The role of neuropeptide somatostatin in the brain and its application in treating neurological disorders.

Somatostatin (SST) is a well-known neuropeptide that is expressed throughout the brain. In the cortex, SST is expressed in a subset of GABAergic neurons and is known as a protein marker of inhibitory interneurons. Recent studies have identified the key functions of SST in modulating cortical circuits in the brain and cognitive function. Furthermore, reduced expression of SST is a hallmark of various neurological disorders, including Alzheimer's disease and depression. In this review, we summarize the current knowledge on SST expression and function in the brain. In particular, we describe the physiological roles of SST-positive interneurons in the cortex. We further describe the causal relationship between pathophysiological changes in SST function and various neurological disorders, such as Alzheimer's disease. Finally, we discuss potential treatments and possibility of novel drug developments for neurological disorders based on the current knowledge on the function of SST and SST analogs in the brain derived from experimental and clinical studies.

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.

Somatostatin enhances visual processing and perception by suppressing excitatory inputs to parvalbumin-positive interneurons in V1.

Somatostatin (SST) is a neuropeptide expressed in a major subtype of GABAergic interneurons in the cortex. Despite abundant expression of SST and its receptors, their modulatory function in cortical processing remains unclear. Here, we found that SST application in the primary visual cortex (V1) improves visual discrimination in freely moving mice and enhances orientation selectivity of V1 neurons. We also found that SST reduced excitatory synaptic transmission to parvalbumin-positive (PV+) fast-spiking interneurons but not to regular-spiking neurons. Last, using serial block-face scanning electron microscopy (SBEM), we found that axons of SST+ neurons in V1 often contact other axons that exhibit excitatory synapses onto the soma and proximal dendrites of the PV+ neuron. Collectively, our results demonstrate that the neuropeptide SST improves visual perception by enhancing visual gain of V1 neurons via a reduction in excitatory synaptic transmission to PV+ inhibitory neurons.

Precise Mapping of Single Neurons by Calibrated 3D Reconstruction of Brain Slices Reveals Topographic Projection in Mouse Visual Cortex.

Recent breakthroughs in neuroanatomical tracing methods have helped unravel complicated neural connectivity in whole-brain tissue at single-cell resolution. However, in most cases, analysis of brain images remains dependent on highly subjective and sample-specific manual processing, preventing precise comparison across sample animals. In the present study, we introduce AMaSiNe, software for automated mapping of single neurons in the standard mouse brain atlas with annotated regions. AMaSiNe automatically calibrates misaligned and deformed slice samples to locate labeled neuronal positions from multiple brain samples into the standardized 3D Allen Mouse Brain Reference Atlas. We exploit the high fidelity and reliability of AMaSiNe to investigate the topographic structures of feedforward projections from the lateral geniculate nucleus to the primary visual area by reconstructing rabies-virus-injected brain slices in 3D space. Our results demonstrate that distinct organization of neural projections can be precisely mapped using AMaSiNe.

A Neural Circuit for Auditory Dominance over Visual Perception.

When conflicts occur during integration of visual and auditory information, one modality often dominates the other, but the underlying neural circuit mechanism remains unclear. Using auditory-visual discrimination tasks for head-fixed mice, we found that audition dominates vision in a process mediated by interaction between inputs from the primary visual (VC) and auditory (AC) cortices in the posterior parietal cortex (PTLp). Co-activation of the VC and AC suppresses VC-induced PTLp responses, leaving AC-induced responses. Furthermore, parvalbumin-positive (PV+) interneurons in the PTLp mainly receive AC inputs, and muscimol inactivation of the PTLp or optogenetic inhibition of its PV+ neurons abolishes auditory dominance in the resolution of cross-modal sensory conflicts without affecting either sensory perception. Conversely, optogenetic activation of PV+ neurons in the PTLp enhances the auditory dominance. Thus, our results demonstrate that AC input-specific feedforward inhibition of VC inputs in the PTLp is responsible for the auditory dominance during cross-modal integration.

The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity.

The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of Paired-homeobox 6 (PAX6) is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina. Tgfb1i1-/- mice show elevated α-enhancer activity leading to overproduction of Pax6ΔPD isoform that supports the GABAergic amacrine cell fate maintenance. Consequently, the Tgfb1i1-/- mouse retinas show a sustained light response, which becomes more transient in mice with the auto-stimulation-defective Pax6ΔPBS/ΔPBS mutation. Together, we show the antagonistic regulation of the α-enhancer activity by Pax6 and the LIM protein complex is necessary for the establishment of an inner retinal circuitry, which controls visual adaptation.

Functional dissection of inhibitory microcircuits in the visual cortex.

Cerebral cortex contains various types of GABAergic neurons exerting local inhibition. Although the number of GABAergic inhibitory neurons is much smaller than glutamatergic excitatory neurons, they show greater diversity in their morphological and physiological properties. Genetic markers for distinct sub-classes of GABAergic neurons have been identified, and technical advances achieved in the past few decades have brought about a demonstration of a unique function of each sub-class of GABAergic neurons in the cortex. In particular, visual processing in the cortex requires inhibitory function of various GABAergic neurons. Here, we summarize current understandings on the function of inhibitory neurons in the cortex, especially focusing on their roles in visual processing.