This would then lead to the ability of the fear memory to be weakened, rendering it easier to extinguish. Finally, the effects of FGF2 on fear conditioning exhibit site-specificity. When it was administered into the basolateral amygdala, FGF2 enhanced extinction and reduced renewal and reinstatement similar to the peripheral injection findings in adult rats. In summary, FGF2 plays a role in fear conditioning, FXR agonist extinction, and reinstatement, as well as reacquisition and re-extinction. Moreover, FGF2 has both developmental and long-term effects on the memory of fearful events. Glutamate receptors in the amygdala may

also play an important role in the functions of FGF2. Thus, the ability of FGF2 to modulate affective behavior includes both spontaneous anxiety as well as conditioned emotional responses, all of which may contribute to long-lasting negative affect as seen in mood disorders. This body of work underscores the role of FGF2 at the interface of affect, learning, and memory. The FGF system plays a role in the cellular Selleck MDV3100 and behavioral neuroadaptations to stress. As will be discussed below, these adaptations take place across a wide range of developmental time points ranging from embryonic to adulthood. Moreover, the impact of stress on FGF expression appears to be dynamic within a given developmental window. In general, neuroprotective

molecules such as FGF2 are induced by short-term stress or exposure to glucocorticoids, and these FGFs may play an important role in coping with acute stress. Their Calpain induction may also buffer against the potential negative impact of high steroid levels (Molteni et al., 2001). However, with repeated or sustained stress, this induction is not sustained, and the expression

of the protective FGF molecules and receptors is in fact reduced relative to control levels, likely contributing to the long-term negative sequelae of chronic stress. Early animal work by the Fuxe laboratory demonstrated that acute and subchronic corticosterone administration can increase FGF2 protein levels in the substantia nigra (Chadi et al., 1993). This induction is indeed consistent with a neuroprotective response, as FGF2 can protect neurons from excitotoxic, metabolic, and oxidative insults (Mark et al., 1997). Similarly, FGF9 can protect dopaminergic neurons from MPTP-induced cell death (Huang et al., 2009). In contrast to its induction by acute glucocorticoids in adulthood, FGF2 is typically reduced by early life stress, and this effect is manifested into adulthood. Embryonic stress has been reported to decrease FGF2 expression in the adult hippocampus (Molteni et al., 2001). This manipulation also changed the response of the adult brain to subsequent stress or to corticosterone administration. Furthermore, perinatal anoxia decreased basal levels of FGF2 in the ventral tegmental area in adulthood while simultaneously enhancing the response of FGF2 to an acute stressor (Flores et al., 2002).