Recent studies show that, even in constant environments, the tuning of single neurons changes over time in a variety of brain regions. This representational drift has been suggested to be a consequence of continuous learning under noise, but its properties are still not fully understood. To investigate the underlying mechanism, we trained an artificial network on a simplified navigational task. The network quickly reached a state of high performance, and many units exhibited spatial tuning. We then continued training the network and noticed that the activity became sparser with time. Initial learning was orders of magnitude faster than ensuing sparsification. This sparsification is consistent with recent results in machine learning, in which networks slowly move within their solution space until they reach a flat area of the loss function. We analyzed four datasets from different labs, all demonstrating that CA1 neurons become sparser and more spatially informative with exposure to the same environment. We conclude that learning is divided into three overlapping phases: (i) Fast familiarity with the environment; (ii) slow implicit regularization; and (iii) a steady state of null drift. The variability in drift dynamics opens the possibility of inferring learning algorithms from observations of drift statistics.

Nociceptive sensory neurons convey pain-related signals to the CNS using action potentials. Loss-of-function mutations in the voltage-gated sodium channel Na_V1.7 cause insensitivity to pain (presumably by reducing nociceptor excitability) but clinical trials seeking to treat pain by inhibiting Na_V1.7 pharmacologically have struggled. This may reflect the variable contribution of Na_V1.7 to nociceptor excitability. Contrary to claims that Na_V1.7 is necessary for nociceptors to initiate action potentials, we show that nociceptors can achieve similar excitability using different combinations of Na_V1.3, Na_V1.7, and Na_V1.8. Selectively blocking one of those Na_V subtypes reduces nociceptor excitability only if the other subtypes are weakly expressed. For example, excitability relies on Na_V1.8 in acutely dissociated nociceptors but responsibility shifts to Na_V1.7 and Na_V1.3 by the fourth day in culture. A similar shift in Na_V dependence occurs in vivo after inflammation, impacting ability of the Na_V1.7-selective inhibitor PF-05089771 to reduce pain in behavioral tests. Flexible use of different Na_V subtypes exemplifies degeneracy – achieving similar function using different components – and compromises reliable modulation of nociceptor excitability by subtype-selective inhibitors. Identifying the dominant Na_V subtype to predict drug efficacy is not trivial. Degeneracy at the cellular level must be considered when choosing drug targets at the molecular level.