Table of Contents

Critical Periods and Beyond: Dynamic Functions of Perineuronal Nets in Cognition, Development, and Disease

  1. Barbara A. Sorg9
  1. 1Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada
  2. 2Integrated Program in Neuroscience, McGill University, Montreal, Quebec H3A 1A1, Canada
  3. 3Department of Neuroscience, University of Florida, Gainesville, Florida 32610
  4. 4Department of Medicinal Chemistry, University of Washington, Seattle, Washington 98195
  5. 5Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08540
  6. 6Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996
  7. 7Department of Behavioral and Systems Neuroscience, Oregon Health and Science University, Portland, Oregon 97239
  8. 8Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
  9. 9R.S. Dow Neurobiology, Legacy Research Institute, Portland, Oregon 97232

  1. Author contributions: J.T.S., K.M.A., E.J.D., K.K., N.E.P.M., A.I.R., X.W., and B.A.S. wrote the paper.

 
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Abstract

First discovered by Golgi, perineuronal nets (PNNs) are extracellular matrices that surround various neuron types in the nervous system. They have been found to emerge at the end of developmental critical periods and serve as “molecular brakes” on plasticity. Perineuronal nets have traditionally been studied in the context of sensory and cognitive plasticity, but recent studies extend their contributions to brain plasticity involved in substance use disorders, metabolism, neurodegeneration, and more. This review will summarize recent discoveries about the functions of PNNs across diverse circuits, contexts, and species, across different stages of life, and between disease and nondisease states and will integrate fundamental and clinical studies to identify conserved and novel functions of PNNs. Given the recent map of extensive PNN expression, we hope to encourage investigators researching diverse neural systems to examine PNN contributions to circuit function and behavior.

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Introduction

First discovered by Golgi, perineuronal nets (PNNs) are extracellular matrix (ECM) structures that surround various neuronal populations in the brain and spinal cord. Classic studies discovered that PNNs emerge at the end of critical periods in development and surround neurons that play central roles in plasticity [e.g., parvalbumin (PV) neurons: Takesian and Hensch, 2013; Sorg et al., 2016; Reichelt et al., 2019; Fawcett et al., 2022; Sanchez et al., 2024]. Consequently, they have been predominantly studied in the context of neural and behavioral plasticity, especially as “molecular brakes” on plasticity.

Many studies have investigated PNN function in sensory processing areas, especially with regard to their role in developmental plasticity (McRae et al., 2007; Sale et al., 2007; Happel et al., 2014; Stodieck et al., 2014; Krishnan et al., 2015; Lee et al., 2017; Wen et al., 2018; Schiff et al., 2023). For example, the emergence of PNNs in the visual cortex early in life corresponds with the closure of the critical period for visual plasticity, and degradation of these PNNs reinstates the ability of visual inputs to shape the organization of the visual cortex (Pizzorusso et al., 2002; Takesian and Hensch, 2013; Lensjø et al., 2017). The emergence of PNNs in the auditory cortex has been implicated in developmental changes in auditory processing, including speech perception (Werker and Hensch, 2015; Cisneros-Franco et al., 2018), and PNNs in the somatosensory cortex are modulated by sensory experiences during development (McRae et al., 2007). Further, pharmacological manipulations that alter the timing of critical periods (e.g., re-open windows of plasticity) in sensory circuits often alter the timing of PNN expression (Maya-Vetencourt et al., 2008; Umemori et al., 2018; Reichelt et al., 2019).

Recent research has highlighted the presence and diverse roles of PNNs outside of sensory processing and plasticity and outside the context of developmental critical periods. Here we discuss recent advances in our understanding of PNN function, highlighting its role in a wide diversity of neural systems, behaviors, and cognitive processes across species and the lifespan (Fig. 1). We highlight PNN contributions to episodic and social memory, substance use disorders, social behaviors, motor learning and performance, and metabolism. We further discuss the influence of PNN composition on their stability and function, PNN modulation of circuit function, and some key mechanisms by which PNNs are regulated.

Figure 1.
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Figure 1.

Contributions of perineuronal nets throughout the lifespan. During early development, PNNs begin to appear in the early postnatal period and continue to increase in expression with age. At this time, PNNs are primarily characterized by a chondroitin-6-sulfated (C6S) “child” sulfation pattern and support emerging social behaviors, motor skills, vocal learning, and spatial memory across different species. In adulthood, PNNs are densely expressed throughout the brain, and a chondroitin-4-sulfated (C4S) “adult” sulfation pattern becomes predominant. Adult PNNs support social memory, facilitate the onset of maternal behaviors, and influence substance use disorders. As aging progresses, PNNs accumulate to an unhealthy degree, impairing memory formation and recall. However, low PNN levels are also associated with some neurodegenerative diseases, like Alzheimer's disease. Pictured: A PV interneuron (red) with a PNN (cyan) in the barrel field of the primary somatosensory cortex (S1BF) in a prairie vole pup. Importantly, this list is not exhaustive, and ongoing work continues to identify contributions of PNNs across developmental stages and species.

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Episodic-Like and Social Memory

Several years after PNNs were identified as molecular brakes on critical period plasticity in the developing sensory cortex (Pizzorusso et al., 2002), Gogolla et al. (2009) discovered that the formation of PNNs in the basolateral amygdala (BLA) of mice closes a critical period for fear memory erasure. Following this discovery, several studies have demonstrated diverse roles for PNNs in the BLA and cortex in the consolidation, retrieval, and flexibility of fear memory (Happel et al., 2014; Yang et al., 2016; Banerjee et al., 2017; Morikawa et al., 2017; Thompson et al., 2018; Lavertu-Jolin et al., 2023; Poli et al., 2023). In contrast, the specific functions of PNNs to other types of memory are less understood. In this section, we describe recent research on the contributions of PNNs in the hippocampus to episodic-like memory and social memory.

Episodic memories (or episodic-like memories in animals) are memories for events bound to their spatial and/or temporal context (Tulving, 2002; Allen and Fortin, 2013). The ability to form episodic-like memories emerges over development: whereas adults form memories for events that are context specific and long lasting, juveniles form event memories that are not context specific (i.e., generalized) and that are forgotten over time (Anderson and Riccio, 2005; Akers et al., 2014; Travaglia et al., 2016; Ramsaran et al., 2019, 2023; Bevandić et al., 2024). Episodic-like memory function is supported by the hippocampus, and accordingly, recent studies point toward a role for PNNs within the trisynaptic circuit of the hippocampus—subregions cornu ammonis (CA) 1, CA3, and dentate gyrus (DG)—in regulating both the precision and persistence of episodic-like memories. First, the developmental emergence of hippocampal PNNs enables the formation of context-specific (rather than generalized) memories. Removing PNNs in CA1 of adult mice using chondroitinase ABC (ChABC) or viral manipulations of hyaluronan and proteoglycan link protein 1 (HAPLN1) reverts adults to form juvenile-like memories that generalize across contexts, whereas accelerating the development of PNNs in CA1 using recombinant BDNF or overexpression of HAPLN1 makes juveniles form adult-like memories that are context specific (Ramsaran et al., 2023, 2025). Other studies indicate that PNNs also regulate the persistence of memory (Hylin et al., 2013; Shi et al., 2019; Jovasevic et al., 2021).

Perineuronal nets in the hippocampus are thought to promote the precision and persistence of memories via mechanisms similar to how PNNs regulate plasticity within sensory cortices. As in sensory cortices, PNNs in the CA1 predominately surround PV interneurons (Yamada and Jinno, 2013; Yamada et al., 2015; Lensjø et al., 2017), promoting the structural and functional maturation of PV interneurons in part by stabilizing excitatory inputs onto these cells (Doischer et al., 2008; Favuzzi et al., 2017; Que et al., 2021). Via feedforward inhibition, mature PV interneurons regulate the sparseness of neuronal ensembles (based on immediate early gene expression, such as c-FOS) whose activity encodes a memory (i.e., memory trace or engram; Morrison et al., 2016; Lesuis et al., 2025). Therefore, the condensation of PNNs around PV interneurons in the CA1 enables the formation of sparse engrams to encode precise memories (Ramsaran et al., 2023), paralleling the reduction in cortical immediate early gene expression as mice age out of the visual critical period (Jenks et al., 2017). In addition to altering memories at the engram level, PNNs in the CA1 or other subregions of the hippocampus may also support memory precision and persistence by sharpening the tuning and stability of neuronal stimulus representations, such as place coding by hippocampal neurons (Langston et al., 2010; Wills et al., 2010; Christensen et al., 2021). The development of hippocampal PNNs or perisynaptic ECMs may also act to stabilize synaptic connections that store memories (Nguyen et al., 2020; Dembitskaya et al., 2021; Strackeljan et al., 2021; Lev-Ram et al., 2024) and maintain memory-related synaptic plasticity (e.g., long-term potentiation; LTP; Bukalo et al., 2001; Zhou et al., 2001; Brakebusch et al., 2002; Kochlamazashvili et al., 2010; Shi et al., 2019), thereby promoting memory persistence.

In contrast to PNNs in the CA1, PNNs in the CA2 region of the hippocampus surround excitatory pyramidal cells as well as PV interneurons (Brückner et al., 2003) and are involved in memory for individuals (i.e., social memory; Diethorn and Gould, 2023b). They begin to emerge during the developmental onset of CA2-dependent social memory and social novelty preference in mice (Carstens et al., 2016, 2021; Diethorn and Gould, 2023a), and optimal levels of PNNs in the CA2 are important for social memory formation in adulthood (Sgadò et al., 2013; Domínguez et al., 2019; Cope et al., 2022; Mattioni et al., 2024; Alexander et al., 2025). Support for a positive contribution of PNNs in the CA2 comes from studies demonstrating that degrading PNNs decreases social memory (e.g., preference for novel individuals) in mice (Cope et al., 2022) and that augmenting PNNs (using the growth factor neuregulin 1) in Tg2576 mice, a mouse model that has been found to express social memory deficits and reduced PNN expression in the CA2, improves social memory (Rey et al., 2022). On the other hand, in mouse models of autism spectrum disorder (ASD), including En−/− and BTBR mice, an excess of PNNs and upregulation of ECM regulation genes in the CA2 are related to impaired sociability and loss of social novelty preference, and degrading excess PNNs improves social recognition and memory (Sgadò et al., 2013; Cope et al., 2022; Mattioni et al., 2024). Similarly, age-induced increases in CA2 PNN expression are associated with impaired social memory, and degrading PNNs in later adulthood restores function (Mehak et al., 2025).

PNNs may support hippocampal-dependent social memory in part by promoting afferent innervation of the cells they surround (Carulli et al., 2013; Briones et al., 2021). In early development, PNNs can sequester molecules that help guide axons; for example, semaphorin 3A is enriched in PNNs in the developing brain and modulates synapse elimination (Vo et al., 2013; Uesaka et al., 2014). For this reason, atypical PNNs in pathological states may impede typical circuit development and contribute to behavioral impairments. Supporting this notion, Carstens et al. (2016) identified that LTP can be induced at excitatory synapses before, but not after, PNN appearance in CA2. Early PNN onset truncates this window for LTP in Mecp2−/− mice, a model of Rett syndrome characterized by regressive developmental milestones, but this can be reversed by digesting excess PNNs (Carstens et al., 2021). Conversely, PNN emergence promotes inhibitory long-term depression (iLTD) at local CA2 PV cell synapses by facilitating their maturation via neuregulin 1, and disrupting PNN integrity alters this signaling pathway (Domínguez et al., 2019). Since CA2-dependent social memories begin to emerge during this developmental window (Laham et al., 2021; Diethorn and Gould, 2023a), disruptions in PNN maturation at this stage may interfere with the establishment of excitatory/inhibitory (E/I) balance, ultimately impairing circuit formation critical to forming healthy social memory.

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Substance Use Disorders

Repeated exposures to substances of abuse produce persistent memories, and thus, addiction to these substances (substance use disorders) appear as a maladaptive form of learning and memory (Hyman et al., 2006). Consistent with the ideas that these drugs promote memory and that PNNs modulate memory formation (see above), studies on acute and repeated exposures to drugs (which have largely been done during adulthood) show altered density and intensity of PNNs in a wide range of brain regions implicated in reward and memory. These regions include the medial prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex, nucleus accumbens, insula, hypothalamus, hippocampus, ventral tegmental area, and cerebellum (reviews: Lasek et al., 2018; Brown and Sorg, 2023). Although not discussed in detail here, early life stress in animals predisposes individuals to later substance use disorders (Sinha, 2024), which in part may be due to altered development of PNNs and/or PV neurons during critical periods (Spijker et al., 2020; Laham and Gould, 2021; Tanti et al., 2022; Aguilar and Lasek, 2024; Theberge et al., 2024).

Developmental and adult drug exposure modulates PNN expression and PV neurons in a variety of cortical regions, with variation in effects that depend on the timing and duration of exposure as well as brain region (Brown and Sorg, 2023). Most developmental drug exposures have been examined after ethanol. Exposure to ethanol early in development increases the staining density of PNNs as well as their components, brevican and neurocan, in the orbital frontal cortex (Coleman et al., 2014) and increases the number of PNNs around PV neurons in the orbital frontal cortex (Coleman et al., 2014), medial prefrontal cortex (Dannenhoffer et al., 2022), and the anterior insular cortex (Sullivan et al., 2024). However, other findings reveal regional heterogeneity in the effects of ethanol, with early postnatal ethanol exposure decreasing or increasing PNNs across different cortical areas and stages of development (Lewin et al., 2018; Saito et al., 2019). In addition to showing developmental changes after early exposures, some studies have shown specific developmental windows over which drug exposure impacts adult PV or PNN development; for example, methamphetamine increases PV neurons or PNNs in the medial prefrontal cortex when given in early and young adulthood but not when given during later adolescence in rats (Brinks et al., 2025).

Drug experience-dependent changes in PNN expression resemble the effects of other types of experience on memory formation. However, in contrast to the findings that PNNs generally inhibit the formation of memories, PNNs in many of the aforementioned areas may facilitate the formation of strong, persistent memories, evidenced by findings that PNN removal attenuates drug-associated memories (but see Hazlett et al., 2024). Removal of PNNs or the PNN component brevican in cortical regions (Slaker et al., 2015; Lubbers et al., 2016; Huang et al., 2024; Wingert et al., 2024) or the lateral hypothalamus (Blacktop and Sorg, 2019) disrupts the acquisition or reconsolidation of cocaine-associated memories in rats. Similarly, ChABC-induced degradation of PNNs in the medial prefrontal cortex or amygdala decreases cocaine- or morphine-primed reinstatement (Xue et al., 2014) and methamphetamine-primed reinstatement (Yao et al., 2024). In summary, disrupting PNN stability in numerous brain areas has been successful at reducing drug-seeking behaviors. Additional work is needed to determine the extent to which the facilitatory effect of PNNs on memory formation is specific to drugs versus other rewarding stimuli, such as highly palatable food, which also alters PNNs in various brain regions (Brown and Sorg, 2023). The drug-induced changes in memories may be driven by their ability to produce supra-physiological levels of dopamine, which facilitates learning (Wise, 2004; Keiflin and Janak, 2015). Future studies should focus on the mechanisms that trigger PNN plasticity, including regional and compositional variation in PNNs, and the types of PNN-induced circuit-level changes that are needed to disrupt the drug-induced rigidity of reward circuitry, termed “drug-induced metaplasticity” (Neuhofer and Kalivas, 2018).

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Social Behaviors

Social isolation and contact and maternal deprivation

Social memory formation is but one of many aspects of social behavior, and PNNs in the prefrontal cortex and sensory cortices have recently been found to be modulated by species-typical social interactions (Baker et al., 2017; Horii-Hayashi et al., 2017; Ueno et al., 2017; Uriarte et al., 2020; Ciccarelli et al., 2021; Zhang et al., 2021; Gandhi et al., 2023; Lupori et al., 2023). Social isolation during a sensitive postweaning period of development reduces social approach and increases adult aggression, with a concomitant increase in the intensity of PNNs and PV neurons in the prefrontal cortex of rats (Bicks et al., 2020; Biro et al., 2023). Similarly, knock-out of contactin-associated protein-like 2 (CNTNAP2) decreases sociability and increases PNN expression in the prefrontal cortex of mice, and this social deficit is rescued with PNN degradation (Gandhi et al., 2023). In the hippocampus, social isolation during adulthood can alter inhibitory innervation onto PNN-surrounded PV cells in ventral CA1 (Gore et al., 2024). Maternal deprivation in developing rats leads to lasting changes in social interaction and reductions in PNN density in the dorsal hippocampus, BLA, and prefrontal cortex (Holland et al., 2014; Farrell et al., 2016; Gildawie et al., 2020; Jakovljevic et al., 2022). Ongoing experiments suggest that PNNs in the somatosensory cortex could also regulate social contact, as developmental changes in PNN expression in the somatosensory cortex of the socially monogamous prairie vole mirrors the developmental decline in huddling behavior (Milman et al., 2025).

Maternal behaviors

Maternal behavior is a multifaceted, multisensory, and complex social behavior that has various effects on PNN expression. For example, maternal behavior leads to increases in mature PNNs in the primary somatosensory cortex in adult female rodents (Lau et al., 2020b). The timing of this PNN increase is important, as experimental models (Mecp2-heterozygous mice used to model Rett syndrome) and manipulations that increase PNN expression in auditory or somatosensory cortices before parturition (e.g., knockdown of oxytocin receptors in the midbrain dorsal raphe) can decrease maternal behaviors and lead to inefficient pup retrieval and atypical and prolonged tactile interactions (Krishnan et al., 2017; Lau et al., 2020b; Grieb et al., 2021; Stevenson et al., 2021; Mykins et al., 2023). Changes in PNN expression also impact the function of PV neurons in the context of maternal behavior (Lau et al., 2020a; Rupert et al., 2023). Given the complexity and multisensory nature of maternal behavior, studies are underway to determine the extent of PNN changes in the whole brain before, during, and after maternal exposure.

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Motor Learning and Performance

While less abundant than in sensory areas, PNNs are prevalent within motor circuits (including the motor cortex, basal ganglia, cerebellum, and spinal cord) across a variety of species (Hausen et al., 1996; Alpár et al., 2006; Brückner et al., 2008; Balmer et al., 2009; Lupori et al., 2023; Wang et al., 2023; Benacom et al., 2025). Perineuronal nets in basal ganglia circuitry, for example, seem to play a crucial role in motor development; they emerge in the striatal matrix during the second postnatal week in mice, coinciding with the transition from immature crawling to mature gait patterns (Lee et al., 2012). Environmental enrichment can accelerate both the emergence of coordinated motor behaviors and PNN formation in the striatum (Simonetti et al., 2009). Together, these data suggest that PNNs help consolidate circuits necessary for adult-like motor control. Consistent with a role in maintaining precise motor control and movement coordination, degradation of striatal PNNs causes measurable alterations in motor behavior, including significantly larger mean step width and greater step width variability (Lee et al., 2012).

Songbirds are a powerful animal model system to reveal how PNNs in motor circuitry regulate motor learning and performance. Like humans, songbirds learn their vocalizations during restricted periods in development and possess specialized and discrete circuitry (“song system”) for vocal motor learning and performance that resembles mammalian motor cortical and basal ganglia circuitry (Leblois and Perkel, 2020; Sakata and Yazaki-Sugiyama, 2020). Neurons in the song system that regulate the acquisition and performance of vocalizations in songbirds are enriched with PNNs (Balmer et al., 2009; Cornez et al., 2018; Wang et al., 2023; Wan et al., 2025). Perineuronal nets have been implicated in vocal motor learning because they become more abundant in the song system as the critical period for song learning closes and as learned vocalizations become more stereotyped (Balmer et al., 2009; Cornez et al., 2017, 2018, 2020b; Wang et al., 2023; Wan et al., 2025); because they are more abundant in species with less adult vocal plasticity (Cornez et al., 2017); and because they change with manipulations that modulate vocal plasticity (Balmer et al., 2009; Cornez et al., 2020a). Furthermore, published and ongoing studies indicate that degradation of PNNs in vocal motor circuitry alters the performance of learned vocalizations (Cornez et al., 2021; Wan et al., 2025) and could modulate vocal plasticity and development (X.W. and J.T.S., unpublished data).

In cerebellar-dependent motor learning, PNNs demonstrate a dynamic relationship with memory formation and consolidation in adult mice (Carulli et al., 2020). Eyeblink conditioning involves individuals learning to close their eyes upon hearing a cue. Perineuronal nets in the deep cerebellar nuclei are diminished during memory acquisition but are restored when memories are fully consolidated. Consistent with these findings, enzymatic digestion of PNNs accelerates the acquisition but decreases the retention of this memory. Removal of PNNs initiates a cascade of synaptic remodeling, causing significant increases in inhibitory synapses, decreases in excitatory synapses, and reduced spontaneous firing activity of neurons in deep cerebellar nuclei (Carulli et al., 2020).

The effects of PNNs on motor plasticity can vary across regions. Following spinal cord injury, the thickness of PNNs decreases as a result of decreased motoneuron activity, but this change can be reversed through physical rehabilitation (Sánchez-Ventura et al., 2022). Degrading PNNs at the injury site in the spinal cord combined with motor training promotes functional recovery by degrading growth-inhibiting chondroitin sulfate proteoglycans (CSPGs) in the fibro-glial scar (Orlando and Raineteau, 2015). In contrast, digesting PNNs in the motor cortex impairs recovery and reduces compensatory sprouting of corticospinal tract fibers (Orlando and Raineteau, 2015; but see Benacom et al., 2025). It will be important for future studies to elucidate how both PNNs in the brain and fibro-glial scarring in the spinal cord differentially interact with extracellular factors to modulate functional recovery and motor plasticity (see Conclusions).

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Metabolism

It has recently become evident that PNNs surround neurons involved not only in cognition, perception, and behavior, but also in homeostasis and metabolism. For example, neuroendocrine cells in the hypothalamic arcuate nucleus-median eminence (ARC-ME) junction are surrounded by densely packed PNNs. In particular, PNNs tightly enmesh neurons in the ARC-ME that are involved in the sensing of hormones (i.e., neurons expressing the leptin receptor) and nutrients (i.e., neurons expressing neuropeptide-Y; Mirzadeh et al., 2019; Alonge et al., 2020). The appearance of these PNNs aligns with the maturation of GABAergic circuits in the ARC-ME and requires circulating developmental leptin, a hormone associated with satiety, for their proper formation. In addition to enmeshing neurons involved in leptin signalling, the abundance of ARC-ME PNNs is nutritionally modulated and regulated by the flux of ghrelin (Kohnke et al., 2021; Kuczynski-Noyau et al., 2024), an intestinal protein that suppresses appetite (Yanagi et al., 2018). Notably, the abundance and composition of ARC-ME PNNs appears disrupted in preclinical models of adult type 2 diabetes (Alonge et al., 2020), obesity (Beddows et al., 2024), and maternal high fat diet (Valdearcos et al., 2025), suggesting a direct role for hypothalamic PNNs in mediating brain regulation of energy expenditure and glucose control under normal and diseased states.

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Mechanisms of PNN Regulation

Variation in PNN composition

The function and impact of PNNs vary depending on their composition, sulfation patterns, and interactions with other components of ECMs. PNNs are considered a specialized ECM subtype that contain CSPGs belonging to the lectican family (also called aggrecan family), including aggrecan, brevican, neurocan, and versican (reviewed in Fawcett et al., 2019; Sanchez et al., 2024). Attached to the CSPG core proteins are sulfated chondroitin sulfate-glycosaminoglycan (CS-GAG) chains that modulate recognition and binding of PNN/CS-GAGs to extracellular proteins (Djerbal et al., 2017). The CSPGs themselves bind together in a lattice-like formation through glycoprotein tenascin-R (TnR) linkages on the CSPG C-terminal (Carulli et al., 2010) that are then attached to hyaluronan scaffolding by link proteins (e.g., HAPLN1 and HAPLN4) on the CSPG N-terminal. Many molecules (including neurotrophins, semaphorin 3A, and the transcription factor OTX2) bind to the CS-GAG chains to allow PNNs to be associated with ion channels and other aspects of the synapse (Srinivasan et al., 1998; Dick et al., 2013; Fawcett et al., 2022; Tewari et al., 2024).

Notably, the constituents of PNNs and their associated glycoprotein stabilizers vary across brain areas. Although both cortical and hypothalamic PNNs are composed of heavily glycosylated aggrecan and phosphacan CSPGs (Mirzadeh et al., 2019; Kuczynski-Noyau et al., 2024), cortical PNNs form stable, net-like formations, while ARC-ME PNNs appear structurally diffuse (Alonge et al., 2020). PNN destabilization specific to the ARC-ME region may in part be due to the lack of stabilizing glycoproteins (i.e., HAPLN1) that are required to form traditional lattice formations. These key differences in matrix stability between cortical and hypothalamic matrices might allow ARC-ME PNNs to quickly adapt to constant nutritional fluxes and metabolic states and serve as an interface between circulating nutritional cues with their target neural populations.

Development, adult experiences, and changes in internal milieu remodel PNNs by changing PNN components. The stability of the PNN matrix is tightly linked to their attached CS-GAG composition, which comprises repeating glucuronic acid and N-acetylgalactosamine (GlcA-GalNAc) disaccharide units that are modified by non-, mono-, and di-sulfate attachments (Alonge et al., 2019). The diffuse appearance of PNNs during early development may largely be driven by the incorporation of the mono-sulfated C6S isomer into the PNN CS-GAG chains. Prior to the critical period of neurodevelopment, mice exhibit increased expression of the C6S (i.e., “Child”) isomer that is thought to prevent stable PNN formation by targeting PNN proteoglycans for degradation (Miyata and Kitagawa, 2016). The destabilization of mature PNN matrices through C6S-driven degradation facilitates neurite outgrowth and inhibitory innervation onto GABAergic PV interneurons (Foscarin et al., 2017; Yang et al., 2021). As mice age, C6S expression decreases and is steadily replaced with the C4S (i.e., “Adult”) isomer (Foscarin et al., 2017). Unlike C6S, the C4S isomer has been linked to PNN maturation and stabilization and, moreover, recently identified as a key target limiting neurocircuit plasticity in the adult brain. In support of the regulatory role of CS isomer composition driving neurocircuit maturation, overexpression of the C6S isomer in the adult brain reverses firing patterns of PNN-surrounded GABAergic neurons to a juvenile-like state and induces memory plasticity (Miyata et al., 2012; Yang et al., 2021), providing evidence for a spatiotemporal ECM-driven “extracellular-to-intracellular” mechanism of circuit maturation and plasticity over time.

Contributors to PNN regulation

In contrast to the steady increase in PNN matrix formation in the hypothalamus, cortex, and hippocampus throughout natural development and aging (Ueno et al., 2018; Lehner et al., 2024; but see also Brewton et al., 2016; Cisneros-Franco et al., 2018), neurological disorders (e.g., Alzheimer's disease, schizophrenia, traumatic brain injury) are associated with a loss of stable PNN matrices (Enwright et al., 2016; Alonge et al., 2021; Logsdon et al., 2024). Current studies show neuroinflammation as a large contributor driving PNN loss in the adult brain (Crapser et al., 2020), and inhibition of microglia using the PLX5622 compound in mice increases PNN abundance in both normal and diseased states (Liu et al., 2021, 2025; Barahona et al., 2022). The outcomes of these preclinical studies suggest that microglia not only regulate PNN stability in neurological diseases but also contribute to baseline PNN maintenance in normal brain aging. Although mechanisms underlying microglia-driven PNN loss in neurological disorders is of high interest in the biomedical community, recent studies investigating PNN changes in human subjects with Alzheimer's disease show a perplexing increase in the abundance of the PNN matrix destabilizing C6S isomer in disease-affected brain regions (Logsdon et al., 2022; Hendrickson et al., 2024), an effect also observed in human subjects diagnosed with schizophrenia (Pantazopoulos et al., 2015). At this time, it is unclear whether the recoding of PNN CS-GAGs is mechanistically linked to microglia-driven PNN matrix degradation in human brain disorders.

Cellular activity induces the formation of PNNs (Dityatev et al., 2007), and neuromodulators that regulate neural activity can also regulate PNN expression and function. Substances of abuse increase dopamine levels (Di Chiara and Imperato, 1988; Nestler, 2025), and stimulation of dopamine D1 receptors induces proteolysis of the PNN components aggrecan and brevican at perisynaptic sites (Mitlohner et al., 2020). Dopamine-induced changes in PV neuron activity (Gorelova et al., 2002) and PV levels (Tripodi et al., 2018) may alter PNN intensity levels through different mechanisms, including activity-dependent recycling of PNN components (Dankovich et al., 2021) or alterations in the orthodenticle homeobox protein 2 (OTX2; Beurdeley et al., 2012) or neural pentraxin-2 (Van’t Spijker et al., 2019).

Sex steroid hormone concentrations also affect PNN expression across brain areas in rodents and songbirds, especially brain areas replete with sex steroid hormone receptors (Horii-Hayashi et al., 2017; Uriarte et al., 2020; Ciccarelli et al., 2021; Zhang et al., 2021; Cornez et al., 2020a,c). Pregnancy and parturition lead to increases in PNN expression in the medial preoptic area (Uriarte et al., 2020), and in canaries, testosterone concentrations positively affect PNN expression in areas in the forebrain that express high concentrations of androgen receptors (Cornez et al., 2020a,c). Manipulating sex steroids before puberty alters PNNs in the CA1 in adult female mice, where the number and intensity of PNNs around PV interneurons changes, depending on the stage of estrous, with higher PNN levels associated with higher estrogen states (Laham et al., 2022; Hernández-Vivanco et al., 2025). In female rats, PNNs in the prelimbic prefrontal cortex rise steadily over development but temporarily decrease immediately following puberty (Drzewiecki et al., 2020). This small but growing body of literature suggests that steroid activity modulates PNN expression throughout the lifespan and should be considered in studies of PNN regulation.

Changes to PNN expression not only vary across brain regions but also across hemispheres in an age-, strain-, and experience-specific manner. Lateralization of function in the rodent brain is a topic of long-standing yet sporadic interest in the field (Glick and Ross, 1981; Kim et al., 2012; Marlin et al., 2015; Soma et al., 2017; Ocklenburg and Guo, 2024). For example, whereas PNN expression is similar across hemispheres in early postnatal and adolescent wild-type female mice, adult wild-type female mice exhibit increases in mature PNN expression in the right primary somatosensory cortex (Lau et al., 2020b; Emery et al., 2023; Mykins et al., 2023). This laterality is impacted by maternal behavior, depending on the mouse strain. When adult wild-type female mice engage in alloparental behavior, they maintain lateralized PNN expression. However, Mecp2-heterozygous female mice, a model for Rett syndrome, lose lateralized expression of mature PNNs after engaging in maternal behavior (Lau et al., 2020b). In a limited bedding model of early life stress, early stress differentially programs synaptic plasticity and PNN development in the left and right basolateral amygdala of male and female mice, which is important for fear conditioning (Guadagno et al., 2020). These studies highlight the potential importance of lateralized PNN regulation on behavioral learning and performance, and investigations into the contribution of lateralized PNN expression in sensory cortices to behavior are currently underway.

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Role of PNNs in Oscillations and Circuit Function

It is clear that one of the ways in which PNNs regulate plasticity is through their effects on neural dynamics. Perineuronal nets preferentially surround PV neurons, which critically shape neural oscillations, including theta, beta, and gamma oscillations within and between brain areas and sharp wave ripples in the hippocampus (Buzsáki and Draguhn, 2004; Cardin et al., 2009; Sohal et al., 2009; Buzsáki and Wang, 2012; Wingert and Sorg, 2021). Additionally, the effects of PNN degradation on motor performance (Lee et al., 2012; Cornez et al., 2021; Wan et al., 2025) are likely to be caused by changes in dynamic interactions between neural populations regulating the sequencing, timing, and composition of motor gestures.

With regard to the effects of PNNs on brain oscillations, most studies have examined how PNN removal alters gamma oscillations, with mixed results (Gurevicius et al., 2004; Cabungcal et al., 2013; Steullet et al., 2014; Lensjø et al., 2017; Faini et al., 2018; Thompson et al., 2018; Shi et al., 2019; Carceller et al., 2020; Wingert et al., 2024; Liu et al., 2025). In most cases, PNN removal enhances the power of high-frequency oscillations (beta or gamma; Cabungcal et al., 2013; Steullet et al., 2014; Lensjø et al., 2017). However, changes in these oscillations can differ depending on the animal's state; for example, under oxidative stress challenge, gamma power is reduced following PNN removal (Cabungcal et al., 2013). Changes in gamma power in response to visual and auditory stimuli have also been found, with no changes (Lensjø et al., 2017) or increases after evoked visual (Faini et al., 2018) or auditory stimuli (Hussain and Razak, 2025).

Theta oscillations are also altered in response to PNN manipulations depending on the state of the animal, generally with increases in theta power following PNN reduction (Gurevicius et al., 2004; Lensjø et al., 2017; Christensen et al., 2021). However, reducing PNNs can also decrease spontaneous theta power (Devienne et al., 2021; Feng et al., 2025) or theta responses to conditioned fear (Shi et al., 2019) and social novelty (Alexander et al., 2025). Interestingly, in aged mice, reduced theta oscillations accompanied by increases in PNNs in the CA2 as a consequence of aging are rescued by ChABC treatment (Mehak et al., 2025).

Hippocampal sharp wave ripples, most prominent during nonrapid eye movement sleep, are a key contributor to memory consolidation in mammals (Buzsáki, 2015), yet only a few studies have examined how PNN removal or attenuation affects hippocampal sharp wave ripples. One study showed ChABC-induced increases in the number of sharp wave ripple events in acute hippocampal tissue slices (Sun et al., 2018), but another showed no changes in tenascin-R KO mice (Gurevicius et al., 2004), potentially due to compensatory changes during development in these mice.

Neural oscillations also interact within and across brain regions in the form of precise coupling of neuronal firing with the phases of rhythms or between phase and amplitude (e.g., theta phase coupled to gamma amplitude); this coupling is critical for several types of memory (Jones and Wilson, 2005; Siapas et al., 2005; Benchenane et al., 2010; Fries, 2015; Maingret et al., 2016; Tamura et al., 2017). PNN removal in one brain area can reduce coherence between brain regions and accompany deficits in memory expression (Thompson et al., 2018). A recent study showed that ChABC removal of PNNs in the medial prefrontal cortex, which regulates relapse-like behavior to cocaine (McFarland and Kalivas, 2001), not only reduces cocaine-associated memory but also disrupts the synchrony of neural oscillations between the medial prefrontal cortex and dorsal hippocampus (Wingert et al., 2024). These data suggest that PNNs in this cortical region are important for maintaining communication across brain regions required for motivation, decision-making, and higher-level cognition.

Here we discussed how PNN manipulation alters oscillation amplitude, but other features (e.g., peak frequency, duration, or number of oscillations) and conditions (e.g., spontaneous vs stimulus-driven) are also important to consider. Overall, the changes in oscillatory activity after PNN removal may reflect instability in the network that could promote new learning; however, future studies need to verify the contribution of oscillatory rhythms through the use of closed-loop systems that manipulate oscillations during ongoing behavioral tasks. Given variation in the effects of PNN manipulations on different types of plasticity (see above), it will also be important to further reveal variation in the effects of PNN manipulations on oscillations and coupling across different circuits.

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Perineuronal Nets versus General Extracellular Matrices and Other Considerations

Neurons are surrounded by ECMs, with PNNs being a specialized type of ECM. Some have argued that ECMs in general serve as modulators of plasticity and found that manipulations that modulate plasticity affect an array of ECM-related genes (Nardou et al., 2023). In this respect, one important caveat to consider in interpreting the contribution of PNNs to behaviors is that the majority of the studies that have manipulated PNNs use an enzyme (ChABC) that degrades not only PNNs but also interstitial matrices (Yamagata et al., 1968; Deepa et al., 2006). However, knock-out mice missing specific PNN components still show enhanced plasticity states (Apostolova et al., 2006; Rowlands et al., 2018), and additional ChABC treatment in knock-out mice lacking the gene for the PNN-specific protein Crtl1 show no further changes in object recognition memory (Romberg et al., 2013). While these studies strongly suggest that the enhanced plasticity is due to changes in PNNs, it is important to consider the effects of ChABC on ECM molecules besides those that contribute to PNNs when interpreting results.

What the effects of ChABC infusions (or other manipulations) are compared with and how PNNs are visualized are also important to consider for interpreting results. Reporting and using proper controls (e.g., administration of penicillinase or a heat-inactivated version of the ChABC protein as a control) when manipulating PNNs in vivo is necessary to account for inflammatory responses in the brain (Lin et al., 2007). Additionally, ChABC digestion zones should be visualized using CS “stub” antibodies (e.g., 2B6) that are capable of detecting digested CS chains up to 6 months after treatment (Brückner et al., 1998). Intact PNNs are most commonly visualized and quantified using the plant lectin Wisteria floribunda agglutinin (WFA), but the extent to which this lectin binding accurately reflects PNN expression varies across brain regions (Fawcett et al., 2019; Belliveau et al., 2024); this is because WFA measures only the nonsulfated sugar moieties of proteoglycans, and thus, measurement of other PNN proteins (e.g., aggrecan, HAPLN1) could reveal different degrees of PNN glycosylation and expression (Nadanaka et al., 2020; Härtig et al., 2022; Scarlett et al., 2022).

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Conclusion

Here we provide a broad overview of the contribution of PNNs to memory formation, including episodic, social, and drug-induced memories, and to plasticity that underlies motor learning, social behaviors, and metabolic function (Fig. 1). Although this review is not exhaustive, we refer readers to important reviews (Fawcett et al., 2019, 2022; Sanchez et al., 2024) and synthesize new and important directions for PNN research.

Our review highlights commonalities and deviations in how PNNs regulate plasticity and behavior, and it will be important for future research to reveal mechanisms underlying these different contributions of PNNs. Overall, it would appear that PNN removal or attenuation induces and may modulate states of metaplasticity. That is, PNN removal modifies the threshold for activity-dependent changes that reshape the response to incoming stimuli. These stimuli include physiological stimuli that induce normal learning and memory as well as stronger stimuli that impose their own states of metaplasticity, such as highly salient stressors or substances of abuse. The consequences of PNN removal are therefore likely to reflect competing local, regional, and interregional effects of outside stimuli on the circuit driving the behavior.

Most studies demonstrate that PNN removal promotes plasticity, including those discussed above. While there are some exceptions, PNN removal seems to enhance plasticity induced by weaker stimuli in which incremental learning occurs over days or under more physiological learning conditions (novel object, spatial learning, motor learning). These types of memories may be similar to “provisional reinforced learning” that can lead to low PV expression (Donato et al., 2015). Paradoxically, however, removal of PNNs largely attenuates responses to stimuli that induce strong and persistent memories, such as those created by exposure to substances of abuse (Brown and Sorg, 2023) or fear conditioning (Sanchez et al., 2024), which may be considered as “definite reinforced learning” that can lead to high PV expression (Donato et al., 2015). In these cases, PNN removal may prevent or compete with the metaplasticity induced by stress or drugs of abuse, as mentioned above. Ultimately, the consequences of attenuating PNNs are likely to be dependent on the specific task demands and how a particular brain region in which PNN removal occurs contributes to the circuit guiding that behavior. In addition, it is likely that regional variation in the effects of PNN manipulations are related to the types of neurons that PNNs surround (e.g., subtypes of interneurons vs projection neurons, inhibitory vs excitatory neurons) and how PNN manipulations impact oscillations and coupling within and between brain regions. Further, given that different chondroitin sulfate isomers have effects on brain function and plasticity (see above), it would be important to investigate variation in the sulfation pattern of PNNs across neuronal populations that restrict versus promote plasticity or memory formation in adulthood (Yang et al., 2021; Huang et al., 2023).

How PNNs modulate memory formation and maintenance is also complex. If PNNs are present during the formation of a memory, that memory may be maintained even when PNNs are removed (Ruzicka et al., 2022; Wingert et al., 2024). As others have mentioned (Christensen et al., 2021) and as alluded to above in the discussion of episodic-like memories, PNNs may be needed to maintain discrete neural ensembles to separate memories without interfering with representations of older memories. PNN removal may make the network more susceptible to experience-dependent changes and in turn promote new memories, but, depending on conditions, may also interfere with old memories when new information is presented. For example, PNN removal renders the memory or circuitry more malleable to extinction-induced processes (Gogolla et al., 2009), to sensory experiences (Pizzorusso et al., 2002; Lensjø et al., 2017) or to the presentation of novel information. Evidence of the latter is provided by the findings that PNN removal in the entorhinal cortex disrupts the grid cell network for a spatial memory, but when animals are challenged with a novel environment to form a new memory, PNN removal degrades spatial representation of both the new and old memories (Christensen et al., 2021), similar to findings for familiar versus novel cocaine-mediated memories (Wingert et al., 2024).

Critical to advancements in the field is a fuller understanding of the mechanistic underpinnings that regulate PNNs at all levels, from bidirectional influences of synaptic activity and PNN expression to regional and interregional circuit-level influences of PNNs across all developmental phases, ranging from early prenatal and postnatal stages to old age. It will also be important for future work to address sex, regional, hemispheric, and species variation in PNN function (Guadagno et al., 2020; Martins de Carvalho et al., 2023; Galán-Llario et al., 2024; Santos-Silva et al., 2024; Brinks et al., 2025). And it will be valuable to understand key elements that underlie the combined effects of PNN removal with experience, such as environmental enrichment, which together remodel the circuit and shape behavior (Bouisset et al., 2025; Ramsaran et al., 2025). This broad reach of understanding PNN contributions to plasticity and behavior at a detailed level has vast implications for how PNNs could be modified to optimize normal physiological functions such as learning and memory and to alleviate imbalances in a wide range of developmental and neurological disorders. With the advent of new tools to monitor and manipulate PNNs (e.g., in vivo imaging of PNNs: Benbenishty et al., 2023), we look forward to new insights into the diverse roles of PNNs.

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Footnotes

    • Received May 28, 2025.
    • Revision received August 6, 2025.
    • Accepted August 12, 2025.

  • This work was supported by the National Institutes of Health (AI171150 to K.M.A.; R01MH116831 to Elizabeth Gould; F31MH120920 to A.I.R.; F31MH136684 to N.E.P.M.; R01MH131592 to Miranda Lim and Brendon Watson; DA055645 and NS131645 to B.A.S.; NS131645 to A.I.R.), the Canadian Institutes of Health Research (PJT-519714 to J.T.S.; PJT180530 to Paul Frankland), the National Science Foundation (2336907 to K.K.), the Natural Sciences and Research Council (#03747 to J.T.S.), Department of Defense (AZ210089 to K.M.A.), American Diabetes Association (11-22-IBSPM-06 to K.M.A.), Canadian Neurodevelopmental Research Training Platform (A.I.R.), SickKids Retracomp (A.I.R.), and Good Samaritan Foundation of Legacy Health (B.A.S.).

  • The authors declare no competing financial interests.

  • Correspondence should be addressed to Jon T. Sakata at jon.sakata{at}mcgill.ca or Barbara A. Sorg at bsorg{at}downeurobiology.org.
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