The Hebb Synapse Before Hebb: Theories of Synaptic Function in Learning and Memory Before Hebb (1949), With a Discussion of the Long-Lost Synaptic Theory of William McDougall

Since the work of Semon was rediscovered by Schacter in 1978, there has been a renewed interest is searching for the “engram” as the locus of memory in the brain and Hebb’s cell assembly has been equated with Semon’s engram. There have been many theories of memory involving some concept of synaptic change, culminating in the “Hebb Synapse” theory in 1949. However, Hebb said that the idea that any two cells or systems of cells that are repeatedly active at the same time will tend to become “associated,” was not his idea, but an old one. In this manuscript we give an overview of some of the theories of the neural basis of learning and memory before Hebb and describe the synaptic theory of William McDougall, which appears to have been an idea ahead of its time; so far ahead of its time that it was completely ignored by his contemporaries. We conclude by examining some critiques of McDougall’s theory of inhibition and with a short discussion on the fate of neuroscientists whose ideas were neglected when first presented but were accepted as important many decades later.

Optimal plasticity for memory maintenance during ongoing synaptic change

Synaptic connections in many brain circuits fluctuate, exhibiting substantial turnover and remodelling over hours to days. Surprisingly, experiments show that most of this flux in connectivity persists in the absence of learning or known plasticity signals. How can neural circuits retain learned information despite a large proportion of ongoing and potentially disruptive synaptic changes? We address this question from first principles by analysing how much compensatory plasticity would be required to optimally counteract ongoing fluctuations, regardless of whether fluctuations are random or systematic. Remarkably, we find that the answer is largely independent of plasticity mechanisms and circuit architectures: compensatory plasticity should be at most equal in magnitude to fluctuations, and often less, in direct agreement with previously unexplained experimental observations. Moreover, our analysis shows that a high proportion of learning-independent synaptic change is consistent with plasticity mechanisms that accurately compute error gradients.

Study of pre-synaptic internalisation in human schizophrenia brains

AimsEfficient synaptic communication is crucial to maintain healthy behavioural and cognitive processes. Individuals affected by schizophrenia present behavioural symptoms and alterations in decision-making, suggesting altered synaptic integrity as the support of the illness. It is currently unknown how this synaptic change is mediated in schizophrenia, but microglia have been proposed to act as the culprit, actively removing synapses pathologically. Here, we aimed to explore the interaction between microglia and synaptic uptake in human post-mortem tissue.MethodsWe assessed microglial activation and synaptic internalisation by microglia in a post-mortem human tissue of 10 control and 10 schizophrenia cases. Immunohistochemistry was performed to identify microglia (Iba1 and CD68) and the presynaptic terminals (synapsin I).ResultsWe found no difference in microglial expression, nor a difference in pre-synaptic protein level phagocyted by microglia between the two groups.ConclusionsOur findings are consistent with the brain imaging studies in schizophrenia implying that microglia play a role mainly during the early phases of the disease, by example in active synapse remodelling, which is not detected in the chronic stage of the illness.

Connectomes across development reveal principles of brain maturation in C. elegans

From birth to adulthood, an animal’s nervous system changes as its body grows and its behaviours mature. However, the extent of circuit remodelling across the connectome is poorly understood. Here, we used serial-section electron microscopy to reconstruct the brain of eight isogenic C. elegans individuals at different ages to learn how an entire wiring diagram changes with maturation. We found that the overall geometry of the nervous system is preserved from birth to adulthood, establishing a constant scaffold upon which synaptic change is built. We observed substantial connectivity differences among individuals that make each brain partly unique. We also observed developmental connectivity changes that are consistent between animals but different among neurons, altering the strengths of existing connections and creating additional connections. Collective synaptic changes alter information processing of the brain. Across maturation, the decision-making circuitry is maintained whereas sensory and motor pathways are substantially remodelled, and the brain becomes progressively more modular and feedforward. These synaptic changes reveal principles that underlie brain maturation.

Association

Association is the only concept in cognition that is as general, simple, and useful as classic theories in physics. Aristotle claimed that sensory-based events were the elementary units of memory. Such memories then became linked together through learning. The process of linkage—association—led to a powerful, creative computational structure. The ability to form networks of associations was unique to humans. William James extended Aristotle’s ideas by proposing a cognitive system that moved well beyond rote linkage in power and flexibility. Some of the mechanics of associative memory can be explained by synaptic change mechanisms such as the correlational Hebb synapse. Also discussed are examples of the problems caused by a “too good” memory along with use of associative memory aids like mnemonics.

Asymmetry of Neuronal Combinatorial Codes Arises from Minimizing Synaptic Weight Change

Synaptic change is a costly resource, particularly for brain structures that have a high demand of synaptic plasticity. For example, building memories of object positions requires efficient use of plasticity resources since objects can easily change their location in space and yet we can memorize object locations. But how should a neural circuit ideally be set up to integrate two input streams (object location and identity) in case the overall synaptic changes should be minimized during ongoing learning? This letter provides a theoretical framework on how the two input pathways should ideally be specified. Generally the model predicts that the information-rich pathway should be plastic and encoded sparsely, whereas the pathway conveying less information should be encoded densely and undergo learning only if a neuronal representation of a novel object has to be established. As an example, we consider hippocampal area CA1, which combines place and object information. The model thereby provides a normative account of hippocampal rate remapping, that is, modulations of place field activity by changes of local cues. It may as well be applicable to other brain areas (such as neocortical layer V) that learn combinatorial codes from multiple input streams.

Reinstatement of long-term memory following erasure of its behavioral and synaptic expression in Aplysia

Long-term memory (LTM) is believed to be stored in the brain as changes in synaptic connections. Here, we show that LTM storage and synaptic change can be dissociated. Cocultures of Aplysia sensory and motor neurons were trained with spaced pulses of serotonin, which induces long-term facilitation. Serotonin (5HT) triggered growth of new presynaptic varicosities, a synaptic mechanism of long-term sensitization. Following 5HT training, two antimnemonic treatments—reconsolidation blockade and inhibition of PKM—caused the number of presynaptic varicosities to revert to the original, pretraining value. Surprisingly, the final synaptic structure was not achieved by targeted retraction of the 5HT-induced varicosities but, rather, by an apparently arbitrary retraction of both 5HT-induced and original synapses. In addition, we find evidence that the LTM for sensitization persists covertly after its apparent elimination by the same antimnemonic treatments that erase learning-related synaptic growth. These results challenge the idea that stable synapses store long-term memories.