  Recent findings show that single, non-neuronal cells are also able to learn
signalling responses developing cellular memory. In cellular learning nodes of
signalling networks strengthen their interactions e.g. by the conformational
memory of intrinsically disordered proteins, protein translocation, miRNAs,
lncRNAs, chromatin memory and signalling cascades. This can be described by a
generalized, unicellular Hebbian learning process, where those signalling
connections, which participate in learning, become stronger. Here we review
those scenarios, where cellular signalling is not only repeated in a few times
(when learning occurs), but becomes too frequent, too large, or too complex and
overloads the cell. This leads to desensitisation of signalling networks by
decoupling signalling components, receptor internalization, and consequent
downregulation. These molecular processes are examples of anti-Hebbian learning
and forgetting of signalling networks. Stress can be perceived as signalling
overload inducing the desensitisation of signalling pathways. Aging occurs by
the summative effects of cumulative stress downregulating signalling. We
propose that cellular learning desensitisation, stress and aging may be placed
along the same axis of more and more intensive (prolonged or repeated)
signalling. We discuss how cells might discriminate between repeated and
unexpected signals, and highlight the Hebbian and anti-Hebbian mechanisms
behind the fold-change detection in the NF-\k{appa}B signalling pathway. We
list drug design methods using Hebbian learning (such as chemically-induced
proximity) and clinical treatment modalities inducing (cancer, drug allergies)
desensitisation or avoiding drug-induced desensitisation. A better
discrimination between cellular learning, desensitisation and stress may open
novel directions in drug design, e.g., helping to overcome drug-resistance.
