Aging is associated with sex-specific alteration in the expression of genes encoding for neuroestradiol synthesis and signaling proteins in the mouse trigeminal somatosensory input.

Pain perception is influenced by sex and aging, with previous studies indicating the involvement of aromatase, the estradiol synthase enzyme, in regulating pain perception. Previous research has established the presence of aromatase in dorsal root ganglia sensory neurons and its role in modulating pain perception. The present study aims to explore the implications of aging and sex on the expression of aromatase and estrogen receptors in the trigeminal ganglion. The study examined mRNA levels of aromatase, ERs, and the androgen receptor (AR) in the trigeminal ganglion of 3-month-old and 27-month-old male and female mice, as well as 3-month-old mice from the four-core genotype (FCG) transgenic model. The latter facilitates the assessment of gonadal hormone and sex chromosome implications for sex-specific traits. Aromatase localization in the ganglion was further assessed through immunohistochemistry. Aromatase immunoreactivity was observed for the first time in sensory neurons within the trigeminal ganglion. Trigeminal ganglion gene expressions were detected for aromatase, ERs, and AR in both sexes. Aromatase, ERß, and GPER gene expressions were higher in young males versus young females. Analyses of the FCG model indicated that sex differences depended solely on gonadal sex. The aging process induced an enhancement in the expression of aromatase, ERs, and AR genes across both sexes, culminating in a reversal of the previously observed gender-based differences. the potential impact of estrogen synthesis and signaling in the trigeminal ganglion on age and sex differences warrants consideration, particularly in relation to trigeminal sensory functions and pain perception.

Sex chromosome complement interacts with gonadal hormones in determining regional-specific neuroactive steroid levels in plasma, hippocampus, and hypothalamus. A study using the four core genotype mouse model.

An important aspect of the neuromodulatory and neuroprotective actions exerted by neuroactive steroids is that they are sex-specific, as determined by the sexually dimorphic levels of these molecules in plasma and the nervous tissue. Thus, the identification of the factors that generate the sex-dimorphic levels of neuroactive steroids may be crucial from a neuroprotectant perspective. The main driver for sex determination in mammals is the SRY gene and the subsequent presence of a specific gonad: testes for males and ovaries for females, thus producing hormonal compounds, primarily androgens and estrogens, respectively. Nowadays, it is well established that despite the relevance of gonads, other factors control sexual features, and, among them, sex chromosome complement is highly relevant. In this study, neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in the hypothalamus, the hippocampus, and plasma of the four core genotype mouse model, to determine the relative contribution of sex chromosome complement and gonads in determining their sex dimorphic levels. The data obtained reveal that although gonads are the main contributing factor for sex differences in neuroactive steroid levels, the levels of some neuroactive steroids, including testosterone, are also influenced in brain and plasma by tissue-specific actions of sex chromosomes. The data presented here adds a new piece to the puzzle of steroid level regulation, which may be useful in designing sex-specific neuroprotective approaches to pathological conditions affecting the nervous system.

Kif21B mediates the effect of estradiol on the morphological plasticity of mouse hippocampal neurons.

Introduction: Neurons are polarized cells, and their ability to change their morphology has a functional implication in the development and plasticity of the nervous system in order to establish new connections. Extracellular factors strongly influence neuronal shape and connectivity. For instance, the developmental actions of estradiol on hippocampal neurons are well characterized, and we have demonstrated in previous studies that Ngn3 mediates these actions. On the other hand, Kif21B regulates microtubule dynamics and carries out retrograde transport of the TrkB/brain-derived neurotrophic factor (BDNF) complex, essential for neuronal development. Methods: In the present study, we assessed the involvement of kinesin Kif21B in the estradiol-dependent signaling mechanisms to regulate neuritogenesis through cultured mouse hippocampal neurons. Results: We show that estradiol treatment increases BDNF expression, and estradiol and BDNF modify neuron morphology through TrkB signaling. Treatment with K252a, a TrkB inhibitor, decreases dendrite branching without affecting axonal length, whereas. Combined with estradiol or BDNF, it blocks their effects on axons but not dendrites. Notably, the downregulation of Kif21B abolishes the actions of estradiol and BDNF in both the axon and dendrites. In addition, Kif21B silencing also decreases Ngn3 expression, and downregulation of Ngn3 blocks the effect of BDNF on neuron morphology. Discussion: These results suggest that Kif21B is required for the effects of estradiol and BDNF on neuronal morphology, but phosphorylation-mediated activation of TrkB is essential only for axonal growth. Our results show that the Estradiol/BDNF/TrkB/Kif21B/Ngn3 is a new and essential pathway mediating hippocampal neuron development.

IGF-1 regulates astrocytic phagocytosis and inflammation through the p110α isoform of PI3K in a sex-specific manner.

Insulin-like growth factor-I (IGF-I) signaling plays a key role in neuroinflammation. Here we show that IGF-1 also regulates phagocytosis of reactive astrocytes through p110α isoform of phosphatidylinositol 3-kinase (PI3K), differentially in both sexes. Systemic bacterial lipopolysaccharide (LPS)-treatment increased the expression of GFAP, a reactive astrocyte marker, in the cortex of mice in both sexes and was blocked by IGF-1 only in males. In primary astrocytes, LPS enhanced the mRNA expression of Toll-like receptors (TLR2,4) and proinflammatory factors: inducible nitric oxide synthase (iNOS), chemokine interferon-γ-inducible protein-10 (IP-10) and cytokines (IL-1ß, IL-6, and IL-10) in male and female. Treatment with IGF-1 counteracted TLR4 but not TLR2, iNOS, and IP10 expression in both sexes and cytokines expression in males. Furthermore, reactive astrocyte phagocytosis was modulated by IGF-1 only in male astrocytes. IGF-1 was also able to increase AKT-phosphorylation only in male astrocytes. PI3K inhibitors, AG66, TGX-221, and CAL-101, with selectivity toward catalytic p110α, p110ß, and p110δ isoforms respectively, reduced AKT-phosphorylation in males. All isoforms interact physically with IGF-1-receptor in both sexes. However, the expression of p110α is higher in males while the expression of IGF-1-receptor is similar in male and female. AG66 suppressed the IGF-1 effect on cytokine expression and counteracted the IGF-1-produced phagocytosis decrease in male reactive astrocytes. Results suggest that sex-differences in the effect of IGF-1 on the AKT-phosphorylation could be due to a lower expression of the p110α in female and that IGF-1-effects on the inflammatory response and phagocytosis of male reactive astrocytes are mediated by p110α/PI3K subunit.

The spectral sensitivity of Drosophila photoreceptors.

Drosophila melanogaster has long been a popular model insect species, due in large part to the availability of genetic tools and is fast becoming the model for insect colour vision. Key to understanding colour reception in Drosophila is in-depth knowledge of spectral inputs and downstream neural processing. While recent studies have sparked renewed interest in colour processing in Drosophila, photoreceptor spectral sensitivity measurements have yet to be carried out in vivo. We have fully characterised the spectral input to the motion and colour vision pathways, and directly measured the effects of spectral modulating factors, screening pigment density and carotenoid-based ocular pigments. All receptor sensitivities had significant shifts in spectral sensitivity compared to previous measurements. Notably, the spectral range of the Rh6 visual pigment is substantially broadened and its peak sensitivity is shifted by 92 nm from 508 to 600 nm. We show that this deviation can be explained by transmission of long wavelengths through the red screening pigment and by the presence of the blue-absorbing filter in the R7y receptors. Further, we tested direct interactions between inner and outer photoreceptors using selective recovery of activity in photoreceptor pairs.

Binocular Encoding in the Damselfly Pre-motor Target Tracking System.

Akin to all damselflies, Calopteryx (family Calopterygidae), commonly known as jewel wings or demoiselles, possess dichoptic (separated) eyes with overlapping visual fields of view. In contrast, many dragonfly species possess holoptic (dorsally fused) eyes with limited binocular overlap. We have here compared the neuronal correlates of target tracking between damselfly and dragonfly sister lineages and linked these changes in visual overlap to pre-motor neural adaptations. Although dragonflies attack prey dorsally, we show that demoiselles attack prey frontally. We identify demoiselle target-selective descending neurons (TSDNs) with matching frontal visual receptive fields, anatomically and functionally homologous to the dorsally positioned dragonfly TSDNs. By manipulating visual input using eyepatches and prisms, we show that moving target information at the pre-motor level depends on binocular summation in demoiselles. Consequently, demoiselles encode directional information in a binocularly fused frame of reference such that information of a target moving toward the midline in the left eye is fused with information of the target moving away from the midline in the right eye. This contrasts with dragonfly TSDNs, where receptive fields possess a sharp midline boundary, confining responses to a single visual hemifield in a sagittal frame of reference (i.e., relative to the midline). Our results indicate that, although TSDNs are conserved across Odonata, their neural inputs, and thus the upstream organization of the target tracking system, differ significantly and match divergence in eye design and predatory strategies. VIDEO ABSTRACT.