Insights from extracellular matrix studies in the hypothalamus: structural variations of perineuronal nets and discovering a new perifornical area of the anterior hypothalamus

The hypothalamus controls metabolism, stress responses, and instinctive behaviors for individual survival and species preservation. Recent studies suggest that hypothalamic neurons retain plasticity throughout adulthood, which enables these neurons to respond to various kinds of changes in environment, nutrients, and fluctuating hormones. One of the mechanisms underlying the regulation of neural plasticity is the formation of a stable extracellular matrix (ECM) structure called perineuronal nets (PNNs). PNNs are large aggregates of heterogeneous ECM molecules such as chondroitin sulfate proteoglycans (CSPGs), hyaluronan, their link proteins, and tenascin-R. PNNs surround the cell body and proximal dendrites of a subset of neurons and limit adult neural plasticity. This review describes the CSPG-based ECM, including the PNNs, with a special focus on the hypothalamus of mice. We first provide an overview of PNNs in terms of their structure, molecular components, and functions, most of which have been demonstrated by extrahypothalamic studies. Second, we show the presence or absence of PNNs within individual hypothalamic regions and then describe non-PNN-formed ECM containing CSPGs that can be observed in particular hypothalamic regions. Finally, we will introduce a newly identified mouse hypothalamic area that we named the perifornical area of the anterior hypothalamus (PeFAH), which contains a cluster of PNN-positive neurons. PeFAH neurons express enkephalin and have bidirectional connections with the lateral septum. The anterior hypothalamus and lateral septum are thought to regulate defensive behaviors; therefore, the PeFAH neurons and PNNs around them could be involved in the regulation of defensive behaviors.