An Instructor's Guide to (Some of) the Most Amazing Papers in Neuroscience.

Although textbooks are still assigned in many undergraduate science courses, it is now not uncommon, even in some of the earliest courses in the curriculum, to supplement texts with primary source readings from the scientific literature. Not only does reading these articles help students develop an understanding of specific course content, it also helps foster an ability to engage with the discipline the way its practitioners do. One challenge with this approach, however, is that it can be difficult for instructors to select appropriate readings on topics outside of their areas of expertise as would be required in a survey course, for example. Here we present a subset of the papers that were offered in response to a request for the "most amazing papers in neuroscience" that appeared on the listserv of the Faculty for Undergraduate Neuroscience (FUN). Each contributor was subsequently asked to describe briefly the content of their recommended papers, their pedagogical value, and the audiences for which these papers are best suited. Our goal is to provide readers with sufficient information to decide whether such articles might be useful in their own classes. It is not our intention that any article within this collection will provide the final word on an area of investigation, nor that this collection will provide the final word for the discipline as a whole. Rather, this article is a collection of papers that have proven themselves valuable in the hands of these particular educators. Indeed, it is our hope that this collection represents the inaugural offering of what will become a regular feature in this journal, so that we can continue to benefit from the diverse expertise of the FUN community.

Synaptic generation of an intracellular retrograde signal requires activation of the tyrosine kinase and mitogen-activated protein kinase signaling cascades in Aplysia.

Cellular changes underlying memory formation can be generated in an activity-dependent manner at specific synapses. Thus an important question concerns the mechanisms by which synaptic signals communicate with the cell body to mediate these cellular changes. A monosynaptic circuit that is enhanced by sensitization in Aplysia is well-suited to study this question because three different subcellular compartments: (i) the sensorimotor SN-MN synapses, (ii) the SN projections to MNs via axonal connections, (iii) the SN cell bodies, can all be manipulated and studied independently. Here, we report that activity-dependent (AD) training in either the entire SN-MN circuit or in only the synaptic compartment, activates MAPK in a temporally and spatially specific pattern. Specifically, we find (i) MAPK activation is first transiently generated at SN-MN synapses during training, (ii) immediately after training MAPK is transiently activated in SN-MN axonal connections and persistently activated in SN cell bodies, and finally, (iii) MAPK is activated in SN cell bodies and SN-MN synapses 1h after training. These data suggest that there is an intracellularly transported retrograde signal generated at the synapse which is later responsible for delayed MAPK activation at SN somata. Finally, we find that this retrograde signal requires activation of tyrosine kinase (TK) and MEK signaling cascades at the synapses.

Temporal phases of activity-dependent plasticity and memory are mediated by compartmentalized routing of MAPK signaling in aplysia sensory neurons.

An activity-dependent form of intermediate memory (AD-ITM) for sensitization is induced in Aplysia by a single tail shock that gives rise to plastic changes (AD-ITF) in tail sensory neurons (SNs) via the interaction of action potential firing in the SN coupled with the release of serotonin in the CNS. Activity-dependent long-term facilitation (AD-LTF, lasting >24hr) requires protein synthesis dependent persistent mitogen-activated protein kinase (MAPK) activation and translocation to the SN nucleus. We now show that the induction of the earlier temporal phase (AD-ITM and AD-ITF), which is translation and transcription independent, requires the activation of a compartmentally distinct novel signaling cascade that links second messengers, MAPK and PKC into a unified pathway within tail SNs. Since both AD-ITM and AD-LTM require MAPK activity, these collective findings suggest that presynaptic SNs route the flow of molecular information to distinct subcellular compartments during the induction of activity-dependent long-lasting memories.

Intermediate-term processes in memory formation.

Neuroscientists have invested considerable effort in attempting to elucidate the molecular mechanisms that mediate short-term and long-term forms of learning and memory. For instance, the discovery of long-term potentiation inspired a field that has produced hundreds of studies examining both early and late forms of long-term potentiation. And at the behavioral level, most neuroscientists investigate either short- or long-term forms of memory or some combination of the two. The general belief that plasticity was restricted to short- and long-term temporal domains lasted for many years because of the apparent continuity of memory and its molecular characterization from one domain to the other. In cellular studies of plasticity, the short-term stage typically lasts in the range of minutes, and requires modification of pre-existing proteins, whereas long-term changes, such as synaptic growth, last for hours to days and require transcription and translation. As both behavioral and cellular studies covered a wider range of temporal domains, from the initiation of brief memory to the expression of long-lasting memory, it was at least tacitly assumed that these studies also captured any intervening domains as well. However, between these two temporal extremes lies a unique form of intermediate-term synaptic plasticity and memory, which mechanistically is a blend of the early and late forms.

A tropomyosin-related kinase B ligand is required for ERK activation, long-term synaptic facilitation, and long-term memory in aplysia.

BDNF, which acts through tropomyosin-related kinase B (TrkB) receptors during mammalian development, also enhances long-term synaptic facilitation (LTF) in adult Aplysia. Because LTF is a substrate for long-term memory (LTM) in Aplysia, we examined the requirement of a secreted TrkB ligand in LTM formation at molecular, synaptic, and behavioral levels. Using an extracellular fusion protein that sequesters secreted TrkB ligands, we show that TrkB function is required for serotonin-induced activation of extracellular signal-regulated kinase, tail nerve shock-induced LTF in the CNS, and tail shock-induced LTM but is not necessary for short-term synaptic facilitation or short-term memory. These results show that a secreted growth factor, acting through a TrkB signaling cascade, is critical for the induction of long-lasting plasticity and memory formation in Aplysia.