Collateral Pathways from the Ventromedial Hypothalamus Mediate Defensive Behaviors

Abstract

Summary The ventromedial hypothalamus (VMH) was thought to be essential for coping with threat, although its circuit mechanism remains unclear. To investigate this, we optogenetically activated steroidogenic factor 1 (SF1)-expressing neurons in the dorsomedial and central part of VMH (VMHdm/c), and observed a range of context dependent somatomotor and autonomic responses resembling animals' natural defensive behaviors. By activating independent pathways emanating from VMHdm/c, we demonstrated that VMHdm/c projection to the dorsolateral periaqueductal gray (dlPAG) induces inflexible immobility, while the VMHdm/c to anterior hypothalamic nucleus (AHN) pathway promotes avoidance. Furthermore, consistent with the behavior changes induced by VMH to AHN pathway activation, direct activation of the AHN elicited avoidance and escape jumping but not immobility. Finally, retrograde tracing studies revealed that nearly 50% of PAG- projecting VMHdm/c neurons send collateral projection to the AHN and vice versa. Thus, VMHdm/c neurons employ a one-to-many wiring configuration to orchestrate multiple aspects of defensive behaviors.

Periaqueductal Gray Neuronal Activities Underlie Different Aspects of Defensive Behaviors

“…Together, this and our results show that the dPAG is necessary and sufficient to induce defensive behavior. Intriguingly, it is reported that optogenetic activation of the ventromedial hypothalamus (VMH)-dorsolateral PAG pathway produces immobility, but not flight or avoidance (Wang et al, 2015). Given that the induction of flight or avoidance may require additional threat inputs that are not provided by the VMH, the behavioral effect of VMH-PAG pathway activation should be further tested in the presence of a live predator or a predatory odor.…”

The neural circuits of innate fear: detection, integration, action, and memorization

“…These three highly interconnected nuclei are selectively recruited by predator exposure (and not by conspecific threat or pain), receive inputs from sensory circuits detecting predatory cues, and target defense output structures like the PAG (Canteras 2002). Accordingly, inhibition of these nuclei impairs defensive responses to predators while their artificial activation promotes defensive responses in both rodents and primates (Lipp and Hunsperger 1978;Canteras et al 1997;Blanchard et al 2005;Wilent et al 2010;Pavesi et al 2011;Silva et al 2013;Kunwar et al 2015;Wang et al 2015).…”

“…For example, blockade of the VMHdm or PMD impairs freezing, avoidance, escape, risk assessment, anxiety, and autonomic responses (Blanchard et al 2003Silva et al 2013;Cheung et al 2015;Kunwar et al 2015), while optogenetic activation of the VMHdm induces flights, freezing, autonomic activation, and the interruption of ongoing behaviors (Lin et al 2011;Kunwar et al 2015;Wang et al 2015). Interestingly, VMH activation seems to evoke defensive behaviors in a scalable fashion, with less intense stimulation inducing freezing and more intense stimulation evoking activity bursts (Kunwar et al 2015).…”

“…Different VMH outputs may regulate different defensive behaviors, with projections to the PAGd mediating freezing and projections to the AH mediating risk assessment and flight , although both outputs must presumably eventually reach the PAG to produce defensive responses. The VMH also activates sympathetic nervous system responses including pupil dilation, tachycardia, and hyperventilation (Satoh et al 1999;Wang et al 2015), which may be mediated by its direct projections to the rostral ventrolateral medulla (RVLM) (Lindberg et al 2013) a structure harboring catecholaminergic neurons and capable of mediating sympathetic outflow (Burke et al 2011). …”

“…The dorsal columns of the PAG (PAGd) represent the main output structures of the medial hypothalamic defensive system (Canteras et al 1994;Canteras 2002;Gross and Canteras 2012) as well as of the SC and IC (Canteras et al 1992) and mediate active defensive responses to imminent threats like predators and aggressive conspecifics (Sukikara et al 2006;Motta et al 2009;Silva et al 2013). Such active defensive strategies include escape, freezing associated with muscular tension, tachycardia, hypertension, hypervigilance, and hyperreactivity (Schenberg et al 2014;Sukikara et al 2006;Wang et al 2015). The dorsal columns of the PAG project to downstream brain stem structures, including the cuneiform nucleus, periabducens region of the rostral dorsomedial pons, the locus coeruleus, and the ventromedial, ventrolateral, and dorsal medulla (Bandler and Shipley 1994).…”