ABSTRACT
BACKGROUND: Chronic immunosuppression following pancreas transplantation carries significant risk, including posttransplant lymphoproliferative disease (PTLD). We sought to define the incidence, risk factors, and long-term outcomes of PTLD following pancreas transplantation at a single center. METHODS: All adult pancreas transplants between February 1, 1983 and December 31, 2023 at the University of Minnesota were reviewed, including pancreas transplant alone (PTA), simultaneous pancreas-kidney transplants (SPK), and pancreas after kidney transplants (PAK). RESULTS: Among 2353 transplants, 110 cases of PTLD were identified, with an overall incidence of 4.8%. 17.3% were diagnosed within 1 year of transplant, 32.7% were diagnosed within 5 years, and 74 (67.3%) were diagnosed after 5 years. The overall 30-year incidence of PTLD did not differ by transplant type-7.4% for PTA, 14.2% for SPK, and 19.4% for PAK (p = 0.3). In multivariable analyses, older age and Epstein-Barr virus seronegativity were risk factors for PTLD, and PTLD was a risk factor for patient death. PTLD-specific mortality was 32.7%, although recipients with PTLD had similar median posttransplant survival compared to those without PTLD (14.9 year vs. 15.6 year, p = 0.9). CONCLUSIONS: PTLD following pancreas transplantation is associated with significant mortality. Although the incidence of PTLD has decreased over time, a high index of suspicion for PTLD following PTx should remain in EBV-negative recipients.
Subject(s)
Graft Survival , Lymphoproliferative Disorders , Pancreas Transplantation , Postoperative Complications , Humans , Pancreas Transplantation/adverse effects , Male , Lymphoproliferative Disorders/etiology , Lymphoproliferative Disorders/epidemiology , Female , Adult , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Follow-Up Studies , Risk Factors , Prognosis , Middle Aged , Incidence , Survival Rate , Retrospective Studies , Graft Rejection/etiology , Graft Rejection/mortality , Kidney Transplantation/adverse effects , Young AdultABSTRACT
BACKGROUND: In total pancreatectomy with islet autotransplantation (TPIAT), a greater number of islets transplanted produces more favorable outcomes. We aimed to determine predictors of islet isolation outcomes. METHODS: We investigated factors associated with islet isolation outcomes expressed as islet number (IN), islet equivalents (IEQ; standardized to an islet with 150 µm diameter), IN/kg, or IEQ/kg using data from the multicenter Prospective Observational Study of TPIAT. Single-predictor linear regression was used to estimate the association of individual patient and disease characteristics with islet isolation outcomes, and augmented backward elimination was used to select variables to include in multivariable analyses. RESULTS: In multivariable analyses, only elevated hemoglobin A1c was associated with worse outcomes for all measures (Pâ <â 0.001 for all). Total IEQ obtained for transplant was higher for participants with Hispanic ethnicity (Pâ =â 0.002) or overweight status pre-TPIAT (Pâ <â 0.001) and lower with non-White race (Pâ =â 0.03), genetic pancreatitis (Pâ =â 0.02), history of lateral pancreaticojejunostomy (Pâ =â 0.03), and presence of atrophy (Pâ =â 0.006) or ductal changes (Pâ =â 0.014) on imaging. IEQ/kg was higher in females (Pâ =â 0.01) and Hispanic participants (Pâ =â 0.046) and generally lower with older age (nonlinear association, Pâ <â 0.001) and pancreatic atrophy (Pâ <â 0.001) on imaging. Total IN and IN/kg showed trends similar, but not identical, to IEQ and IEQ/kg, respectively. CONCLUSIONS: Patient demographics and certain pancreatic disease features were associated with outcomes from islet isolation. Hemoglobin A1c before TPIAT was the metabolic testing measure most strongly associated with islet isolation results.
ABSTRACT
OBJECTIVE: To describe the evolution of pancreas transplantation, including improved outcomes and factors associated with improved outcomes over the past five decades. BACKGROUND: The world's first successful pancreas transplant was performed in December 1966 at the University of Minnesota. As new modalities for diabetes treatment mature, we must carefully assess the current state of pancreas transplantation to determine its ongoing role in patient care. METHODS: A single-center retrospective review of 2,500 pancreas transplants performed over >50 years in bivariate and multivariable models. Transplants were divided into six eras; outcomes are presented for the entire cohort and by era. RESULTS: All measures of patient and graft survival improved progressively through the six transplant eras. The overall death censored (DC) pancreas graft half-lives were >35 years for simultaneous pancreas and kidney (SPK), 7.1 years for pancreas after kidney (PAK), and 3.3 years for pancreas transplants alone (PTA). The 10-year DC pancreas graft survival rate in the most recent era was 86.9% for SPK recipients, 58.2% for PAK recipients, and 47.6% for PTA. Overall graft loss was most influenced by patient survival in SPK transplants, whereas graft loss in PAK and PTA recipients was more often due to graft failures. Predictors of improved pancreas graft survival were primary transplants, bladder drainage of exocrine secretions, younger donor age, and shorter preservation time. CONCLUSIONS: Pancreas outcomes have significantly improved over time via sequential, but overlapping, advances in surgical technique, immunosuppressive protocols, reduced preservation time, and the more recent reduction of immune-mediated graft loss.
ABSTRACT
Indications for liver transplants have expanded to include patients with alcohol-associated liver disease (ALD) over the last decade. Concurrently, the liver allocation policy was updated in February 2020 replacing the Donor Service Area with Acuity Circles (ACs). The aim is to compare the transplantation rate, waitlist outcomes, and posttransplant survival of candidates with ALD to non-ALD and assess differences in that effect after the implementation of the AC policy. Scientific Registry for Transplant Recipients data for adult candidates for liver transplant were reviewed from the post-AC era (February 4, 2020-March 1, 2022) and compared with an equivalent length of time before ACs were implemented. The adjusted transplant rates were significantly higher for those with ALD before AC, and this difference increased after AC implementation (transplant rate ratio comparing ALD to non-ALD = 1.20, 1.13, 1.61, and 1.32 for the Model for End-Stage Liver Disease categories 37-40, 33-36, 29-32, and 25-28, respectively, in the post-AC era, p < 0.05 for all). The adjusted likelihood of death/removal from the waitlist was lower for patients with ALD across all lower Model for End-Stage Liver Disease categories (adjusted subdistribution hazard ratio = 0.70, 0.81, 0.84, and 0.70 for the Model for End-Stage Liver Disease categories 25-28, 20-24, 15-19, 6-14, respectively, p < 0.05). Adjusted posttransplant survival was better for those with ALD (adjusted hazard ratio = 0.81, p < 0.05). Waiting list and posttransplant mortality tended to improve more for those with ALD since the implementation of AC but not significantly. ALD is a growing indication for liver transplantation. Although patients with ALD continue to have excellent posttransplant outcomes and lower waitlist mortality, candidates with ALD have higher adjusted transplant rates, and these differences have increased after AC implementation.
ABSTRACT
The instant blood-mediated inflammatory response (IBMIR) causes islet loss and compromises diabetes outcomes after total pancreatectomy with islet autotransplant (TPIAT). We previously reported a possible benefit of etanercept in maintaining insulin secretion 3 months post-TPIAT. Here, we report 2-year diabetes outcomes and peri-operative inflammatory profiles from a randomized trial of etanercept and alpha-1 antitrypsin (A1AT) in TPIAT. We randomized 43 TPIAT recipients to A1AT (90 mg/kg IV x6 doses, n = 13), etanercept (50 mg then 25 mg SQ x 5 doses, n = 14), or standard care (n = 16). Inflammatory cytokines, serum A1AT and unmethylated insulin DNA were drawn multiple times in the perioperative period. Islet function was assessed 2 years after TPIAT with mixed meal tolerance test, intravenous glucose tolerance test and glucose-potentiated arginine induced insulin secretion. Cytokines, especially IL-6, IL-8, IL-10, and MCP-1, were elevated during and after TPIAT. However, only TNFα differed significantly between groups, with highest levels in the etanercept group (p = 0.027). A1AT increased after IAT in all groups (p < 0.001), suggesting endogenous upregulation. Unmethylated insulin DNA ratios (a marker of islet loss) and 2 years islet function testing were similar in the three groups. To conclude, we found no sustained benefit from administering etanercept or A1AT in the perioperative period.
Subject(s)
Diabetes Mellitus , Islets of Langerhans Transplantation , Humans , Etanercept/therapeutic use , Autografts , Transplantation, Autologous , Insulin , Inflammation , Cytokines , DNA , Pancreatectomy , Treatment OutcomeABSTRACT
BACKGROUND: Total pancreatectomy with islet autotransplant (TPIAT) can improve quality of life for individuals with pancreatitis but creates health risks including diabetes, exocrine insufficiency, altered intestinal anatomy and function, and asplenia. METHODS: We studied survival and causes of death for 693 patients who underwent TPIAT between 2001 and 2020, using the National Death Index with medical records to ascertain survival after TPIAT, causes of mortality, and risk factors for death. We used Kaplan Meier curves to examine overall survival, and Cox regression and competing-risks methods to determine pre-TPIAT factors associated with all-cause and cause-specific post-TPIAT mortality. RESULTS: Mean age at TPIAT was 33.6 years (SD = 15.1). Overall survival was 93.1% (95% CI 91.2, 95.1%) 5 years after surgery, 85.2% (95% CI 82.0, 88.6%) at 10 years, and 76.2% (95% CI 70.8, 82.3%) at 15 years. Fifty-three of 89 deaths were possibly related to TPIAT; causes included chronic gastrointestinal complications, malnutrition, diabetes, liver failure, and infection/sepsis. In multivariable models, younger age, longer disease duration, and more recent TPIAT were associated with lower mortality. CONCLUSIONS: For patients undergoing TPIAT to treat painful pancreatitis, careful long-term management of comorbidities introduced by TPIAT may reduce risk for common causes of mortality.
Subject(s)
Cause of Death , Islets of Langerhans Transplantation , Pancreatectomy , Humans , Pancreatectomy/adverse effects , Pancreatectomy/mortality , Female , Male , Islets of Langerhans Transplantation/adverse effects , Adult , Risk Factors , Middle Aged , Transplantation, Autologous , Young Adult , Retrospective Studies , Risk Assessment , Time Factors , Adolescent , Treatment Outcome , Pancreatitis/mortality , Pancreatitis/etiology , Pancreatitis, Chronic/surgery , Pancreatitis, Chronic/mortalityABSTRACT
Background: Although diabetes after total pancreatectomy and islet autotransplantation (TP-IAT) is one of the biggest concerns for TP-IAT recipients and physicians, reliable prediction of post-TP-IAT glycemic control remains unestablished. This study was conducted to identify early predictors of insulin independence and goal glycemic control by hemoglobin A1c (HbA1c) ≤ 6.5% after TP-IAT. Methods: In this single-center, retrospective study, patients who underwent TP-IAT (nâ =â 227) were reviewed for simple metabolic markers or surrogate indices of ß-cell function obtained 3 mo after TP-IAT as part of standard clinical testing. Long-term metabolic success was defined as (1) insulin independence and (2) HbA1c ≤ 6.5% 1, 3, and 5 y after TP-IAT. Single- and multivariate modeling used 3-mo markers to predict successful outcomes. Results: Of the 227 recipients, median age 31 y, 30% male, 1 y after TP-IAT insulin independence, and HbA1c ≤ 6.5% were present in 39.6% and 72.5%, respectively. In single-predictor analyses, most of the metabolic markers successfully discriminated between those attaining and not attaining metabolic goals. Using the best model selected by random forests analysis, we accurately predicted 1-y insulin independence and goal HbA1c control in 77.3% and 86.4% of the patients, respectively. A simpler "clinically feasible" model using only transplanted islet dose and BETA-2 score allowed easier prediction at a small accuracy loss (74.1% and 82.9%, respectively). Conclusions: Metabolic testing measures performed 3 mo after TP-IAT were highly associated with later diabetes outcomes and provided a reliable prediction model, giving valuable prognostic insight early after TP-IAT and help to identify recipients who require early intervention.
ABSTRACT
Traumatic events result in vivid and enduring fear memories. Suppressing the retrieval of these memories is central to behavioral therapies for pathological fear. The medial prefrontal cortex (mPFC) and hippocampus (HPC) have been implicated in retrieval suppression, but how mPFC-HPC activity is coordinated during extinction retrieval is unclear. Here we show that after extinction training, coherent theta oscillations (6-9 Hz) in the HPC and mPFC are correlated with the suppression of conditioned freezing in male and female rats. Inactivation of the nucleus reuniens (RE), a thalamic hub interconnecting the mPFC and HPC, reduces extinction-related Fos expression in both the mPFC and HPC, dampens mPFC-HPC theta coherence, and impairs extinction retrieval. Conversely, theta-paced optogenetic stimulation of RE augments fear suppression and reduces relapse of extinguished fear. Collectively, these results demonstrate a role for RE in coordinating mPFC-HPC interactions to suppress fear memories after extinction.
Subject(s)
Fear , Midline Thalamic Nuclei , Rats , Male , Female , Animals , Midline Thalamic Nuclei/physiology , Rats, Long-Evans , Fear/physiology , Prefrontal Cortex/physiology , Hippocampus/physiology , Extinction, Psychological/physiologyABSTRACT
Chronic pancreatitis is a progressive and irreversible process of pancreatic inflammation and fibrosis that can lead to intractable abdominal pain and severely impaired quality of life (QoL). Often patients are refractory to standard medical or endoscopic treatments. Total pancreatectomy (TP) and islet auto-transplantation (TP-IAT) can offer pain relief to patients by removing the entire pancreas and the auto-transplant component ameliorates the resulting diabetes. QoL is significantly improved after TP-IAT when insulin independence is present. Recent data support offering TP-IAT rather than TP alone and treating with exogenous insulin for patients with debilitating chronic pancreatitis.
Subject(s)
Islets of Langerhans Transplantation , Pancreatitis, Chronic , Humans , Pancreatectomy/methods , Quality of Life , Treatment Outcome , Pancreatitis, Chronic/surgery , Islets of Langerhans Transplantation/methods , Insulin , Transplantation, Autologous , Insulin, Regular, HumanABSTRACT
BACKGROUND: In total pancreatectomy with islet auto-transplantation, successful diabetes outcomes are limited by islet loss from the instant blood mediated inflammatory response. We hypothesized that blockade of the inflammatory response with either etanercept or alpha-1-antitrypsin would improve islet function and insulin independence. METHODS: We randomized 43 participants to receive A1AT (90 mg/kg x 6 doses, n = 13), or etanercept (50 mg then 25 mg x 5 doses, n = 14), or standard care (n = 16), aiming to reduce detrimental effects of innate inflammation on early islet survival. Islet graft function was assessed using mixed meal tolerance testing, intravenous glucose tolerance testing, glucose-potentiated arginine-induced insulin secretion studies, HbA1c, and insulin dose 3 months and 1 year post-TPIAT. RESULTS: We observed the most robust acute insulin response (AIRglu) and acute C-peptide response to glucose (ACRglu) at 3 months after TPIAT in the etanercept-treated group (p ≤ 0.02), but no differences in other efficacy measures. The groups did not differ overall at 1 year but when adjusted by sex, there was a trend towards a sex-specific treatment effect in females (AIRglu p = 0.05, ACRglu p = 0.06), with insulin secretion measures highest in A1AT-treated females. CONCLUSION: Our randomized trial supports a potential role for etanercept in optimizing early islet engraftment but it is unclear whether this benefit is sustained. Further studies are needed to evaluate possible sex-specific responses to either treatment. CLINICAL TRIAL NOTATION: This study was performed under an Investigational New Drug Application (IND #119828) from the Food and Drug Administration and was registered on clinicaltrials.gov (NCT#02713997).
Subject(s)
Diabetes Mellitus , Islets of Langerhans Transplantation , Pancreatitis, Chronic , Female , Humans , Male , Diabetes Mellitus/surgery , Etanercept/pharmacology , Etanercept/therapeutic use , Glucose , Insulin/therapeutic use , Pancreatectomy , Pancreatitis, Chronic/surgery , Pilot Projects , Transplantation, Autologous , Treatment Outcome , ThymalfasinABSTRACT
BACKGROUND: Insulin hypersensitivity reactions are rare but serious and significantly affect the treatment of diabetes in children. METHODS: A 13-year-old girl with type 1 diabetes, hypoglycemic unawareness, and treatment refractory allergy to available insulin preparations underwent a solitary pancreas transplant. Before the pancreas transplantation, she was receiving a continuous subcutaneous infusion of rapid-acting insulin with an increasing need for antihistamines and steroids, negatively impacting her cognitive and social development. Her diabetes was poorly controlled, and her quality of life was progressively worsening. RESULTS: Following the transplant, she recovered well from surgery and achieved euglycemia without needing exogenous insulin. She had two biopsy proven episodes of acute cellular rejection, successfully treated. Her cognitive development also accelerated. Notable improvement was noted both in her personal quality of life and her family's overall well-being. CONCLUSIONS: This is the youngest pancreas transplant recipient with over 1-year graft survival reported in the literature. Pancreas transplant alone in a teenager without indications for kidney transplantation could be considered a last resort treatment for diabetes when continuing insulin therapy presents a high level of morbidity. A pancreas transplant is a feasible treatment modality for patients with refractory insulin allergy.
Subject(s)
Diabetes Mellitus, Type 1 , Hypersensitivity , Pancreas Transplantation , Female , Adolescent , Humans , Child , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/surgery , Quality of Life , Insulin/therapeutic use , Graft SurvivalABSTRACT
Long-term outcome data by induction type in simultaneous pancreas-kidney (SPK) is limited. Methods: Utilizing the Scientific Registry of Transplant Recipients, we examined all primary SPK transplants between 2000 and 2020, excluding crossmatch-positive recipients. We grouped recipients according to induction regimen into 3 groups: rabbit anti-thymocyte globulin (r-ATG) (n = 5678), alemtuzumab (n = 1199), and interleukin-2 receptor antagonist (IL-2RA; n = 1593). We analyzed the 10-y recipient and composite (kidney and pancreas) graft survival using the Kaplan-Meier survival function. Cox-proportion hazard models were generated to examine the association between induction type, the 10-y recipient, and graft survival. Models were adjusted for recipient age, sex, ethnicity, HLA-mismatch, diabetes type, dialysis dependency, cold-ischemia time, local versus imported organs, panel reactive antibody, steroid maintenance, and Pancreas Donor Risk Index. Results: r-ATG was associated with the lowest 1-y kidney and pancreas rejection rates compared with other agents (P < 0.001). In the univariable analysis, induction type was not associated with recipient (log-rank P = 0.11) or graft survival (log-rank P = 0.36). In the multivariable model for the composite graft survival, alemtuzumab use was associated with 22% increased kidney or pancreas graft loss compared with r-ATG (adjusted hazard ratio, 1.22; 95% confidence interval, 1.05-1.42), whereas IL-2RA use was not a predictor of graft survival. Induction type did not influence recipient survival in the adjusted model. Conclusions: r-ATG use was associated with the lowest SPK rejection rates. Compared with r-ATG, alemtuzumab but not IL-2RA was associated with worse long-term death-censored SPK graft outcome. Our analysis supports the common use of r-ATG for induction in US primary SPK recipients.
ABSTRACT
Background: Of late, numerous randomised controlled trials report platelet-rich plasma (PRP) to be ineffective with preparation protocols of low platelet yield despite using expensive commercial PRP kits. Objective: This study aims to identify and standardize a preparation protocol for PRP with maximum platelets yield and concentration to obtain favourable results without the use of commercial preparation kits. Materials & methods: Blood samples were collected from 40 healthy volunteers who signed informed consent for participation in the study. The double spin protocol of PRP preparation was analyzed for variables such as centrifugal acceleration, time, and volume of blood processed and final product utilized. The final PRP prepared was investigated for platelet recovery, concentration, integrity, and viability. Each protocol investigated with technical and biological duplicates to avoid reporting and sampling bias. Results: We noted maximum platelet recovery (86-99%) with a consistent 6.4 ± 0.8 times the baseline concentration of platelets with first centrifugation at 100g for 15 min followed by second centrifugation at 1600g for 20 min. We did not note a loss of integrity or viability of the platelets in the final product from the above-said protocol. We also validated the protocol among all the study participants demonstrating consistency. Conclusion: The preparation of PRP by the double-spin protocol using 10 ml of blood at 100 g followed by 1600 g for 15 and 20 min respectively in a 15 ml tube and using the lower 1/3rd of the final product demonstrated consistent high platelet recovery (86-99%) and concentration (6x) without disturbing the platelet integrity or viability.
ABSTRACT
Recent data reveal that the thalamic nucleus reuniens (RE) has a critical role in the extinction of conditioned fear. Muscimol (MUS) infusions into the RE impair within-session extinction of conditioned freezing and result in poor long-term extinction memories in rats. Although this suggests that RE inactivation impairs extinction learning, it is also possible that it is involved in the consolidation of extinction memories. To examine this possibility, we examined the effects of RE inactivation on the consolidation and reconsolidation of fear extinction in male and female rats. Twenty-four hours after auditory fear conditioning, rats underwent an extinction procedure (45 CS-alone trials) in a novel context and were infused with saline (SAL) or MUS within minutes of the final extinction trial. Twenty-four hours later, conditioned freezing to the extinguished CS was assessed in the extinction context. Postextinction inactivation of the RE did not affect extinction retrieval. In a second experiment, rats underwent extinction training and, 24 h later, were presented with a single CS to reactivate the extinction memory; rats were infused with SAL or MUS immediately after the reactivation session. Pharmacological inactivation of the RE did not affect conditioned freezing measured in a drug-free retrieval test the following day. Importantly, we found in a subsequent test that MUS infusions immediately before retrieval testing increased conditioned freezing and impaired extinction retrieval, as we have previously reported. These results indicate that although RE inactivation impairs the expression of extinction, it does not impair either the consolidation or reconsolidation of extinction memories. We conclude that the RE may have a critical role in suppressing context-inappropriate fear memories in the extinction context.
Subject(s)
Fear , Midline Thalamic Nuclei , Animals , Extinction, Psychological/physiology , Fear/physiology , Female , Learning/physiology , Male , Memory/physiology , Midline Thalamic Nuclei/physiology , RatsABSTRACT
OBJECTIVE: To determine if islet autotransplantation (IAT) independently improves the quality of life (QoL) in patients after total pancreatectomy and islet autotransplantation (TP-IAT). BACKGROUND: TP-IAT is increasingly being used for intractable chronic pancreatitis. However, the impact of IAT on long-term islet function and QoL is unclear. METHODS: TP-IAT patients at our center >1 year after TP-IAT with ≥1 Short Form-36 QoL measure were included. Patients were classified as insulin-independent or insulin-dependent, and as having islet graft function or failure by C-peptide. The associations of insulin use and islet graft function with QoL measures were analyzed by using a linear mixed model, accounting for time since transplant and within-person correlation. RESULTS: Among 817 islet autograft recipients, 564 patients [median (interquartile range) age: 34 (20, 45) years, 71% female] and 2161 total QoL surveys were included. QoL data were available for >5 years after TP-IAT for 42.7% and for >10 years for 17.3%. Insulin-independent patients exhibited higher QoL in 7 of 8 subscale domains and for Physical Component Summary and Mental Component Summary scores ( P <0.05 for all). Physical Component Summary was 2.91 (SE=0.57) higher in insulin-independent patients ( P <0.001). No differences in QoL were observed between those with and without graft function, but islet graft failure was rare (15% of patients). However, glycosylated hemoglobin was much higher with islet graft failure. CONCLUSIONS: QoL is significantly improved when insulin independence is present, and glycosylated hemoglobin is lower with a functioning islet graft. These data support offering IAT, rather than just performing total pancreatectomy and treating with exogenous insulin.
Subject(s)
Islets of Langerhans Transplantation , Pancreatitis, Chronic , Adult , Female , Glycated Hemoglobin , Humans , Insulin , Male , Pancreatectomy , Pancreatitis, Chronic/complications , Pancreatitis, Chronic/surgery , Quality of Life , Transplantation, Autologous , Treatment OutcomeABSTRACT
Considerable work indicates that instrumental responding is context-dependent, but the neural mechanisms underlying this phenomenon are poorly understood. Given the important role for the hippocampal formation in contextual processing, we hypothesized that reversible inactivation of the hippocampus would impair the context-dependence of active avoidance. To test this hypothesis, we used a two-way signaled active avoidance (SAA) task that requires rats to shuttle across a divided chamber during a tone CS in order to avoid a footshock US. After training, avoidance responding was assessed in an extinction test in both the training context and a novel context in a counterbalanced order. Rats performed significantly more avoidance responses in the training context than in the novel context, demonstrating the context-dependence of shuttle avoidance behavior. To examine the role of the hippocampus in the context-dependence of SAA, we reversibly inactivated either the dorsal (DH) or ventral hippocampus (VH) prior to testing. Inactivation of the VH eliminated the context-dependence of SAA and elevated avoidance responding in the novel context to levels similar to that expressed in the training context. In contrast, DH inactivation had no effect on avoidance in either context, and neither manipulation affected freezing behavior. Therefore, the integrity of the VH, but not DH, is required for the expression of the context-dependence of avoidance behavior.
Subject(s)
Avoidance Learning/physiology , Hippocampus/physiology , Animals , Avoidance Learning/drug effects , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Freezing Reaction, Cataleptic/physiology , GABA-A Receptor Agonists/pharmacology , Hippocampus/drug effects , Male , Muscimol/pharmacology , RatsABSTRACT
Environmental contexts can inform animals of potential threats, though it is currently unknown how context biases the selection of defensive behavior. Here we investigated context-dependent flight responses with a Pavlovian serial-compound stimulus (SCS) paradigm that evokes freeze-to-flight transitions. Similar to previous work in mice, we show that male and female rats display context-dependent flight-like behavior in the SCS paradigm. Flight behavior was dependent on contextual fear insofar as it was only evoked in a shock-associated context and was reduced in the conditioning context after context extinction. Flight behavior was only expressed to white noise regardless of temporal order within the compound. Nonetheless, rats that received unpaired SCS trials did not show flight-like behavior to the SCS, indicating it is associative. Finally, we show that pharmacological inactivation of two brain regions critical to the expression of contextual fear, the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), attenuates both contextual fear and flight responses. All of these effects were similar in male and female rats. This work demonstrates that contextual fear can summate with cued and innate fear to drive a high fear state and transition from post-encounter to circa-strike defensive modes.
Subject(s)
Behavior, Animal/physiology , Brain/physiology , Conditioning, Classical , Escape Reaction , Acoustic Stimulation , Amygdala/drug effects , Animals , Behavior, Animal/drug effects , Brain/anatomy & histology , Brain/drug effects , Conditioning, Classical/drug effects , Conditioning, Classical/physiology , Cues , Escape Reaction/drug effects , Escape Reaction/physiology , Fear , Female , Male , Muscimol/pharmacology , Rats , Rats, Long-Evans , Septal Nuclei/drug effectsABSTRACT
Reconsolidation may be a viable therapeutic target to inhibit pathological fear memories. In the clinic, incidental or imaginal reminders are used for safe retrieval of traumatic memories of experiences that occurred elsewhere. However, it is unknown whether indirectly retrieved traumatic memories are sensitive to disruption. Here we used a backward (BW) conditioning procedure to indirectly retrieve and manipulate a hippocampus (HPC)-dependent contextual fear engram in male rats. We show that conditioned freezing to a BW conditioned stimulus (CS) is mediated by fear to the conditioning context, activates HPC ensembles that can be covertly captured and chemogenetically activated to drive fear, and is impaired by post-retrieval protein synthesis inhibition. These results reveal that indirectly retrieved contextual fear memories reactivate HPC ensembles and undergo protein synthesis-dependent reconsolidation. Clinical interventions that rely on indirect retrieval of traumatic memories, such as imaginal exposure, may open a window for editing or erasure of neural representations that drive pathological fear.
Subject(s)
Conditioning, Psychological/physiology , Extinction, Psychological/physiology , Fear/physiology , Hippocampus/physiology , Memory/physiology , Animals , Male , Memory Consolidation/physiology , Proto-Oncogene Proteins c-fos/metabolism , RatsABSTRACT
Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stress-induced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders.SIGNIFICANCE STATEMENT Patients with post-traumatic stress disorder (PTSD) show heightened amygdala activity; elevated levels of stress hormones, including norepinephrine; and are resistant to the extinction of fear memories. Here, we show that stress increases basolateral amygdala (BLA) spike firing. This could be attenuated by systemic propranolol and mimicked by chemogenetic activation of the locus coeruleus (LC), the source of forebrain norepinephrine (NE). Finally, we show that LC-NE activation is sufficient to produce extinction deficits, and this is blocked by intra-BLA propranolol. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with PTSD and related disorders.
Subject(s)
Action Potentials/physiology , Basolateral Nuclear Complex/physiology , Conditioning, Classical/physiology , Extinction, Psychological/physiology , Learning/physiology , Locus Coeruleus/physiology , Neurons/physiology , Action Potentials/drug effects , Adrenergic beta-Antagonists/pharmacology , Animals , Basolateral Nuclear Complex/drug effects , Conditioning, Classical/drug effects , Extinction, Psychological/drug effects , Learning/drug effects , Locus Coeruleus/drug effects , Neurons/drug effects , Propranolol/pharmacology , RatsABSTRACT
Learning and remembering the context in which events occur requires interactions between the hippocampus (HPC) and medial prefrontal cortex (mPFC). The nucleus reuniens (RE) is a ventral midline thalamic nucleus that coordinates activity in the mPFC and HPC and is involved in spatial and contextual memory. We recently found that the RE is critical for contextual fear conditioning in rats, a form of learning that involves interactions between the HPC and mPFC. Here we examined whether the RE mediates the extinction of contextual fear. After contextual fear conditioning, rats underwent an extinction procedure in which they were merely exposed to the conditioning context; freezing behavior during the extinction procedure and during a retrieval test 24 h later served as an index of conditioned fear. Muscimol inactivation of the RE prior to extinction impaired the acquisition of both short- and long-term extinction memories. Similarly, inactivation of the RE prior to the extinction retrieval test also impaired the expression of extinction; this effect was not state-dependent. Taken together, these results reveal that the extinction of contextual fear memories requires the RE, which is consistent with a broader role for the RE in forms of learning that require HPC-mPFC interactions.