The ventromedial hypothalamus mediates predator fear memory

Abstract

The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ depending on the nature of the threat, with separate pathways identified for predator, conspecific, and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predator. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in VMHdm is required for both the acquisition and recall of predator fear memory, while that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear.

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

“…The diversity of inputs to the MHDS makes it an ideal candidate structure able to respond to a wide variety of sensory information about environmental threats. Accordingly, loss-offunction studies confirm that selective impairment of VMHdm neurons not only reduces defensive responses to a predator (Silva et al 2013) but also reduces tone fear conditioning and anxiety (Kunwar et al 2015), as well as defensive responses to a context previously associated with a predator (Silva et al 2016). …”

“…The mnemonic effects of PAG stimulation may be mediated by PAG projections to PMD, as well as by direct projections to thalamic nuclei including intralaminar, laterodorsal, reuniens, suprageniculate, and subparafascicular thalamic nuclei (Kincheski et al 2012). However, pharmacogenetic inhibition of dorsal PAG does not impair predator learning despite reducing acute fear responses (Silva et al 2016), implying that at least for VMH, the PAG does not mediate the mnemonic effects of MHDS stimulation, but by a so far unknown route.…”

“…For instance, rapid responses to looming stimuli seem to rely on more direct inputs to PAG from SC (Zhao et al 2014;Shang et al 2015) and ultrasound-induce defensive responses may rely mainly on circuits centered in the IC . What is more, recent studies have argued that the MHDS is not only involved in the sensorymotor processing of defensive responses but, at the same time, also actively serves to encode a generalized internal motivational state of fear that may reflect the emotion associated with threat exposure (see below; Kunwar et al 2015;Silva et al 2016). Interestingly, some studies showed that electrical stimulations of the VMH, a nucleus of the MHDS, in humans elicited panic attacks (Wilent et al 2010), pointing to a possible conservation of this predator fear integrator also in humans.…”

“…Lesions and pharmacological inhibition of the PMD and VMHdm reduce acute responses to a predator, but also inhibit defensive responses to the context where the predator was encountered at a later time point (Cezario et al 2008;Do-Monte et al 2008;Silva et al 2013;Silva et al 2016). Similarly, pharmacological activation of b-adrenergic receptors within this structure is sufficient to serve as an unconditioned stimulus to drive contextual fear learning (Pavesi et al 2011) and optogenetic stimulation of VMHdm is sufficient to instruct learning in a conditioned place aversion test (Kunwar et al 2015).…”

“…For example, in the case of the predator fear system, both loss-and gain-of-function studies have demonstrated the causal implication of the MHDS in fear learning: Lesions or pharmacological inhibition of the PMD and of the VMHdm before predator exposure impairs fear responses to the environment where the predator was presented (Cezario et al 2008;Do-Monte et al 2008;Kunwar et al 2015;Silva et al 2016) and their activation is sufficient to induce conditioning (Pavesi et al 2011;Kunwar et al 2015). Communication from the MHDS to the cortico-hippocampal learning unit seems to occur through thalamic projections.…”