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Functional coupling between the amygdala and the dorsomedial prefrontal cortex (dmPFC) has been implicated in the generation of negative affective states; however, the mechanisms by which stress increases amygdala-dmPFC synaptic strength and generates anxiety-like behaviors are not well understood. Here, we show that the mouse basolateral amygdala (BLA)-prelimbic prefrontal cortex (plPFC) circuit is engaged by stress and activation of this pathway in anxiogenic. Furthermore, we demonstrate that acute stress exposure leads to a lasting increase in synaptic strength within a reciprocal BLA-plPFC-BLA subcircuit. Importantly, we identify 2-arachidonoylglycerol (2-AG)-mediated endocannabinoid signaling as a key mechanism limiting glutamate release at BLA-plPFC synapses and the functional collapse of multimodal 2-AG signaling as a molecular mechanism leading to persistent circuit-specific synaptic strengthening and anxiety-like behaviors after stress exposure. These data suggest that circuit-specific impairment in 2-AG signaling could facilitate functional coupling between the BLA and plPFC and the translation of environmental stress to affective pathology.
Copyright © 2019 Elsevier Inc. All rights reserved.
BACKGROUND - Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.
METHODS - Adult male CRF-tomato reporter mice were treatment-naïve, or either exposed to CIE for 2 weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques.
RESULTS - We found that NE depolarized BNST CRF neurons in naïve mice in a β-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE- or stress-exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α-AR-dependent.
CONCLUSIONS - Altogether, these findings suggest that stress and CIE interact with β-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β-AR balance of BNST CRF neuronal excitability. Restoration of α/β-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.
© 2019 by the Research Society on Alcoholism.
Stress contributes to numerous psychiatric disorders. Corticotropin releasing factor (CRF) signaling and CRF neurons in the bed nucleus of the stria terminalis (BNST) drive negative affective behaviors, thus agents that decrease activity of these cells may be of therapeutic interest. Here, we show that acute restraint stress increases cFos expression in CRF neurons in the mouse dorsal BNST, consistent with a role for these neurons in stress-related behaviors. We find that activation of α-adrenergic receptors (ARs) by the agonist guanfacine reduced cFos expression in these neurons both in stressed and unstressed conditions. Further, we find that α- and β-ARs differentially regulate excitatory drive onto these neurons. Pharmacological and channelrhodopsin-assisted mapping experiments suggest that α-ARs specifically reduce excitatory drive from parabrachial nucleus (PBN) afferents onto CRF neurons. Given that the α-AR is a G-linked GPCR, we assessed the impact of activating the G-coupled DREADD hM4Di in the PBN on restraint stress regulation of BNST CRF neurons. CNO activation of PBN hM4Di reduced stress-induced in BNST neurons. Further, using as an additional marker of BNST neuronal identity, we uncovered a female-specific upregulation of the coexpression of in BNST neurons following stress, which was prevented by ovariectomy. These findings show that stress activates BNST CRF neurons, and that α-AR activation suppresses the activity of these cells, at least in part by suppressing excitatory drive from PBN inputs onto CRF neurons. Stress is a major variable contributing to mood disorders. Here, we show that stress increases activation of BNST CRF neurons that drive negative affective behavior. We find that the clinically well tolerated α-AR agonist guanfacine reduces activity of these cells , and reduces excitatory PBN inputs onto these cells Additionally, we uncover a novel sex-dependent coexpression of with in female BNST neurons after stress, an effect abolished by ovariectomy. These results demonstrate input-specific interactions between norepinephrine and CRF, and point to an action by which guanfacine may reduce negative affective responses.
Copyright © 2019 the authors 0270-6474/19/390472-13$15.00/0.
Sustained exposure to stress or corticosteroids is known to cause changes in brain endocannabinoid (eCB) signaling, such that tissue contents of the eCBs N-arachidonylethanolamine (AEA) are generally reduced while 2-arachidonoylglycerol (2-AG) levels increase. These changes in eCB signaling are important for many of the aspects of chronic stress, such as anxiety, reward sensitivity and stress adaptation, yet the mechanisms mediating these changes are not fully understood. We have recently found that the stress-related neuropeptide corticotropin-releasing hormone (CRH), acting through the CRH type 1 receptor (CRHR1), can reduce AEA content by increasing its hydrolysis by the enzyme fatty acid amide hydrolase (FAAH) as well as increase 2-AG contents. As extra-hypothalamic CRH is upregulated by chronic corticosteroid or stress exposure, we hypothesized that increased CRH signaling through CRHR1 contributes to the effects of chronic corticosteroid exposure on the eCB system within the amygdala and prefrontal cortex. Male rats were exposed to 7 days of systemic corticosterone capsules, with or without concurrent exposure to a CRHR1 antagonist, after which we examined eCB content. Consistent with previous studies in the amygdala, sustained corticosterone exposure increases CRH mRNA in the prefrontal cortex. As was shown previously, FAAH activity was increased and AEA contents were reduced within the amygdala and prefrontal cortex following chronic corticosterone exposure. Chronic corticosterone exposure also elevated 2-AG content in the prefrontal cortex but not the amygdala. These corticosteroid-driven changes were all blocked by systemic CRHR1 antagonism. Consistent with these data indicating sustained increases in CRH signaling can mediate the effects of chronic elevations in corticosteroids, CRH overexpressing mice also exhibited increased FAAH-mediated AEA hydrolysis in the amygdala and prefrontal cortex compared to wild type. CRH overexpression increased 2-AG content in the amygdala, but not the prefrontal cortex. These data indicate that chronic elevations in CRH signaling, as is seen following exposure to chronic elevations in corticosterone or stress, drive persistent changes in eCB function. As reductions in AEA signaling mediate the effects of CRH and chronic stress on anxiety, these data provide a mechanism linking these processes.
Copyright © 2016 Elsevier Ltd. All rights reserved.
Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.
Psychosocial stress is a risk factor for development and exacerbation of neuropsychiatric illness. Repeated stress causes biochemical adaptations in endocannabinoid (eCB) signaling that contribute to stress-response habituation, however, the synaptic correlates of these adaptations have not been examined. Here, we show that the synthetic enzyme for the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol (DAG) lipase alpha, is heterogeneously expressed in the amygdala, and that levels of 2-AG and precursor DAGs are increased in the basolateral amygdala (BLA) after 10 days, but not 1 day, of restraint stress. In contrast, arachidonic acid was decreased after both 1 and 10 days of restraint stress. To examine the synaptic correlates of these alterations in 2-AG metabolism, we used whole-cell electrophysiology to determine the effects of restraint stress on depolarization-induced suppression of inhibition (DSI) in the BLA. A single restraint stress exposure did not alter DSI compared with control mice. However, after 10 days of restraint stress, DSI duration, but not magnitude, was significantly prolonged. Inhibition of 2-AG degradation with MAFP also prolonged DSI duration; the effects of repeated restraint stress and MAFP were mutually occlusive. These data indicate that exposure to repeated, but not acute, stress produces neuroadaptations that confer BLA neurons with an enhanced capacity to elevate 2-AG content and engage in 2-AG-mediated short-term retrograde synaptic signaling. We suggest stress-induced enhancement of eCB-mediated suppression of inhibitory transmission in the BLA could contribute to affective dysregulation associated with chronic stress.
OBJECTIVE - Information is needed about patient-initiated device removal to guide quality initiatives addressing regulations aimed at minimizing physical restraint use. Research objectives were to determine the prevalence of device removal, describe patient contexts, examine unit-level adjusted risk factors, and describe consequences.
DESIGN - Prospective prevalence.
SETTING - Total of 49 adult intensive care units (ICUs) from a random sample of 39 hospitals in five states.
METHODS - Data were collected daily for 49,482 patient-days by trained nurses and included unit census, ventilator days, restraint days, and days accounted for by men and by elderly. For each device removal episode, data were collected on demographic and clinical variables.
RESULTS - Patients removed 1,623 devices on 1,097 occasions: overall rate, 22.1 episodes/1000 patient-days; range, 0-102.4. Surgical ICUs had lower rates (16.1 episodes) than general (23.6 episodes) and medical (23.4 episodes) ICUs. ICUs with fewer resources had fewer all-type device removal relative to ICUs with greater resources (relative risk, 0.76; 95% confidence interval, 0.66-0.87) but higher self-extubation rates (relative risk, 1.27; 95% confidence interval, 1.07-1.52). Men accounted for 57% of the episodes, 44% were restrained at the time, and 30% had not received any sedation, narcotic, or psychotropic drug in the previous 24 hrs. There was no association between rates of device removal with restraint rates, proportion of men, or elderly. Self-extubation rates were inversely associated with ventilator days (rs = -0.31, p = .03). Patient harm occurred in 250 (23%) episodes; ten incurred major harm. No deaths occurred. Reinsertion rates varied by device: 23.5% of surgical drains to 88.9% of monitor leads. Additional resources (e.g., radiography) were used in 58% of the episodes.
CONCLUSION - Device removal by ICU patients is common, resulting in harm in one fourth of patients and significant resource expenditure. Further examination of patient-, unit-, and practitioner-level variables may help explain variation in rates and provide direction for further targeted interventions.
PURPOSE - To describe (a) the extent of inter- and intrainstitutional variation in labor, capital, and process-of-care variables related to nursing service on U.S. adult acute and intensive care units; (b) the extent to which resource clustering exists; and (c) an analysis of resource cluster role that explains variation in physical restraint rates.
DESIGN - Descriptive.
METHODS - Staff at 82 adult acute care and 55 intensive care units from 40 randomly selected U.S. hospitals provided data about more than 100 capital, labor, and process variables via (a) a staff nurse survey, and (b) interviews with unit leaders and measurement of unit design. These data described resources during the period in which physical restraint rate was established via direct observation.
FINDINGS - Depending on the resource variable, 7% to 57% of hospitals in which more than one ICU was studied showed resource variation between their ICUs; the comparable statistics for adult acute units were 5% to 45%. Cluster analysis indicated a two-cluster solution for ICUs and a three-cluster solution for non-ICUs. ICU cluster assignment varied within 16% of hospitals in which more than one ICU was studied. Non-ICU cluster assignment varied within 20% of hospitals. Physical restraint use was best explained by patient characteristics, not resource clusters or individual resources.
CONCLUSIONS - Studies of outcomes that are the product of a single unit must include measurement of resources at the unit level, assuming equal resources among units of similar types within a hospital is unwarranted. Further research regarding the effect of resource clusters on nurse sensitive outcomes is suggested.
PURPOSE - To describe physical restraint (PR) rates and contexts in U.S. hospitals.
DESIGN - This 2003-2005 descriptive study was done to measure PR prevalence and contexts (census, gender, age, ventilation status, PR type, and rationale) at 40 randomly selected acute care hospitals in six U.S. metropolitan areas. All units except psychiatric, emergency, operative, obstetric, and long-term care were included.
METHODS - On 18 randomly selected days between 0500 and 0700 (5:00 am and 7:00 am), data collectors determined PR use and contexts via observation and nurse report.
FINDINGS - PR prevalence was 50 per 1,000 patient days (based on 155,412 patient days). Preventing disruption of therapy was the chief reason cited. PR rates varied by unit type, with adult ICU rates the highest obtained. Intra- and interinstitutional variation was as high as 10-fold. Ventilator use was strongly associated with PR use. Elderly patients were over-represented among the physically restrained on some units (e.g., medical) but on many unit types (including most ICUs) their PR use was consistent with those of other adults.
CONCLUSIONS - Wide rate variation indicates the need to examine administratively mediated variables and the promotion of unit-based improvement efforts. Anesthetic and sedation practices have contributed to high variation in ICU PR rates. Determining the types of units to target to achieve improvements in care of older adults requires study of PR sequelae rate by unit type.