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.

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.

Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors.

OBJECTIVE: To examine whether neonatal exposure to sevoflurane induces autism-like behaviors in mice. BACKGROUND: There are continuing reports regarding the potential negative effects of anesthesia on the developing brain. Recently, several studies suggest that neurotoxicity caused by anesthesia may lead to neurodevelopmental impairments. However, unlike reports focusing on learning and memory, there are only a few animal studies focusing on neurodevelopmental disorders after general anesthesia. Therefore, we have focused on autism, a representative neurodevelopmental disorder. METHODS: Neonatal mice (P6-7) were exposed to a titrated dose of sevoflurane for 6 h. Apoptosis was evaluated by assessing the expression level of cleaved (activated) caspase-3. Autism-like behaviors, general activity, anxiety level, and long-term memory were evaluated with multiple behavioral assays. RESULTS: Western blotting confirmed that neonatal exposure to sevoflurane increased the expression level of activated caspase-3, indicative of apoptosis. Mice exposed to sevoflurane also showed impaired long-term memory in fear tests. However, sevoflurane-exposed mice did not exhibit autism-like features in all of the following assays: social interaction (three-chamber test, caged social interaction), social communication (ultrasonic vocalization test), or repetitive behavior (self-grooming test, digging). There were also no differences in general activity (open field test, home cage activity) and anxiety (open field test, light-dark box) after sevoflurane exposure. CONCLUSIONS: Our results confirm previous studies that neonatal sevoflurane exposure causes neurodegeneration and long-term memory impairment in mice. However, sevoflurane did not induce autism-like features. Our study suggests that mice are more vulnerable to long-term memory deficits than autism-like behaviors after exposure to sevoflurane.

Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.

Social deficits are observed in diverse psychiatric disorders, including autism spectrum disorders and schizophrenia. We found that mice lacking the excitatory synaptic signaling scaffold IRSp53 (also known as BAIAP2) showed impaired social interaction and communication. Treatment of IRSp53(-/-) mice, which display enhanced NMDA receptor (NMDAR) function in the hippocampus, with memantine, an NMDAR antagonist, or MPEP, a metabotropic glutamate receptor 5 antagonist that indirectly inhibits NMDAR function, normalized social interaction. This social rescue was accompanied by normalization of NMDAR function and plasticity in the hippocampus and neuronal firing in the medial prefrontal cortex. These results, together with the reduced NMDAR function implicated in social impairments, suggest that deviation of NMDAR function in either direction leads to social deficits and that correcting the deviation has beneficial effects.

Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.

Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.

Two genetic loci control syllable sequences of ultrasonic courtship vocalizations in inbred mice.

BACKGROUND: The ultrasonic vocalizations (USV) of courting male mice are known to possess a phonetic structure with a complex combination of several syllables. The genetic mechanisms underlying the syllable sequence organization were investigated. RESULTS: This study compared syllable sequence organization in two inbred strains of mice, 129S4/SvJae (129) and C57BL6J (B6), and demonstrated that they possessed two mutually exclusive phenotypes. The 129S4/SvJae (129) strain frequently exhibited a "chevron-wave" USV pattern, which was characterized by the repetition of chevron-type syllables. The C57BL/6J strain produced a "staccato" USV pattern, which was characterized by the repetition of short-type syllables. An F1 strain obtained by crossing the 129S4/SvJae and C57BL/6J strains produced only the staccato phenotype. The chevron-wave and staccato phenotypes reappeared in the F2 generations, following the Mendelian law of independent assortment. CONCLUSIONS: These results suggest that two genetic loci control the organization of syllable sequences. These loci were occupied by the staccato and chevron-wave alleles in the B6 and 129 mouse strains, respectively. Recombination of these alleles might lead to the diversity of USV patterns produced by mice.