Ontogenetic Expression of Dopamine-Related Transcription Factors and Tyrosine Hydroxylase in Prenatally Stressed Rats

Abstract

The development of the central nervous system can be permanently affected by insults received during the perinatal period, predisposing the organism to long-term behavioral and neurochemical abnormalities. Rats exposed to different types of stress during the last week of gestation produce offspring that show several alterations, many of which have been attributed to changes in dopamine (DA) neurotransmission that could serve as the neurochemical basis for the development of neuropsychiatric disorders. Employing an immunocytochemical approach, we studied the expression levels of two transcription factors Nurr1 and Pitx3 which are expressed at critical moments of DA neurons differentiation as well as the expression of the rate limiting enzyme in DA synthesis, tyrosine hydroxylase (TH) in mesencephalic areas of the brains of prenatally stressed (PS) offspring at different postnatal ages. Main results show that stress exerted to the gestant mother produces permanent effect in the ontogenetic expression of key factors related to the DA metabolism mainly in the ventral tegmental area (VTA) of the mesencephalon. The immunocytochemical expression of the transcription factor Nurr1 shows an increase at postnatal days (PNDs) 7, 28, and 60 whereas Pitx3 shows a decrease at PND 28 and an increase at 60 PND. The rate limiting step in DA synthesis, the enzyme TH shows a decrease at PND 7 to reach control levels at PNDs 28 and 60. The increase of TFs might be up-regulating TH in order to restore DA levels that were previously seen to be normal before puberty. The area selectivity of the increase of the TFs toward VTA and the mesolimbic pathway indicates that an insult received during the prenatal period will exert mainly motivational, emotional, and reward behavior impairments in the adult life.

Differential neuronal changes in medial prefrontal cortex, basolateral amygdala and nucleus accumbens after postweaning social isolation

“…The number (19,730 ± 2,442.7 TH-positive VTA neurons, unilateral count) is close to previous findings in adult male Sprague-Dawley (SD) rats (Nair-Roberts et al 2008;Johnson et al 2010). Some DA-related transcription factors and number of TH-positive neurons are sensitive to prenatal stress and maternal malnutrition (Katunar et al 2009;Katunar et al 2010;Vucetic et al 2010), indicating the critical time window for the development of midbrain DA neuron is in the prenatal period (Meyer and Feldon 2009). The number and density of VTA TH-positive neurons are therefore not responsive to postweaning life events.…”

Nur transcription factors in stress and addiction

“…Predator stress increases Nur77 mRNA in prelimbic, infralimbic and, ventral and lateral orbital prefrontal cortexes (Schiltz et al, 2007). Nurr1 expression increases while TH decreases at postnatal day 7 in the VTA of prenatally stressed offspring, which suggest a possible compensatory mechanism that may play Nurr1 to counteract the observed reduction of dopamine levels (Katunar et al, 2009, 2010). In addition, dopamine content decreases within the PFC and midbrain of rats subjected to forced swim test, meanwhile Nurr1 expression increases in the same brain areas (Rojas et al, 2010) supporting a role for Nurr1 counteracting the decrease of dopamine content.…”

“…In contrast, in the ventral region of the BNST, we observed a higher number of cells expressing Nur77 after repeated immobilization stress compared with acute stress (Campos-Melo et al, 2011). Interestingly, the data of the group of Marta Antonelli (Katunar et al, 2010) suggest that Nurr1 may be the transcription factor setting up the new parameters of the dopamine system after prenatal stress. Using prenatal restraint stress, they showed that Nurr1 is permanently higher in the VTA, but not in the SN, in the offspring of stressed mothers.…”

Prenatal stress: Role in psychotic and depressive diseases

“…Studies have demonstrated that prenatal stress exposure in rats does, indeed, lead to enhancement of the subcortical dopamine system that can be observed by directly measuring dopamine turnover or output (Alonso et al 1994; Fride and Weinstock 1988; Silvagni et al 2008). The increase in dopaminergic activity may be the consequence of complex changes in the ventral tegmental area dopamine-producing cells following prenatal stress (Katunar et al 2010). Behavioral assays of locomotor activity under either baseline conditions or following psychostimulant treatment can be used to infer subcortical dopamine activity, and there appears to be good agreement about enhanced responsiveness of the subcortical dopamine system involved in regulating locomotor activity (Henry et al 1995; Koenig et al 2005).…”