**8. Outlook**

memories. The ECM reconstitutes after several days to weeks limiting again the promoting effects onto cognitive flexibility (**Figure 3A**). A comparable finding investigated log-term object recognition memory in knockout mice of the link protein Crtl1/Hapln1—a key molecule for stabilization of PNNs. The Ctrl1/Hapln1 knockout mice have attenuated PNNs in the perirhi‐ nal cortex. Long-term object recognition memory, a task depending on perirhinal cortex, was enhanced in these mice. Local injection of chABC in wild-type mice had the same memoryprolonging effect in the object recognition task, but also attenuated over time [43]. In this study, the attenuation of the PNNs was accompanied by enhanced perirhinal LTD, which is thought

**Figure 3. Local enzymatic weakening of the ECM in auditory cortex of Mongolian gerbils enhanced the cognitive flexibility in a relearning paradigm**. (**A**) *Right*, Quantification of ECM weakening after local injection of HYase in uni‐ lateral auditory cortex of Mongolian gerbils (right) compared to control (left) based on WFA staining. *Left*, HYase injec‐ tion significantly weakened the ECM for about 1 week and reconstituted fully after 2 weeks. (**B**) Mongolian gerbils were trained in a two-compartmental go/no-go Shuttle-box in order to discriminate two frequency-modulated sounds (modulation direction indicated by rising and falling arrows). Gerbils showed successful acquisition depending on the contingency of the stimuli as a go-stimulus (red) or Nogo-stimulus (green). In two groups, the contingency was re‐ versed after seven training days (*left and middle*). Conditioned response rates were strongly reduced in both experimen‐ tal groups indicating the active inhibition of the previously established discrimination strategy. HYase-treated animals were significantly better in correcting the behavioral strategy and successfully relearn the task (middle). Interestingly, HYase treatment did not interfere with the recall of already established cortex-dependent auditory memories (*right*).

The both last-mentioned studies therefore promote the view that the perineuronal ECM in the adult brain actively organizes the balance between memory stability and flexibility. Cortical attenuation of the ECM in the mature brain might hence promote the cognitive flexibility that can build on learned behaviors and allows for an enhanced activity-dependent memory re-

Modified from Ref. [42].

to be the major synaptic mechanism underlying object recognition memory.

152 Composition and Function of the Extracellular Matrix in the Human Body

We have summarized recent evidence showing that experimental modulation of the ECM promotes "windows of opportunities" with an increase in learning-related plasticity yielding cognitively flexible adaptation of learned behaviors and the underlying memories. How the ECM, in addition, impacts onto several mental disorders that generally develop after the closure of major critical periods for higher brain functions, as for instance affective disorders or schizophrenia, are exciting new research directions. We are envisaging future challenges in developing new tools for guided neuroplasticity with therapeutic potential for memory disorders, stroke, or neuroprosthetic applications based on ECM manipulations.
