Question: Hi Nina! It's me again. I was reviewing the live chat that we had today and then I thought of this question from the discussion we were having about neurons making new connections. If they don't naturally form synapses with the original neuron, is there no way to encourage the neurons to make similar pairings?

Nina Rzechorzek answered on 8 May 2020:

Hi Lynette – you’re going right to the heart (and the challenge) of brain repair; it’s a huge topic but let’s see if we can distil it down to some key points.

Neural circuitry is mainly ‘set up’ during brain development and occurs mostly prior to birth, guided by cell-to-cell communication through physical contact and by diffusible chemical signals. There is a huge amount of ‘plasticity’ within the brain at this point – connections are formed and destroyed or ‘pruned’; some brain cells die naturally if they don’t make effective connections. While most of the “wires” find their proper place before birth, the final refinement of synaptic connections between brain cells, particularly in the cortex, occurs during infancy and is influenced by the sensory environment. Sensory (visual, taste, smell, hearing, touch etc) and motor systems (ones that coordinate movement) are readily modified by the environment during critical periods of early childhood. In this way, our brain is a product not only of our genes but also of the world in which we grow up (‘nature and nurture’). The end of developmental critical periods does not signify an end to experience-dependent synaptic plasticity in the brain. Indeed, the environment must modify the brain throughout life, or there would be no basis for memory formation. The mechanisms of synaptic plasticity proposed to account for learning bear a close resemblance to those
believed to play a role in synaptic rearrangement during development. It is these plastic mechanisms that we try to harness for repair.

Neurologists have long recognized that, over time, patients who suffer strokes or sustain limited injuries to distinct brain regions often recover some of the deficits seen immediately after the trauma. Movement in paralyzed limbs can improve (especially if physical therapy is included in
the treatment plan), and problems with verbal communication may diminish with intensive speech therapy. Such recovery is not thought to reflect significant regrowth or replacement of damaged neurons. Instead, the available evidence indicates that undamaged brain regions eventually become activated and reorganized to support, at least in part, functions whose primary representation was disrupted. The best understanding of functional recovery comes from studies of the primary motor cortex, where force generation and accuracy of movement can be measured reliably over time after focal damage. Observations made in animals have shown that circuits
in the adult primary motor cortex retain some capacity for use-dependent plasticity, suggesting a biological mechanism for the reorganization and recovery seen in patients. The plasticity of the primary motor cortex reflects that region’s rich array of horizontally spreading axonal connections.
Thus, connections that might not be active when the system is intact can be “unmasked” when there is damage nearby. In addition, plastic changes that favor functional recovery may occur at synapses between intact excitatory or inhibitory neurons, perhaps re-setting the excitatory/inhibitory balance to maximize circuit function. There may also be some modest local growth of axon branches or dendrites as well as new synaptogenesis from intact neurons that further strengthens remaining connections. Finally, altered activity in the undamaged side of the motor cortex may provide activation that can pattern the appropriate movement via spared pathways that cross over to the damaged side. The consequences of motor cortex plasticity can be seen in stroke patients using functional MRI (fMRI) in parallel with observing the patient’s progress during rehabilitation. The most thorough studies have been of patients with focal strokes in the subcortical white matter that results in specific deficits in hand movement and grip strength. In these individuals, the amount of cortical activity, particularly in the hand region of the motor map, is increased and broadened shortly after injury, and declines with improved function. Similar observations have been made in patients with strokes that compromise complex functions such as language. Activation of remaining brain circuits changes overtime following rehabilitation and functional recovery; however, the magnitude, direction and localization of these changes are more variable than changes that occur in the motor cortex. In sum, neural circuits that remain following focal brain damage can reorganize, based on changing patterns of activation, to accommodate functional recovery, even if rules for reorganization remain elusive. The limited nature of this reorganization and its absence in patients with more profound impairments indicate the challenge of re-gaining normal function after the brain has been damaged.

When we consider the adult nervous system as a whole (central = brain and spinal cord, peripheral = nerves), there are three types of cellular repair, in addition to the functional reorganization of surviving neurons and circuits described above. The first and most effective is the regrowth of severed peripheral axons either from peripheral sensory neurons or central motor neurons, usually via the peripheral nerve sheaths once occupied by their predecessors. After regrowth, these axons reestablish sensory and motor synapses on muscles or other targets. During this regeneration, mature Schwann cells (responsible for making ‘myelin sheaths’ in the peripheral nervous system) provide many of the molecules that regulate axon regrowth and targeting; these molecules are mostly those used for the same purpose during initial development. A second, and far more limited, type of repair is local sprouting or longer extension of axons and dendrites at sites of traumatic damage or degenerative pathology in the brain or spinal cord. Major impediments to such local repair include formation of glial scars (scars formed by the activity of the ‘glia’ the non-neuronal supporting cells in the brain); the death of damaged neurons due to nutritional deprivation or other stress; inhibition of axon growth by protein components of myelin; inhibition of neuronal growth by cytokines released during the immune response to brain tissue damage; and the formation of a glial scar by extensive enlargement of existing glial cells plus proliferation of glia at the site of the injury. The role of immune-mediated inflammation in establishing an anti-regenerative state in brain tissue is central. Molecular mediators of inflammation, including cytokines, their receptors, and related signaling intermediates, drive this process and establish barriers to neuronal regrowth. A third type of repair is generation of new neurons in the adult brain. Although there is no evidence for wholesale replacement of neurons and circuits in most vertebrate brains, the capacity for limited ongoing neuronal replacement exists in some species—sometimes in register with ongoing growth of the animal or due to seasonal variations. In most mammals, the olfactory bulb and the hippocampus are the only sites of adult neurogenesis (new neuron generation). In both of these brain regions, new neurons are generated by neural stem cells retained in specific restricted locations in the adult brain. Many of the molecules that regulate the maintenance, proliferation, and differentiation of adult neural stem cells and their progeny are used for similar purposes for neural stem cells in the embryonic brain. The challenge of developing this capacity to generate new neurons and circuits as a strategy for repair following brain injury or degenerative disease continue to capture the imagination of patients, clinicians, and many neuroscientists.

Here’s a nice overview of neuroplasticity with some TED talks that are worth a look:

Neuroplasticity

Two useful books to explore this further:

[Purves, Dale/Augustine, George/Fitzpatrick, David. Neuroscience XE][Purves, Dale/Augustine, George/Fitzpatrick, David. Neuroscience XE]
[Bear, Mark F./Connors, Barry W./Paradiso, Michael A.. Neuroscience][Bear, Mark F./Connors, Barry W./Paradiso, Michael A.. Neuroscience]