This Week in The Journal
- Teresa Esch, Ph.D.
Doublecortin-Expressing Neurons in Adult Sheep Brain
Matteo Piumatti, Ottavia Palazzo, Chiara La Rosa, Paola Crociara, Roberta Parolisi, et al.
(see pages 826–842)
Although most neurons in mammalian brains are born before birth, regions of neurogenesis persist throughout life in the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle. Neurons born in these regions are incorporated into existing neural circuits in the dentate gyrus or olfactory bulb of some species, and they might contribute to circuit plasticity underlying new learning. But if adult-born neurons are important for encoding new memories, why aren't they present in all areas that store memories? One possibility is that these areas contain a population of prenatally born neurons that remain in an immature state until they are needed for circuit plasticity later in life. This hypothesis is supported by the presence of neurons expressing markers of immature neurons—particularly doublecortin and an immature, polysialylated form of neural cell adhesion molecule (PSA-NCAM)—in cortical layer II of several species. Piumatti, Palazzo, et al. identified such doublecortin-expressing neurons in adult sheep brains. These neurons were present throughout the anteroposterior and dorsoventral extents of the cortex, as well as in the external capsule, claustrum, and amygdala. Importantly, no doublecortin-expressing neurons in these areas were labeled with the proliferation marker Ki-67 or BrdU.
Doublecortin-expressing neurons (brown), some of which have complex dendritic arbors, are found in layer II of sheep cortex. See Piumatti, Palazzo, et al. for details.
Most doublecortin-expressing neurons in adult brain were small, with bipolar morphologies, but some were larger with complex dendritic arbors. Although some of the neurons expressed PSA-NCAM, others expressed NeuN or HuC/D, two markers of mature neurons. Notably, NeuN was only found in doublecortin-expressing neurons that had more developed dendritic arbors. In contrast, smaller doublecortin-expressing cortical neurons often expressed Tbr1, a transcription factor found in developing glutamatergic cortical neurons and downregulated in upper-layer neurons as they mature. Finally, the number and density of doublecortin-expressing cortical neurons was approximately four times higher in 1-week-old lambs than in adult sheep.
These data suggest that immature-looking neurons in the cortex of adult sheep are slowly maturing glutamatergic neurons. These neurons could plausibly play a role in plasticity similar to that of adult-born granule cells in the dentate gyrus. Alternatively, they might replace damaged neurons. Future work should investigate whether enriched environments or brain injuries affect the number of these neurons and determine whether selectively killing doublecortin-expressing neurons in adults affects cognitive processes.
Role of Histone Dimethyltransferase in Cocaine Seeking
Ethan M. Anderson, Erin B. Larson, Daniel Guzman, Anne Marie Wissman, Rachael L. Neve, et al.
(see pages 803–813)
Cocaine exposure alters neural circuits involved in reward and motivation, thus promoting future drug seeking and addiction. Cocaine-induced changes include post-translational modification of histone proteins that organize DNA, causing long-term changes in gene expression. For example, repeated cocaine administration decreases dimethylation of lysine 9 of histone H3 (H3K9me2) in the nucleus accumbens (NAc) of mice by reducing expression of the lysine dimethyltransferase G9a. Countering this change by overexpressing G9a in the NAc reduced the ability of cocaine to produce conditioned place preference and prevented cocaine-induced increases in spine density (Maze et al. 2010 Science 327:213). Thus, cocaine-induced reductions in G9a might underlie changes in neural circuitry that promote future drug seeking.
Anderson et al. tested this hypothesis by asking whether overexpression of G9a in the NAc reduced cocaine self-administration in rats. Surprisingly, it did not. In fact, lower doses of cocaine were required to maintain lever pressing in G9a-overexpressing rats than in controls, and G9a-overexpressing rats were willing to press a lever more times for a single cocaine injection. These effects occurred regardless of whether G9a was overexpressed during initial training or during testing. Furthermore, after rats were denied cocaine for 2 weeks and G9a levels returned to normal, delivery of intermittent foot shocks reinstated cocaine seeking to a greater extent in rats that had overexpressed G9a than in controls. Finally, G9a overexpression increased behaviors thought to model anxiety, including biting, scratching, and diarrhea, as well as avoidance of open arms of an elevated plus maze and increased latency to enter the center of an open field.
These and previous results suggest that changes in gene expression resulting from cocaine-induced reductions in histone dimethylation by G9a can enhance or inhibit cocaine seeking under different circumstances. Some of these differences might depend on the type of stress experienced, and some might depend on whether cocaine is administered acutely by the experimenter, as in conditioned place preference, or chronically and voluntarily by operant lever pressing, as in the study by Anderson et al. Such differences highlight both the complexity of motivational processes driving drug seeking and the difficulty in assigning a single role to enzymes that regulate expression of numerous genes.
