Exploration driven by a medial preoptic circuit facilitates fear extinction in mice.

Repetitive exposure to fear-associated targets is a typical treatment for patients with panic or post-traumatic stress disorder (PTSD). The success of exposure therapy depends on the active exploration of a fear-eliciting target despite an innate drive to avoid it. Here, we found that a circuit running from CaMKIIα-positive neurons of the medial preoptic area to the ventral periaqueductal gray (MPA-vPAG) facilitates the exploration of a fear-conditioned zone and subsequent fear extinction in mice. Activation or inhibition of this circuit did not induce preference/avoidance of a specific zone. Repeated entries into the fear-conditioned zone, induced by the motivation to chase a head-mounted object due to MPA-vPAG circuit photostimulation, facilitated fear extinction. Our results show how the brain forms extinction memory against avoidance of a fearful target and suggest a circuit-based mechanism of exposure therapy.

Neural and Genetic Basis of Evasion, Approach and Predation.

Evasion, approach and predation are examples of innate behaviour that are fundamental for the survival of animals. Uniting these behaviours is the assessment of threat, which is required to select between these options. Far from being comprehensive, we give a broad review over recent studies utilising optic techniques that have identified neural circuits and genetic identities underlying these behaviours.

An Inhibitory Medial Preoptic Circuit Mediates Innate Exploration.

Animals have an innate motivation to explore objects and environments with unknown values. To this end, they need to activate neural pathways that enable exploration. Here, we reveal that photostimulation of a subset of medial preoptic area (MPA) neurons expressing the vesicular-GABA transporter gene (vgat+) and sending axonal projections to the ventrolateral periaqueductal gray (vPAG) increases exploration in a chamber but causes no place preference when tested there without photostimulation. Photoinhibition of MPAvgat-vPAG projections leads to no emotional changes as measured by normal activity in an open field assay. Electrophysiological recordings revealed that most GABAergic vPAG neurons are inhibited by MPAvgat neurons. In contrast to a previous report that suggested that MPAvgat-vPAG neurons may impart positive valence to induce place preference, our results suggest that these neurons can increase innate exploration.

Excitatory neuronal CHD8 in the regulation of neocortical development and sensory-motor behaviors.

CHD8 (chromodomain helicase DNA-binding protein 8) is a chromatin remodeler associated with autism spectrum disorders. Homozygous Chd8 deletion in mice leads to embryonic lethality, making it difficult to assess whether CHD8 regulates brain development and whether CHD8 haploinsufficiency-related macrocephaly reflects normal CHD8 functions. Here, we report that homozygous conditional knockout of Chd8 restricted to neocortical glutamatergic neurons causes apoptosis-dependent near-complete elimination of neocortical structures. These mice, however, display normal survival and hyperactivity, anxiolytic-like behavior, and increased social interaction. They also show largely normal auditory function and moderately impaired visual and motor functions but enhanced whisker-related somatosensory function. These changes accompany thalamic hyperactivity, revealed by 15.2-Tesla fMRI, and increased intrinsic excitability and decreased inhibitory synaptic transmission in thalamic ventral posterior medial (VPM) neurons involved in somatosensation. These results suggest that excitatory neuronal CHD8 critically regulates neocortical development through anti-apoptotic mechanisms, neocortical elimination distinctly affects cognitive behaviors and sensory-motor functions in mice, and Chd8 haploinsufficiency-related macrocephaly might represent compensatory responses.

Publisher Correction: Medial preoptic circuit induces hunting-like actions to target objects and prey.

In the version of this article initially published, a sentence in the fifth paragraph of the Results read, "Immunohistochemistry revealed that VGLUT2+ MPA neurons rarely expressed CaMKIIα, which is a putative marker for subcortical glutamatergic neurons." It should have read, "Immunohistochemistry revealed that CaMKIIα+ MPA neurons rarely expressed VGLUT2, which is a putative marker for subcortical glutamatergic neurons." The error has been corrected in the HTML and PDF versions of the article. In the supplementary information originally posted online, the wrong version of Supplementary Fig. 1 was posted and some of the supplementary videos were interchanged. In the corrected Supplementary Fig. 1, the top right subpanel was added and the original Supplementary Fig. 1a was divided into 1a and 1b, with subsequent panels incremented accordingly. The legend was changed from "a. Schematic illustrating electrical lesioning of the rat anterior hypothalamus. Electrical lesion areas (gray) in five representative brain sections are depicted. Scale bar, 1 mm" to "a. Repetitive electrical stimulations of the anterior hypothalamus using bipolar electrodes (Left) caused a lesion at the hypothalamic area (middle, marked by asterisk) successfully in 7 rats (Right, overlapped images of brain sections located from the bregma -0.24 mm). Scale bar, 1 mm. b. Electrical lesion areas (gray) in five representative brain sections from anterior to posterior are depicted." The errors have been corrected online.

Medial preoptic circuit induces hunting-like actions to target objects and prey.

As animals forage, they must obtain useful targets by orchestrating appropriate actions that range from searching to chasing, biting and carrying. Here, we reveal that neurons positive for the α subunit of Ca2+/calmodulin-dependent kinase II (CaMKIIα) in the medial preoptic area (MPA) that send projections to the ventral periaqueductal gray (vPAG) mediate these target-directed actions in mice. During photostimulation of the MPA-vPAG circuit, mice vigorously engaged with 3D objects and chased moving objects. When exposed to a cricket, they hunted down the prey and bit it to kill. By applying a head-mounted object control with timely photostimulation of the MPA-vPAG circuit, we found that MPA-vPAG circuit-induced actions occurred only when the target was detected within the binocular visual field. Using this device, we successfully guided mice to navigate specified routes. Our study explains how the brain yields a strong motivation to acquire a target object along the continuum of hunting behavior.