CA2 inhibition reduces the precision of hippocampal assembly reactivation.

The structured reactivation of hippocampal neuronal ensembles during fast synchronous oscillatory events, termed sharp-wave ripples (SWRs), has been suggested to play a crucial role in the storage and use of memory. Activity in both the CA2 and CA3 subregions can precede this population activity in CA1, and chronic inhibition of either region alters SWR oscillations. However, the precise contribution of CA2 to the oscillation, as well as to the reactivation of CA1 neurons within it, remains unclear. Here, we employ chemogenetics to transiently silence CA2 pyramidal cells in mice, and we observe that although SWRs still occur, the reactivation of CA1 pyramidal cell ensembles within the events lose both temporal and informational precision. These observations suggest that CA2 activity contributes to the fidelity of experience-dependent hippocampal replay.

Optogenetic Approaches to Understand the Neural Circuit Mechanism of Social Deficits Seen in Autism Spectrum Disorders.

Individuals with neurodevelopmental disorders, such as autism spectrum disorders (ASDs), are diagnosed based on nonquantitative objective parameters such as behavioral phenotypes. It is still unclear how any neural mechanism affects such behavioral phenotypes in these patients. In human genetics, a large number of genetic abnormalities including single nucleotide variation (SNV) and copy number variation (CNV) have been found in individuals with ASDs. It is thought that influence of such variations converges on dysfunction of neural circuit resulting in common behavioral phenotypes of ASDs such as deficits in social communication and interaction. Recent studies suggest that an excitatory/inhibitory (E/I) imbalanced state, which induces disruption of neural circuit activities, is one of the pathophysiological abnormalities in ASD brains. To assess the causal relationship between brain abnormalities and behavioral deficits, we can take advantage of optogenetics with animal models of ASDs that recapitulate human genetic mutations. Here, we review optogenetics studies being utilized to dissect neural circuit mechanisms associated with social deficits in model mice of ASD. Optogenetic manipulation of disrupted neural activities would help us understand how neural circuits affect behavioral deficits observed in ASDs.

Comprehensive topographical map of the serotonergic fibers in the male mouse brain.

It is well established that serotonergic fibers distribute throughout the brain. Abnormal densities or patterns of serotonergic fibers have been implicated in neuropsychiatric disorders. Although many classical studies have examined the distribution pattern of serotonergic fibers, most of them were either limited to specific brain areas or had limitations in demonstrating the fine axonal morphology. In this study, we utilize male mice expressing green fluorescence protein under the serotonin transporter (SERT) promoter to map the topography of serotonergic fibers across the rostro-caudal extent of each brain area. We demonstrate previously unreported regional density and fine-grained anatomy of serotonergic fibers. Our findings include: (a) SERT fibers distribute abundantly in the thalamic nuclei close to the midline and dorsolateral areas, in most of the hypothalamic nuclei with few exceptions such as the median eminence and arcuate nuclei, and within the basal amygdaloid complex and lateral septal nuclei, (b) the source fibers of innervation of the hippocampus traverse through the septal nuclei before reaching its destination, (c) unique, filamentous type of straight terminal fibers within the nucleus accumbens, (d) laminar pattern of innervation in the hippocampus, olfactory bulb and cortex with heterogenicity in innervation density among the layers, (e) cortical labeling density gradually decreases rostro-caudally, (f) fibers traverse and distribute mostly within the gray matter, leaving the white fiber bundles uninnervated, and (g) most of the highly labeled nuclei and cortical areas have predominant anatomical connection to limbic structures. In conclusion, we provide novel, regionally specific insights on the distribution map of serotonergic fibers using transgenic mouse.

Development of serotonergic projections to the suprachiasmatic nucleus in the mouse brain.

Serotonin (5-HT) and its innervation have been implicated in various neural functions including circadian systems. Although classical studies have examined the 5-HT innervation pattern in the adult suprachiasmatic nucleus (SCN), the fine-grained morphological study of the development of pathway and terminal projections to the SCN remains scarce. Here, we utilize transgenic mice expressing GFP under the serotonin transporter (SERT) promoter to subserve our developmental mapping study. We demonstrate that the morphology of 5-HT pathway fibers decussating over the supraoptic commissure that projects to the SCN exhibits two distinct developmental patterns. The punctate fibers at the fetal stage gradually become smooth and filamentous, especially during postnatal one week and remain constant thereafter. The innervation field in the SCN develops properly only during postnatal two weeks. Its ventromedial area remains one of the highest 5-HT innervated areas in the adult brain, whereas the dorsolateral area is less innervated. Thus, we provide novel and specific insights on the developmental map of 5-HT system into the SCN using transgenic mouse.

Imaging the Neural Circuit Basis of Social Behavior: Insights from Mouse and Human Studies.

Social behavior includes a variety of behaviors that are expressed between two or more individuals. In humans, impairment of social function (i.e., social behavior and social cognition) is seen in neurodevelopmental and neurological disorders including autism spectrum disorders (ASDs) and stroke, respectively. In basic neuroscience research, fluorescence monitoring of neural activity, such as immediate early gene (IEG)-mediated whole-brain mapping, fiber photometry, and calcium imaging using a miniaturized head-mounted microscope or a two-photon microscope, and non-fluorescence imaging such as functional magnetic resonance imaging (fMRI) are increasingly used to measure the activity of many neurons and multiple brain areas in animals during social behavior. In this review, we overview recent rodent studies that have investigated the dynamics of brain activity during social behavior at the whole-brain and local circuit levels and studies that explored the neural basis of social function in healthy, in brain-injured, and in autistic human subjects. A synthesis of such findings will advance our understanding of brain mechanisms underlying social behavior and facilitate the development of pharmaceutical and functional neurosurgical interventions for brain disorders affecting social function.

Encoding of social exploration by neural ensembles in the insular cortex.

The insular cortex (IC) participates in diverse complex brain functions, including social function, yet their cellular bases remain to be fully understood. Using microendoscopic calcium imaging of the agranular insular cortex (AI) in mice interacting with freely moving and restrained social targets, we identified 2 subsets of AI neurons-a larger fraction of "Social-ON" cells and a smaller fraction of "Social-OFF" cells-that change their activity in opposite directions during social exploration. Social-ON cells included those that represented social investigation independent of location and consisted of multiple subsets, each of which was preferentially active during exploration under a particular behavioral state or with a particular target of physical contact. These results uncover a previously unknown function of AI neurons that may act to monitor the ongoing status of social exploration while an animal interacts with unfamiliar conspecifics.