Review of Kandel's Principles

After its release was pushed back many times, the 5th edition finally came out within the past year, and I have been reading it on my laptop's Kindle app throughout my first year of core PhD courses and in preparing for my qualifying exam. I had read some of the 4th edition during undergrad, as well.

First, I discuss the broad negatives and positives, and then I present some eminently skimmable chapter-by-chapter notes. In general my feelings towards the book are warm, and I do expect that if you read the textbook, dear reader of this review, you will learn a lot from it.

Positives

1) Does a good job of not trying to be Alberts' *Molecular Biology of the Cell*. The sections on cell biology, the central dogma, and non-neuroscience-related signaling pathways are refreshingly bare-boned. Seek resources elsewhere if you want to go ham on transcription, translation, and the MAPKKK-MAPKK-MAPK cascade.

2) Perception, sensation, and movement were not the reasons that I first became interested in neuroscience, and, generalizing from my one example as is de rigueur in book reviews, I think that is true of most students. And while this might be just Stockholm syndrome, I'm actually quite happy that there is so much detail and care put into these sections which make up around 1/3rd of the text. These fields are way more tractable to study than the sexy emotion, learning, and personal identity, yet the most of the principles that have been discovered there are likely to generalize.

As an example of this, consider the work of Charles Sherrington, who among other accomplishments won the 1932 Nobel for explaining spinal reflexes as a balance of excitation and inhibition. And now that we have some fancy techniques like conditional genetic KOs and optogenetics, we know that a variety of other phenomena, from critical periods to anxiety, are also regulated via a very similar balance of excitation and inhibition.

3) Most chapters do an excellent job of motivating their material. For example, they emphasize themes from the history of how people have thought about the brain, e.g. James and Freud. There are also a few references to art and literature, such as Gabriel Garcia-Marquez, that are really money.

4) Most fundamentally, this is the eminent textbook on how your mind works and how you are able to understand the words that you are currently reading. And there are some chapters, especially the last three (65 - 67), that really delve into this. What's there not to love?

Negatives

1) In general neuroscience tries very hard to distinguish itself from psychology and this makes good sense in terms of specialization. But the field is still operating in the wake of Karl Lashley, a famous experimentalist who in the 1930s concluded that brain regions had "equipotentiality" for learning mazes not because his lesions were flawed but because his tasks were not specific enough. Designing behavioral tasks is not trivial. Yet, you will not read much about the principles behind how to do so, and nothing about the matching law or Rescorla-Wagner. (My bias: I did some research in learning and behavior in undergrad.)

2) For one of our classes we read an older (3rd edition) version of Chapter 13 on Neurotransmitters. There were way more equations explaining different models of neurotransmitter vesicle release patterns, e.g. explaining the use of the Poisson distribution as an approximation for the binomial. It doesn't make sense that the text has become less quantitative at the same time that math has become easier to use to explain phenomena, as a result of advances in systems biology and just programming generally.

3) Why does searching for "optogenetics" yield me zero results?

4) I prefer my pedagogical material to be structured in the format of *example 1*, *example 2*, (*optional example 3*), and *inducted principle*. The examples only matter insofar as they motivate the principles. Kandel's textbook strays slightly too far from this, I think. In particular, the text tends to enshrine the examples, such CREB, CamKII, PKA, and the ilk, as worthy of our worship in and of themselves. This sets the trend for how neuroscience courses should be taught and for that reason it is a bit troubling.

Chapters

1) "The Brain and Behavior". A nice historical context, in which phrenologists continue to get no love.

2) "Nerve Cells, Neural Circuitry, and Behavior." Explains the basic functions of neurons and some about how different types vary. Tells us that glia cells might be as heterogenous as neurons. Au contraire, transcriptomics approaches (e.g., Cahoy et al, 2008, PMID: 18171944) suggest that oligodendrocytes and astrocytes as classes are each as heterogenous as neurons, making them moreso when combined. Look, no one's arguing here that the neuron isn't the fundamental unit of cognition, but in the 6th edition, all three major glia types (i.e., OLs, astrocytes, and microglia) need more attention. Ependymal cells, on the other hand, can continue to be safely ignored until further notice.

3) "Genes and Behavior". Good chapter. The section on multigenic traits at the end is very nicely done, summarizing the debate that has been raging over the past decade for each disease about whether there are rare variants with large effects or common variants with small effects. Also does a good job of explaining the concordance of psychiatric diseases among relatives (e.g., fraternal vs identical twins) and what it implies.

4) "The Cells of the Nervous System." This chapter tells us that there are about 100 types of neurons, but doesn't a) tell us why or b) point to a list that actually enumerates them. Also, it continues to propagate the neuron-centric bias.

5) "Ion Channels." Nice chapter on electrophysiology, and does a particularly good job of referencing future chapters and presenting examples as stepping stones for more general principles. One unsolicited suggestion: the fact that Na, Mg, K, and Ca are the major cations used seems arbitrary -- it's like, what's up with that, nature? But once you look at a periodic table this becomes way less arbitrary, because they're all right next to one another. So, I suggest that they include a periodic table as a sub-figure in the 6th Ed.

6) "Membrane Potential." Lots of vocabulary; a necessary chapter but not going to blow anyone away. Assumes you know some basic chemistry, like equilibrium vs steady state.

7) "The Action Potential." Gets the history right, e.g. correctly emphasizing Cole and Curtis's classic experiment correlating the AP to an increase in membrane conductance. Explains the key concept of positive feedback in voltage-gated sodium channel opening well. Could have used more I-V plots.

8) "Synaptic Transmission." Table 8.1 has a nice comparison of gap junctions vs synapses. More information in the book (e.g., different types of ion channels) should be summarized in this format.

9) "Nerve-Muscle Synapse." Could have had slightly more on what the actually muscle does with the potential generated at the NMJ. Also, I would have liked a summary table comparing NMJ to CNS synapse properties, to sort out the differences and similarities.

10) "Synaptic Integration." One of the best chapters, with three money figures: a) Figure 10-4 is a nice way of showing the differences between AMPA and NMDA receptors, b) Figure 10-11 shows nicely how EPSPs and IPSPs can sum linearly, an example of how neurons integrate signals, and c) Figure 10-14 shows why time and length constants matter. It explains the concept of synaptic democracy but doesn't actually say the term -- why not? More people need to be thinking about synaptic democracy.

11) "Modulation of Synaptic Transmission." Kind of a boring chapter -- not enough induction from examples to principles for me. I s'pose some of these pathways, like GPCRs and RTKs are just essential to know. Small aside, a couple of typos in the Kindle edition where beta is mistranscribed as alpha -- I saw it twice so it probably happened in an automated process.

12) "Transmitter Release." Another really nice chapter, describing very fundamental processes at the pre-synaptic terminal. Cooperativity of calcium binding to synaptotagmin is one of the most interesting concepts in the book, reminiscent of the oxygen-hemoglobin binding curve in physiology. Could have expanded upon it further.

13) "Neurotransmitters." Too much focus on the chemistry and the names, not enough focus on the techniques, diversity of neurotransmitters, and history. Also, the four criteria for a molecule to be considered an NT doesn't seem all that canonical, given that others sources seem to differ. Granted, they do discuss the imprecision of the definition. Finally, astrocytes could have been discussed more w/r/t NT reuptake and recycling.

14) "Diseases of the Nerve and Motor Unit." Clinical chapter, almost seems out of place given the basic focus of most of the rest of the nearby chapters. Not very conceptual.

15) "CNS Organization." Lots of anatomy. Why do they say that there are five special senses (touch, vision, hearing, taste, smell)? They can't mean the anatomical definition because that would exclude touch, but they also can't mean all the senses because clearly there are more, like proprioception and vestibular senses. In chapter 21 the authors are much more sensible about this.

16) "Organization of Perception and Movement." Basic overview of sensory and motor systems.

17) "Internal Representations." Lots about sensory maps and their plasticity, which is well explained. Then some about consciousness, which is just so hard to talk about precisely. A nice effort, though.

18) "Organization of Cognition". A fairly comprehensive chapter and a lot of the material on cortical organization is essential. In general I found the discussion of the lesion studies to be somewhat wanting insofar as they were too qualitative; i.e., we are told that a "lesion" in X region leads to Y consequence, without a discussion of the probability A that this will occur, the dependence on the size of the lesion B, and/or the other possible consequences C and D.

19) "Cognitive Premotor Systems." Fairly high-level overview of motor planning regions, which overall seems well put together. One quibble: although it is an attractive hypothesis, in my view mirror neurons in F5 of the inferior frontal gyrus probably do not mediate action understanding; for more on this, see Greg Hickok's 2009 critique.

20) "Functional Imaging." Basic intro to fMRI, PET, and DTI and some relevant results.

21) "Sensory Coding." A nice, quantitative overview of sensory systems. Also contains some subversive writing that demands certain tasks of you as a reader, which makes the experience much more enriching. Recommended.

22) "Somatosensory System." Figure 22-4 has nice models of possible ways that mechanoreceptors could work. Lateral inhibition is a very basic concept and it could have been explained in a diagram of its own.

23) "Touch." Two-point discrimination is explained well and is a cool concept. There is maybe slightly too much detail about S1 subregions than is necessary, especially seeing as the principles themselves (e.g., specificity, bottom-up processing) were not greatly enriched from these details.

24) "Pain." Nice chapter, with cool concepts like gate theory. Delves into a channel level understanding and neuropeptides well. One nit is that referred pain is an important phenomenon and deserved more attention, in my view.

25) "Visual Processing Summary." Probably most people could just read this (and not the subsequent four chapters) and know more than visual neuroscience than they ever realistically intended to.

26) "The Retina." I would have liked to see this chapter discuss artificial retinas, or even better, frame the discussion in terms of how you would make one. Figure 26-13B is cool and looking at it is a nice way to check whether you understand the concept of a receptive field at a low enough level.

27) "Intermediate Visual Processing." Classic visual system material, including explanations of illusions and what they tell us about how the system is working. Hardcore fans only.

28) "High-Level Visual Processing." Section on how sensory experience of an object in a visual field (more of a bottom-up process) and recall of that same image (more of a top-down process) rely on similar representations in the inferior temporal cortex is worth the price of admission.

29) "Visual Processing and Action." One key insight from this chapter is that the motor system likely sends a copy of its planned movement to the parietal system so that the visual field can remain constant despite the ubiquitous presence of saccades.

30) "The Inner Ear." Nicely explained chapter with good diagrams. I liked that they explained how hearing aids worked -- it was a good way to apply the principles one learns earlier in the chapter.

31) "Auditory CNS." I focused on the sections related to the functions of the MSO and LSO, and these were nice. Also, the section on echolocation in insectivorous bats is so cool.

32) "Smell and Taste." Both brief, mainly focusing on the receptor level. In my view, once you've read about one GPCR taste receptor type, you've kind of read about them all. Miraculin, the protein responsible for flavor tripping, should have gotten some play when discussing the sweet receptor.

33) "Movement Organization." I liked the section of speed vs accuracy trade-offs as described by Fitt's law. Also the section on how prediction compensates for delayed sensorimotor feedback is interesting and seems relevant to sports.

34) "The Motor Unit." Figure 34-14 is a very nice example of agonist-antagonist action at a joint, maybe the best I've seen. The section on the sarcomere brought back bad memories; is it really necessary in a neuro text?

35) "Spinal Reflexes." Pretty technical chapter -- these are difficult concepts which require that you expend some APs in thinking about them. Nicely explains the concept of the muscle spindle, the 1a fibers that innervate it, and why you need to couple a-MN activation to g-MN activation to sustain spindle tension.

36) "Locomotion." Hammers in the idea that complex motor patterns are a) programmed at a high level and b) involve alternating contraction of flexors and extensors. Not sure it needed its own chapter, but locomotion itself is a fascinating phenomena and obviously one that has vexed philosophers throughout the ages.

37) "Motor Cortex." The topographically organized motor maps are probably the most interesting part of this chapter.

38) "Parietal and Premotor Cortex." The text at the beginning about having goals, maintaining them, developing possible strategies to achieve them, and then executing actions to do carry out one (or more) of those strategies, were awesome and very pro-rationality. I felt a sense of kindred-spiritedness with the authors. Box 38-1 was a bit vague, and included the words "emergent dynamic", which should just not be put next to one another, ever. Also, some of the descriptions of experiments done to determine findings seemed too long. Finally, the talk of mirror neurons did not appear to be complementary to that discussed in Chapter 19.

39) "Control of Gaze." Figure 39-3 is a beautiful explanation of a phenomenon I spent many, many hours puzzled about when I was much younger, and it ought to be included in every elementary school as a part of the "This is How Your Body Works" class. All in all I think this section is explained more clearly (although it might take longer) than in Drake's *Gray's Anatomy*.

40) "Vestibular System." Kind of a clinical chapter. Section showing the cerebellar feedback onto the vestibular-ocular reflex, and how this needs to be dynamic in the presence of eyeglasses, for example, was particularly well-done.

41) "Posture." Short-ish chapter that makes some useful points about body sway and the maintenance of center of mass. Not very conceptual, though.

42) "Cerebellum." Solid chapter, with a good mix of anatomical and cellular facts and speculations, noted as such, about why things might be set-up that way. The repeated motif in the cerebellum of parallel fiber and climbing fiber innervating Purkinje cells is deeply instilled in the canon of neuroscience.

43) "Basal Ganglia." The "rate-model" of direct and indirect BG function is highly influential, so I think the authors should have spent more time, and maybe a couple of diagrams, explaining precisely what is better about the alternative models.

44) "Genetics of Neurodegeneration." Clinical chapter. A sobering reminder that even though we can know much about a disease, like we do for Huntington's, that alone won't necessarily translate to acceptable treatments.

45) "Direct Brain Stem Functions." The clinical nerve discussion is mostly of interest clinically. Melanospin-containing RGCs deserve more love, they are fascinating and important to the everyman w/r/t minimizing blue-shifted light at night.

46) "Modulatory Brain Stem Functions." Discusses a wide breadth of approaches to the brain stem including connectivity, ion channels, imaging, and clinical relevance. Maybe slightly too ambitious.

47) "The Autonomic NS." In general this is an important topic and probably should be supplemented by material elsewhere if you are at all interested in physiology. The stuff on LHRH was interesting as a model system for neuropeptides. I might have liked to see more on the enteric nervous system.

48) "Emotions." I'm surprised this wasn't a longer chapter given all the work that has been done on the amygdala over the past decade. Figure 48-6A/B is useful as a model for how conditioning changes single cell activity.

49) "Homeostasis and Motivation." I was kind of bored by the osmolarity sensing pathway, in part because I had already learned a lot of it in physiology. The leptin, agouti-related peptide, ghrelin, and cholecytsokinin pathways are very important to health today -- we all can hope they will be drawn upon to develop some good therapies for obesity. Addiction related stuff was dopamine-heavy but explained the concepts well.

50) "Seizures." Pretty clinical chapter, although an atypically conceptual one; also useful as a mini-intro to EEG.

51) "Sleep." We spend so much of our time sleeping and know so little about it that reading this type of material is always interesting. Trigger warning, I do not recommend reading it before you yourself go to sleep, because reading about the disorders might prime you to see them in yourself. Fig 51-2 could profitably be memorized. I would have liked to see a figure describing the relationships of the transcriptional oscillators -- text is too confusing for those kinds of loopy relationships.

52) "Patterning the CNS." I've always found studying neurodevelopment to be mostly about memorizing the alphabet soup -- Hox, Wnt, BMP, etc. At least the images are colorful. Figure 52-17 is a cool example of plasticity; it shows how A1 can be remapped to look like V1 if the MGN gets input from the retina instead of the inferior colliculus.

53) "Neuron Growth." I found the material in the second half of the chapter, on NT plasticity and neurotrophin signaling, to be way more interesting and relevant than that of the first half. To be fair, Figure 53-7 is really cool and shows why nuclear translocation is important in radial migration and why certain related mutations lead to defects in neurodevelopment.

54) "Axon Growth." Some classic neuroscience topics here, like Sherry's frog eye inversion experiment, growth cones, and midline crossing. For the last topic, the robo3 vs robo1/2 expression is a useful but somewhat challenging concept and deserved its own part of a figure.

55) "Synapse Formation." A basic and essential neuro chapter, although it focused maybe slightly too much on the NMJ, which might be different from some of the CNS synapses most readers probably care more about. I mean, each skemcle has more than one nuclei, making its transcriptional patterns just weird.

56) "Synaptic Refinement." Most of this chapter uses ocular dominance columns as a model system for studying synapses. That's useful, but so much of today's work on synapses relies on techniques like two photon microscopy and NT uncaging that I wish more general principles had also been discussed. Sections on neurexin and neureglin were nice, and Figure 55-17 is cool, but then at the end they said that those two adhesion molecules might not actually be that important in vivo and I was a bit let down.

57) "Repairing CNS Damage." Awesome chapter on axon degeneration and iPSCs, seems very modern and hopefully progress here will be plentiful before the 6th edition. Could have gone more into detail about the neural stem cell niche, e.g. the role of ependymal cells there. Myelin-neuron interactions sections were good.

58) "Sexual Dimorphism." This chapter could have gotten *really* clinical but they did a good job of staying general; Figure 58-5 is a good example of this. One thing that slightly put me off was the sentence at the end of the introduction. Where is the evidence that our predecessors were really constrained by the simplistic view that genes and experiences acted independently of one another? I ask because we often paint past thinkers as more to make ourselves look more nuanced, and it's dangerous.

59) "Aging." Really this chapter is on Alzheimer's. A bit amyloid beta heavy for my taste, but I'm probably biased.

60) "Language." High-level chapter; most of the neuro relies on lesion and imaging studies.

61) "Processing Disorders." Fairly basic chapter. The Libet experiment is introduced and explained for the third time. Figure 61-10 is amazing, showing the difference in brain activity in the parahippocampus place area and fusiform face area when people see and think about a face or a house.

62) "Schizophrenia." Short chapter. Clearly this is an important disorder and deserves its own section. I found myself wondering how well some of the findings, such as the decreased dlPFC spine density in Fig 62-4, have been replicated?

63) "Mood and Anxiety Disorders." Has lots of nice figures showing where various drugs are believed to act. At times I found myself wondering, where is the evidence of efficacy? But upon reflection this is beyond the scope of their introductory chapter. Seems slightly much for the authors to assert that ketamine itself is not likely be a successful antidepressant; who can say a priori where the trade-off of some amount of dissociative symptoms vs rapid improvement in depressive symptoms will fall for a particular patient?

64) "Neurodevelopmental Disorders." This is a well-written chapter, using plain English to describe what happens in autism and other developmental disorders. Just barely missed the new DSM-V, which would have affected some of what they wrote.

65) "Learning and Memory." Essential reading -- different types of memory defects, basic and important conditioning paradigms, and a lot of their neurological substrates.

66) "Cellular Memory Storage." Another banger. Lots on Aplysia, which of course is Kandel's classic muse, and in particular learning mechanisms involved in the gill-withdrawal reflex. Fig 66-13 shows amygdala learning electrophysiology at the local field potential level. Fig 66-16 is also really cool. To me it felt a little CREB-heavy, I really wish there were maybe one more example of a transcription factor and then we could induct some principles, but maybe this is more a critique of the field (and really, the funding environment) than the textbook.

67) "The PFC and Hippocampus." Nice chapter to finish on -- they save a lot of cool stuff for the end. Gives nice examples of how LTP relies on a family of processes that are specific to each synapse and tend to covary across brain regions. One nit is that the text focuses a little too much on PKM-z, especially given that a paper came out within the past year since the text was published that largely refutes its role in long-term LTP. Still, Fig 67-9 is a really nice diagram, and Fig 67-16 showing remapping of place field formation with and without LTP, is beautiful.