Prenatal exposure to fluoxetine modulates emotionality and aversive memory in male and female rat offspring.

During pregnancy, women are prone to depression, for which selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are usually the first-line treatment. However, fluoxetine can cross the placental barrier and affect fetuses, causing changes in serotonin levels early in life. Long-term effects in the brain circuits that control cognitive and emotional behavior are related to early fluoxetine exposure during development. In this study, we aimed to investigate whether fluoxetine exposure (10 mg/kg/day) from the 13th gestational day (GD13) to GD21 may lead to behavioral emotional-cognitive changes in male and female rat offspring approximately 90 days postnatally (~PN90). We have analyzed the performance of individuals in the open field and in the plus-maze discriminative avoidance task, which assesses anxiety and learning/memory processing behaviors. We have found that prenatal (GD13-GD21) exposure to fluoxetine strengthened aversive memory and induced higher anxiety levels in males, and quick extinction of aversive memory in females. Taken together, these results suggest that early exposure to fluoxetine impairs the basal state of anxiety and the cognitive functions of rats during adulthood, which may be in a sex-specific manner because males appear more susceptible than females.

Effects of prenatal exposure to fluoxetine on circadian rhythmicity in the locomotor activity and neuropeptide Y and 5-HT expression in male and female adult Wistar rats.

Serotonin (5-HT) reuptake inhibitors, such as fluoxetine, are the most prescribed antidepressant for maternal depression. In this sense, it exposes mothers and the brains of infants to increased modulatory and trophic effects of serotonergic neurotransmission. 5-HT promotes essential brain changes throughout its development, which include neuron migration, differentiation and organisation of neural circuitries related to emotional, cognitive and circadian behavior. Early exposure to the SSRIs induces long-term effects on behavioral and neural serotonergic signalisation. We have aimed to evaluate the circadian rhythm of locomotor activity and the neurochemical content, neuropeptide Y (NPY) and 5-HT in three brain areas: intergeniculate leaflet (IGL), suprachiasmatic nuclei (SCN) and raphe nuclei (RN), at two zeitgebers (ZT6 and ZT18), in male and female rat's offspring early exposed (developmental period GD13-GD21) to fluoxetine (20 mg/kg). First, we have conducted daily records of the locomotor activity rhythm using activity sensors coupled to individual cages over 4 weeks. We have lastly evaluated the immunoreactivity of NPY in both SCN and IGL, as well the 5-HT expression in the dorsal and medial RN. In summary, our results showed that (1) prenatal fluoxetine affects phase entrainment of the rest/activity rhythm at ZT6 and ZT18, more in male than female specimens, and (2) modulates the NPY and 5-HT expression. Here, we show male rats are more susceptible to phase entrainment and the NPY and 5-HT misexpression compared to female ones. The sex differences induced by early exposure to fluoxetine in both the circadian rhythm of locomotor activity and the neurochemical expression into SCN, IGL and midbrain raphe are an important highlight in the present work. Thus, our results may help to improve the knowledge on neurobiological mechanisms of circadian rhythms and are relevant to understanding the "broken brains" and behavioral abnormalities of offspring early exposed to antidepressants.

Medial prefrontal cortex (A32 and A25) projections in the common marmoset: a subcortical anterograde study.

This study was aimed at establishing the subcorticals substrates of the cognitive and visceromotor circuits of the A32 and A25 cortices of the medial prefrontal cortex and their projections and interactions with subcortical complexes in the common marmoset monkey (Callithrix jacchus). The study was primarily restricted to the nuclei of the diencephalon and amygdala. The common marmoset is a neotropical primate of the new world, and the absence of telencephalic gyrus favors the mapping of neuronal fibers. The biotinylated dextran amine was employed as an anterograde tracer. There was an evident pattern of rostrocaudal distribution of fibers within the subcortical nuclei, with medial orientation. Considering this distribution, fibers originating from the A25 cortex were found to be more clustered in the diencephalon and amygdala than those originating in the A32 cortex. Most areas of the amygdala received fibers from both cortices. In the diencephalon, all regions received projections from the A32, while the A25 fibers were restricted to the thalamus, hypothalamus, and epithalamus at different densities. Precise deposits of neuronal tracers provided here may significantly contribute to expand our understanding of specific connectivity among the medial prefrontal cortex with limbic regions and diencephalic areas, key elements to the viscerocognitive process.

Pattern of tyrosine hydroxylase expression during aging of mesolimbic pathway of the rat.

Senescence is a physiological and progressive event that leads to the impairment of normal functions of the organism. The nervous system is one of the most affected systems during aging, presenting both structural and functional alterations associated with a decline in normal brain functions. In the present study we aimed to evaluate the impact of senescence on the mesolimbic pathway (nucleus accumbens - NAc and ventral tegmental area - VTA) of the rat, through immunohistochemistry for tyrosine hydroxylase (TH) enzyme, in young (3 months old), middle-aged (10 months old) and aged animals (18 months old). There was a significant decrease in the TH-immunoreactivity across NAc in aged animals as compared to the young and middle-aged ones, as revealed by optical densitometry. Medium and caudal regions of the VTA in the young animals possessed a higher number of TH-immunoreactive neurons as compared to the more aged groups. Comparisons among VTA regions in young animals revealed a difference in the number of cell bodies when the medium region was compared to the rostral and caudal regions whilst in both the middle-aged and aged groups comparisons between rostral vs caudal and medium vs caudal regions were significant. Our results show that aging impacts the mesolimbic pathway across its rostrocaudal axis, with a decrease of TH-reactivity in NAc and loss of neurons in VTA. These events may be involved with behavioral alterations observed throughout aging.

Passiflora cincinnata Extract Delays the Development of Motor Signs and Prevents Dopaminergic Loss in a Mice Model of Parkinson's Disease.

Passiflora cincinnata Masters is a Brazilian native species of passionflower. This genus is known in the American continent folk medicine for its diuretic and analgesic properties. Nevertheless, few studies investigated possible biological effects of P. cincinnata extracts. Further, evidence of antioxidant actions encourages the investigation of possible neuroprotective effects in animal models of neurodegenerative diseases. This study investigates the effect of the P. cincinnata ethanolic extract (PAS) on mice submitted to a progressive model of Parkinson's disease (PD) induced by reserpine. Male (6-month-old) mice received reserpine (0.1 mg/kg, s.c.), every other day, for 40 days, with or without a concomitant treatment with daily injections of PAS (25 mg/kg, i.p.). Catalepsy, open field, oral movements, and plus-maze discriminative avoidance evaluations were performed across treatment, and immunohistochemistry for tyrosine hydroxylase was conducted at the end. The results showed that PAS treatment delayed the onset of motor impairments and prevented the occurrence of increased catalepsy behavior in the premotor phase. However, PAS administration did not modify reserpine-induced cognitive impairments. Moreover, PAS prevented the decrease in tyrosine hydroxylase immunostaining in the substantia nigra pars compacta (SNpc) induced by reserpine. Taken together, our results suggested that PAS exerted a neuroprotective effect in a progressive model of PD.

The cytoarchitectonic and TH-immunohistochemical characterization of the dopamine cell groups in the substantia nigra, ventral tegmental area and retrorubral field in a bat (Artibeus planirostris).

The dopamine (DA) neurons of the retrorubral field (RRF - A8), the substantia nigra (SN - A9), and the ventral tegmental area (VTA - A10) have been implicated in motor regulation, reward, aversion, cognition, and several neuropsychiatric disorders. A series of studies have identified subdivisions of these cell groups in rodents, but these cell groups have not been well described in bats. An understanding of the motor system organization in bats would provide a context for comparing motor systems across rodent, primate, and bat phylogenies. The aim of this work was to determine whether typical subdivisions of RRF, SN, and VTA are present in Artibeus planirostris, a common frugivorous bat species found throughout South America. Coronal and sagittal sections of bat brain were subjected to Nissl staining and TH immunohistochemistry. The organizational pattern of the nuclei in A. planirostris showed a conspicuous tail in the SN, which has been not described in bats to date, and also contained a well-defined substantia nigra reticulata (SNR) not previously reported in microbats. This work provides for the first time a morphometric analysis of DA neurons in a microchiropteran species, enabling a comparative investigation of vertebrates. Our analysis revealed an apparent phylogenetic stability in these structures, although the SN tail might represent a functional specialization in this species.

Evolutionary history of the PER3 variable number of tandem repeats (VNTR): idiosyncratic aspect of primate molecular circadian clock.

The PER3 gene is one of the clock genes, which function in the core mammalian molecular circadian system. A variable number of tandem repeats (VNTR) locus in the 18th exon of this gene has been strongly associated to circadian rhythm phenotypes and sleep organization in humans, but it has not been identified in other mammals except primates. To better understand the evolution and the placement of the PER3 VNTR in a phylogenetical context, the present study enlarges the investigation about the presence and the structure of this variable region in a large sample of primate species and other mammals. The analysis of the results has revealed that the PER3 VNTR occurs exclusively in simiiforme primates and that the number of copies of the primitive unit ranges from 2 to 11 across different primate species. Two transposable elements surrounding the 18th exon of PER3 were found in primates with published genome sequences, including the tarsiiforme Tarsius syrichta, which lacks the VNTR. These results suggest that this VNTR may have evolved in a common ancestor of the simiiforme branch and that the evolutionary copy number differentiation of this VNTR may be associated with primate simiiformes sleep and circadian phenotype patterns.