Dataset of active avoidance in Wistar-Kyoto and Sprague Dawley rats: Experimental data and reinforcement learning model code and output.

Data were collected from 40 Wistar-Kyoto (WKY) and 40 Sprague Dawley (SD) rats during an active escape-avoidance experiment. Footshock could be avoided by pressing a lever during a danger period prior to onset of shock. If avoidance did not occur, a series of footshocks was administered, and the rat could press a lever to escape (terminate shocks). For each animal, data were simplified to the presence or absence of lever press and stimuli in each 12-second time frame. Using the pre-processed dataset, a reinforcement learning (RL) model, based on an actor-critic architecture, was utilized to estimate several different model parameters that best characterized each rat's behaviour during the experiment. Once individual model parameters were determined for all 80 rats, behavioural recovery simulations were run using the RL model with each animal's "best-fit" parameters; the simulated behaviour generated avoidance data (percent of trials avoided during a given experimental session) that could be compared across simulated rats, as is customarily done with empirical data. The datasets representing both the experimental data and the model-generated data can be interpreted in various ways to gain further insight into rat behaviour during avoidance and escape learning. Furthermore, the estimated parameters for each individual rat can be compared across groups. Thus, possible between-strain differences in model parameters can be detected, which might provide insights into strain differences in learning. The software implementing the RL model can also be applied to or serve as a template for other experiments involving acquisition learning. Reference for Co-Submission: K.M. Spiegler, J. Palmieri, K.C.H. Pang, C.E. Myers, A reinforcement-learning model of active avoidance behavior: Differences between Sprague-Dawley and Wistar-Kyoto rats. Behav. Brain Res. (2020 Jun 22[epub ahead of print])  doi: 10.1016/j.bbr.2020.112784.

A reinforcement-learning model of active avoidance behavior: Differences between Sprague Dawley and Wistar-Kyoto rats.

Avoidance behavior is a typically adaptive response performed by an organism to avert harmful situations. Individuals differ remarkably in their tendency to acquire and perform new avoidance behaviors, as seen in anxiety disorders where avoidance becomes pervasive and inappropriate. In rodent models of avoidance, the inbred Wistar-Kyoto (WKY) rat demonstrates increased learning and expression of avoidance compared to the outbred Sprague Dawley (SD) rat. However, underlying mechanisms that contribute to these differences are unclear. Computational modeling techniques can help identify factors that may not be easily decipherable from behavioral data alone. Here, we utilize a reinforcement learning (RL) model approach to better understand strain differences in avoidance behavior. An actor-critic model, with separate learning rates for action selection (in the actor) and state evaluation (in the critic), was applied to individual data of avoidance acquisition from a large cohort of WKY and SD rats. Latent parameters were extracted, such as learning rate and subjective reinforcement value of foot shock, that were then compared across groups. The RL model was able to accurately represent WKY and SD avoidance behavior, demonstrating that the model could simulate individual performance. The model determined that the perceived negative value of foot shock was significantly higher in WKY than SD rats, whereas learning rate in the actor was lower in WKY than SD rats. These findings demonstrate the utility of computational modeling in identifying underlying processes that could promote strain differences in behavioral performance.

Anhedonia following mild traumatic brain injury in rats: A behavioral economic analysis of positive and negative reinforcement.

Psychiatric disorders affect nearly 50% of individuals who have experienced a traumatic brain injury (TBI). Anhedonia is a major symptom of numerous psychiatric disorders and is a diagnostic criterion for depression. It has recently been appreciated that reinforcement may be separated into consummatory (hedonic), motivational and decisional components, all of which may be affected differently in disease. Although anhedonia is typically assessed using positive reinforcement, the importance of stress in psychopathology suggests the study of negative reinforcement (removal or avoidance of aversive events) may be equally important. The present study investigated positive and negative reinforcement following a rat model of mild TBI (mTBI) using lateral fluid percussion. Hedonic value and motivation for reinforcement was determined by behavioral economic analyses. Following mTBI, the hedonic value of avoiding foot shock was reduced. In contrast, the hedonic value of escaping foot shock or obtaining a sucrose pellet was not altered by mTBI. Moreover, motivation to avoid or escape foot shock or to acquire sucrose was not altered by mTBI. Our results suggest that individuals experiencing mTBI find avoidance of aversive events less reinforcing, and therefore are less apt to utilize proactive control of stress.

Danger and safety signals independently influence persistent pathological avoidance in anxiety-vulnerable Wistar Kyoto rats: A role for impaired configural learning in anxiety vulnerability.

Pathological avoidance behavior in anxiety and anxiety-related disorders has a large role in the persistence and severity of disease. Individuals are cued to avoid potential aversive events by learned danger and safety signals in the environment. Individuals with anxiety demonstrate a bias to utilize danger signals more than safety signals, in contrast to those without these disorders. Therefore, the present study investigated if danger and safety signals differentially influenced persistent avoidance in an animal model of anxiety-vulnerability, the Wistar Kyoto (WKY) rat, relative to the outbred Sprague Dawley (SD) rat. Persistent avoidance was assessed using extinction protocols. When danger or safety signals were present during extinction, WKY rats were slower to extinguish the avoidance response compared to SD rats. In contrast, when danger and safety signals were both present during extinction, WKY and SD rats extinguished at a similar rate. Differences in contextual and configural learning were explored as potential causes of the strain differences in the use of safety and danger signals in avoidance extinction. Strains did not differ in avoidance extinction when context was manipulated. However, WKY rats were impaired in configural learning using a negative patterning task. The results indicate that danger and safety signals may impair avoidance extinction in anxiety-vulnerable individuals due to impaired configural learning. These findings have important implications for understanding the etiology of anxiety disorders and may improve their diagnosis and treatment.

Neurocognitive and Fine Motor Deficits in Asymptomatic Adolescents during the Subacute Period after Concussion.

Adolescents are at high risk for sustaining concussions. There is considerable controversy regarding the sensitivity of neurocognitive tests to detect and track dysfunction in the aftermath of concussion. Two neurocognitive test batteries were compared during the subacute phase of recovery from concussion to determine sensitivity to concussion. Adolescents (ages 11-17 years) with a concussion diagnosis (eight males, seven females, 9-69 days after injury) were recruited through a concussion clinic and compared with community nonconcussed volunteers (11 males, three females). Adolescents completed the online version of the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT) on a desktop computer and the Defense Automated Neurobehavioral Assessment (DANA) on a handheld device, as well as the Grooved Pegboard Test, which assessed manual dexterity and motor speed. There were no differences in self-reported symptoms on the Post-Concussion Symptom Scale comparing concussed and nonconcussed adolescents. No significant between-groups differences were observed in ImPACT performance. Performance deficits were apparent for the DANA assessment, reflecting lower throughput scores for simple reaction time and response inhibition parameters in those with concussion. Concussed adolescents also had slower Grooved Pegboard Test performance when using the nondominant hand. Both the DANA test battery and the Grooved Pegboard Test appear to have promise as tools to detect persistent cognitive and motor dysfunction in the subacute period after concussion.

Abdominal wall reconstruction after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreduction surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival and decrease recurrence of peritoneal metastasis in a select population of patients. Abdominal wall resection is often needed to achieve complete CRS and the extent of abdominal wall resection may necessitate abdominal wall reconstruction (AWR). We sought to investigate if postoperative morbidity and mortality was increased in patients who underwent AWR with CRS-HIPEC (AWR group) compared to CRS-HIPEC without AWR (non-AWR group) and to identify if patient, tumor, and operative risk factors were associated with poor outcomes following AWR. We postulate that AWR is a safe and viable treatment option in appropriately selected patients with peritoneal disease. METHODS: A retrospective chart review was conducted from 2012 to 2015. Demographics, comorbidities, intraoperative variables, and postoperative outcomes were analyzed and compared between the non-AWR group and the AWR group. RESULTS: A total of 30 patients underwent CRS-HIPEC at our institution; 19 recruited in non-AWR group and 11 in the AWR arm. Median follow-up was 19.1 mo for the non-AWR group and 15.6 mo for AWR. Overall survival and complications were not significantly different between groups. Six patients in the non-AWR group and three patients in AWR group died during the follow-up period (32% versus 27%, P = 0.75). Grade III/IV Clavien-Dindo complications were similar in AWR compared to non-AWR group (64% versus 50%, P = 0.46) however estimated blood loss (1000 mL versus 450 mL, P = 0.01) and operative time (663 min versus 510 min, P = 0.02) were significantly increased in the AWR group. CONCLUSIONS: The results of this study demonstrate that AWR is a safe and viable option and can improve wound closure and strength in select patient populations undergoing CRS-HIPEC. AWR is not associated with an increase in mortality or complication rate. Future studies will need larger sample sizes and randomization to identify patient and operative factors that increase morbidity with AWR and identify the ideal timing of AWR.

Differential use of danger and safety signals in an animal model of anxiety vulnerability: The behavioral economics of avoidance.

Differential processing of danger and safety signals may underlie symptoms of anxiety disorders and posttraumatic stress disorder. One symptom common to these disorders is pathological avoidance. The present study examined whether danger and safety signals influence avoidance differently in anxiety-vulnerable Wistar-Kyoto (WKY) rats and Sprague Dawley (SD) rats. SD and WKY rats were tested in a novel progressive ratio avoidance task with and without danger or safety signals. Two components of reinforcement, hedonic value and motivation, were determined by fitting an exponentiated demand equation to the data. Hedonic value of avoidance did not differ between SD and WKY rats, but WKY rats had greater motivation to avoid than SD rats. Removal of the safety signal reduced motivation to avoid in SD, but not WKY, rats. Removal of the danger signal did not alter avoidance in either strain. When danger and safety signals were presented simultaneously, WKY rats responded to the danger signals, whereas SD rats responded to the safety signal. The results provide evidence that 1) safety signals enhance motivation to avoid in SD rats, 2) both danger and safety signals influence motivation in WKY rats, and 3) danger signals take precedence over safety signals when presented simultaneously in WKY rats. Thus, anxiety vulnerability is associated with preferential use of danger signals to motivate avoidance. The differential use of danger and safety signals has important implications for the etiology and treatment of pathological avoidance in anxiety disorders and posttraumatic stress disorder.

Startle suppression after mild traumatic brain injury is associated with an increase in pro-inflammatory cytokines, reactive gliosis and neuronal loss in the caudal pontine reticular nucleus.

Mild traumatic brain injury (mTBI) can produce somatic symptoms such as headache, dizziness, fatigue, sleep disturbances and sensorimotor dysfunction. Sensorimotor function can be measured by tests such as the acoustic startle reflex (ASR), an evolutionarily conserved defensive response to a brief yet sharp acoustic stimulus. mTBI produces a long-lasting suppression of ASR in rodents and humans; however, the mechanism of this suppression is unknown. The present study examined whether inflammatory processes in the brainstem (particularly the caudal pontine reticular nucleus, PnC) could account for the suppression of ASR after mTBI, because the PnC is an essential nucleus of the ASR circuit. Furthermore, while inflammation after mTBI is commonly observed in brain regions proximal to the site of impact (cortex and hippocampus), the effects of mTBI in brainstem structures remains largely understudied. The present study demonstrated a suppression of ASR one day after injury and lasting at least three weeks after an mTBI, replicating previous findings. Within the PnC, transient elevations of IL-1ß and TNF-α mRNA were observed at one day after injury, while IL-1α mRNA exhibited a delayed increase at three weeks after injury. Reactive gliosis (via IBA-1-ir for microglia and GFAP-ir for astrocytes) were also observed in the PnC, at one day and seven days after injury, respectively. Finally, the number of giant neurons (the major functional cell population in the PnC) was decreased three weeks after injury. The results indicate that glial activation precedes neuronal loss in the PnC, and correlates with the behavioral suppression of the ASR. The results also raise implications for brainstem involvement in the development of post-traumatic symptoms.

Self-Structures, Negative Events, and Adolescent Depression: Clarifying the Role of Self-Complexity in a Prospective, Multiwave Study.

The purpose of this multiwave longitudinal study was to examine the structure of self-complexity, and its relation to depressive symptoms, in 276 adolescents (M = 12.55; SD = 1.04). Self-complexity, depressive symptoms, and negative events were assessed during a laboratory assessment at baseline, and then depressive symptoms and negative events were tracked every 3 months over the next 2 years. Findings from the present research showed that girls had higher levels of Overlap (e.g., the degree to which one sees his or her roles as similar) and NASPECTS (the number of aspects) compared with boys, and that older adolescents had lower levels of Overlap. Furthermore, the present study demonstrated that low levels of positive Overlap (e.g., utilizing the same positive adjectives to describe numerous roles) predicted depressive symptoms, especially in the presence of negative events. Other findings along with developmental and clinical implications for this research are discussed.

Voluntary aerobic exercise increases the cognitive enhancing effects of working memory training.

Increases in performance on tests of attention and learning are often observed shortly after a period of aerobic exercise, and evidence suggests that humans who engage in regular exercise are partially protected from age-related cognitive decline. However, the cognitive benefits of exercise are typically short-lived, limiting the practical application of these observations. Here, we explored whether physical exercise might induce lasting changes in general cognitive ability if that exercise was combined with working memory training, which is purported to broadly impact cognitive performance. Mice received either exercise treatment (6 weeks of voluntary running wheel access), working memory training (in a dual radial-arm maze), both treatments, or various control treatments. After this period of exercise, working memory training was initiated (alternating with days of exercise), and continued for several weeks. Upon completion of these treatments, animals were assessed (2-4 weeks later) for performance on four diverse learning tasks, and the aggregate performance of individual animals across all four learning tasks was estimated. Working memory training alone promoted small increases in general cognitive performance, although any beneficial effects of exercise alone had dissipated by the time of learning assessments. However, the two treatments in combination more than doubled the improvement in general cognitive performance supported by working memory training alone. Unlike the transient effects that acute aerobic exercise can have on isolated learning tasks, these results indicate that an acute period of exercise combined with working memory training can have synergistic and lasting impact on general cognitive performance.