Human postmortem studies have demonstrated that fibroblast growth factor-2 (FGF2) expression is decreased in the brain of depressed individuals. It remained unclear, however, whether this is a consequence of the illness or whether FGF2 plays a primary role in the control of mood and emotions. In this series of studies, we first ask whether endogenous FGF2 expression correlates with spontaneous anxiety, a trait associated with vulnerability to severe mood disorders in humans. This is tested in two genetically distinct groups of rats selectively bred to differ dramatically in their response to novelty and anxiety-provoking conditions (HRs ϭ low anxiety/high response to novelty vs LRs ϭ high anxiety/low response to novelty). We demonstrate that high-anxiety LRs have significantly lower levels of hippocampal FGF2 mRNA relative to low-anxiety HRs. We then demonstrate that FGF2 expression is modifiable by environmental factors that alter anxiety-thus, environmental complexity reduces anxiety behavior and induces FGF2 expression in hippocampus, particularly in highanxiety LRs. Finally, we directly test the role of FGF2 as an anxiolytic and show that a 3 week treatment regimen of peripherally administered FGF2 is highly effective at blunting anxiety behavior, specifically in high-anxiety LRs. This treatment is accompanied by an increase in survival of adult-born hippocampal cells, both neurons and astrocytes, most clearly in LRs. These findings implicate hippocampal FGF2 as a central integrator of genetic and environmental factors that modify anxiety, point to hippocampal neurogenesis and gliogenesis as key in this modulation, and underscore FGF2's potential as a new target for treatment of depression and anxiety disorders.
Hippocampal plasticity (e.g., neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and BrdU for older cells born prior to sensitization. Results show that: (1) bHRs exhibited greater psychomotor response to cocaine than bLRs. (2) Acute cocaine did not alter cell proliferation in bLR/bHR rats. (3) Chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence. (4) Neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype. (5) Cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine. (6) Cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR versus bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization.
The neurobiological bases of increased vulnerability to substance abuse remain obscure. We report here that rats that were selectively bred for greater drug-seeking behavior exhibited higher levels of FGF2 gene expression. We then asked whether a single FGF2 administration (20ng/g, s.c.) on postnatal day 2 (PND2) can have a lifelong impact on drug-taking behavior, spatial and appetitive learning and the dopaminergic system. Indeed, early life FGF2 enhanced the acquisition of cocaine self-administration in adulthood. However, early life FGF2 did not alter spatial or operant learning in adulthood. Furthermore, early life FGF2 did not alter gene expression in the dopaminergic system in adulthood. These results suggest that elevated levels of FGF2 may lead to increased drug-taking behavior without altering learning. Thus, FGF2 may be an antecedent of vulnerability for drug-taking behavior and may provide clues to novel therapeutic approaches for the treatment of addiction.
This chapter provides a broad overview of the state of current research in the genetics of the major anxiety disorders. In addition tosummarizing findings regarding the individual clinical syndromes, we present data supporting genetic hypotheses that explain their comorbidity with each other and with related phenotypessuch as anxious personality traits and depression. We conceptually divide the chapter into three main sections based upon methodology: (1) genetic epidemiology of adult and pediatric anxiety (twin and family studies), (2) human molecular genetics (linkage and association), and (3) animal genetic models. These approaches provide complimentary and concurring evidence supporting the genetic basis underlying anxiety disorders as well as preliminary insight into the genetic mechanisms involved in their expression.
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