It really is an embarrassment of riches here at Nature these days, what with so many excellent neuroscience-related studies emerging. Just in the last couple of weeks, we’ve had the following studies:

• Covert learning by a basal ganglia circuit, despite no participating in the behavioral practice.
• Reach and grasp by people with tetraplegia using a neurally-controlled robotic arm.
• A non-transcriptional circadian cycle conserved across all domains of life.
• Identification of mechanisms linking cerebro-vascular integrity to neurodegeneration.
• Metabolic coupling of glia with axons in the long-term maintenance of axonal integrity.

So really, a lot to write about from a science perspective. However, this blog is dedicated to bringing you the editorial back-story, so I wanted to touch on yet another interesting study, published in print today. This new paper offers an opportunity to discuss an important editorial issue: the manuscript appeal process. For more details, you can always read the appropriate section in our guide to authors. But it’s often helpful to follow a particular [successful] example in order to illustrate the process.

Initially, the lab of Bernardo Sabatini submitted the manuscript “Recurrent network activity drives striatal synaptogenesis,” which we found to be interesting since it explored activity-dependent circuit maturation in a brain area other than sensory cortex. They looked at the basal ganglia, which lack the lamination and structure of cortical tissue as well as sensory input. With these nuclei important for not only complex motor behavior, but also reward-based learning, understanding the development of this network is important. Here’s the requisite background:

Excitatory input from the cortex and thalamus enters the basal ganglia through the striatum, where it is locally processed and transformed into two inhibitory, GABAergic outputs called the direct and indirect pathways⁷. Each pathway arises from a distinct class of spatially intermixed medium spiny neurons (MSNs) with differing projections and molecular characteristics⁸. These projection patterns suggest opponent effects on basal ganglia output: direct pathway MSNs form synapses in substantia nigra reticulata (SNr), the basal ganglia output nucleus, whereas indirect pathway MSNs form synapses in globus pallidus, which in turn inhibits the SNr⁹. Because the SNr provides GABAergic inhibition to the thalamus, which subsequently activates cortex through glutamatergic synapses, the interactions of basal ganglia, thalamus and cortex can be simplified as a closed loop, differentially controlled by the direct and indirect pathways (Supplementary Fig. 1). Anatomical evidence supports this model^{10, 11} and the opponent roles of the two pathways on motor behaviour have been recently demonstrated in adult rodents^{12, 13}. In addition, in vivo recordings and circuit tracing indicate that different corticostriatal inputs are processed through segregated, parallel networks^{6, 10, 11, 14}. Given this organization, establishing correct wiring of the cortex-basal ganglia–thalamus circuitry poses a significant developmental challenge, requiring that functional interactions be maintained over polysynaptic networks comprised of mixed inhibitory and excitatory projections.

So how to probe the maturation of these looped pathways? To make the initial observations, Sabatini and colleagues made transgenic mice incapable of releasing GABA from either the direct or indirect pathway in the basal ganglia during early postnatal development. A technical tour-de-force followed to produce the basic result: silencing of the direct pathway led to hypo-innervation of the stratum by excitatory inputs, while silencing of the indirect pathway resulted in the opposite, excitatory hyper-innervation. Therefore, the balance of activity between the direct and indirect pathways dictated the extent of postnatal excitatory innervation in the striatum. Or, to put it more simply, these data demonstrated how this circuit essentially wired itself, with the output controlling the development of the input.

Initially, the referees were encouraging, but found significant technical deficiencies involving the specificity of the genetic methods, amongst other concerns. All the refs had suggestions for important controls and without them. had dampened enthusiasm for publication. Addressing these concerns would be a significant amount of work, but not beyond the scope of an ambitious researcher or beyond the scope of a paper attempting to make new claims about striatal circuit development. Alone, such concerns would have easily persuaded the editors to invite back a revision. However there were other lingering concerns that together with the technical shortcomings soured the mood on this study. The reviewers also raised general novelty issues, since it is well-known from many brain areas that any manipulation of circuits on a gross level can lead to innervation changes. A somewhat broad damnation, but worth considering nonetheless. This criticism also related to the next, namely that to really make a valuable contribution to the competitive field of circuit development, the authors would need to expand this study further, supplying additional data allowing a better understanding of other components within the circuit. For example, exploring how exactly the corticostriatal inputs influence basal ganglia synaptogenesis. It begged the question: do the authors understand the physiology and timing well enough to predict how their manipulations would affect the striatum, not by disrupting the striatum itself, but through control of the descending cortical circuits? Such an extension would indeed be a strong component to the story, but would also represent a commitment to future experimentation. On balance, we rejected the paper, believing that such an extension would be important for the story to remain editorially viable. Simply fixing the technical concerns would not be enough.

The authors, holding a comprehensive “road map” to publication in hand (the reviews) and knowing that they had the capacity to address all concerns, decided to improve the story based on the referees’ recommendations and contacted me months later to gauge interest in a revised manuscript. They had completed an extensive re-analysis of the genetic specificity of their animals, documented the extent of their experimental system’s “leakiness,” added additional transgenic lines to corroborate their previous conclusions and completed the desired extension. The authors manipulated corticostriatal inputs independently of basal ganglia output and observed the same synaptogenic phenotypes across different developmental time windows. With these new data, the authors “closed the loop” of their circuit, demonstrating the validity of the proposed synaptogenic model. With regards to the novelty criticisms, the authors argued that their story went well beyond “gross manipulations” and that this represented the first study exploring synapse development in a region containing multiple nuclei and intermingled circuits. In addition, unlike most circuit activity manipulation studies in sensory cortex, which often involve large-scale disruptions like eye suture or whisker plucking, this study utilized specific genetic targeting to single-out a neuronal subtype for manipulation. We were (editorially) cool with this updated novelty assessment and argument.

Of course, any consideration of a manuscript without an invitation to resubmit would be considered as an appeal of our original decision. Thus, the authors uploaded a new version of the manuscript, along with a rebuttal to the reviewers and an appeal letter to the editors, explaining why further consideration of the study was merited. In this particular case, the rejection had been (bear with me) a “soft hard-rejection.” Many consider a “soft rejection” one in which the journal invites back a revision. A hard rejection is one without review or one after review in which the editor sees no path to publication, even if technical concerns were satisfied (in other words, the editor screwed up on gauging editorial interest and novelty within that community.) A “soft hard-rejection” would fall in between, when an editor could see a place for the conceptual story within the journal, but feels the journey to that point would be too great or beyond the scope of a single manuscript. In my notes on the first version of this paper, I explicitly conveyed to my colleagues that if an extended story ever did return, we would be wise to re-consider.

So if we liked the story, even just a little, why not simply invite back a revision in the first place? Well science is not done in a vacuum and all too often, the complexities of “real-life” interfere with scientific progress. The lead author has found another job and wants to leave the lab ASAP. The mouse colony was infected with a virus and now all of those precious transgenic animals are in quarantine for three months. Maybe it’s time to just get over that hurdle of publication, dedicating the mental energy and experimental effort to the next project. These aren’t editorial choices for those who work for a journal. These are choices to be made by the lab and authors. In cases where there is an extensive amount of work required, more than perhaps we feel is reasonable (meaning the manuscript is only a more modest advance,) we feel it is important to not instill false hope through an invitation of a revision when there is a strong chance that even the revision will fall short of reviewer demands. This may allow the authors an opportunity to ponder the future of the study, free of a mind clouded by the non-guaranteed prospects of publication that an invited revision might offer. After this sober assessment has been made, if the extra 2-6 months of work (or more??) are embraced, upon completion, the appeal process allows the authors back in the door for reconsideration.

Sabatini’s appeal was granted by the editors and the revision was well-received by the reviewers. The end result is essentially what you see now, in press.