Connectional architecture of a mouse hypothalamic circuit node controlling social behavior

Abstract

Type 1 Estrogen receptor-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl Esr1 ) play a causal role in the control of social behaviors including aggression. Here we use six different viral-genetic tracing methods to map the connectional architecture of VMHvl Esr1 neurons. These data reveal a high level of input convergence and output divergence ("fan-in/fan-out") from and to over 30 distinct brain regions, with a high degree (~90%) of recurrence. Unlike GABAergic populations in other hypothalamic nuclei controlling feeding and parenting behavior, VMHvl Esr1 glutamatergic neurons collateralize to multiple targets. However, we identify two anatomically distinct subpopulations with anterior vs. posterior biases in their collateralization patterns. Surprisingly, these two subpopulations receive indistinguishable inputs. These studies suggest an overall system architecture in which an anatomically feed-forward sensory-to-motor processing stream is integrated with a dense, highly recurrent central processing circuit. This architecture differs from the "brain-inspired" feed-forward circuits used in certain types of artificial intelligence networks. 3 SIGNIFICANCEHow the cellular heterogeneity of brain nuclei maps onto circuit connectivity, the relationship of this anatomical mapping to behavioral function, and whether there are general principles underlying this relationship, remains poorly understood. Here we systematically map the connectivity of estrogen receptor-1-expressing neurons in the ventromedial hypothalamus (VMHvl Esr1 ), which control aggression and other social behaviors. We find that a relatively sparse, anatomically feed-forward sensory-to-motor processing stream is integrated with a dense, highly recurrent central processing circuit. Further, the VMHvl contains at least two subpopulations of Esr1 + neurons with different cell body characteristics and locations, with distinct patterns of collateralization to downstream targets. Nevertheless, these projectiondefined subpopulations receive similar inputs. This input-output organization appears distinct from those described in other hypothalamic nuclei.

Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior

“…It will be interesting to determine whether these different forms of synaptic plasticity employ similar molecular mechanisms. Pvl neurons collateralize such that individual neurons that project to AVPV also project to other target regions (Lo et al, 2019). We observed estrous state-dependent changes in projections to AVPV but not POA or PAG, indicating that the structural plasticity of Pvl termini is restricted to specific projection targets.…”

The structural and electrophysiological properties of progesterone receptor expressing neurons vary along the anterior-posterior axis of the ventromedial hypothalamus and undergo local changes across the reproductive cycle

“…Moreover, it was recently shown that ER-expressing neurons in the anterior portion of the VMHvl are important for self-defense in males (Wang et al, 2019). The connectivity of ER-expressing neurons also varies across the AP axis, further supporting the idea of topographic heterogeneity within this small nucleus (Lo et al, 2019).…”

“…Several studies have shown a large diversity of neuronal types with a wide variety of cellular identities within the VMHvl (Flanagan-Cato, 2011; Kim et al, 2019; McClellan et al, 2006). In addition, the generation of Cre lines providing access to ER- and PR-expressing neurons uncovered further anatomical and functional subdivisions across the nucleus’ anterior-posterior axis (AP axis) (Flanagan-Cato, 2011; Hashikawa et al, 2017; Inoue et al, 2019; Kim et al, 2019; Lo et al, 2019; McClellan et al, 2006; Wang et al, 2019), revealing a much broader role of this hypothalamic region in the control of different aspects of female socio-sexual behavior. While regulation of female sexual receptivity seems to be localized to the most posterior-lateral part of the VMHvl, its posterior-medial division is involved in aggressive behavior towards intruders in mothers (Hashikawa et al, 2017).…”

Dynamic encoding of social threat and spatial context in the hypothalamus

“…Our observation that a large fraction of neurons in VMHvl were activated during risk assessment both close and far from the social stimulus could be explained by the multi-sensory inputs that VMHvl receives (Canteras et al, 1995; Garfield et al, 2014; Lo et al, 2019; Wong et al, 2016). In particular, our earlier observation that VMHdm is required for the expression of defensive behaviors in a context previously associated with a predator suggested that the medial hypothalamus can be recruited by stimulus-associated cues (Silva et al, 2016) and is consistent with evidence for activation of VMHvl during nose poke in anticipation of aggression (Falkner et al, 2016).…”

“…VMHvl receives major afferents from the medial amygdala that encodes information about conspecific identity (Canteras, 1995; Swanson & Petrovich, 1998; Li et al, 2017). However, VMH also receives inputs from lateral septum and subiculum that could convey contextual information (Risold & Swanson, 1997; Silva, et al, 2016; Wong et al, 2016; Lo et al, 2019) and both of these input pathways are able to modulate aggression (Wong et al, 2016; Leroy et al, 2018) suggesting that VMHvl is in a position to integrate sensory and spatial information to guide social behavior. Finally, ensemble neural activity elicited in VMHvl during social investigation can be reshaped by sexual experience, demonstrating a capacity for experience-dependent changes in VMHvl (Remedios et al, 2017).…”