Why an animal needs a brain.

In Principles of Neural Design (2015, MIT Press), inspired by Charles Darwin, Sterling and Laughlin undertook the unfashionable task of distilling principles from facts in the technique-driven, data-saturated domain of neuroscience. Their starting point for deriving the organizing principles of brains are two brainless single-celled organisms, Escherichia coli and Paramecium, and the 302-neuron brain of the nematode Caenorhabditis elegans. The book is an exemplar in how to connect the dots between simpler and (much) more complex organisms in a particular area. Here, they have generously agreed to republish an abridged version of Chapter 2 (Why an Animal Needs a Brain), in which many of their principles are first described.

What Can the Health Humanities Contribute to Our Societal Understanding of and Response to the Deaths of Despair Crisis?

Deaths of Despair (DoD), or mortality resulting from suicide, drug overdose, and alcohol-related liver disease, have been rising steadily in the United States over the last several decades. In 2020, a record 186,763 annual despair-related deaths were documented, contributing to the longest sustained decline in US life expectancy since 1915-1918. This forum feature considers how health humanities disciplines might fruitfully engage with this era-defining public health catastrophe and help society better understand and respond to the crisis.

Why Deaths of Despair Are Increasing in the US and Not Other Industrial Nations-Insights From Neuroscience and Anthropology.

The US National Academy of Sciences reports rising mortality for US adults, most steeply for White adults with a secondary education or less. The rise is largely attributable to deaths of despair (suicide and poisoning by alcohol and drugs) with strong contributions from the cardiovascular effects of rising obesity. Although the report does acknowledge a crisis, it proposes mild measures to manage it, such as strengthening programs to support recovery, prevent relapse, increase resilience, and perform more research toward clinically useful definitions of despair. The US National Academy of Sciences report notes that mortality is decreasing in a control group of 16 wealthy nations (including countries in Western Europe, Canada, Australia, and Japan), but it does not ask what protects those nations from despair. It has been observed that human beings are constrained by evolutionary strategy (ie, huge brain, prolonged physical and emotional dependence, education beyond adolescence for professional skills, and extended adult learning) to require communal support at all stages of the life cycle. Without support, difficulties accumulate until there seems to be no way forward. The 16 wealthy nations provide communal assistance at every stage, thus facilitating diverse paths forward and protecting individuals and families from despair. The US could solve its health crisis by adopting the best practices of the 16-nation control group.

Why I joined the Freedom Rides.

Peter Sterling expands upon his recent Q & A article by discussing his participation in the Freedom Rides and the reasons for his involvement in the civil rights movement.

Peter Sterling.

Interview with Peter Sterling, author of Principles of Neural Design and What Is Health?

Allostasis: A Brain-Centered, Predictive Mode of Physiological Regulation.

Although the concept of allostasis was proposed some 30 years ago, doubts persist about its precise meaning and whether it is useful. Here we review the concept in the context of recent studies as a strategy to efficiently regulate physiology and behavior. The brain, sensing the internal and external milieu, and consulting its database, predicts what is likely to be needed; then, it computes the best response. The brain rewards a better-than-predicted result with a pulse of dopamine, thereby encouraging the organism to learn effective regulatory behaviors. The brain, by prioritizing behaviors and dynamically adjusting the flows of energy and nutrients, reduces costly errors and exploits more opportunities. Despite significant costs of computation, allostasis pays off and can now be recognized as a core principle of organismal design.

Predictive regulation and human design.

Organisms evolving toward greater complexity were selected across aeons to use energy and resources efficiently. Efficiency depended on prediction at every stage: first a clock to predict the planet's statistical regularities; then a brain to predict bodily needs and compute commands that dynamically adjust the flows of energy and nutrients. Predictive regulation (allostasis) frugally matches resources to needs and thus forms a core principle of our design. Humans, reaching a pinnacle of cognitive complexity, eventually produced a device (the steam engine) that converted thermal energy to work and were suddenly awash in resources. Today boundless consumption in many nations challenges all our regulatory mechanisms, causing obesity, diabetes, drug addiction and their sequelae. So far we have sought technical solutions, such as drugs, to treat complex circuits for metabolism, appetites and mood. Here I argue for a different approach which starts by asking: why does our regulatory system, which evolution tuned for small satisfactions, now constantly demand 'more'?

How scientists can reduce their carbon footprint.

Cutting down on long-distance air travel is the best way to reduce the emission of greenhouse gases by the scientific community.

Why do axons differ in caliber?

CNS axons differ in diameter (d) by nearly 100-fold (∼0.1-10 µm); therefore, they differ in cross-sectional area (d(2)) and volume by nearly 10,000-fold. If, as found for optic nerve, mitochondrial volume fraction is constant with axon diameter, energy capacity would rise with axon volume, also as d(2). We asked, given constraints on space and energy, what functional requirements set an axon's diameter? Surveying 16 fiber groups spanning nearly the full range of diameters in five species (guinea pig, rat, monkey, locust, octopus), we found the following: (1) thin axons are most numerous; (2) mean firing frequencies, estimated for nine of the identified axon classes, are low for thin fibers and high for thick ones, ranging from ∼1 to >100 Hz; (3) a tract's distribution of fiber diameters, whether narrow or broad, and whether symmetric or skewed, reflects heterogeneity of information rates conveyed by its individual fibers; and (4) mitochondrial volume/axon length rises ≥d(2). To explain the pressure toward thin diameters, we note an established law of diminishing returns: an axon, to double its information rate, must more than double its firing rate. Since diameter is apparently linear with firing rate, doubling information rate would more than quadruple an axon's volume and energy use. Thicker axons may be needed to encode features that cannot be efficiently decoded if their information is spread over several low-rate channels. Thus, information rate may be the main variable that sets axon caliber, with axons constrained to deliver information at the lowest acceptable rate.

Allostasis: a model of predictive regulation.

The premise of the standard regulatory model, "homeostasis", is flawed: the goal of regulation is not to preserve constancy of the internal milieu. Rather, it is to continually adjust the milieu to promote survival and reproduction. Regulatory mechanisms need to be efficient, but homeostasis (error-correction by feedback) is inherently inefficient. Thus, although feedbacks are certainly ubiquitous, they could not possibly serve as the primary regulatory mechanism. A newer model, "allostasis", proposes that efficient regulation requires anticipating needs and preparing to satisfy them before they arise. The advantages: (i) errors are reduced in magnitude and frequency; (ii) response capacities of different components are matched -- to prevent bottlenecks and reduce safety factors; (iii) resources are shared between systems to minimize reserve capacities; (iv) errors are remembered and used to reduce future errors. This regulatory strategy requires a dedicated organ, the brain. The brain tracks multitudinous variables and integrates their values with prior knowledge to predict needs and set priorities. The brain coordinates effectors to mobilize resources from modest bodily stores and enforces a system of flexible trade-offs: from each organ according to its ability, to each organ according to its need. The brain also helps regulate the internal milieu by governing anticipatory behavior. Thus, an animal conserves energy by moving to a warmer place - before it cools, and it conserves salt and water by moving to a cooler one before it sweats. The behavioral strategy requires continuously updating a set of specific "shopping lists" that document the growing need for each key component (warmth, food, salt, water). These appetites funnel into a common pathway that employs a "stick" to drive the organism toward filling the need, plus a "carrot" to relax the organism when the need is satisfied. The stick corresponds broadly to the sense of anxiety, and the carrot broadly to the sense of pleasure. This design constrains anxieties to be non-adapting and pleasures to be brief -- fast-adapting -- to make way for the next anxiety. The stick/carrot mechanisms evolved early and expanded so that in humans they govern higher level learning and social organization. Correspondingly, the "funnel" widened to allow innumerable activities and experiences to each provide non-adapting anxieties and brief pleasures, their reward values depending partly on the effort expended. But modern life narrows the variety of small pleasures and reduces effort, thereby reducing their reward value and requiring larger portions for equivalent satisfaction - a cycle that generates addictive behaviors. Homeostasis and allostasis locate pathology at different levels. Homeostasis identifies proximate causes; for example, it attributes essential hypertension to excess salt water in too small a vascular reservoir. Thus it directs pharmacotherapy toward reducing salt and water, expanding the reservoir, and blocking feedbacks that would counteract these measures. Allostasis attributes essential hypertension to the brain. Chronically anticipating a need for higher pressure, the brain mobilizes all the low level mechanisms in concert: kidney to retain salt and water, vascular system to tighten, and salt appetite to rise. Correspondingly, allostasis would direct therapy toward higher levels - to reduce demand and increase sense of control -- so that the brain can down-shift its prediction and relax all the low-level mechanisms in concert. For disorders of addiction homeostasis pursues pharmacological treatments: drugs to treat drug addiction, obesity, and other compulsive behaviors. Allostasis suggests broader approaches - such as re-expanding the range of possible pleasures and providing opportunities to expend effort in their pursuit.

Natural images from the birthplace of the human eye.

Here we introduce a database of calibrated natural images publicly available through an easy-to-use web interface. Using a Nikon D70 digital SLR camera, we acquired about six-megapixel images of Okavango Delta of Botswana, a tropical savanna habitat similar to where the human eye is thought to have evolved. Some sequences of images were captured unsystematically while following a baboon troop, while others were designed to vary a single parameter such as aperture, object distance, time of day or position on the horizon. Images are available in the raw RGB format and in grayscale. Images are also available in units relevant to the physiology of human cone photoreceptors, where pixel values represent the expected number of photoisomerizations per second for cones sensitive to long (L), medium (M) and short (S) wavelengths. This database is distributed under a Creative Commons Attribution-Noncommercial Unported license to facilitate research in computer vision, psychophysics of perception, and visual neuroscience.

Cone synapses in macaque fovea: I. Two types of non-S cones are distinguished by numbers of contacts with OFF midget bipolar cells.

L and M cones, divided into two groups by absorption spectra, have not been distinguished by structure. Here, we report what may be such a difference. We reconstructed the synaptic terminals of 16 non-S cones and the dendritic arbors of their ON and OFF midget bipolar cells from high-magnification electron micrographs of serial thin sections of a small region of macaque fovea. Each cone terminal contacted a similar number (~16) of invaginating central elements provided by its ON midget bipolar cell. By contrast, the numbers of connections between a cone terminal and its OFF midget bipolar cell were grouped into two clusters: 30-37 versus 43-50 basal contacts in the triad-associated position and 41-47 versus 61-74 Outer Densities within those basal contacts. The coefficients of variation of these distributions were all in the range of 10% or lower, characteristic of single populations. If these two clusters correspond to M- and L-cone circuits, the results reveal structural differences between M and L cones and between their corresponding OFF midget bipolar cells.

Cone synapses in macaque fovea: II. Dendrites of OFF midget bipolar cells exhibit Inner Densities similar to their Outer synaptic Densities in basal contacts with cone terminals.

As described in the companion paper, the synaptic terminal of a cone photoreceptor in macaque monkey makes an average of 35 or 46 basal contacts with the tips of the dendrites of its OFF midget bipolar cell. Each basal contact has one or more symmetrically thickened dense regions. These "Outer Densities," averaging 48 or 67 in number, harbor clusters of ionotropic glutamate receptors and are ~0.8 µm (and ~1-ms diffusion time) from active zones associated with synaptic ribbons. Here, we show similarly appearing "Inner Densities," averaging 53 or 74 in number, located more proximally on the dendrites of these OFF midget bipolar cells, ~0.4 µm inward from the tips of the dendrites and out of contact with the basal surface of the cone terminal. Compared to desmosome-like junctions, Inner Densities are closer to the terminal and are less dense and less thick. Each Inner Density is shared with another cell, the partners including diffuse bipolar cells, ON midget bipolar cells, and horizontal cells. Given the diversity of the partners, the OFF midget bipolar cells are unlikely to be in a synaptic relationship with the partners. Instead, Inner Densities are near enough to the active zones associated with synaptic ribbons to receive pulses of glutamate at concentrations effective for glutamate receptors. The role of Inner Densities is not known, but they might represent additional clusters of glutamate receptors.

Retina is structured to process an excess of darkness in natural scenes.

Retinal ganglion cells that respond selectively to a dark spot on a brighter background (OFF cells) have smaller dendritic fields than their ON counterparts and are more numerous. OFF cells also branch more densely, and thus collect more synapses per visual angle. That the retina devotes more resources to processing dark contrasts predicts that natural images contain more dark information. We confirm this across a range of spatial scales and trace the origin of this phenomenon to the statistical structure of natural scenes. We show that the optimal mosaics for encoding natural images are also asymmetric, with OFF elements smaller and more numerous, matching retinal structure. Finally, the concentration of synapses within a dendritic field matches the information content, suggesting a simple principle to connect a concrete fact of neuroanatomy with the abstract concept of information: equal synapses for equal bits.

Design of a trichromatic cone array.

Cones with peak sensitivity to light at long (L), medium (M) and short (S) wavelengths are unequal in number on the human retina: S cones are rare (<10%) while increasing in fraction from center to periphery, and the L/M cone proportions are highly variable between individuals. What optical properties of the eye, and statistical properties of natural scenes, might drive this organization? We found that the spatial-chromatic structure of natural scenes was largely symmetric between the L, M and S sensitivity bands. Given this symmetry, short wavelength attenuation by ocular media gave L/M cones a modest signal-to-noise advantage, which was amplified, especially in the denser central retina, by long-wavelength accommodation of the lens. Meanwhile, total information represented by the cone mosaic remained relatively insensitive to L/M proportions. Thus, the observed cone array design along with a long-wavelength accommodated lens provides a selective advantage: it is maximally informative.

Receptive fields and functional architecture in the retina.

Functional architecture of the striate cortex is known mostly at the tissue level--how neurons of different function distribute across its depth and surface on a scale of millimetres. But explanations for its design--why it is just so--need to be addressed at the synaptic level, a much finer scale where the basic description is still lacking. Functional architecture of the retina is known from the scale of millimetres down to nanometres, so we have sought explanations for various aspects of its design. Here we review several aspects of the retina's functional architecture and find that all seem governed by a single principle: represent the most information for the least cost in space and energy. Specifically: (i) why are OFF ganglion cells more numerous than ON cells? Because natural scenes contain more negative than positive contrasts, and the retina matches its neural resources to represent them equally well; (ii) why do ganglion cells of a given type overlap their dendrites to achieve 3-fold coverage? Because this maximizes total information represented by the array--balancing signal-to-noise improvement against increased redundancy; (iii) why do ganglion cells form multiple arrays? Because this allows most information to be sent at lower rates, decreasing the space and energy costs for sending a given amount of information. This broad principle, operating at higher levels, probably contributes to the brain's immense computational efficiency.

How the optic nerve allocates space, energy capacity, and information.

Fiber tracts should use space and energy efficiently, because both resources constrain neural computation. We found for a myelinated tract (optic nerve) that astrocytes use nearly 30% of the space and >70% of the mitochondria, establishing the significance of astrocytes for the brain's space and energy budgets. Axons are mostly thin with a skewed distribution peaking at 0.7 microm, near the lower limit set by channel noise. This distribution is matched closely by the distribution of mean firing rates measured under naturalistic conditions, suggesting that firing rate increases proportionally with axon diameter. In axons thicker than 0.7 microm, mitochondria occupy a constant fraction of axonal volume--thus, mitochondrial volumes rise as the diameter squared. These results imply a law of diminishing returns: twice the information rate requires more than twice the space and energy capacity. We conclude that the optic nerve conserves space and energy by sending most information at low rates over fine axons with small terminal arbors and sending some information at higher rates over thicker axons with larger terminal arbors but only where more bits per second are needed for a specific purpose. Thicker axons seem to be needed, not for their greater conduction velocity (nor other intrinsic electrophysiological purpose), but instead to support larger terminal arbors and more active zones that transfer information synaptically at higher rates.