Mental health disorders often arise as a combination of environmental and genetic factors. The
gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for ...stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (
) and GABAergic (
) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.
Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly ...associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders.
It has been shown previously (Sotnikov et al., ) that mice selectively inbred for high anxiety‐related behavior (HAB) vs. low anxiety‐related behavior in the elevated plus maze differentially respond ...to trimethylthiazoline (TMT), a synthetic fox fecal odor. However, less is known about whether environmental factors can rescue these extreme phenotypes. Here, we found that an enriched environment (EE) provided during early adolescence induced anxiolytic effects in HAB (HAB‐EE) mice, rescuing their strong avoidance behavior induced by TMT. In a series of experiments, the contribution of maternal, juvenile and adolescent behavior to the anxiolytic effects elicited by EE was investigated. At the molecular level, using c‐fos expression mapping, we found that the activity of the medial and basolateral amygdala was significantly reduced in HAB‐EE mice after TMT exposure. We further analysed the expression of Crhr1, as its amount in the amygdala has been reported to be important for the regulation of anxiety‐related behavior after EE. Indeed, in situ hybridisation indicated significantly decreased Crhr1 expression in the basolateral and central amygdala of HAB‐EE mice. To further test the involvement of Crhr1 in TMT‐induced avoidance, we exposed conditional glutamatergic‐specific Crhr1‐knockout mice to the odor. The behavioral response of Crhr1‐knockout mice mimicked that of HAB‐EE mice, and c‐fos expression in the amygdala after TMT exposure was significantly lower compared with controls, thereby further supporting a critical involvement of Crhr1 in environmentally‐induced anxiolysis. Altogether, our results indicate that EE can rescue strong avoidance of TMT by HAB mice with Crhr1 expression in the amygdala being critically involved.
High anxiety‐related behavior mice housed in enriched environment displayed reduced TMT avoidance, which is potentially mediated via decreased amygdala activity as indicated by lower c‐fos expression. Lower Crhr1 expression in the amygdala of enriched mice is likely to be critically involved in this phenomenon. Indeed, Crhr1 glutamatergic‐specific knock‐out mice showed decreased TMT avoidance and c‐fos expression in the amygdala compared to wild type.
Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic ...pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL‐1β, and tumor necrosis factor‐receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p‐P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats.
Upregulated P2Y12 in satellite glial cells (SGCs) of dorsal root ganglia (DRG) was involved in diabetic neuropathic pain. Targeting the P2Y12 receptor by short hairpin RNA decreased the upregulated expression of the P2Y12 receptor in DRG SGCs and relieved mechanical and thermal hyperalgesia in type 2 DM rats.
For >15 generations, CD1 mice have been selectively and bidirectionally bred for either high-anxiety-related behavior (HAB-M) or low-anxiety-related behavior (LAB-M) on the elevated plus-maze. ...Independent of gender, HAB-M were more anxious than LAB-M animals in a variety of additional tests, including those reflecting risk assessment behaviors and ultrasound vocalization, with unselected CD1 "normal" control (NAB-M) and cross-mated (CM-M) mice displaying intermediate behavioral scores in most cases. Furthermore, in both the forced-swim and tail-suspension tests, LAB-M animals showed lower scores of immobility than did HAB-M and NAB-M animals, indicative of a reduced depression-like behavior. Using proteomic and microarray analyses, glyoxalase-I was identified as a protein marker, which is consistently expressed to a higher extent in LAB-M than in HAB-M mice in several brain areas. The same phenotype-dependent difference was found in red blood cells with NAB-M and CM-M animals showing intermediate expression profiles of glyoxalase-I. Additional studies will examine whether glyoxalase-I has an impact beyond that of a biomarker to predict the genetic predisposition to anxiety- and depression-like behavior.
Recent evidence showed that the endocannabinoid system plays an important role in the behavioral adaptation of stress and fear responses. In this study, we chose a behavioral paradigm that includes ...criteria of both fear and stress responses to assess whether the involvement of endocannabinoids in these two processes rely on common mechanisms. To this end, we delivered a footshock and measured the fear response to a subsequently presented novel tone stimulus. First, we exposed different groups of cannabinoid receptor type 1 (CB1)‐deficient mice (CB1−/−) and their wild‐type littermates (CB1+/+) to footshocks of different intensities. Only application of an intense footshock resulted in a sustained fear response to the tone in CB1−/−. Using the intense protocol, we next investigated whether endocannabinoids mediate their effects via an interplay with corticotropin‐releasing hormone (CRH) signaling. Pharmacological blockade of CB1 receptors by rimonabant in mice deficient for the CRH receptor type 1 (CRHR1−/−) or type 2 (CRHR2−/−), and in respective wild‐type littermates, resulted in a sustained fear response in all genotypes. This suggests that CRH is not involved in the fear‐alleviating effects of CB1. As CRHR1−/− are known to be severely impaired in stress‐induced corticosterone secretion, our observation also implicates that corticosterone is dispensable for CB1‐mediated acute fear adaptation. Instead, conditional mutants with a specific deletion of CB1 in principal neurons of the forebrain (CaMK‐CB1−/−), or in cortical glutamatergic neurons (Glu‐CB1−/−), showed a similar phenotype as CB1−/−, thus indicating that endocannabinoid‐controlled glutamatergic transmission plays an essential role in acute fear adaptation.
Dysregulation of the corticotropin-releasing factor (CRF)-urocortin (UCN) system has been implicated in stress-related psychopathologies such as depression and anxiety. It has been proposed that ...CRF-CRF receptor type 1 (CRFR1) signalling promotes the stress response and anxiety-like behaviour, whereas UCNs and CRFR2 activation mediate stress recovery and the restoration of homeostasis. Recent findings, however, provide clear evidence that this view is overly simplistic. Instead, a more complex picture has emerged that suggests that there are brain region- and cell type-specific effects of CRFR signalling that are influenced by the individual's prior experience and that shape molecular, cellular and ultimately behavioural responses to stressful challenges.
Abstract Corticotropin-releasing hormone (CRH) coordinates neuroendocrine and behavioral adaptations to stress. Acute CRH administration in vivo activates extracellular signal-regulated kinase 1/2 ...(ERK1/2) in limbic brain areas, acting through the CRH receptor type 1 (CRH-R1). In the present study, we used CRH-COE-Cam mice that overexpress CRH in limbic-restricted areas, to analyze the effect of chronic CRH overexpression on ERK1/2 activation. By immunohistochemistry and confocal microscopy analysis we found that pERK1/2 levels in the basolateral amygdala (BLA) were similar in control and CRH overexpressing mice under basal conditions. Acute stress caused comparably increased levels of corticosterone in both control (CRH-COEcon -Cam) and CRH overexpressing (CRH-COEhom -Cam) animals. CRH-COEhom -Cam mice after stress showed reduced pERK1/2 immunoreactivity in the BLA compared to CRH-COEhom -Cam animals under basal conditions. Radioligand binding and in situ hybridization revealed higher density of CRH-R1 in the amygdala of CRH-COEhom mice under basal conditions compared to control littermates. A significant reduction of the receptor levels was observed in this area after acute stress, suggesting that stress may trigger CRH-R1 internalization/downregulation in these CRH overexpressing mice. Chronic CRH overexpression leads to reduced ERK1/2 activation in response to acute stress in the BLA.
Neural activity either enhances or impairs de novo synaptogenesis and circuit integration of neurons, but how this activity is mechanistically relayed in the adult brain is largely unknown. ...Neuropeptide-expressing interneurons are widespread throughout the brain and are key candidates for conveying neural activity downstream via neuromodulatory pathways that are distinct from classical neurotransmission. With the goal of identifying signaling mechanisms that underlie neuronal circuit integration in the adult brain, we have virally traced local corticotropin-releasing hormone (CRH)-expressing inhibitory interneurons with extensive presynaptic inputs onto new neurons that are continuously integrated into the adult rodent olfactory bulb. Local CRH signaling onto adult-born neurons promotes and/or stabilizes chemical synapses in the olfactory bulb, revealing a neuromodulatory mechanism for continued circuit plasticity, synapse formation, and integration of new neurons in the adult brain.
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•Viral transsynaptic tracing reveals functional interneuron-neuron connectivity•Local CRH+ interneurons provide inputs to adult-born neurons•CRH signaling promotes adult-born neuron survival and circuit integration•Neuropeptidergic interneurons promotes synapse formation and function
Neuropeptide-expressing interneurons are important candidates for conveying neural activity via neuromodulatory pathways distinct from classical neurotransmission. Using viral transsynaptic tracing, Garcia et al. uncover a role for neuropeptigerdic inhibitory interneurons in guiding synaptogenesis and circuit plasticity in the mouse olfactory bulb through functional neuromodulatory interactions with adult-born neurons.
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