In a 1981 article in The Sciences, Leon Cooper and Michel Imbert summarized the status of the Brown/Collège de France theory of experience-dependent development of orientation selectivity in cat visual cortex — the 'threshold passive modification' theory, built on labile and non-labile synapses, that became the Bienenstock–Cooper–Munro (BCM) theory of synaptic plasticity — and listed the issues they considered unresolved: the biological substrate of the postulated synapse classes; the untested prediction that noise exposure with particular correlation statistics shifts the orientation preference of entire orientation columns; the then-unpublished binocular extension and its testable consequences; whether in-vivo input correlations match the model's assumptions; the adequacy of the aspecific/immature/specific cell classification; the molecular mechanisms of the interplay between experience-independent maturation and experience-dependent plasticity; and the applicability of these mechanisms to other cortical areas and higher cognitive functions. The binocular extension's central prediction — an activity-dependent sliding modification threshold — has received experimental confirmation (metaplasticity); the modification substrate was identified as bidirectional synaptic plasticity gated by NMDA receptors (glutamate-activated ion channels that open only when pre- and postsynaptic activity coincides); and in-vivo input statistics were measured, while the two-synapse-class and three-cell-class constructs were superseded rather than resolved. The open questions that remain are the molecular implementation of the sliding-threshold modification rule, the mechanisms gating it during the critical period, the still-untested correlation-based map-reorganization predictions, and the mapping of the mechanism onto other cortical areas.

Background

In the mammalian primary visual cortex (V1, also called striate cortex or area 17), most neurons respond selectively to the orientation of edges and contours, and neurons of similar preference are grouped into 'orientation columns' that together form a cortical map. In cats and monkeys this selectivity matures during an early postnatal 'critical period': it emerges largely before patterned visual experience begins, and its maintenance and refinement then depend on vision — rearing in darkness, or closing one eyelid (monocular deprivation), during this window degrades or distorts cortical responses. Experiments from Michel Imbert's laboratory at the Collège de France and others, as summarized in Cooper, Liberman and Oja (1979), classified developing cortical cells by responsiveness into 'aspecific' (no detectable stimulus preference), 'immature' (weak bias) and 'specific' (sharply tuned) categories, and found two developmental periods: until roughly postnatal week three, orientation selectivity matures without requiring vision; afterwards it requires patterned input. Against this background, Leon Cooper's group at Brown University proposed a quantitative theory (Cooper, Liberman and Oja 1979). It postulates two kinds of synapses from the lateral geniculate nucleus (the thalamic relay of retinal input) onto cortical cells: 'labile' synapses that modify their strength according to a threshold rule — presynaptic activity strengthens or weakens the synapse depending on whether postsynaptic activity exceeds a fixed threshold — and 'non-labile' synapses that carry a permanent, experience-independent bias. Simulations reproduced the gain of specificity under normal vision, its loss under dark rearing (treated as exposure to unpatterned 'noise' whose correlation structure determines the outcome), and recovery after return of patterned input. Cooper and Imbert's 1981 article 'Seat of Memory' was a popular summary of this theory–experiment collaboration, and its closing outlook listed the unresolved issues that define this problem. The binocular extension mentioned there was published the next year as the Bienenstock–Cooper–Munro (BCM) theory of synaptic plasticity, which dropped the two synapse classes in favor of a single modifiable synapse whose modification threshold is not fixed but 'slides' as a slowly varying function of the time-averaged postsynaptic activity, giving the rule stability under repeated input. This construct was later named 'metaplasticity' — the plasticity of synaptic plasticity — and was tied to bidirectional long-term potentiation and long-term depression (LTP and LTD: long-lasting strengthening and weakening of synapses) induced by strong versus weak activation of NMDA-type glutamate receptors (receptor channels that open only with coincident pre- and postsynaptic activity, admitting calcium into the postsynaptic cell).

Problem Statement

The problem is the completion of the biological grounding and experimental verification of the threshold-modification theory of experience-dependent development in visual cortex, restricted to the components that the literature has left unresolved (the binocular extension's central predictions, the identification of the modification substrate, and the in-vivo input-statistics assumptions having been substantially resolved or reframed). All components serve one objective: a causally complete account, at molecular resolution, of how experience modifies cortical synapses during development. Concretely, the open questions are: (1) Molecular substrate of the modification rule — the modification substrate itself is established as bidirectional, activity-dependent synaptic modification gated by NMDA receptors; the open question is the molecular machinery that computes the slowly varying time-averaged postsynaptic activity and slides the modification threshold (the metaplasticity of the BCM theory). (2) Developmental gating — identify the molecular and cellular mechanisms by which experience-independent maturation gates experience-dependent plasticity during the critical ('second') period: what opens, maintains, and closes the window in which input statistics can reshape cortical selectivity, and how maturation and plasticity interact within it. (3) Remaining experimentally testable predictions — specify at least one falsifiable test, with its predicted outcome, for the as-yet-untested 1981 prediction that exposure to noise with controlled correlation structure shifts the orientation preference of entire orientation columns, reformulated for current experimental methods — and, for each further correlation-based prediction you advance from the theory, at least one falsifiable test with its predicted outcome. (4) Scope of applicability — determine whether, and if so where, the same modification mechanisms operate in other cortical areas and serve functions beyond sensory development, including the higher cognitive functions. The research target is to identify the implementing molecular machinery, to explain the gating of the developmental window, to specify at least one falsifiable test, with its predicted outcome, for the 1981 noise-correlation prediction and for each further correlation-based prediction advanced from the theory, and, for each claimed cortical area and function, to establish the cross-area mapping of the mechanisms by explicit mechanistic reasoning linking it to the identified mechanism. For component (3), the falsifiable test and its predicted outcome for the 1981 prediction are asked; for component (4), a definite verdict on whether and where the mechanisms operate beyond V1 is asked. The four open questions are jointly posed.

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