Academic Background

In the mammalian neocortex, somatostatin (SST)-expressing neurons are a major class of inhibitory interneurons that exhibit diversity in electrophysiology and morphology, and are involved in various cognitive functions such as learning, memory, and sensory processing. However, despite extensive research on the diversity of SST neurons, the specific functional roles of their subtypes remain unclear. In recent years, with the advancement of single-cell transcriptomics, researchers have discovered that SST neurons can be further subdivided into dozens of subtypes, which may exhibit significant differences in morphology, electrophysiological properties, and function. Understanding the diversity of these subtypes and their specific roles in brain function is of great importance for revealing the fine regulatory mechanisms of the neocortex.

This review, published in the February 2025 issue of Trends in Neurosciences, is co-authored by Eunsol Park, Matthew B. Mosso, and Alison L. Barth from the Department of Biological Sciences and the Center for the Neural Basis of Cognition at Carnegie Mellon University. The article summarizes recent advances in the diversity of neocortical SST neurons and their roles in cognition and learning, with a focus on the classification of SST subtypes, their regulatory mechanisms, and their functions in brain circuits.

Main Content of the Article

1. Diversity of SST Neurons

SST neurons are one of the most heterogeneous classes of inhibitory interneurons in the neocortex. Through integrated studies of single-cell transcriptomics, morphology, and electrophysiology, researchers have discovered that SST neurons can be divided into multiple subtypes, with estimates ranging from 12 to 40 subtypes. The article highlights that although the diversity of SST neurons is widely recognized, linking these subtypes to specific functions remains a pressing challenge. For example, Martinotti cells and nNOS+ (nitric oxide synthase-positive) cells are associated with the regulation of arousal and sleep states, respectively. The diversity of these subtypes may reflect their distinct functional roles in cortical circuits.

2. Regulatory Mechanisms of SST Neurons

The activity of SST neurons is regulated by various factors, including brain states, behavior, and sensory inputs. The article points out that SST neurons exhibit highly heterogeneous responses to different stimuli, which may be influenced by subtype, brain region, and experimental conditions. For instance, SST neurons may exhibit completely different response patterns under different brain states, such as sleep and wakefulness. Additionally, studies have shown that SST neurons display significant plasticity during learning and memory processes, particularly in task-related learning.

3. Role of SST Neurons in Cognitive Functions

The article provides a detailed discussion on the critical role of SST neurons in cognitive functions, particularly in sensory processing, attention, and prediction error detection. Studies have shown that SST neurons exhibit strong responses to sensory stimuli, especially in processing large-scale sensory inputs. Moreover, SST neurons play an important role in detecting novelty and prediction errors. For example, in the visual and auditory systems, SST neurons show enhanced responses to “oddball stimuli,” suggesting that they may play a key role in detecting unexpected events.

4. Plasticity of SST Neurons in Learning

SST neurons exhibit significant plasticity during learning. The article highlights that in various learning tasks, such as sensory learning, reward-based learning, and motor learning, the activity patterns of SST neurons undergo notable changes. For example, in sensory cortex, as animals become proficient in a task, the population activity of SST neurons gradually decreases, while in motor cortex, motor learning leads to increased activity of SST neurons. Additionally, studies have found that specific SST subtypes (e.g., npas4+ neurons) display unique response patterns during learning, suggesting that these subtypes may play an important role in establishing new neuronal circuits.

5. Subtype-Specific Functions of SST Neurons

The article also discusses the roles of SST subtypes in specific functions. For example, SST neurons expressing the chodl gene (SST-chodl subtype) exhibit long-range projections and play a crucial role in sleep regulation. Studies have shown that activation of SST-chodl neurons can induce cortical synchrony, a hallmark of slow-wave sleep. Furthermore, SST neurons expressing the calb2 gene (SST-calb2 subtype) exhibit significant plasticity during motor learning, indicating that different subtypes may play distinct roles in specific behavioral tasks.

Significance and Value of the Article

This review not only summarizes a wide range of recent studies on the diversity and functions of SST neurons but also provides important directions for future research. The article highlights that although the diversity and functional heterogeneity of SST subtypes have been preliminarily revealed, many questions remain to be explored. For example, the specific mechanisms by which different subtypes contribute to brain functions, how they operate in various cognitive tasks, and how their regulatory mechanisms are influenced by brain states and behaviors.

Additionally, the article emphasizes the importance of new technologies for understanding the functions of SST neurons. For instance, the integration of single-cell transcriptomics, optogenetics, and calcium imaging has enabled researchers to dissect the functional and connectivity patterns of individual neurons. The development of these techniques provides powerful tools for unraveling the complex roles of SST neurons in brain function.

This review not only provides neuroscience researchers with the latest findings on SST neurons but also offers a theoretical foundation for understanding the fine regulatory mechanisms of the neocortex. By revealing the diversity and functions of SST neurons, researchers can gain deeper insights into how the brain processes information, regulates behavior, and develop novel approaches for the treatment of neuropsychiatric disorders.