Developmental pathway genes and neural plasticity underlying emotional learning and stress-related disorders.

The manipulation of neural plasticity as a means of intervening in the onset and progression of stress-related disorders retains its appeal for many researchers, despite our limited success in translating such interventions from the laboratory to the clinic. Given the challenges of identifying individual genetic variants that confer increased risk for illnesses like depression and post-traumatic stress disorder, some have turned their attention instead to focusing on so-called "master regulators" of plasticity that may provide a means of controlling these potentially impaired processes in psychiatric illnesses. The mammalian homolog of Tailless (TLX), Wnt, and the homeoprotein Otx2 have all been proposed to constitute master regulators of different forms of plasticity which have, in turn, each been implicated in learning and stress-related disorders. In the present review, we provide an overview of the changing distribution of these genes and their roles both during development and in the adult brain. We further discuss how their distinct expression profiles provide clues as to their function, and may inform their suitability as candidate drug targets in the treatment of psychiatric disorders.

Increased doublecortin (DCX) expression and incidence of DCX-immunoreactive multipolar cells in the subventricular zone-olfactory bulb system of suicides.

Postmortem studies have confirmed the occurrence of adult hippocampal neurogenesis in humans and implicated this process in antidepressant response, yet neurogenesis in other regions remains to be examined in the context of depression. Here we assess the extent of subventricular zone-olfactory bulb (SVZ-OB) neurogenesis in adult humans having died by suicide. Protein expression of proliferative and neurogenic markers Sox2, proliferating cell nuclear antigen, and doublecortin (DCX) were examined in postmortem SVZ and OB samples from depressed suicides and matched sudden-death controls. In the SVZ, DCX-immunoreactive (IR) cells displayed phenotypes typical of progenitors, whereas in the olfactory tract (OT), they were multipolar with variable size and morphologies suggestive of differentiating cells. DCX expression was significantly increased in the OB of suicides, whereas SVZ DCX expression was higher among unmedicated, but not antidepressant-treated, suicides. Although very few DCX-IR cells were present in the control OT, they were considerably more common in suicides and correlated with OB DCX levels. Suicides also displayed higher DCX-IR process volumes. These results support the notion that OB neurogenesis is minimal in adult humans. They further raise the possibility that the differentiation and migration of SVZ-derived neuroblasts may be altered in unmedicated suicides, leading to an accumulation of ectopically differentiating cells in the OT. Normal SVZ DCX expression among suicides receiving antidepressants suggests a potentially novel mode of action of antidepressant medication. Given the modest group sizes and rarity of DCX-IR cells assessed here, a larger-scale characterization will be required before firm conclusions can be made regarding the identity of these cells.

Amygdalar expression of proteins associated with neuroplasticity in major depression and suicide.

INTRODUCTION: Doublecortin (DCX) and polysialilated neural cell adhesion molecule (PSA-NCAM), two proteins associated with immature neuronal phenotypes and elevated neuroplasticity in the adult brain, have recently been identified in the mammalian amygdala, and evidence from rodent studies suggests that stress may modify their expression in this brain region. The purpose of the present study was to investigate whether the expression of proteins involved in neuroplasticity is altered in the amygdala of individuals with depression. METHODS: Basolateral amygdala (BLA) and central amygdala (CeA) postmortem human brain samples were collected from individuals with a history of depression (n = 22 and 25, respectively) and psychiatrically healthy controls (CTRL; n = 14). Proteins associated with neuroplasticity were quantified using Western blotting. RESULTS: Immunoblots revealed that depressed subjects displayed increased expression of DCX (p = 0.033) and PSA-NCAM (p = 0.027) in the BLA as compared to CTRLs. Subsequent analyses revealed that this effect was due primarily to a subset of depressed subjects who had not died by suicide (DNS). DNS subjects displayed higher DCX than CTRLs (p < 0.001) and depressed suicides (p = 0.001), and higher PSA-NCAM than CTRLs (p = 0.007). Conversely, within the CeA, DNS subjects displayed a tendency toward lower DCX expression than CTRLs (p = 0.062), and higher BDNF levels than DS subjects (p = 0.045). CONCLUSION: These results suggest that the BLA and CeA display contrasting patterns of neuroplasticity in depression, and that greater impairment of amygdalar neuroplasticity may be associated with increased risk of suicide.

Callosal oligodendrocyte number in postpartum Sprague-Dawley rats.

Prolactin (PRL), an anterior pituitary hormone with neurogenic properties associated with pregnancy, has been implicated in oligodendrocyte proliferation during gestation, contributing to increased myelination in the maternal brain. However, PRL is elevated during lactation as well, suggesting that the postpartum (PP) period may contribute to additional gliogenesis in lactating females. In the present study, we assessed oligodendrocyte number in the corpus callosum (CC) of female Sprague-Dawley rats near the end of gestation, and at two weeks postpartum in both lactating and non-lactating dams, and in virgins. Though pregnant females did not differ significantly from any other group, lactating females had significantly more oligodendrocytes in the CC than virgins (p=.01), and in medial regions of the CC than non-lactating dams (p<.02). Oligodendrocyte number in the CC of pregnant and PP females correlated positively with the number of pups in their litter (r(2)=.68, p<.005). These results suggest that the gestational period contributes to oligodendrocyte proliferation or survival, likely mediated by an endocrine hormone whose concentration varies with the size of the litter. The PP period also contributes to increases in CC oligodendrocyte number, though it is unclear whether endocrine influences and/or pup-interaction underlie the differences in myelination between lactating and non-lactating groups. Further investigation is required in order to confirm whether the effects observed are mediated by members of the PRL-family, experience, and/or other gestational/PP endocrine hormones.