Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, ...metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and
FKBP5
polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of
Fkbp5
in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of
Fkbp5
in Sim1
+
neurons dampens the acute stress response and increases GR sensitivity. In contrast,
Fkbp5
overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of
Fkbp5
expression in full
Fkbp5
KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of
Fkbp5
in the PVN and showed that
Fkbp5
expression is specifically upregulated in
Crh
+
neurons after stress. Finally,
Crh
-specific
Fkbp5
overexpression alters
Crh
neuron activity, but only partially recapitulates the PVN-specific
Fkbp5
overexpression phenotype. Together, the data establish the central and cell-type-specific importance of
Fkbp5
in the PVN in shaping HPA axis regulation and the acute stress response.
Sex differences and social context independently contribute to the development of stress-related disorders. However, less is known about how their interplay might influence behavior and physiology. ...Here we focused on social hierarchy status, a major component of the social environment in mice, and whether it influences behavioral adaptation to chronic stress in a sex-specific manner. We used a high-throughput automated behavioral monitoring system to assess social dominance in same-sex, group-living mice. We found that position in the social hierarchy at baseline was a significant predictor of multiple behavioral outcomes following exposure to chronic stress. Crucially, this association carried opposite consequences for the two sexes. This work demonstrates the importance of recognizing the interplay between sex and social factors and enhances our understating of how individual differences shape the stress response.
Most people experience chronic stress at some point in their life, which may increase their chances of developing depression or anxiety. There is evidence that chronic stress may more negatively impact the well-being of women, placing them as higher risk of developing these mental health conditions. The biological factors that underlie these differences are not well understood, which leaves clinicians and scientists struggling to develop and provide effective treatments.
The social environment has a powerful influence on how people experience and cope with stress. For example, a person’s social and socioeconomic status can change their perception of and reaction to everyday stress. Researchers have found differences in how men and women relate to their social standing. One way for scientists to learn more about the biological processes involved is to study the effect of social standing and chronic stress in male and female mice.
Now, Karamihalev, Brivio et al. show that social status influences the behavior of stressed mice in a sex-specific way. In the experiments, an automated observation system documented the behavior of mice living in all female or male groups. Karamihalev, Brivio et al. determined where each animal fit into the social structure of their group. Then, they exposed some groups of mice to mild chronic stress and compared their behaviors to groups of mice housed in normal conditions. They found that both the sex and social status of each played a role in how they responded to stress. For example, subordinate males displayed more anxious behavior under stressful circumstances, while dominant females acted bolder and less anxious.
More studies in mice are needed to understand the biological basis of these social- and sex-based differences in stress response. Learning more may help scientists understand why some individuals are more susceptible to the effects of stress and lead to the development of personalized prevention or treatment strategies for anxiety and depression.
Stress-related psychiatric disorders and the stress system show prominent differences between males and females, as well as strongly divergent transcriptional changes. Despite several proposed ...mechanisms, we still lack the understanding of the molecular processes at play. Here, we explore the contribution of cell types to transcriptional sex dimorphism using single-cell RNA sequencing. We identify cell-type-specific signatures of acute restraint stress in the paraventricular nucleus of the hypothalamus, a central hub of the stress response, in male and female mice. Further, we show that a history of chronic mild stress alters these signatures in a sex-specific way, and we identify oligodendrocytes as a major target for these sex-specific effects. This dataset, which we provide as an online interactive app, offers the transcriptomes of thousands of individual cells as a molecular resource for an in-depth dissection of the interplay between cell types and sex on the mechanisms of the stress response.
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•ARS elicits a cell-type- and sex-specific transcriptional response in the PVN•Exposure to CMS influences the ability of different cell types to respond to ARS•Oligodendrocytes are highly stress susceptible in a sex-specific way•Male oligodendrocytes in the PVN have an altered maturation state after stress
Brivio et al. generated a rich single-cell RNA sequencing dataset of the mouse paraventricular nucleus of the hypothalamus (PVN) to show that the response to acute stress is encoded differently in cell types and sexes. This approach identified oligodendrocytes as cells susceptible to stress.
Major depression is a highly prevalent, multidimensional disorder. Although several classes of antidepressants (ADs) are currently available, treatment efficacy is limited, and relapse rates are ...high; thus, there is a need to find better therapeutic strategies. Neuroplastic changes in brain regions such as the hippocampal dentate gyrus (DG) accompany depression and its amelioration with ADs. In this study, the unpredictable chronic mild stress (uCMS) rat model of depression was used to determine the molecular mediators of chronic stress and the targets of four ADs with different pharmacological profiles (fluoxetine, imipramine, tianeptine, and agomelatine) in the hippocampal DG. All ADs, except agomelatine, reversed the depression-like behavior and neuroplastic changes produced by uCMS. Chronic stress induced significant molecular changes that were generally reversed by fluoxetine, imipramine, and tianeptine. Fluoxetine primarily acted on neurons to reduce the expression of pro-inflammatory response genes and increased a set of genes involved in cell metabolism. Similarities were found between the molecular actions and targets of imipramine and tianeptine that activated pathways related to cellular protection. Agomelatine presented a unique profile, with pronounced effects on genes related to Rho-GTPase-related pathways in oligodendrocytes and neurons. These differential molecular signatures of ADs studied contribute to our understanding of the processes implicated in the onset and treatment of depression-like symptoms.
Chromatographic retention time information is valuable, orthogonal information to MS and MS/MS data that can be used in metabolite identification. However, while comparison of MS data between ...different instruments is possible to a certain degree, retention times (RTs) can vary extensively, even when nominally the same phase system is used. Different factors such as column dead volumes, system extra column volume, and gradient dwell volume can influence absolute retention times. Retention time indexing (RTI), routinely employed in gas chromatography (e.g., Kovats index), allows compensation for deviations in experimental conditions. Different systems have been reported for RTI in liquid chromatography, but none of them have been applied to metabolomics to the same extent as they have with GC. Recently, a more universal RTI system has been reported based on a homologous series of N-alkylpyridinium sulfonates (NAPS). These reference standards ionize in both positive and negative ionization modes and are UV-active. We demonstrate the NAPS can be used for retention time indexing in reversed-phase-liquid chromatography-mass spectrometry (RP-LC–MS)–based metabolomics. Having measured >500 metabolite standards and varying flow rate and column dimension, we show that conversion of RT to retention indices (RI) substantially improves comparability of retention information and enables to use of RI for metabolite annotation and identification., NRC publication: Yes
A single sub-anesthetic dose of ketamine produces a rapid and sustained antidepressant response, yet the molecular mechanisms responsible for this remain unclear. Here, we identified ...cell-type-specific transcriptional signatures associated with a sustained ketamine response in mice. Most interestingly, we identified the Kcnq2 gene as an important downstream regulator of ketamine action in glutamatergic neurons of the ventral hippocampus. We validated these findings through a series of complementary molecular, electrophysiological, cellular, pharmacological, behavioral, and functional experiments. We demonstrated that adjunctive treatment with retigabine, a KCNQ activator, augments ketamine's antidepressant-like effects in mice. Intriguingly, these effects are ketamine specific, as they do not modulate a response to classical antidepressants, such as escitalopram. These findings significantly advance our understanding of the mechanisms underlying the sustained antidepressant effects of ketamine, with important clinical implications.
The endocannabinoid system is an important regulator of the hormonal and behavioral stress responses, which critically involve corticotropin‐releasing factor (CRF) and its receptors. While it has ...been shown that CRF and the cannabinoid type 1 (CB1) receptor are co‐localized in several brain regions, the physiological relevance of this co‐expression remains unclear. Using double in situ hybridization, we confirmed co‐localization in the piriform cortex, the lateral hypothalamic area, the paraventricular nucleus, and the Barrington's nucleus, albeit at low levels. To study the behavioral and physiological implications of this co‐expression, we generated a conditional knockout mouse line that selectively lacks the expression of CB1 receptors in CRF neurons. We found no effects on fear and anxiety‐related behaviors under basal conditions nor after a traumatic experience. Additionally, plasma corticosterone levels were unaffected at baseline and after restraint stress. Only acoustic startle responses were significantly enhanced in male, but not female, knockout mice. Taken together, the consequences of depleting CB1 in CRF‐positive neurons caused a confined hyperarousal phenotype in a sex‐dependent manner. The current results suggest that the important interplay between the central endocannabinoid and CRF systems in regulating the organism's stress response is predominantly taking place at the level of CRF receptor‐expressing neurons.
Male mice deficient of CB1 in CRF neurons show an increased acoustic startle response.
•PPARγ is found in multiple brain areas.•PPARγ levels are altered by different physiological states in a site-specific manner.•Activated PPARγ impair motivational behavior and associative learning.
...Like other members of the superfamily of nuclear receptors, the peroxisome proliferator-activated receptor γ (PPARγ), is a ligand-activated transcription factor known for its insulin-sensitizing actions in the periphery. Despite only sparse evidence for PPARγ in the CNS, many reports suggest direct PPARγ-mediated actions in the brain. This study aimed to (i) map PPARγ expression in rodent brain areas, involved in the regulation of cognitive, motivational, and emotional functions, (ii) examine the regulation of central PPARγ by physiological variables (age, sex, obesity); (iii) chemotypically identify PPARγ-expressing cells in the frontal cortex (FC) and hippocampus (HP); (iv) study whether activation of PPARγ by pioglitazone (Pio) in FC and HP cells can induce target gene expression; and (v) demonstrate the impact of activated PPARγ on learning behavior and motivation. Immunoreactive PPARγ was detectable in specific sub-nuclei/subfields of the FC, HP, nucleus accumbens, amygdala, hypothalamus, thalamus, and granular layers of the cerebellum. PPARγ protein levels were upregulated during aging and in high fat diet-induced obesity. PPARγ mRNA expression was upregulated in the amygdala of females (but not males) that were made obese. Neural precursor cells, mature neurons, and astrocytes in primary FC and HP cultures were shown to express PPARγ. Pioglitazone dose-dependently upregulated PPARγ target genes in manner that was specific to the origin (FC or HP) of the cultures. Lastly, administration of Pio impaired motivation and associative learning. Collectively, we provide evidence for the presence of regulatable PPARγ in the brain and demonstrate their participation the regulation of key behaviors.
Dissection of the HPA axis using single-cell RNA sequencing uncovers adrenal ABCB1 as an important player of stress adaptation.
Chronic activation and dysregulation of the neuroendocrine stress ...response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type–specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of
Abcb1b
+
cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing’s syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism’s nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
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