEsr1 neurons project to VMHvl and the anatomically overlapping hypothalamic attack multiple targets. However, we identify two anatomically distinct area (HAA) (40) have been extensively mapped in rats, using con- subpopulations with anterior vs. posterior biases in their collater- ventional anterograde and retrograde tracers (41, 42). In mice, one alization targets. Nevertheless, these two subpopulations receive study using a genomically integrated axonal tracer, PLAP, mapped a indistinguishable inputs. These studies suggest an overall system subset of projections from progesterone receptor-expressing VMHvl architecture in which an anatomically feed-forward sensory-to- neurons, which are highly overlapping with VMHvlEsr1 neurons (32). NEUROSCIENCE motor processing stream is integrated with a dense, highly recur- However, inputs to and projections from VMHvlEsr1 neurons, the rent central processing circuit. This architecture differs from the extent of their collateralization, and the relationships between spe- “brain-inspired,” hierarchical feed-forward circuits used in certain cific inputs and outputs have not been systematically investigated. types of artificial intelligence networks. In this study we have used six different genetically targeted viral tracing methods to map the meso-scale connectivity of VMHvlEsr1 hypothalamus | aggression | social behavior | VMHvl | connectivity neurons. Collectively, these methods reveal that these neurons he hypothalamus controls an array of innate survival behav- Significance Tiors and associated internal motivational states, including feeding, drinking, predator defense, and social behaviors, such as How hypothalamic cellular heterogeneity maps onto circuit mating and fighting (1, 2). It is comprised of multiple nuclei, connectivity, and the relationship of this anatomical mapping each of which is thought to play a role in one or more behavioral to behavioral function, remain poorly understood. Here we functions. The connectivity of these nuclei has been extensively systematically map the connectivity of estrogen receptor-1– mapped using classic anterograde and retrograde tracing tech- expressing neurons in the ventromedial hypothalamus (VMHvlEsr1), niques (reviewed in refs. 3 and 4), revealing complex inputs to which control aggression and related social behaviors, using and outputs from these structures, as well as dense inter- multiple viral-genetic tracers. Rather than a simple feed-forward connectivity between them (5). It is increasingly clear, however, sensory-to-motor processing stream, we find high convergence that hypothalamic nuclei are both functionally (6, 7) and cellu- (fan-in) and divergence (fan-out) in VMHvlEsr1 inputs and pro- larly (8, 9) heterogeneous. How this cellular heterogeneity maps jections, respectively, with massive feedback. However, outputs onto connectivity, the relationship of this anatomical mapping to are split into two subpopulations that project either posteriorly, behavioral function, and whether there are any general princi- to premotor structures, or anteriorly back to the amygdala and ples underlying this relationship, remains poorly understood. hypothalamus. This fan-in/-out system architecture is consistent Genetic targeting of neuronal subpopulations and viral tools with “antenna” and “broadcasting” functions for VMHvlEsr1 for tracing neuronal connectivity (10, 11), have provided a neurons, with the feedback pathway possibly controlling be- powerful approach to this problem in other brain systems (12– havioral decisions and internal state. 19). In the hypothalamus, viral tracers have been used to map the + outputs of Agrp neurons in the arcuate (ARC) nucleus, which Author contributions: L.L., D.-W.K., D.J.A., and B.W. designed research; L.L. and D.-W.K. performed research; S.Y., A.C., J.H., and H.Z. contributed new reagents/analytic tools; L.L., control the motivation to eat (20, 21). Although the ARC as a D.-W.K., D.J.A., and B.W. analyzed data; and L.L., D.J.A., and B.W. wrote the paper. whole projects to ∼six different regions, these studies suggested Agrp Reviewers: C.B.S., Harvard Medical School, Beth Israel Deaconess Medical Center; and that different subsets of ARC neurons project to different R.B.S., Vanderbilt University. targets (22). Similarly, viral collateralization mapping of Galanin- The authors declare no conflict of interest. expressing neurons in the medial preoptic area (MPOA) (23) have GAl This open access article is distributed under Creative Commons Attribution-NonCommercial- indicated that different MPOA neurons controlling different NoDerivatives License 4.0 (CC BY-NC-ND). functions (pup-gathering, reward, etc.) project to distinct down- 1L.L. and S.Y. contributed equally to this work. stream targets (24). Together, these and other data (25, 26) have 2To whom correspondence may be addressed. Email: [email protected] or bweissb@ provided examples of hypothalamic nuclei that contain multiple gmail.com. functionally and connectionally distinct neuronal subpopula- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. tions. In other examples employing classic retrograde tracers, 1073/pnas.1817503116/-/DCSupplemental. however, collateralization to dual targets has been observed (27–29). www.pnas.org/cgi/doi/10.1073/pnas.1817503116 PNAS Latest Articles | 1of10 Downloaded by guest on October 1, 2021 display a high degree of convergence, divergence, and bidirection- subiculum (SUBv), as well as from the medial prefrontal cortex ality in their inputs and outputs, respectively. However, unlike (mPFC) (Fig. 1 F–J and L and SI Appendix,Fig.S1B). ARCAgrp (22), MPOAGal (24), and DMHGal (26) GABAergic neu- Strikingly, with a few notable exceptions (see below), mono- rons, VMHvlEsr1 neurons collateralize to multiple downstream targets. synaptic retrograde labeling was found in the majority of struc- + Nevertheless, we identify Esr1 neuronal subsets with broad but tures to which VMHvlEsr1 neurons also project (Fig. 1 K–P and anatomically distinct patterns of collateralization. Together, SI Appendix,Fig.S1A and B). Because many of these input re- + thesedatasuggestasystemarchitectureinwhichVMHvlEsr1 gions themselves contain Esr1 neurons, we were concerned that neurons receive sparse input from anteriorly located sensory the Cre-dependent, transcomplementing AAV encoding TVA- structures and relay this information through two divergent 2A-rabies glycoprotein (RG) injected into the VMHvl might in- + processing streams: a sparse feed-forward relay targeting posterior fect axons from these VMH-extrinsic Esr1 inputs, subsequently (premotor) regions, and a highly recurrent amygdalo–hypothalamic allowing for primary infection of those terminals by the EnvA- network that may control decision-making and internal states. pseudotyped rabies virus (and therefore GFP expression in their cell bodies, creating a false impression of retrograde mono- Results synaptic labeling). To control for this, a separate cohort of mice Extensive Bidirectional Connectivity of Projections and Inputs of were injected with a control Cre-dependent AAV encoding only Esr1 VMHvl Neurons. Inputs to and projections from the VMHvl TVA, and not RG. With the exception of local expression of GFP have been mapped in several studies using classic techniques in in VMHvl, expression of the rabies-encoded nuclear GFP marker – rodents (e.g., CTb and PHAL) (40 48). However, these techniques was not detected in input regions (SI Appendix, Fig. S1 C and D), are unable to distinguish genetically defined cell populations within indicating that
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