Home > Work > The Heart of the Brain: The Hypothalamus and Its Hormones
1 " We must consider what we mean when we say that the spiking activity of a neuron 'encodes' information. We normally think of a code as something that conveys information from a sender to a recipient, and this requires that the recipient 'understands' the code. But the spiking activity of every neuron seems to encode information in a slightly different way, a way that depends on that neuron's intrinsic properties. So what sense can a recipient make of the combined input from many neurons that all use different codes? It seems that what matters must be the 'population code' - not the code that is used by single cells, but the average or aggregate signal from a population of neurons.In a now classic paper, Shadlen and Newsome considered how information is communicated among neurons of the cortex - neurons that typically receive between 3,000 and 10,000 synaptic inputs.They argued that, although some neural structures in the brain may convey information in the timing of successive spikes, when many inputs converge on a neuron the information present in the precise timing of spikes is irretrievably lost, and only the information present in the average input rate can be used. They concluded that 'the search for information in temporal patterns, synchrony and specially labeled spikes is unlikely to succeed' and that 'the fundamental signaling units of cortext may be pools on the order of 100 neurons in size.' The phasic firing of vasopressin cells is an extreme demonstration of the implausibility of spike patterning as a way of encoding usable information, but the key message - that the only behaviorally relevant information is that which is collectively encoded by the aggregate activity of a population - may be generally true. "
― , The Heart of the Brain: The Hypothalamus and Its Hormones
2 " What we have seen does not sit comfortably with conventional views of the brain. Electrophysiology has been a powerful tool and its returns have permeated our thinking about how the brain works, but the resulting understanding is cursed by overinterpretation. Because spike activity appears to have so much capacity for encoding information, we are tempted to think it in fact conveys a huge volume of information. When we find, in the spike activity of some neuron or another, correlation between some facet and some particular external events, it is tempting to think this is the message the cell is conveying.A message is only a message if it can be understood by its recipient. Neurons can't decipher long and complex sentences. They have a short attention span, are easily distracted, and much of the time they aren't even listening. A neuron that is quiet at a particular time is likely also to be less sensitive to an input; a cell that is very active might be saturated; and a cell recently activated might be refractory to further activation.Spike activity is not the output of any neuron, only one of several means by which some of its chemical signals are generated. These signals are generated unreliably and erratically and are recognized imperfectly by their targets. The message carried by the spike activity of a vasopressin cell makes no sense when considered alone. The important signal is generated by a cacophony of noisy and messy cells , and the miracle that demands to be recognized is that this population response is indeed clean, refined and fit for purpose. "
3 " The realization that the brain used so many different kind of chemicals, in addition to classical neurotransmitters, to communicate beween neurons was just the first step in a major conceptual shift in neuroscience. Many of these substances are neuropeptides, and most of those affect mood and behavior. The specificity of their effects resides not in the anatomical connectivity between neurons, but in the distribution of receptors within the brain. Different receptors have very different patterns of distribution, and the distributions differ between species in ways that correlate with differences in behavior.The mere fact of a receptor-peptide mismatch in a particular brain area might have no great importance. It might be that many cells are promiscuous in the receptors that they express: If some receptors see no ligand, the cost to the cells is negligible. Profligate receptor expression might contribute to the evolvability of neural systems, and might be common because organisms with a liberal attitude to receptor expression are those most likely to acquire novels functions. Because extrasynaptic signaling does not require precise point-to-point connectivity, it is intrinsically 'evolvable': a minor mutation in the regulatory region of a peptide receptor gene, by altering the expression pattern, could have functional consequences without any need for anatomical rewiring.That peptide receptors have distinctive patterns of expression, and that peptides produce coherent behavioral effects when given quite crudely into the brain, suggests that volume transmission is used as a signaling mechanism by many different populations of peptidergic neurons. We thus must see neuropeptides as 'hormones of the brain'. "
4 " Endrocrine cells have neither dendrites nor axons, but many are like neurons in other ways. Some are electrically exitable: when pancreatic beta cells see an increase in extracellular glucose concentration they fire in bursts of spikes that are like the phasic bursts of vasopressin neurons; these bursts lead to calcium entry and trigger insulin secretion. In both neurons and endocrine cells, peptides are packages in vesicles just as neurotransmitters are. Typically, peptide secretion is the result of the same process as that by which neurotransmitters are released: exocytosis is triggered in both cases by an increase in intracellular calcium. In neurons, this happens when spikes depolarize the neuron, opening voltage-sensitive calcium channels, and the same occurs in spiking endocrine cells.However, endocrine cells have another trick. Th cell bodies of all eukaryotic cells contain rough endoplasmic reticulum, which sequesters free calcium, and activation of receptors for some neurotransmitters or hormones can release calcium from these stores. In many endocrine cells, this 'calcium mobilization' can trigger exocytosis of vesicles without any involvement of spikes. There is no rough endoplasmic reticulum in axon terminals, so spikes are necessarily involved in the release of synaptic vesicles. "
5 " This heterogeneity [of vasopressin cells] is not by design but by accident. The patterns of gene expression in any neuron are not rigidly fixed by genetic nature, they arise from the unique experience of each cell in its life from birth to adulthood. The innervation of each cell is not predetermined with precision. Axons that reach the supraoptic nucleus may be guided there by developmental cues, but which particular cells each axon contacts is an opportunistic accident. There are mistakes; developmental cues are imperfect and some axons get lost or misled and make inappropriate connections. The brain has to be robust against such imperfection; the cost of doing everything perfectly is too high.Vasopressin cells are complex, but this does not make them clever, and the differences between cells certainly do mot make each cell uniquely clever. I am not interested in the idea that the brain does clever things because it hosts 100 billion clever machines. The wonder is that it does clever things with machines that are messy, noisy, and imperfect. "
6 " Peptides operate on multiple scales: they have feedback effects on the cells of origin that modulate activity patterning, and local effects on neighboring cells to coordinate the behavior of a population; and the hormone-like release of peptides from cell populations can have organizational effects on distant targets. It's a mode of communication quite different from neurotransmitter release. Oxytocin, as we have seen, by its priming actions, can affect how oxytocin cells communicate with each other. How common such priming actions are we don't know. But all peptides can affect gene expression and can alter the behavior of neurons by changing what receptors they express and what they secrete. These actions of peptides together underlie what we might see as a reprogramming of communication in the brain. "
