Homeostasis Is More than Treading Water
If you were to watch a person treading water in a murky lake, you might assume she is standing on a shallow bottom. She might look calm and be talking to you, but below the surface a lot of kicking and stroking going on. That’s a bit like homeostasis, a broad term for maintaining internal stability in a dynamic environment. Here we will look at recent discoveries showing the complexity of systems required to keep organisms functioning while the surroundings are changing.
Frog Breath
Consider the case of a frog maintaining its breathing reflex while the temperature is dropping. Like us, it must keep the oxygen coming in and the CO2 going out, but without endothermy, breathing might drop to a standstill in the cold or accelerate too quickly when the temperature rises. What keeps the frog happily breathing?
In Current Biology, Tara A. Janes and Richard Kinkead review a study by Cannon and Santin also in Current Biology. The researchers identified specific neurons, signals and receptors involved in maintaining the rhythm. Janes and Kinkead comment that breath homeostasis is anything but boring:
Respiratory networks, like most networks, aim to maintain relative stability in their activity level over time. Traditionally, this has been described in terms of activity-dependent mechanisms where neurons respond to their own level of activity. At the cellular level, this often involves responses to intracellular calcium signallingthat occur proportional to activity. Neurons can also stabilise network function by fine-tuning ion channel density, synaptic strengths, and intrinsic excitability.
Before Cannon and Santin’s work, they say, much of what was known about homeostatic networks came from studies on rodents which benefit from endothermy. How do frogs keep up their autonomic breathing rhythm without that luxury? Even more challenging, how do they maintain oxygen intake when undergoing metamorphosis from tadpole to adult?
A fundamental principle is that as body temperature goes down, so does metabolism and drive to breathe. Remarkably, frogs survive and thrive in the face of these environmental fluctuations by maintaining activity in the respiratory rhythm-generating networks for air-breathing. So how do they do it?
By altering temperatures in brainstem-spinal cord preparations from bullfrogs which can survive in vitro for a day, Cannon and Santin in “a clever set of experiments” found “a novel, environment-driven mechanism regulating network activity that is capable of driving compensatory changes in respiratory function in response to cold exposure.”
First, they determined that temperature alone acts as a trigger for certain changes at the cellular level. At 10°C motor activity ceased, but became hyper-excited as the temperature returned to 22°C. “This suggests that cold exposure elicits increased network excitability in an attempt to restore respiratory motor output,” the commentators say. But much more is involved: production of norepinephrine in the locus coeruleus (LC), “a compact and highly homogeneous group of neurons located rostral to the respiratory networks,” which triggers changes in calcium ion channels.
Ensuing pharmacological experiments showed that in response to acute temperature changes, inhibition of the electrogenic Na+ pump serves as a critical transduction step, which then activates network compensation via β-adrenergic receptor signalling
And so to keep breathing when it’s cold, a frog depends on the coordinated responses of temperature sensors, hormones, LC neurons, neural circuits, sodium pumps, receptors, calcium ions and muscles. The research does not explain everything, but
the authors propose novel ideas that are certainly worthy of further exploration. One that caught our attention is the suggestion that central respiratory circuits switch from CO2/pH-sensing to temperature-sensing as an important source of drive to breathe at cool temperatures. In this way, temperature sensitivity allows the network to restore activity under conditions where it might be needed, while maintaining the ability of the network to fall silent when it is adaptive to do so.
Speaking as air-breathers themselves, Janes and Kinkead conclude, “Despite our respiratory bias, we humbly acknowledge that neural circuits regulate other important physiological processes beyond breathing.”
Synapse Traffic Control
In my 2024 article on the synapse, I shared my bewilderment at how those nanoscopic signal transducers work and perform rapidly and reliably despite multiple transitions in information-bearing media. A new paper adds to my bewilderment by claiming that synapses bring order out of randomness. (For more on how life brings order out of chaos, see this article.)
Krisha Aghi et al., writing in Current Biology about fruit flies, find that “spatial distribution of facilitating and depressing synapses is random” and yet the neurons maintain stable transmission anyway. How?
Synaptic strength can vary greatly between synapses. Optical quantal analysis at Drosophila glutamatergic motor neuron synapses shows that short-term plasticity also varies greatly between synapses, even those made by an individual motor neuron. Strong and weak synapses are randomly distributed in the motor neuron nerve terminal, as are facilitating and depressing synapses. Although synapses exhibit highly heterogeneous basal strength at low-action potential firing frequency and undergo varied plasticity when firing frequency increases, the overall distribution of strength across synapses remains remarkably constant due to a balance between the number of synapses that facilitate versus depress and to their degree of plasticity and basal synaptic weight.Constancy in transmitter release can ensure robustness across changing behavioral conditions.
The robustness of the transmitted signal despite individual variations in synaptic plasticity allows fruit flies to fly, but this method also enables us to live and move. How this “method in madness” mechanism is able to work automatically in the nervous system from infant in the womb to athlete to senior citizen must cause us all to stand in awe.
Clearing Up Clock Confusion
Imagine having to follow two clocks that run at different rates. It would be like trying to play drum or trumpet in Symphony No. 4 by Charles Ives, who in one movement called for two conductors waving their batons at different tempos.
Because we have minds and large brains, we humans can track lunar cycles, solar cycles, and orbital cycles simultaneously with the help of experience, language, charts, and computers. But how does a crustacean do it? Here’s a case of life cycle homeostasis. If a crustacean gets out of rhythm, it might become desiccated on rocks or fail to reproduce.
How marine species cope with both diurnal and tidal cycles is unclear. A new study in crustaceans identifies distinct brain cells that exhibit either 24- or 12.4-hour rhythms of gene expression, thus providing a mechanism for tracking multiple environmental cycles.
So begin Victoria Lewis and Patrick Emery in a Dispatch within the same issue of Current Biology. They say that the circadian clock (day/night cycle) is fairly well understood:
The nuclear accumulation and subsequent degradation of the repressor complex are dependent on kinases and phosphatases that adjust the period of the circadian pacemaker to ∼24 hours (h). The circadian clock is primarily entrained by the light–dark (LD) cycle, but also responds to the temperature cycle and other relevant cues. With the elucidation of the molecular mechanisms underlying circadian clocks comes a key question: are similar mechanisms implicated in other biological rhythms?
Indeed they are. They comment on research reported in the same issue by Oliphant et al. who “present evidence supporting the idea that the circadian clock machinery is retooled to allow marine organisms to cope with tidal cycles through dedicated brain cells.”
The new study helps narrow down three hypotheses about how marine crustaceans can keep up with two tempos: the circadian rhythm and the circatidal rhythm. But how do the resulting proteins interact when regulated by different brain cells? “The extent of the mechanistic overlap between the two clocks,” they remark, “still needs to be determined.” Indeed, “considerable work is still needed to understand how circatidal rhythms are entrained and generated.” Yet the humble sand flea gets along without a thought.
Much More to Homeostasis
These three studies illustrate the complexity of homeostasis, but there are many thousands more that could be drawn from. Other recent examples in my pile include, in brief:
A “mitochondrial contact site and cristae organizing system” that keeps the membranes intact in these cellular powerhouses (Current Biology).
A system to prevent crowding in epithelial tissues which otherwise might cause cell damage and loss (Northwestern University Medicine).
Spatiotemporal control of mitosis by cyclin-dependent kinase (CDK) to keep order during the many rapid changes across the cell (Nature).
A relationship between the cell cycle, circadian clock, and sense of taste that can cause food to taste differently at different times of day (PNAS)
A new organelle in the cell, dubbed the hemifusome, that “could fundamentally reshape our understanding of how cells recycle their contents and sort and direct intracellular cargo” (University of Virginia School of Medicine).
Homeostasis is a tremendously varied and complex field ripe for discoveries from a design perspective. It adds an essential time dimension to irreducible complexity, revealing the interactions of multiple IC components working in cooperation to keep an organism stable in a changing environment. And so while admiring the smiling swimmer’s face above water, we must not be unaware of the vigorously beating legs and arms under the surface that are keeping her afloat.
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