Ventral hippocampus mediates inter-trial responding in signaled active avoidance.

The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context. Rats that received muscimol performed significantly fewer ITRs, but equivalent avoidance responses, compared to controls. Next, we asked whether chemogenetic VH activation would increase ITR vigor. In male and female rats expressing excitatory (hM3Dq) DREADDs, systemic CNO administration produced a robust ITR increase that was not due to nonspecific locomotor effects. Then, we examined whether chemogenetic VH activation potentiated ITRs in an alternate (non-training) test context and found it did. Finally, to determine if context-US associations mediate ITRs, we exposed rats to the training context for three days after SAA training to extinguish the context. Rats submitted to context extinction did not show a reliable decrease in ITRs during a retrieval test, suggesting that context-US associations are not responsible for ITRs. Collectively, these results reveal an important role for the VH in context-dependent ITRs during SAA. Further work is required to explore the neural circuits and associative basis for these responses, which may be underlie pathological avoidance that occurs in humans after threat has passed.

Ventral hippocampus mediates inter-trial responding in signaled active avoidance.

The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context. Rats that received muscimol performed significantly fewer ITRs, but equivalent avoidance responses, compared to controls. Next, we asked whether chemogenetic VH activation would increase ITR vigor. In male and female rats expressing excitatory (hM3Dq) DREADDs, systemic CNO administration produced a robust ITR increase that was not due to nonspecific locomotor effects. Then, we examined whether chemogenetic VH activation potentiated ITRs in an alternate (non-training) test context and found it did. Finally, to determine if context-US associations mediate ITRs, we exposed rats to the training context for three days after SAA training to extinguish the context. Rats submitted to context extinction did not show a reliable decrease in ITRs during a retrieval test, suggesting that context-US associations are not responsible for ITRs. Collectively, these results reveal an important role for the VH in context-dependent ITRs during SAA. Further work is required to explore the neural circuits and associative basis for these responses, which may be underlie pathological avoidance that occurs in humans after threat has passed.

Nucleus reuniens inactivation does not impair consolidation or reconsolidation of fear extinction.

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.

The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy: a systematic review.

PURPOSE: Electroanatomic mapping (EAM) has been utilized as a modality to improve the sensitivity of endomyocardial biopsy (EMB). We sought to systematically review published medical literature on the efficacy and safety of EAM-guided EMB. METHODS: We searched Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central, Scopus, and Web of Science for studies where EAM was used for EMB. Data abstracted included demographics, indications, final diagnoses, histology findings, and technical details of biopsy extraction. Test characteristics including sensitivity (Se), specificity (Sp), and area under curve (AUC) were calculated on a per-patient and per-biopsy level. RESULTS: Seventeen studies (9 case series, 8 case reports) were included in this systematic review. EAM-guided EMB was performed in 148 patients and results of 207 individual biopsies were available for analysis. The most common indications for EAM-guided EMB were suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), myocarditis, and cardiac sarcoidosis (CS). The pooled sensitivity and specificity for EAM-guided EMB for the diagnosis of cardiomyopathies (ARVC, myocarditis, CS, and other specific diagnoses) were 92 and 58% on per-biopsy analysis and 100 and 39% on per-patient analysis. Among the individual components of abnormal EGMs, abnormal unipolar EGM had the best AUC on per-biopsy (0.81, 95% CI 0.68-0.90) and per-patient analysis (0.84, 95% CI 0.68-0.92). EAM-guided EMB appears safe. Adverse events included 1 hemopericardium, 2 minimal asymptomatic pericardial effusions, and 1 femoral hematoma. CONCLUSIONS: EAM-guided EMB is a safe and efficacious method and might improve test characteristics over conventional fluoroscopy-guided biopsy.

Novel Techniques in Epilepsy Management: Venous Pacing and Capture of Electrical Activity in the Primate Cortex.

OBJECTIVE: Pharmacotherapy for epilepsy is limited with 30% of patients refractory to this approach of suppressing seizures. Current surgical options are invasive and carry significant morbidities including infection, bleeding, and the potential for deleterious neurocognitive effects. As a result, there is a burgeoning need for innovation to develop safer and efficacious interventions. METHODS: Four distinct catheters (2 existing: Cardima catheter, Standard EPT Blazer catheter; 2 new prototypes: balloon catheter, basket catheters) were tested in 12 baboons (21-30 kg, 100% male). For each, we assessed whether or not the catheter was able to be maneuvered safely in various locations of the cerebral venous system, provide adequate cortical tissue contact to record signals, detect these signals as normal or abnormal, successfully stimulate the cortex, and capture the cortical tissue. Locations trialed included the petrosal sinus, straight sinus, vein of Galen, and occipital vein. Pacing cycle length and pacing thresholds varied among experiments. RESULTS: Successful mapping was conducted in all 12 baboons. The pacing cycle length varied from 75 ms to 650 ms depending on location of the cortex. Pacing threshold was recorded in 4/12 (33%) of the experiments; data is not available for the remaining 8/12 experiments. The threshold values ranged from 0.3 - 20 mAmps. Capture of cortical electrical activity was observed in 11/12 (91.7 %) experiments though the number of successful capture and stimulation attempts varied among experiments. The most reliable and consistent capture occurred with the use of our novel prototyped over-the-wire balloon catheter (9/12; 75%) and basket catheter (3/3; 100%). Necropsy and histology were performed post-experimentation, and only minimal complications were noted (Table 1). CONCLUSION: New electrode design can be maneuvered safely in the venous system, provide adequate cortical tissue contact to record signals, detect these signals as normal or abnormal, successfully stimulate the cortex, and capture cortical tissue. These novel devices merit further study in chronic baboons to establish long-term efficacy of continuous seizure recording.