The times they are a-changin': a proposal on how brain flexibility goes beyond the obvious to include the concepts of "upward" and "downward" to neuroplasticity

Abstract

Since the brain was found to be somehow flexible, plastic, researchers worldwide have been trying to comprehend its fundamentals to better understand the brain itself, make predictions, disentangle the neurobiology of brain diseases, and finally propose up-to-date treatments. Neuroplasticity is simple as a concept, but extremely complex when it comes to its mechanisms. This review aims to bring to light an aspect about neuroplasticity that is often not given enough attention as it should, the fact that the brain's ability to change would include its ability to disconnect synapses. So, neuronal shrinkage, decrease in spine density or dendritic complexity should be included within the concept of neuroplasticity as part of its mechanisms, not as an impairment of it. To that end, we extensively describe a variety of studies involving topics such as neurodevelopment, aging, stress, memory and homeostatic plasticity to highlight how the weakening and disconnection of synapses organically permeate the brain in so many ways as a good practice of its intrinsic physiology. Therefore, we propose to break down neuroplasticity into two sub-concepts, "upward neuroplasticity" for changes related to synaptic construction and "downward neuroplasticity" for changes related to synaptic deconstruction. With these sub-concepts, neuroplasticity could be better understood from a bigger landscape as a vector in which both directions could be taken for the brain to flexibly adapt to certain demands. Such a paradigm shift would allow a better understanding of the concept of neuroplasticity to avoid any data interpretation bias, once it makes clear that there is no morality with regard to the organic and physiological changes that involve dynamic biological systems as seen in the brain.

Fig. 1. The overflowing unmatured brain - a pruning-based window of opportunities.

Although the unmatured brain overflows with synaptic connections, such a developmental program goes beyond any triviality. Excessive synapses are extremely important for the brain to be able to readily fine-tune idiosyncratic connections to the demands of a rather “naïve” brain. In this way, seemingly superfluous connections make the brain prone to adapt, evolve and be molded around the behavioral repertoires that best predict continued future success. Within a concept, the time frame of promiscuous synapses could be understood as a window of opportunity in which the set of actions involving synaptic disconnections would be the tools that really makes this a good and profitable occasion. So, since the very newborn brain beginning, connections are ready to be plastically refined under the guidance of neuronal activities that mirror the nearby niche of an ever-changing environment. Furthermore, from an evolutionary perspective, pruning-based neuronal refinement of a redundant brain is likely a highly conserved mechanism as it can be found from insects to humans.

Fig. 2. The aged and shrunken brain.

After a period of developmental neural refinement based on synaptic pruning, all organisms undergo non-pathological, cumulative, and irreversible synaptic deterioration as they age. Morphological changes in aged brains may be subtle as they are region-specific and often restricted to neuronal types or dendritic branches, usually resulting in synaptic strength deficits and some sort of brain shrinkage. Although synaptic corrosion in the elderly is usually associated with some level of cognitive decline, healthy aging is expected to be unrelated to any pathological problem. However, even for healthy aging, a small cognitive decline associated with synaptic pruning can be a burden in practice as it makes the individual less able to readily adapt to the surrounding environment.

Fig. 3. The stressed brain.

As an extrinsic factor capable of altering the brain, the concept of stress is based on nothing more than our bodily ability to perceive threats, real or imagined, actual or anticipated, emotional or physical. Such a realization is then accompanied by a sense of emotional inconvenience and extensive physiological changes that should, in principle, help us orchestrate the best adaptive behavior for survival, but which may actually lead to maladaptive behavioral adjustments. Indeed, a myriad of conditions can be perceived as stressful and the extent of brain effects may vary depending on the interplay between individual resilience and how long that stress lasts. Such effects include microstructural and subsequent macrofunctional changes, both of which are usually, but not only, coupled with the triggering of synaptic disconnections. Interestingly, stress-induced brain morphofunctional changes are generally recoverable. The effects of stress can overlap with the effects of neurodevelopment and aging on the brain, as we are all susceptible to stressors throughout our lives.

Fig. 4. Negative plasticity is the sine qua non of memory.

Downward structural changes such as spine removal and/or dendritic shrinkage underlie the functional weakening of synaptic strength that happens during LTD and in some specific phases of memory. Each memory phase has its particular cellular mechanism, however some of them are shared. The bottom figure abridges how AMPAR/GluA2 internalization triggered by NMDAR/GluN2B-mediated LTD is a fundamental shared cellular mechanism by which synaptic weakening happens in all these memory processes.

Fig. 5. Homeostatic mechanisms controlling fluctuations on brain activity.

Homeostatic plasticity is a global mechanism that comprises several forms of controlling brain activity within adequate physiological levels. Hyperactivity mobilizes downward homeostatic mechanisms that act by braking down and constraining neuronal activity over a physiological range. On another hand, a counteracting upward homeostatic force is recruited following hypoactivity. Regular cognitive process such as memory are tempered by homeostatic plasticity. The same regulation happens when individuals have to deal with stressful challenges. Since neurodevelopment, homeostatic mechanisms are observed and expressed in particular ways depending on the brain area, cell-type and age investigated. Also, homeostatic dysregulation may explain some of the aging-related phenomena such as hyperexcitability.

Fig. 6. Downward neuroplasticity within the larger and complementary perspective of an entangled brain.

The main goal of this review is to work on the idea of how neuroplasticity, in all its complexity, should be conceptually understood as a balance between what we have called here as “upward and downward neuroplasticity”. Developing brains, and partially also the adult ones, are flexible, moldable, and as it is, any capability for decreasing the density levels or structural complexity of spines and/or dendrites should be considered part of the neuroplasticity program, rather than being a deficiency of it. Thus, comparable to how puzzles fit together, upward and downward neuroplasticity work to complement each other so that the brain would eventually be able to reshape its connections by neuronal tuning to optimize network’s efficiency under certain demands. Within a broader landscape as seen with assembled puzzles, although neuroplasticity happens at first glance from the microscale changes of spines and dendrites according to a neuronal perspective, its consequences expand toward a macroscale outlook where individual orchestrated changes integrate into the account of different neuronal populations and neurocircuits. So, any cause or consequence neuroplastic change from an entangled brain, whether up or down, may be directly or indirectly connected to at least some other part of the brain that could still show a completely opposite direction of neuroplasticity. The orange, red and gray puzzles represent different populations of neurons that in the sum of the events globally present upward plasticity, while the green, yellow and purple puzzles represent different populations of neurons that in the sum of the events present global downward plasticity. Meanwhile, the blue and white puzzles represent neurons with a balanced number of events that represent both upward and downward neuroplasticity. Their connections should maintain the brain largescale of neuroplasticity at zero sum when considering downward and upward neuroplasticity within the topography of neuronal matter.