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Ch-Ch-Ch-Ch Changes!  What Causes Depression and How Do Antidepressants Work, Part II

Five years ago, I reviewed some of the scientific literature on the neuroplasticity model of depression – a fascinating new way to think about mood disorders.  Departing from the earlier, monoamine-based ideas – too little serotonin or dopamine –  this model suggests that depressive states are associated with a reduction in the brain’s ability to change in response to experience.  In my earlier review of neuroplasticity, I described how our brains are not fixed organs but are instead constantly changing in response to novel information and new learning.  These changes involve strengthening or weakening of synaptic connections along with growth or shrinkage of neurons.  In health, there is a constant growth, sculpting and refinement of neural pathways. This plasticity becomes impaired in depression:  the brain becomes less malleable, there is reduced new learning and people become trapped in despair.  The neuroplasticity model is a radically different way of thinking about mood disorders.  What follows is an update on research on this area, which has focused on several major developments.  These include the following: 1) investigations of brain plasticity based on visual evoked potentials (VEPs); 2) the use of learning and memory tests to evaluate structural change in the CNS and; 3) emerging research on the impact of antidepressants on neuroplasticity.

While initial investigations of neuroplasticity involved animal research, more recent work has examined correlates of brain modifiability in living humans.   The issue was this: it’s hard to count and measure neurons in healthy adults. Technically near-impossible and ethically impermissible. If the theory holds that changes in the structure and function of neurons mediate mood, how can this be evaluated in human subjects?  Turns out, there are a couple of neat ways to get at this: electroencephalographically (EEG) and behaviorally. In the first case, Normann and colleagues in Freiburg, Germany used the standard brain changes in electrical activity that occur after visual stimulation to evaluate neuroplasticity [1].  The idea is simple: if you present an image of something to a person, neurons in the visual cortex will analyze and register the new stimulus and electrically fire at a certain strength and frequency. Repeat the process and the neuron will fire more strongly indicating that learning and structural change in the brain has taken place and the stimulus is now recognized.  Voila! Using this format, Normann found that these post-stimulation electrical discharges, termed visual evoked potentials (VEPs) are reduced in depressed as opposed to healthy controls.  Evidence entry number one.

The second method uses what is thought to be the prime behavioral marker of neuroplasticity:  learning as indexed by memory. Here too, the logic is straightforward: if new learning is thought to be mediated by microscopic changes in synaptic strength, neuron size and branching, then we should see reduced assimilation of new information and memory integrity in depressed compared to healthy individuals.  Using this experimental design, Nissen and colleagues documented exactly these predictions [2]. In the first case, subjects were instructed to associate one word to another and then remember the pairing. This type of declarative memory is supported by the hippocampus. Depressed patients were significantly impaired compared to their non-depressed brethren.  In the second case, subjects were given mild electrical shocks paired to certain neutral stimuli. Here, depressed patients demonstrated a heightened, amygdala-based, fear conditioning compared to healthy subjects; this suggested abnormally increased neuroplasticity in brain fear pathways in depression.  Human evidence entry number two.

But what’s this got to do with antidepressants?  This brings us to the third and final area of this review.  If structural remodeling and strength tuning cycles are necessary for mental health, what bearing does this have on past and future antidepressant medications?  First, in a 2017 article, Segi-Neshida and colleagues, examined the neuroplastic effects of standard serotonergic antidepressants [6]. Even though these drugs were thought to act through standard monoamine pathways, they outlined previously under-appreciated serotonergic effects on neurogenesis in the hippocampus.  In addition, these drugs also are capable of rolling back or dematuring cells in the hippocampus to a less defined, more pluripotent state. This reversion also supports increased neuroplasticity as the cells can evolve to serve different functions. It appears then that some of the effectiveness of our current crop of antidepressants may be due to their change-inducing properties on neurons.  A group in Italy has taken this idea to the extreme, proposing that depression medications act primarily by enhancing neuroplastic potential and that the actual source of improvement itself, is caused by our life circumstances.  Based on a reanalysis of the STAR-D clinical depression trials and new animal research, they advance the idea that antidepressants serve to loosen things up, so to speak, in our brains and that once we return to a state of optimal responsiveness and reactivity, that the (hopefully) beneficial effects of our psychosocial environments can kick in and lift our spirits [7, 8].  Wow!

In addition to this re-examination of the mechanism of action of existing antidepressants, current research is exploring the design of new antidepressants that specifically target hippocampal neurogenesis.  This is huge! For the past fifty years, antidepressant drug development has largely been a process of repetition and minor-tinkering; these drugs have been designed to inhibit the reuptake of various monoamines and alleviate depression in the process.  While confined to animal research, Mohammed and colleagues recently reported that inhibition of a particular kinase protein in the hippocampus stimulated new cell production and alleviated anxiety [9]. They close their paper by advocating the targeting of this molecule as an avenue for novel therapies against affective disorders.  Hence, neuroplasticity appears to have been a hidden component of past depression treatments and is now an overt target for new antidepressant drug development.

For those of you that have found this area of interest and want to learn about additional new research pertaining to the role of sleep in regulating neuroplasticity, click here.

To summarize, the major developments in the past five years in the field of neuroplasticity and mood include the following headlines:

Using clever new methods, research on neuroplasticity is moving from predominantly animal-based to clinical studies with human subjects.

Sleep and the sleep-wake cycle is a major driver of daily cycles of growth, breakdown, sculpting and refinement of our neural architecture.  Our brains expand and contract on a nightly basis by 20%!

Existing antidepressant medications appear to have previously unappreciated effects on neurogenesis that may contribute to their mood-lifting effects.

New antidepressant medications are being designed to specifically target hippocampal neuroplasticity.

Stay tuned!

John Gottlieb, M.D.

1. Normann, C., et al., Long-Term Plasticity of Visually Evoked Potentials in Humans is Altered in Major Depression. Biological Psychiatry, 2007. 62(5): p. 373-380.
2. Nissen, C., et al., Learning as a Model for Neural Plasticity in Major Depression. Biological Psychiatry, 2010. 68(6): p. 544-552.
3. Tononi, G. and C. Cirelli, Sleep and synaptic homeostasis: a hypothesis. Brain Research Bulletin, 2003. 62(2): p. 143-150.
4. de Vivo, L., et al., Ultrastructural evidence for synaptic scaling across the wake/sleep cycle. Science, 2017. 355(6324): p. 507-510.
5. Diering, G.H., et al., Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science, 2017. 355(6324): p. 511-515.
6. Segi-Nishida, E., The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors. Frontiers in Cellular Neuroscience, 2017. 11: p. 142.
7. Alboni, S., et al., Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Molecular Psychiatry, 2015. 22: p. 552.
8. Chiarotti, F., et al., Citalopram amplifies the influence of living conditions on mood in depressed patients enrolled in the STAR*D study. Translational Psychiatry, 2017. 7: p. e1066.
9. Mohammad, H., et al., JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche. Mol Psychiatry, 2016.

Neuroplasticity: What’s Sleep Got to Do with It?

Neuroplasticity: What’s Sleep Got to Do with It?

We start with a powerhouse team of neuroscience researchers at the University of Wisconsin:  Giulio Tononi and Chiara Cirelli. These two have been wrestling to understand the basic function of mammalian sleep:  why do we do it? What critical functions does it serve?   In 2003, using a collection of EEG, fMRI and some behavioral memory data, they formulated a new theory on the role of sleep:  The Synaptic Homeostasis Theory, or SHY, for short [3].   This theory asserts four main points:

.   Waking life is characterized by a strengthening of synaptic connections (synaptic potentiation) and a growth of neurons and their component parts.

.   In order to prevent a runaway process of strengthening and growth, which would be taxing on energy supplies and the bony limits of our skull size, sleep selectively reverses these wake-based increases in structure and function through a downscaling, which removes the weaker, newer connections and preserves the more established and important ones.  The growth and revision actions are ultimately balanced resulting in a regulated and constant neuronal weight and size, a homeostasis of synapses., or SHY.

.   The downscaling of synaptic size and function is accomplished by a nightly component of our sleep assemblage, slow wave brain activity (SWA or slow wave sleep, SWS).  Tononi and Chiarelli review the electrochemical magic of how SWS accomplishes this downscaling in depth.

.   Last, they posit that this turnover process of neuronal growth and selective pruning allows for optimal human learning and memory.  It is the basis for taking in and remembering new information.

This theory has received a great deal of attention since its original publication in 2003.

It extends and magnifies the idea of neuroplasticity, suggesting that it occurs not only in adult mammals but that it occurs every night!  Day in and day out.  Again, nearly mind-blowing.

While Tononi and Cirelli marshalled lots of circumstantial evidence to support their original claim, their ideas remained untested until last year.  At that time, two research teams, using different and new technical methods, conducted a pair of studies that were able to evaluate this proposition in decisive fashion.

Published in Science, last year, De Vivo et al used electron microscopy to measure the size of a particular part of the synapse, the axon-spine interface, in over 7000 neurons from two different areas of mouse brain, that were obtained during sleep, on awakening, and after 8 hours of being awake [4].  The results were astonishing. Synaptic area was reduced by approximately 20% after each sleep period. Our brains selectively expand and contract on a nightly basis by 20%!   In further support of their theory, they found that the downscaling preferentially culled the weaker, newer synapses. That last point is relevant in the following way:  each day, we’re each exposed to thousands of new words, sounds, images, sensations, ideas, and interactions. If we remembered everything, our minds would become cluttered and inefficient. To improve the signal to noise ratio, we engage in ‘smart forgetting’ at night that allows us to dispense with the unimportant noisy inputs we all receive and hang on to only the most important new bits.  Though it used mice and not human brains, there is every reason to think that these cycles of daily growth and nightly reduction measured by this study captured a universal micro-architectural turnover process that occurs throughout the central nervous systems of all mammals.

The second examination of SHY was led by Graham Diering at John Hopkins, using another novel method [5].  Instead of counting and examining synapse size, this group measured the cellular signatures and molecular breadcrumbs left behind whenever neurons shift size, change their strength, or form new wiring attachments.  Just like any other building project, when the brain undertakes construction and rehab work on neuronal assemblies, it requires energy, materials and chemical support, the latter termed, trophic support. Trophic support comes in the form of special molecules like BDNF (Brain Derived Neurotrophic Factor) and NGF (Nerve Growth Factor) that encourage growth and neuronal sprouting.  Once construction is started, evidence of the renovation work can be found in several areas. One of the main ways, which brain cells enlarge, is through the incorporation of specialized glutamatergic receptors on their outer membranous layer. Another bulk-adding sign occurs when these receptors become activated through a chemical process of phosphorylation. Employing sophisticated protein fractionation techniques; the team isolated and measured the number of glutamate receptors, their activation level, and density in mice brains comparing the results between the waking and sleep states.  This molecular detective work produced complementary findings to the Di Vivo paper: the number and activation levels, thus the overall weight, of these major synaptic ingredients were reduced by approximately 20% after sleep compared to after wake. Together, these companion publications in one of the world’s most rigorous scientific journals, moves the synaptic homeostasis theory from proposition towards established fact. In so doing, it highlights, like nothing before, the reality and magnitude of neuroplasticity and its indispensability for emotional and cognitive health. Sleep downscales our brain on a nightly basis in the service of memory, and learning.

John Gottlieb, M.D.