Autonomic Control and the Hypothalamus

A thirsty mouse that starts to drink quiets a population of its thirst neurons within a minute, yet five minutes later the salt in its blood is still raised.

If the brain only corrected errors it had measured in the blood, that could not happen. This lesson builds the machinery the hypothalamus uses to run the body’s interior, two autonomic divisions and two pituitary lobes, then treats homeostasis as a feedback loop you can calculate, and ends with the mouse experiments that show the brain acting ahead of the error.

Two divisions, two neurons each

The autonomic nervous system controls cardiac muscle, smooth muscle and glands. Its basic unit is a chain of two neurons. The first, the preganglionic neuron, has its cell body in the brainstem or spinal cord and sends its axon out to a ganglion, a cluster of neuron cell bodies outside the central nervous system. The second, the postganglionic neuron, sits in that ganglion and sends its axon to the target. Autonomic ganglion neurons come from the neural crest, as neural crest explains; here they are mature relay stations.

The sympathetic division leaves the spinal cord from the thoracic and upper lumbar segments, so it is called thoracolumbar. Its preganglionic axons are relatively short. They end in the paravertebral chain of ganglia beside the vertebral column or in prevertebral ganglia in the abdomen, and the postganglionic axons are relatively long. The parasympathetic division is conventionally called craniosacral: its preganglionic neurons lie in brainstem nuclei, whose axons leave in cranial nerves, and in the sacral cord. Its preganglionic axons are long and end in ganglia near or inside the target, so its postganglionic axons are short. The word “conventionally” matters, because a 2016 study in mice argued that the sacral outflow is sympathetic, and others dispute it.

Now the transmitters, which you met in transmitter systems. Learn them as a wiring diagram:

• Every preganglionic neuron, in both divisions, releases acetylcholine, which acts on nicotinic receptors, ligand-gated cation channels that excite the postganglionic neuron fast.
• Parasympathetic postganglionic neurons release acetylcholine onto muscarinic receptors on the target.
• Most sympathetic postganglionic neurons release noradrenaline, which acts on alpha and beta adrenergic receptors.
• The sympathetic fibres to sweat glands are cholinergic and act on muscarinic receptors.
• The adrenal medulla is a modified sympathetic ganglion. Preganglionic fibres end on its chromaffin cells, which have no axons and release adrenaline and noradrenaline into the blood.

Muscarinic and adrenergic receptors are G-protein-coupled receptors; how they signal belongs to G proteins. So “sympathetic” does not mean “noradrenaline at every synapse”: the first synapse is always cholinergic.

Two further corrections. Not every organ has dual innervation: most arteries receive sympathetic fibres and no parasympathetic ones, as do sweat glands and the adrenal medulla. Such a vessel is set by turning one input up or down, like a single tap. And the divisions are not a switch between “fight or flight” and “rest and digest”. Both are active at rest, at a tonic level, and many organs are set by the balance of the two at once.

The hypothalamus and its two pituitaries

The hypothalamus is a small region at the base of the forebrain, below the thalamus, built of nuclei, clusters of neuron cell bodies inside the brain. It receives visceral sensory information, as do brainstem centres, and it reaches the body in two ways: through descending pathways to the autonomic preganglionic neurons, and through the pituitary gland below it. The pituitary has two lobes, controlled in completely different ways.

The anterior pituitary is reached by blood. Neurons in hypothalamic nuclei send axons to the median eminence at the base of the hypothalamus and release peptides into capillaries there. Those capillaries drain into the long hypophysial portal veins, which run down the stalk and open into a second capillary bed in the anterior pituitary. A portal system is two capillary beds joined in series, so a releasing hormone reaches the gland at high concentration before it is diluted in the general circulation.

Two axes show the pattern. In the HPA axis, corticotropin-releasing hormone (CRH), made mainly in the paraventricular nucleus (PVN), stimulates corticotroph cells of the anterior pituitary to release ACTH, and ACTH stimulates the adrenal cortex to make and release cortisol. Cortisol then inhibits the axis at both the hypothalamus and the pituitary. In the HPT axis, thyrotropin-releasing hormone (TRH) stimulates the pituitary to release thyroid-stimulating hormone (TSH), and TSH is the main regulator of the thyroid, and thyroid hormones feed back at both levels. Cortisol and thyroid hormone act on intracellular receptors (nuclear receptors). The HPA axis in stress belongs to emotion and stress.

The posterior pituitary is reached by axons. Large, magnocellular neurons in the supraoptic nucleus (SON) and the PVN make vasopressin (AVP) and oxytocin in their cell bodies, carry them down their axons, and release them from terminals in the posterior pituitary into the systemic blood. The posterior pituitary stores and releases vasopressin; it does not make it. In the kidney, vasopressin acts on V2 receptors of collecting-duct cells and, through cAMP (cAMP and PKA), increases the aquaporin-2 water channels in their membranes, so more water returns to the blood (membrane transport covers osmosis).

Feedback: set points, thresholds and gains

Any homeostatic loop has four parts. The regulated variable is what is held steady, here plasma osmolality, the concentration of osmotically active particles per kilogram of water. A sensor measures it: osmosensitive neurons in the lamina terminalis, the front wall of the third ventricle, which includes the SFO and the organum vasculosum (OVLT). These are circumventricular organs, sites with an incomplete blood-brain barrier. A comparator decides how far the variable is from where it should be, and an effector pushes back: vasopressin to save water at the kidney, thirst to take water in. The loop is negative feedback, because the response opposes the error.

“Set point” sounds like one number, but a hormone loop has at least two. The threshold is the value at which the response starts. The gain is how much the response grows per unit of error above threshold. Endotext’s review summarizes healthy adults under controlled hypertonic stimulation with a regression line:

AVP (pmol/L) = 0.43 × (Posm − 284), for Posm above 284 mOsm/kg

Here 284 mOsm/kg is the threshold and 0.43 pmol/L per mOsm/kg is the gain. Treat both as illustrative averages: thresholds and slopes vary between individuals.

Worked problem. A hypothetical adult follows this line. Plasma osmolality is 294 mOsm/kg, and after drinking it is 290 mOsm/kg. Assume the same relation holds at both times and that AVP has reached steady state for each value.

Step 1: the first error. 294 − 284 = 10 mOsm/kg above threshold. AVP = 0.43 × 10 = 4.30 pmol/L.

Step 2: the second error. 290 − 284 = 6 mOsm/kg. AVP = 0.43 × 6 = 2.58 pmol/L.

Step 3: the change. 2.58 − 4.30 = −1.72 pmol/L. Check it another way: 0.43 × (290 − 294) = 0.43 × (−4) = −1.72 pmol/L. Less error, less hormone, less water saved.

Step 4: below threshold. At 280 mOsm/kg the formula would give 0.43 × (−4) = −1.72 pmol/L, which is impossible. The line describes release only above threshold, so it predicts no osmotically driven release there, not a negative one.

Step 5: threshold against gain. Now compare two made-up people at 290 mOsm/kg. Person P has a threshold of 280 and a gain of 0.43: 0.43 × 10 = 4.30 pmol/L. Person Q has a threshold of 284 and a gain of 0.86: 0.86 × 6 = 5.16 pmol/L. Solve 0.43 × (Posm − 280) = 0.86 × (Posm − 284) and the lines cross at 288 mOsm/kg, where both give 3.44 pmol/L. Between 280 and 288, P releases more; above 288, Q does; at or below 280 both release none. Two people can give the same output by different routes, so a “set point” is not one fixed number.

This is a static calculation, not a prediction of how fast anyone rehydrates. Fever offers a contrast: in the standard model, the thermoregulatory set point is raised, so a person shivers and feels cold while body temperature is still normal. Most work on the prostaglandin E2 mechanism behind that shift comes from rodents.

Thirst: acting before the blood changes

A pure feedback loop reacts to an error it has measured. Feedforward control responds to a disturbance that is expected. Mouse experiments show that thirst uses both.

Start with what the SFO can do. In 2015 Oka, Ye and Zuker drove excitatory SFO neurons with light in water-satiated mice, and the mice drank; driving inhibitory SFO neurons in thirsty mice cut licking by more than 80%. That shows the cells are enough to push drinking up or down. It does not show they are the only route, or that the SFO is a “thirst centre”.

The next question was what these neurons do during ordinary drinking. Christopher Zimmerman, Zachary Knight and colleagues used fibre photometry, an optical fibre that collects the fluorescence of a calcium indicator from a whole population, to record SFO neurons that express the enzyme Nos1, in awake mice.

Design problem

Zimmerman and colleagues (Nature, 2016) report, in water-restricted mice: SFO Nos1 population activity falls within one minute after water becomes available and the mice drink, while plasma osmolality, measured by freezing-point osmometry, is still raised five minutes after water access. Seeing water without being allowed to drink does not lower the activity. In salt-challenged mice, licking an empty bottle does not lower it. In fasted mice, eating raises it. What do these data show, and what experiment would you do next to find where the signal comes from?

Prediction of this kind returns for feeding in motivation and reward and for daily timing in sleep and rhythms.