Science Guide

This is how we are going to gain genetic control over specific neural populations. I was searching for Pasko Rakic's latest stuff, since he's about to receive his Kavli prize. The same factors that control the trajectory of neuronal differentiation are going to be co-opted in the next few years for our engineering purposes.

fgf8chart, originally uploaded by kaleidoscopikr.

I love how he gives us a little pep talk about having to memorize acronyms at the beginning of his article.

The papers in the Journal of Comparative Neurology used to contain complicated neuroanatomiacal diagrams with acronyms that annoyed molecular biologists, such as, PF (prefrontal cortex) is reciprocally connected with MD (medial dorsal nucleus) and projects to the NS (neostriatum) and PGN (pontine gray nuclei) of the RB (rombencephalon), with the arrows and T-shaped lines indicating, respectively, excitatory and inhibitory influences. Now, molecular biologists have their revenge with such diagrams where FGF8 is connected reciprocally with Sp8, BMPs, WNTs, Emx2, and one way to Foxg1 (Fig. 1). Still, we all have to learn to live with an ever-growing number of acronyms, because it would not be possible, in the limited space available, to explain complex neuronal or molecular interactions without them. The instructive case is the development of the mammalian neocortex that is both bolstered and cursed by its seemingly innumerable dimensions that make it exciting, but also challenging, to understand and investigate.

The most obvious dimensions of analysis include timing, sequence, genesis of phenotypes, columns, layer formation, and evolution of species-specific differences in areal parcellation. The latter of these, the functional area assignments across the cortical landscape, are often ignored in otherwise complex studies for the sake of simplicity. Although the radial unit and inside-out paradigms hold true throughout developing dorsal telencephalon (Rakic,[1988]), the specifics are likely fine-tuned and adjusted in an area-specific fashion from as early as the birth of the preplate (Fukuchi-Shimogori and Grove,[2003]) or even before the onset of neurogenesis (Bystron at al.,[2008]), the essence of the protomap theory (Rakic,[1988]). Ongoing work continues to show pronounced differences in the developmental scheme of neocortex when several unique areas are examined. The manifestations of such areal differences can be as varied as the shorter cell cycle length seen in primate area 17 vs. 18 (Kornack and Rakic,[1998]; Lukaszewicz et al.,[2005]) to the earlier birth of infragranular layers seen in murine area 3 vs. 6 (Polleux et al.,[1997]). The factors controlling this patterning are founded and epitomized in the protomap model (Rakic,[1988]), yet molecular mechanisms underlying this specification remain to be unveiled. An integrated scheme based in genetic suppression as much as in enhancement can generate a complex map from a few landmark centers such as those at the cortical hem and commissural plate (Mallamaci and Stoykova,[2006]).

You can see it playing out in the neuromodulatory systems as well. One hopes that developmental lineage has some relationship to adult function.

Redefining the serotonergic system by genetic lineage

Patricia Jensen, Anna F Farago, Rajeshwar B Awatramani, Michael M Scott, Evan S Deneris & Susan M Dymecki

Central serotonin-producing neurons are heterogeneous—differing in location, morphology, neurotoxin sensitivity and associated clinical disorders—but the underpinnings of this heterogeneity are largely unknown, as are the markers that distinguish physiological subtypes of serotonergic neurons. Here we redefined serotonergic subtypes on the basis of genetic programs that are differentially enacted in progenitor cells. We uncovered a molecular framework for the serotonergic system that, having genetic lineages as its basis, is likely to have physiological relevance and will permit access to genetically defined subtypes for manipulation.

On the other end of the spectrum we have Borhegyi et al 2004 trying to classify interneurons in the medial septum based on firing patterns, phase preference, and parvalbumin staining. Ugh. It's a mess as far as I can see. No classification scheme correlates with any other. Morphology isn't helpful either:

The morphological variables that could be analyzed under the present experimental conditions revealed no correlation between morphological characteristics and firing pattern of neurons. In recent in vitro studies, remarkable physiological heterogeneity of PV-IR or GABAergic (GAD67 expressing) medial septal neurons was found: among GAD67 mRNA-containing GABAergic neurons, different firing modes could be observed (Sotty et al., 2003). In a recent work examining five electrophysiologically identified neuron types in the medial septum the putative PV-IR cells (fast firing and burst firing) could not be clearly distinguished morphologically (Morris et al., 1999). Furthermore, fast spiking, PV-IR neurons were morphologically homogenous, except for their axon terminal type [en passant or basket (Henderson et al., 2004)]. Based on the latter characteristics, two subgroups could be distinguished, but the physiological correlates of this morphological difference were not reported.

Godspeed genetic classification schemes for interneurons!