Neurogenesis decreases during brain maturation from adolescence to adulthood

Abstract

Adolescence is an important stage of brain development. Recent studies have indicated that neurogenesis in the brain occurs throughout life prompting comparisons of adolescent and adult neurogenesis. Since insulin-like growth factor 1 (IGF-1) has been implicated in promoting neurogenesis we investigated the levels of neurogenesis in adolescents (PND30) and adults (PND120) using IGF-1 over-expressing mice and IGFBP-1 (IGF binding protein-1) over-expressing mice. Proliferation and differentiation of neuroprogenitors were determined using bromodeoxyuridine (BrdU)- and doublecortin (DCX)-labeling. High levels of neurogenesis were found in both the hippocampal dentate gyrus (DG) and the forebrain subventricular zone (SVZ) of the adolescents as compared with the adults. Both adolescent IGF-1 and IGFBP-1 transgenic mice as well as their wildtype controls have significantly higher expression of BrdU and DCX in the hippocampus and SVZ when compared with their adult counterparts. However, no significant differences on BrdU-labeling were found when either of transgenic mice were compared with their wildtype littermates in both age groups. These studies indicate that adolescent mice have high levels of neurogenesis compared to adults suggesting a dramatic loss of neurogenesis during the transition from adolescence to adulthood. However, the role of IGF-1 during adolescent development is still unclear.

Introduction

Human adolescence is an important stage for both neuro-maturation, particularly in cortical and limbic brain regions, and behavioral maturation, especially in complex learning such as social interaction skills. Adolescence in humans and other vertebrate species is defined by characteristic behaviors that include high levels of risk-taking, high exploration, novelty and sensation seeking, social interaction, high activity and play behaviors that likely promote the acquisition of skills for maturation and independence (Spear, 2000). Adolescence is also characterized by marked changes in hormones and growth factors. The significant neurochemical and neuroanatomical remodeling during this highly plastic postnatal development shapes neuronal networks and behavioral characteristics that persist into adulthood. On one hand, various studies using adolescent rodent models have shown that overproduction of axons and synapses occurs during early puberty and is followed by a rapid pruning later in adolescence (Giedd et al., 1999, Andersen et al., 2000, Andersen and Teicher, 2004), which likely contributes to maturation of the brain and the transition to adult. On the other hand, neurogenesis (generation of new neurons) in forebrain subventricular zone (SZV) and hippocampal dentate gyrus (DG) continues throughout life in both humans and rodents (Kempermann et al., 2003). Therefore, we proposed to determine if neurogenesis changes during the transition from adolescence to adulthood.

Insulin-like growth factor 1 (IGF-1) is an important growth factor during postnatal development known to enhance neurogenesis in developing mice (Aberg et al., 2000). Studies have found that insulin-like growth factor 1 (IGF-1) promotes the survival and proliferation of neuroprogenitor cells postnatally leading to increased neurogenesis and synaptogenesis in both in vitro and in vivo models (Aberg et al., 2000, Anderson et al., 2002, Perez-Martin et al., 2003, Poulsen et al., 2005). Interestingly, exercise-induced enhancement in adult neurogenesis has been suggested to be secondary to increased brain IGF-1 (Ding et al., 2006). During brain development IGF-1 expression occurs in coordination with rapid neuronal growth consistent with a large body of evidence that supports a role for IGF-1 in promoting neuroprogenitor cell proliferation, survival and differentiation in fetal development and during the brain growth spurt that occurs just after birth in humans and rodents (Ye and D'Ercole, 2006). Transgenic mice that over-express IGF-1 exhibit overgrowth of the brain resulting in higher brain weight as compared to the wildtype controls (Ye et al., 1995). In contrast, the transgenic mice that over-express IGF binding protein-1 (IGFBP-1), whose activation inhibits IGF-1 bioactivity, reduces neurogenesis leading to brain growth retardation (Ye et al., 1995). These findings prompted the current investigation of neurogenesis in adolescents and adults using the transgenic mice with over-expression of either heterozygote IGF-1 or IGFBP-1 and their wildtype controls (Wt).

In order to accurately measure the level of neurogenesis, both exogenous mitotic marker bromodeoxyuridine (BrdU) and endogenous neuronal marker doublecortin (DCX) were used in the current study. As a uridine analog, BrdU is incorporated into all proliferating cells shortly after its administration. It is a widely used marker for studying neurogenesis, particularly proliferation of neuroprogenitors as used in this study (Kempermann et al., 1997, Cameron and McKay, 2001, Crews et al., 2004). In addition, DCX is a cytoskeletal protein that expresses transiently in newborn neurons only (Brown et al., 2003) and is a marker of progenitors that are differentiating into neurons. Therefore, we and others use DCX to directly quantify neurogenesis (Brown et al., 2003). As an endogenous marker, DCX can overcome the limitations of bromodeoxyuridine (BrdU) labeling (Palmer et al., 2000, Kuan et al., 2004) and provide an independent validation on progenitors and neurogenesis.