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TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner.

ABSTRACT: Dysregulations of the central serotoninergic system have been implicated in several psychopathologies, characterized by different susceptibility between males and females. We took advantage of tryptophan hydroxylase 2 (TPH2) deficient rats, lacking serotonin specifically in the brain, to investigate whether a vulnerable genotype can be associated with alterations of neuronal plasticity from the early stage of maturation of the brain until adulthood. We found a significant increase, in both gene and protein expression, of the neurotrophin brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) of adult TPH2-deficient (TPH2-/-) male and female rats in comparison to wild type (TPH2+/+) counterparts. Interestingly, a development-specific pattern was observed during early postnatal life: whereas the increase in Bdnf expression, mainly driven by the modulation of Bdnf isoform IV was clearly visible after weaning at postnatal day (pnd) 30 in both sexes of TPH2-/- in comparison to TPH2+/+ rats, at early stages (pnd1 and pnd10) Bdnf expression levels did not differ between the genotypes, or even were downregulated in male TPH2-/- animals at pnd10. Moreover, to establish if hyposerotonergia may influence the response to a challenging situation, we exposed adult rats to an acute stress. Although the pattern of corticosterone release was similar between the genotypes, neuronal activation in response to stress, quantified by the expression of the immediate early genes activity regulated cytoskeleton associated protein (Arc) and Fos Proto-Oncogene (cFos), was blunted in both sexes of animals lacking brain serotonin. Interestingly, although upregulation of Bdnf mRNA levels after stress was observed in both genotypes, it was less pronounced in TPH2-/- in comparison to TPH2+/+ rats. In summary, our results demonstrated that serotonin deficiency affects neuroplastic mechanisms following a specific temporal pattern and influences the response to an acute stress.

SUBMITTER: Brivio P

PROVIDER: S-EPMC6218558 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner.

Brivio Paola P Sbrini Giulia G Peeva Polina P Todiras Mihail M Bader Michael M Alenina Natalia N Calabrese Francesca F

Frontiers in molecular neuroscience 20181030

Dysregulations of the central serotoninergic system have been implicated in several psychopathologies, characterized by different susceptibility between males and females. We took advantage of tryptophan hydroxylase 2 (TPH2) deficient rats, lacking serotonin specifically in the brain, to investigate whether a vulnerable genotype can be associated with alterations of neuronal plasticity from the early stage of maturation of the brain until adulthood. We found a significant increase, in both gene ...[more]

PMID: 30425618

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Project description:Several studies have consistently reported a detrimental effect of chronic stress on recognition memory. However, the effects of acute stress on this cognitive ability have been poorly investigated. Moreover, despite well-documented sex differences in recognition memory observed in clinical studies, most of the preclinical studies in this field of research have been carried out by using solely male rodents. Here we tested the hypothesis that acute stress could affect the consolidation of different types of recognition memory in a sex-dependent manner. For this purpose, male and female C57BL6/J mice were exposed to 2-h of restrain stress immediately after the training session of both the novel object recognition (NOR) test and novel object location (NOL) tasks. Acute restraint stress did not affect memory performance of male and female mice, after a 4-h delay between the training session and the test phase of both tasks. By contrast, acute restraint stress altered memory performance in a sex-dependent manner, after a 24-h delay. While stressed mice of both sexes were impaired in the NOL test, only male stressed mice were impaired in the NOR test. Because ionotropic glutamate receptors-mediated neurotransmission is essential for shaping recognition memory, we further tested the hypothesis that post training acute stress could induce sex-dependent transcriptional changes of ionotropic glutamate receptor subunits in the dorsal hippocampus. We uncovered that acute stress induced sex-, time- and type of memory-dependent transcriptional changes of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. These findings suggest that the effect of acute stress on recognition memory can be strongly biased by multiple factors including sex. These findings also indicate that the same stress-induced memory impairment observed in both sexes can be triggered by different sex-dependent molecular mechanisms. At the therapeutic level, this should not be overlooked in the context of personalized and targeted treatments.

Project description:Women are more susceptible to numerous stress-linked psychological disorders (e.g., depression) characterized by dysfunction of corticolimbic brain regions critical for emotion regulation and cognitive function. Although sparsely investigated, a number of studies indicate sex differences in stress effects on neuronal structure, function, and behaviors associated with these regions. We recently demonstrated a basal sex difference in- and differential effects of stress on- microglial activation in medial prefrontal cortex (mPFC). The resident immune cells of the brain, microglia are implicated in synaptic and dendritic plasticity, and cognitive-behavioral function. Here, we examined the effects of acute (3h/day, 1 day) and chronic (3h/day, 10 days) restraint stress on microglial density and morphology, as well as immune factor expression in orbitofrontal cortex (OFC), basolateral amygdala (BLA), and dorsal hippocampus (DHC) in male and female rats. Microglia were visualized, classified based on their morphology, and stereologically counted. Microglia-associated transcripts (CD40, iNOS, Arg1, CX3CL1, CX3CR1, CD200, and CD200R) were assessed in brain punches from each region. Expression of genes linked with cellular stress, neuroimmune state, and neuron-microglia communication varied between unstressed male and female rats in a region-specific manner. In OFC, chronic stress upregulated a wider variety of immune factors in females than in males. Acute stress increased microglia-associated transcripts in BLA in males, whereas chronic stress altered immune factor expression in BLA more broadly in females. In DHC, chronic stress increased immune factor expression in males but not females. Moreover, acute and chronic stress differentially affected microglial morphological activation state in male and female rats across all brain regions investigated. In males, chronic stress altered microglial activation in a pattern consistent with microglial involvement in stress-induced dendritic remodeling across OFC, BLA, and DHC. Together, these data suggest the potential for microglia-mediated sex differences in stress effects on neural structure, function, and behavior.

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TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner.

Publications

TPH2 Deficiency Influences Neuroplastic Mechanisms and Alters the Response to an Acute Stress in a Sex Specific Manner.

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