Very long-term memories may be stored in the pattern of holes in the perineuronal net

Abstract

A hypothesis and the experiments to test it propose that very long-term memories, such as fear conditioning, are stored as the pattern of holes in the perineuronal net (PNN), a specialized ECM that envelops mature neurons and restricts synapse formation. The 3D intertwining of PNN and synapses would be imaged by serial-section EM. Lifetimes of PNN vs. intrasynaptic components would be compared with pulse-chase 15 N labeling in mice and 14 C content in human cadaver brains. Genetically encoded indicators and antineoepitope antibodies should improve spatial and temporal resolution of the in vivo activity of proteases that locally erode PNN. Further techniques suggested include genetic KOs, better pharmacological inhibitors, and a genetically encoded snapshot reporter, which will capture the pattern of activity throughout a large ensemble of neurons at a time precisely defined by the triggering illumination, drive expression of effector genes to mark those cells, and allow selective excitation, inhibition, or ablation to test their functional importance. The snapshot reporter should enable more precise inhibition or potentiation of PNN erosion to compare with behavioral consequences. Finally, biosynthesis of PNN components and proteases would be imaged.

Perineuronal nets labeled by monoclonal antibody VC1.1 ensheath interneurons expressing parvalbumin and calbindin in the rat amygdala

“…It remains to be determined how PNNs are critical for this change and whether chondroitin sulphate proteoglycans in the neuropil (diffuse extracellular matrix), which are also degraded by chondroitinase, play a role. It has been proposed that long-term memories are stored in the pattern of holes in PNNs occupied by axon terminals (Tsien, 2013). …”

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

“…In particular, MMPs are crucial proteins during ECM remodeling process [58,59]. The activities of MMPs influence neural progenitor cell proliferation, migration, and lineage commitment [32,[45][46][47][48], and were suggested to play a role in long-term brain memory [60,61]. Therefore, understanding dynamic cell-matrix interactions and differential response of neuronal subtypes to MMP inhibition is important to regulate neural tissue development and understand neurological disease pathology.…”

Weaving a Net of Neurobiological Mechanisms in Schizophrenia and Unraveling the Underlying Pathophysiology

“…The PNN is a reticular structure of the neural extracellular matrix (ECM) found surrounding many neurons in the central nervous system (CNS) (32-34). The developmental pattern of increasing PNN formation corresponds to the ending of the “critical period”, a time window of postnatal life which is critical for experience-dependent formation of synaptic connections and wiring of functionally related neuronal pathways that underlie sensory, motor, cognitive, social, and language abilities (35), deficits in which have been linked to schizophrenia (36).…”