Massive redundancy: The great majority of nerve cells in the intact brain are permanently silent, in inhibited state at high energetic costs, until stress and disease attack, developing psychiatric symptoms

The dark matter of the brain. Saak V. Ovsepian. Brain Structure and Function, https://link.springer.com/article/10.1007/s00429-019-01835-7

Abstract: The bulk of brain energy expenditure is allocated for maintenance of perpetual intrinsic activity of neurons and neural circuits. Long-term electrophysiological and neuroimaging studies in anesthetized and behaving animals show, however, that the great majority of nerve cells in the intact brain do not fire action potentials, i.e., are permanently silent. Herein, I review emerging data suggesting massive redundancy of nerve cells in mammalian nervous system, maintained in inhibited state at high energetic costs. Acquired in the course of evolution, these collections of dormant neurons and circuits evade routine functional undertakings, and hence, keep out of the reach of natural selection. Under penetrating stress and disease, however, they occasionally switch in active state and drive a variety of neuro-psychiatric symptoms and behavioral abnormalities. The increasing evidence for widespread occurrence of silent neurons warrants careful revision of functional models of the brain and entails unforeseen reserves for rehabilitation and plasticity.

Keywords: Silent neurons Brain evolution fMRI Synchronous activity Schizophrenia; disinhibition; neuronal plasticity

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Similar to cosmology and genomic research, advances in functional brain imaging have been also highly contin-gent on the arrival of cutting-edge technologies and research tools. The glorious custom of functional brain studies set by Hans Berger, Charles Sherrington, Graham Brown, and others prompted major breakthroughs, which climaxed in arrival of innovative methods enabling non-invasive visuali-zation of intrinsic and task-driven changes in brain activity and metabolism (Roy and Sherrington 1890; Berger 1940; Logothetis 2008). The gold standard here has been relat-ing selected brain structures to specific neural functions, to gain critical information for elucidating normal and diseased brain activity and assisting in diagnostics of neu-rological and psychiatric disease. Like in cosmology and genomic studies, the explosive advances in neuroscience research and imaging have unveiled major and surprising unknowns at the core of functional models of the brain. In particular, analysis of energy consumption changes related to brain activity showed that baseline expenditure of calo-ries at rest is remarkably stable, with extra energy required for processing environmental inputs comprising only a very small percentage (~ 1%) of the total energy usage. While the general notion is that bulk of the brain energy is allocated for maintenance of intrinsic activity, the nature and func-tionality of processes absorbing massive amount of calories remain to be determined. According to Raichle, the meta-bolic state of the brain circuits could be the cause, rather than the consequence of neural activity, with best part of neural energy expenditure remaining unaccounted (Raichle 2010, 2015). Recent estimates, which are largely based on positron emission tomography (PET) and functional mag-netic resonance imaging (fMRI) are especially revealing, and propose that with a fierce appetite for glucose and oxygen, the human brain, which constitutes only ~ 2% of the body weight, consumes over ~ 20% of the total body energy. The mechanistic analysis of this intriguing phenomenon is cur-rently hindered by limited sensitivity and resolution of imag-ing methods, which despite major improvements, remain indirect and crude sensors of neuronal mass action, unable to distinguish even basic neurobiological processes such as excitation and inhibition (Logothetis 2008; Poplawsky et al. 2017). Remarkably, hemodynamic measurements combined with autoradiography studies showed that similar to excita-tion, inhibition can be associated with increased perfusion of neural tissue and rise in metabolic activity, although these effects can vary depending on the experimental paradigm, partly owning to effects GABA on micro-vessel dynamics (Jueptner and Weiller 1995).Despite the results of cost-based analysis suggesting greater significance of intrinsic as opposed to evoked brain activity, single-unit electrophysiological recordings and cellular resolution imaging in animal models show that the overwhelming majority of neurons (60–90%) in anesthetized and awake animals are permanently silent (i.e., do not fire action potentials) or show very sparse firing (Berger 1940; Shoham et al. 2006) (Table 1). These findings not only prompt questions concerning the share of inactive neurons in brain energy expenditure, but also their neurochemical identity, phylogenetic origin, and place in functional brain models. In the following, I consider emerging data suggest-ing that vast numbers of inactive neurons are not a result of experimental intervention but reflect the generic state of brain affairs. I discuss numerous evidence, implying that these neurons could emerge as a result of the trade-off for high conservation of neural evolution, through selection of loss of function, which favored retention of dormant neu-rons in permanently inhibited state. I review remarkable examples of reactivation of silent neurons and circuits by disinhibition, with their entry into the realm of psyche and behavior, producing an array of maladaptive fits or relict activity. Finally, I propose that neural circuits neutralized by persistent inhibition can afford vast reserves for plasticity and neo-functionalization, with invigorating or disruptive consequence.